 Provide framework, protect soft tissues, provide attachments for  muscles, produce blood cells, store inorganic salts    Detect changes, receive and interpret sensory information,  stimulate muscles and glands    Return tissue fluid to the blood, carry certain absorbed food  molecules, defend the body against infection   Digestive Mouth, tongue, teeth, salivary glands, pharynx, esophagus,  stomach, liver, gallbladder, pancreas, small and large intestines    Intake and output of air, exchange of gases between air and blood    Remove wastes from blood, maintain water and electrolyte  balance, store and eliminate urine    Produce and maintain sperm cells, transfer sperm cells into  female reproductive tract    Produce and maintain egg cells, receive sperm cells, support  development of an embryo, and function in birth process    FIGURE 1.20 The organ systems in humans interact in ways that maintain homeostasis.    Aging refers to the changes in the body that occur with the passage  of time. It is the process of becoming mature or old, and is a part  of life. Because the passage of time is inevitable, so, too, is aging,  despite common claims for the anti-aging properties of various  diets, cosmetics, pills, and skin-care products.   Aging happens everywhere in the body, from the microscopic  to the whole-body level. Although programmed cell death begins  in the fetus, as structures form, we are usually not very aware of  aging until the third decade of life, when a few gray hairs, faint  lines etched into facial skin, and minor joint stiffness in the morn-  ing remind us that time marches on. A woman over the age of  thirty-five attempting to conceive a child might be shocked to  learn that she is of “advanced maternal age,” because the chances  of conceiving an offspring with an abnormal chromosome number  increase with the age of the egg. In both sexes, by the fourth or  fifth decade, as hair color fades and skin wrinkles, the first signs  of adult-onset disorders may appear, such as elevated blood pressure  that one day may be considered hypertension, and slightly high  blood glucose that could become type 2 diabetes mellitus. A per-  son with a strong family history of heart disease, coupled with  unhealthy diet and exercise habits, may be advised to change his  or her lifestyle, and perhaps begin taking a drug to lower serum  cholesterol levels. The sixth decade sees grayer or whiter hair, more  and deeper skin wrinkles, and a waning immunity that makes vac-  cinations against influenza and other infectious diseases important.  Yet many, if not most, people in their sixties and older have sharp  minds and are capable of many types of physical activities.   Changes at the tissue, cell, and molecular levels explain the  familiar signs of aging. Decreased production of the connective  tissue proteins collagen and elastin account for the stiffening of  skin, and diminished levels of subcutaneous fat are responsible  for wrinkling. Proportions of fat to water in the tissues change,  with the percentage of fats increasing steadily in women, and  increasing until about age sixty in men. These alterations explain  why the elderly metabolize certain drugs at different rates than do  younger people. As a person ages, tissues atrophy, and as a result,  organs shrink.   Cells mark time too, many approaching the end of a limited  number of predetermined cell divisions as their chromosome tips  whittle down. Such cells reaching the end of their division days  may enlarge or die. Some cells may be unable to build the appara-  tus that pulls apart replicated chromosomes in a cell on the verge  of division. Impaired cell division slows wound healing, yet at the  same time, the inappropriate cell division that underlies cancer  becomes more likely. Certain subcellular functions lose efficiency,  including repair of DNA damage and transport of substances into  and out of cells. Aging cells are less efficient at extracting energy  from nutrients and breaking down aged or damaged cell parts.   As changes at the tissue level cause organ-level signs of aging,  certain biochemical changes fuel cellular aging. Lipofuscin and  ceroid pigments accumulate when a cell can no longer prevent the  formation of oxygen free radicals. A protein called beta amyloid  may build up in the brain, contributing, in some individuals, to the  development of Alzheimer disease. A generalized metabolic slow-  down results from a dampening of thyroid gland function, impairing    glucose use, the rate of protein synthesis, and production of digestive  enzymes. At the whole-body level, we notice slowed metabolism as  diminished tolerance to cold, weight gain, and fatigue.   Several investigations are identifying key characteristics, par-  ticularly gene variants, which people who live more than 100 years  share. These fortunate individuals, called centenarians, fall into  three broad groups: about 20% of them never get the diseases that  kill most people; 40% get these diseases but at much older ages  than average; and the other 40% live with and survive the more  common disorders of aging. Environmental factors are important,  too—another trait centenarians share is never having smoked.   Our organs and organ systems are interrelated, so aging-related  changes in one influence the functioning of others. Several chapters  in this book conclude with a “Life-Span Changes” section that dis-  cusses changes specific to particular organ systems. These changes  reflect the natural breakdown of structure and function that  accompanies the passage of time, as well as events in our genes  (“nature”) and symptoms or characteristics that might arise as a  consequence of lifestyle choices and circumstances (“nurture’’).    25 List some aging-related changes at the microscopic and whole-  body levels.    To communicate effectively with one another, investigators over the  ages have developed a set of terms with precise meanings for dis-  cussing the human body and its parts. These terms concern the rela-  tive positions of body parts, refer to imaginary planes along which  cuts may be made, or describe body regions. Using such terms  assumes that the body is in the anatomical position—standing  erect; face forward; upper limbs at the sides, palms forward.    Terms of relative position are used to describe the location of one  body part with respect to another. They include the following  (many of these terms are illustrated in figure 1.21):    1. Superior means a part is above another part. (The thoracic  cavity is superior to the abdominopelvic cavity.)   2. Inferior means a part is below another part. (The neck is  inferior to the head.)   3. Anterior (ventral) means toward the front. (The eyes are  anterior to the brain.)   4. Posterior (dorsal) means toward the back. (The pharynx is  posterior to the oral cavity.)   5. Medial refers to an imaginary midline dividing the body into  equal right and left halves. A part is medial if it is closer to  midline than another part. (The nose is medial to the eyes.)   6. Lateral means toward the side, away from midline. (The ears  are lateral to the eyes.)   7. Bilateral refers to paired structures, one on each side. (The  lungs are bilateral.)    8. Ipsilateral refers to structures on the same side. (The right  lung and the right kidney are ipsilateral.)  9. Contralateral refers to structures on the opposite side.  (A patient with a fractured right leg would have to bear  weight on the contralateral—in this case, left—lower limb.)  10. Proximal describes a part closer to a point of attachment to  the trunk than another body part. (The elbow is proximal to  the wrist.) Proximal may also refer to another reference point  such as the proximal tubules, which are closer to the filtering  structures in the kidney.  11. Distal is the opposite of proximal. It means a particular  body part is farther from a point of attachment to the trunk.  (The fingers are distal to the wrist.) Distal may also denote  another reference point, such as decreased blood flow distal  to blockage of a coronary artery.  12. Superficial means near the surface. (The epidermis is the  superficial layer of the skin.)  13. Deep describes more internal parts. (The dermis is the deep  layer of the skin.)   To observe the relative locations and arrangements of internal  parts, it is necessary to cut, or section, the body along various  planes (figs. 1.22 and 1.23). The following terms describe such  planes and sections:    1. Sagittal refers to a lengthwise cut that divides the body into  right and left portions. If a sagittal section passes along the  midline and divides the body into equal parts, it is called  median (midsagittal). A sagittal section lateral to midline is  called parasagittal.   2. Transverse (horizontal) refers to a cut that divides the body  into superior and inferior portions.   3. Frontal (coronal) refers to a section that divides the body into  anterior and posterior portions.    Sometimes a cylindrical organ such as a blood vessel is sec-  tioned. In this case, a cut across the structure is called a cross section,  an angular cut is called an oblique section, and a lengthwise cut is  called a longitudinal section (fig. 1.24).    Parts of the axial portion of the body can be described using  terms similar to the names of the cavities within them. The trunk  includes the thorax (chest), the pelvis (area associated with the  hips), and the abdomen (area below the chest and above the pelvis).   The appendicular portion can be described in more detail as  well. The upper limbs include the arms (from shoulder to elbow)  and the forearms (from elbow to hand). Similarly, the lower  limbs include the thigh (from hip to knee) and the leg (from knee  to foot).    FIGURE 1.23 A human brain sectioned along (a) a sagittal plane, (b) a transverse plane, and (c) a frontal plane.   groin (groin) depressed area of the abdominal wall near the  thigh (inguinal)   lumbar (lum’bar) region of the lower back between the ribs  and the pelvis (loin)    A number of terms designate body regions. The abdominal patellar (pah-tel’ar) anterior part of the knee  area, for example, is subdivided into the following regions, as pectoral (pek’tor-al) anterior chest  shown in figure 1.25a: pedal (ped’al) foot    pelvic (pel’vik) pelvis  perineal (per’i-ne’al) the inferior-most region of the trunk  between the thighs and the buttocks (perineum)  plantar (plan’tar) sole of the foot  popliteal (pop”li-te’al) area posterior to the knee  sacral (sa’kral) posterior region between the hip bones  sternal (ster’nal) middle of the thorax, anteriorly  sural (su’ral) calf of the leg  tarsal (tahr’sal) ankle  umbilical (um-bil’i-kal) navel    1. The epigastric region is the upper middle portion.  2. The right and left hypochondriac regions are on the right/  left side of the epigastric region.   4. The right and left lateral (lumbar) regions are on the right/  left side of the umbilical region.   6. The right and left inguinal (iliac) regions are on the right/  left side of the pubic region.    : >  1. Right upper quadrant (RUQ)  2. Right lower quadrant (RLQ) R PRACTICE.  3. Left upper quadrant (LUQ) 26 Describe the anatomical position.  4. Left lower quadrant (LLQ) 27 Using the appropriate terms, describe the relative positions of    several body parts.  The following adjectives are commonly used when referring 28    to various body parts and regions. Figure 1.26 illustrates some of  these regions.   buccal (buk’al) cheek dermatology (der”mah-tol’o-je) Study of skin and its diseases.  carpal (kar’pal) wrist endocrinology (en’do-kri-nol’o-je) Study of hormones,  celiac (se’le-ak) abdomen hormone-secreting glands, and associated diseases.  cephalic (sé-fal’ik) head epidemiology (ep”i-de”me-ol’o-je) Study of the factors that  cervical (ser’vi-kal) neck contribute to determining the distribution and frequency of  costal (kos’tal) ribs health-related conditions within a defined human population.    gastroenterology (gas”tro-en” ter-ol’o-je) Study of the  stomach and intestines, as well as their diseases.   geriatrics (jer’e-at’riks) Branch of medicine dealing with  older individuals and their medical problems.   gerontology (jer”on-tol’o-je) Study of the process of aging  and the various problems of older individuals.   gynecology (gi”’né-kol-o-je) Study of the female reproductive  system and its diseases.   histology (his-tol’o-je) Study of the structure and function  of tissues (microscopic anatomy).   neonatology (ne”o-na-tol’o-je) Study of newborns and the  treatment of their disorders.   nephrology (né-frol’o-je) Study of the structure, function,  and diseases of the kidneys.    FIGURE 1.25 (AP|R} The abdominal area is commonly subdivided in two ways: (a) into nine regions and  (b) into quadrants    neurology (nu-rol’o-je) Study of the nervous system in  health and disease.   pathology (pah-thol’o-je) Study of structural and functional  changes within the body associated with disease.  pediatrics (pe”de-at’riks) Branch of medicine dealing with  children and their diseases.   pharmacology (fahr’mah-kol’o-je) Study of drugs and their  uses in the treatment of diseases.   Acromial 7 Se 2 (point of shoulder)  (point of shoulder) ‘| E Pectoral Vertebral  Axillary (armpit) = ae (spinal column)  Mammary (breast) Brachial (arm)  Brachial — ’ Dorsal (back)  (arm)   S Umbilical b. F Cubital (elbow)  Antecubital — i (navel)  (front of elbow) > Lumbar  Abdominal ‘ ean (lower back)  (abdomen) = ¢ ‘. g Sacral (between hips)    FIGURE 1.26 fAP|R) Some terms used to describe body regions. (a) Anterior regions. (b) Posterior regions.    podiatry (po-di’ah-tre) Study of the care and treatment of toxicology (tok’si-kol’o-je) Study of poisonous substances  the feet. and their effects on physiology.   psychiatry (si-ki’ah-tre) Branch of medicine dealing with urology (u-rol’o-je) Branch of medicine dealing with the  the mind and its disorders. urinary and male reproductive systems and their diseases. Hl    radiology (ra”de-ol’o-je) Study of X rays and radioactive  substances, as well as their uses in diagnosing and treating  diseases.    Early interest in the human body probably developed as  people became concerned about injuries and illnesses.   Early doctors began to learn how certain herbs and potions  affected body functions.   The idea that humans could understand forces that caused  natural events led to the development of modern science.   A set of terms originating from Greek and Latin formed the  basis for the language of anatomy and physiology.   Much of what we know about the human body was  discovered using the scientific method.   The function of a part depends upon the way it is constructed.    The body is composed of parts that can be considered at  different levels of organization.    Matter is composed of atoms, which are composed of  subatomic particles.   Cells, composed of organelles, are the basic units of  structure and function of the body.   Cells are organized into layers or masses called tissues.  Tissues are organized into organs.   These parts vary in complexity progressively from one  level to the next.    Metabolism is the acquisition and use of energy by  an organism.    The structures and functions of body parts maintain the life of  the organism.   a. Water is used in many metabolic processes, provides  the environment for metabolic reactions, and carries  substances.   b. Nutrients from food supply energy, raw materials  for building substances, and chemicals necessary in  vital reactions.   c. Oxygen is used in releasing energy from nutrients;  this energy drives metabolic reactions.   d. Heat is part of our environment and is a product of  metabolic reactions; heat helps control rates of these  reactions.   e. Pressure is an application of force; in humans,  atmospheric and hydrostatic pressures help breathing  and blood movements, respectively.   a. If an organism is to survive, the conditions within its  body fluids must remain relatively stable.   b. The tendency to maintain a stable internal  environment is called homeostasis.   c. Homeostatic mechanisms involve sensory receptors,  a control center with a set point, and effectors.   d. Homeostatic mechanisms include those that regulate  body temperature, blood pressure, and blood glucose  concentration.    Body cavities  a. The axial portion of the body contains the cranial  cavity and vertebral canal, as well as the thoracic  and abdominopelvic cavities, which are separated  by the diaphragm.  b. The organs within thoracic and abdominopelvic cavities  are called viscera.  c. Other body cavities include the oral, nasal, orbital, and  middle ear cavities.  Thoracic and abdominopelvic membranes  Parietal serous membranes line the walls of these cavities;  visceral serous membranes cover organs within them. They  secrete serous fluid.  a. Thoracic membranes  (1) Pleural membranes line the thoracic cavity and  cover the lungs.  (2) Pericardial membranes surround the heart and  cover its surface.  (3) The pleural and pericardial cavities are potential  spaces between these membranes.  b. Abdominopelvic membranes  (1) Peritoneal membranes line the abdominopelvic  cavity and cover the organs inside.  (2) The peritoneal cavity is a potential space between  these membranes.    The human organism consists of several organ systems.  Each system includes interrelated organs.  a. Integumentary system   (2) It includes the skin, hair, nails, sweat glands, and  sebaceous glands.   (3) It protects underlying tissues, regulates body  temperature, houses sensory receptors, and  synthesizes substances.   (1) The skeletal system is composed of bones and the  ligaments and cartilages that bind bones together.   (2) It provides framework, protective shields, and  attachments for muscles; it also produces blood  cells and stores inorganic salts.   (2) It moves body parts, maintains posture, and  produces body heat.   (1) The nervous system consists of the brain, spinal  cord, nerves, and sense organs.   (2) It receives signals from sensory receptors,  interprets this information, and acts by causing  muscles or glands to respond.   (3) Itincludes the pituitary gland, thyroid gland,  parathyroid glands, adrenal glands, pancreas,  ovaries, testes, pineal gland, and thymus.   (1) The cardiovascular system includes the heart,  which pumps blood, and the blood vessels, which  carry blood to and from body parts.   (1) The lymphatic system is composed of lymphatic  vessels, lymph nodes, the thymus, and the spleen.   (2) It transports lymph from tissue spaces to the  bloodstream and carries certain fatty substances  away from the digestive organs. Lymphocytes  defend the body against disease-causing agents.   (1) The digestive system receives foods, breaks down  nutrients into forms that can pass through cell  membranes, and eliminates unabsorbed materials.   (3) The digestive system includes the mouth, tongue,  teeth, salivary glands, pharynx, esophagus, stomach,  liver, gallbladder, pancreas, small intestine, and  large intestine.   (1) The respiratory system takes in and releases  air and exchanges gases between the blood and  the air.   (2) It includes the nasal cavity, pharynx, larynx,  trachea, bronchi, and lungs.   (1) The urinary system includes the kidneys, ureters,  urinary bladder, and urethra.   (2) It filters wastes from the blood and helps maintain  fluid and electrolyte balance.   (2) The male reproductive system produces, maintains,  and transports male sex cells. It includes the  scrotum, testes, epididymides, ductus deferentia,  seminal vesicles, prostate gland, bulbourethral  glands, urethra, and penis.   (3) The female reproductive system produces,  maintains, and transports female sex cells; it also  supports the development and birth of offspring. It  includes the ovaries, uterine tubes, uterus, vagina,  clitoris, and vulva.    Aging occurs from conception on and has effects at the cell,  tissue, organ, and organ system levels.    The first signs of aging are noticeable in one’s thirties.  Female fertility begins to decline during this time.   Older people may metabolize certain drugs at different  rates than younger people.   Cells divide a limited number of times. As DNA repair  falters, mutations may accumulate.   Oxygen free radical damage produces certain pigments.  Metabolism slows, and beta amyloid protein may build up  in the brain.    Investigators use terms with precise meanings to effectively  communicate with one another.   These terms describe the location of one part with respect  to another part.   Body sections are planes along which the body may be  cut to observe the relative locations and arrangements of  internal parts.    Describe how an early interest in the human body  eventually led to the development of modern medical  science. (p. 10)   Distinguish between anatomy and physiology. (p. 11)  Explain the relationship between the form and function of  body parts and give three examples. (p. 11)    Describe the relationship between each of the following  pairs: molecules and cells, tissues and organs, organs  and organ systems. (p. 12)    Which characteristics of life can you identify in yourself? (p. 14)  Identify those characteristics of living organisms that relate  to metabolism. (p. 14)    Compare your own needs for survival with the requirements of  organisms described in the chapter. (pp. 14-15)   Explain the relationship between homeostasis and the  internal environment. (p. 15)   Describe a general physiological control system, including  the role of negative feedback. (p. 16)   Describe the homeostatic mechanisms that help regulate  blood pressure and blood glucose—what do they have in  common and how are they different? (p. 16)   Explain the difference between the axial and appendicular  portions of the body. (p. 18)   Identify the cavities within the axial portion of the body.  (p. 18)   Name the body cavity that houses each of the following  organs: (p. 18)    List the cavities of the head and the contents of each cavity.  (p. 20)   Describe the general contribution of each of the organ  systems to maintaining homeostasis. (pp. 22-25)    List the major organs that compose each organ system and  identify their functions. (pp. 22-25)    1.7 Life-Span Changes  21 Describe physical changes associated with aging that occur  during each decade past the age of thirty. (p. 27)  22 List age-associated changes that occur at the molecular,  cellular, tissue and/or organ levels. (p. 27)  1.8 Anatomical Terminology  23 Write complete sentences using each of the following terms  to correctly describe the relative locations of specific body  parts: (pp. 27-28)  a. Superior h. Ipsilateral  b. Inferior i. Contralateral  c. Anterior j- Proximal  d. Posterior k. Distal  e. Medial |. Superficial  f. Lateral m. Peripheral  g. Bilateral n. Deep  24 Sketch the outline of a human body, and use lines to indicate  each of the following sections: (p. 28)  a. Sagittal  b. Transverse  c. Frontal  25 Sketch the abdominal area, and indicate the locations of the  following regions: (p. 30)  a. Epigastric d. Lateral  b. Hypochondriac e. Pubic  c. Umbilical f. Inguinal  26 Sketch the abdominal area, and indicate the location of the  following regions: (p. 30)  a. Right upper quadrant  b. Right lower quadrant  c. Left upper quadrant  d. Left lower quadrant  27 Provide the common name for the region to which each of  the following terms refers: (p. 30)  a. Acromial n. Orbital  b. Antebrachial o. Otic  c. Axillary p. Palmar  d. Buccal q. Pectoral  e. Celiac r. Pedal  f. Coxal s. Perineal  g. Crural t. Plantar  h. Femoral u. Popliteal  i. Genital v. Sacral  j. Gluteal w. Sternal  k. Inguinal x. Tarsal  |. Mental y. Umbilical  m. Occipital z. Vertebral  CHAPTER 1 | Introduction to Human Anatomy and Physiology 35    1. Which characteristics of life does a computer have? Why is a  computer not alive?    2. Put the following in order, from smallest and simplest, to  largest and most complex, and describe their individual roles in  homeostasis: organ, molecule, organelle, atom, organ system,  tissue, organism, cell, macromolecule.    3. What environmental conditions would be necessary for a human  to survive on another planet?    4. In health, body parts interact to maintain homeostasis. Illness  can threaten the maintenance of homeostasis, requiring  treatment. What treatments might be used to help control a  patient's (a) body temperature, (b) blood oxygen level, and  (c) blood glucose level?    5. How might health-care professionals provide the basic  requirements of life to an unconscious patient? Describe the  body parts involved in the treatment, using correct directional  and regional terms.    6. Suppose two individuals develop benign (noncancerous)  tumors that produce symptoms because they occupy space  and crowd adjacent organs. If one of these persons has the  tumor in the thoracic cavity and the other has the tumor in  the abdominopelvic cavity, which person would be likely  to develop symptoms first? Why? Which might be more  immediately serious? Why?    7. Ifa patient complained of a “stomachache” and pointed to the  umbilical region as the site of discomfort, which organs located  in this region might be the source of the pain?    Connect Interactive Questions Reinforce your knowledge using  assigned interactive questions covering levels of organization,  anatomical terminology, homeostasis, body organization, and more.    Anatomy & Physiology Revealed Go more in depth into the  human body by exploring body regions, planes of sections, and  organ systems.    The following series of plates includes illustrations of the major organs of the human torso and human  cadaver photos. The first plate shows the anterior surface of the human torso and reveals the muscles on  one side. Then, plates 2—7 expose deeper organs, including those in the thoracic, abdominal, and pelvic  cavities. Plates 8-25 are photographs of sagittal sections, transverse sections, and anterior views of the  torso of a human cadaver. These plates will help you visualize the proportional relationships between  the major anatomical structures of actual specimens.   Variations exist in anatomical structures among humans. The illustrations in this textbook represent    PLATE ONE Human female torso showing the anterior surface on one side and the superficial muscles exposed on the other side. (m. stands for  muscle, and v. stands for vein)    Deltoid m. Coracobrachialis m.  Cephalic Pectoralis  vein minor m.  Pectoralis  major m. Long head  biceps  brachii m.  Latissimus Short head  dorsi m. biceps  brachii m.  Serratus  anterior m.  Rectus abdominis m.  External  oblique m.  (cut) Transversus  abdominis m.  Internal  oblique m. Linea alba  (cut)  Rectus  Transversus abdominis m. (cut)  abdominis m.  Tensor fasciae  latae m.  Femoral n.  Femoral a.  Femoral v. Sartorius m.    PLATE TWO Human male torso with the deeper muscle layers exposed. (a. stands for artery, m. stands for muscle, n. stands for nerve, and  v. stands for vein)    Urinary bladder iliac spine  Small intestine  Inguinal canal  Femoral n.  Spermatic cord  : Femoral a.  Penis  Sartorius m. Femoral v.    PLATE THREE Human male torso with the deep muscles removed and the abdominal viscera exposed. (a. stands for artery, m. stands for muscle, mm.  stands for muscles, n. stands for nerve, and v. stands for vein)   Urinary bladder  Append Ductus deferens  Femoral n. Adductor longus m.  Penis (cut) Vastus lateralis m.  Epididymis  Testis Rectus femoris m.  Scrotum    PLATE FOUR Human male torso with the thoracic and abdominal viscera exposed. (a. stands for artery, m. stands for muscle, n. stands for nerve,  v. stands for vein, and wv. stands for veins)    PLATE FIVE Human female torso with the lungs, heart, and small intestine sectioned and the liver reflected (lifted back). (a. stands for artery,  m. stands for muscle, and v. stands for vein)    PLATE SIX Human female torso with the heart, stomach, liver, and parts of the intestine and lungs removed. (a. stands for artery, m. stands for muscle,    PLATE SEVEN Human female torso with the thoracic, abdominal, and pelvic viscera removed. (a. stands for artery and m. stands for muscle)    PLATE TWELVE Viscera of the pelvic cavity, sagittal section. (m. stands for muscle)    PLATE THIRTEEN Transverse section of the head above the eyes, superior view.    PLATE FOURTEEN Transverse section of the head at the level of the eyes, superior view. (m. stands for muscle)    Spinal cord Pharynx  Tongue  PLATE FIFTEEN Transverse section of the neck, inferior view.  Spinal cord  Aorta Lung  Rib  Esophagus  Heart    PLATE SIXTEEN Transverse section of the thorax through the base of the heart, superior view. (m. stands for muscle)    PLATE SEVENTEEN Transverse section of the thorax through the heart, superior view.    PLATE NINETEEN Transverse section of the abdomen through the pancreas, superior view. (m. stands for muscle)    PLATE TWENTY-ONE Thoracic viscera, anterior view. (Brachiocephalic veins have been removed  to better expose the brachiocephalic artery and the aorta.)    PLATE TWENTY-THREE Thorax with the heart and lungs removed, anterior view.    PLATE TWENTY-FIVE Abdominal viscera with the greater omentum removed, anterior view. (Small intestine has been  displaced to the left.)    This partial model of DNA, the blueprint for an organism, shows carbon atoms  black, oxygen red, nitrogen blue, phosphorus yellow, and hydrogen white.    At the cellular level of organization, biology, in a sense, becomes  chemistry. A cell’s working parts—its organelles—are intricate  assemblies of molecules. Because the molecules that build the cells  that build tissues and organs are themselves composed of atoms,  the study of anatomy and physiology begins with chemistry.   Chemistry in the body can show up in surprising ways. The  ability of your nervous system to send signals at speeds of over  100 meters per second depends on the movement of chemical  substances called ions. The force that your muscles generate to  lift your textbook, or to walk up a flight of stairs, comes entirely  from chemicals called proteins in your muscles pulling at each  other at a microscopic level.    After you have studied this chapter, you should be able to:    Give examples of how the study of living materials  requires an understanding of chemistry. (p. 58)    Describe how atomic structure determines how atoms  interact. (pp. 60 and 63-65)    Explain how molecular and structural formulas symbolize  the composition of compounds. (pp. 62 and 64)    Explain the pH scale. (p. 67)  Explain the function of buffers. (p. 68)   List the major inorganic chemicals common in cells and  explain the function(s) of each. (p. 68)   Describe the general functions of the main classes of  organic molecules in cells. (pp. 70-76)   iso-, equal: isotope—atom that has the  same atomic number as another atom  but a different atomic weight.    Chemistry considers the composition of substances and how they  change. It is possible to study anatomy without much reference to  chemistry. However understanding the basics of chemistry is essen-  tial for understanding physiology, because body functions result  from cellular functions that, in turn, result from chemical changes.  The human body consists of chemicals, including salts, water, carbo-  hydrates, lipids, proteins, and nucleic acids. The food that we eat,  liquids that we drink, and medications that we take are chemicals.   Not only are physiological processes based on chemistry, but  all anatomical structures are as well. Bones are in large part a com-  position of calcium, phosphorus, and proteins. Muscles, mostly  formed of proteins, are held together and attached to bones by yet  other types of proteins. Even water, the main component of the intra-  cellular and extracellular fluids, is a chemical.   As interest in the chemistry of living organisms grew and knowl-  edge of the subject expanded, a field of life science called biological  chemistry, or biochemistry, emerged. Biochemistry has been  important not only in helping to explain physiological processes  but also in developing ways to detect, diagnose, and treat disease.    Smallest particle of an element that has the properties  of that element    weight; carries a negative electrical charge and is in  constant motion around an atomic nucleus   poly-, many: polyunsaturated—molecule  with two or more double bonds  between its carbon atoms.    Relatively large particle within an atom; carries a positive  electrical charge and is found within an atomic nucleus    Matter is anything that has weight and takes up space. This includes  all the solids, liquids, and gases in our surroundings as well as in our  bodies. All matter consists of particles that are organized in specific  ways. Table 2.1 lists some particles of matter and their characteristics.    The simplest examples of matter with specific chemical properties  are the elements (el’é-mentz). At present, 98 naturally occurring  elements are known and at least 20 more have been created in the  laboratory. Among these elements are such common materials as  iron, copper, silver, gold, aluminum, carbon, hydrogen, and oxygen.  Some elements exist in a pure form, but these and other elements    Strictly speaking, matter has mass (rather than weight) and takes  up space. Mass refers to the amount of a substance, whereas  weight refers to how heavy it is. If your weight on earth is  150 pounds, on the moon it would be only 25 pounds, but your  mass (in kilograms) would be the same in both places. That is,    your composition is the same on the moon as it is on earth and  takes up the same volume of space, but you weigh less on the  moon, because the force of gravity is lower there. Because we  are dealing with life on earth and constant gravity, we can con-  sider mass and weight as roughly equivalent. Many of our stu-  dents find it easier to think in terms of weight rather than mass.    Relatively large particle within an atom; about the same  weight as a proton; uncharged and thus electrically  neutral; found within an atomic nucleus    Particle, formed from an atom, that is electrically charged  because it has gained or lost one or more electrons    Particle formed by the chemical union of two or  more atoms   Elements the body requires in large amounts—such as car-  bon, hydrogen, oxygen, nitrogen, sulfur, and phosphorus—are  termed bulk elements. These elements make up more than 95%  (by weight) of the human body (table 2.2). Elements required in  small amounts are called trace elements. Many trace elements are  important parts of enzymes, which are proteins that regulate the  rates of chemical reactions in living organisms. Some elements  that are toxic in large amounts, such as arsenic, may be vital in  very small amounts, and these are called ultratrace elements.   An atom (at’om) is the smallest unit of an element that has the  chemical properties of that element. The atoms that make up each  element are chemically identical but they differ from the atoms that  make up other elements. Atoms vary in size, weight, and the ways  they interact with other atoms. Some atoms can combine with atoms  like themselves or with other atoms by forming attractions called  chemical bonds, while other atoms cannot form such bonds.    An atom consists of a central portion called the nucleus (nu’kle-us)  and one or more electrons (e-lek’tronz) that constantly move  around the nucleus (fig. 2.1). The nucleus contains one or more  relatively large particles, protons (pro’tonz) and usually neutrons    an atom of the element lithium, three electrons encircle a nucleus that  consists of three protons and four neutrons.    The woman has never undergone surgery before, and is  anxious. The night before the procedure to remove her  cancerous thyroid gland, an anesthesiologist assistant  (AA) visits. After taking a detailed health history and  performing a physical examination, the AA explains the  sequence of events that will make the procedure as pain-  free as possible, from the initial anti-anxiety medication  and the administration of the anesthesia, to the quick  zip of discomfort as the breathing tube is removed in  the recovery room, to post-procedure pain relief  options. The AA aids the anesthesiologist throughout  the procedure, carefully monitoring the patient's status  and providing or assisting in life-support procedures  should they become necessary.   Training to become an anesthesiologist assistant is  rigorous. The profession requires premedical courses  (general and organic chemistry, advanced college math,  general and advanced biology courses such as anatomy and  physiology, and physics), a bachelor’s degree, and taking the  medical school admissions test (MCAT) or graduate record  exam (GRE).   Becoming an AA also requires a master’s-level degree  from an accredited program affiliated with a medical school,  which typically takes a minimum of two years to complete.  Graduate training includes hundreds of hours of classroom,  laboratory, and clinical education, plus experience  administering anesthesia in at least 600 cases. An exam  is required for certification, and forty hours of continuing  medical education is required every two years.   Anesthesiology assistants work in many hospital  settings, including intensive care units and in general  surgery, and in clinics where surgical procedures are  performed. In addition to assisting in the administration of  techniques such as echocardiography and pulmonary artery  catheterization, the AA provides a continuity of care that  may prove very comforting to a fearful patient.    For more detail, see Appendix D, Periodic Table of the Elements    (nu’tronz). Protons and neutrons are about equal in weight, but they  have different electrical properties. Each proton carries a single,  positive electrical charge (p*). Neutrons are uncharged and thus are  electrically neutral (n°). Electrons, so small that they have almost no  weight, carry a single, negative charge (e>) (fig. 2.1).   The nucleus contains protons, so this part of an atom is always  positively charged. However, the number of electrons outside the  nucleus equals the number of protons. Therefore, a complete atom  has no net charge and is thus electrically neutral.   The atoms of different elements have different numbers  of protons. The number of protons in the atoms of a particular  element is called its atomic number. Hydrogen, for example,  whose atoms have one proton, has atomic number |; carbon,  whose atoms have six protons, has atomic number 6.   The weight of an atom of an element is primarily due to the pro-  tons and neutrons in its nucleus, because the electrons are so light.  For this reason, the number of protons plus the number of neutrons  in each of an element’s atoms essentially equals the atomic weight  of that atom. The atomic weight of a hydrogen atom, which has only  one proton and no neutrons, is approximately 1. The atomic weight  of a carbon atom, with six protons and six neutrons, is approxi-  mately 12 (table 2.3).    All the atoms of a particular element have the same atomic num-  ber because they have the same number of protons and electrons.  However, the atoms of an element vary in the number of neutrons  in their nuclei; thus, they vary in atomic weight. For example, all  oxygen atoms have eight protons in their nuclei. Some, however,  have eight neutrons (atomic weight 16), others have nine neutrons  (atomic weight 17), and still others have ten neutrons (atomic  weight 18). Atoms that have the same atomic number but differ-  ent atomic weights are called isotopes (i’so-t6pz) of an element.  A sample of an element is likely to include more than one isotope,    so the atomic weight of the element is often considered to be the  average weight of the isotopes present. (See Appendix D, Periodic  Table of the Elements.)   The ways atoms interact reflect their numbers of electrons. An  atom has the same number of electrons and protons, so all the iso-  topes of a particular element have the same number of electrons and  chemically react in the same manner. For example, any of the iso-  topes of oxygen can have the same function in metabolic reactions.   Isotopes of an element may be stable, or they may have unsta-  ble atomic nuclei that decompose, releasing energy or pieces of  themselves until they reach a stable form. Such unstable isotopes  are called radioactive, and the energy or atomic fragments they emit  are called atomic radiation. Elements that have radioactive isotopes  include oxygen, iodine, iron, phosphorus, and cobalt. Some radioac-  tive isotopes are used to detect and treat disease (From Science to  Technology 2.1).   Atomic radiation includes three common forms called alpha (a),  beta (B), and gamma (y). Each type of radioactive isotope produces  one or more of these forms of radiation. Alpha radiation consists of  particles from atomic nuclei, each of which includes two protons  and two neutrons, that move slowly and cannot easily penetrate mat-  ter. Beta radiation consists of much smaller particles (electrons) that  travel faster and more deeply penetrate matter. Gamma radiation is  a form of energy similar to X-radiation and is the most penetrating  form of atomic radiation. From Science to Technology 2.2 examines  how radiation that moves electrons can affect human health.    What is the relationship between matter and elements?  Which elements are most common in the human body?  Where are electrons, protons, and neutrons located within an atom?    Vicki L. arrived early at the nuclear medicine department of the  health center. As she sat in an isolated cubicle, a doctor in full  sterile dress approached with a small metal canister marked with  warnings. The doctor carefully unscrewed the top, inserted a  straw, and watched as the young woman sipped the fluid within. It  tasted like stale water but was a solution containing a radioactive  isotope, iodine-131.   Vicki’s thyroid gland had been removed three months earlier,  and this test was to determine whether any active thyroid tissue  remained. The thyroid is the only part of the body to metabolize  iodine, so if Vicki’s body retained any of the radioactive drink, it  would mean that some of her cancerous thyroid gland remained.  By using a radioactive isotope, her physicians could detect iodide  uptake using a scanning device called a scintillation counter  (fig. 2A). Figure 2B illustrates iodine-131 uptake in a complete  thyroid gland.   The next day, Vicki returned for the scan, which showed that  a small amount of thyroid tissue was left and functioning. Another  treatment would be necessary. Vicki would drink enough radioac-  tive iodide to destroy the remaining tissue. This time, she drank  the solution in an isolation room lined with paper to keep her from  contaminating the floor, walls, and furniture. The same physician  administered the radioactive iodide. Vicki's physician had this  job because his thyroid had been removed many years earlier,  because he, too, had cancer, and therefore the radiation couldn't  harm him.   After two days in isolation, Vicki went home with a list of odd  instructions. She was to stay away from her children and pets,  wash her clothing separately, use disposable utensils and plates,  and flush the toilet three times each time she used it. These  precautions would minimize her contaminating her family—mom  was radioactive!   lodine-131 is a medically useful radioactive isotope because it  has a short half-life, a measurement of the time it takes for half of  an amount of an isotope to decay to a nonradioactive form. The    half-life of iodine-131 is 8.1 days. With the amount of radiation in  Vicki's body dissipating by half every 8.1 days, after three months  hardly any would be left. If all went well, any remaining cancer cells  would leave her body along with the radioactive iodine.   Isotopes of other elements have different half-lives. The half-  life of iron-59 is 45.1 days; that of phosphorus-32 is 14.3 days; that  of cobalt-60 is 5.26 years; and that of radium-226 is 1,620 years.   A form of thallium-201 with a half-life of 73.5 hours is com-  monly used to detect disorders in the blood vessels supplying the  heart muscle or to locate regions of damaged heart tissue after a  heart attack.   Gallium-67, with a half-life of 78 hours, is used to detect and  monitor the progress of certain cancers and inflammatory ill-  nesses. These medical procedures inject the isotope into the  blood and follow its path using detectors that record images on  paper or film.   Radioactive isotopes are also used to assess kidney function,  estimate the concentrations of hormones in body fluids, measure  blood volume, and study changes in bone density. Cobalt-60 is a  radioactive isotope used to treat some cancers. The cobalt emits  radiation that damages cancer cells more readily than it does  healthy cells.    (b)  FIGURE 2B (a) A scan of the thyroid gland twenty-four hours after    (a) resembles the shape of the thyroid gland shown in (b).    Alpha, beta, and gamma radiation are called ionizing radiation  because their energy removes electrons from atoms (fig. 2C).  Electrons dislodged by ionizing radiation can affect nearby atoms,  disrupting physiology at the chemical level in a variety of ways—  causing cancer, clouding the lens of the eye, and interfering with  normal growth and development.   In the United States, some people are exposed to very low  levels of ionizing radiation, mostly from background radiation,  which originates from natural environmental sources (table 2A).  For people who live near sites of atomic weapons manufacture,  exposure is greater. Epidemiologists are investigating medical  records that document illnesses linked to long-term exposure to  ionizing radiation in a 1,200-square-kilometer area in Germany.   The lake near Oberrothenback, Germany, which appears  inviting, harbors enough toxins to kill thousands of people. It is  polluted with heavy metals, low-level radioactive chemical waste,  and 22,500 tons of arsenic. Radon, a radioactive by-product  of uranium, permeates the soil. Many farm animals and pets  that have drunk from the lake have died. Cancer rates and respi-  ratory disorders among the human residents nearby are well  above normal.    FIGURE 2C Ionizing radiation removes electrons from atoms.  (a) lonizing radiation may dislodge an electron from an electrically  neutral hydrogen atom. (b) Without its electron, the hydrogen atom  becomes a positively charged hydrogen ion (H’*).    Two or more atoms may combine to form a distinctive type of  particle called a molecule. A molecular formula is shorthand  used to depict the numbers and types of atoms in a molecule.  It consists of the symbols of the elements in the molecule with  numerical subscripts that indicate how many atoms of each ele-  ment are present. For example, the molecular formula for water  is H,O, which indicates two atoms of hydrogen and one atom of    Radioactive elements in consumer  products (luminescent dials, smoke  detectors, color TV components)    used to build atomic bombs for the former Soviet Union. In the  early 1950s, nearly half a million workers labored here and in sur-  rounding areas in factories and mines. Records released in 1989,  after the reunification of Germany, reveal that workers were given  perks, such as alcoholic beverages and better wages, to work in  the more dangerous areas. The workers paid a heavy price: many  died of lung ailments.   Until recently, concern over the health effects of exposure to  ionizing radiation centered on the U.S. government's plan to trans-  port tens of thousands of metric tons of high-level nuclear waste  from 109 reactors around the country for burial beneath Yucca  Mountain, in Nevada, which is about 100 miles from Las Vegas,  by 2021. The waste, stored near the reactors, was to be buried  in impenetrable containers under the mountain by robots. In the  reactors, nuclear fuel rods contain uranium oxide, which produces  electricity as it decays to plutonium, which gives off gamma rays.  Periodically the fuel rods must be replaced, and the spent ones  buried. In 2010 the federal government ended funding for the  controversial Yucca Mountain plan. The search continues for an  isolated place to store the nuclear waste.    oxygen in each molecule. The molecular formula for the sugar  glucose, C,H,,O,, indicates six atoms of carbon, twelve atoms of  hydrogen, and six atoms of oxygen.   If atoms of the same element combine, they produce molecules  of that element. Gases of hydrogen (H,), oxygen (O,), and nitro-  gen (N,) consist of such molecules. If atoms of different elements  combine, molecules of compounds form. Two atoms of hydrogen,  for example, can combine with one atom of oxygen to produce a    FIGURE 2.2 Under certain conditions, hydrogen molecules can combine with oxygen molecules, forming water molecules.    molecule of the compound water (H,O), as figure 2.2 shows. Table  sugar, baking soda, natural gas, beverage alcohol, and most drugs  are compounds.   A molecule of a compound always consists of definite types  and numbers of atoms. A molecule of water (H,O), for instance,  always has two hydrogen atoms and one oxygen atom. If two  hydrogen atoms combine with two oxygen atoms, the compound  formed is not water, but hydrogen peroxide (H,O,).    Atoms combine with other atoms by forming links called bonds.  Chemical bonds result from interactions of electrons.   The electrons of an atom occupy one or more regions of space  called electron shells that encircle the nucleus. Because electrons  have a level of energy characteristic of the particular shell they are  in, the shells are also called energy shells. Each electron shell can  hold a limited number of electrons. The maximum number of elec-  trons that each of the first three shells can hold for elements of  atomic number 18 and under is:    More complex atoms may have as many as eighteen electrons in  the third shell.   Simplified diagrams such as those in figure 2.3 are used to  show electron configuration in atoms. The single electron of a  hydrogen atom is in the first shell; the two electrons of a helium  atom fill its first shell; and of the three electrons of a lithium atom,  two are in the first shell and one is in the second shell (fig. 2.3a).  Lower energy shells, closer to the nucleus, must be filled first.  Figure 2.3b depicts a more complex atom, of the element sodium,  and how the atomic number derives from the number of protons  and the atomic weight from the number of protons and neutrons.   The number of electrons in the outermost shell of an atom  determines whether it will react with another atom. Atoms react in  a way that leaves the outermost shell completely filled with elec-  trons, achieving a more stable structure. This is called the octet  rule, because, except for the first shell, eight electrons are required  to fill the shells in most of the atoms important in living organisms.   Atoms such as helium, whose outermost electron shells are  filled, already have stable structures and are chemically inactive    FIGURE 2.3 Electrons orbit the atomic nucleus. (a) The single electron  of a hydrogen atom moves within its first shell. The two electrons of a  helium atom fill its first shell. Two of the three electrons of a lithium atom  are in the first shell, and one is in the second shell. (6) A sodium atom has  11 protons and 12 neutrons in its nucleus, and 11 electrons that move  within three shells.    or inert (they cannot form chemical bonds). Atoms with incom-  pletely filled outer shells, such as those of hydrogen or lithium,  tend to gain, lose, or share electrons in ways that empty or fill their  outer shells. In this way, they achieve stable structures.   Atoms that gain or lose electrons become electrically charged  and are called ions (i’onz). An atom of sodium, for example, has  eleven electrons: two in the first shell, eight in the second shell,  and one in the third shell. This atom tends to lose the electron from  its outer (third) shell, which leaves the second (now the outermost)  shell filled and the new form stable (fig. 2.4a). In the process,  sodium is left with eleven protons (11*) in its nucleus and only  ten electrons (10°). As a result, the atom develops a net electrical  charge of *1 and is called a sodium ion, symbolized Na’.    A chlorine atom has seventeen electrons, with two in the  first shell, eight in the second shell, and seven in the third shell.  An atom of this type tends to accept a single electron, filling its  outer (third) shell and becoming stable. In the process, the chlorine  atom is left with seventeen protons (17*) in its nucleus and eigh-  teen electrons (18°). As a result, the atom develops a net electrical  charge of “1 and is called a chloride ion, symbolized CI.   Positively charged ions are called cations (kat’i-onz), and  negatively charged ions are called anions (an’i-onz). Ions with  opposite charges attract, forming ionic bonds (i-on’ik bondz).  Sodium ions (Na*) and chloride ions (CI-) unite in this manner to    (a) Separate atoms  If a sodium atom loses an electron to a chlorine atom, the sodium  atom becomes a sodium ion (Na*), and the chlorine atom becomes    Sodium chloride  (b) Bonded ions  These oppositely charged particles attract electrically and join by  an ionic bond.    (c) Salt crystal  lonically bonded substances form arrays such as a crystal of NaCl.    FIGURE 2.4 (AP|R) An ionic bond forms when (a) one atom loses    and another atom gains one or more electrons and then (b) oppositely  charged ions attract. (c) lonically bonded substances may form crystals.    form the compound sodium chloride (NaCl), or table salt (fig. 2.4).  Similarly, hydrogen atoms may lose their single electrons and  become hydrogen ions (H*). Hydrogen ions can form ionic bonds  with chloride ions (Cl-) to form hydrogen chloride (HCl, which  reacts in water to form hydrochloric acid). Some ions have an  electrical charge greater than 1—for example, Ca* (or Ca**).   Cations and anions attract each other in all directions, form-  ing a three-dimensional structure, so ionically bound compounds  do not form specific particles and they do not exist as molecules.  Rather, they form arrays, such as crystals of sodium chloride  (fig. 2.4c). The molecular formulas for compounds such as sodium  chloride (NaCl) give the relative amounts of each element.   Atoms may also bond by sharing electrons rather than by  gaining or losing them. A hydrogen atom, for example, has one  electron in its first shell but requires two electrons to achieve a  stable structure. It may fill this shell by combining with another  hydrogen atom in such a way that the two atoms share a pair of  electrons. As figure 2.5a shows, the two electrons then encircle the  nuclei of both atoms, filling the outermost shell, and each atom  becomes stable. A chemical bond between atoms that share elec-  trons is called a covalent bond (ko’va-lent bond). Figure 2.5b  shows the covalent bonding that joins the atoms of a very familiar  molecule—water.   Usually atoms of each element form a specific number of  covalent bonds. Hydrogen atoms form one bond, oxygen atoms  form two bonds, nitrogen atoms form three bonds, and carbon  atoms form four bonds. Atomic symbols and lines can be used to  represent the bonding capacities of these atoms, as follows:    Atomic symbols and lines show how atoms bond and are  arranged in various molecules. One pair of shared electrons, a sin-  gle covalent bond, is depicted with a single line. Sometimes atoms  may share two pairs of electrons (a double covalent bond), or  even three pairs (a triple covalent bond), represented by two and  three lines, respectively. [lustrations of this type, called struc-  tural formulas (fig. 2.6), are useful, but they cannot adequately  capture the three-dimensional forms of molecules. In contrast, fig-  ure 2.7 shows a three-dimensional (space-filling) representation  of a water molecule.   In ionic bonds, one or more electrons of one atom are pulled  entirely toward another atom. In covalent bonds, atoms share elec-  trons equally. In between these two extremes lies the covalent bond  in which electrons are shared, but are not shared equally, such that  the shared electrons move more toward one of the bonded atoms.  This results in a molecule with an uneven distribution of charges.  Such a molecule is called polar. Unlike an ion, a polar molecule  has an equal number of protons and electrons, but more of the  electrons are at one end of the molecule, making that end slightly  negative, while the other end of the molecule is slightly positive.  Typically, polar covalent bonds form where hydrogen atoms bond  to oxygen or nitrogen atoms. Water is a polar molecule (fig. 2.8a).    FIGURE 2.5 A covalent bond forms when (a) two hydrogen atoms share a pair of electrons to form a hydrogen molecule. (b) Hydrogen  molecules can combine with oxygen molecules, forming water molecules. The overlapping shells represent the shared electrons of covalent bonds.    FIGURE 2.6 Structural and molecular formulas depict molecules  of hydrogen, oxygen, water, and carbon dioxide. Note the double  covalent bonds. (Triple covalent bonds are also possible between  some atoms.)    FIGURE 2.7 A three-dimensional model represents this water  molecule (H,O). The white parts represent the hydrogen atoms,  and the red part represents oxygen.    The attraction of the positive hydrogen end of a polar molecule  to the negative nitrogen or oxygen end of another polar molecule is  called a hydrogen bond. These bonds are relatively weak. For exam-  ple, below 0°C, the hydrogen bonds between water molecules shown  in figure 2.8b are strong enough to form ice. As the temperature  rises, increased molecular movement breaks the hydrogen bonds,  and water becomes liquid. At body temperature, hydrogen bonds are  important in protein and nucleic acid structure. In these cases, many  hydrogen bonds form between polar regions of a single, very large  molecule. Together, these individually weak bonds provide strength.    & ) -PRACTICE  8 Distinguish between a molecule and a compound.  9 What is an ion?  10 Describe two ways that atoms may combine with other atoms.  11. What is a molecular formula? A structural formula?    Chemical reactions form or break bonds between atoms, ions, or  molecules. The starting materials changed by the chemical reaction  are called reactants (re-ak’tantz). The atoms, ions, or molecules  formed at the reaction’s conclusion are called products. When    FIGURE 2.8 Water is a polar molecule. (a) Water molecules have equal  numbers of electrons and protons but are polar because the electrons are  shared unequally, creating slightly negative ends and slightly positive ends.  (b) Water molecules form hydrogen bonds with each other.    © How does the number of protons in a water molecule  compare with the number of electrons?    two or more atoms, ions, or molecules bond to form a more com-  plex structure, as when hydrogen and oxygen atoms bond to form  molecules of water, the reaction is called synthesis (sin’thé-sis).  Such a reaction can be symbolized as:    If the bonds of a reactant molecule break to form simpler  molecules, atoms, or ions, the reaction is called decomposition  (de-kom” po-zish’un). For example, molecules of water can decom-  pose to yield the products hydrogen and oxygen. Decomposition is  symbolized as:    Synthetic reactions, which build larger molecules from smaller  ones, are particularly important in growth of body parts and repair  of worn or damaged tissues. Decomposition reactions digest nutri-  ent molecules into molecules small enough to be absorbed into the  bloodstream in the small intestine.    In a third type of chemical reaction, an exchange reaction  (replacement reaction), parts of two different types of molecules  trade positions as bonds are broken and new bonds are formed.  The reaction is symbolized as:    An example of an exchange reaction is an acid reacting with a  base, producing water and a salt. The following section discusses  this type of reaction.   Many chemical reactions are reversible. This means the  product or products can change back to the reactant or reactants.  A reversible reaction is symbolized using a double arrow:    Whether a reversible reaction proceeds in one direction or  another depends on the relative proportions of reactant (or reac-  tants) and product (or products) as well as the amount of energy  available. Catalysts (kat’ah-listz) are molecules that influence  the rates (not the direction) of chemical reactions but are not con-  sumed in the process.    When ionically bound substances are placed in water, the ions  are attracted to the positive and negative ends of the water mol-  ecules and tend to leave each other, or dissociate. In this way, the  polarity of water dissociates the salts in the internal environment.  Sodium chloride (NaCl), for example, ionizes into sodium ions  (Na*) and chloride ions (CI) in water (fig. 2.9). This reaction is  represented as:    The resulting solution has electrically charged particles  (ions), so it conducts an electric current. Substances that release  ions in water are, therefore, called electrolytes (e-lek’tro-litz).   Electrolytes that dissociate to release hydrogen ions (H*) in  water are called acids (as’idz). For example, in water, the com-  pound hydrochloric acid (HCl) releases hydrogen ions (H*) and  chloride ions (CI):    Substances that release ions that combine with hydrogen  ions are called bases. The compound sodium hydroxide (NaOH)  in water releases hydroxide ions (OH), which can combine with  hydrogen ions to form water. Thus, sodium hydroxide is a base:    (Note: Some ions, such as OH-, consist of two or more atoms.  However, such a group behaves as a unit and usually remains  unchanged during a chemical reaction.)   Bases can react with acids to neutralize them, forming water  and electrolytes called salts. For example, hydrochloric acid and  sodium hydroxide react to form water and sodium chloride:    FIGURE 2.9 fAP|R) The polar nature of water molecules dissociates  sodium chloride (NaCl) in water, releasing sodium ions (Na*) and  chloride ions (Ch).    Concentrations of acids and bases affect the chemical reactions  that constitute many life processes, such as those controlling  breathing rate. Therefore, the concentrations of these substances in  body fluids are of special importance.   Hydrogen ion concentration can be measured in grams of ions  per liter of solution. However, because hydrogen ion concentration  can vary over a wide range (gastric juice has 0.01 grams H*/liter;  household ammonia has 0.00000000001 grams H*/liter), short-  hand called the pH scale is used. This system tracks the number  of decimal places in a hydrogen ion concentration without writing  them out. For example, a solution with a hydrogen ion concentration  of 0.1 grams per liter has a pH of 1.0; a concentration of 0.01 g H*/L  has pH 2.0; 0.001 g H*/L is pH 3.0; and so forth. Each whole number  on the pH scale, which extends from 0 to 14, represents a tenfold  difference in hydrogen ion concentration. As the hydrogen ion  concentration increases, the pH number decreases. For example,    Salt Substance formed by  the reaction between  an acid and a base    a solution of pH 6 has ten times the hydrogen ion concentration as  a solution with pH 7. Therefore, small changes in pH reflect large  changes in hydrogen ion concentration.   In pure water, which ionizes only slightly, the hydrogen ion  concentration is 0.0000001 g/L, and the pH is 7.0. Water ionizes to  release equal numbers of acidic hydrogen ions and basic hydroxide  ions, so it is neutral.    Many bases are present in body fluids, but because of the way  bases react in water, the concentration of hydroxide ions is a good  estimate of the total base concentration. The concentrations of  hydrogen ions and hydroxide ions in body fluids are always in bal-  ance such that if one increases, the other decreases, and vice versa.  Solutions with more hydrogen ions than hydroxide ions are acidic.  That is, acidic solutions have pH values less than 7.0 (fig. 2.10).  Solutions with fewer hydrogen ions than hydroxide ions are basic  (alkaline); they have pH values greater than 7.0.   Table 2.5 summarizes the relationship between hydrogen ion  concentration and pH. Chapter 21 (pp. 812-813) discusses the reg-  ulation of hydrogen ion concentrations in the internal environment.   Negative feedback mechanisms such as those described  in chapter 1 (p. 16) regulate the pH of the internal environment  within a narrow pH range. Illness results when pH changes. The  normal pH of blood, for example, is 7.35 to 7.45 (pH values can be  decimals, in this case between 7 and 8). Because the pH of blood  is normally slightly alkaline, we need terms other than acidic and  alkaline to refer to abnormal blood pH. Blood pH of 7.5 to 7.8 is  called alkalosis (al”kah-lo’sis), and makes one feel agitated and  dizzy. This can be caused by breathing rapidly at high altitudes,  taking too many antacids, high fever, anxiety, or mild to moderate  vomiting that rids the body of stomach acid. Acidosis (as’i-do’sis),    Grams of H* per Liter pH  0.00000000000001 14 |  0.0000000000001 13  0.000000000001 12  0.00000000001 11  | 0.0000000001 10  | 0.000000001 a)  0.00000001 8 Increasingly basic  0.0000001 7 Neutral—neither acidic nor basic  , 0.000001 6 Increasingly acidic |  | 0.00001 5)  0.0001 4  0.001 3  0.01 2  0.1 1  1.00 0  CHAPTER 2 | Chemical Basis of Life 67    FIGURE 2.10 The pH scale reflects the hydrogen ion (H*) concentration. As the concentration of H* increases, a solution becomes  more acidic and the pH value decreases. As the concentration of ions that bond with H* (such as hydroxide ions) increases, a solution  becomes more basic (alkaline) and the pH value increases. The pH values of some common substances are shown.    © How does the hydrogen ion concentration compare between a solution of pH 6.4 and a solution of pH 8.4?    in which blood pH falls to 7.0 to 7.3, makes one feel disoriented  and fatigued, and breathing may become difficult. This condition  can result from severe vomiting that empties the alkaline small  intestinal contents, diabetes, brain damage, impaired breathing,  and lung and kidney disease.   Buffers are chemicals that resist pH change. They combine  with hydrogen ions when these ions are in excess, or they donate  hydrogen ions when these ions are depleted. Chapter 21 discusses  buffers (pp. 814-815).    14 Compare the characteristics of an acid, a base, and a salt.  15 What does the pH scale measure?  16 What is a buffer?    Chemicals, including those that take part in metabolism (the cell’s  energy reactions), are of two general types. Organic (or-gan’ik)  compounds have carbon and hydrogen. All other chemicals are  inorganic (in’or-gan’ik). Many organic molecules have long  chains or ring structures that can form because of a carbon atom’s  ability to form four covalent bonds.    The word organic has several meanings. Technically, it refers to  carbon-containing chemical compounds (except carbon diox-  ide), as opposed to inorganic compounds that do not contain  carbon. “Organic” may also refer to a substance obtained from  an organism or, even more generally, indicate a fundamental  characteristic. In agriculture, “organic” refers to growing crops  using only naturally occurring chemicals.    Inorganic substances usually dissolve in water and dissoci-  ate, forming ions. Therefore, they are electrolytes. Many organic  compounds dissolve in water, but most dissolve in organic liq-  uids such as ether or alcohol. Most organic compounds that  dissolve in water do not release ions and are therefore called  nonelectrolytes.    Common inorganic substances in cells include water, oxygen, carbon  dioxide, and inorganic salts.    Water (H,O) is the most abundant compound in living material and  accounts for about two-thirds of the weight of an adult human. It  is the major component of blood and other body fluids, including  fluids in cells.   When substances dissolve in water, the polar water molecules  separate molecules of the substance, or even dissociate them into  ions. These liberated particles are much more likely to react.  Consequently, most metabolic reactions occur in water.   Water is also important in transporting chemicals in the body.  Blood, which is mostly water, carries oxygen, sugars, salts, vita-  mins, and other vital substances from organs of the digestive and  respiratory systems to cells. Blood also carries waste materials,  such as carbon dioxide and urea, from cells to the lungs and kid-  neys, respectively, which remove them from the blood and release  them outside the body.   Water absorbs and carries heat. Blood brings heat released  from muscle cells during exercise from deeper parts of the body  to the surface. At the body surface, skin cells secrete water as  part of sweat that can release heat by evaporation.   The body regularly gains and loses water, but it must be  present in the correct concentration in the extracellular fluid, to  maintain homeostasis. Such a condition, where gains and losses  are equal, is called water balance.   Molecules of oxygen gas (O,) enter the internal environment  through the respiratory organs and are carried throughout the body  by the blood, especially by red blood cells. In cells, organelles use  oxygen to release energy from nutrient molecules. The energy  then drives the cell’s metabolic activities. A continuing supply of  oxygen is necessary for cell survival and, ultimately, for the sur-  vival of the organism.   Carbon dioxide (CO,) is a simple, carbon-containing inorganic  compound. It is a waste product of the release of energy during cer-  tain metabolic reactions. As carbon dioxide moves from cells into  the interstitial fluid and blood, most of it reacts with water to form  a weak acid (carbonic acid, H,CO,). This acid ionizes, releasing  hydrogen ions (H*) and bicarbonate ions (HCO,), which the blood  carries to the respiratory organs. There, the chemical reactions  reverse, and carbon dioxide gas is produced and is then exhaled.    Inorganic salts are abundant in body fluids. They are the sources  of many necessary ions, including ions of sodium (Na‘*), chlo-  ride (Cl), potassium (K*), calcium (Ca*’), magnesium (Mg*’),  phosphate (PO, *), carbonate (CO,”*), bicarbonate (HCO, ), and  sulfate (SO,*). These ions play important roles in metabolism,  helping to maintain proper water concentrations in body fluids,  controlling pH, blood clotting, bone development, energy transfer    NO (nitric oxide) and CO (carbon monoxide) are two small  chemicals that can harm health, yet are also important to normal  physiology. NO is found in smog, cigarettes, and acid rain. CO is  a colorless, odorless, gas that is deadly when it leaks from home  heating systems or exhaust pipes in closed garages. However,    NO and CO are important biological messenger molecules.  NO is involved in digestion, memory, immunity, respiration, and  circulation. CO functions in the spleen, which recycles old red  blood cells, and in the parts of the brain that control memory,  smell, and vital functions.    in cells, and muscle and nerve functions. The body regularly gains  and loses these electrolytes, but they must be present in certain  concentrations, in the extracellular fluid, to maintain homeostasis.  Such a condition, where gains and losses are equal, is called elec-  trolyte balance. Table 2.6 summarizes the functions of some of  the inorganic substances in the body.    17 What are the general differences between an organic molecule  and an inorganic molecule?    18 What is the difference between an electrolyte and a nonelectrolyte?    Major component of body fluids (chapter 21, p. 805); medium in which most biochemical reactions occur; carries    various chemical substances (chapter 14, p. 541); helps regulate body temperature (chapter 6, p. 189)    Used in release of energy from glucose molecules (chapter 4, p. 131)    Waste product that results from metabolism (chapter 4, p. 129); reacts with water to form carbonic acid    Necessary for bone development (chapter 7, p. 207); muscle contraction (chapter 9, p. 298), and blood clotting    Component of bone tissue (chapter 7, p. 211); required for certain metabolic processes (chapter 18, p. 714)    Required for synthesis of ATP and nucleic acids (chapter 4, pp. 126 and 133); component of bone tissue    Required for polarization of cell membranes (chapter 10, p. 372); help maintain water balance (chapter 21, p. 809)    Bicarbonate HCO, Help maintain acid-base balance (chapter 21, p. 814)  ions  Calcium ions Gai  (chapter 14, fig. 14.19, p. 545)  Carbonate ions CO Component of bone tissue (chapter 7, p. 211)  Chloride ions Gl Help maintain water balance (chapter 21, p. 805)  Hydrogen ions Ht pH of the internal environment (chapters 19 and 20, pp. 752 and 787)  yarog  Magnesium ions Mg*?  Phosphate ions RO  (chapter 7, p. 211); help maintain polarization of cell membranes (chapter 10, p. 374)  Potassium ions K+ Required for polarization of cell membranes (chapter 10, p. 372)  Sodium ions Na*  Sulfate ions SO    Help maintain polarization of cell membranes (chapter 10, p. 374) and acid-base balance (chapter 21, p. 805)    Important groups of organic chemicals in cells include carbohy-  drates, lipids, proteins, and nucleic acids.   Carbohydrates (kar’bo-hi’dratz) provide much of the energy that  cells require. They also supply materials to build certain cell struc-  tures and they often are stored as reserve energy supplies.   Carbohydrates are water-soluble molecules that include  atoms of carbon, hydrogen, and oxygen. Most of these molecules  have twice as many hydrogen as oxygen atoms, which is the ratio  of hydrogen to oxygen in water molecules (H,O). This ratio is  easy to see in the molecular formulas of the carbohydrates glucose  (C,H,,O,) and sucrose (C,,H,,O,,).   Carbohydrates are classified by size. Simple carbohydrates, or  sugars, include the monosaccharides (mon”o-sak’ah-ridz) (sin-  gle sugars) and disaccharides (di-sak’ah-ridz) (double sugars). A  monosaccharide may include from three to seven carbon atoms, in    (a) Some glucose molecules  (CgHj20¢) have a straight  chain of carbon atoms.    a straight chain or a ring (fig. 2.11). Monosaccharides include the  five-carbon sugars ribose and deoxyribose, as well as the six-carbon  sugars glucose, dextrose (a form of glucose), fructose, and galactose  (fig. 2.12a). Disaccharides consist of two 6-carbon units (fig. 2.12).  Sucrose (table sugar) and lactose (milk sugar) are disaccharides.   Complex carbohydrates, also called polysaccharides (pol”e-  sak’ah-ridz), are built of simple carbohydrates linked to form  larger molecules of different sizes (fig. 2.12c). Cellulose is a poly-  saccharide abundant in plants. It is made of many bonded glucose  molecules. Humans cannot digest cellulose. It is considered to be  dietary fiber, passing through the gastrointestinal tract without being  broken down and absorbed into the bloodstream. Plant starch is  another type of polysaccharide. Starch molecules consist of highly  branched chains of glucose molecules connected differently than  in cellulose. Humans easily digest starch.   Humans synthesize a polysaccharide similar to starch called  glycogen, which is stored in the liver and skeletal muscles. Its  molecules also are branched chains of sugar units; each branch  consists of up to a dozen glucose units.    FIGURE 2.12 Carbohydrate molecules vary in size. (a) A monosaccharide molecule consists of one 6-carbon atom building block.  (b) A disaccharide molecule consists of two of these building blocks. (c) A polysaccharide molecule consists of many of these building blocks.   Lipids (lip’idz) are a group of organic chemicals that are insol-  uble in water but soluble in organic solvents, such as ether and  chloroform. Lipids include a number of compounds, such as  fats, phospholipids, and steroids, that have vital functions in cells  and are important constituents of cell membranes (see chapter 3,  p. 86). The most abundant lipids are the fats, primarily used to sup-  ply energy for cellular activities. Fat molecules can supply more  energy gram for gram than can carbohydrate molecules.   Like carbohydrates, fat molecules are composed of carbon,  hydrogen, and oxygen atoms. However, fats have a much smaller  proportion of oxygen than do carbohydrates. The formula for the fat  tristearin, C,H, ,,O,, illustrates these characteristic proportions.   The building blocks of fat molecules are fatty acids (fat’e  as’idz) and glycerol (glis’er-ol). Although the glycerol portion of  every fat molecule is the same, there are many types of fatty acids  and, therefore, many types of fats. All fatty acid molecules include  a carboxyl group (—COOH) at the end of a chain of carbon atoms.    Fatty acids differ in the lengths of their carbon atom chains,  which usually have an even number of carbon atoms. The fatty  acid chains also may vary in the ways the carbon atoms join. In  some molecules, single carbon-carbon bonds link all the carbon  atoms. This type of fatty acid is called a saturated fatty acid;  that is, each carbon atom binds as many hydrogen atoms as pos-  sible and is thus saturated with them. In contrast, the chains of  unsaturated fatty acids have one or more double bonds between  carbon atoms. Fatty acids with one double bond are called mono-  unsaturated fatty acids, and those with two or more double bonds  are polyunsaturated fatty acids (fig. 2.13).   A glycerol molecule combines with three fatty acid molecules to  form a single fat molecule, or triglyceride (figs. 2.14 and 2.15a). The  fatty acids of a triglyceride may have different lengths and degrees of  saturation, making the fats very diverse. Fat molecules that have only  saturated fatty acids are called saturated fats (sat’u-rat”ed fatz), and  those that have unsaturated fatty acids are called unsaturated fats  (unsat’u-rated fatz). Each type of fat molecule has distinct properties.    FIGURE 2.13 Fatty acids. (a) A molecule of saturated fatty acid and (b) a molecule of unsaturated fatty acid.  Double bonds between carbon atoms are shown in red. They cause a “kink” in the shape of the molecule.    FIGURE 2.14 A triglyceride molecule (fat) consists of a glycerol portion and three fatty acid portions. This is an example  of an unsaturated fat. The double bond between carbon atoms in the unsaturated fatty acid is shown in red.    Saturated fats are more abundant in fatty foods that are solids  at room temperature, such as butter, lard, and most animal fats.  Unsaturated fats are in foods that are liquid at room tempera-  ture, such as soft margarine and seed oils (corn, grape, sesame,  soybean, sunflower, and peanut). Coconut and palm kernel oils  are unusual in that they are high in saturated fats but are liq-  uids at room temperature. The most heart-healthy fats are olive  and canola (rapeseed) oils, which are monounsaturated—that is,  they have one carbon-carbon double bond.   Manufacturers add hydrogen atoms to certain vegetable  oils to make them harder and easier to use. This process, called  hydrogenation, produces fats that are partially unsaturated and  also “trans.” (“Trans” refers to atoms in a molecule on opposite  sides of a backbone-like structure, like stores on opposite sides  of a street. Atoms on the same side—like stores on the same  side of a street—are called “cis.”)    A phospholipid molecule is similar to a fat molecule in that it  includes a glycerol and fatty acid chains. The phospholipid, how-  ever, has only two fatty acid chains and, in place of the third, has a  portion containing a phosphate group (fig. 2.15b). This phosphate-    containing part is soluble in water (hydrophilic) and forms the “head”  of the molecule, whereas the fatty acid portion is insoluble in water  (hydrophobic) and forms a “tail” (fig. 2.15c). The fact that phospho-  lipids are both attracted to and repelled by water allows them to  form biological membranes, discussed in chapter 3 (pp. 86-87).  Steroid molecules are complex structures that include con-  nected rings of carbon atoms (fig. 2.16). Among the more important  steroids are: cholesterol, found in all body cells and used to synthe-  size other steroids; sex hormones, such as estrogen, progesterone,  and testosterone; and several hormones from the adrenal glands.  Chapters 13, 18, 20, 21, and 22 discuss these steroids. Table 2.7  summarizes the molecular structures and characteristics of lipids.    Proteins (pro’tenz) have a great variety of functions. The human  body has more than 200,000 types of proteins. Some are structural  materials, energy sources, and chemical messengers (hormones).  Other proteins combine with carbohydrates (forming glycoproteins)  and function as receptors on cell surfaces, allowing cells to respond  to specific types of molecules that bind to them. Antibody proteins  recognize and destroy substances foreign to the body, such as cer-  tain molecules on the surfaces of infecting bacteria. Proteins such as  hemoglobin and myoglobin carry oxygen in the blood and muscles,    FIGURE 2.15 Fats and phospholipids. (a) A triglyceride molecule (fat) consists of a glycerol and three fatty acids. (b) Ina  phospholipid molecule, a phosphate-containing group replaces one fatty acid. (c) Schematic representation of a phospholipid.    FIGURE 2.16 Steroid structure. (a) The general structure of a steroid. (b) The structural formula for cholesterol, a steroid    widely distributed in the body and a component of cell membranes.    Two fatty acid molecules and a phosphate group bound  to a glycerol molecule (may also include a nitrogen-  containing molecule attached to the phosphate group)    (a) General structure of an  amino acid. The portion  common to all amino acids  is within the oval. It includes  the amino group (—NH,)  and the carboxyl group  (—COOH). The “R group”,  or the “rest of the molecule,”  varies and is what makes  each type of amino acid unique.    Most common lipid in the body; stored in fat tissue as an energy  supply; fat tissue also provides insulation beneath the skin    Used as structural components in cell membranes; large amounts  are in the liver and parts of the nervous system    Widely distributed in the body with a variety of functions; includes  cholesterol, sex hormones, and certain hormones of the adrenal glands    FIGURE 2.17 Amino acid structure. (a) An amino acid has an amino group, a carboxyl group, and a hydrogen atom that are common to all  amino acid molecules, and a specific R group, all bonded to a central carbon. (b) and (c) Some representative amino acids and their structural  formulas. Each type of amino acid molecule has a particular shape due to its different R group.    respectively, and actin and myosin are contractile proteins that pro-  vide muscle action. Many proteins play vital roles in metabolism  as enzymes (en’zimz), which are catalysts in living systems. That  is, they speed specific chemical reactions without being consumed.  (Enzymes are discussed in chapter 4, pp. 123-124.)   Proteins are similar to carbohydrates and lipids in that they  consist of atoms of carbon, hydrogen, and oxygen. In addition, all  proteins contain nitrogen atoms, and some contain sulfur atoms. The  building blocks of proteins are amino acids (ah-me’no as’idz).   Twenty types of amino acids comprise proteins in organisms.  Amino acid molecules have an amino group (—NH,) at one end  and a carboxyl group (—COOH) at the other end. Between these  groups is a single carbon atom known as the central carbon. This  central carbon is bonded to a hydrogen atom and to another group  of atoms called a side chain or R group (“R” may be thought of as  the “Rest of the molecule’’). The composition of the R group distin-  guishes one type of amino acid from another (fig. 2.17).   Proteins have complex three-dimensional shapes, called  conformations, yet they are assembled from simple chains of  amino acids connected by peptide bonds. These are covalent    bonds that link the amino end of one amino acid with the carboxyl  end of another. Figure 2.18 shows two amino acids connected by a  peptide bond. The resulting molecule is a dipeptide. Adding a third  amino acid creates a tripeptide. Many amino acids connected in  this way constitute a polypeptide.   Proteins have four levels of structure: primary, secondary,  tertiary, and quaternary. The primary structure is the amino acid  sequence of the polypeptide chain (fig. 2.19a). The primary struc-  ture may range from fewer than 100 to more than 5,000 amino  acids. The amino acid sequence is characteristic of a particular  protein. Hemoglobin, actin, and an antibody protein have very  different amino acid sequences.    (b) Secondary structure—The  polypeptide chain of a protein  molecule is often either pleated  or twisted to form a coil. Dotted  lines represent hydrogen bonds.  R groups (see fig. 2.17) are  highlighted in orange. Examples  of individual amino acids are  highlighted in yellow.    (c) Tertiary structure—  The pleated and coiled  polypeptide chain of a  protein molecule folds  into a unique three-  dimensional structure.    (d) Quaternary structure—Two or more  proteins, often different, may combine  to form a single, larger protein molecule.    FIGURE 2.19 All levels of protein structure contribute  to the overall three-dimensional conformation, which is  vital to the protein's function.    In the secondary structure, the polypeptide chain either forms  a springlike coil (alpha helix) or folds back and forth on itself  (beta-pleated sheet) or into other shapes (fig. 2.19b). Secondary  structure arises from hydrogen bonding. Recall that polar mole-  cules result when electrons are not shared equally in certain cova-  lent bonds. In amino acids, this unequal sharing results in slightly  negative oxygen and nitrogen atoms and slightly positive hydro-  gen atoms. Hydrogen bonding between oxygen and hydrogen  atoms in different parts of the polypeptide chain determines the  secondary structure. Depending on the sequence of amino acids, a  single very long polypeptide may include helices, sheets, and less  common shapes with such colorful names as zippers, hairpins,  loops, and fingers. These general shapes that arise from secondary  structure are called motifs.   Hydrogen bonding and even covalent bonding between atoms  in different parts of a polypeptide can impart another, larger level  of folding, the tertiary structure (fig. 2.19c). The points of attach-  ment in the tertiary structure are farther apart along the amino acid  sequence than are the attachments that form the secondary structure.  Altogether, the primary, secondary, and tertiary structures contribute  to a protein’s distinct conformation, which determines its function.  Some proteins are long and fibrous, such as the keratins that form  hair and the threads of fibrin that knit a blood clot. Myoglobin and  hemoglobin are globular proteins, as are many enzymes.   For some proteins, slight reversible changes in conforma-  tion are part of their normal functions. For example, some of the  proteins that interact to contract muscle exert a pulling force as a  result of such a shape change, leading to movement. The revers-  ibility of these changes enables the protein to function repeatedly.   Various treatments can more dramatically change or denature  the secondary and tertiary structures of a protein’s conformation.  Because the primary structure (amino acid sequence) remains,  sometimes the protein can regain its shape when normal condi-  tions return. High temperature, radiation, pH changes, and certain  chemicals (such as urea) can denature proteins.   A familiar example of irreversible protein denaturation is the  response of the protein albumin to heat. This happens when cooking  an egg white, which consists mostly of albumin. Some chemical    Protein misfolding can cause disease. In some cases of cystic  fibrosis, a protein cannot fold into its final form, which pre-  vents it from anchoring in the cell membrane, where it would  normally control the movement of chloride ions. Certain  body fluids thicken, which impairs respiration and digestion.  Illnesses called transmissible spongiform encephalopathies,  which includes “mad cow disease,” result when a type of pro-  tein called a prion folds into an abnormal, infectious form—  that is, it converts normal prion protein into the pathological  form, which riddles the brain with holes. Alzheimer disease  results from the cutting of a protein called beta amyloid into  pieces of a certain size. The proteins misfold, attach, and  accumulate, forming structures called plaques in parts of the  brain controlling memory and cognition. Spool-like structures  in cells, called proteasomes, normally dismantle misfolded  proteins before they can accumulate and cause illness.    treatments that curl hair also cause protein denaturation. The  chemicals first break apart the tertiary structure formed when sul-  fur-containing amino acids attract each other within keratin mol-  ecules. The denaturation relaxes the hair. When the chemicals are  washed out of the set hair, the sulfur bonds reform, but in different  places. The appearance of the hair changes.    Crack an egg and place the egg white into some  vinegar (a strong acid) for a few days, and it will turn hard  and white just as if it were cooked, because the albumin  protein denatures. Similarly, body fluids with too high or  too low pH can denature the proteins that carry out cellular  metabolism, disrupting their functions. Chapter 21 describes  the homeostatic mechanisms for maintaining the pH of the  internal environment.    Not all proteins are single polypeptide chains. In some pro-  teins, several polypeptide chains are connected in a fourth level,  or quaternary structure, to form a very large molecule (fig. 2.19d).  Hemoglobin is a quaternary protein made up of four separate  polypeptide chains.   A protein’s conformation determines its function. The amino  acid sequence and interactions among the amino acids in a protein  determine the conformation. Thus, it is the amino acid sequence  of a protein that determines its function in the body. Nucleic acids  (nu-kle’ik as’idz) carry the instructions, in the form of genes (see  chapter 4, p. 132), that control a cell’s activities by encoding the  amino acid sequences of proteins.    The very large and complex nucleic acids include atoms of carbon,  hydrogen, oxygen, nitrogen, and phosphorus, which form build-  ing blocks called nucleotides (nu’kle-o-tidz). Each nucleotide  consists of a 5-carbon sugar (ribose or deoxyribose), a phosphate  group, and one of several nitrogen-containing organic bases,  called nitrogenous bases (fig. 2.20). Such nucleotides, in a chain,  form a polynucleotide (fig. 2.21).    A human body has more than 200,000 types of proteins, but  only about 20,325 genes. The numbers are not the same  because parts of some genes encode sequences of amino acids  found in more than one type of protein. The fact that proteins  outnumber genes is a little like assembling a large and diverse  wardrobe from a few basic pieces of clothing.    FIGURE 2.20 A nucleotide consists of a 5-carbon sugar (S = sugar),  a phosphate group (P = phosphate), and a nitrogenous base (B = base).    FIGURE 2.21 A schematic representation of nucleic acid structure. A nucleic acid molecule consists of (a) one (RNA) or (b) two (DNA)  polynucleotide chains. DNA chains are held together by hydrogen bonds (dotted lines) and they twist, forming a double helix. That the  sugars of each chain point in opposite directions affects the way that the information in genes is “read.” Chapter 4 (pp. 132-134, 136)  discusses gene structure and function, and chapter 24 (p. 906) covers heredity.    There are two major types of nucleic acids. RNA (ribonucleic HOCH, oO OH  acid) is composed of nucleotides that have ribose sugar. Most |  RNA molecules are single-stranded polynucleotide chains, but ¢ l  they can fold into shapes that enable them to interact with DNA. HG CoH   The second type of nucleic acid, DNA (deoxyribonucleic acid), | | a ‘\  has deoxyribose sugar. DNA is a double polynucleotide chain  wound into a double helix. Hydrogen bonds hold the two chains Ribose Deoxyribose  together. Figure 2.22 compares the structures of ribose and deoxy-  ribose, which differ by one oxygen atom. DNA and RNA also  differ in that DNA molecules store the information for protein syn-  thesis and RNA molecules use this information to construct specific  protein molecules. RNA molecules are of several types. These will  be discussed further in chapter 4 (pp. 138-139).   DNA molecules have a unique ability to make copies of, or  replicate, themselves. They replicate prior to cell division, and  each newly formed cell receives an exact copy of the original cell’s    FIGURE 2.22 The molecules of ribose and deoxyribose differ by a  single oxygen atom.    DNA molecules. Chapter 4 (pp. 138-142) discusses the storage of  information in nucleic acid molecules, use of the information to  manufacture protein molecules, and how these proteins control  metabolic reactions.   Table 2.8 summarizes the four groups of organic compounds.  Figure 2.23 shows three-dimensional (space-filling) models of  some important molecules, illustrating their shapes. From Science  to Technology 2.3 describes two techniques used to view human    have polar regions where nitrogen or oxygen bond with hydro- BELONG ANCE PEYSIIOEY:  gen. Such molecules, including carbohydrates, proteins, and »>  nucleic acids, dissolve easily in water. They are water soluble, or R ‘| _PRACTICE  hydrophilic (“liking” water). Molecules that do not have polar 20 Compare the chemical composition of carbohydrates, lipids,  regions, such as triglycerides and steroids, do not dissolve in proteins, and nucleic acids. How does an enzyme affect a  water (“oil and water don’t mix”). Such molecules do dissolve in chemical reaction?  lipid and are said to be lipophilic (“liking” lipid). Water solubility 21 What is likely to happen to a protein molecule exposed to  and lipid solubility are important factors in drug delivery and in intense heat or radiation?   acid, and (f) collagen (a protein). White = hydrogen, ah EN  red = oxygen, blue = nitrogen, black = carbon. (f)    C,H,O (often P) Triglycerides Provide energy, cell structure Fat  Phospholipids  Steroids Cholesterol    C,H,O,N (often S) Polypeptide chain Provide cell structure, enzymes, energy Albumins, hemoglobin    Physicians use two techniques—computerized tomography (CT)  scanning and positron emission tomography (PET) imaging—to  paint portraits of anatomy and physiology, respectively.   In CT scanning, an X-ray-emitting device is positioned around  the region of the body being examined. At the same time, an X-ray  detector is moved in the opposite direction on the other side of the  body. As these parts move, an X-ray beam passes through the body  from hundreds of different angles. Because tissues and organs of  varying composition absorb X rays differently, the intensity of X rays  reaching the detector varies from position to position. A computer  records the measurements from the X-ray detector and combines  them mathematically, creating a three-dimensional sectional image  of internal body parts (fig. 2D). In contrast, ordinary X-ray tech-  niques produce two-dimensional images known as radiographs,  X rays, or films.   ACT scan clearly differentiates soft tissues of slightly different  densities, such as the liver and kidneys, which a conventional X-ray  image cannot distinguish. In this way, a CT scan can detect abnor-  mal tissue, such as a tumor. For example, a CT scan can tell whether  a sinus headache that does not respond to antibiotic therapy is  caused by a drug-resistant infection or by a tumor.   PET imaging uses radioactive isotopes that naturally emit  positrons, which are atypical positively charged electrons, to  detect biochemical activity in a specific body part. Useful isotopes  in PET imaging include carbon-11, nitrogen-13, oxygen-15, and  fluorine-18. When one of these isotopes releases a positron, it inter-  acts with a nearby negatively charged electron. The two particles    destroy each other in an event called annihilation. At the moment  of destruction, two gamma rays form and move apart. Special  equipment detects the gamma radiation.   To produce a PET image of biochemically active tissue, a per-  son is injected with a metabolically active compound that includes  a bound positron-emitting isotope. To study the brain, for exam-  ple, a person is injected with glucose containing fluorine-18. After  the brain takes up the isotope-tagged compound, the person rests  the head within a circular array of radiation detectors. A device  records each time two gamma rays are emitted simultaneously and  travel in opposite directions (the result of annihilation). A computer  collects and combines the data and generates a cross-sectional  image. The image indicates the location and relative concentration  of the radioactive isotope in different regions of the brain and can  be used to study those parts metabolizing glucose.   PET images reveal the parts of the brain affected in such dis-  orders as Huntington disease, Parkinson disease, epilepsy, and  Alzheimer disease, and they are used to study blood flow in ves-  sels supplying the brain and heart. The technology is invaluable  for detecting the physiological bases of poorly understood behav-  ioral disorders, such as obsessive-compulsive disorder. In this con-  dition, a person repeatedly performs a certain behavior, such as  washing hands, showering, locking doors, or checking to see that  the stove is turned off. PET images of people with this disorder  reveal intense activity in two parts of the brain that are quiet in the  brains of unaffected individuals. Knowing the site of altered brain  activity can help researchers develop more directed drug therapy.   In addition to highlighting biochemical activities behind ill-  ness, PET scans allow biologists to track normal brain physiology.  Figure 2E shows different patterns of brain activity associated with  different experiences.    FIGURE 2E These PET images demonstrate brain changes that accompany  different kinds of brain function. The upper left pattern represents sight, the  upper right represents hearing, the lower left shows a tactile response such  as feeling the bumps of braille print, and the lower right shows thoughts  expressed as words.    FIGURE 2D CT scans of (a) the head and (b) the abdomen.    Chemistry deals with the composition of substances and  how it changes. The human body is composed of chemicals.  Biochemistry is the chemistry of living organisms.    Structure of Matter (page 58)  Matter is anything that has weight and takes up space.    Elements are composed of atoms.  Atoms of different elements vary in size, weight, and  ways of interacting.    An atom consists of electrons surrounding a nucleus,  which has protons and neutrons. The exception is  hydrogen, which has only a proton in its nucleus.    or molecules break or form. Starting materials are  called reactants; the resulting atoms or molecules  are called products.   Three types of chemical reactions are synthesis, in  which large molecules build up from smaller ones;  decomposition, in which molecules break down; and  exchange reactions, in which parts of two different  molecules trade positions.   Many reactions are reversible. The direction of a  reaction depends upon the proportion of reactants and  products and the energy available.   Catalysts (enzymes) influence the rate (not the  direction) of the reaction.    Compounds that ionize in water are electrolytes.  Electrolytes that release hydrogen ions are acids, and  those that release hydroxide or other ions that react  with hydrogen ions are bases.   Acids and bases react to form water and electrolytes  called salts.    b. Electrons are negatively charged, protons positively  charged, and neutrons uncharged. 8. Acid and base concentrations  c. A complete atom is electrically neutral. a. pH represents the concentration of hydrogen ions (H*)  d. The atomic number of an element is equal to the and hydroxide ions (OH) in a solution.  number of protons in each atom; the atomic weight b. A solution with equal numbers of H* and OH is  is equal to the number of protons plus the number of neutral and has a pH of 7.0; a solution with more H*  neutrons in each atom. than OH is acidic (pH less than 7.0); a solution with  3. Isotopes fewer H* than OH is basic (pH greater than 7.0).  a. Isotopes are atoms with the same atomic number but c. A tenfold difference in hydrogen ion concentration  different atomic weights (due to differing numbers separates each whole number in the pH scale.  of neutrons). d. Buffers are chemicals that resist pH change.  b. All the isotopes of an element react chemically in the  saeco Sia a fates 2.3 Chemical Constituents of Cells (page 68)  c. Some isotopes are radioactive and release atomic radiation.    Molecules containing carbon and hydrogen atoms are  organic and are usually nonelectrolytes; other molecules    a. Two or more atoms may combine to form a molecule. 5 .  b. A molecular formula represents the numbers and are Inorganic and are usually electrolytes.  types of atoms in a molecule. 1. Inorganic substances  c. If atoms of the same element combine, they produce a. Water is the most abundant compound in the body. Many  molecules of that element. chemical reactions take place in water. Water transports  d. If atoms of different elements combine, they form chemicals and heat and helps release excess body heat.    Oxygen releases energy for metabolic activities from  glucose and other molecules.    a. When atoms form links called bonds, they gain, lose,  or share electrons. processes release energy.   c. Atoms with completely filled outer shells are inert, e. Electrolytes must be present in certain concentrations  whereas atoms with incompletely filled outer shells inside and outside of cells.  gain, lose, or share electrons and thus become stable. 2. Organic substances   d. Atoms that lose electrons become positively charged a. Carbohydrates provide much of the energy cells  (cations); atoms that gain electrons become negatively require and are built of simple sugar molecules.  charged (anions). b. Lipids, such as fats, phospholipids, and steroids, supply   e. Ions with opposite charges attract and join by ionic bonds; energy and are used to build cell parts; their building  atoms that share electrons join by covalent bonds. blocks are molecules of glycerol and fatty acids.   f. A structural formula represents the arrangement of c. Proteins serve as structural materials, energy sources,  atoms in a molecule. hormones, cell surface receptors, antibodies, and   h. Hydrogen bonds may form between polar molecules. (1) The building blocks of proteins are amino acids.    (2) Proteins vary in the numbers and types of their  constituent amino acids; the sequences of  these amino acids; and their three-dimensional  structures, or conformations.   (3) Primary structure is the amino acid sequence.  Secondary structure comes from attractions between  amino acids that are close together in the primary  structure. Tertiary structure reflects attractions of  far-apart amino acids and folds the molecule.    The Importance of Chemistry in Anatomy and Physiology  Define chemistry. (p. 58)   Identify the major parts of an atom and indicate where they   (3) DNA molecules store information that cell parts  use to construct specific proteins.   (5) DNA molecules are replicated, and an exact copy  of the original cell’s DNA is passed to each of the  newly formed cells resulting from cell division.   Identify three major types of chemical reactions. (p. 66)  Define reversible reaction. (p. 66)   Define electrolyte, acid, base, and salt. (pp. 66-67)  Explain pH and how to use the pH scale. (p. 67)   Describe the functions of water and oxygen in the human  body. (pp. 68-69)   List the three main types of lipids found in cells. (pp. 71-72)  Explain the difference between saturated and unsaturated  fats. (p. 71)   List at least three functions of proteins. (p. 72)  Describe the function of an enzyme. (p. 73)  Identify the four levels of protein structure. (pp. 73-75)  Identify two types of macromolecules in which hydrogen  bonds are important parts of the structure. (pp. 75-76)  Describe how the change in shape of a protein may be either  abnormal or associated with normal function. (p. 75)  Describe the general characteristics of nucleic acids. (p. 75)  Explain the general functions of nucleic acids. (p. 76)    1. The thyroid gland metabolizes iodine, the most common form  of which has a molecular weight of 127 (iodine-127). A physician  wants to use a radioactive isotope of iodine (iodine-131) to  test whether a patient's thyroid gland is metabolizing normally.  Based on what you know about how atoms react, do you think  this physician's plan makes sense?    2. How would you reassure a patient about to undergo CT scanning  for evaluation of a tumor and fears becoming a radiation hazard  to family members?    3. What acidic and basic substances do you encounter in your  everyday activities? What acidic foods do you eat regularly?  What basic foods do you eat?    5. How would you explain the importance of amino acids and  proteins in a diet to a person following a diet composed  primarily of carbohydrates?    6. Explain why the symptoms of many inherited diseases result  from abnormal protein function.    7. A friend, while frying eggs, points to the change in the egg white  (which contains a protein called albumin) and explains that if the  conformation of a protein changes, it will no longer have the  same properties and will lose its ability to function. Do you agree  or disagree with this statement?    Connect Integrated Activity Maintaining pH is important to  homeostasis. How well do you understand acids, bases, and buffers?    Anatomy & Physiology Revealed View animations on atomic  structure, chemical bonds, and electrolytes.    After you have studied this chapter, you should be able to:    Describe the general characteristics of a composite cell.  (pp. 83 and 85)    Explain how the components of a cell’s membrane  provide its functions. (pp. 86-87)    Describe each kind of cytoplasmic organelle and explain  its function. (pp. 90-93)    Describe the various cellular structures that are parts of  the cytoskeleton and explain their functions. (pp. 94-96)   Explain how substances move into and out of cells.  (pp. 99-106)    Control of Cell Division  Describe several controls of cell division. (pp. 110-111)    Explain how stem cells and progenitor cells make  possible growth and repair of tissues. (pp. 112-113)    Explain how two differentiated cell types can have the  same genetic information, but different appearances  and functions. (p. 113)    This falsely colored scanning electron micrograph depicts two cells  emerging from one after cell division (5,100x).    The cell is the smallest unit of life, and an average human consists  of about 37 trillion of them. Inside your body, in what we call the  internal environment, conditions are ideal for all cells. This doesn’t  happen by accident. The 290 different varieties of cells making  up a human body work with each other, as tissues, organs (such  as the heart), and organ systems (such as the cardiovascular sys-  tem), to maintain the internal environment that keeps them and  you alive, despite ever-changing conditions on the outside.   Most cells are part of a larger structure, such as a tissue  or an organ, whereas others, such as certain white blood cells,  move about. Each cell, like an organ or organ system, is a won-  der of organization, but on a much smaller scale. An outer layer  protects each cell. Inside a cell, a genetic headquarters oversees  biochemical activities, and a production line that winds through  a cell packages and routes various substances for use inside the  cell or for export. Tiny parts that act as power plants continually  extract energy from digested nutrients to keep the cell function-  ing. A cell even has its own garbage removal apparatus. Cells  are, simply, the basis of life.    apo-, away, off, apart: apoptosis—a form  of cell death in which cells are shed from  a developing structure.    Cells vary considerably in size, which we measure in units called  micrometers (mi’kro-me”terz). A micrometer equals one thousandth  of a millimeter and is symbolized um. A human egg cell is about  140 um in diameter and is just barely visible to an unaided eye.  An egg is large when compared to a red blood cell, which is about  7.5 um in diameter, or the most common types of white blood cells,  which are 10 to 12 um in diameter. Smooth muscle cells are 20 to  500 um long. Figure 3.1 compares four specialized cell types.   Cells generally have distinctive three-dimensional forms  that make possible their functions (fig. 3.2). For instance, nerve  cells that have threadlike extensions many centimeters long con-  duct bioelectric impulses from one part of the body to another.  Epithelial cells that are part of the skin are thin, flattened, and  tightly packed, somewhat like floor tiles. They form a barrier that  shields underlying tissue. Muscle cells, slender and rodlike, con-  tract and pull structures to which they are attached closer together.   Cells with specialized characteristics are termed differenti-  ated. Such specialized cells form from less specialized cells that  divide and express specific genes. A cell is like the Internet, harbor-  ing a vast store of information in its genome. However, like a person  accessing only a small part of the Internet, a cell uses only some of  the information in its genome to build structures and to carry out  both the basic functions of life as well as its specialized functions.   hep PRACTICE  1 What unit of measurement is used in describing cell size?  2 What is a differentiated cell?    It is not possible to describe a typical cell, because cells vary  greatly in size, shape, content, and function. We can, however,  consider a hypothetical composite cell that includes many well-  studied cell structures (fig. 3.3).   iso-, equal: isotonic—solution that has an  osmotic pressure equal to that of the    The three major parts of a cell—the nucleus (nu’kle-us), the  cytoplasm (si’to-plazm), and the cell membrane—if appropriately  stained, are easily seen under the light microscope. In many cell  types the nucleus is innermost and is enclosed by a thin membrane  called the nuclear envelope. The nucleus contains the genetic mate-  rial (DNA), which directs the cell’s functions.   The cytoplasm includes specialized structures called cyto-  plasmic organelles (or-gan-elz) that are suspended in a liquid  called cytosol (si’to-sol). Organelles divide the labor in a cell by    The woman has been tired for months, but blames it on  frequent respiratory infections. When she notices several  bruises, she visits her primary care physician, who sends  a sample of her blood to a laboratory for analysis.   The cytotechnologist, who prepares a microscope slide  from the blood sample and examines it, finds that there are  too many white blood cells and too few red blood cells, and  suspects that the patient has leukemia—a blood cancer.   A cytotechnologist recognizes signs of illness in cells.  The job requires a bachelor’s degree in biology, chemistry,  or a related field that includes one to two years of an accredited  program in cytotechnology. Further certification is available  for Specialist in Cytotechnology and Technologist in  Molecular Pathology, which may open up jobs in education  and management. Cytotechnologists work independently  but may consult with pathologists.   Cytotechnologists work in hospitals, doctors’ offices,  outpatient clinics, and diagnostic laboratories. Some  tests performed on cells use automated equipment to  identify cancerous or infected cells, but others require the  cytotechnologist’s judgment, based on experience with  and knowledge of cell biology.   A career in cytotechnology can be very rewarding,  because detecting disease on the cellular level is critical to  accurate diagnosis of many conditions. Cytotechnologists can  also work in research settings or sell laboratory equipment.    10-12 um in diameter; (c) human egg  cell, 140 pm in diameter; (d) smooth 200 um  muscle cell, 20-500 pm in length. (d)    (a) A nerve cell’s long extensions enable it to conduct electrical impulses from one body part to another.    . (b) The sheetlike organization of epithelial (c) The alignment of contractile proteins within  FIGURE 3.2 Cells vary in shape cells enables them to protect underlying cells. muscle cells enables them to contract, pulling  and function. closer together the structures to which they attach.    FIGURE 3.3 (AP|R) A composite cell illustrates the organelles and other structures found in cells. Specialized cells differ  in the numbers and types of organelles, reflecting their functions. Organelles are not drawn to scale.    partitioning off certain areas or providing specific functions, such busy place! The cell membrane (also called a plasma membrane)  as dismantling debris, extracting energy from nutrients, or pack- contains the cytoplasm, which surrounds the nucleus.  aging secretions. Cells with different specializations have dif- >»    ferent numbers of particular organelle types. Organelles are not R ‘) PRACTICE  static and still, as figure 3.3 might suggest. Some organelles move  within the cell as part of their function, and even those that stay in  one place are the sites of ongoing biochemical activity. A cell is a    Cells with nuclei, such as those of the human body (except red  blood cells), are termed eukaryotic, meaning “true nucleus.” In  contrast are the prokaryotic ("before nucleus”) cells of bacteria.  Although bacterial cells lack nuclei and other membrane-bound  organelles and thus have fewer components than eukaryotic cells,    the bacteria are widespread and have existed much longer than  eukaryotic cells. Viruses are simpler than cells. They consist of  genetic material in a protein coat and cannot reproduce outside  of a host cell (the cell they infect).    The cell membrane is the outermost limit of a cell. Not just a simple  boundary, the cell membrane is an actively functioning part of the  living material. Many important metabolic reactions take place on  its inner and outer surfaces, and it includes molecules that enable  cells to communicate with each other and to interact.    The cell membrane is extremely thin. It is visible only with the  aid of an electron microscope (fig. 3.4). The cell membrane is  flexible and somewhat elastic. The intricate features of a cell  membrane, with its many outpouchings and infoldings, greatly  increase the surface area of the cell. The cell membrane quickly  seals tiny breaks; but if it is extensively damaged, the cell dies.   In addition to maintaining the integrity of the cell, the cell  membrane controls the entrance and exit of substances, allowing  some in while excluding others. A membrane that functions in this  manner is selectively permeable (per’me-ah-bl). The cell membrane  is crucial because it is a conduit between the cell and the extracel-  lular fluids in the body’s internal environment. It allows the cell  to receive and respond to incoming messages, in a process called  signal transduction.    The cell membrane is mainly composed of roughly equal amounts  of lipids and proteins, with some carbohydrate. The lipid com-    The maximum effective magnification possible using a light micro-  scope is about 5,000x. A confocal microscope is a type of light  microscope that passes white or laser light through a pinhole and  lens to impinge on the object, which greatly enhances resolution  (ability to distinguish fine detail). A transmission electron microscope  (TEM) provides an effective magnification of nearly 1,000,000x,  whereas a scanning electron microscope (SEM) can provide about  50,000x. Photographs of microscopic objects (micrographs) pro-  duced using the light microscope and the transmission electron  microscope are typically two-dimensional, but those obtained with  the scanning electron microscope have a three-dimensional quality  (fig. 3.5). Scanning probe microscopes work differently from light  or electron microscopes. They move a sharp tipped probe over a  surface. Selective sensors detect up and down movements of the  probe, and translate the movements into an image. These micro-  scopes can image clusters of individual atoms and molecules.    ponent provides the physical properties, whereas the proteins  provide specific functions. The basic framework of the cell mem-  brane is a double layer, or bilayer, of phospholipid molecules (see  fig. 2.15) that self-assemble so that their water-soluble (hydro-  philic) “heads,” containing phosphate groups, form the intra-  cellular and extracellular surfaces of the membrane, and their  water-insoluble (hydrophobic) “tails,” consisting of fatty acid  chains, make up the interior (the middle) of the membrane (see  fig. 3.3 inset and fig. 3.6). The lipid molecules collectively form a  thin but stable fluid film.    The middle portion of the cell membrane consists largely of  the fatty acid portions of the phospholipid molecules, which make  it oily. Molecules soluble in lipids, such as oxygen, carbon dioxide,  and steroid hormones, can pass through the phospholipid bilayer  easily. However, the bilayer is impermeable to water-soluble mol-  ecules, such as amino acids, sugars, proteins, nucleic acids, and  various ions. Many cholesterol molecules embedded in the interior  of the membrane also help make it impermeable to water-soluble  substances. Additionally, the relatively rigid structure of the choles-  terol molecules helps stabilize the cell membrane. However, some  lipids and the proteins can move, so the cell membrane is described  as a “fluid mosaic,” to recognize its dynamic nature.    FIGURE 3.5 Human red blood cells as viewed using (a) a light  microscope (1,200x), (b) a transmission electron microscope (12,000x),  and (c) a scanning electron microscope (3,900x).    A cell membrane includes only a few types of lipid molecules but  many types of proteins (fig. 3.7), which provide specialized func-  tions. Membrane proteins are classified by shape, their positions  within the phospholipid bilayer, and function (table 3.1).   Proteins may be shaped like globs, rods, or fibers. Based on  position, a membrane protein may be integral or peripheral. An  integral protein extends into the lipid bilayer and may protrude  from one or both sides. If it extends through both sides, it is called    a transmembrane protein. In contrast, peripheral membrane pro-  teins associate with one side of the bilayer, from an outside attach-  ment rather than being embedded within it.    Many transmembrane proteins are tightly coiled rods that  function as receptors. They bind to specific incoming molecules,  such as hormones, triggering responses from within the cell.    Certain compact and globular integral proteins provide routes  for small molecules and ions to cross the otherwise impermeable  phospholipid bilayer. Some of these proteins form “pores” that  admit water. Other membrane proteins are highly selective and form  channels that admit only particular types of ions. In nerve cells,  for example, selective channels control the movements of sodium  and potassium ions across the cell membrane (see chapter 10,  pp. 375-376). Clinical Application 3.1 discusses how abnormal  ion channels cause disease.   Peripheral proteins have a variety of functions. Many act as  receptors responding to extracellular signals. Others are enzymes  (see chapter 4, pp. 123-124), and many of these are parts of sig-  nal transduction pathways. Other peripheral proteins enable cer-  tain cells to touch or bind. Peripheral proteins also indicate a  cell’s identity. Carbohydrate groups attached to some peripheral  proteins form glycoproteins that branch from a cell’s surface, pro-  viding distinctive features that enable cells to recognize and inter-  act with each other. These cell-cell interactions are important as  cells aggregate and attach to form tissues during development, and  throughout life.   Cell surface glycoproteins also mark the cells of an individual  as “self,’ and distinguish particular differentiated cell types. The  immune system can distinguish “self” cell surfaces from “nonself”  cell surfaces that may indicate a potential threat, such as infection.  Blood and tissue typing for transfusions or transplants consider  the patterns of proteins and glycoproteins on cell surfaces.   Often cells must interact dynamically and transiently, rather  than form permanent attachments. Proteins called cellular adhe-  sion molecules, or CAMs for short, guide cells on the move.  Consider a white blood cell moving in the bloodstream to the site  of an injury, where it is required to fight infection. Imagine that  such a cell must reach a woody splinter embedded in a person’s  palm (fig. 3.8). Once near the splinter, the white blood cell must  slow down in the turbulence of the bloodstream. A type of CAM    the cell membrane; transduce signals  Peripheral proteins  Receptor proteins Respond to extracellular signals    FIGURE 3.6 The cell membrane is a  phospholipid bilayer. (a) A transmission electron |,  micrograph of a cell membrane (600,000x);    a double layer of phospholipid molecules. In  actuality, many other molecules are embedded Cell membrane  in and extend from the phospholipid bilayer. (a)    FIGURE 3.7 (AP|R) The cell membrane is  composed primarily of phospholipids (and some  cholesterol), with proteins embedded throughout    the lipid bilayer. Parts of the membrane-  associated proteins that extend from the outer Cytoplasmic side  surface help to establish the identity of the cells of membrane    called a selectin does this by coating the white blood cell and  providing traction. The white blood cell slows to a roll and binds to  carbohydrates on the inner capillary surface. Clotting blood, bac-  teria, and decaying tissue at the injury site release biochemicals  (chemoattractants) that attract the white blood cell. Finally, a type    of CAM called an integrin contacts an adhesion receptor protein  protruding into the capillary space near the splinter. The integrin  then pushes up through the capillary cell membrane, grabbing  the passing slowed white blood cell and directing it between the  tilelike cells of the capillary wall. White blood cells collecting at    What do abnormal pain intensity, irregular heartbeats, and cystic  fibrosis have in common? All result from abnormal ion channels in  cell membranes.   lon channels are protein-lined tunnels in the phospholipid  bilayer of a biological membrane. These passageways permit elec-  trical signals to pass in and out of membranes as ions (charged  particles). Many ion channels open or close like a gate in response  to specific ions under specific conditions. These situations include  a change in electrical forces across the membrane, binding of a  molecule, or receiving biochemical messages from inside or out-  side the cell. In order for our cells to function normally, mem-  branes must allow certain types of ions in and out at specific rates.  lon channels control these movements. lon channels are specific  for calcium (Ca*?), sodium (Na*), potassium (K*), or chloride (CI).  A cell membrane may have a few thousand ion channels specific  for each of these ions. Ten million or more ions can pass through  an ion channel in one second! Drugs may act by affecting ion chan-  nels (table 3A), and abnormal ion channels cause certain disorders,  including the following:    Because ion channels are built of proteins, genetic mutations  (changes) can affect their functioning. At least ten genes encode  proteins that form sodium channels, and mutations in them  affect the sensation of pain. Mutations that hamper the function-  ing of the sodium channels cause inability to feel pain, whereas  mutations that enable channels to function too efficiently cause  extreme pain conditions.   A boy living in Pakistan was completely unable to feel pain.  He was a performer, stabbing knives through his arms and walking  on hot coals to entertain astonished crowds. Several of his rela-  tives had the condition, too. He died at age 13 from jumping off  a roof! In contrast, in erythermalgia, or “burning man syndrome,”  sodium channels become hypersensitive, causing extreme pain in  the hands and feet, so that just putting on socks becomes unbear-  able. In another condition, “paroxysmal extreme pain disorder,” the  sodium channels stay open too long, causing excruciating pain in  the rectum, jaw, and eyes. Researchers are using the information  from these genetic studies to develop new painkillers.    an injury site produce inflammation and, with the dying bacteria,  form pus. (The role of white blood cells in body defense is dis-  cussed further in chapter 14 on page 538.)   Cellular adhesion is critical to many functions. CAMs guide  cells surrounding an embryo to grow toward maternal cells  and form the placenta, the supportive organ linking a pregnant  woman to the fetus (see fig. 23.10 p. 878). Sequences of CAMs  help establish the connections between nerve cells that underlie  learning and memory.   Abnormal cellular adhesion affects health. Lack of cellular  adhesion, for example, eases the journey of cancer cells as they    Long-OQT Syndrome and Potassium Channels  Four children in a Norwegian family were born deaf, and three of  them died at ages four, five, and nine. All of the children had inher-  ited from unaffected carrier parents “long-OQT syndrome associ-  ated with deafness.” They had abnormal potassium channels in  the heart muscle and in the inner ear. In the heart, the malfunc-  tioning channels disrupted electrical activity, causing a fatal distur-  bance to the heart rhythm. In the inner ear, the abnormal channels  caused an increase in the extracellular concentration of potassium  ions, impairing hearing.    Cystic Fibrosis and Chloride Channels  A seventeenth-century English saying, “A child that is salty to taste  will die shortly after birth,” described the consequence of abnor-  mal chloride channels in cystic fibrosis (CF), inherited from carrier  parents. The major symptoms—difficulty breathing, frequent severe  respiratory infections, and a clogged pancreas that disrupts diges-  tion—result from buildup of extremely thick mucous secretions.  Abnormal chloride channels in cells lining the lung passageways  and ducts of the pancreas cause the symptoms of CF. The primary  defect in the chloride channels also causes sodium channels to mal-  function. The result: very salty sweat and abnormally thick mucus.  Experimental gene therapy supplies the cells lining a patient's  lungs with instructions to produce normal chloride channels.    spread from one part of the body to another. Arthritis may occur  when white blood cells are captured by the wrong adhesion mol-  ecules and inflame a joint where there isn’t an injury.    What is a selectively permeable membrane?  Describe the chemical structure of a cell membrane.    FIGURE 3.8 Cellular adhesion molecules (CAMs) direct white blood  cells to injury sites, such as this splinter. (1) CAMs called selectins coat the  white blood cell, slowing it. (2) CAMs called adhesion receptor proteins  on the inside face of the blood vessel lining cell bind CAMs called  integrins on the white blood cell, directing it between cells of the wall (3).   Cytoplasm usually appears clear with scattered specks when viewed  through a light microscope. The higher magnification of a transmis-  sion electron microscope (see fig. 3.4) reveals vast and complex  networks of membranes and organelles suspended in the cytosol. In  addition to organelles, cytoplasm contains chemicals called inclu-  sions. These usually are in a cell temporarily. Inclusions include  stored nutrients, such as glycogen and lipids, and pigments, such  as melanin in the skin. Cytoplasm also contains abundant protein  rods and tubules that form a supportive framework called the cyto-  skeleton (si’to-skel-é-ton).   The activities of a cell occur largely in its cytoplasm, where nutrient  molecules are received, processed, and used in metabolic reactions.  The following are cytoplasmic organelles and their specific functions:    1. Ribosomes (ri’bo-s6mz) are tiny, spherical structures com-  posed of protein and RNA. They provide a structural support  and enzymatic activity to link amino acids to synthesize  proteins (see chapter 4, p. 140). Unlike many of the other  organelles, ribosomes are not composed of or contained in    membranes. They are scattered in the cytoplasm and also  bound to the endoplasmic reticulum, another organelle.    (ER) is a complex organelle composed of membranous flat-  tened sacs, cylinders, and fluid-filled bubblelike sacs called  vesicles (fig. 3.9). These parts are interconnected, and they  interact with the cell membrane, the nuclear envelope, and  certain other organelles. ER is widespread in the cytoplasm,  providing a tubular transport system for molecules through-  out the cell. It winds from the nucleus out toward the cell  membrane, like a rail system leading from a large city out to  the suburbs. The ER participates in the synthesis of protein  and lipid molecules. These molecules may leave the cell as  secretions or be used in the cell for such functions as produc-  ing new ER or cell membrane as the cell grows.   The outer surface of some ER is studded with many  ribosomes that give the ER a textured appearance when  viewed with an electron microscope. Such endoplasmic  reticulum is termed rough ER. Proteins synthesized on  ribosomes associated with rough ER then move through the  tubules of the endoplasmic reticulum, where they fold into  their characteristic three-dimensional shapes, and then go to  another organelle, the Golgi apparatus, for further processing.   It appears more cylindrical than the rough ER (fig. 3.9).  Along the smooth ER are enzymes that are important in  synthesizing lipids, absorbing fats from the digestive tract,  and breaking down drugs. Lipids are synthesized in the  smooth ER and are added to proteins arriving from the rough  ER. Smooth ER is especially abundant in liver cells that  break down alcohol and drugs.    port substances within a cell. They vary in size and contents.  Larger vesicles that contain mostly water form when part of the  cell membrane folds inward and pinches off, bringing mate-  rial from outside the cell into the cytoplasm. Smaller vesicles  shuttle material from the rough ER to the Golgi apparatus as  part of secretion. Overall, the transport of substances into and  out of cells by fleets of vesicles is called vesicle trafficking.    to eight flattened, membranous sacs called cisternae that  resemble a stack of pancakes. This organelle refines, pack-  ages, and delivers proteins synthesized on the rough ER  (fig. 3.10). A cell may have several Golgi apparatuses.   Proteins arrive at a Golgi apparatus enclosed in vesicles  composed of membrane from the ER. These sacs fuse to  the membrane at the innermost end of the Golgi apparatus,  which is an area specialized to receive proteins. Previously,  in the ER, sugar molecules were attached to these protein  molecules, forming glycoproteins.   As the glycoproteins pass from layer to layer through  the Golgi stacks, they are modified chemically. For example,  sugar molecules may be added or removed, or proteins  shortened. When the altered glycoproteins reach the  outermost layer, they are packaged in bits of Golgi apparatus  membrane that bud off and form transport vesicles. Such  a vesicle may then move to the cell membrane, where it    FIGURE 3.9 (AP|R) The endoplasmic  reticulum is the site of protein and lipid synthesis,  and serves as a transport system. (a) A transmission  electron micrograph of rough endoplasmic  reticulum (ER) (28,500x). (b) Rough ER is dotted  with ribosomes, whereas (c) smooth ER does not  have ribosomes. The membranes of the ER consist  of phospholipid bilayers.    and produce vesicles that enclose  = - secretions. The membrane of a Golgi  (b) Cell membrane apparatus is a phospholipid bilayer.    fuses and releases its contents to the outside of the cell as a  secretion. This is an example of a process called exocytosis,  discussed in section 3.3. Other vesicles may transport  glycoproteins to organelles in the cell, as figure 3.11 shows  for the process of milk secretion. A Golgi apparatus tags and  sorts the molecules that travel through it so that they can be  delivered to the appropriate places within the cell or marked  for export, like activities in a warehouse.   Some cells, including certain liver cells and white  blood cells (lymphocytes), secrete glycoprotein molecules  as rapidly as they are synthesized. However, certain other  cells, such as those that manufacture protein hormones,  release vesicles containing newly synthesized molecules only  when the cells are stimulated. Otherwise, the loaded vesicles  remain in the cytoplasm.   Secretory vesicles that originate in the ER not only  release substances outside the cell, but also provide new cell  membrane. This is especially important during cell growth.   proteins that mitochondria use are encoded in the DNA of the  nucleus. These proteins are synthesized elsewhere in the cell   A mitochondrion (mi”to-kon’dre-on) has two layers—  an outer membrane and an inner membrane. The inner  membrane folds extensively inward, forming shelflike  partitions called cristae that dramatically increase the surface  area on which chemical reactions can occur (fig. 3.12).   From the cristae arise small stalked particles that contain  enzymes. These enzymes and others dissolved in the fluid   and other nutrients in a process called cellular respiration.  The mitochondrion captures and transfers this newly  released energy into special chemical bonds of the molecule  adenosine triphosphate (ATP), that cells can readily use  (chapter 4, p. 126). ATP is used to power many cellular  activities and can therefore be thought of as “cellular energy,    @® Most proteins are synthesized  on ribosomes associated with  membranes of the rough ER,  using amino acids in the cytosol.    ©) Sugars are synthesized  in the smooth ER and  Golgi apparatus and may  be attached to proteins  or secreted in vesicles.    @ Proteins are secreted from  vesicles that bud off of the    © Fat droplets pick up a  layer of the cell membrane  as they exit the cell.    FIGURE 3.11 Milk secretion illustrates how  organelles interact to synthesize, transport, store,  and export biochemicals (1-5). When the baby  suckles, he or she receives a chemically complex  secretion—milk.    (a) (b)  FIGURE 3.12 fAP|R) A mitochondrion is a major site of energy    reactions. (a) A transmission electron micrograph of a mitochondrion  (28,000x). (b) Cristae partition this saclike organelle. The mitochondrial  membranes consist of phospholipid bilayers.   A typical cell has about 1,700 mitochondria, but cells  with very high energy requirements, such as skeletal muscle  cells, have many thousands of mitochondria. This abundance  is why common symptoms of illnesses affecting mitochondria  are exercise intolerance and weak, flaccid muscles. Some  cells, such as red blood cells, lack mitochondria.    9 Distinguish between organelles and inclusions.  10 What are the functions of the endoplasmic reticulum?  11. Describe how the Golgi apparatus functions.   Lysosomes can be difficult to identify because  their shapes vary, but many are small, membranous  sacs (fig. 3.13). Lysosomes bud off of sections of Golgi  membrane. They contain powerful enzymes that break down  proteins, carbohydrates, and nucleic acids, including those  of foreign particles that the cell has taken in. For example,  lysosomes digest bacteria that certain white blood cells  engulf. In liver cells, lysosomes break down cholesterol,  toxins, and drugs.    Lysosomes destroy worn cellular parts. In certain  scavenger cells they may engulf and digest entire smaller  body cells that have been damaged. How the lysosomal  membrane is able to withstand being digested is not well  understood, but this organelle sequesters enzymes that can  function only under very acidic conditions, preventing them  from destroying the cellular contents around them. Human  lysosomes contain 43 types of enzymes. An abnormality  in just one type of lysosomal enzyme can be devastating to  health (see Clinical Application 3.2).    resemble lysosomes in size and shape. They are in all  human cells but are most abundant in cells of the liver and  kidneys. Peroxisomes contain enzymes, called peroxidases,  that catalyze metabolic reactions that release hydrogen  peroxide (H,O,), which is toxic to cells. Peroxisomes also  contain an enzyme called catalase, which decomposes  hydrogen peroxide.   The outer surface of a peroxisome membrane contains  some forty types of enzymes, which catalyze a variety of  biochemical reactions, including:   ¢ breakdown of lipids called very-long-chain fatty acids  ¢ degradation of rare biochemicals    FIGURE 3.13 (AP|R) Falsely colored transmission electron  micrograph of lysosomes (27,000x). Lysosomes are membranous sacs that  contain enzymes that dismantle debris in a process called autophagy.    German physiologist Rudolph Virchow envisioned disease at the  cellular level in the 1850s. Today, treatments for many disorders  are a direct result of understanding a disease process at the cel-  lular level. Following are three examples of how abnormalities in  organelles cause whole-body symptoms.    Sharon was small, easily fatigued, slightly developmentally  delayed, and had difficulty with schoolwork. She also had seizures,  and at age eleven she suffered a stroke. An astute physician who  observed Sharon’s mother, Lillian, suspected that the girl's symp-  toms were related and resulted from abnormal mitochondria, the  organelles that house the biochemical reactions that extract energy  from nutrients.   The doctor noticed that Lillian was uncoordinated and had  numb hands. Another clue was that Lillian had frequent migraine  headaches, as did her two sisters and one brother. All four sib-  lings also had diabetes mellitus and muscle weakness. Blood tests  revealed that mother and daughter had elevated levels of bio-  chemicals (pyruvic acid and lactic acid) that indicated they were  unable to extract maximal energy from nutrients. Their muscle  cells had abnormal mitochondria. Accumulation of these mito-  chondria in smooth muscle cells in blood vessel walls in the brain  caused Sharon's stroke, migraines, and seizures.   The affected family members had MELAS, which stands for the  major symptoms—mitochondrial encephalomyopathy, lactic acido-  sis, and strokelike episodes. Their mitochondria cannot synthesize  some of the proteins required to carry out the energy reactions.  The mutant gene is part of the DNA in mitochondria, and Lillian’s  mother transmitted it to all of her children. Mitochondria are inher-  ited only from the mother because the mitochondria are excluded  from the part of a sperm that enters an egg cell. For this reason,  Lillian’s brother will not pass MELAS to his children.    Hunter was born in 1997. At first he cried frequently and had dif-  ficulty feeding, and his limbs were stiff. He became less alert, and  his motor skills stopped progressing. When he was nine months  old, Hunter was diagnosed with Krabbe disease, which he had  inherited from his parents, who are carriers. Hunter’s body could  not make a lysosomal enzyme that is necessary to break down  galactolipids into chemicals nerve cells use to produce myelin, a  mixture of fatty molecules and proteins that electrically insulates    the nerve cells. Without the enzyme certain galactolipids cannot be  broken down, and they accumulate in the cells that make myelin.  Accumulation of the toxic biochemicals damaged Hunter's ner-  vous system. He ceased moving and responding, lost hearing and  vision, and was tube fed.   Hunter lived for eight years. Had he been born today, he  would have been tested for Krabbe disease, along with dozens of  other “inborn errors of metabolism,” with a few drops of blood  from his heel taken shortly after birth. A cord blood stem cell  transplant from a donor could have prevented his symptoms.   Lysosomal storage diseases, like Krabbe, result from a defi-  ciency of one of the organelle’s enzymes. There are several types  of these rare conditions that affect about 10,000 people world-  wide. Treatments use several strategies: replacing the enzyme or  gene, using a drug to reduce the biochemical buildup, or using  a drug that can unfold and correctly refold a misfolded enzyme.    Adrenoleukodystrophy (ALD) and Peroxisomes  For young Lorenzo, the first sign of adrenoleukodystrophy was dis-  ruptive behavior in school. When he became lethargic, weak, and  dizzy, his teachers and parents realized that his problem was not  just temper tantrums. His skin darkened, blood sugar levels plum-  meted, heart rhythm altered, and the levels of electrolytes in his  body fluids changed. He lost control over his limbs as his nervous  system continued to deteriorate. Lorenzo's parents took him to  many doctors. Finally, one of them tested the child’s blood for an  enzyme normally manufactured in peroxisomes.   Lorenzo's peroxisomes lacked the second most abundant  protein in the outer membrane, which normally transports an  enzyme into the organelle. The enzyme controls breakdown of a  type of very-long-chain fatty acid. Without the enzyme, the fatty  acid builds up in cells in the brain and spinal cord, stripping these  cells of their myelin. Without the myelin sheaths, the nerve cells  cannot transmit messages fast enough. Death comes in a few  years. Boys inherit ALD from carrier mothers.   A 1992 film, Lorenzo’s Oil, told the story of Lorenzo’s parents’  efforts to develop a mixture of oils to slow the buildup of the very-  long-chain fatty acids. Lorenzo lived much longer than his doctors  expected, to age thirty, either due to the oil or the excellent sup-  portive care. At the time of Lorenzo’s death, he could not talk or  see and communicated with finger movements and eye blinks.  Today, ALD is treated with stem cell transplants or experimental  gene therapy that delivers a functional version of the mutant gene.   Several other cellular structures are not organelles, but are parts of  the cytoskeleton. They are vitally important for the ability of cells  to divide and to move.    of three. The centrioles usually lie at right angles to each  other. During cell division, the centrioles migrate to either  side of the nucleus, where they produce spindle fibers that  pull on and distribute chromosomes (kro’mo-sémz), which  carry DNA information to the newly forming cells (fig. 3.14).  Centrioles also produce the internal parts of cell membrane  projections called cilia and flagella.    1. A centrosome (sen’tro-s6m) (central body) is a structure  located in the cytoplasm near the nucleus. It is nonmembranous  and consists of two cylinders, called centrioles, built of tube-    extensions of the cell membranes of certain cell types. They surfaces of some epithelial cells. Each cilium is a hairlike  are structurally similar and differ mainly in their length and structure about 10 um long, which attaches just beneath the  abundance. Internally, both cilia and flagella consist of nine cell membrane to a modified centriole called a basal body.  groups of three microtubules with two additional microtu- Cilia extend from cells in distinct patterns. They move in a  bules in the center, forming a distinct cylindrical pattern. coordinated “‘to-and-fro”manner so that rows of cilia beat    one after the other, generating a wave that sweeps across the  surface. Ciliary action moves an egg toward the uterus, and  early in development controls movement of cells as they  form organs. Waving cilia propel mucus over the lining of  the respiratory tract (fig. 3.15). Chemicals in cigarette smoke  destroy cilia, which impairs the respiratory tract’s ability to  expel bacteria. Infection may result.   pull apart chromosome  sets as cells divide. (a) A  transmission electron  micrograph of the two  centrioles in a centrosome  (120,000x). (b) The  centrioles lie at right angles  (a) (b) to one another.    FIGURE 3.15 fAP|R) Cilia are sweeping hairlike extensions. (a) They fringe certain cells, such as those forming the inner lining of the respiratory tubes  (5,400x). (b) Cilia that can move have a power stroke and a recovery stroke that create a “to-and-fro” movement that sweeps fluids across the tissue surface.    The cilia that wave secretions out of the respiratory  system or move an egg toward the uterus are called motile  cilia. Another type of this organelle, called a primary or  nonmotile cilium, functions as a “cellular antenna,” sensing  signals and sending them into cells to control growth and  maintain tissues. Compared to the many motile cilia that  fringe cells, primary cilia are shorter and may be one per cell.  Nearly all human cell types have them and diseases in which  they are abnormal typically affect several organ systems.  Such conditions are called “ciliopathies”—sick cilia.   A flagellum is much longer than a cilium. Cilia and  flagella work in the same way, but in contrast to the sweeping  movements caused by cilia, where the cells are fixed in  position, the flagellum instead causes the cell to move. The  tail of a sperm cell is a flagellum that generates swimming  movements (fig. 3.16 and chapter 22, p. 829). It is the only  known flagellum in humans.   3. Microfilaments and microtubules are two types of threadlike  structures in the cytoplasm. They are distinguished by protein  type, diameter, and how they assemble. Other proteins connect  microtubules and microfilaments, creating the cytoskeleton  that provides strength and the cell’s ability to resist force and  maintain shape.   Microfilaments are tiny rods of the protein actin that  form meshworks or bundles and provide certain cellular  movements (fig. 3.17). For example, microfilaments  constitute myofibrils, which shorten or contract muscle cells.  In other cell types, microfilaments associated with the inner  surface of the cell membrane aid cell motility.   Microtubules are long, slender tubes with diameters two  or three times greater than those of microfilaments. They  are composed of the globular protein tubulin. Microtubules  are usually rigid, which helps maintain the shape of the cell  (fig. 3.18). In cilia and flagella, microtubule interactions  provide movement (see figs. 3.15 and 3.16). Microtubules  also move organelles and other cellular structures. They form  centrioles and provide conduits for organelles, like the tracks  of a roller coaster.   4. Intermediate filaments are a third class of cytoskeletal  component. Unlike the microtubules that are all tubulin  protein and the microfilaments that are all actin protein,  intermediate filaments are composed of any of several  types of proteins and take the general form of dimers (pro-  tein pairs) entwined into nested, coiled rods. Intermediate   micrograph of microfilaments (red) and microtubules (green) in the  Diseases result from abnormal intermediate filaments. In dys- cytoplasm (500x).  trophic epidermolysis bullosa, skin layers separate due to    axonal neuropathy, intermediate filaments normally built of a  protein called gigaxonin overfill motor neurons, robbing chil-  dren of mobility. Most striking is progeria, in which abnormal  lamin intermediate filaments cause extremely rapid aging.  An affected child resembles a very elderly person by adoles-  cence, and typically dies soon after from diseases that usually  strike the very aged.    filaments made of proteins called keratins are abundant in  the actively dividing cells in the deepest part of the outer skin  layer, the epidermis. Here they form a strong inner scaffolding  that helps the cells attach to form a barrier.   In all cells, intermediate filaments composed of proteins  called /amins support the inner surface of the membranous  envelope that defines the nucleus. Lamins interact with DNA,  influencing which genes a cell uses to manufacture proteins.    FIGURE 3.18 (AP|R) The cytoskeleton provides an inner scaffolding for a cell. (a) Microfilaments built of actin and microtubules built of  tubulin help maintain the shape of a cell by forming an internal framework beneath the cell membrane and in the cytoplasm. (b) In this falsely    A nucleus is a relatively large, usually spherical, structure that  contains the genetic material (DNA) that directs the activities of  the cell. The extremely long molecules of DNA are complexed  with proteins to form fibers called chromatin.   The nucleus is enclosed in a double-layered nuclear envelope,  which consists of an inner and an outer lipid bilayer membrane.  These two membranes have a narrow space between them, but are  joined at places that surround openings called nuclear pores. These  pores are not bare holes, but channels whose walls consist of mul-  tiple copies of thirty types of proteins. Nuclear pores allow certain  dissolved substances to move between the nucleus and the cyto-  plasm (fig. 3.19). A nuclear pore lets out molecules of messenger  RNA that carry genetic information, but does not let out the DNA,  which must stay in the nucleus to maintain the genetic information.   The nucleus contains a fluid (nucleoplasm) in which other  structures are suspended. These structures include the following:    1. Chromatin consists of the cell’s 46 chromosomes, each of  which contains DNA wound around many proteins, like a  very long thread wound around multiple spools (see fig. 4.20,    p. 135). When cell division begins, chromatin fibers coil so  tightly that the individual chromatin fibers become visible,  when stained properly, under the light microscope.   The DNA molecules include genes, the information for  synthesis of proteins. The tightness with which chromatin  locally folds varies along the chromosomes, depending upon  which genes are being accessed for their information at a  particular time. The position of chromatin in the nucleus is  not random, but reflects which genes are active.   2. A nucleolus (nu-kle’o-lus) (“little nucleus’) is a small,  dense body largely composed of RNA and protein. It has  no surrounding membrane and is formed in specialized  regions of certain chromosomes. The nucleolus is the site of  ribosome production. Once ribosomes form, they migrate  through the nuclear pores to the cytoplasm. A cell may have  more than one nucleolus. The nuclei of cells that synthesize  abundant protein, such as those of glands, may have  especially large nucleoli.    15 How are the nuclear contents separated from the cytoplasm?  16 What is the function of the nucleolus?    FIGURE 3.19 fAP|R) The nucleus is the genetic  headquarters of the cell. (a) The nuclear envelope is  selectively permeable and allows certain substances to pass  between the nucleus and the cytoplasm. Nuclear pores are  more complex than depicted here. The nuclear envelope  consists of two phospholipid bilayers. (b) Transmission  electron micrograph of a cell nucleus (11,250x). The nucleus  contains a nucleolus and masses of chromatin.   Nonmembranous structure composed of two rodlike centrioles  Motile projections attached to basal bodies beneath the    Selectively permeable double membrane that separates  the nuclear contents from the cytoplasm    Maintains integrity of the cell, controls the passage of materials  into and out of the cell, and provides for signal transduction    Transports materials within the cell, provides attachment for  ribosomes, and synthesizes lipids    Contain substances that recently entered the cell, store and  transport newly synthesized molecules    Release energy from food molecules and convert the energy  into a usable form (ATP)    Contain enzymes capable of digesting worn cellular parts or  substances that enter cells    Contain enzymes called peroxidases, important in the  breakdown of many organic molecules    Helps distribute chromosomes to new cells during cell  division, initiates formation of cilia    Maintains the integrity of the nucleus, controls the passage of  materials between the nucleus and cytoplasm    The cell membrane is a selective barrier that controls which sub-  stances enter and leave the cell. Oxygen and nutrient molecules  enter through this membrane, whereas carbon dioxide and other  wastes leave through it. Movements of substances into and out  of cells use physical (or passive) processes, such as diffusion,  osmosis, facilitated diffusion, and filtration, and physiological  (or active) processes, such as active transport, endocytosis, and  exocytosis, which require energy from ATP. Understanding the  mechanisms that transport substances across the cell membrane is  important for understanding many aspects of physiology.    The details of membrane transport are important beyond  the cellular level. The functional units of the kidneys—the  nephrons—use filtration, diffusion, facilitated diffusion, osmosis,  and active transport in forming urine. Activities across nephron  cell membranes are important because substances that do not exit  in the urine contribute to the extracellular fluid. In this way, the  kidneys play a major role in maintaining the internal environment.    Diffusion (di-fu’zhun) (also called simple diffusion) is the ten-  dency of atoms, molecules, and ions in a liquid or air solution to  move from areas of higher concentration to areas of lower con-  centration, thus becoming more evenly distributed, or more dif-  fuse. Diffusion occurs because atoms, molecules, and ions are in  constant motion. Each particle travels in a separate path along a  straight line until it collides with another particle and bounces off  in anew direction until it collides again and changes direction once  more. As a result, there is a net movement of particles from an area  of higher concentration to an area of lower concentration. This dif-  ference in concentrations is called a concentration gradient, and  atoms, molecules, and ions are said to diffuse down a concentra-    tion gradient. With time, the concentration of a given substance  becomes uniform throughout a solution. In this situation, called  diffusional equilibrium (di-fu’zhun-ul e”’kwi-lib’re-um), random  movements continue but there is no further net movement, and the  concentration of a substance remains uniform throughout the solu-  tion. Diffusional equilibrium is a little like people at a party mov-  ing back and forth between two rooms, and the number of people  in each room remaining constant, even though they may be differ-  ent individuals in each room at different times.    Random motion mixes molecules. At body temperature, small  molecules such as water move at more than a thousand miles per  hour. However, the internal environment is crowded from a mol-    ecule’s point of view. A single molecule may collide with other  molecules a million times each second.    Sugar (a solute) put into a glass of water (a solvent) illustrates  diffusion (fig. 3.20). The sugar at first remains in high concen-  tration at the bottom of the glass. As the sugar molecules move,  they may collide or miss each other. They are less likely to col-  lide where there are fewer of them, so sugar molecules gradually  diffuse from areas of higher concentration and eventually become  uniformly distributed in the water.   Diffusion of a substance across a cell membrane can occur only  if (1) the cell membrane is permeable to that substance and (2) a  concentration gradient exists such that the substance is at a higher  concentration on one side of the membrane or the other (fig. 3.21).  Consider oxygen and carbon dioxide. Cell membranes are permeable  to both. In the body, oxygen diffuses into cells and carbon dioxide  diffuses out of cells, but equilibrium is never reached. Intracellular  oxygen is always low because oxygen is constantly used up in meta-  bolic reactions. Extracellular oxygen is maintained at a high level by  homeostatic mechanisms in the respiratory and cardiovascular sys-  tems. In this way, a concentration gradient always allows oxygen to  diffuse into cells (fig. 3.22).    FIGURE 3.20 A dissolving sugar cube illustrates diffusion. (1-3) A sugar cube placed in water slowly disappears as the sugar molecules dissolve and  then diffuse from regions where they are more concentrated toward regions where they are less concentrated. (4) Eventually, the sugar molecules are    The level of carbon dioxide, produced as a waste product of  metabolism, is always higher inside cells. Homeostasis maintains a  lower extracellular carbon dioxide level, so a concentration gradient  always favors carbon dioxide diffusing out of cells (fig. 3.22).   Diffusional equilibrium does not normally occur in organisms.  Instead, organisms tend to reach a physiological steady state, where  concentrations of diffusing substances are unequal but stable.   A number of factors influence the diffusion rate, but those  most important in the body are distance, the concentration gradi-  ent, and temperature. In general, diffusion is more rapid over shorter  distances, larger concentration gradients, and at higher temperatures.  Homeostasis maintains all three of these factors at optimum levels.    Some of the previous examples considered hypothetical membranes  with specific permeabilities. For the cell membrane, permeability is  more complex because of its selective nature. Lipid-soluble sub-  stances, such as oxygen, carbon dioxide, steroids, urea, ethanol, and  general anesthetics, freely cross the cell membrane by simple diffu-  sion. Small solutes that are not lipid-soluble, such as ions of sodium,  potassium, and chloride, may diffuse through specific protein chan-  nels in the membrane, described in Clinical Application 3.1. (Water  molecules diffuse through similar channels, called aquaporins.) This  type of movement follows the concentration gradient, and because    FIGURE 3.22 Diffusion  enables oxygen to enter  cells and carbon dioxide  to leave.   a passive movement of molecules. (1) A  membrane permeable to water and solute  molecules separates a container into two  compartments. Compartment A contains both  types of molecules, while compartment B  contains only water molecules. (2) As a result  of molecular motions, solute molecules diffuse  from compartment A into compartment B;  water molecules diffuse from compartment    it requires membrane proteins it is considered a form of facilitated  diffusion (fah-sil”i-tat’ed di-fu’zhun) meaning that it is “helped”  (fig. 3.23). (Facilitated diffusion is also called facilitated transport.)  Facilitated diffusion includes not only ion and water channels,  but also proteins that function as carriers (also known as transport-  ers) to bring larger water-soluble molecules, such as glucose and  amino acids, across the cell membrane down a concentration gra-  dient. (Most sugars and amino acids are insoluble in lipids, and    FIGURE 3.23 (AP|R) Facilitated diffusion includes carrier molecules  and channels that transport some substances into or out of cells, from   a region of higher concentration to one of lower concentration. The  larger spheres depict transported substances that cross through protein  carrier molecules, and the small spheres represent ions, which cross the  membrane through ion channels.    they are too large to pass through cell membrane channels.) In  the facilitated diffusion of glucose, for example, a glucose mol-  ecule combines with a specific carrier molecule at the surface of  the cell membrane. This union of glucose and its carrier molecule  changes the shape of the carrier in a way that moves glucose to  the inner surface of the membrane. Here, the glucose is released,  and the carrier molecule returns to its original shape and may pick  up another glucose molecule. The hormone insulin, discussed in  chapter 13 (pp. 514-515), promotes facilitated diffusion of glucose  through the membranes of certain cells.   Facilitated diffusion can move molecules only down a con-  centration gradient and is specific for a particular solute (a glu-  cose carrier can only carry glucose, for example). The number of  carrier molecules or channels limits the rate at which solutes can  cross the membrane.    Osmosis (0z-mo’sis) is the movement of water across a selectively  permeable membrane into a compartment containing solute that  cannot cross that membrane (impermeant solute). One can think  of impermeant solute as solute that is “trapped” on one side of the  membrane. If impermeant solute is present on both sides of the  membrane, water will move by osmosis to the side with the greater  impermeant solute concentration. Osmosis is sometimes sum-  marized as “water follows salt,” but water will move by osmosis  toward any impermeant solute.   A number of mechanisms explaining osmosis have been pro-  posed, but they are beyond the scope of this discussion. Just remem-  ber that if there is a difference in solute concentration across a cell  membrane or a even a layer of cells, water will flow by osmosis  into the compartment with the higher concentration of impermeant  (trapped) solute.   In figure 3.24, the selectively permeable membrane is perme-  able to water (the solvent) and impermeable to protein (the solute  in this example). The protein concentration is greater in compart-  ment A. Therefore, water moves from compartment B across the  selectively permeable membrane and into compartment A by osmo-  sis. Protein, on the other hand, cannot move out of compartment A  because the selectively permeable membrane is impermeable to it.   Note in figure 3.24 that as osmosis occurs, the level of water  on side A rises. This ability of osmosis to generate enough pres-  sure to lift a volume of water is called osmotic pressure. When  the height of the column of water in A reaches a certain point, the  downward force (hydrostatic pressure) will prevent any further net  osmotic movement of water. This is a condition known as osmotic  equilibrium. Because the solute cannot cross the membrane,  osmotic equilibrium must be achieved by the osmotic movement  of water alone.   The greater the concentration of impermeant solute particles  (protein in this example) in a solution, the greater the osmotic pres-  sure of that solution. Water always tends to move by osmosis toward  solutions of greater osmotic pressure. That is, water moves toward  regions of trapped solute—whether in a lab exercise or in the body.   Cell membranes are generally permeable to water, so water  equilibrates by osmosis throughout the body, and the concen-  tration of water and solutes everywhere in the intracellular and  extracellular fluids is essentially the same. Therefore, the osmotic    separates the container into two compartments. At first, compartment A  contains a higher concentration of protein than compartment B. Water  moves by osmosis from compartment B into compartment A. (2) The  membrane is impermeable to proteins, so equilibrium can only be reached  by movement of water. As water accumulates in compartment A, the water  level on that side of the membrane rises.    pressure of the intracellular and extracellular fluids is the same.  Any solution, such as a 0.9% NaCl solution (normal saline), that  has the same osmotic pressure as body fluids is called isotonic.  Cells will not change size in this solution.   Solutions that have a higher osmotic pressure than body fluids  are called hypertonic. If cells are put into a hypertonic solution,  there will be a net movement of water by osmosis out of the cells  into the surrounding solution, and the cells shrink. Conversely, cells  put into a hypotonic solution, which has a lower osmotic pressure  than body fluids, gain water by osmosis and swell. Although cell  membranes are somewhat elastic, the cells may swell so much that  they burst. In the case of red blood cells, this is called hemolysis.  Figure 3.25 illustrates the effects of the three types of solutions on  red blood cells.    Filtration (fil-tra’shun) is another process that forces molecules  through membranes by exerting pressure. Filtration is commonly  used to separate solids from water. One method is to pour a mix-  ture of solids and water onto filter paper in a funnel (fig. 3.26). The  paper is a porous membrane through which the small water mol-  ecules pass, leaving the larger solid particles behind. Hydrostatic  pressure forces the water molecules through to the other side. An  example of filtration is making coffee by the drip method, using a  filter paper cone or basket.   In the body, tissue fluid forms by filtration when water and  dissolved substances are forced out through the thin, porous walls  of blood capillaries, but larger particles such as plasma protein  molecules remain inside (fig. 3.27). The force for this movement  that forms tissue fluid comes from blood pressure, generated largely    (c)  FIGURE 3.25 fAP|R) (a) In an isotonic solution, equal volumes    of water enter and leave the red blood cells, so they maintain their  characteristic sizes and shapes. (b) In a hypertonic solution, more water  leaves than enters, so cells shrink. (c) In a hypotonic solution, more water  enters than leaves, so cells swell and may burst (15,000x).    by heart action, which is greater inside the vessel than outside it.  However, the large proteins left inside capillaries oppose filtration  by drawing water into blood vessels by osmosis, preventing the  formation of excess tissue fluid, which causes a condition called  edema. Although a heart beating is an active body process, filtra-  tion is considered passive because it can occur from the pressure  of gravity alone. It is a little like the difference between preparing  coffee by forcing water through coffee grounds using a French press  (active) or by the drip method (passive). Filtration is discussed fur-  ther in chapters 15 (p. 581) and 20 (p. 779).    FIGURE 3.26 In filtration of water and solids, gravity forces water  through filter paper, while tiny openings in the paper do not allow the  solids to pass through. This process is similar to the drip method of  preparing coffee.    smaller molecules through tiny openings in the capillary wall. The larger  molecules remain inside.    When molecules or ions pass through cell membranes by diffu-  sion or facilitated diffusion, their net movement is from regions  of higher concentration to regions of lower concentration. In  some situations, however, the net movement of particles passing  through membranes is in the opposite direction, from a region of  lower concentration to one of higher concentration. Sodium ions,  for example, can diffuse slowly through cell membranes. Yet the  concentration of these ions is many times greater outside cells (in  the extracellular fluid) than inside cells (in the intracellular fluid).  This is because sodium ions are continually moved through the cell  membrane from regions of lower concentration (inside) to regions of    higher concentration (outside). Movement against a concentration  gradient is called active transport (ak’tiv trans’port). It requires  energy, which comes from cellular metabolism, that is released as  ATP molecules split.   Active transport is similar to facilitated diffusion in that it  uses carrier molecules within cell membranes. As figure 3.28  shows, these carrier molecules are proteins that have binding sites  that combine with the specific particles being transported. Their  union triggers release of energy from ATP, which alters the shape  of the carrier protein, driving the “passenger” molecules through  the membrane. Once on the other side, the transported particles  are released, and the carrier molecules can return to their original  shapes and accept new passenger molecules at their binding sites.  Because these carrier proteins transport substances from regions  of lower concentration to regions of higher concentration, they are  called “pumps.” Many pumps can transport more than one type of  ion. A sodium/potassium pump, for example, transports sodium  ions out of cells and potassium ions into cells.    concentration gradient. (a) During active transport, a molecule or an ion  combines with a carrier protein, whose shape changes as a result. (b) This  process, which requires cellular energy, transports the particle across the  cell membrane.    Particles moved across cell membranes by active transport  include sugars, amino acids, and ions of sodium, potassium, cal-  cium, and hydrogen. Some of these substances are actively trans-  ported into cells, and others are actively transported out. Movements  of this type are important to cell survival, particularly maintenance  of homeostasis. Subsequent chapters describe some of these move-  ments as they apply to specific organ systems.    The energy we must expend just to stay alive is called the  basal metabolic energy. The body uses close to 40% of the basal  metabolic energy to actively transport sodium and potassium ions  across cell membranes. Imagine learning that 40% of your household  budget went for one item—it had better be important! In this case it  is. The concentration gradients for sodium and potassium ions that  the sodium/potassium pumps establish throughout the body are  essential for muscle and nerve cells to function. Chapters 9 and 10  further discuss the functioning of these important cell types.    Energy from ATP may be used to move substances into or out of  a cell without actually crossing the cell membrane. Different pro-  cesses transport substances in each direction across the cell mem-  brane. Endocytosis (en”do-si-to’sis) conveys molecules or other  particles, that are too large to enter a cell by other means, to the  inside of the cell in a vesicle that forms from a section of the cell  membrane budding inward.   The three forms of endocytosis are pinocytosis, phagocytosis,  and receptor-mediated endocytosis. In pinocytosis (pi’-no-si-to’sis),  cells take in tiny droplets of liquid from their surroundings, as a small  portion of cell membrane indents (invaginates) (fig. 3.29). The open  end of the tubelike part that forms then seals off and detaches from  the cell membrane, producing a small vesicle about 0.1 um in diam-  eter in the cytoplasm. For a time, the vesicular membrane separates  its contents from the rest of the cell. Eventually, the vesicular mem-  brane breaks down, releasing the liquid inside into the cytoplasm. In  this way, a cell can take in water and the molecules dissolved in it,  such as proteins, that otherwise might be too large to enter.   Phagocytosis (fag”o-si-to’sis) is similar to pinocytosis, but  the cell takes in solids rather than liquids. Certain types of cells,  including some white blood cells, are called phagocytes because  they can take in solid particles such as bacteria and cellular debris.  When a phagocyte first encounters such a particle, the particle  attaches to the cell membrane. This stimulates a portion of the  membrane to project outward, surround the particle, and slowly  draw it inside the cell. The part of the membrane surrounding the  solid detaches from the cell’s surface, forming a vesicle, called a  phagosome, that contains the particle (fig. 3.30). A phagosome  may be several micrometers in diameter.   Usually, a lysosome joins a phagosome, forming a phagolyso-  some. The lysosomal digestive enzymes decompose the contents  (fig. 3.31). The products of this decomposition may then diffuse out  of the phagolysosome and into the cytoplasm, where they may be  used as raw materials in metabolic processes. Exocytosis, discussed  in the next section, may expel any remaining residue. In this way,  phagocytic cells dispose of foreign objects, such as dust particles;    FIGURE 3.29 A cell may use pinocytosis to take in a tiny droplet of fluid from its surroundings. The fluid is encapsulated in a vesicle that forms from    FIGURE 3.30 (AP|R) A cell may use phagocytosis to take in a solid particle from its surroundings. The particle is encapsulated in a portion of the    FIGURE 3.31 §AP|RI when a lysosome envelops a vesicle that contains a phagocytized particle, its digestive enzymes may destroy the particle.  The products of this intracellular digestion diffuse into the cytoplasm. Exocytosis may expel any residue.    remove damaged cells or cell parts that are no longer functional; or  destroy disease-causing microorganisms. Phagocytosis is an impor-  tant line of defense against infection.   Pinocytosis and phagocytosis engulf nonspecifically. In con-  trast is the more discriminating receptor-mediated endocytosis,  which moves very specific types of particles into the cell. This pro-  cess uses protein molecules that extend through the cell membrane  and are exposed on its outer surface. These proteins are receptors  to which specific molecules from the fluids surrounding the cell  can bind and selectively enter the cell, while other types of mol-  ecules are left outside (fig. 3.32). Molecules that bind specifically  to receptors are called ligands.    Cholesterol molecules enter cells by receptor-mediated endocy-  tosis. Cholesterol molecules synthesized in liver cells are packaged  into large spherical particles called low-density lipoproteins (LDL).  An LDL particle has a coating that contains a binding protein called  apolipoprotein-B. The membranes of various body cells (includ-  ing liver cells) have receptors for apolipoprotein-B. When the liver  releases LDL particles into the blood, cells with apolipoprotein-B  receptors recognize and bind the LDL particles. Formation of the  receptor-ligand combination stimulates the cell membrane to indent  and form a vesicle around the LDL particle. The vesicle then trans-  ports the LDL particle to a lysosome, where enzymes digest it and  release the cholesterol molecules for cellular use.    FIGURE 3.32 Receptor-mediated endocytosis brings specific molecules into a cell. (a, b) A specific molecule (ligand) binds to a receptor protein,  forming a receptor-ligand combination. (c) The binding of the ligand to the receptor protein stimulates the cell membrane to indent. (d) Continued  indentation forms a vesicle, which encloses and then transports the molecule into the cytoplasm.    Receptor-mediated endocytosis is particularly important  because it allows cells with the appropriate receptors to remove and  process specific types of substances from their surroundings, even  when these substances are present in very low concentrations. In  short, receptor-mediated endocytosis provides specificity (fig. 3.32).    More than 25 million people in the United States take cholesterol-  lowering drugs called statins. The drugs inhibit an enzyme,  HMG-CoA reductase, which cells use to produce cholesterol—  in addition to the cholesterol that we eat. Feedback is at play.  When levels of the enzyme drop with taking the drug, liver cells  are stimulated to make more LDL receptors. With statin use not  only does the body make less cholesterol, but the more abun-  dant LDL receptors remove cholesterol from the bloodstream  more efficiently.    Exocytosis (ex-o-si-to’sis) is not a simple reversal of endocyto-  sis, because the details of the steps differ. However, the overall  result is the opposite: packaging substances made in the cell into  vesicles that fuse with the cell membrane and are released outside  the cell. Nerve cells use exocytosis to release the neurotransmit-  ter chemicals that signal other nerve cells, muscle cells, or glands  (fig. 3.33). Many cell types use exocytosis to secrete proteins.    Endocytosis brings a substance into a cell, and exocytosis trans-  ports a substance out of a cell. Another process, transcytosis  (tranz-si-to’sis), combines endocytosis and exocytosis to selec-  tively and rapidly transport a substance or particle from one end  of a cell to the other (fig. 3.34). Transcytosis moves substances  across barriers formed by tightly connected cells. The process  occurs in normal physiology and in disease.    Transcytosis enables the healthy immune system to monitor  pathogens in the small intestine, protecting against some forms  of food poisoning. It takes place in rare M cells that are among  the epithelial cells lining the small intestine. M cells are so-named  because the sides that face into the intestine have microfolds that  maximize their surface area. The other sides of the M cells appear  punched in, forming pockets where immune system cells gather.  An M cell can bind to and take in a bacterium from the intestinal  side by endocytosis, then transport it through the cell to the side  that faces the immune system cells, where exocytosis releases it.  The immune system cells bind parts of the bacterium, and, if they  recognize surface features of a pathogen, they signal other cells  to mature into antibody-producing cells. The antibodies are then  secreted into the bloodstream and travel back to the small intes-  tine, where they destroy the infecting bacteria before the person  becomes ill.   HIV, the virus that causes AIDS, uses transcytosis to cross  epithelial cells in the anus, mouth, and female reproductive tract  (fig. 3.34). The virus enters certain cells in mucous secretions,  and the secretions then carry the infected cells to an epithelial  barrier. Near these lining cells, viruses rapidly exit the infected  cells and are quickly enveloped by the lining cell membranes in  receptor-mediated endocytosis. HIV particles are ferried, in ves-  icles, through the lining cell, without infecting (taking over) the  cell, to exit from the cell membrane on the other side of the cell.  After transcytosis, the HIV particles enter cells beyond the epi-  thelial barrier and infection begins.   Another type of transport between cells uses vesicles called  exosomes that bud from one cell and then travel to, merge with,  and enter other cells. Exosomes are only 30 to 100 nanome-  ters (billionths of a meter) in diameter. They may carry proteins,  lipids, and RNA, and have been identified in many cell types.  They remove debris, transport immune system molecules from  cell to cell, and provide a vast communication network among  cells. Table 3.3 summarizes the types of movements into and out  of the cell.    FIGURE 3.33 Exocytosis releases particles, such as newly synthesized proteins, from cells.    FIGURE 3.34 Transcytosis transports HIV across the lining of the anus or vagina.    Source of  Process Characteristics Energy Example  |. Passive (Physical) Processes  A. Diffusion Molecules move through the phospholipid bilayer from regions of Molecular Exchange of oxygen and carbon  higher concentration toward regions of lower concentration. motion dioxide in the lungs  B. Facilitated lons move through channels, or molecules move by carrier proteins, Molecular Movement of glucose through a  diffusion across the membrane from a region of higher concentration to one motion cell membrane  of lower concentration.  C. Osmosis Water molecules move through a selectively permeable membrane Molecular Distilled water entering a cell  toward the solution with more impermeant solute (greater osmotic motion    A. Active transport Carrier molecules transport molecules or ions through membranes from ATP  regions of lower concentration toward regions of higher concentration.    C. Exocytosis Vesicles fuse with membrane and release contents outside of the cell. ATP Protein secretion, neurotransmitter  release  D. Transcytosis Receptor-mediated endocytosis and exocytosis combine to ferry ATP HIV crossing a cell layer    23 How are facilitated diffusion and active transport similar? How  are they different?    24 What is the difference between pinocytosis and phagocytosis?  25 Describe receptor-mediated endocytosis.    The series of changes that a cell undergoes, from the time it forms  until it divides, is called the cell cycle (fig. 3.35). This cycle may  seem straightforward—a newly formed cell grows for a time, and  then divides in half to form two new cells, called daughter cells,  which, in turn, may grow and divide. However, the specific events  of the cell cycle are quite complex. For ease of study, the cell cycle  is considered in distinct stages: interphase, mitosis (mi-to’sis; divi-  sion of the nucleus), and cytokinesis (si’’to-ki-ne’sis; division of  the cytoplasm). Then the resulting daughter cells may change fur-  ther, becoming specialized.    Membrane engulfs droplets containing dissolved molecules from ATP  Membrane engulfs solid particles from surroundings. ATP    FIGURE 3.35 The cell cycle is divided into interphase, when cellular  components duplicate, and cell division (mitosis and cytokinesis), when the   cell splits in two, distributing its contents into two daughter cells. Interphase   is divided into two gap phases (G, and G,), when specific molecules and  structures duplicate, and a synthesis phase (S), when DNA replicates. Mitosis  can be considered in stages—prophase, metaphase, anaphase, and telophase.    The actions of several types of proteins form “checkpoints” that  control the cell cycle. One particularly important checkpoint deter-  mines a cell’s fate, whether it will: continue in the cell cycle and  divide; stay specialized and alive, yet not divide; or die.    Once thought to be a time of rest, interphase is actually a very active  period. During interphase, the cell grows and maintains its routine  functions as well as its contributions to the internal environment.   If the cell is developmentally programmed to divide, it must  amass important biochemicals and duplicate much of its contents  so that two cells can form from one. The cell must replicate all of  its DNA (discussed in chapter 4, pp. 134 and 136) and synthesize  and assemble the parts of membranes, ribosomes, lysosomes, per-  oxisomes, and mitochondria.   Interphase is divided into phases based on the sequence of  activities. DNA is replicated during S phase (S stands for synthe-  sis) and is bracketed by two G phases, G, and G, (G stands for gap  or growth). Structures other than DNA are synthesized during the  G phases. Cellular growth occurs then, too (fig. 3.35).   Mitosis and cytokinesis constitute a form of cell division that  occurs in somatic (nonsex) cells and produces two daughter cells  from an original cell (fig. 3.36). These new cells are genetically  identical, each with the full complement of 46 chromosomes that  is typical of humans. In contrast to mitosis is meiosis, a second  form of cell division that occurs only in the cells that give rise to  sex cells (sperm and eggs). Meiosis halves the chromosome num-  ber. In this way, when a sperm fertilizes an egg, the total number  of 46 chromosomes is restored. Chapter 22 (pp. 824-825) considers  meiosis in detail.   During mitosis, the nuclear contents divide in an event called  karyokinesis, which means “nucleus movement.” Then, in cytoki-  nesis, which means “cell movement,” the cytoplasm is apportioned  into the two daughter cells. Mitosis must be very precise so that  each new cell receives a complete copy of the genetic information.  The chromosomes were duplicated in interphase, but it is in mitosis  that the identical chromosome sets are evenly distributed between  the two forming cells.   Mitosis is a continuous process, but it is described in stages that  indicate the sequence of major events as follows:    1. In prophase the chromatin fibers condense, making the indi-  vidual chromosomes visible under magnification. As a result  of DNA replication (during interphase), each chromosome  consists of two identical structures, called sister chromatids,  temporarily attached by a region on each called a centromere.    Mitosis is sometimes called cellular reproduction, because  it results in two cells from one—the cell reproduces. This may  be confusing, because meiosis is the prelude to human sexual  reproduction. Both mitosis and meiosis are forms of cell division,  with similar steps but different outcomes, and occurring in dif-  ferent types of cells.    The centrioles of the centrosome replicate just before the  onset of mitosis, and during prophase, the two newly formed  pairs of centrioles move to opposite sides of the cell (fig. 3.36).  Soon the nuclear envelope and the nucleolus disperse and are  no longer visible. Microtubules are assembled from tubulin  proteins in the cytoplasm, and these structures associate with  the centrioles and chromosomes. A spindle-shaped array of  microtubules (spindle fibers) forms between the centrioles as  they move apart (fig. 3.36b).   2. In metaphase spindle fibers attach to the centromeres so that a  fiber accompanying one chromatid attaches to one centromere  and a fiber accompanying the other sister chromatid attaches  to its centromere (fig. 3.36c). The chromosomes move along  the spindle fibers, and microtubules help align them about  midway between the centrioles.   3. In anaphase the centromeres of the chromatids separate, and  the sister chromatids are now considered individual chromo-  somes. The separated chromosomes move in opposite direc-  tions, again as the result of microtubule activity. The spindle  fibers shorten and pull their attached chromosomes toward  the centrioles at opposite sides of the cell (fig. 3.36d).   4. In telophase, the final stage of mitosis, the chromosomes  complete their migration toward the centrioles. It is much like  the reverse of prophase. As the identical sets of chromosomes  approach their respective centrioles, they begin to elongate  and unwind from rodlike structures to threadlike structures.  A nuclear envelope forms around each chromosome set, and  nucleoli become visible within the newly formed nuclei.  Finally, the microtubules disassemble into free tubulin  molecules (fig. 3.36e).   Cytoplasmic division (cytokinesis) begins during anaphase when the  cell membrane starts to constrict around the middle, which it contin-  ues to do through telophase. The musclelike contraction of a ring  of actin microfilaments pinches off two cells from one (fig. 3.37).    Chromatin condenses into chromosomes; centrioles move  to opposite sides of cytoplasm; nuclear membrane and  nucleolus disperse; microtubules assemble and associate  with centrioles and the two sister chromatids making up  each chromosome.    Spindle fibers from the centrioles attach to the  centromeres of the sister chromatids of each  chromosome; chromosomes align midway between  the centrioles.   move apart, with each chromatid now an individual  chromosome; spindle fibers shorten and pull these  new individual chromosomes toward the centrioles.    Chromosomes elongate and form chromatin threads;  nuclear membranes form around each chromosome  set; nucleoli form; microtubules break down.   4 replication, as well as  replication of centrioles  and mitochondria, and  | synthesis of extra   Chromosomes condense and  become visible. Nuclear  envelope and nucleolus  disperse. Spindle apparatus  forms.    Nuclear envelopes begin to  reassemble around two daughter  nuclei. Chromosomes decondense.  Spindle disappears. Division of    FIGURE 3.36 (AP|R) Mitosis and cytokinesis produce two cells from one. (a) During interphase, before mitosis, chromosomes are visible only  as chromatin fibers. A single pair of centrioles is present, but not visible at this magnification. (b) In prophase, as mitosis begins, chromosomes have  condensed and are easily visible when stained. The centrioles have replicated, and each pair moves to an opposite end of the cell. The nuclear envelope  and nucleolus disappear, and spindle fibers associate with the centrioles and the chromosomes. (c) In metaphase, the chromosomes line up midway  between the centrioles. (d) In anaphase, the centromeres are pulled apart by the spindle fibers, and the chromatids, now individual chromosomes, move  in opposite directions. (e) In telophase, chromosomes complete their migration and become chromatin, the nuclear envelope re-forms, and microtubules    disassemble. Cytokinesis, which began during anaphase, continues during telophase. Not all chromosomes are shown in these drawings. (Micrographs  approximately 360x)    The microfilaments assemble in the cytoplasm and attach to the  inner surface of the cell membrane. The contractile ring forms at  right angles to the microtubules that pulled the chromosomes to  opposite ends of the cell during mitosis. As the ring pinches, it sep-  arates the two newly formed nuclei and apportions about half of the  organelles into each of the daughter cells. The newly formed cells  may differ slightly in size and number of organelles and inclu-  sions, but they have identical chromosomes and thus contain  identical DNA information. How that DNA is expressed (used to  manufacture proteins) determines the specialization of the cell, a  point we return to at the chapter’s end.   27 Why is precise division of the genetic material during mitosis  important?    How often a cell divides is strictly controlled and varies with cell  type. Skin cells, blood-forming cells, and cells that line the intes-  tine, for example, divide often and continually. In contrast, the  immature cells that give rise to neurons divide a specific number  of times, and then cease—neurons are specialized and alive, but  they no longer divide.   Most types of human cells divide from forty to sixty times  when grown in the laboratory. Adherence to this cell division  limit can be startling. A connective tissue cell from a human fetus  divides thirty-five to sixty-three times, with an average of about  fifty times. However, a similar cell from an adult divides only  fourteen to twenty-nine times, as if the cell “knows” how many  times it has already divided. In a body, however, signals from the  immediate environment also influence mitotic potential.   A physical basis for this mitotic clock is the DNA at the tips  of chromosomes, called telomeres. Here the same six-nucleotide  sequence repeats hundreds of times. Each mitosis removes up to  1,200 nucleotides from the tip, a little like a candle burning down.  When the chromosome tips are shortened to a certain point, this  signals the cell to cease dividing. Severe psychological or emo-  tional stress can hasten telomere shortening. This may be one way  that stress can harm health.   Other external and internal factors influence the timing and  frequency of mitosis. Within cells, fluctuating levels of proteins  called kinases and cyclins control the cell cycle. Another internal  influence on readiness for cell division is the ratio between the  surface area of the cell membrane and the cell volume it contains;  that is, cell size. The larger the cell, the more nutrients it requires  to maintain the activities of life. However, the ability of a cell to  take up nutrients (by diffusion and various transport processes) is  limited by the surface area of the cell membrane. Because volume  increases faster than does surface area, a cell can grow too large to  efficiently obtain nutrients. Cell division solves this growth prob-  lem. The resulting daughter cells are smaller than the original cell  and thus have a more favorable surface area-to-volume relation-  FIGURE 3.37 Cytoplasmic division (cytokinesis) is seen in these ship. The smaller cells require less energy and fewer nutrients,  scanning electron micrographs (a—c. 2,200x). and diffusion into and out of them is faster.    External controls of cell division include hormones and growth  factors. Hormones are biochemicals manufactured in a gland and  transported in the bloodstream to a site where they exert an effect.  Hormones signal mitosis in the lining of a woman’s uterus each month,  building up the tissue to nurture a possible pregnancy. Similarly, a  pregnant woman’s hormones stimulate mitosis in her breasts when  their function as milk-producing glands will soon be required.   Growth factors function like hormones but act closer to their  sites of synthesis. Epidermal growth factor, for example, stimu-  lates growth of new skin beneath a scab. Salivary glands also pro-  duce this growth factor, which is why an animal’s licking a wound  may speed healing.    Some people who have cancer may benefit from drugs that  affect growth factors. Granulocyte colony stimulating factor  (G-CSF, sold under several brand names) is given as a drug to  boost white blood cell counts, which plummet during chemo-  therapy. In contrast, anti-angiogenesis drugs work oppositely on  vascular endothelial growth factor (VEGF), cutting off a tumor’s  blood supply.    Space availability is another external factor that influences  the timing and rate of cell division. Healthy cells do not divide if  they are surrounded by other cells. This response to crowding is  called contact (density-dependent) inhibition.   Control of cell division is crucial to health. With too infre-  quent mitoses, an embryo could not develop, a child could not  grow, and wounds would not heal. However, too frequent mitoses,  or those that continue unabated, produce an abnormal growth, or  neoplasm, which may form a disorganized mass called a tumor.   Tumors are of two types. A benign tumor remains in place like  a lump, and if it enlarges will eventually interfere with the function  of healthy tissue. A malignant, or cancerous, tumor looks differ-  ent from a benign tumor. A malignant tumor is invasive, extending  into surrounding tissue. A growing malignant tumor may roughly  resemble a crab with outreaching limbs. (The word “cancer” comes  from the Latin for “the crab.”) Cancer cells, if not stopped, even-  tually reach the circulation and spread, or metastasize, to other  sites in the body. Table 3.5 lists characteristics of cancer cells, and  figure 3.38 illustrates how cancer cells infiltrate healthy tissue.    | Loss of cell cycle control  Heritability (a cancer cell divides to form more cancer cells) |    Transplantability (a cancer cell implanted into another individual will  cause cancer to develop) |    Dedifferentiation (loss of specialized characteristics)  Loss of contact inhibition  Ability to induce local blood vessel formation (angiogenesis)    FIGURE 3.38 A cancer cell is rounder and less specialized than  surrounding healthy cells. It secretes biochemicals that cut through nearby  tissue (invasiveness) and other biochemicals that stimulate extension of  blood vessels that nurture the tumor’s growth (angiogenesis) (2,200).    Cancer is a collection of disorders distinguished by their site  of origin, the affected cell type, mutations (genetic variants) pres-  ent in the affected cells, and differences in gene expression. Many  cancers are treatable with surgery, radiation, chemicals (chemo-  therapy), or immune system substances used as drugs. A newer,  more targeted approach to treating cancer is to use molecules that  bind to receptors unique to, or unusually abundant on, cancer cells,  blocking the signals to divide.   Two major types of genes cause cancer. Oncogenes are abnor-  mal variants of genes that normally control the cell cycle, but are  overexpressed, increasing cell division rate. Tumor suppressor  genes normally hold mitosis in check. When tumor suppressor  genes are removed or inactivated, this lifts control of the cell cycle,  and uncontrolled cell division leading to cancer results (fig. 3.39).  Cancer cells are said to be “immortal” because they do not cease  dividing at the 40 to 60 division limit that other cells follow.    As the number of mutations (genetic changes) increases a  cancer progresses. Such mutations are described as being either  “drivers” or “passengers.” Just as a driver of a vehicle takes it to  the destination, a driver mutation provides the selective growth  advantage to a cell that makes it cancerous. Just as a passenger  goes along for the ride, a passenger mutation does not cause  or propel the cancer’s growth or spread. A cancer generally has  two to eight driver mutations, but more than 99% of the muta-  tions in cancer cells are passengers. Tumors vary greatly in the  numbers of each type of mutation.    Malignancy often results from a  series of mutations. An affected  cell divides more often than the  cell type it descends from and  eventually loses its specialized  characteristics.    Environmental factors, such as exposure to toxic chemicals  or radiation, may induce cancer by altering (mutating) oncogenes  and tumor suppressor genes in body (somatic) cells. Cancer may  also be the consequence of a failure of normal programmed cell  death (apoptosis), resulting in overgrowth.    30 Which factors control the number of times and the rate at which  cells divide?    31 How can too infrequent or too frequent cell division affect health?  32 What is the difference between a benign and a malignant tumor?    Cells come from preexisting cells, by the processes of mitosis and  cytokinesis. Cell division explains how a fertilized egg develops  into an individual consisting of trillions of cells, but not how all of  these cells become specialized. There are at least 290 specialized  types of cells, including 14 types that are unique to the embryo or  fetus. The process of specialization is called differentiation.   of blood vessels that nourish them, and  cancers spread when their cells break away  from their original location. The cells further  mutate as they travel, resisting treatments.    cell In a healthy cell, oncogenes are not overexpressed, and tumor  suppressor genes are expressed. As a result, cell division rate is  under control. Cancer begins in a single cell when an oncogene   is turned on or a tumor suppressor gene is turned off, lifting controls  on cell division and making the cell “immortal.” This initial step may  result from an inherited mutation, or from exposure to radiation,  viruses, or chemicals that cause mutation in a somatic (nonsex) cell.    A body must generate new cells in order to grow and to repair  injured tissues. A stem cell satisfies this requirement by dividing  mitotically to yield either two daughter cells like itself that can  continue dividing without specializing, or one daughter cell that is  a stem cell and one that is partially specialized. One defining char-  acteristic of a stem cell is its ability, called self-renewal, to divide  to give rise to other stem cells. A stem cell can also differentiate as  any of many cell types, given appropriate biochemical signals.   A partly specialized cell that is the daughter of a stem cell but  is intermediate between a stem cell and a fully differentiated cell is  termed a progenitor cell. It is said to be “committed” because its  daughter cells can become any of a restricted number of cell types  (fig. 3.40). For example, a neural stem cell divides to give rise to  progenitor cells that in turn give rise to the specialized neurons  and neuroglia that make up neural tissue. Such neural progeni-  tor cells, however, would not give rise to cell types that are part  of muscle or bone tissue. All of the differentiated cell types in a  human body can be traced back through lineages of progenitor and  stem cells.   Stem cells and progenitor cells are described in terms of their  potential, according to the possible fates of their daughter cells.  A fertilized egg and cells of the very early embryo, when it is a  small ball of cells, are totipotent, which means that their daughter  cells can specialize as any cell type. In contrast, stem cells present    FIGURE 3.40 Stem cells and progenitor cells. A true stem cell divides  mitotically to yield two stem cell daughters, or a stem cell and a progenitor  cell, which may show the beginnings of differentiation. Progenitor cells give  rise to progenitors or more differentiated cells of a restricted lineage.    later in development, as well as progenitor cells, are pluripotent,  which means that their daughter cells can follow any of several  pathways, but not all of them. Figure 3.41 depicts the lineages of  skin and nervous tissue, which share a progenitor.   Some stem cells in the adult body were set aside during  embryonic or fetal development as repositories for future healing.  Many organs have very small populations of stem or progenitor  cells, which are stimulated to divide when injury or illness occurs.  For example, one in 10,000 to 15,000 bone marrow cells is a  hematopoietic stem cell, which can give rise to blood and several  other cell types. Some stem cells or progenitor cells may travel  from bone marrow to replace damaged or dead cells in response to  signals sent from injured or diseased tissues elsewhere.   All cells in the human body (except red blood cells, which  expel their nuclei), have the same set of genetic instructions, but  as cells specialize, they use some genes and ignore others. An  immature bone cell (osteoblast) forms from a progenitor cell by  manufacturing proteins necessary to bind bone mineral, as well  as alkaline phosphatase, an enzyme required for bone formation.  An immature muscle cell (myoblast), in contrast, forms from a  muscle progenitor cell and accumulates the contractile proteins  that define a muscle cell. The term blast is used for immature  differentiated cells, such as osteoblast and myoblast. The osteo-  blast does not produce contractile proteins, just as the myoblast  does not produce mineral-binding proteins and alkaline phospha-  tase. The process of differentiation is like using only some of the  information in a database. From Science to Technology 3.1 looks  at how stem cells are being investigated for use in health care.    34 Distinguish between a stem cell and a progenitor cell.  35 Distinguish between totipotent and pluripotent.  36 Explain how cells differentiate.    A cell that does not divide or differentiate has another option—  death. Apoptosis (ap”o-to’sis) is a form of cell death also called  “programmed cell death” because it is a normal part of devel-  opment. Apoptosis sculpts organs from tissues that naturally  overgrow. In the fetus, apoptosis carves away webbing between  developing fingers and toes, prunes extra brain cells, and preserves  only those immune system cells that recognize the body’s cell sur-  faces. If it weren’t for apoptosis, a child’s lung or liver couldn’t  grow to adult size and maintain its characteristic form. Apoptosis  is also protective. After a sunburn, this form of cell death peels  away damaged skin cells that might otherwise turn cancerous.   In contrast to apoptosis is necrosis, which is cell death result-  ing from damage. The steps of the two processes are very differ-  ent. Apoptosis is a normal event, whereas necrosis is not.   Apoptosis is a fast, orderly, contained destruction that pack-  ages cellular remnants into membrane-enclosed pieces that are  then removed. It is a little like packaging up the contents of a  messy room into plastic bags.   Like mitosis, apoptosis is a continuous, stepwise process. It  begins when a “death receptor” on the doomed cell’s cell mem-  brane receives a signal to die. Within seconds, enzymes called cas-  pases are activated inside the cell, where they cut up various cell  components. These enzymes:   e dismantle the cytoskeletal threads that support the nucleus,  which collapses, condensing the DNA within   e fracture mitochondria, which release molecules that trigger  further caspase activity, cut off the cell’s energy supply, and  destroy other organelles   ¢ transport certain phospholipids from the inner surface of the  cell membrane to the outside, where they attract phagocytes  that break down debris    A cell dying from apoptosis has a characteristic appearance  (fig. 3.42). It rounds up as contacts with other cells are cut off, and  the cell membrane undulates, forming bulges called blebs. The  nucleus bursts under the multiple strains, releasing same-sized  DNA pieces. Mitochondria decompose. Finally, the cell shatters.  Almost instantly, pieces of membrane encapsulate the fragments,  which prevents the signaling that triggers inflammation. Within an  hour of the first release of caspases, the cell that underwent apop-  tosis is gone.   Mitosis and apoptosis are synchronized throughout develop-  ment, maturation, and aging, and as a result, tissues and organs  neither overgrow nor shrink. Disruptions in either process can  cause cancer.    In the human body, lineages of dividing stem cells and progenitor  cells produce the specialized (differentiated) cell types that assem-  ble and interact to form tissues and organs. Stem and progenitor  cells are essential for growth and healing (fig. 3A). Stem cell tech-  nology is part of an emerging field, called regenerative medicine,  that harnesses the body's ability to generate new cells to treat certain  diseases and injuries.   Stem cells to treat disease come from donors or from the  patient. Donor stem cells include umbilical cord stem cells saved  from newborns that are used to treat a variety of blood disor-  ders and certain metabolic conditions. Stem cells derived from  a patient have two sources: their natural sites or cultured from  “reprogrammed” differentiated cells.   A use of stem cells from their natural site is an autologous bone  marrow transplant, in which a person's immune system is destroyed  with drugs or radiation after stem cells are set aside. The stem cells  are then infused to repopulate the bone marrow.   Reprogramming differentiated cells is a promising approach  to producing therapeutic stem and progenitor cells. A fibroblast  taken from a skin sample, for example, can be given genetic  instructions to produce key proteins that return the cell to a state    FIGURE 3A Using stem cells to heal. (a) Stem cells from donors  (bone marrow or umbilical cord blood) are already in use. (b) A person's  cells may be used, unaltered, to replace damaged tissue, such as   bone marrow. (c) It is possible to “reprogram” a person's cells in  culture, taking them back to a less specialized state and then nurturing  them to differentiate as a needed cell type. The goal is to implant  reprogrammed cells back into donors and stimulate the cells to correct  the disease.    that resembles a stem cell from an embryo. Then a cocktail of  specific biochemicals is added to guide differentiation. The altered  cell divides in culture, specializing and passing on its new character-  istics to its daughter cells.   In the future, reprogrammed cells may be used therapeuti-  cally, but for now they are a research tool. Rett syndrome, an  inherited condition that affects females, illustrates what research-  ers can learn from experiments using reprogrammed cells. Girls  with Rett syndrome move their hands in a characteristic and  uncontrollable way, and gradually lose muscle tone and the abil-  ity to speak. Head growth slows, and many girls become disabled  by the time they reach their teens. The disease is difficult to study  at the cellular level in neurons taken from a patient, because this  cell type does not divide. However, neurons can be continually  cultured from reprogrammed cells. Reprogrammed neurons cul-  tured from skin samples taken from four girls with the syndrome  were too small, with too few connections and abnormal signaling.  Drugs that helped mice with a form of Rett syndrome also cor-  rected the defect in the reprogrammed cells from the four girls.  The next step: developing a treatment based on what researchers  observe in the reprogrammed cells.    Progenitor  cell  FIGURE 3.41 Cells specialize along cell lineage pathways. All cells    in the human body ultimately descend from stem cells, through the i  processes of mitosis and differentiation. This simplified view depicts S  a few of the pathways that cells follow, grouping the cell types by the  closeness of their lineages. A progenitor cell may yield daughter cells  of the same type, such as bone cells, or daughter cells of different  types, such as a neuron and an astrocyte. Imagine the complexity of  the lineages of the more than 290 human cell types!    Death receptor on doomed cell  binds signal molecule. Caspases  are activated within.    Caspases destroy various  proteins and other cell components.  Cell becomes deformed.   2. The shapes of cells are important in determining their  functions.    1. The three major parts of a cell are the nucleus, the  cytoplasm, and the cell membrane.   2. Cytoplasmic organelles suspended in the cytosol perform  specific vital functions, but the nucleus, as the genetic  headquarters, controls the overall activities of the cell.   3. Cell membrane  a. The cell membrane forms the outermost limit of the   b. It acts as a selectively permeable passageway that  controls the movements of substances between the cell  and its surroundings.   d. The cell membrane framework mainly consists of a  double layer (bilayer) of phospholipid molecules.   e. Molecules that are soluble in lipids pass through the  membrane easily, but water-soluble molecules do not.    g. Proteins provide the special functions of the membrane,  as transporters, receptors, enzymes, cell surface  markers of self, and cellular adhesion molecules.   a. Cytoplasm contains networks of membranes and  organelles suspended in fluid, and may also contain  nonliving cellular products, such as nutrients and  pigments, called inclusions.   (1) Ribosomes are structures of protein and RNA  that function in protein synthesis.   (2) Endoplasmic reticulum is composed of  connected membranous sacs, canals, and vesicles  that provide a tubular communication system and  an attachment for ribosomes; it also is the site of  synthesis of lipids.   (4) The Golgi apparatus is a stack of flattened,  membranous sacs that package glycoproteins  for secretion.   (5) Mitochondria are membranous sacs containing  enzymes that catalyze the reactions that release  energy from nutrient molecules and change it into  a usable form.   (6) Lysosomes are membranous sacs containing  digestive enzymes that destroy debris and  worn-out organelles.    c. Other cellular structures are not organelles, including  some that are parts of the cytoskeleton.   (1) The centrosome is a nonmembranous structure  consisting of two centrioles that aid in the  distribution of chromosomes during cell division.   (a) Motile cilia are tiny, hairlike structures that  wave, moving fluids across cell surfaces.  Cells have many motile cilia.   (3) Microfilaments and microtubules are threadlike  structures built of actin and tubulin proteins,  respectively, that aid cellular movements and  support and stabilize the cytoplasm.   (4) Intermediate filaments serve a variety of functions  and are composed of different proteins in different  body parts.   a. The nucleus is enclosed in a double-layered nuclear  envelope that has nuclear pores that control movement  of substances between the nucleus and cytoplasm.   b. Chromatin is composed of loosely coiled fibers of  protein and DNA that coil tightly into chromosomes  during cell division.   c. A nucleolus is a dense body of protein and RNA where  ribosome synthesis occurs.    Movement of substances into and out of the cell may use  physical or physiological processes.  1. Diffusion  a. Diffusion is due to the random movement of atoms,  molecules, or ions in air or liquid solution.   b. Diffusion is movement of atoms, molecules, or  ions from regions of higher concentration toward  regions of lower concentration (down a concentration  gradient).  It exchanges oxygen and carbon dioxide in the body.   d. The most important factors determining the rate  of diffusion in the body include distance, the  concentration gradient, and temperature.   a. Facilitated diffusion uses protein channels or carrier  molecules in the cell membrane.   b. This process moves substances such as ions, sugars,  and amino acids from regions of higher concentration  to regions of lower concentration.   a. Osmosis is a process in which water molecules move  through a selectively permeable membrane toward the  solution with greater osmotic pressure.   b. Osmotic pressure increases as the number of impermeant  solute particles dissolved in a solution increases.   c. A solution is isotonic when it contains the same  concentration of dissolved particles as the cell contents.    gain water when placed in hypotonic solutions.  4. Filtration  a. In filtration, molecules move through a membrane  from regions of higher hydrostatic pressure toward  regions of lower hydrostatic pressure.  b. Blood pressure filters water and dissolved substances  through porous capillary walls.  5. Active transport  a. Active transport moves molecules or ions from  regions of lower concentration to regions of higher  concentration.    b. It requires ATP and carrier molecules in the cell membrane.    6. Endocytosis  a. In pinocytosis, a cell membrane engulfs tiny droplets  of liquid.    c. In receptor-mediated endocytosis, receptor  proteins combine with specific molecules in the cell    7. Exocytosis  a. Exocytosis has the reverse effect of endocytosis but the  steps differ.  b. In exocytosis, vesicles containing secretions fuse with the  cell membrane, releasing the substances to the outside.  8. Transcytosis  a. Transcytosis combines endocytosis and exocytosis.  b. In transcytosis, a substance or particle crosses a cell.  c. Transcytosis is specific.    1. The cell cycle includes interphase, mitosis, and  cytokinesis.  2. Interphase  a. Interphase is the stage when a cell grows, DNA  replicates, and new organelles form.  b. It terminates when the cell begins mitosis.  3. Mitosis  a. Mitosis is the division and distribution of DNA to  daughter cells.    3 The three major parts of a cell are . (p. 83)  a. the nucleus, the nucleolus, and the nuclear envelope  b. the nucleus, the cytoplasm, and the cell membrane  c. the lysosomes, ribosomes, and vesicles    b. The stages of mitosis are prophase, metaphase,  anaphase, and telophase.  4. Incytokinesis the cytoplasm divides, distributing  organelles to the two daughter cells.   2. Chromosome tips that shorten with each mitosis provide a  mitotic clock, usually limiting the number of divisions to  about fifty.   4. Asacell grows, its surface area increases to a lesser degree  than its volume, and eventually the surface area limits the  cell’s ability to take in nutrients. Cell division restores the  more favorable surface area—volume relationship.   6. Cancer is the consequence of a loss of cell cycle control.    1. Astem cell divides to yield another stem cell and a  partially differentiated progenitor cell.   2. Cells that may give rise to any differentiated cell type are  totipotent. Cells with more restricted fates are pluripotent.   3. Stem cells are present in adult organs and migrate from the  bone marrow to replace damaged cells.   4. As cells specialize, they express different sets of genes that  provide their distinct characteristics.    1. Apoptosis is a form of cell death that is part of normal  development and growth.   2. Itis a fast, orderly multistep process that begins when a  cell surface receptor receives a signal to die. Caspases  start a chain reaction that cuts up the cell into membrane-  bounded pieces. A phagocyte destroys the remains.   3. Apoptosis and mitosis are synchronized throughout  development, maturation, and aging.   State a way that cellular adhesion is essential to health and    sacs that contain enzymes that  catalyze a variety of specific  biochemical reactions    12 List the parts of the nucleus and explain why each is    13 Distinguish between active and passive mechanisms of  movement across cell membranes. (p. 99)   14 Match the movements into and out of the cell on the left  with their descriptions on the right. (pp. 99-105)    gradient through an ion channel  or with a carrier protein, without  energy from ATP    cell when the vesicle containing it  merges with the cell membrane    permeable membrane into a  region of greater concentration of  impermeant solute   Explain why interphase is not a period of rest for a cell.  (p. 108)   Explain how meiosis differs from mitosis. (pp. 108)  Describe the events of mitosis in sequence. (p. 108)  occur simultaneously. (pp. 108-110)  a. G, phase and G, phase   List five factors that control when and if a cell divides.  (pp. 110-111)   Explain why it is important for the cell cycle to be highly  regulated. (p. 111)   Discuss the consequences of too little cell division and too  much cell division. (p. 111)   Distinguish between the ways that mutations in oncogenes  and tumor suppressor genes cause cancer. (p. 111)    d. Stem cells in the early embryo are totipotent and progeni-    tor cells are pluripotent.  Describe a general function of stem cells in the body.  (p. 112)    Explain how apoptosis (cell death) can be a normal part of  development. (p. 113)    1. Liver cells are packed with glucose. What mechanism could  transport more glucose into a liver cell? Why would only this  mode of transport work?    2. What characteristic of cell membranes may explain why fat-soluble  substances such as chloroform and ether rapidly affect cells?    3. For experimental stem cell therapy, state the part of a cell  reprogrammed to function like that of a stem cell and stimulated  to differentiate in a particular way.    4. Organelles compartmentalize a cell. What advantage does  this offer a large cell? Cite two examples of organelles and the  activities they compartmentalize.    5. Exposure to tobacco smoke immobilizes and destroys motile  cilia. How might this effect explain why smokers have an  increased incidence of coughing and respiratory infections?    6. Which process—diffusion, osmosis, or filtration—is used in the  following situations?  a. Injection of a drug hypertonic to the tissues stimulates pain.  b. The urea concentration in the dialyzing fluid of an artificial  kidney is decreased.  c. A person with extremely low blood pressure stops producing  urine.    7. Reports in the media about stem cells usually state that they  “turn into any kind of cell in the body.” Explain why this  statement is only partially correct, including a description of how  a stem cell maintains the population of stem cells.    Connect Interactive Questions Reinforce your knowledge  using assigned interactive questions covering the cell membrane,  organelles, movement through the cell membrane, and stem cells.    Connect Integrated Activity Can you predict the effect diseases  or drugs might have on the cell membrane or organelles?    Anatomy & Physiology Revealed Go more in depth into the  human body by viewing parts of a cell under a microscope and  viewing animations of the cell cycle.    After you have studied this chapter, you should be able to:   Explain how ATP stores chemical energy and makes it  available to a cell. (p. 126)    Explain how the reactions of cellular respiration release  chemical energy. (p. 127)    Compare and contrast DNA and RNA. (p. 136)  Describe the steps of protein synthesis. (pp. 139-142)    Changes in Genetic Information  Describe how genetic information can be altered. (p. 142)    Explain how a mutation may or may not affect an  organism. (p. 143)    Chromosomes consist of long molecules of DNA complexed with proteins.  The DNA sequences instruct cells to build specific proteins—including  enzymes essential to metabolism (36,000x).    In every human cell, even in the most sedentary individual, thou-  sands of chemical reactions essential to life take place every  second. Many metabolic reactions occur one after the other in  a sequence, with the products of one reaction serving as start-  ing materials for the next. These reactions form pathways and  cycles that intersect where they share intermediate compounds.  Special types of proteins called enzymes control the rate of  each reaction, enabling them to proceed fast enough to sustain  life. The sum total of chemical reactions in the cell constitutes  cellular metabolism.    co-, with: coenzyme—substance that unites  with a protein to complete the structure  of an active enzyme molecule.    Metabolic reactions and pathways are of two types: anabolism and  catabolism. In anabolism (ah-nab’o-liz”-ém), small molecules  are built up into larger ones, requiring energy. In catabolism (ka-  tab’o-liz”-ém), larger molecules are broken down into smaller  ones, releasing energy. About 60% of the energy released as large  molecules are dismantled escapes as heat. The rest of the energy is  used to build molecules and to drive various activities of the cell.    Anabolism provides all the materials a cell requires for mainte-  nance, growth, and repair. For example, a type of anabolic process  called dehydration synthesis (de”hi-dra’shun sin’the-sis) joins  many simple sugar molecules (monosaccharides) to form larger  molecules of glycogen, which store energy in their chemical  bonds. When a runner eats pasta the night before a race, diges-  tion breaks down the plant-based complex carbohydrates in the  food to monosaccharides. These smaller molecules are absorbed  into the bloodstream, which carries the energy-rich molecules to  body cells. Here, dehydration synthesis joins the monosaccha-  rides to form glycogen, which stores energy that the runner may  need later, as the finish line nears. First, two monosaccharides join  to form a disaccharide. When monosaccharide units join, an —OH  (hydroxyl group) from one monosaccharide molecule and an —H  (hydrogen atom) from an —OH group of another are removed. As  the —H and —OH react to produce a water molecule, the mono-    saccharides are joined by a shared oxygen atom, as figure 4.1  shows (read from left to right). As the process repeats, the molecu-  lar chain extends, forming a polysaccharide.   Dehydration synthesis also links glycerol and fatty acid mol-  ecules in fat cells (adipose tissue) to form triglyceride molecules.  Figure 4.2 shows (read from left to right) how a triglyceride forms  as three hydrogen atoms are removed from a glycerol molecule    The 45-year-old man’s physician advised him to start an  exercise program to lose weight, so the man joined a gym.  But he hadn't been to one in many years, and the rows of  machines looked daunting. So he hired a personal trainer  to develop an exercise routine that would be just what the  doctor ordered.   A personal trainer assesses a client’s fitness level and  guides the client in using specific machines and doing mat  exercises. The trainer offers advice on which weight-lifting  machines to use, how many repetitions to begin with,  and how often to increase repetitions. The trainer might  advise the client to lift weights only every other day, so that  muscles will have time to recover from the microscopic tears  caused by weight lifting. Using a mat, a trainer might lead  a client through a series of exercises to strengthen the core  abdominal muscles.   The personal trainer is part coach, part cheerleader,  encouraging exercisers to push their limits. Trainers work in  athletic clubs, at corporate fitness centers, in senior centers,  and at other types of facilities that have exercise equipment.  Some personal trainers even train clients at their homes.   Minimal requirements to become a personal trainer  include a high school diploma, cardiopulmonary resuscitation  (CPR) training, and completion of a personal trainer course,  which generally takes from a few months to a year. Passing  a certification exam is required. Personal trainers tend to be  outgoing, friendly people who enjoy helping others become  physically fit.    FIGURE 4.1 Building up and breaking down molecules. A disaccharide is formed from two monosaccharides in a dehydration synthesis reaction  (arrows pointing to the right). In the reverse reaction, hydrolysis, a disaccharide is broken down into two monosaccharides (arrows pointing to the left).    FIGURE 4.2 Forming a fat. A  glycerol molecule and three fatty acid  molecules react, yielding a fat molecule  (triglyceride) in a dehydration synthesis  reaction (arrows pointing to the right).  In the reverse reaction, hydrolysis, a  triglyceride is broken down into three  fatty acids and a glycerol (arrows  pointing to the left).    FIGURE 4.3 Peptide bonds link amino acids. When dehydration synthesis unites two amino acid molecules, a peptide bond forms between a carbon  atom and a nitrogen atom, resulting in a dipeptide molecule (arrows pointing to the right). In the reverse reaction, hydrolysis, a dipeptide molecule is    broken down into two amino acids (arrows pointing to the left).    and an —OH group is removed from each of three fatty acid mol-  ecules. The result of this reaction is three water molecules and  a single fat molecule whose glycerol and fatty acid portions are  bound by shared oxygen atoms.   In cells, dehydration synthesis also builds protein molecules  by joining amino acid molecules. When two amino acid molecules  are united, an —OH from the —COOH group of one and an —H  from the —NH, group of another are removed. A water molecule  forms, and the amino acid molecules join by a bond between a car-  bon atom and a nitrogen atom (fig. 4.3; read from left to right).  This type of bond, called a peptide bond, holds the amino acids  together. Two such bound amino acids form a dipeptide, and many  joined in a chain form a polypeptide. Generally, a polypeptide  consisting of 50 or more amino acid molecules is called a protein,  although the boundary between polypeptides and proteins is not    precisely defined. Some proteins consist of more than one poly-  peptide chain. The large protein that carries oxygen in the blood  (hemoglobin), for example, consists of four polypeptide chains,  each wound into a globular shape.   Nucleic acids are also formed by dehydration synthesis. This  process is described later in the chapter.    Catabolic reactions break down larger molecules into smaller  ones. An example of catabolism is hydrolysis (hi-drol’i-sis),  which can decompose carbohydrates, lipids, and proteins. A water  molecule is used for each bond that breaks. Hydrolysis of a disac-  charide, for instance, yields two monosaccharide molecules (see  fig. 4.1; read from right to left). The bond between the simple sugars    breaks, and the water molecule supplies a hydrogen atom to one  sugar molecule and a hydroxyl group to the other. Hydrolysis is  the reverse of dehydration synthesis.   Hydrolysis breaks down carbohydrates into monosaccharides;  fats into glycerol and fatty acids (see fig. 4.2; read from right to  left); proteins into amino acids (see fig. 4.3; read from right to  left); and nucleic acids into nucleotides. It does not occur auto-  matically, even though in the body water molecules are readily  available to provide the necessary —H and —OH. For example,  water-soluble substances, such as the disaccharide sucrose (table  sugar), dissolve in a glass of water but do not undergo hydrolysis.  Like dehydration synthesis, hydrolysis requires specific enzymes,  discussed in the next section, Control of Metabolic Reactions.   Many of the reactions of metabolism are reversible. However,  the enzyme that speeds, or catalyzes, an anabolic reaction may be  different from the enzyme that catalyzes the corresponding cata-  bolic reaction.   Both catabolism and anabolism must be carefully controlled  so that the breakdown or energy-releasing reactions occur at rates  adjusted to the requirements of the building up or energy-utilizing  reactions. Any disturbance in this balance is likely to damage or  kill cells. From Science to Technology 4.1 discusses a systematic  approach to identifying all the molecules that are part of metabo-  lism in a human body.    2 What type of molecule is formed by the anabolism of  monosaccharides? Of glycerol and fatty acids? Of amino acids?    Metabolic reactions and pathways can be subgrouped.  Intermediary metabolism refers to the processes that obtain,  release, and use energy. Another way to classify metabolic reac-  tions is by their necessity. Primary metabolites are products of  metabolism essential to survival. Secondary metabolites are not  essential to survival, but may provide an advantage or enhance-  ment. Secondary metabolites are best studied in plants, where  they usually help to defend against predators because they are  toxins. Some of our most successful drugs are plant secondary  metabolites. The vinca alkaloids, for example, protect the rosy  Madagascar periwinkle that produces them by sickening animals  that eat the vegetation, but we use these biochemicals to treat  cancer. Their effect is to destabilize microtubule formation.    Different types of cells carry out specialized metabolic processes,  but all cells perform certain basic reactions, such as the buildup  and breakdown of carbohydrates, lipids, proteins, and nucleic  acids. These common reactions include hundreds of very spe-  cific chemical changes that must occur in particular sequences.  Enzymes control the rates of these metabolic reactions.    Metabolic reactions require energy (activation energy) before they  proceed, just like any chemical reaction. This is why in laboratory  experiments heat is used to increase the rates of chemical reac-  tions. Heat energy increases the rate at which molecules move and  the frequency of their collisions. These collisions increase the like-  lihood of interactions among the electrons of the molecules that  can form new chemical bonds. The temperature conditions in cells  are usually too mild to adequately promote the reactions of life.  Enzymes make these reactions possible.   Most enzymes are globular proteins that catalyze specific  chemical reactions in cells by lowering the activation energy  required to start these reactions. Enzymes can speed metabolic  reactions by a factor of a million or more. This acceleration of  chemical reaction rate is called catalysis, and an enzyme is an  organic catalyst.   Enzymes are required in small amounts, because as they work,  they are not consumed and can, therefore, function repeatedly.  Because of this, a few enzyme molecules can have a powerful  effect. Each enzyme type is specific, acting only on a particular mol-  ecule, called its substrate (sub’strat). For example, the substrate of  an enzyme called catalase (found in the peroxisomes of liver and  kidney cells) is hydrogen peroxide, a toxic by-product of certain  metabolic reactions. This enzyme’s only function is to decompose  hydrogen peroxide into water and oxygen, an action that helps pre-  vent accumulation of hydrogen peroxide, which damages cells.    The action of the enzyme catalase is obvious when using  hydrogen peroxide to cleanse a wound. Injured cells release  catalase, and when hydrogen peroxide contacts them, bubbles  of oxygen are set free. The resulting foam removes debris from  inaccessible parts of the wound.    Many enzyme names are derived from the names of their sub-  strates, with the suffix -ase. A lipid-splitting enzyme is a lipase,  a protein-splitting enzyme a protease, and a starch (amylum)-  splitting enzyme an amylase. Enzyme names may be specific. For  example, sucrase splits the sugar sucrose, maltase splits the sugar  maltose, and lactase splits the sugar lactose.   Each enzyme must be able to “recognize” its specific sub-  strate. This ability to identify a substrate depends upon the shape  of an enzyme molecule. That is, each enzyme’s polypeptide chain  twists and coils into a unique three-dimensional conformation that  fits the particular shape of its substrate molecule.    During an enzyme-catalyzed reaction, a region of the enzyme  molecule called the active site temporarily combines with a specific  part of the substrate, forming an enzyme-substrate complex. (Most  enzymes have only one active site.) This interaction strains chemi-  cal bonds in the substrate in a way that makes a particular chemical  reaction require less energy to occur. When it does, the enzyme is    A generation ago, prehealth profession students had to memo-  rize a complex chart of biochemical pathways that represent  all of the energy reactions in a cell. The cellular respiration path-  ways ran down the center, with branches radiating outward and  in some places interconnecting into a giant web. Today, several  technologies as well as the ability to store massive amounts of  data have made possible the Human Metabolome Database.  “Metabolome” refers to all of the small molecules that are  part of metabolism in a cell, tissue, organ, or an entire organism.  The database is a vast, annotated catalog of those molecules,  “metabolites.” The government of Canada is supporting the  effort to search all published papers and books that describe  metabolites and link that information with experimental data.  The techniques of electrophoresis and chromatography are  used to separate metabolites, and mass spectrometry (MS) and    released in its original form, able to bind another substrate molecule  (fig. 4.4). Many enzyme-catalyzed reactions are reversible and in  some cases the same enzyme catalyzes both directions. An enzyme-  catalyzed reaction can be summarized as follows:    The rate of an enzyme-catalyzed reaction depends partly on the  number of enzyme and substrate molecules in the cell. The reaction  is faster if the concentration of the enzyme or the concentration of  the substrate increases. The efficiency of different types of enzymes  varies greatly. Some enzymes can catalyze only a few reactions per  second, whereas others can catalyze hundreds of thousands.   Biochemists estimate that human cells have at least 2,500 dif-  ferent metabolites, but fewer than half have been identified. Far  fewer have been analyzed for their concentrations in different  cell types under different conditions. In the Human Metabolome  Database, each entry has an electronic “MetaboCard” that  includes 90 data fields, half with clinical data (such as associated  diseases and drug interactions) and half with biochemical data  (such as pathways and enzymes that interact with the metabolite).  Each entry is also hyperlinked to other databases, interfacing with  1,500 drugs and 3,600 foods and food additives. The information  in the Human Metabolome Database is being used in drug discov-  ery, toxicology, transplant monitoring, clinical chemistry, disease  diagnosis, and screening of newborns for metabolic disorders.    The shapes (conformations) of enzymes are critical to their  functions. Exposure to excessive heat, radiation, electricity, cer-  tain chemicals, or fluids with extreme pH values can denature,  or alter, the conformation of an enzyme. Many enzymes become  inactive at 45°C, and nearly all are denatured at 55°C. Some poi-  sons denature enzymes.    Cellular metabolism includes hundreds of different chemical  reactions, each controlled by a specific type of enzyme. Enzyme-  catalyzed reactions form pathways when the product of one reac-  tion is the substrate of another reaction. Metabolic pathways  lead to the synthesis or breakdown of particular biochemicals  (fig. 4.5).    FIGURE 4.4 fAP|R) An enzyme-catalyzed reaction. (Many enzyme-catalyzed reactions, as depicted here, are reversible.) In the forward reaction (dark-  shaded arrows), (a) the shapes of the substrate molecules fit the shape of the enzyme’s active site. (b) When the substrate molecules temporarily combine with  the enzyme, a chemical reaction proceeds. (c) The result is a product molecule and an unaltered enzyme. The active site changes shape as the substrate binds,  such that formation of the enzyme-substrate complex is more like a hand fitting into a glove, which has some flexibility, than a key fitting into a lock.    FIGURE 4.5 A metabolic pathway consists of a series of enzyme-controlled reactions leading to formation of a product.    FIGURE 4.6 Anegative feedback mechanism may control a rate-limiting enzyme in a metabolic pathway. The product of the pathway inhibits the enzyme.    In many metabolic pathways, a regulatory enzyme that cata-  lyzes one step sets the rate for the entire sequence of reactions.  The number of molecules of such a regulatory enzyme is limited.  Consequently, these enzymes can become saturated when the  substrate concentration exceeds a certain level. Once this hap-  pens, increasing the substrate concentration no longer affects  the reaction rate. Because the enzyme does not work at high sub-  strate concentrations, it is termed a rate-limiting enzyme. Such  an enzyme is often the first in the series of reactions that com-  prises the metabolic pathway (fig. 4.6). This position is important  because an intermediate product of the pathway might accumu-  late if an enzyme occupying another position in the sequence  were rate-limiting.   For some metabolic pathways, the product inhibits the rate-  limiting regulatory enzyme. This type of control is an example of  negative feedback. Accumulating product inhibits the pathway, and  synthesis of the product falls. When the concentration of product  decreases, the inhibition lifts and more product is synthesized. In  this way, a single enzyme can control a whole pathway, stabilizing  the rate of product formation (fig. 4.6). Clinical Application 4.1 dis-  cusses “inborn errors of metabolism,” which result from deficit or  lack of an enzyme.    An enzyme may be inactive until it combines with a nonprotein  component called a cofactor, which helps the active site fold  into its appropriate conformation or helps bind the enzyme to its  substrate. A cofactor may be an ion of an element, such as cop-  per, iron, or zinc, or a small organic molecule, called a coenzyme  (ko-en’zim). Many coenzymes are composed of vitamin molecules  or incorporate altered forms of vitamin molecules.   Vitamins are essential organic molecules that human cells  cannot synthesize (or may not synthesize in sufficient amounts)  and therefore must come from the diet. Vitamins provide coen-  zymes that can, like enzymes, function repeatedly. This is why  cells require small amounts of vitamins. Coenzyme A, for exam-  ple, is derived from the vitamin pantothenic acid and is necessary  for one of the reactions of cellular respiration, discussed in the  next section. Chapter 18 (pp. 708-711) discusses vitamins further.    Energy is the capacity to change something; it is the ability to do  work. Therefore, we recognize energy by what it can do. Common  forms of energy are heat, light, sound, electrical energy, mechani-  cal energy, and chemical energy.   Energy cannot be created or destroyed, but it can change from  one form to another. For example, compact fluorescent and light-  emitting diode bulbs change electrical energy into heat and light.  An automobile engine changes the chemical energy in gasoline to  heat and mechanical energy.   Cellular respiration is the process that transfers energy from  molecules such as glucose and makes it available for cellular use.  The chemical reactions of cellular respiration must occur in a par-  ticular sequence, each one controlled by a different enzyme. Some  of these enzymes are in the cell’s cytosol, whereas others are in  the mitochondria. The precision of activity and location within  the cell suggests that the enzymes are physically positioned in the  exact sequence as that of the reactions they control. The enzymes  responsible for some of the reactions of cellular respiration are  located in tiny, stalked particles on the membranes (cristae) in the  mitochondria (see chapter 3, pp. 92-93).   Energy transfer powers the activities of life at the cellular  level. Therefore, all metabolic reactions involve energy in some  form. Most metabolic reactions use chemical energy.    Adenosine triphosphate (ATP) is a molecule that carries energy  in a form that the cell can use. It is the primary energy-carrying  molecule in a cell. Even though a cell has other energy carriers,  cells quickly die without enough ATP. Each ATP molecule consists  of three main parts—an adenine, a ribose, and three phosphates  in a chain (fig. 4.7). The second and third phosphates of ATP are  attached by high-energy bonds, and the chemical energy stored    In a type of inherited disease called an inborn error of metabo-  lism, a deficient or absent enzyme causes a block in the biochemi-  cal pathway that it catalyzes. As a result, the biochemical that the  enzyme normally acts upon builds up, and the biochemical result-  ing from the enzyme’s normal action becomes scarce. The effect  of an impaired enzyme in a metabolic pathway is like a twist in a  garden hose that cuts off the flow of water: pressure builds behind  the block, but no water comes out after the block.   Inborn errors of metabolism were initially described with  the help of a mother of two young physically and intellectually  disabled children in Norway, in 1931. The mother noted a musty  odor to the children’s urine, and her husband then mentioned it  to an acquaintance who was a physician interested in biochem-  istry. Intrigued, the doctor analyzed the foul urine in a lab at the  University of Oslo, with help from the mother, who brought him  samples. The physician identified the problem in the children’s  metabolism—later named phenylketonuria (PKU)—and then  found it among people in mental institutions.   An ATP (adenosine triphosphate)  molecule consists of an adenine, a  ribose, and three phosphates. The  wavy lines connecting the last two    in one or both high-energy bonds may be quickly transferred to  another molecule in a metabolic reaction. Energy from the break-  down of ATP powers cellular work such as skeletal muscle con-  traction, active transport across cell membranes, secretion, and  many other functions.   An ATP molecule that loses its terminal (end) phosphate  becomes an adenosine diphosphate (ADP) molecule, which has  only two phosphates. ADP can be converted back into ATP using    In PKU, a missing or nonworking enzyme blocks the meta-  bolic pathway that converts the amino acid phenylalanine into  another amino acid, tyrosine. Excess phenylalanine spills into the  urine and the blood, and poisons the brain. In the early 1960s a  physician and microbiologist who had PKU in his family devel-  oped a test to detect the disease using drops of blood taken from  a newborn's heel. It was the first newborn screening test to iden-  tify biochemicals in blood (using an analytical chemistry technique  called mass spectrometry) to detect inborn errors of metabolism.  Understanding PKU enabled researchers to develop a “medical  food” that severely restricts phenylalanine, countering the bio-  chemical abnormality. If begun very soon after birth, this special  diet, followed for many years and sometimes for life, can com-  pletely prevent the symptoms of intellectual disability.   Today newborns are screened for dozens of inborn errors of  metabolism. Some of these disorders, such as PKU, have dietary  treatments, and others may respond better to different treat-  ments if they are begun early.    energy released from cellular respiration to attach a third phos-  phate, in a process called phosphorylation (fos for-i-la’shun). As  figure 4.8 shows, ATP and ADP molecules shuttle back and forth  between the energy-releasing reactions of cellular respiration and  the energy-utilizing reactions of the cell.    Most metabolic processes require chemical energy stored in ATP.  This form of energy is initially held in the chemical bonds that  link atoms into molecules and is released when these bonds break.  Burning a marshmallow over a campfire releases the chemical  energy held in the bonds of the molecules that make up the marsh-  mallow as heat and light. Similarly, when we eat a marshmallow,  the digestive system first breaks the sweet-tasting sugar sucrose into  its constituent molecules of glucose and fructose. Inside cells, fruc-  tose ultimately reacts to form glucose. A process called oxidation  (ok”si-da’ shun) releases the energy from the glucose, which is  harnessed to power cellular metabolism.    Oxidation of substances inside cells and the burning of sub-  stances outside them have important differences. Burning in  nonliving systems (such as starting a fire in a fireplace) usually  requires a great deal of energy to begin, and most of the energy  released escapes as heat or light. In cells, enzymes initiate oxidation  by lowering the activation energy. Also, by transferring energy  to ATP, cells are able to capture almost half of the energy that is  released in the form of chemical energy. About 60% of the energy  escapes as heat, which helps maintain body temperature.    Cellular respiration occurs in three distinct, yet interconnected,  series of reactions: glycolysis (gli-kol’I-sis), the citric acid cycle,  and the electron transport chain (oxidative phosphorylation).  Glycolysis and the electron transport chain are pathways similar  to those depicted in figures 4.5 and 4.6. Figure 4.9 shows how a  metabolic pathway can form a cycle if the final product reacts to  replenish the original substrate.   Cellular respiration requires glucose and oxygen. The prod-  ucts of these reactions include carbon dioxide (CO,), water, and  energy. Although most of the energy is lost as heat, almost half is  captured as ATP. Figure 4.10 shows how the three components of  cellular respiration connect.   Cellular respiration includes aerobic (a”er-db’ik) reactions,  which require oxygen, and anaerobic (an-a”er-db’ik) reactions,  which do not. For each glucose molecule decomposed completely    FIGURE 4.9 A metabolic cycle. A metabolic pathway forms a  metabolic cycle when the product undergoes a reaction that replenishes  the initial substrate.    by cellular respiration, up to thirty-eight molecules of ATP can  be produced. All but two of the ATP molecules form in the aero-  bic reactions.   Both aerobic and anaerobic pathways begin with glycolysis.  “Glycolysis” means “the breaking of glucose.” It is a series of ten  enzyme-catalyzed reactions that break down the 6-carbon glucose  molecule into two 3-carbon pyruvic acid molecules. Glycolysis  occurs in the cytosol, and because it does not require oxygen, it is  sometimes referred to as the anaerobic phase of cellular respiration.    1. First, two phosphate groups are added to a glucose molecule,  one at each end, in a step called phosphorylation. This step  requires energy from two ATPs, which are used to “prime”  the glucose so that it is activated for some of the energy-  releasing reactions that will happen.   2. Second, the 6-carbon glucose molecule is cleaved into two  3-carbon molecules.   3. Third, the electron carrier NADH is produced, ATP is synthe-  sized, and two 3-carbon pyruvic acid molecules result.   Some of the reactions of glycolysis release hydrogen  atoms. The electrons of these hydrogen atoms contain much  of the energy from the chemical bonds of the original glucose  molecule. To keep this energy from glucose in a form the  cell can use, these hydrogen atoms are passed in pairs to  molecules of the hydrogen carrier NAD* (nicotinamide adenine  dinucleotide). In this reaction, two of the electrons and one  hydrogen nucleus bind to NAD* to form NADH. The remaining  hydrogen nucleus (a hydrogen ion) is released as follows:    NADH delivers these high-energy electrons to the  electron transport chain elsewhere in the mitochondria,  where most of the ATP will be synthesized. Therefore,  NADH is called an electron carrier. Four ATPs are also  synthesized directly. Subtracting the two ATPs used in the  priming step gives a net yield of two ATPs per molecule of  glucose from glycolysis. The reactions of glycolysis are  described in more detail in Appendix E, Cellular Respiration  (see fig. E.1).    12 What are the final products of cellular respiration?  13 Distinguish the aerobic from the anaerobic reactions.    For glycolysis to continue, NADH + H* must be able to deliver elec-  trons to the electron transport chain, replenishing the cellular supply  of NAD*. In the presence of oxygen, this is exactly what happens.  Oxygen acts as the final electron acceptor at the end of the electron  transport chain, enabling the chain to continue processing electrons  and recycling NAD*.   ) The 6-carbon sugar glucose is broken down in the cytosol  into two 3-carbon pyruvic acid molecules with a net gain  of 2 ATP and the release of high-energy electrons.   @The 3-carbon pyruvic acids generated by glycolysis enter  the mitochondria separately. Each loses a carbon  (generating CO.) and is combined with a coenzyme to  form a 2-carbon acetyl coenzyme A (acetyl CoA). More    @ Each acetyl CoA combines with a 4-carbon oxaloacetic  acid to form the 6-carbon citric acid, for which the cycle  is named. For each citric acid, a series of reactions  removes 2 carbons (generating 2 CO,’s), synthesizes  1 ATP, and releases more high-energy electrons.   The figure shows 2 ATP resulting directly from 2  turns of the cycle per glucose molecule that enters  glycolysis.    @The high-energy electrons still contain most of the  chemical energy of the original glucose molecule.  Special carrier molecules bring the high-energy electrons  to a series of enzymes that transfer much of the remaining  energy to more ATP molecules. The electrons eventually  combine with hydrogen ions and an oxygen atom to form  water. The function of oxygen as the final electron acceptor  in this last step is why the overall process is called aerobic  respiration.    FIGURE 4.10 Glycolysis takes place in the cytosol and does not require oxygen. Aerobic respiration takes place in the mitochondria and only in the  presence of oxygen. The products of glycolysis and the aerobic pathway of cellular respiration include ATP, heat, carbon dioxide, and water. Glycolysis  generates 2 ATP, the citric acid cycle generates 2 ATP, and the electron transport chain generates 32-34. Therefore, the total yield of ATP molecules per  glucose molecule is 36-38, depending on the cell type. (The ratio of the mitochondrion to surrounding cytosol volume is exaggerated to emphasize the  metabolic pathways.)    (Q) Identify the part of the cell where glycolysis occurs and where aerobic respiration occurs.    Under anaerobic conditions the electron transport chain has no R A GLIMPSE AHEAD | To Chapter 9    oxygen, and therefore nowhere to unload its electrons, and as a result The intensity of muscle activity may exceed the ability of    it can no longer accept new electrons from NADH. As an alternative, the muscle cells to produce ATP aerobically. When this happens,  NADH + H* can give its electrons and hydrogens back to pyruvic acid the shift to anaerobic metabolism may lead to muscle fatigue. This  in a reaction that forms lactic acid. Although this reaction regenerates is part of the reason why you can walk around the mall all day, but if  NAD*, the buildup of lactic acid eventually inhibits glycolysis, and you try to run to catch the bus, you may tire after a short distance.  ATP production declines. The lactic acid diffuses into the blood, and Chapter 9 further discusses muscle fatigue and its relationship to  when oxygen levels return to normal the liver converts the lactic acid exercise patterns.    back into pyruvic acid, which can finally enter the aerobic pathway.    Phase 3  oxidation and  formation of  ATP and release  of high-energy  electrons    FIGURE 4.11 (AP|R) Glycolysis breaks down glucose in three  phases: (1) phosphorylation, (2) splitting, and (3) production of NADH  and ATP. Each glucose molecule broken down by glycolysis yields a net  gain of 2 ATP.    If enough oxygen is available, the pyruvic acid generated by gly-  colysis can continue through the aerobic pathways (see fig. 4.10).  These reactions include the synthesis of acetyl coenzyme A  (as’é-til ko-en’zim A) or acetyl CoA, the citric acid cycle, and  the electron transport chain. In addition to carbon dioxide and  water, the aerobic reactions yield up to thirty-six ATP molecules  per glucose. The theoretical yield of the aerobic reactions is up to  thirty-six ATP per glucose molecule. In fact, more energy may be  required to complete these reactions than once thought. Estimates  taking this into account indicate a yield of ATP less than the theo-  retical maximum.   The aerobic reactions begin with pyruvic acid produced  in glycolysis moving from the cytosol into the mitochondria  (fig. 4.12). From each pyruvic acid molecule, enzymes inside the    mitochondria remove two hydrogen atoms, a carbon atom, and  two oxygen atoms, generating NADH and a CO, and leaving a  2-carbon acetic acid. The acetic acid then combines with a mol-  ecule of coenzyme A to form acetyl CoA. CoA “carries” the acetic  acid into the citric acid cycle.    Ingestion of the element arsenic kills cells by blocking the action  of the enzyme (pyruvate dehydrogenase) that catalyzes the reac-  tion that produces acetyl CoA from pyruvic acid. Given in a single  large dose, arsenic causes chest pain, vomiting, diarrhea, shock,  coma, and death. Many small doses cause dark skin lesions that  feel as if they are burning, numbness in hands and feet, and  eventually skin cancer. Such gradual poisoning, called arsenico-  sis, may progress to paralysis and organ failure. Arsenicosis can  result from contact with pesticides or other environmental pol-  lutants. The world’s largest outbreak, however, is due to natural  exposure to arsenic in groundwater in India and Bangladesh.    The citric acid cycle begins when a 2-carbon acetyl CoA molecule  combines with a 4-carbon oxaloacetic acid molecule to form the  6-carbon citric acid and CoA (fig. 4.12). The citric acid is changed  through a series of reactions back into oxaloacetic acid. The CoA  can be used again to combine with acetic acid to form acetyl CoA.  The cycle repeats as long as the mitochondrion receives oxygen  and pyruvic acid.  The citric acid cycle has three important consequences:    1. One ATP is produced directly for each citric acid molecule  that goes through the cycle.   2. For each citric acid molecule, eight hydrogen atoms with  high-energy electrons are transferred to the hydrogen  carriers NAD* and the related molecule FAD (flavine  adenine dinucleotide):    3. As the 6-carbon citric acid reacts to form the 4-carbon  oxaloacetic acid, two carbon dioxide molecules are produced.    The carbon dioxide produced by the formation of acetyl CoA  and in the citric acid cycle dissolves in the cytoplasm, diffuses from  the cell, and enters the bloodstream. Eventually, the respiratory sys-  tem excretes the carbon dioxide. The details of the citric acid cycle  are covered in Appendix E, Cellular Respiration (see fig. E.2).    The hydrogen and high-energy electron carriers (NADH and  FADH,) generated by glycolysis and the citric acid cycle now hold  most of the energy contained in the original glucose molecule. To  couple this energy to ATP synthesis, the high-energy electrons  are handed off to the electron transport chain, which is a series of    FIGURE 4.12 (AP|RY Each turn of the citric acid cycle (two “turns” or citric acids per glucose) produces one ATP directly and two CO, molecules. Eight  hydrogens with high-energy electrons are released. (The ratio of the mitochondrial to cytosolic volumes is exaggerated to emphasize the metabolic pathways.)    enzyme complexes that pass electrons. Complexes of the electron  transport chain dot the folds of the inner mitochondrial membranes  (see chapter 3, pp. 92-93), which, if stretched out, may be forty-five  times as long as the cell membrane in some cells. As an electron  passes along the electron transport chain, it gradually loses energy.    That energy is transferred to ATP synthase, an enzyme complex that  uses the energy to add a phosphate to ADP to form ATP (fig. 4.13).  These reactions are known as oxidation/reduction reactions.  Neither glycolysis nor the citric acid cycle uses oxygen  directly, although they are part of the aerobic metabolism of    glucose. Instead, the final enzyme of the electron transport chain  gives up a pair of electrons that combine with two hydrogen ions  (provided by the hydrogen carriers) and an atom of oxygen to  form a water molecule:    Oxygen is therefore the final electron “carrier.” In the absence  of oxygen, electrons cannot continue to pass through the electron  transport chain, and the aerobic reactions of cellular respiration  stop. Appendix E, Cellular Respiration discusses the details of the  electron transport chain (see fig. E.3). Figure 4.14 summarizes the  steps in glucose metabolism.    Cyanide is a deadly poison because it halts ATP production in  cells. It binds to an iron atom that is part of the enzyme that  enables NADH from the citric acid cycle to transfer electrons  to oxygen. Cyanide is absorbed through the skin, gastrointes-  tinal tract, and respiratory tract, and exposure to it can kill in  minutes. One source of cyanide is bitter almonds (not the sweet    type that people prefer), which produce a compound called  amygdalin that an enzyme in the human small intestine breaks  down, releasing the poison. Cyanide is encountered in certain  industrial processes, including metal plating, gold extraction,  and in the raw materials for plastics. Rat poison and fumigants  also contain cyanide.    Carbohydrate Storage \ chain  Metabolic pathways are interconnected in ways that enable certain  molecules to enter more than one pathway. For example, carbohy-  drate molecules from foods may enter catabolic pathways and be used  to supply energy, or they may enter anabolic pathways and be stored  or react to form some of the twenty different amino acids (fig. 4.15).   Excess glucose in cells may enter anabolic carbohydrate path-  ways and be linked into storage forms such as glycogen. Most cells  can produce glycogen; liver and muscle cells store the greatest  amounts. Following a meal, when blood glucose concentration FIGURE 4.14 An overview of cellular respiration, including the net  is relatively high, liver cells obtain glucose from the blood and yield of ATP at each step per molecule of glucose.    FIGURE 4.15 Hydrolysis breaks down carbohydrates from foods into  monosaccharides. The resulting molecules may enter catabolic pathways  and be used as energy sources, or they may enter anabolic pathways and  be stored as glycogen or fat, or react to yield amino acids.    synthesize glycogen. Between meals, when blood glucose concen-  tration is lower, the reaction reverses, and glucose is released into  the blood. This mechanism ensures that cells throughout the body  have a continual supply of glucose to support cellular respiration.   Glucose can also react to form fat molecules, which are later  deposited in adipose tissue. This happens when a person takes in  more carbohydrates than can be stored as glycogen or are required  for normal activities. The body has an almost unlimited capacity to  perform this type of anabolism. This is why overeating carbohy-  drates can increase body fat.   This section has considered the metabolism of glucose. Lipids  and proteins can also be broken down to release energy for ATP  synthesis. For all three, the final process is aerobic respiration, and  the most common entry point is into the citric acid cycle as acetyl  CoA (fig. 4.16). These pathways are described in detail in chapter 18  (pp. 697-699).    17 State the products of the aerobic reactions.  18 List the products of the citric acid cycle.  19 Explain the function of the electron transport chain.    Enzymes control the metabolic pathways essential for cell sur-  vival. They oversee the use of all four major groups of organic  molecules—carbohydrates, lipids, nucleic acids, and many other  proteins important in physiology, such as blood proteins, the pro-  teins that form muscle and connective tissues, and the antibodies  that protect against infection.   The information that instructs a cell to synthesize a particular  protein is held in the sequence of building blocks of deoxyribo-  nucleic acid (DNA), the genetic material. The correspondence  between a unit of DNA information and a particular amino acid  constitutes the genetic code (jé-net’ik k6d).    Children resemble their parents because of inherited traits, but  what passes from parents to a child is genetic information, in the  form of DNA molecules from the parents’ sex cells. Long mol-  ecules of DNA and associated proteins are organized into chromo-  somes. The opening image for this chapter (p. 120) shows human  chromosomes. As an offspring develops, mitosis passes the infor-  mation in the DNA sequences of the chromosomes to new cells.  Genetic information “tells” cells how to construct a great vari-  ety of protein molecules, each with a specific function. A DNA  sequence that contains the information for making a particular  polypeptide is called a gene (jén).    The complete set of genetic instructions in a cell, includ-  ing the genes as well as other sequences, constitutes the genome  (jéndm’). Only a small part of the human genome encodes protein  and it is called the exome (x-om). Much of the rest of the genome  controls which proteins are produced in a particular cell under par-  ticular circumstances and the amounts produced, which is called  gene expression. Studies of gene expression can reveal molecules  and pathways that are part of physiological processes. Chapter 24  (pp. 906-907) discusses the human genome.    The human genome includes about 20,325 protein-encoding  genes among 3.2 billion DNA nucleotides in each set of 23 chro-  mosomes. Most cells have two chromosome sets. Sequencing  the first human genomes took fifteen years and billions of dollars.  Tens of thousands of people have had their genomes sequenced.  It takes less than a day, but interpretation of the findings takes  longer. Health-care professionals are learning how to incorporate  information from the human genome into clinical practice.    Nucleotides are the building blocks of nucleic acids, as dis-  cussed in chapter 2 (pp. 75—76). A nucleotide consists of a 5-carbon  sugar (ribose or deoxyribose), a phosphate group, and one of  several nitrogenous bases (fig. 4.17). DNA and RNA nucleotides  form long strands (polynucleotide chains) as dehydration synthe-  sis alternately joins their sugars and phosphates, forming a “back-  bone” structure (fig. 4.18).   A DNA molecule is double-stranded, consisting of two poly-  nucleotide chains. The nitrogenous bases project from the sugar-  phosphate backbone of one strand and bind, or pair, by hydrogen  bonding to the nitrogenous bases of the second strand (fig. 4.19).  The resulting molecular structure is like a ladder in which the rails  represent the alternating sugar and phosphate backbones of the  two strands and the rungs represent the paired nitrogenous bases.  The sugars forming the two backbones point in opposite directions.  For this reason, the two strands are called antiparallel.   A DNA molecule has a highly regular structure because the  bases pair in only two combinations. A DNA base is one of four  types: adenine (A), thymine (T), cytosine (C), or guanine (G).    Proteins Carbohydrates Fats  (egg white) (toast, hash browns) (butter) tacts  Amino acids Simple sugars Glycerol Fatty acids  (glucose)    @ Complete oxidation  of acetyl coenzyme A  to CO, and H20 produces  high-energy electrons  (carried by NADH and  FADH,), which yield much  ATP via the electron  transport chain    FIGURE 4.16 A summary of the breakdown (catabolism) of proteins, carbohydrates, and fats.    A and G are purines (pu’rénz), and they consist of two organic  ring structures. T and C are pyrimidines (pe-rimi-denz), and they  have a single organic ring structure. A binds to T, and G binds  to C. That is, a purine always binds to a pyrimidine, and this is  what establishes the constant width of the DNA molecule. These  pairs—A with T, and G with C—are called complementary base  pairs (fig. 4.20a). The sequence of one DNA strand can always be  derived from the other by following the “base-pairing rules.” If the    FIGURE 4.17 Each nucleotide of a nucleic acid consists of a 5-carbon  sugar (S); a phosphate group (P); and an organic, nitrogenous base (B).    FIGURE 4.18 A polynucleotide chain consists of nucleotides  connected by a sugar-phosphate backbone.    FIGURE 4.19 DNA is double-stranded, consisting of two polynucleotide  chains. Hydrogen bonds (dotted lines) hold the nitrogenous bases of one  strand to their partners on the other strand. The sugars point in opposite  directions—that is, the strands are antiparallel.    sequence of one strand of the DNA molecule is G, A, C, T, then the  complementary strand’s sequence is C, T, G, A. It is the nucleotide  sequence that provides the information in a molecule of DNA.   The double-stranded DNA molecule twists, forming a double  helix (fig. 4.20b). A single gene may be thousands or even mil-  lions of bases long. In the nucleus, DNA is wound around proteins  called histones clustered in groups of eight to form chromatin, a  little like thread wound around spools (fig. 4.20b). The position of  the chromatin plays a still poorly understood role in which genes  are being accessed to synthesize proteins. Histones and other  molecules come on and off different parts of the genome as some  genes are expressed and others are silenced. During mitosis chro-  matin condenses, forming chromosomes that are visible under the  microscope (fig. 4.20c). Investigators can use DNA sequences to  identify individuals (From Science to Technology 4.2). Appendix F,  A Closer Look at DNA and RNA Structures, shows more detail.    When a cell divides, each newly formed cell must receive a copy  of the entire genome so it can synthesize the proteins necessary to  build basic cellular parts and metabolize, as well as the proteins  that give a cell type its distinctive features. All cells except the  sperm and egg receive two copies of the genome, in two sets of  chromosomes, one inherited from each parent. DNA replication  (re” pli-ka’shun) is the process that creates an exact copy of a DNA  molecule. It happens during interphase of the cell cycle.    The double-stranded structure of the DNA molecule makes  replication possible. As DNA replication begins, hydrogen bonds  break between the complementary base pairs of the two strands.  Then the strands unwind and separate, exposing unpaired bases.  New nucleotides pair with the exposed bases, forming hydrogen  bonds. An enzyme, DNA polymerase, catalyzes this base pairing.  Other enzymes then knit together the new sugar-phosphate back-  bone. In this way, a new strand of complementary nucleotides  forms and extends along each of the old (original) strands. Two  complete DNA molecules result, each with one new and one origi-  nal strand (fig. 4.21). During mitosis, the two DNA molecules that  form the two chromatids of each of the chromosomes separate so  that one of these DNA molecules passes to each of the new cells.   23 What is the structure of DNA?  24 Explain why DNA must replicate.  25 List the steps of DNA replication.    Genetic information specifies the correct sequence of amino acids  in a polypeptide chain. Each of the twenty different types of amino  acids is represented in a DNA molecule by a triplet code, consisting   New (a) The two polynucleotide strands of a DNA molecule point   seeee in opposite directions (antiparallel) and are held together by  Sener hydrogen bonds between complementary base pairs. (b) The  Sota molecular “ladder” of a DNA molecule twists into a double helix.  es (c) Histone proteins enable the long double helix to assume more  compact forms (chromosome and chromatin). Histones move  when sections of the DNA are accessed for gene expression.    The human genome sequence differs from person to person  because it includes 3.2 billion bits of information. Techniques  called DNA profiling (or fingerprinting) compare the most vari-  able parts of the genome among individuals for several pur-  poses—to identify remains at crime scenes or after natural  disasters; to confirm or rule out “blood” relationships; and,  increasingly, to establish innocence when other types of evi-  dence are questionable. The Innocence Project is a national liti-  gation and public policy organization that provides DNA testing  to people who claim that they have been wrongfully convicted.  The Innocence Project has exonerated hundreds of people since  it began in 1992.   One exonerated man had served four and a half years of a  twenty-five-year sentence for rape when DNA profiling estab-  lished his innocence. He and a friend had become suspects after a  woman in Houston identified them as the men who had raped and  threatened her with a gun, leaving her in a field. The two young  men supplied saliva and blood samples, from which DNA profiles    of sequences of three nucleotides. That is, the sequence C, G, T in  a DNA strand represents one type of amino acid; the sequence G,  C, A represents another type. Other sequences encode instructions  for beginning or ending the synthesis of a protein molecule, and for  determining which genes are accessed for their information.    The genetic code is said to be universal because all species use  the same DNA base triplets to specify the same amino acids.  Researchers deciphered the code in the 1960s. When the media  mentions an individual's genetic code, they really are referring  to the sequence of DNA bases comprising a certain gene or  genome—not the genetic code (the correspondence between  DNA triplet and amino acid).    DNA is in the nucleus, and protein synthesis occurs in the cyto-  plasm. Because the cell must keep a permanent copy of the genetic  instructions, a copy of the genetic information must move from the  nucleus into the cytoplasm for the cell to use it. This copying and  transfer of genetic information is a little like downloading a docu-  ment: the original remains on the server. RNA (ribonucleic acid)  molecules accomplish the transfer of information.They can exit the  nucleus because they are single-stranded and much shorter than the  DNA molecules that comprise chromosomes.    RNA molecules differ from DNA molecules in several ways  (table 4.1). RNA nucleotides have ribose rather than deoxyribose  sugar. Like DNA, RNA nucleotides each have one of four nitrog-  enous bases, but whereas adenine, cytosine, and guanine nucleo-    were done and compared to DNA profiles from semen found in  the victim and in her car. At the trial, an employee of the crime  lab doing the DNA analysis testified that the probability that the  suspect’s DNA matched that of the evidence by chance was 1 in  694,000—a number that led jurors to convict him, even though he  did not fit the victim's description of her assailant.   A DNA profile analyzes thirteen parts of the genome that  vary in most populations. Usually this is sufficient information to  rule out a suspect. Using these criteria, the suspect’s DNA at first  seemed to match the evidence. The problem, though, wasn’t in  the DNA, but in the population to which it was compared.   Proclaiming his innocence all along, the man had asked right  away for an independent DNA test, but was told he couldn't  afford one. Two journalists began investigating the Houston  crime laboratory. They sent information on a few cases to a pro-  fessor of criminology, who immediately saw the errors made in  the suspect's DNA analysis. Retesting his DNA, and comparing it  to a relevant population, proved his innocence.    tides are part of both DNA and RNA, thymine nucleotides are only  in DNA. In place of thymine nucleotides, RNA molecules have  uracil (U) nucleotides (fig. 4.22 and Appendix F, A Closer Look  at DNA and RNA Structures). In RNA U pairs with A (fig. 4.23).  Different types of RNA have different size ranges and functions.  The process of copying DNA information into an RNA sequence  is called transcription (trans-krip’-shun).   The first step in delivering information from the nucleus to  the cytoplasm is the synthesis of messenger RNA (mRNA). As  its name suggests, this form of RNA carries a gene’s information  on how to build a specific polypeptide. As mRNA is synthesized,  its nucleotides form complementary base pairs with one of the two  strands of DNA that encodes a particular protein. However, just as  the words in a sentence must be read in the correct order to make  sense, the base sequence of a strand of DNA must be “read” in the  correct direction and from the correct starting point. Furthermore,  only one of the two antiparallel strands of DNA contains the  genetic message. An enzyme called RNA polymerase recognizes  the correct DNA strand and the right direction for RNA synthe-  sis. The “sentence” always begins with the mRNA base sequence  AUG (fig. 4.24).   In mRNA synthesis, RNA polymerase binds to a promoter,  which is a DNA base sequence that begins a gene. Then a section of  the double-stranded DNA unwinds and pulls apart, exposing part  of the base sequence. RNA polymerase moves along the strand,  exposing other sections of the gene. At the same time, a molecule  of mRNA forms as RNA nucleotides complementary to those  along the DNA strand are joined. For example, if the sequence  of DNA bases is TACCCGAGG, the complementary bases in the  developing mRNA molecule are AUGGGCUCC, as figure 4.24  shows. For different genes, different strands of the DNA molecule  may be used to manufacture RNA.    FIGURE 4.21 (API DNA replication forms two double  helices from one. When DNA replicates, its original strands  separate locally. A new strand of complementary nucleotides  forms along each original strand. The dots represent hydrogen  bonds. Three hydrogen bonds form between C and G and two  form between A and T. The inset traces DNA replication on a  symbolic four chromosomes through the cell cycle.   Nitrogenous bases included Cytosine, guanine, adenine, thymine Cytosine, guanine, adenine, uracil    synthesis, replicates prior to mitosis as template for synthesis of protein molecules; transfer RNA carries amino  acids to messenger RNA; ribosomal RNA provides structure for ribosomes    molecule is synthesized beside a strand of DNA, complementary nucleotides  bond as in a double-stranded DNA molecule, with one exception: RNA  contains uracil nucleotides (U) in place of thymine nucleotides (T).    Transcription of this gene is complete for now, although genes  may be transcribed over and over.   Each amino acid in a protein is specified by a series of three  bases in DNA and then by a series of three bases in mRNA, called  codons (ko’donz). To complete protein synthesis, mRNA must leave  the nucleus and associate with a ribosome. There, the mRNA is trans-  lated from the “language” of nucleic acids to the “language” of amino  acids. This process is fittingly called translation (fig. 4.24). A cell  FIGURE 4.22 RNA differs from DNA in that it is single-stranded, has many ribosomes, and many mRNAs can be transcribed from a    contains ribose rather than deoxyribose, and has uracil (U) rather than gene, so protein synthesis is a very fast and efficient process.  thymine (T) as one of its four bases.    RNA polymerase continues to move along the DNA strand, called introns are spliced out of messenger RNA molecules  exposing successive sections of the base sequence, until it reaches before the molecules are used to synthesize proteins. Cells can  a special DNA base sequence (termination signal) that indicates transcribe and assemble different combinations of exons from a  the end of the gene. At this point, the RNA polymerase releases particular gene, creating slightly different forms of a protein that    the newly formed mRNA molecule and leaves the DNA. The DNA can function in different cell types under specific conditions.  then rewinds and assumes its previous double helix structure.    the start of a gene, and brings the first amino  acid into position Amino acids  attached to  specific  ( tRNAs  ®    Translation continues as  specific tRNA molecules bring  the correct amino acids to the  growing polypeptide chain    © tRNA molecules can pick up  another molecule of the same  amino acid and be reused    @At the end of the mRNA, the  ribosome releases the new  polypeptide chain    FIGURE 4.24 Protein synthesis. DNA information is transcribed into mRNA, which in turn is translated into a sequence of amino acids.    Q) How are DNA, RNA, and proteins alike, and how are they different?    Synthesizing a protein molecule requires that the specified  amino acid building blocks in the cytoplasm align in the proper  sequence along an mRNA, and then attach. A second type of  RNA molecule, called transfer RNA (tRNA), aligns amino acids  in a way that enables enzymes to bond them to each other. A  tRNA molecule consists of seventy to eighty nucleotides and has  a complex three-dimensional shape, somewhat like a cloverleaf.  Like mRNA, tRNA is transcribed in the nucleus and then sent  into the cytoplasm.   The two ends of the tRNA molecule are “connectors,” bringing  together mRNA and the growing chain of amino acids (fig. 4.24).  At one end, each tRNA molecule forms hydrogen bonds with a  particular amino acid. At least one type of tRNA specifies each of  the twenty amino acids. An amino acid must be activated for a tRNA  to pick it up. Special enzymes catalyze this step. ATP provides the  energy for an amino acid and its tRNA to bond (fig. 4.25). The other  end of each tRNA molecule includes a specific three-nucleotide    sequence, called the anticodon, unique to that type of tRNA. An  anticodon bonds only to the complementary mRNA codon. In this  way, the appropriate tRNA carries its amino acid to the correct  place in the mRNA sequence (fig. 4.25).   The genetic code specifies more than enough information to  encode the proteins that a human body requires. Although only  twenty types of amino acids need be encoded, the four types of  bases can form sixty-four different mRNA codons. Therefore,  some amino acids correspond to more than one codon (table 4.2).  Three of the codons do not have a corresponding tRNA. They pro-  vide a “stop” signal, indicating the end of protein synthesis, much  like the period at the end of this sentence. The mRNA sequence  AUG is the “initiation codon,” specifying the amino acid methi-  onine and the start of the encoded protein. Sixty-one different  tRNAs are specific for the remaining sixty-one codons, which  means that more than one type of tRNA can correspond to the  same amino acid type.    @ The tRNA holding the first  amino acid is attached to  its complementary codon  on mRNA. A second tRNA,  complementary to the next    codon, attaches to bring G Messenger  the second amino acid into ... RNA  position on the ribosome.  Peptide bond  @ A peptide bond forms, linking  the second amino acid to the  first amino acid.  Anticodon  @ Messenger  ... RNA  Codons  Next  @ The tRNA molecule that amino acid  brought the first amino acid  to the ribosome is released Transfer  to the cytoplasm, and will be RNA  used again. The ribosome  moves to a new position at  the next codon on mRNA. @ Messenger  ... RNA  Amino acids  represented  > Ribosome ——»>  t- Codon 1 “oe |  t- Codon 2 Glycine  . @A new tRNA complementary to Next  |_ Codon 3 Serine the third codon on mRNA brings amino acid  es, the third amino acid to be added  to the growing polypeptide chain. Transfer  L_ Codon 4 Alanine In the same way a fourth amino RNA  acid, then a fifth, and eventually  fifty or more amino acids will be Messenger  |-Codon5 Threonine added to the polypeptide chain RNA  = in exactly the same way.  t- Codon 6 Alanine  xen t- Codon 7 Glycine    FIGURE 4.25 (AP|R} A closer look at protein synthesis. Molecules of transfer RNA (tRNA) attach to and carry specific amino acids, aligning them in  the sequence determined by the codons of mRNA. These amino acids, connected by peptide bonds, form a polypeptide chain of a protein molecule. Protein  synthesis occurs on ribosomes. The inset shows some examples of the correspondence between mRNA codons and the specific amino acids they encode.    The binding of tRNA and mRNA occurs in close association  with a ribosome. A ribosome is an organelle that is a tiny particle of  two unequal-sized subunits composed of ribosomal RNA (rRNA)  and protein molecules. The smaller subunit of a ribosome binds to a  molecule of mRNA near the first codon. A tRNA with the comple-  mentary anticodon brings its attached amino acid into position, tem-  porarily joining to the ribosome. A second tRNA, complementary  to the second mRNA codon, then binds (with its activated amino  acid) to an adjacent site on the ribosome. The first tRNA molecule  releases its amino acid, providing the energy for a peptide bond to  form between the two amino acids (fig. 4.25). This process repeats  as the ribosome moves along the mRNA, adding amino acids one at  a time to the extending polypeptide chain. The enzymatic activity nec-  essary for bonding of the amino acids comes from ribosomal proteins  and some RNA molecules (ribozymes) in the larger subunit of the  ribosome. This subunit also holds the growing chain of amino acids.   Protein synthesis is economical. A molecule of mRNA usually  associates with several ribosomes at the same time. Multiple ribo-  somes can associate with mRNA at different points along its length,  simultaneously synthesizing the same protein. Such a group of  ribosomes is called a polyribosome. Several copies of the protein,  each in a different stage of formation, may be present at any given  moment. As the polypeptide forms, proteins called chaperones  fold it into its unique shape, and when the process is completed,  the polypeptide is released as a separate functional molecule. The  tRNA molecules, ribosomes, mRNA, and the enzymes can func-  tion repeatedly in protein synthesis. Cells have a protein misfolding  response that ensures that proteins folded incorrectly are destroyed  or refolded in the proper conformation.    ATP molecules provide the energy for protein synthesis.  A protein may consist of many hundreds of amino acids and the  energy from three ATP molecules is required to link each amino  acid to the growing chain. Much of a cell’s energy supply supports  protein synthesis. Table 4.3 summarizes protein synthesis.   The number of molecules of a particular protein that a cell  synthesizes is generally proportional to the number of correspond-  ing mRNA molecules. The rate at which mRNA is transcribed  from DNA in the nucleus and the rate at which enzymes (ribo-  nucleases) destroy the mRNA in the cytoplasm therefore control  protein synthesis.   Certain types of proteins called transcription factors activate  certain genes, moving aside the surrounding histone proteins to  expose the promoter DNA sequences that start genes. Extracellular  signals such as hormones and growth factors activate transcrip-  tion factors. These actions are called “chromatin remodeling,” and  they control which proteins a cell produces and how many copies  form under particular conditions. A connective tissue cell might  have many mRNAs representing genes that encode the proteins  collagen and elastin; a muscle cell would have abundant mRNAs  encoding contractile proteins, such as actin and myosin.    ™  ie i) PRACTICE  26 Explain how genetic information is carried from the nucleus to  the cytoplasm.  27 List the steps of protein synthesis.    (Pe meme ©) o> ©) (= Rel Memes ©) 2 © ©    Transcription (In the Nucleus)  1. RNA polymerase binds to the DNA base sequence ofagene. |  2. This enzyme unwinds and exposes part of the DNA molecule.    3. RNA polymerase moves along one strand of the exposed  gene and catalyzes synthesis of an mRNA, whose nucleotides  are complementary to those of the strand of the gene.    4. When RNA polymerase reaches the end of the gene, the  newly formed mRNA is released.    6. The mRNA passes through a pore in the nuclear envelope  and enters the cytoplasm.    1. Aribosome binds to the mRNA near the codon at the  beginning of the messenger strand.    2. AtRNA molecule that has the complementary anticodon  brings its amino acid to the ribosome.    3. Asecond tRNA brings the next amino acid to the ribosome.    4. Apeptide bond forms between the two amino acids, and the  first tRNA is released.    5. This process repeats for each codon in the mRNA sequence  as the ribosome moves along its length, forming a chain of  amino acids.    6. The growing amino acid chain folds into the unique  conformation of a functional protein.    7. The completed protein molecule is released. The mRNA,  ribosome, and tRNA are recycled.    Remarkably, we are more alike than different—human genome  sequences are 99.9% the same among individuals. The tenth of a  percent of the human genome that can vary from person to per-  son includes rare DNA sequences that affect health or appear-  ance, as well as common DNA base variations that do not exert  any observable effects.    Like typing a long text message, the long process of DNA replica-  tion can result in errors, adding a different nucleotide base than  the one specified to a new DNA molecule. These errors produce  changes, called mutations (mu-ta’shunz), in the DNA sequence.   To visualize the concept of mutation, imagine a simplified  DNA sequence of twelve adenines:    AAAAAAAAAAAA  The sequence corresponds to an mRNA sequence of twelve uracils:    which specifies four linked molecules of the amino acid phenyl-  alanine.   Now imagine that the process of mutation changes the fourth  DNA base in the sequence of AAA ... toaC:    The corresponding mRNA—U UU GUUUUUUU U—  now encodes the amino acid sequence phenylalanine-valine-  phenylalanine-phenylalanine. (Use table 4.2 to assign amino acids  to mRNA codon sequences.) The genetic information has changed.    A mutation that replaces one type of amino acid with a differ-  ent kind is called a missense mutation. A mutation that changes  an amino acid-encoding codon into a stop codon prematurely  shortens the encoded protein, and is called a nonsense muta-  tion. An example of a nonsense mutation is a change of CGA  (arginine) to UGA (stop).    Mutations occur in two general ways—they may be sponta-  neous or induced. A spontaneous mutation arises from the chem-  ical tendency of free nitrogenous bases to exist in two slightly  different structures. For extremely short times, a base can be in  an unstable form. If, by chance, such an unstable base is inserted  into newly forming DNA, an error in sequence will be generated  and perpetuated when the strand replicates. Another replication  error that can cause mutation is when the existing (parental)  DNA strand slips, adding nucleotides to or deleting nucleotides  from the sequence.   Induced mutations are a response to exposure to certain  chemicals or radiation, called mutagens (mu’tah-jenz). A famil-  iar mutagen is ultraviolet radiation, which is part of sunlight.  Prolonged exposure to ultraviolet radiation can cause an extra  bond to form between two adjacent thymine DNA bases that  are part of the same DNA strand in a skin cell. This extra bond  kinks the double helix, causing an incorrect base to be inserted  during replication. The cell harboring such a mutation may not  be affected, may be so damaged that it dies and peels off, or it  may become cancerous. This is one way that too much sun expo-  sure can cause skin cancer (see Clinical Application 6.1, p. 182).  Mutagens are also found in hair dye, food additives, smoked  meats, flame retardants, and cigarette smoke.   Both spontaneous and induced mutations can harm health if  they alter the amino acid sequence of the encoded protein so that  it malfunctions or isn’t produced at all, and there is not enough of  the normal form of the protein to compensate. For example, the  muscle weakness of Duchenne muscular dystrophy results from a  mutation in the gene encoding the protein dystrophin. This protein  normally enables muscle cell membranes to withstand the force of  contraction. The mutation may be a missing or changed nucleotide  base or absence of part or all of the dystrophin gene. Without the  normal protein, muscle cells collapse and muscles throughout the  body weaken and break down. Figure 4.26 shows how the change    FIGURE 4.26 An example of mutation. (a) The DNA code for the amino acid glutamic acid is CTT. (b) If the first T is changed to A, the DNA code changes  to CAT, which specifies the amino acid valine. If this happens to both copies of the DNA that encodes the sixth amino acid in a subunit of the protein  hemoglobin, sickle cell disease results. The abnormal hemoglobin makes red blood cells sticky and bendable, and they lodge in narrow blood vessels,    of one base causes another inherited illness, sickle cell disease.  Rarely, a mutation confers an advantage. One such helpful muta-  tion protects against HIV infection. In these individuals, the recep-  tors (cell surface molecules) to which HIV must bind in order to  enter cells are incomplete. HIV cannot enter.   Once DNA changes, the new sequence is transmitted every  time the cell in which it originated divides. If that cell is an egg or  sperm, then the change is passed to the next generation. We return  to this point in the next section.    Cells can detect mutations and correct them. Special “repair  enzymes” recognize and remove mismatched nucleotides and fill  the resulting gap with the accurate, complementary nucleotides.  This mechanism, called the DNA damage response or DNA repair,  restores the original DNA sequence.   Disorders of DNA repair can make life difficult. Xeroderma  pigmentosum, for example, causes extreme sun sensitivity. A child  with the condition must completely cover up, applying sunblock  on any exposed skin to prevent freckles, sores, and cancer. Special  camps and programs allow these children to play outdoors at night,  away from the danger of the sun.   The nature of the genetic code protects against mutation, to a  degree. Sixty-one codons specify the twenty types of amino acids,  and therefore, some amino acids correspond to more than one codon  type. Usually, two or three codons specifying the same amino acid  differ only in the third base of the codon. A mutation that changes  the third codon base can encode the same amino acid. For exam-  ple, the DNA triplets GGA and GGG each specify the amino acid    proline. If a mutation changes the third position of GGA to a G,  the amino acid for that position in the encoded protein does not  change—tt is still proline.   If a mutation alters a base in the second position, the substi-  tuted amino acid is often similar in overall shape to the correct  one, and the protein is not changed enough to affect its function.  (An important exception is the mutation shown in fig. 4.26.) Yet  another protection against mutation is that a person has two copies  of each chromosome, and therefore of each gene. If one copy  is mutated, the other may provide enough of the gene’s normal  function to maintain health. (This is more complicated for the sex  chromosomes, X and Y, discussed in chapter 24, pp. 914-916.)   Timing of a mutation influences effects on health. A mutation  in a sperm cell, egg cell, or fertilized ovum is repeated in every cell  of the individual, causing an inherited disease or variant of a trait. A  mutation in one cell of an embryo might be devastating because much  of the body is still to develop, and many cells will inherit the mutation.  In contrast, a mutation in a body cell of an adult would most likely  have no effect because it would be only one among trillions of cells  that do not have the mutation. However, if such a somatic (body cell)  mutation confers a faster cell cycle and therefore cells bearing the  mutation have a division advantage, cancer can result.    29 What is a mutation?  30 How do mutations arise?  31. How do mutations affect health or appearance?    Metabolic reactions and pathways are of two types: anabolism  and catabolism.  1. Anabolism   b. In dehydration synthesis, hydrogen atoms and hydroxyl  groups are removed, water forms, and smaller molecules  bind by sharing atoms.   c. Anabolic reactions include complex carbohydrates  synthesized from monosaccharides, fats synthesized  from glycerol and fatty acids, and proteins synthesized  from amino acids.   b. In hydrolysis, a water molecule adds a hydrogen  atom to one portion of a molecule and a hydroxyl  group to a second portion, breaking the bond between  these parts.   c. Catabolic reactions include complex carbohydrates  decomposed into monosaccharides, fats decomposed  into glycerol and fatty acids, and proteins broken down  into amino acids.    Metabolic processes have many steps that occur in a specific  sequence and are interconnected.   b. Most enzymes are proteins that increase the rate of  (catalyze) specific metabolic reactions.   c. Enzymes are usually named according to their  substrates, with -ase at the end.   d. An enzyme acts when its active site temporarily  combines with the substrate, altering its chemical  structure. This enables the substrate to react, forming  a product. The enzyme is released in its original form.   e. The rate of enzyme-controlled reactions depends upon  the numbers of enzyme and substrate molecules and the  efficiency of the enzyme.   f. Enzymes can be denatured by heat, radiation, electricity,  chemicals, and extreme pH values.   d. A negative feedback mechanism in which the product  of a pathway inhibits the regulatory enzyme may  control the regulatory enzyme.   e. The rate of product formation usually remains stable in  a pathway because of feedback mechanisms.    3. Cofactors and coenzymes  a. Cofactors are additions to some enzymes that are  necessary for their function.  b. A cofactor may be an ion or a small organic molecule  called a coenzyme.  c. Some vitamins, the sources of coenzymes, cannot be  synthesized by human cells in adequate amounts.    Energy is a capacity to produce change or to do work. Forms  of energy include heat, light, sound, and electrical, mechanical,  and chemical energies. The reactions of cellular respiration  use and release chemical energy.  1. ATP molecules  a. Energy is captured in the bond of the terminal  phosphate of ATP.  b. Captured energy is released when the terminal  phosphate bond of an ATP molecule breaks.  c. ATP that loses its terminal phosphate becomes ADP.  d. ADP can become ATP by capturing energy and a  phosphate.  e. ATP is the primary energy-carrying molecule in a cell.  2. Release of chemical energy  a. Most metabolic processes use chemical energy released  when molecular bonds break.  b. The energy liberated from glucose during cellular  respiration is used for metabolism.  c. Enzymes in the cytoplasm and mitochondria control  cellular respiration.    Cellular respiration transfers energy from molecules such as  glucose and makes it available for cellular use. This process  occurs in three distinct, interconnected series of reactions:  glycolysis, the citric acid cycle, and the electron transport  chain. Some of the steps require oxygen (aerobic) and some  do not (anaerobic). Up to 38 ATPs form from breakdown of  one glucose molecule.   a. Glycolysis, the first step of glucose catabolism, occurs  in the cytosol and does not require oxygen.   c. Some of the energy is in the form of high-energy  electrons attached to hydrogen carriers.   a. Inthe anaerobic reactions, NADH and H* donate  electrons and hydrogens to pyruvic acid, generating  lactic acid.   b. Lactic acid builds up, eventually inhibiting glycolysis  and ATP formation.   c. When oxygen returns, in liver cells lactic acid reacts to  form pyruvic acid.    The second phase of glucose catabolism occurs in the  mitochondria and requires oxygen.   These reactions include the citric acid cycle and the  electron transport chain.   Considerably more energy is transferred to ATP during  the aerobic reactions than during glycolysis.   The products of the aerobic reactions of cellular  respiration are heat, carbon dioxide, water, and energy.  The citric acid cycle decomposes molecules, releases  carbon dioxide, releases hydrogen atoms that have  high-energy electrons, and forms ATP.   High-energy electrons from hydrogen atoms enter an  electron transport chain. Energy released from the chain  is used to form ATP.   Each metabolized glucose molecule yields up to thirty-  eight ATP molecules.   Excess carbohydrates may enter anabolic pathways  and be linked into and stored as glycogen or react to  produce fat.    DNA molecules contain and maintain information that tells  a cell how to synthesize polypeptides, which comprise or  associate to form proteins. The correspondence between a  sequence of DNA nucleotides and a particular amino acid is  the genetic code.   A gene is a portion of a DNA molecule that includes,  in its nucleotide base sequence, the genetic information  for making a polypeptide.   All of the DNA in a cell is called the genome. The  protein-encoding part is called the exome.    Each new cell requires a copy of the original cell’s  genetic information.    . Each new DNA molecule consists of one old strand and    Three nucleotides in a DNA sequence code for one type  of amino acid.   RNA molecules transfer genetic information from the  nucleus to the cytoplasm.    RNA molecules are usually single-stranded, have ribose  instead of deoxyribose, and uracil in place of thymine.    Messenger RNA (mRNA) molecules, synthesized in the  nucleus, have a nucleotide sequence complementary to  that of an exposed strand of DNA.   Messenger RNA molecules move into the cytoplasm,  associate with ribosomes, which consist of proteins and  ribosomal RNAs, and are templates for the synthesis of  polypeptide molecules in the process of translation.    Molecules of transfer RNA (tRNA) position amino  acids along a strand of mRNA.   A ribosome binds to an MRNA and allows a tRNA to  recognize its correct position on the mRNA.   The ribosome has enzymes required for the synthesis  of the polypeptide and holds the polypeptide until it is  completed.   As the polypeptide forms, it folds into a unique shape.  ATP provides the energy for protein synthesis.    Mutations are rare and alter health or appearance.  Mutations may be spontaneous or induced.   A protein synthesized from an altered DNA sequence  may or may not function normally.    have more effects than a later mutation because a greater  proportion of cells bear the mutation.    Distinguish between anabolism and catabolism. (p. 121)  Distinguish between dehydration synthesis and hydrolysis.  (pp. 121-122)   Give examples of a dehydration synthesis reaction and a  hydrolysis reaction. (pp. 121-123)   State two factors that influence the rate of an enzyme-  catalyzed reaction. (p. 124)   Explain the importance of a rate-limiting enzyme. (p. 125)  Describe how negative feedback involving a rate-limiting  enzyme controls a metabolic pathway. (p. 125)   Discuss the relationship between a coenzyme and a vitamin.  (p. 125)   Explain the importance of ATP and its relationship to ADP.  (pp. 125-126)   Explain how the oxidation of molecules inside cells differs  from the burning of substances outside cells. (pp. 126-127)    C. pyruvic acid molecules enter  mitochondria, and become acetyl  CoA that enter this series of  reactions    Identify the final acceptor of the electrons released in the  reactions of cellular respiration. (p. 131)  Excess glucose in cells may be linked and be stored as    The genetic code is . (p. 132)  the bonding of purine to pyrimidine  b. the correspondence between DNA triplet and amino acid  c. the correspondence between DNA triplet and RNA triplet  d. the controls that determine where the instructions   for a polypeptide chain start and stop  DNA information provides instructions for the cell to   manufacture carbohydrate molecules  . extract energy  manufacture RNA from amino acids  . synthesize protein molecules  Distinguish among a gene, an exome, and a genome. (p. 132)  Define gene expression. (p. 132)  If a DNA strand has the sequence ATGCGATCCGC then the  sequence on the complementary DNA strand is :  (pp. 133-134)  a. ATGCGATCCGC  b. TACGCTAGGCG  c. UACGCUAGGCG  d. AUGCGAUCCGC  Explain why DNA replication is essential. (p. 134)  Describe the events of DNA replication. (p. 134)  Identify the part of a DNA molecule that encodes  information. (pp. 134-136)  Calculate the number of amino acids that a DNA sequence  of twenty-seven nucleotides encodes. (p. 136)  List three ways that RNA differs from DNA. (p. 136)  If one strand of a DNA molecule has the sequence of  ATTCTCGACTAT, the complementary mRNA has the  sequence . (p. 136)  a. ATTCTCGACTAT  b. AUUCUCGACUAU  c. TAAGAGCTGATA  d. UAAGAGCUGAUA  Distinguish between transcription and translation.  (pp. 136-138)  Distinguish the functions of mRNA, rRNA, and tRNA.  (pp. 136-141)  Describe the function of a ribosome in protein synthesis.  (p. 141)  List the steps of protein synthesis. (pp. 136-141)    Explain how a mutation can alter the sequence of amino  acids in a polypeptide. (p. 142)   Discuss two major ways that mutation occurs. (p. 142)  Explain why DNA repair is necessary. (p. 143)   Discuss three ways that the genetic code protects against  the effects of a mutation. (p. 143)    1. How can the same molecule be both a reactant (starting  material) and a product of a biochemical pathway?    2. What effect might changes in the pH of body fluids or body  temperature that accompany illness have on cells?    3. Michael P. was very weak from birth, with poor muscle tone,  difficulty breathing, and great fatigue. By his third month, he  began having seizures. Michael's medical tests were normal  except for one: his cerebrospinal fluid (the fluid that bathes  the brain and spinal cord) was unusually high in glucose.  Hypothesizing that the boy could not produce enough ATP,  doctors gave him a diet rich in certain fatty acids that caused the  cellular respiration pathway to resume at the point of acetyl CoA  formation. Michael rapidly improved. Explain what caused his  symptoms.    4. In cyanide poisoning, levels of ATP in the brain plummet,  but levels of lactic acid increase markedly. Explain how both  effects occur.    5. Astudent is accustomed to running 3 miles at a leisurely  jogging pace. In a fitness class, she has to run a mile as fast as  she can. Afterward, she is winded and has sharp pains in her  chest and leg muscles. What has she experienced, in terms of  energy metabolism?    a. Write the sequence of the DNA strand that would be  replicated from this one.   b. Write the sequence of the RNA molecule that would be  transcribed from the DNA strand.   e. Use table 4.2 to write the sequence of amino acids that this  DNA sequence encodes.    7. Some antibiotic drugs fight infection by interfering with DNA  replication, transcription, or translation in bacteria. Indicate  whether each of the following effects is on replication,  transcription, or translation:   c. Quinolone blocks an enzyme that prevents bacterial DNA  from unwinding.    Connect Interactive Questions Reinforce your knowledge using  assigned interactive questions covering metabolism, cellular  respiration, and protein synthesis.    Anatomy & Physiology Revealed Go more in depth, and view  animations on cellular respiration, DNA structure and replication,  and protein synthesis.    After you have studied this chapter, you should be able to:    5.1 Cells Are Organized Into Tissues  1 Describe how cells are organized into tissues. (p. 149)  2. Identify the intercellular junctions in tissues. (p. 149)  3 List the four major tissue types in the body. (p. 149)    4 Describe the general characteristics and functions of  epithelial tissue. (pp. 150-152)    5 Name the types of epithelium and identify an organ in  which each is found. (pp. 152-156)    8 Compare and contrast the components, cells, fibers, and  extracellular matrix (where applicable) in each type of  connective tissue. (pp. 163-168)    9 Describe the major functions of each type of connective  tissue. (pp. 163-168)  5.4 Types of Membranes  10 Describe and locate each of the four types of  membranes. (pp. 168-169)  5.5 Muscle Tissues  11 Distinguish among the three types of muscle tissue. (p. 170)    12 Describe the general characteristics and functions of  nervous tissue. (pp. 170-171)    Falsely colored transmission electron micrograph (TEM) of a portion of a  mast cell. The large, orange oval is the cell’s nucleus, and the red granules  contain histamine and heparin (4,800x).    In all complex organisms, cells are organized into tissues, which  are layers or groups of similar cells. Tissues associate, assemble,  and interact to form organs that have specialized functions. The  study of tissues (histology) will assist understanding in later dis-  cussions of the physiology of organs and organ systems and  their conbtributions to homeostasis.    Cells are organized into tissues (tish’uz). Some cells in the body,  such as blood cells, are separated from each other in fluid-filled  spaces or intercellular (in”ter-sell’u-lar) spaces. Many other cell  types, however, are tightly packed, with structures called intercel-  lular junctions that connect their cell membranes.   In one type of intercellular junction, called a tight junc-  tion, the membranes of adjacent cells converge and fuse. The  area of fusion surrounds the cell like a belt, and the junction  closes the space between the cells. Tight junctions typically  join cells that form sheetlike layers, such as those that line the  inside of the digestive tract. The linings of tiny blood vessels in  the brain consist of cells held tightly together (From Science to  Technology 5.1).   Another type of intercellular junction, called a desmosome,  rivets or “spot welds” skin cells, enabling them to form a rein-  forced structural unit. The cell membranes of certain other cells,  such as those in heart muscle and muscle of the digestive tract,  are interconnected by tubular channels called gap junctions. These  channels link the cytoplasm of adjacent cells and allow ions, nutri-  ents (such as sugars, amino acids, and nucleotides), and other  small molecules to move between them (fig. 5.1). Table 5.1 sum-  marizes intercellular junctions.   Tissues can be distinguished from each other by variations  in cell size, shape, organization, and function. The tissues of the  human body include four major types: epithelial, connective, mus-  cle, and nervous. These tissues associate, assemble, and interact to  form organs that have even more specialized functions. Table 5.2  compares the four major tissue types. This chapter examines epi-  thelial and connective tissues in detail, and introduces muscle and  nervous tissues. Chapter 9 discusses muscle tissue in more detail,  and chapters 10, 11, and 12 examine nervous tissue.   Tissues are three-dimensional structures in the body.  Micrographs are photos of extremely thin slices (sections) of pre-  pared tissue specimens. The advantage of the thin slices is that  light passes through them more readily, making structures easier    It is 5 am and the tissue recovery technician reaches for her  cell phone. A young man has died in a car crash from head  trauma, but his skin is intact and healthy. The technician  drives to a funeral home just a few miles out of the city,  relieved that she doesn’t have to travel as far as she did the  last time she was on call. She is available to recover tissue for  five 24-hour periods each month.   At the funeral home, the technician puts on mask and  gloves, sterilizes the area of the skin of the corpse that  she will excise, and then removes the tissue, using surgical  instruments. She stores and packages the tissue, then  ships it to a tissue bank, carefully recording details of the  procedure. The technician is comfortable working with a  corpse. She knows that even though the accident had a tragic  end, several burn victims may receive grafts from the donor,  after the tissue bank determines which patients will be most  compatible with the grafts.   Recovering tissue, which is stored, is less stressful than  recovering organs, which must be used quickly. In addition to  skin, tissue banks store bone, corneas, tendons, ligaments,  cartilage, blood vessels, and heart valves. A tissue recovery  technician therefore must have excellent fine motor skills and  knowledge of anatomy. The job also requires standing for  long periods and possibly lifting bodies.   Getting a job as a tissue recovery technician requires  completing a certification program from the American  Association of Tissue Banks as a “certified tissue bank  specialist.” On-the-job training is typically provided. Tissue  recovery technicians may be medical students or emergency  medical technicians, or they might hold associates degrees in  surgical technology.   A tissue recovery technician must feel comfortable  working with corpses. In addition to funeral homes, the  job may take the technician to hospital operating rooms or  coroners’ offices.    Nanotechnology is helping drug developers to circumvent a prob-  lem in drug delivery based on an anatomical impediment—the  close attachments of the cells that form tiny blood vessels in the  brain. Like a tight line of police officers keeping out a crowd, the  blood-brain barrier is a 400-mile network of capillaries in the brain  whose cells are firmly attached by overlapping tight junctions. These  cells lack the windowlike clefts in other capillaries. In addition, star-  shaped brain cells called astrocytes wrap around the barrier.   The blood-brain barrier shields brain tissue from toxins and  biochemical fluctuations that could be overwhelming. It also  allows selective drug delivery. Certain antihistamines, for example,  do not cause drowsiness because they cannot breach the barrier.  But this protection has a trade-off—the brain cannot take up many  therapeutic drugs that must penetrate to be effective.   For decades researchers have attempted to deliver drugs  across the barrier by tagging compounds to substances that can    to see and photograph, but the relationship of the structures in  three dimensions may not be obvious. Figure 5.2 shows how a  tubular structure would appear (a) in an oblique section and (b) in  a longitudinal section (see also fig. 1.24, page 30). Throughout this  chapter, three-dimensional line drawings (for example, fig. 5.3a)  are included with each micrograph (for example, fig. 5.3), c) to  emphasize the orientation and distinguishing characteristics of the  specific tissues, as well as locator icons (as in fig. 5.3) indicating  where in the body the particular tissue may be found.   R r] -PRACTICE  1 What is a tissue?  2 What are the different types of intercellular junctions?    Epithelial (ep”i-the’le-al) tissues are found throughout the body.  Epithelium covers the body surface and organs, forms the inner lin-  ing of body cavities, lines hollow organs, and composes glands. It  always has a free (apical) surface exposed to the outside or internally  to an open space. A thin, extracellular layer called the basement  membrane anchors epithelium to underlying connective tissue.    Cancer cells secrete a substance that dissolves basement mem-  branes, enabling the cells to invade tissue layers. Cancer cells    also produce fewer adhesion proteins, or none at all, which  allows them to spread into surrounding tissue.    cross, and injecting substances that temporarily relax the tight  junctions. More recently, researchers have applied nanotech-  nology to the problem of circumventing the blood-brain bar-  rier. Nanotechnology is the application of structures smaller than  0.1 micrometers (100 nanometers) in at least one dimension.   Nanoparticles that can cross the blood-brain barrier are made  of combinations of oils and polymers, with a neutral or slightly neg-  ative charge. In one application, anesthetics or chemotherapeutics  are loaded into phospholipid bubbles (liposomes). This delivery  system masks the part of the drug that cannot cross the barrier.   In another application, insulin is delivered in inhaled nanopar-  ticles 10 to 50 nanometers in diameter. Originally developed to  provide insulin to people with diabetes instead of injecting it,  nanoparticle delivery of insulin may also be helpful in maintain-  ing memory in people who have mild cognitive impairment or  Alzheimer disease, according to early findings in clinical trials.    FIGURE 5.1 Intercellular junctions. Tight junctions fuse cell  membranes, desmosomes are “spot welds,” and gap junctions form  channels linking the cytoplasm of adjacent cells.    @ Which intercellular junction is the most likely to allow  substances to move from one cell to another?    (a) Circles or ovals indicate a cross section or  oblique section through a tubular structure.    FIGURE 5.2 Tissue sections. SS Serer ae  (a) Oblique section (600). (b) Rows of cells with a space in between  (b) Longitudinal section (165x). indicate a longitudinal section through a tube.    Tight junctions Close space between cells by fusing cell membranes Cells that line the small intestine  Desmosomes Bind cells by forming “spot welds” between cell membranes Cells of the outer skin layer    Gap junctions Form tubular channels between cells that allow exchange of substances Muscle cells of the heart and digestive tract    Connective Bind, support, protect, fill spaces, store Widely distributed throughout the Mostly have good blood supply, cells are  fat, produce blood cells body farther apart than epithelial cells, with  extracellular matrix in between    Nervous Conduct impulses for coordination, Brain, spinal cord, nerves Cells communicate with each other and  regulation, integration, and sensory other body parts  reception    As a rule, epithelial tissues lack blood vessels. However, cells that line the stomach and intestines are continually damaged  nutrients diffuse to epithelium from underlying connective tissues, and replaced.  which have abundant blood vessels. Epithelial cells are tightly packed. In many places, desmo-  Epithelial cells readily divide, so injuries heal rapidly as new somes attach epithelial cells, forming protective barriers in such  cells replace lost or damaged ones. For example, skin cells and the structures as the outer layer of the skin and the lining of the   Epithelial tissues are classified according to cell shape and  the number of cell layers. Epithelial tissues composed of thin, flat-  tened cells are squamous; those with cubelike cells are cuboidal;  and those with elongated cells are columnar. Epithelium composed  of a single layer of cells is simple and with two or more layers of  cells, stratified. In the following descriptions, modifications of the  free surfaces of epithelial cells reflect their specialized functions.    Simple squamous (skwa’ mus) epithelium consists of a single layer  of thin, flattened cells. These cells fit tightly together, somewhat like  floor tiles, and their nuclei are usually broad and thin (fig. 5.3).  Substances pass rather easily through simple squamous epi-  thelium. This tissue is common at sites of diffusion and filtration.  Simple squamous epithelium lines the air sacs (alveoli) of the lungs  where oxygen and carbon dioxide are exchanged. It also forms the    walls of capillaries, lines the insides of blood and lymph vessels,  and is part of the membranes that line body cavities and cover the  viscera. However, because it is so thin and delicate, simple squa-  mous epithelium is easily damaged.    Simple cuboidal epithelium consists of a single layer of cube-  shaped cells. Most of these cells have centrally located, spherical  nuclei (fig. 5.4).   Simple cuboidal epithelium lines the follicles of the thyroid  gland, covers the ovaries, and lines the kidney tubules and ducts of  certain glands, where the free surface faces the hollow channel or  lumen. In the kidneys, it functions in tubular secretion and tubular  reabsorption; in glands, it secretes glandular products.    Simple columnar epithelium is composed of a single layer of cells  that are longer than they are wide and whose nuclei are typically at  about the same level, near the basement membrane (fig. 5.5). The  cells of this tissue can be ciliated or nonciliated. Motile cilia, 7 to  10 um in length, extend from the free surfaces of the cells, and they  move constantly (see figure 3.15, p. 95). In the female, motile cilia  aid in moving the egg cell through the uterine tube to the uterus.    FIGURE 5.3 (AP|R} Simple squamous epithelium consists of a single layer of tightly packed, flattened cells. (a) Idealized representation of simple  squamous epithelium. Micrographs of (b) a surface view (250x) and (c) a side view of a section through simple squamous epithelium (250x).    FIGURE 5.4 (AP|R) Simple cuboidal epithelium consists of a single layer of    cuboidal epithelium. (b) Micrograph of a section through simple cuboidal epithelium (165x).    FIGURE 5.5 fAP|R) Simple columnar epithelium consists of a single layer of elongated cells. (a) Idealized representation of simple columnar  epithelium. (b) Micrograph of a section through simple columnar epithelium (400x).    Nonciliated simple columnar epithelium lines the uterus and  portions of the digestive tract, including the stomach and small and  large intestines. Because its cells are elongated, this tissue is thick,  which enables it to protect underlying tissues. Simple columnar  epithelium also secretes digestive fluids and absorbs nutrients  from digested food. Cells specialized for absorption typically have  many tiny, cylindrical processes, called microvilli, extending from  their free surfaces. Microvilli are 0.5 to 1.0 um long, and they  increase the surface area of the cell membrane where it is exposed  to substances being absorbed (fig. 5.6).    Specialized flask-shaped glandular cells are scattered among  the cells of simple columnar epithelium. These cells, called goblet  cells, secrete a protective fluid called mucus onto the free surface  of the tissue (see fig. 5.5).    The cells of pseudostratified (soo’do-strat’i-fid) columnar epi-  thelium appear stratified or layered, but they are not. A layered  effect occurs because the nuclei are at two or more levels in the    row of aligned cells. However, the cells, which vary in shape, all  reach the basement membrane, even though some of them may not  contact the free surface.   Pseudostratified columnar epithelial cells commonly have cilia,  which extend from their free surfaces. Goblet cells scattered through-  out this tissue secrete mucus, which the cilia sweep away (fig. 5.7).   Pseudostratified columnar epithelium lines the passages of the  respiratory system. Here, the mucous-covered linings are sticky and  trap dust and microorganisms that enter with the air. The cilia move  the mucus and its captured particles upward and out of the airways.    The different types of stratified epithelium are named for the shape  of the cells forming the outermost layer. Stratified squamous  epithelium consists of many layers of cells, making this tissue rel-  atively thick. Cells nearest the free surface are flattened the most,  whereas those in the deeper layers, where cell division occurs,  are cuboidal or columnar. As the newer cells grow, older ones are  pushed farther and farther outward, where they flatten (fig. 5.8).  The superficial portion of the skin (epidermis) is stratified    squamous epithelium. As the older cells are pushed outward, they  accumulate proteins called keratins, then harden and die. This  “keratinization” produces a covering of dry, tough, protective  material that prevents water and other substances from escaping  from underlying tissues and blocks chemicals and microorganisms  from entering.   Stratified squamous epithelium also lines the oral cavity,  esophagus, vagina, and anal canal. In these parts, the tissue is not  keratinized; it stays soft and moist, and the cells on its free sur-  faces remain alive.    Stratified cuboidal epithelium consists of two or three layers  of cuboidal cells that form the lining of a lumen (fig. 5.9). The  layering of the cells provides more protection than the single  layer affords.   Stratified cuboidal epithelium lines the ducts of the mam-  mary glands, sweat glands, salivary glands, and pancreas. It also  forms the lining of developing ovarian follicles and seminiferous  tubules, which are parts of the female and male reproductive sys-  tems, respectively.    which fringe the free surfaces of some columnar epithelial cells (33,000x).    FIGURE 5.7 (AP|R) Pseudostratified columnar epithelium appears stratified because the cell nuclei are located at different levels. (a) Idealized  representation of pseudostratified columnar epithelium. (b) Micrograph of a section through pseudostratified columnar epithelium (1,000x).    FIGURE 5.8 (AP|R) Stratified squamous epithelium consists of many layers of cells. (a) Idealized representation of stratified squamous epithelium.  (b) Micrograph of a section through stratified squamous epithelium (65x).    FIGURE 5.9 (AP|R Stratified cuboidal epithelium consists of two or three layers of cube-shaped cells  surrounding a lumen. (a) Idealized representation of stratified cuboidal epithelium. (b) Micrograph of a section  through stratified cuboidal epithelium (600x).    Stratified columnar epithelium consists of several layers of cells  (fig. 5.10). The superficial cells are elongated, whereas the basal  layers consist of cuboidal cells. Stratified columnar epithelium is  found in part of the male urethra and lining the larger ducts of exo-  crine glands.    Transitional epithelium (uroepithelium) is specialized to change  in response to increased tension. It forms the inner lining of the  urinary bladder and lines the ureters and the superior urethra.  When the wall of one of these organs contracts, the tissue consists  of several layers of irregular-shaped cells. When the organ is dis-  tended, however, the tissue stretches, and the cells elongate. While  distended, the tissue appears to contain only a few layers of cells  (fig. 5.11). In addition to providing an expandable lining, transi-  tional epithelium forms a barrier that helps prevent the contents of  the urinary tract from diffusing back into the internal environment.    Up to 90% of human cancers are carcinomas, growths that  originate in epithelium. Most carcinomas begin on surfaces  that contact the external environment, such as skin, linings of    the airways in the respiratory tract, or linings of the stomach  or intestines in the digestive tract. Carcinomas may also arise  internally, such as in a duct in a breast or in the prostate gland.    Glandular epithelium is composed of cells specialized to pro-  duce and secrete substances into ducts or into body fluids. Such  cells are usually found within columnar or cuboidal epithelium,  and one or more of these cells constitute a gland. Glands that  secrete their products into ducts that open onto surfaces, such as  the skin or the lining of the digestive tract, are called exocrine  glands. Glands that secrete their products into tissue fluid or  blood are called endocrine glands. (Chapter 13 discusses endo-  crine glands.)   An exocrine gland may consist of a single epithelial cell (uni-  cellular gland), such as a mucous-secreting goblet cell, or it may  be composed of many cells (multicellular gland). In turn, the mul-  ticellular glands can be structurally subdivided into two groups—  simple and compound.   A simple gland communicates with the surface by means of  a duct that does not branch before reaching the glandular cells or  secretory portions. A compound gland has a duct that branches  repeatedly before reaching the secretory portion. These two types  of glands can be further classified according to the shapes of their  secretory portion. Glands that consist of epithelial-lined tubes are  called tubular glands; those whose terminal portions form saclike  dilations are called alveolar glands (acinar glands). The secretory  portions may also branch or coil. Figure 5.12 illustrates several  types of exocrine glands classified by structure. Table 5.3 summa-  rizes the types of exocrine glands, lists their characteristics, and  provides an example of each type.   Exocrine glands are also classified according to the ways  these glands secrete their products. Glands that release fluid prod-  ucts by exocytosis are called merocrine (mer’o-krin) glands.  Glands that lose small portions of their glandular cell bodies  during secretion are called apocrine (ap’o-krin) glands. Glands  that release entire cells are called holocrine (ho’lo-krin) glands.    FIGURE 5.10 fAP|R) Stratified columnar epithelium consists of a superficial layer of columnar cells overlying several layers of cuboidal cells.  (a) Idealized representation of stratified columnar epithelium. (b) Micrograph of a section through stratified columnar epithelium (230x).    FIGURE 5.11 §AP|RJ Transitional epithelium. (a and c) Idealized representations of transitional epithelium. (b and d) Micrographs of sections through  transitional epithelium (675x).When the smooth muscle in the organ wall contracts, transitional epithelium is unstretched and consists of many layers.  When the organ is distended, the tissue stretches and appears thinner.    After release, the cells containing accumulated secretory prod-  ucts disintegrate, liberating their secretions (figs. 5.13 and 5.14).  Table 5.4 summarizes these glands and their secretions.    ~< To Chapter 3, Movements Into and Out of the Cell,  page 105.    Most exocrine secretory cells are merocrine, and they can be  subclassified based on their secretion of serous fluid or mucus.  Serous fluid is typically watery and slippery. Serous cells secret-  ing this fluid, which lubricates, are commonly associated with the  visceral and parietal membranes of the thoracic and abdomino-  pelvic cavities. The thicker fluid, mucus, is rich in the glycopro-  tein mucin. Cells in the inner linings of the digestive, respiratory,    Bulbourethral glands of male (see fig. 22.4)  Mammary glands (see fig. 23.28)    FIGURE 5.13 fAP|R) Glandular secretions. (a) Merocrine glands release secretions without losing cytoplasm. (b) Apocrine glands lose small portions  of their cell bodies during secretion. (c) Holocrine glands release entire cells filled with secretory products.    FIGURE 5.14 The sebaceous gland associated with a hair follicle is a  simple-branched alveolar gland that secretes entire cells (40x).    and reproductive systems secrete abundant mucus, which is pro-  tective. Mucous cells and goblet cells secrete mucus, but in different  parts of the body. Table 5.5 summarizes the characteristics of the  different types of epithelial tissues.    8 Distinguish between exocrine and endocrine glands.  9 Explain how exocrine glands are classified.    Cellular product and  portions of the free ends  of glandular cells pinch off  during secretion    Connective (k6-nek’tiv) tissues comprise much of the body and  are the most abundant type of tissue by weight. They bind struc-  tures, provide support and protection, serve as frameworks, fill  spaces, store fat, produce blood cells, protect against infections,  and help repair tissue damage.   Connective tissue cells are farther apart than epithelial cells,  and they have abundant extracellular matrix (eks” trah-sel’u-lar  ma’triks) between them. This extracellular matrix is composed of  protein fibers and a ground substance consisting of nonfibrous pro-  tein and other molecules, and fluid. The consistency of the extra-  cellular matrix varies from fluid to semisolid to solid. The ground  substance binds, supports, and provides a medium through which  substances may be transferred between the blood and cells of the    Protection, secretion, absorption  Protection, secretion, absorption  Protection, secretion, movement  of mucus and substances  Protection    Air sacs of lungs, walls of capillaries, linings of  blood and lymph vessels, part of the membranes  lining body cavities and covering viscera    Surface of ovaries, linings of kidney tubules,  and linings of ducts of certain glands    Superficial portion of skin and linings of oral  cavity, vagina, and anal canal    Linings of ducts of mammary glands, sweat  glands, salivary glands, and pancreas    Part of the male urethra and lining of larger  ducts of excretory glands    Inner lining of urinary bladder and linings of  ureters and part of urethra    tissue. Some connective tissues, such as bone and cartilage, are  rigid. Loose connective tissue and dense connective tissue are  more flexible. Clinical Application 5.1 discusses the extracellular  matrix and its relationship to disease.   Most connective tissue cells can divide. Connective tissues  typically have good blood supplies and are well nourished, but  the density of blood vessels (vascularity) varies.    Connective tissues include a variety of cell types. Some of them  are called fixed cells because they reside in the specific connective  tissue type for an extended period. These include fibroblasts and  mast cells. Other cells, such as macrophages, are wandering cells.  They move through and appear in tissues temporarily, usually in  response to an injury or infection.   Fibroblasts (fi’bro-blastz) are the most common type of fixed  cell in connective tissues. These large, star-shaped cells produce  fibers by secreting proteins into the extracellular matrix of connec-  tive tissues (fig. 5.15).   Macrophages (mak’ro-fajez), or histiocytes, originate as  white blood cells (see chapter 14, p. 537) and are almost as  numerous as fibroblasts in some connective tissues. They are usu-  ally attached to fibers but can detach and actively move about.  Macrophages are specialized to carry on phagocytosis. As scav-  enger cells, they can clear foreign particles from tissues, providing  an important defense against infection (fig. 5.16). Macrophages  play additional roles in immunity (see chapter 16, p. 629).   Mast cells are large and widely distributed in connective tis-  sues, where they are usually near blood vessels (fig. 5.17). They  release heparin, a compound that prevents blood clotting. Mast    FIGURE 5.15 Scanning electron micrograph of fibroblasts, the most  abundant cell type of connective tissue (1,500x).    cells also release histamine, which is a substance that promotes  some of the reactions associated with inflammation and allergies,  such as asthma and hay fever (see chapter 16, p. 636).    Release of histamine stimulates inflammation by dilating the  small arterioles that feed capillaries, the tiniest blood vessels.  The increased blood flow, with the resulting swelling and red-  ness, is inhospitable to infectious bacteria and viruses and also  dilutes toxins. Inappropriate histamine release as part of an  allergic response can be most uncomfortable. Allergy medica-  tions called antihistamines counter this misplaced inflammation.    FIGURE 5.16 Macrophages are scavenger cells common in  connective tissues. This scanning electron micrograph shows a  macrophage engulfing a bacterium (7,500x).    FIGURE 5.17 Scanning electron micrograph of a mast cell, which  releases heparin and histamine (1,750x).    The extracellular matrix (ECM) is more than  a “filler” between cells. It is a complex and  changing mix of molecules that modifies  the tissue to suit different organs and con-  ditions. The ECM serves as a scaffolding to  organize cells into tissues, and also relays  the biochemical signals that control cell  division, cell differentiation, tissue repair,  and cell migration.   The ECM has two basic components:  the basement membrane that anchors epi-  thelium to underlying connective tissues,  and the rest of the material between cells,  called the interstitial matrix. The basement  membrane is mostly composed of tightly  packed collagen fibers from which large,  cross-shaped glycoproteins called laminins  extend. The laminins (and other glycopro-  teins such as fibronectin, the proteogly-  cans, and tenascin) traverse the interstitial  matrix and contact receptors, called integ-  rins, on other cells (fig. 5A). In this way, the  ECM connects cells into tissues. At least  twenty types of collagen and precursors of  hormones, enzymes, growth factors, and  immune system biochemicals (cytokines)  comprise the various versions of the ECM.  The precursor molecules are activated  under certain conditions.   The components of the ECM are always changing, as its cells  synthesize proteins while enzymes called proteases break down  specific proteins. The balance of components is important to  maintaining and repairing organ structure. Disrupt the balance,  and disease can result. Here are three common examples:    The spread of a cancerous growth takes advantage of the nor-  mal ability of fibroblasts to contract as they close a wound,  where they are replaced with normal epithelium. Chemical sig-  nals from cancer cells make fibroblasts (an abundant type of con-  nective tissue cell) a more contractile cell type (myofibroblasts),  and they take on the characteristics of cancer cells. At the same  time, alterations in laminins loosen the connections of the fibro-  blasts to surrounding cells. This abnormal flexibility enables the  changed fibroblasts to migrate, helping the cancer spread.    In fibrosis, which is a part of all chronic liver diseases, collagen  deposition increases so that the ECM exceeds its normal 3% of  the organ. Healthy liver ECM sculpts a framework that supports  the epithelial and vascular tissues of the organ. In liver fibrosis,  hepatic stellate cells secrete collagen fibers in the areas where  the epithelium and blood vessels meet, in response to a dam-    FIGURE 5A The extracellular matrix (ECM) is a complex and dynamic meshwork of various  proteins and glycoproteins. Collagen is abundant. Other common components include integrins  that anchor the ECM to cells, proteoglycans, and fibronectin. The ECM may also include precursors  of growth factors, hormones, enzymes, and cytokines. It is vital to maintaining the specialized  characteristics of tissues and organs.    aging agent such as a virus, alcohol, or a toxic drug. Such lim-  ited fibrosis seals off the affected area, preventing spread of  the damage. But if the process continues—if an infection is not  treated or the noxious stimulus not removed—the ECM grows  and eventually blocks the interaction between liver cells and the  bloodstream. Scarring of liver tissue occurs, with loss of normal  function, resulting in a dangerous condition called cirrhosis.    The heart’s ECM organizes cells into a three-dimensional net-  work that coordinates their contractions into the rhythmic  heartbeat necessary to pump blood. This ECM consists of col-  lagen, fibronectin, laminin, and elastin surrounding cardiac  muscle cells and myofibroblasts and is also in the walls of arter-  ies. Some forms of heart failure reflect imbalances of collagen  production and degradation. In heart muscle, as in the liver, the  natural response of ECM buildup is to wall off an area where  circulation is blocked, but if it continues, the extra scaffolding  stiffens the heart, which can lead to heart failure. During a myo-  cardial infarction (heart attack), collagen synthesis and deposi-  tion increase in affected and nonaffected heart parts, which is  why damage can continue even after pain stops. In atheroscle-  rosis, excess ECM accumulates on the interior linings of arter-  ies, blocking blood flow.    Fibroblasts produce three types of connective tissue fibers: colla-  gen fibers, elastic fibers, and reticular fibers. Collagen and elastic  fibers are the most abundant.   Collagen (kolah-jen) fibers are thick threads of the protein  collagen, the major structural protein of the body. Collagen fibers  are grouped in long, parallel bundles, and they are flexible but only  slightly elastic (fig. 5.18). More importantly, they have great ten-  sile strength—that is, they can resist considerable pulling force.  Thus, collagen fibers are important components of body parts that  hold structures together, such as ligaments (which connect bones  to bones) and tendons (which connect muscles to bones).   Tissue containing abundant collagen fibers is called dense  connective tissue. It appears white, and for this reason collagen  fibers of dense connective tissue are sometimes called white fibers.  Loose connective tissue, on the other hand, has sparse collagen  fibers. Clinical Application 5.2 describes disorders that result from  abnormal collagen.    FIGURE 5.18 Scanning electron micrograph of collagenous fibers  (shades of white to gray) and elastic fibers (yellow) (4,100x).    When skin is exposed to prolonged and intense sunlight, connec-  tive tissue fibers lose elasticity, and the skin stiffens and becomes  leathery. In time, the skin may sag and wrinkle. Collagen injec-    tions may temporarily smooth out wrinkles. However, collagen  applied as a cream to the skin does not combat wrinkles because  collagen molecules are far too large to penetrate the skin.    Elastic fibers are composed of a springlike protein called  elastin. These fibers branch, forming complex networks in various  tissues. Elastic fibers are weaker than collagen fibers, but they are  easily stretched or deformed and will resume their original lengths  and shapes when the force acting upon them is removed. Elastic  fibers are abundant in body parts normally subjected to stretching,  such as the vocal cords and air passages of the respiratory system.  They are also called yellow fibers, because tissues amply supplied  with them appear yellowish (fig. 5.18).   Reticular fibers are thin collagen fibers. They are highly  branched and form delicate supporting networks in a variety of  tissues, including those of the spleen. Table 5.6 summarizes the  components of connective tissue.    >  R r] -PRACTICE  11. What are the general characteristics of connective tissue?  12 What are the major types of cells in connective tissue?  13 What is the primary function of fibroblasts?    Connective tissue is divided into two major categories. Connective  tissue proper includes loose connective tissue (areolar, adipose, retic-  ular) and dense connective tissue (dense regular, dense irregular, elas-  tic). The specialized connective tissues include cartilage, bone, and  blood. The following sections describe each type of connective tissue.    Widely distributed, large, star-shaped cells  Motile cells sometimes attached to fibers    Release substances that may help prevent blood  clotting (heparin) and promote inflammation (histamine)    Much of the human body consists of the protein collagen. It  accounts for more than 60% of the protein in bone and cartilage  and provides 50% to 90% of the dry weight of skin, ligaments, ten-  dons, and the dentin of teeth. Collagen is in the eyes, blood vessel  linings, basement membranes, and connective tissue. Because of  collagen’s abundance and wide distribution in the body, defects in  this protein cause a variety of medical problems.   Collagen is especially vulnerable to disruption because it  has an extremely precise structure. A slight alteration that might  exert little noticeable effect on other proteins can destroy colla-  gen’s molecular structure. Collagen is produced from a precursor  molecule called procollagen. Three polypeptide chains coil and  entwine into a triple helix to form procollagen.   Once secreted from the cell, the helices are trimmed. The  resulting pieces continue to associate outside the cell, building the  networks of collagen fibers that hold the body together. Collagen is  rapidly synthesized and assembled into its rigid architecture. Many    Areolar (ah-re’o-lar) connective tissue forms delicate, thin  membranes throughout the body. The cells of this tissue, mainly  fibroblasts, are located some distance apart and are separated by a  gel-like ground substance that contains collagen and elastic fibers  that fibroblasts secrete (fig. 5.19).   Areolar connective tissue is found in the subcutaneous layer  beneath the skin and surrounding organs. It underlies most lay-  ers of epithelium, where its many blood vessels nourish nearby  epithelial cells.   Adipose (ad’i-pés) tissue develops when certain cells (adipocytes)  store fat in droplets in their cytoplasm. At first, these cells resemble  fibroblasts, but as they accumulate fat, they enlarge, and their nuclei  are pushed to one side (fig. 5.20). When adipocytes become so abun-    types of mutations can disrupt the protein’s structure, including  missing procollagen chains, kinks in the triple helix, failure to cut  procollagen, and defects in aggregation outside the cell.   Table 5A details some collagen disorders. Knowing which spe-  cific mutations cause disorders offers a way to identify the condi-  tion before symptoms arise. This can be helpful if early treatment  can follow. A person who has a high risk of developing heredi-  tary osteoporosis, for example, might take calcium supplements  before symptoms appear. Aortic aneurysm is a more serious con-  nective tissue disorder that can be presymptomatically detected if  an underlying mutation is discovered. In aortic aneurysm, a weak-  ened aorta (the largest blood vessel in the body, which emerges  from the heart) swells and may burst. Knowing that the mutant  gene has not been inherited can ease worries. Knowing that it  has been inherited can warn affected individuals to have frequent  ultrasound exams to detect aortic weakening early enough for  corrective surgery.    dant that they crowd out other cell types, they form adipose tissue.  This tissue lies beneath the skin, in spaces between muscles, around  the kidneys, behind the eyeballs, in certain abdominal membranes,  on the surface of the heart, and around certain joints. Adipose tissue  cushions joints and some organs, such as the kidneys. It also insu-  lates beneath the skin, and it stores energy in fat molecules.    Adipose tissue can be described as white adipose tissue (white  fat) or brown adipose tissue (brown fat). White fat stores nutri-  ents for nearby cells to use in the production of energy. Brown  fat cells have many mitochondria that can break down nutri-  ents to generate heat to warm the body. Infants have brown  fat mostly on their backs to warm them. Adults have brown fat  in the armpits, neck, and around the kidneys.    FIGURE 5.19 (AP|R) Areolar tissue contains numerous fibroblasts that produce collagen and elastic  fibers. (a) Idealized representation of areolar tissue. (b) Micrograph of a section through areolar tissue (800x).   Reticular connective tissue is composed of thin, reticular fibers  in a three-dimensional network. It helps provide the framework of  certain internal organs, such as the liver and spleen (fig. 5.21).   Dense regular connective tissue consists of many closely packed,  thick, collagen fibers; a fine network of elastic fibers; and a few  cells, mostly fibroblasts. Collagen fibers of dense regular connec-  tive tissue are very strong, enabling the tissue to withstand pulling    FIGURE 5.20 (AP|R) Adipose tissue cells contain large fat droplets that push the nuclei close to the cell  membranes. (a) Idealized representation of adipose tissue. (b) Micrograph of a section through adipose tissue (400x).    forces (fig. 5.22). It often binds body structures as part of tendons  and ligaments. The blood supply to dense regular connective tissue  is poor, slowing tissue repair. This is why a sprain, which damages  tissues surrounding a joint, may take considerable time to heal.    Fibers of dense irregular connective tissue are thicker, interwoven,  and more randomly distributed than fibers of dense regular connec-  tive tissue. The irregularly placed fibers allow the tissue to sustain  tension exerted from many different directions. Dense irregular  connective tissue is in the dermis, which is the deep skin layer.    FIGURE 5.21 fAP|R) Reticular connective tissue is a network of thin reticular fibers, which contains numerous fibroblasts and white blood cells.  (a) Idealized representation of reticular connective tissue. (b) Micrograph of a section through reticular connective tissue (1,000x).    Fibroblasts  Collagen  fibers  [-  FIGURE 5.22 (AP|RJ Dense regular connective tissue consists largely of tightly packed collagen fibers.  (a) Idealized representation of dense regular connective tissue. (b) Micrograph of a section through dense regular  connective tissue (500x).    Dense irregular connective tissue surrounds individual  skeletal muscles (fascia), and separates each muscle into bundles of  skeletal muscle cells called fascicles. Each muscle cell is surrounded  by areolar connective tissue.    Elastic connective tissue mainly consists of yellow, elastic fibers  in parallel strands or in branching networks. Between these fibers  are collagen fibers and fibroblasts. This tissue is found in the attach-  ments between bones of the spinal column (ligamenta flava). It is  also in the layers within the walls of certain hollow internal organs,  including the larger arteries; some portions of the heart; and the  larger airways, where it imparts an elastic quality (fig. 5.23).    Cartilage (kar’ti-lij) is a rigid connective tissue. It provides sup-  port, frameworks, and attachments; protects underlying tissues;  and forms structural models for many developing bones.  Cartilage extracellular matrix is abundant and is largely  composed of collagen fibers embedded in a gel-like ground sub-  stance. This ground substance is rich in a protein-polysaccharide    FIGURE 5.23 (AP|R) Elastic connective tissue contains many elastic fibers with collagen fibers between them. (a) Idealized representation of elastic  connective tissue. (b) Micrograph of a section through elastic connective tissue (160x).    FIGURE 5.24 (AP|R) Cartilage cells (chondrocytes) are located in lacunae, which are in turn surrounded  by extracellular matrix containing very fine collagen fibers. (a) Idealized representation of hyaline cartilage, the  most common type of cartilage. (b) Micrograph of a section through hyaline cartilage (160x).    complex (chondromucoprotein) and contains a large volume of  water. Cartilage cells, called chondrocytes (kon’dro-sitz), occupy  small chambers called /acunae and lie completely within the  extracellular matrix.   A cartilaginous structure is enclosed in a covering of connective  tissue called perichondrium. Although cartilage tissue lacks a direct  blood supply, blood vessels are in the surrounding perichondrium.  Cartilage cells near the perichondrium obtain nutrients from these  vessels by diffusion, aided by the water in the extracellular matrix.  This lack of a direct blood supply is why torn cartilage heals slowly  and why chondrocytes do not divide frequently. The three types of  cartilage are distinguished by their types of extracellular matrix.   Hyaline cartilage (fig. 5.24), the most common type, has very  fine collagen fibers in its extracellular matrix and looks somewhat  like white glass. It is found on the ends of bones in many joints, in  the soft part of the nose, and in the supporting rings of the respira-  tory passages. Parts of an embryo’s skeleton begin as hyaline carti-  lage “models” that bone gradually replaces. Hyaline cartilage is    also important in the development and growth of most bones (see  chapter 7, p. 204).   Elastic cartilage (fig. 5.25) is more flexible than hyaline car-  tilage because its extracellular matrix has a dense network of elas-  tic fibers. It provides the framework for the external ears and parts  of the larynx.   Fibrocartilage (fig. 5.26), a very tough tissue, has many col-  lagen fibers. It is a shock absorber for structures subjected to pres-  sure. For example, fibrocartilage forms pads (intervertebral discs)  between the individual bones (vertebrae) of the spinal column. It  also cushions bones in the knees and in the pelvic girdle.    Bone (osseous tissue) is the most rigid connective tissue. Its hard-  ness is largely due to mineral salts, such as calcium phosphate and  calcium carbonate, between cells. This extracellular matrix also  contains abundant collagen fibers, which are flexible and reinforce  the mineral components of bone.    FIGURE 5.25 fAP|R} Elastic cartilage contains many elastic fibers in its extracellular matrix. (a) Idealized  representation of elastic cartilage. (b) Micrograph of a section through elastic cartilage (1,200x).    FIGURE 5.26 (AP|R) Fibrocartilage contains many collagen fibers in its extracellular matrix.  (a) Idealized representation of fibrocartilage. (b) Micrograph of a section through fibrocartilage (100x).    Bone internally supports body structures. It protects vital  structures in the cranial and thoracic cavities and is an attachment  for muscles. Bone also contains red marrow, which forms blood  cells. It stores and releases inorganic chemicals such as calcium  and phosphorus.   In compact bone, cells called osteoblasts deposit bony matrix  in thin layers called /amellae, which form concentric patterns  around longitudinal tubes called central, or Haversian, canals  which contain capillaries. Once osteoblasts are in lacunae sur-  rounded by matrix, they are called osteocytes and are rather evenly  spaced within the lamellae (fig. 5.27).   The osteocytes and layers of extracellular matrix, concen-  trically clustered around a central canal, form a cylinder-shaped  unit called an osteon, also known as a Haversian system. Many  of these units cemented together make up the more solid appear-  ing compact bone that forms the outer portion of a bone (see  chapter 7, p. 201).   Each central canal contains blood vessels, so every bone cell  is fairly close to a nutrient supply. In addition, the bone cells have    many cytoplasmic processes that extend outward and pass through  tiny tubes in the extracellular matrix called canaliculi. Gap junc-  tions attach these cellular processes to the processes of nearby  cells. As a result, materials can move rapidly between blood ves-  sels and bone cells. Thus, despite its inert appearance, bone is an  active tissue. Injured bone heals much more rapidly than does  injured cartilage.   The interior portion of a bone is composed of spongy bone  in which bone matrix is deposited around osteocytes, forming  bony plates with spaces between them. These spaces lighten the  weight of the bone and provide spaces for bone marrow. (The  microscopic structure of bone is described in more detail in  chapter 7, pp. 201-202.)    Blood, another type of connective tissue, is composed of cells sus-  pended in a fluid extracellular matrix called plasma. These cells  include red blood cells, white blood cells, and cellular fragments    FIGURE 5.27 fAP|R) Bone tissue. (a) Idealized representation of bone tissue. Bone matrix is deposited in concentric layers around central canals.  (b) Micrograph of a section through bone tissue (200x). (c) Falsely colored scanning electron micrograph of an osteocyte within a lacuna (6,000x).    called platelets (fig. 5.28). Red blood cells transport gases; white  blood cells fight infection; and platelets are involved in blood  clotting. Most blood cells form in special tissues (hematopoietic  tissues) in red marrow within the hollow parts of certain bones.  Chapter 14 describes blood.   Red blood cells are the only type of blood cells that function  entirely in the blood vessels. In contrast, white blood cells typi-  cally migrate from the blood through capillary walls to connective  tissues, where they carry on their major activities until they die.  Table 5.7 lists the characteristics of the connective tissues.    19 Explain why injured bone heals more rapidly than does injured  cartilage.    After discussing epithelial and connective tissues, sheets of cells  called membranes are better understood because they can include  both of these tissue types. Many epithelial membranes are thin  structures that are composed of epithelium and underlying con-  nective tissue. They cover body surfaces and line body cavities.  The three major types of epithelial membranes are serous, mucous,  and cutaneous.   Serous (se’rus) membranes line the body cavities that do not  open to the outside and reduce friction between the organs and  cavity walls. They form the inner linings of the thorax and abdo-  men, and they cover the organs in these cavities (see figs. 1.12  and 1.13, p. 21). A serous membrane consists of a layer of sim-  ple squamous epithelium (mesothelium) and a thin layer of areo-  lar connective tissue. Cells of a serous membrane secrete watery  serous fluid, which helps lubricate membrane surfaces.    FIGURE 5.28 fAP|R) Blood tissue consists of red blood cells, white blood cells, and platelets suspended in plasma. (a) Idealized representation    @ What is the consistency of the extracellular matrix of blood?    Mucous (mu’kus) membranes line the cavities and tubes  that open to the outside of the body. These include the oral and  nasal cavities and the tubes of the digestive, respiratory, urinary,  and reproductive systems. A mucous membrane consists of epi-  thelium overlying a layer of areolar connective tissue. The type of  epithelium varies with the location of the membrane. For example,  stratified squamous epithelium lines the oral cavity, pseudostrati-  fied columnar epithelium lines part of the nasal cavity, and simple  columnar epithelium lines the small intestine. Goblet cells within  a mucous membrane secrete mucus.   Supports, protects, provides framework  Supports, protects, provides flexible  Supports, protects, absorbs shock    Beneath the skin, around the kidneys, behind the  eyeballs, on the surface of the heart    Connecting parts of the spinal column, in walls of  arteries and airways    Ends of bones, nose, and rings in walls of  respiratory passages    Between bony parts of spinal column, parts of  pelvic girdle, and knee    Throughout the body in a closed system of blood  vessels and heart chambers    Another epithelial membrane is the cutaneous (ku-ta’ne-us)  membrane, more commonly called skin. It is part of the integumen-  tary system described in detail in chapter 6.   A type of membrane composed entirely of connective tissues is  a synovial (si-no’ve-al) membrane. It lines joints and is discussed  further in chapter 8 (p. 271).    21 Name the four types of membranes, and explain how they differ.    Muscle tissues are contractile; they can shorten and thicken.  As they contract, muscle cells pull at their attached ends, which  moves body parts. The cells that comprise muscle tissues are also  called muscle fibers because they are elongated.   Approximately 40% by weight of the body is skeletal muscle,  and almost another 10% is smooth and cardiac muscle combined.  The three types of muscle tissue, skeletal, smooth, and cardiac, are  introduced here and discussed further in chapter 9.    Skeletal muscle tissue (fig. 5.29) forms muscles that typically attach  to bones and can be controlled by conscious effort. For this rea-  son, it is also called voluntary muscle tissue. Skeletal muscle cells  are long—up to or more than 40 mm in length—and narrow—less  than 0.1 mm in width. These threadlike cells have alternating light  and dark cross-markings called striations. Each cell has many nuclei  (multinucleate). For a skeletal muscle cell to contract, it must be  stimulated by a nerve cell. Then the muscle cell relaxes when stimu-  lation stops. Skeletal muscles move the head, trunk, and limbs and  enable us to make facial expressions, write, talk, and sing, as well as  chew, swallow, and breathe.    Smooth muscle tissue (fig. 5.30) is called smooth because its cells  do not have striations. Smooth muscle cells are shorter than those of  skeletal muscle and are spindle-shaped, each with a single, centrally  located nucleus. This tissue comprises the walls of hollow internal  organs, such as the stomach, intestines, urinary bladder, uterus, and  blood vessels. Unlike skeletal muscle, smooth muscle usually can-  not be stimulated to contract by conscious effort. Thus, its actions    FIGURE 5.29 (AP|R) Skeletal muscle tissue is composed of striated muscle fibers with many nuclei.  (a) Idealized representation of skeletal muscle. (b) Micrograph of a section through skeletal muscle (400x).    are involuntary. For example, smooth muscle tissue moves food  through the digestive tract, constricts blood vessels, and empties the  urinary bladder.    Cardiac muscle tissue is only in the heart (fig. 5.31). Its cells, stri-  ated and branched, are joined end-to-end, and interconnected in  complex networks. Each cardiac muscle cell has a single nucleus.  Where one cell touches another cell is a specialized intercellular  junction called an intercalated disc, seen only in cardiac tissue and  discussed further in chapter 9 (pp. 308-309).   Cardiac muscle, like smooth muscle, is controlled involun-  tarily. Cardiac muscle can continue to function without nervous  stimulation. This tissue makes up the bulk of the heart and pumps  blood through the heart chambers and into blood vessels.    Nervous (ner’vus) tissues are found in the brain, spinal cord, and  peripheral nerves. The basic cells are called neurons, and they are  highly specialized. Neurons sense certain types of changes in their  surroundings. Incoming signals stimulate cellular processes called  dendrites, which may cause neurons to respond by conducting  electrical impulses along cellular processes called axons to other  neurons or to muscles or glands (fig. 5.32). As a result of the pat-  terns by which neurons communicate with each other and with  muscle and gland cells, they can coordinate, regulate, and inte-  grate many body functions.    FIGURE 5.30 (AP|RJ Smooth muscle tissue consists of spindle-shaped cells, each with a large nucleus.  (a) Idealized representation of smooth muscle. (b) Micrograph of a section through smooth muscle (400x).    (Note that the plane of section does not always reveal the nucleus.)    with a single nucleus each. (a) Idealized representation of cardiac muscle.  (b) Micrograph of a section through cardiac muscle (400x).    In addition to neurons, nervous tissue includes abundant neu-  roglia, shown in figure 5.32. Neuroglia divide and are crucial to  the functioning of neurons. These cells support and bind the com-  ponents of nervous tissue, carry on phagocytosis, and help sup-  ply growth factors and nutrients to neurons by connecting them to  blood vessels. They also play a role in cell-to-cell communications.  Chapter 10 discusses nervous tissue.   Table 5.8 summarizes the general characteristics of muscle  and nervous tissues. From Science to Technology 5.2 discusses  tissue engineering, part of a field called regenerative medicine.    The cells of different tissues vary greatly in their abilities to  divide. Cells that divide continuously include the epithelial cells  of the skin and the inner lining of the digestive tract, and the  connective tissue progenitor cells that form blood cells in red  bone marrow. However, skeletal and cardiac muscle cells and  nerve cells do not usually divide at all after differentiating.    Fibroblasts respond rapidly to injuries by increasing in num-  ber and fiber production. They help to repair tissues that have  limited abilities to regenerate. For instance, fibroblasts form  scar tissue where a heart attack occurs. Many organs include  pockets of stem or progenitor cells that can divide and replace  damaged, differentiated cells, under certain conditions.    If an appliance part is damaged or fails, replacing it is simple. Not  so for the human body. Donor organs and tissues for transplant  are in short supply, so in the future spare parts may come from  tissue engineering. In this technology, a patient's cells, extracellu-  lar matrix, and other biochemicals are grown with a synthetic scaf-  fold to form an implant. The cells come from the patient, so the  immune system does not reject them. Tissue engineering has pro-  vided skin, cartilage, bone, and blood vessels. Combining engi-  neered tissues into structures that can replace organs is where the  creativity comes in. Consider the replacement bladder.   Each year in the United States, about 10,000 people need  their urinary bladders repaired or replaced. Typically a urologic  surgeon replaces part of the bladder with part of the large intes-  tine. However, the function of the intestine is to absorb, and the  function of the bladder is to hold waste. Tissue engineering is pro-  viding a better replacement bladder. The natural organ is balloon-    FROM SCIENCE TO TECHNOLOGY 5.2  Tissue Engineering: Building a Replacement Bladder    like, with layers of smooth muscle, connective tissue, and a lining  called urothelium.   Researchers pioneered replacement bladders in children who  have birth defects in which the malfunctioning bladder can harm  the kidneys. Each patient donated a postage-stamp-size sample  of bladder tissue that consisted of about a million cells, from which  the researchers separated two types of progenitor cells—for  smooth muscle and urothelium—and let them divide in culture ina  specific “cocktail” of growth factors. Within seven weeks the mil-  lion cells had divided to yield 1.5 billion cells, which were seeded  onto domes made of a synthetic material. The confluent layers  of cells that formed were attached to the lower portions of the  patients’ bladders, after removing the upper portions. The scaf-  folds degenerated over time, leaving new bladders built from the  patients’ own cells. Today tissue-engineered bladders are also  used in adults whose bladders have been removed to treat cancer.    FIGURE 5.32 (AP|RJ A neuron has cellular processes that extend into its surroundings. (a) Idealized representation of a neuron  and neuroglia. (b) Micrograph of a section through nervous tissue (350x). Note that only the nuclei of the neuroglia are stained.    Long, threadlike cells, striated, many Voluntary movements of skeletal parts Muscles usually attached to bones    Smooth muscle tissue Shorter cells, single, central nucleus Involuntary movements of internal organs Walls of hollow internal organs    Nervous tissue Sensory reception and conduction of Brain, spinal cord, and peripheral    Cells are organized in layers or groups to form tissues.  Specialized intercellular junctions (tight junctions,  desmosomes, and gap junctions) connect cells.   The four major types of human tissue are epithelial,  connective, muscle, and nervous.   a. Epithelial tissue covers all free body surfaces, forms the  inner lining of body cavities, lines hollow organs, and is  the major tissue of glands.   b. A basement membrane anchors epithelium to  connective tissue. Epithelial tissue lacks blood vessels,  has cells that are tightly packed, and is continuously  replaced.   d. Epithelial tissues are classified according to cell shape  and the number of cell layers.   a. This tissue consists of a single layer of thin, flattened cells  through which substances pass easily.   b. It functions in the gas exchange in the lungs and  lines blood vessels, lymph vessels, and is part of the  membranes lining body cavities and covering viscera.   a. This tissue consists of a single layer of cube-shaped cells.   b. It carries on secretion and absorption in the kidneys and  various glands.   a. This tissue is composed of elongated cells whose nuclei  are near the basement membrane.   b. It lines the uterus and digestive tract, where it functions  in protection, secretion, and absorption.   a. This tissue appears stratified because the nuclei are at  two or more levels.   b. Its cells may have cilia that move mucus over the  surface of the tissue.   a. This tissue is composed of many layers of cells; the top  layers are flattened.   c. Itis the superficial portion of the skin and lines the oral  cavity, esophagus, vagina, and anal canal.   a. This tissue is composed of two or three layers of cube-  shaped cells.   b. It lines the ducts of the mammary glands, sweat glands,  salivary glands, and pancreas.   a. The cells in the top layer of this tissue are column-  shaped. Cube-shaped cells make up the bottom layers.   b. Itis in part of the male urethra and lining of the larger  ducts of exocrine glands.   c. Ithelps prevent the contents of the urinary passageways  from diffusing out.    a. Glandular epithelium is composed of cells specialized  to secrete substances.  b. A gland consists of one or more cells.   c. Exocrine glands are classified according to the  organization of their cells.   (1) Simple glands have ducts that do not branch before  reaching the secretory portion.   (2) Compound glands have ducts that branch  repeatedly before the secretory portion.   (4) Alveolar glands consist of saclike dilations  connected to the surface by narrowed ducts.   d. Exocrine glands are classified according to the  composition of their secretions.   (1) Merocrine glands secrete watery fluids without  loss of cytoplasm. Most secretory cells are  merocrine.   (a) Serous cells secrete watery fluid.  (b) Mucous cells secrete mucus.    a. Connective tissue connects, supports, protects,  provides frameworks, fills spaces, stores fat, produces  blood cells, protects against infection, and helps repair  damaged tissues.   b. Connective tissue cells usually have considerable  extracellular matrix between them.   c. This extracellular matrix consists of fibers and a ground  substance.    a. Fibroblasts produce collagen and elastic fibers.  b. Macrophages are phagocytes.  c. Mast cells may release heparin and histamine.    a. Collagen fibers have great tensile strength.  b. Elastic fibers are composed of elastin and are stretchy.  c. Reticular fibers are fine collagen fibers.    a. Connective tissue proper includes loose connective  tissue (areolar, adipose, reticular) and dense connective  tissue (dense regular, dense irregular, elastic).    a. Areolar connective tissue forms thin membranes  between organs and binds them.   a. Adipose tissue is a specialized form of connective  tissue that stores fat, cushions, and insulates.   b. It is found beneath the skin; in certain abdominal  membranes; and around the kidneys, heart, and  various joints.   a. Reticular connective tissue largely consists of thin,  branched reticular fibers.   fibers and imparts an elastic quality to the walls of certain   b. Its extracellular matrix is composed of fibers and a gel-   It lacks a direct blood supply and is slow to heal.   d. Most cartilaginous structures are enclosed in a  perichondrium, which contains blood vessels.   f. Cartilage is at the ends of various bones; in the ear; in  the larynx; and in the pads between the bones of the  spinal column, pelvic girdle, and knees.   a. The extracellular matrix of bone contains mineral salts  and collagen.   b. The cells of compact bone are arranged in a bony  matrix of concentric circles around central canals,  whereas the cells of spongy bone are embedded in  bony plates with spaces between the plates. Canaliculi  connect the cells.   b. Blood cells are formed by special tissue in the hollow  parts of certain bones.    a. Serous membranes  (1) Serous membranes line body cavities that do not open  to the outside and cover the organs in these cavities.    (2) They are composed of epithelium and areolar  connective tissue.  (3) Cells of serous membranes secrete watery serous  fluid that lubricates membrane surfaces.  b. Mucous membranes  (1) Mucous membranes line cavities and tubes  opening to the outside of the body.  (2) They are composed of epithelium and areolar  connective tissue.  (3) Cells of mucous membranes secrete mucus.  c. The cutaneous membrane is the external body  covering commonly called skin.  Synovial membranes are composed of connective tissue  only, and line joints.   a. Muscles containing this tissue usually attach to bones  and can be controlled by conscious effort.   b. Muscle cells are long and threadlike, containing several  nuclei, with alternating light and dark cross-markings  (striations).   c. A muscle cell contracts when stimulated by a nerve  cell, then relaxes when no longer stimulated.   a. This tissue of spindle-shaped cells, each with one  nucleus, is in the walls of hollow internal organs.   b. Striated cells, each with a single nucleus, are joined by  intercalated discs and form branched networks.   a. Neurons sense changes and respond by conducting  electrical impulses to other neurons or to muscles or  glands.   Describe three types of intercellular junctions. (p. 149)  Which of the following is a major tissue type in the body?  (p. 149)   cells divide rapidly  . there is much extracellular matrix between cells  Distinguish between simple epithelium and stratified  epithelium. (p. 152)  Explain how the structure of simple squamous epithelium  provides its function. (p. 152)  Match the epithelial tissue on the left to an organ in which  the tissue is found. (pp. 152-156)    epithelium D. salivary glands  (5) stratified squamous E. air sacs of lungs  epithelium F. respiratory passages  (6) ae cuboidal G. part of male urethra  t  He rere H. lining of kidney  (7) stratified columnar tubules  epithelium    Distinguish between an exocrine gland and an endocrine  gland. (p. 156)    of their ducts and the organization of their cells. (p. 156)   A gland that secretes substances by exocytosis is a(n)  gland. (p.156)   Define extracellular matrix and ground substance. (p. 159)  Describe three major types of connective tissue cells. (fp. 160)  Thick fibers that have great tensile strength and are flexible,  but only slightly elastic, are fibers. (p. 162)  a. reticular   Describe areolar connective tissue, and indicate where it is  found in the body. (p. 163)   Explain how the amount of adipose tissue in the body  reflects diet. (p. 163)   Explain why injured dense regular connective tissue and  cartilage are usually slow to heal. (pp. 164-166)   Name the major types of cartilage, and describe their  differences and similarities. (pp. 166)   Contrast the structure of epithelial membranes to that of  synovial membranes. (pp. 168-169)   Identify locations in the body of the four types of  membranes. (pp. 168-169)   Compare and contrast skeletal, smooth, and cardiac muscle  tissues in terms of location, cell appearance, and control.  (p. 170)    Describe the general characteristics of nervous tissue. (p. 170)  Distinguish between the functions of neurons and neuroglia.  (pp. 170-171)    1. Tissue engineering combines living cells with synthetic materials  to create functional substitutes for human tissues. What  components would you use to engineer replacement for (a) skin,  (b) bone, (c) muscle, and (d) blood?    2. Inthe lungs of smokers, a process called metaplasia occurs  where normal lining cells of the lung are replaced by squamous  metaplastic cells (many layers of squamous epithelial cells).  Functionally, why is this an undesirable body reaction to  tobacco smoke?    3. Cancer-causing agents (carcinogens) usually act on dividing  cells. Which of the four tissues would carcinogens most  influence? Least influence?    4. Mucous cells may secrete excess mucus in response to irritants.  What symptoms might this produce in the (a) digestive tract or  (b) respiratory passageway?    5. Disorders of collagen are characterized by deterioration of  connective tissues. Why would such diseases produce widely  varying symptoms?    6. Collagen and elastin are added to many beauty products. What  type of tissues are they normally part of?    7. Joints such as the shoulder, elbow, and knee contain considerable  amounts of cartilage and dense regular connective tissue. How  does this composition explain that joint injuries are often slow  to heal?    8. Answer the following questions with respect to the micrograph  below (80x). (a) Identify the organ depicted. (b) What type of  tissue is depicted (green arrow, yellow arrow)? (c) To what cell  does the arrow point (red arrow, black arrow)?    Connect Integrated Activity Could you help a pathologist  identify the anatomical source of a biopsied tissue sample?    Anatomy & Physiology Revealed Go more in depth into the  human body by using a virtual microscope to view a variety of  tissues that are labeled.    Scanning electron micrograph (SEM) of hair (22x). The light, bristlelike  structures are hairs, and the pink at the base of the hairs is skin.    Two or more types of tissues structurally connected and per-  forming shared specialized functions constitute an organ. The  skin, the largest organ in the body by weight, and its various  accessory structures (hair, nails, sensory receptors, and glands)  make up the integumentary system. Skin is a strong yet flexible  covering of our bodies.    After you have studied this chapter, you should be able to:    1 Describe the structure of the layers of the skin.  (pp. 178-184)    3 Describe the accessory structures associated with the  skin. (pp. 184-187)    4 Explain the functions of each accessory structure of the  skin. (pp. 184-187)  6.3 Skin Functions  5 List various skin functions, and explain how the skin helps  regulate body temperature. (p. 189)  6.4 Healing of Wounds and Burns  6 Describe wound healing. (p. 190)  7 Distinguish among the types of burns, including a  description of healing with each type. (p. 192)  6.5 Life-Span Changes    The skin is composed of several types of tissues (fig. 6.1). Also  known as the cutaneous membrane, the skin includes two distinct  layers: epithelial tissue overlying connective tissue. The outer layer,  called the epidermis (ep’i-der’mis), is composed of stratified squa-  mous epithelium. The inner layer, or dermis (der’mis), is thicker  than the epidermis and is made up of connective tissue containing  collagen and elastic fibers, smooth muscle tissue, nervous tissue, and  blood. A basement membrane anchored to the dermis by short fibrils  separates the two skin layers.   Beneath the dermis, masses of areolar and adipose tissues  bind the skin to underlying organs. These tissues are not part of  the skin. They form the subcutaneous (sub’ku-ta’ne-us) layer, or  hypodermis (fig. 6.2). The collagen and elastic fibers of this layer  are continuous with those of the dermis. Most of these fibers run  parallel to the surface of the skin, extending in all directions. As    FIGURE 6.1 An organ, such as the skin, is composed of several types  of tissues (30x).    (Q) What other tissues, besides those labeled in this figure,  are found in the skin?    a result, no sharp boundary separates the dermis and the subcu-  taneous layer. The adipose tissue of the subcutaneous layer insu-  lates, helping to conserve body heat. The subcutaneous layer also  contains the major blood vessels that supply the skin. Branches of  these vessels form a network (rete cutaneum) between the dermis  and the subcutaneous layer. They, in turn, give off smaller vessels  that supply the dermis above and the underlying adipose tissue.    Intradermal injections are administered into the skin.  Subcutaneous injections are administered through a hol-  low needle into the subcutaneous layer beneath the skin.  Subcutaneous injections and intramuscular injections, adminis-  tered into muscles, are also called hypodermic injections.  Some substances are introduced through the skin by  means of an adhesive transdermal patch that includes a small    reservoir containing the drug. The drug passes from the reser-  voir through a permeable membrane at a known rate. It then  diffuses into the epidermis and enters the blood vessels of the  dermis. Transdermal patches deliver drugs that protect against  motion sickness, alleviate chest pain associated with heart  disease, and lower blood pressure. A transdermal patch that  delivers nicotine is used to help people stop smoking.    1 Name the tissues in the outer and inner layers of the skin.  2 Name the tissues in the subcutaneous layer beneath the skin.   The epidermis is composed entirely of stratified squamous epi-  thelium, and therefore it lacks blood vessels. Cells in the deepest  layer of the epidermis, called the stratum basale (stratum germi-  nativum), are near the dermis and are nourished by dermal blood  vessels. As the cells (basal cells) of this layer divide and grow,  the older epidermal cells (keratinocytes) are pushed away from  the dermis toward the skin surface. The farther the cells move, the  poorer their nutrient supply becomes, and in time, they die.    The cell membranes of older skin cells thicken and develop  many desmosomes that fasten them to each other (see chapter 5,  p. 149). At the same time, these older cells begin to harden, in  a process called keratinization (ker’ah-tin’i-za’shun). Strands  of tough, fibrous, waterproof keratin proteins are synthesized  and stored in the cell. As a result, many layers of tough, tightly  packed dead cells accumulate in the epidermis, forming an out-  ermost layer called the stratum corneum. These dead cells are  eventually shed. Rubbing the skin briskly with a towel sheds  dead cells.    Cells of the epidermis can die if they cannot receive nutrients  from blood vessels in the dermis. This may happen when a bed-  ridden person lies in one position for a prolonged period—the  weight of the body pressing against the bed blocks the skin’s  blood supply. If cells die (necrosis), the tissues break down, and  a pressure ulcer (also called a decubitus ulcer or bedsore) may  appear. If the person moves, shear forces and friction from rub-  bing may damage the tissue further.   Pressure ulcers usually form in the skin overlying bony  projections, such as on the hip, heel, elbow, or shoulder.  Frequently changing body position or massaging the skin to  stimulate blood flow in regions associated with bony promi-  nences can prevent pressure ulcers. For a paralyzed person  who cannot feel pressure or respond to it by shifting position,  caregivers must turn the body often to prevent pressure ulcers.  Motorized beds and other specialized equipment can periodi-  cally shift the patient, lowering the risk of developing pressure  ulcers. Keeping affected areas of skin clean, eating a healthy  diet, and not smoking can minimize the discomfort and dam-    The structural organization of the epidermis varies from  region to region. It is thickest on the palms of the hands and the  soles of the feet, where it may be 0.8—1.4 millimeters (mm) thick.  In most areas, only four layers are distinguishable. They are the  stratum basale (stratum germinativum, or basal cell layer), the  deepest layer; the stratum spinosum; the stratum granulosum;  and the stratum corneum, a fully keratinized outermost layer. An  additional layer, the stratum lucidum (between the stratum gran-  ulosum and the stratum corneum) is in the thickened skin of the  palms and soles. The cells of these layers change shape as they  are pushed toward the surface (fig. 6.3).   In body regions other than the palms and soles, the epidermis is  usually thin, averaging 0.07—0.12 mm. The stratum lucidum may be  missing where the epidermis is thin. Table 6.1 describes the charac-  teristics of each layer of the epidermis.   In healthy skin, production of epidermal cells in the stratum  basale closely balances loss of dead cells from the stratum cor-  neum. As a result, skin does not completely wear away. The rate  of cell division increases where the skin is rubbed or pressed reg-  ularly, causing the growth of thickened areas called calluses on  the palms and soles and keratinized conical masses on the toes  called corns.    In psoriasis, a chronic skin disease, cells in the epidermis divide  seven times more frequently than normal. Excess cells accu-  mulate, forming bright red patches covered with silvery scales,  which are keratinized cells. Medications used to treat cancer,  such as methotrexate, are used to treat severe cases of psoria-  sis. Immune suppressing medications, such as topical cortico-  steroids, and drugs that block the actions of an inflammatory  protein called tumor necrosis factor, are used for treatment of  chronic psoriasis. About 7.5 million people in the United States  (about 2% of the population) and 125 million people worldwide  (about 2-3%) have psoriasis. People with dark skin are less likely  to develop the condition.   she noticed a cat trapped inside, scratching frantically  against a basement window. The woman grabbed a rock,  smashed the window, and reached in for the cat, just as  flame whooshed from the side, scorching her arms. First  responders soon arrived, and within minutes they had  transported the woman to a nearby medical center that,  fortunately, had a burn unit.   At the emergency department, in a sterile environment,  a physician quickly determined that the burns were full  thickness, destroying both skin layers. A burn technician  assisted the physician in removing dead skin and other  tissue (debridement), and then gently cleaned the areas  and applied sterile cloths. Over the following few days,  the burn technician changed dressings, debrided and  drained the affected areas, and helped the patient with  hydrotherapy, which is a shower where the patient sits as  warm water flows over the burns to aid healing and lower  the risk of infection.   As an integral part of the burn treatment team, the  burn technician assists with procedures, including grafting  healthy skin from the patient to cover the burned areas and  escharotomy, which is making a cut to release the pressure  from accumulating fluid in surrounding areas where damaged  skin has lost its elasticity. Without the cut, blood supply can  be blocked.   The burn technician changes a patient's dressings several  times a day, monitors the graft site and the areas of donor  skin, and applies antimicrobial ointments to the affected and  surrounding areas. Careful record-keeping and being alert to  complications are important parts of the job.   Requirements include a high school diploma, basic  cardiac life support certification, and certification as a nursing  assistant or more advanced nursing training. Many burn  technicians are nursing students or nurses. The job requires  the ability to stand for long periods with frequent bending  and lifting. A good rapport with people is helpful, because  burn patients may be traumatized by their experience.    (b) A light micrograph depicting the layered structure of the skin (75x).    Stratum lucidum Between stratum corneum and  (only present in stratum granulosum on soles and  thick skin) palms    Many layers of keratinized, dead epithelial cells that are flattened and non-nucleated    Cells appear clear; nuclei, organelles, and cell membranes are no longer visible    Three to five layers of flattened granular cells that contain shrunken fibers of keratin  and shriveled nuclei    Many layers of cells with centrally located, large, oval nuclei and developing fibers of    The epidermis has important protective functions. It shields  the moist underlying tissues against excess water loss, mechanical  injury, and the effects of harmful chemicals. When intact, the epider-  mis also keeps out disease-causing microorganisms (pathogens).    A single row of cuboidal or columnar cells that divide and grow; this layer also  includes melanocytes    Specialized cells in the epidermis called melanocytes pro-  duce the pigment melanin (mel’ah-nin) from the amino acid  tyrosine in organelles called melanosomes (fig. 6.4a). Melanin  provides skin color. Melanin also absorbs ultraviolet radiation in  sunlight, which would otherwise cause mutations in the DNA of  skin cells and other damaging effects. Clinical Application 6.1 dis-  cusses one consequence of excess sun exposure—skin cancer.   Melanocytes lie in the stratum basale of the epidermis. They  are the only cells that can produce melanin, but the pigment may  also appear in nearby epidermal cells. Melanocytes have long,  pigment-containing cellular extensions that pass upward between    FIGURE 6.3 (AP|RI Epidermis of thick skin. (a) The layers of the epidermis are distinguished by changes in cells as they are pushed toward the  surface of the skin. (b) Light micrograph of skin (500x).    FIGURE 6.4 A melanocyte. (a) Transmission electron micrograph of a melanocyte with pigment-containing granules (melanosomes) (4,500x).  (b) A melanocyte may have pigment-containing extensions that pass between epidermal cells and transfer pigment into them. Much of the melanin  is deposited above the nucleus, where the pigment can absorb UV radiation from outside before the DNA is damaged.    A deep, dark tan was once considered desirable. In the 1960s a  teenager might have spent hours on a beach, skin glistening with  oil, maybe even using a reflecting device to concentrate sun expo-  sure on the face. Today more than 40 million people in the United  States use indoor tanning beds to temporarily darken their skin,  but at a health cost. Rates of new skin cancer cases, particularly  among young women, have skyrocketed since 1992, paralleling  the increased use of tanning beds by this group.   Usually DNA repair, discussed in chapter 4 (p. 143), protects  against sun overexposure. Solar radiation activates a gene that  encodes a protein called p53 that normally mediates harmful  effects of environmental insults in various tissues. In the skin, p53  stimulates a series of responses to sunning: keratinocytes pro-  duce signaling molecules that promote the redness (erythema)  and swelling of inflammation. Meanwhile, melanocytes make  more melanin, which enters keratinocytes. Tanning results. Use of  tanning booths is dangerous because it bathes the skin in doses  of ultraviolet radiation that can overwhelm the skin’s natural pro-  tection against cancer.   Researchers hypothesize that the tanning response evolved  about a million years ago, when our ancestors lived near the  equator. Biology may also explain why we like to sunbathe—it  stimulates keratinocytes to release beta-endorphin, a molecule  related to opiates that promotes a sense of well-being.   Skin cancer begins when the sun (or tanning bed) exposure  overwhelms the protection provided by p53. Most skin cancers  arise in nonpigmented epithelial cells in the deep layer of the epi-  dermis or from melanocytes. Skin cancers originating from epi-  thelial cells are called cutaneous carcinomas (basal cell carcinoma  or squamous cell carcinoma); those arising from melanocytes are  cutaneous melanomas (melanocarcinomas or malignant melano-  mas) (fig. 6A).   Cutaneous carcinomas are the most common type of skin  cancer, affecting mostly light-skinned people over forty years of    FIGURE 6A Skin cancer. (a) Basal cell carcinoma. (b) Squamous cell carcinoma. (c) Malignant melanoma.    age regularly exposed to sunlight. It typically develops from a  hard, dry, scaly growth with a reddish base. The lesion may be flat  or raised and usually firmly adheres to the skin, appearing most  often on the neck, face, or scalp. Surgical removal or radiation  treatment usually cures these slow-growing cancers.   A cutaneous melanoma is pigmented with melanin, often  with a variety of colored areas—variegated brown, black, gray, or  blue. A melanoma usually has irregular rather than smooth out-  lines and may feel bumpy. The “ABCDE” rule provides a check-  list for melanoma: A for asymmetry; B for border (irregular); C for  color (more than one); D for diameter (more than 6 millimeters);  and E for elevation. Melanoma accounts for only 4% of skin can-  cers but for 80% of skin cancer deaths.   People of any age may develop a cutaneous melanoma.  These cancers are caused by short, intermittent exposure to  high-intensity sunlight, such as when a person who usually stays  indoors occasionally sustains a blistering sunburn.   Light-skinned people who burn rather than tan are at higher  risk of developing a cutaneous melanoma. The cancer usually  appears in the skin of the trunk, especially the back, or the limbs,  arising from normal-appearing skin or from a mole (nevus). The  lesion spreads horizontally through the skin, but eventually may  thicken and grow downward, invading deeper tissues. Surgical  removal during the horizontal growth phase arrests the cancer in  six of every seven cases. However, once the lesion thickens and  deepens, it becomes more difficult to treat, and the survival rate  is low. Melanomas in people who regularly use tanning beds tend  to be thicker and more widely spread at the time of diagnosis  than other early melanomas.   To reduce risk of developing skin cancer, avoid exposure to  high-intensity sunlight in the environment and tanning beds, use  sunscreens and sunblocks, and examine the skin regularly. Report  any “ABCDE" lesions to a physician.    neighboring epidermal cells (fig. 6.4b). These extensions transfer  melanin granules in melanosomes into neighboring keratinocytes.  The neighboring cells may accumulate more melanin than the  melanocytes do.   Skin color is determined by heredity, as well as by environ-  mental and physiological factors. Regardless of racial origin, all  people have about the same number of melanocytes in their skin.  Differences in skin color result from differences in the amount of  melanin these cells produce, which is controlled by several genes.  The more melanin, the darker the skin. The distribution and size  of pigment granules in melanocytes also influence skin color. The  granules in very dark skin are single and large; those in lighter skin  aggregate in clusters of two to four smaller granules. People who  inherit mutations in melanin genes have a condition called albi-  nism, which includes nonpigmented skin. Albinism affects people  of all races (fig. 6.5).   Environmental factors such as sunlight, ultraviolet light from  sunlamps, and X rays affect skin color. These factors rapidly  darken existing melanin, and they stimulate melanocytes to pro-  duce more pigment and transfer it to nearby epidermal cells within  a few days. Unless exposure to sunlight continues, the tan fades  as pigmented keratinocytes that have been pushed toward the skin  surface wear away.   Blood in the dermal vessels adds color to the skin. When  blood is well oxygenated, the blood pigment hemoglobin is bright  red, making the skin of light-complexioned people appear pinkish.  When the blood oxygen concentration is low, hemoglobin is dark  red, and the skin appears bluish—a condition called cyanosis.   The state of the blood vessels also affects skin color. If the  vessels are dilated, more blood enters the dermis, reddening the  skin of a light-complexioned person. This may happen when a per-  son is overheated, embarrassed, or under the influence of alcohol.  Conversely, conditions that constrict blood vessels cause the skin  to lose this reddish color. Thus, if body temperature drops abnor-  mally or if a person is frightened, the skin may appear pale.   A yellow-orange plant pigment called carotene, found in  yellow vegetables, can give skin a yellowish cast if a person con-  sumes too much of it. The skin color results from accumulation of    FIGURE 6.5 The pale irises, skin, and hair of a person with albinism  reflect lack of melanin. Albinism is inherited.    carotene in the adipose tissue of the dermis and subcutaneous lay-  ers. Diseases may also affect skin color. A yellowish skin tone can  indicate jaundice, which is a consequence of liver malfunction.    A newborn who develops the yellowish skin of jaundice shortly  after birth may have a blood incompatibility, an underdeveloped  liver, or an inborn error of metabolism. An observant British  hospital nurse discovered a treatment for newborn jaundice in  1958. When taking her tiny charges out in the sun, she noticed  that a child whose skin had a yellow pallor developed normal  pigmentation when he lay in sunlight. However, the part of the  child’s body covered by a diaper and therefore not exposed  to the sun remained yellow. Further investigation showed that  sunlight enables the body to break down bilirubin, the liver  substance that accumulates in the skin. Today, newborns who  develop persistently yellowish skin may have to lie under artifi-  cial “bili lights” for a few days, clad only in protective goggles.    7 What is the function of melanin?  8 How do genetic factors influence skin color?  9 Which environmental factors influence skin color?    The boundary between the epidermis and the dermis is typically  uneven, because ridges from the epidermis project inward and  cone-shaped dermal papillae extend from the dermis into the  spaces between the ridges (see figs. 6.2 and 6.3). Dermal papillae  increase the surface area where epidermal cells receive oxygen and  nutrients from dermal capillaries.   Dermal papillae are found in the skin all over the body, but they  are most abundant in the hands and feet. The friction ridges that the  dermal papillae form leave a patterned impression—a fingerprint—  when a finger presses against a surface. Fingerprints are used to  identify individuals because they are unique. Genes determine gen-  eral fingerprint patterns. Subtle, individual variations called papil-  lary minutiae form as the fetus presses the developing ridges against  structures within the uterus. No two fetuses move exactly alike, so  even the fingerprints of identical twins are not exactly the same.   The dermis binds the epidermis to the underlying tissues.  Although no distinct boundary is visible, the dermis has two lay-  ers. The upper or papillary layer is composed of areolar connective  tissue. The lower or reticular layer is dense irregular connective tis-  sue that includes tough collagen fibers and elastic fibers in a gel-like  ground substance. Networks of these fibers give the skin toughness  and elasticity. On average, the dermis is 1.0—2.0 mm thick; however,  it may be as thin as 0.5 mm or less, such as on the eyelids, or as thick  as 3.0 mm, such as on the soles of the feet.   The dermis also contains muscle fibers. Some regions, such as  the skin that encloses the testes (scrotum), contain many smooth    muscle cells that can wrinkle the skin when they contract. Other  smooth muscle in the dermis is associated with accessory struc-  tures such as hair follicles and glands. Many skeletal muscle fibers  are anchored to the dermis in the skin of the face. They help pro-  duce the voluntary movements associated with facial expressions.   Dermal blood vessels supply nutrients to all skin cells. These  vessels help regulate body temperature, as explained later in this  chapter on page 189.   Nerve cell processes are scattered throughout the dermis.  Motor nerve cell processes conduct impulses to dermal muscles and  glands, and sensory nerve cell processes conduct impulses away  from specialized sensory receptors (see fig. 6.2).   The dermis contains different types of sensory receptors.  One type of sensory receptor in the deeper dermis, lamellated  (Pacinian) corpuscles, responds to heavy pressure, whereas  another type in the upper dermis, tactile (Meissner’s) corpuscles,  senses light touch and texture. Still other receptors (free nerve  endings) extend into the epidermis and respond to temperature  changes or to factors that can damage tissues. Sensory receptors  are discussed in chapter 12 (p. 446). The dermis also contains  accessory structures, including hair follicles, sebaceous (oil-  producing) glands, and sweat glands.    To make a tattoo, needles inject inks into the dermis. The  color is permanent, because dermal cells are not shed, unlike  cells of the epidermis. To remove a tattoo, a laser shatters the    ink molecules, and the immune system removes the result-  ing debris. Before laser removal became available in the late  1980s, unwanted tattoos were scraped, frozen, or cut away—  all painful procedures.    FIGURE 6.6 (AP|R) Nail. (a) Longitudinal section and (b) dorsal view of nail exterior.    (Q) What is the most actively growing region of the nail?    Accessory structures of the skin originate from the epidermis and  include nails, hair follicles, and skin glands. As long as acces-  sory structures remain intact, severely burned or injured dermis  can regenerate.    Nails are protective coverings on the ends of the fingers and toes.  Each nail consists of a nail plate that overlies a surface of skin called  the nail bed. Specialized epithelial cells continuous with the epi-  thelium of the skin produce the nail bed. The whitish, thickened,  half-moon-shaped region (lunula) at the base of a nail plate is the  most active growing region. The epithelial cells here divide, and the  newly formed cells become keratinized. This gives rise to tiny, kera-  tinized scales that become part of the nail plate, pushing it forward  over the nail bed. In time, the plate extends beyond the end of the  nail bed and with normal use gradually wears away (fig. 6.6).    Hair is present on all skin surfaces except the palms, soles, lips,  nipples, and parts of the external reproductive organs. However,  in some places it is not well developed. For example, hair on the  forehead is very fine in many people.    Hairs cycle through phases of active growth and being inac-  tive. At any time, 90% of hair is in the growth phase. Each hair  develops from a group of epidermal stem cells at the base of a  tubelike depression called a hair follicle (har fol’i-kl). These  stem cells originate from a region near the bottom of the hair  follicle, known as the hair bulge, and migrate downward. The fol-  licle, containing the hair root, extends from the surface into the  dermis and sometimes into the subcutaneous layer. The epider-  mal cells in the hair bulb at its base are nourished from dermal  blood vessels in a projection of connective tissue (hair papilla)  at the deep end of the follicle. As these epidermal cells divide  and grow, they push older cells toward the surface. The cells that  move upward and away from the nutrient supply become keratin-  ized and die. Their remains constitute the structure of a develop-  ing hair shaft that extends away from the skin surface. In other  words, a hair is composed of dead epidermal cells (figs. 6.7 and  6.8). Both hair and epidermal cells develop from the same types  of stem cells.   A healthy person loses from twenty to 100 hairs a day as part  of the normal growth cycle of hair. A hair typically grows for two  to six years, then does not grow for two to three months anchored  in its follicle. Later, a new hair begins to grow from the base of    the follicle, pushing the old hair outward until it drops off. If hairs  shed from the scalp are not replaced, baldness results. Clinical  Application 6.2 discusses several types of hair loss.   Genes determine hair color by directing the type and  amount of pigment that epidermal melanocytes produce. Dark  hair has more of the brownish-black eumelanin (u-mel’ah-nin),  whereas blonde hair and red hair have more of the reddish-yellow  pheomelanin (fe’’o-mel’ah-nin). The white hair of a person with  albinism lacks melanin altogether. A mixture of pigmented hairs  and unpigmented hairs appears gray.   A bundle of smooth muscle cells, forming the arrector pili  muscle (see figs. 6.2a and 6.7a), attaches to each hair follicle.  When the muscle contracts, a short hair in the follicle stands on  end. If a person is emotionally upset or very cold, nervous stimula-  tion causes the arrector pili muscles to contract, producing goose-  flesh, or goose bumps. Each hair follicle is also associated with  one or more sebaceous (oil-producing) glands.    Sebaceous glands (se-ba’shus glandz) (see fig. 6.2) contain groups  of specialized epithelial cells and are usually associated with hair  follicles. They are holocrine glands (see chapter 5, p. 156), and    FIGURE 6.7 fAP|R) Hair follicle. (a) A hair grows from the base of a hair follicle when epidermal cells divide and older cells move outward and    About 1.4 billion people worldwide are bald. The most common  type of baldness in adults is pattern baldness, in which the top of  the head loses hair. Pattern baldness affects 40 million men and  21 million women in the United States and is also common else-  where. The women tend to be past menopause, when lowered  amounts of the hormone estrogen contribute to hair loss, which  occurs more evenly on the scalp than it does in men. Pattern bald-  ness is called androgenic alopecia because it is associated with  testosterone, an androgenic (male) hormone. Analysis of scalp  samples from the hairless and hairy parts of affected men’s heads  reveals that hair progenitor cells are lacking in the bald regions,  although stem cells from which they descend are present. Abnor-  mal hormone levels that mimic menopause may cause hair loss in  young women.   Another type of baldness is alopecia areata, in which the  body manufactures antibodies that attack the hair follicles. This  action results in oval bald spots in mild cases but complete loss of  scalp and body hair in severe cases. About 6.5 million people in  the United States have alopecia areata.   Temporary hair loss has several causes. Lowered estrogen  levels shortly before and after giving birth may cause a woman's  hair to fall out in clumps. Taking birth control pills, cough medi-  cations, certain antibiotics, vitamin A derivatives, antidepressants,  and many other medications can also cause temporary hair loss.  A sustained high fever may prompt hair loss six weeks to three  months later.   Many people losing their hair seek treatment (fig. 6B). One  treatment is minoxidil (Rogaine), a drug originally used to lower  high blood pressure. Rogaine causes new hair to grow in 10% to  14% of cases, and in 90% of people, it slows hair loss. However,    FIGURE 6.8 This scanning electron micrograph shows a hair emerging  from its follicle (875x).   be beautiful, but  many people with  hair loss seek ways  to grow hair.    when a person stops taking it, any new hair falls out. Hair transplants  move hair follicles from a hairy body part to a bald part. They work.  Several other approaches, however, can damage the scalp or lead  to infection. These include suturing on hair pieces and implants of  high-density artificial fibers. Products called “thinning hair supple-  ments” are ordinary conditioners that make hair feel thicker. They  are concoctions of herbs and the carbohydrate polysorbate.   A future approach to treating baldness may harness the abil-  ity of stem cells to divide and differentiate to give rise to new hair  follicles. Stem cells from the hair bulge can produce hair as well  as epidermal cells and sebaceous glands. The first clue to the  existence of these cells was that new skin in burn patients arises  from hair follicles. Manipulating stem cells could someday treat  extreme hairiness (hirsutism) as well as baldness.    their cells produce globules of a fatty material that accumulate,  swelling and bursting the cells. The resulting mixture of fatty mate-  rial and cellular debris is called sebum.   Sebum is secreted into hair follicles through short ducts and  helps keep the hairs and the skin soft, pliable, and waterproof  (fig. 6.9). Acne results from excess sebum secretion (Clinical  Application 6.3).   Sebaceous glands are scattered throughout the skin but are not  on the palms and soles. In some regions, such as the lips, the cor-  ners of the mouth, and parts of the external reproductive organs,  sebaceous glands open directly to the surface of the skin rather than  being connected to hair follicles.   Sweat (swet) glands, also called sudoriferous glands, are  widespread in the skin. Each gland consists of a tiny tube that  originates as a ball-shaped coil in the deeper dermis or superficial  subcutaneous layer. The coiled portion of the gland is closed at  its deep end and is lined with sweat-secreting epithelial cells. The  most numerous sweat glands called merocrine sweat glands, also  known as eccrine sweat glands, respond throughout life to body  temperature elevated by environmental heat or physical exercise    FIGURE 6.9 (AP|R) A sebaceous gland secretes sebum into a hair    (fig. 6.10). These sweat glands, although located all over the body,  are abundant on the forehead, neck, and back, where they produce  profuse sweat on hot days or during intense physical activity. They  also release the moisture that appears on the palms and soles when  a person is emotionally stressed.   A tube (duct) that opens at the surface as a pore carries the  sweat that the merocrine sweat glands secrete (fig. 6.11). Sweat  is mostly water, but it also contains small amounts of salts and  wastes such as urea and uric acid. Thus, sweating is also an excre-  tory function.   The secretions of certain sweat glands, called apocrine  (ap’o-krin) sweat glands, develop a scent as skin bacteria metabo-  lize them (see fig. 6.10). Although these glands are called apocrine,  they secrete by exocytosis. Apocrine sweat glands become active  at puberty and can wet certain areas of the skin when a person is  emotionally upset, frightened, or in pain. They are also active dur-  ing sexual arousal. Apocrine sweat glands are most numerous in  axillary regions and the groin. Ducts of these sweat glands open  into hair follicles. The secretions of these sweat glands include  proteins and lipids, which, when metabolized by bacteria in the  skin, produce body odor.   Other sweat glands are structurally and functionally modified  to secrete specific fluids, such as the ceruminous glands of the exter-  nal acoustic meatus that secrete ear wax (see chapter 12, p. 456)  and the female mammary glands that secrete milk (see chapter 23,  pp. 891-893). Table 6.2 summarizes the types of skin glands.    Many young people are all too familiar with acne vulgaris, a disor-  der of the sebaceous glands (fig. 6C). Excess sebum and squamous  epithelial cells clog the glands, producing blackheads and white-  heads (collectively comedones). The blackness is not dirt but results    Treatment for severe acne requires a doctor's care. Laser  treatments, dermabrasion, or surgery may be used to remove  scars caused by severe acne. Drug combinations are tailored to  the severity of the condition (table 6A).    from the accumulated cells blocking light. In addition, the clogged  sebaceous gland provides an attractive environment for anaero-  bic bacteria. Their presence signals the immune system to trigger  inflammation. The inflamed, raised area is a pimple (pustule).   Acne is a common skin disease, affecting 80% of people at  some time between the ages of eleven and thirty. It is usually hor-  monally induced. Just before puberty, the adrenal glands increase  production of androgens, which stimulate increased secretion of  sebum. At puberty, sebum production surges again. Acne usu-  ally develops because the sebaceous glands are extra responsive  to androgens, but in some cases, androgens may be produced  in excess.   Sometimes, acne can lead to scarring. Fortunately, several  highly effective treatments are available, and dermatologists can  tailor combinations of them to help individual patients.    FIGURE 6C Acne is a common skin condition usually associated  with a surge of androgen activity.    Acne is not caused by uncleanliness or eating too much chocolate  or greasy food. Although cleansing products containing soaps,  detergents, or astringents can remove surface sebum, they do not  stop the flow of oil that contributes to acne. Abrasive products are  harmful because they irritate the skin and increase inflammation.   Most acne treatments take weeks to months to work. Women  with acne are sometimes prescribed certain types of birth control  pills because the estrogens counter androgen excess. Isotretinoin  is a very effective derivative of vitamin A but has side effects and  causes birth defects. Systemic antibiotics can treat acne by clear-  ing bacteria from sebaceous glands. Topical treatments include  tretinoin (another vitamin A derivative), salicylic acid (an aspi-  rin solution), and benzoyl peroxide. Exposure to blue light and  chemical peels are other acne treatments.    Near or connected to hair follicles, everywhere  but on palms and soles    Originate in deep dermis or subcutaneous  layer and open to surface on forehead, neck,  and back    Wet skin during pain, fear, Near hair follicles in armpit and groin  emotional upset, and sexual    Ceruminous glands Modified sweat glands Secrete ear wax External acoustic meatus    The skin is one of the most versatile organs of the body and is vital  in maintaining homeostasis. As a protective covering, the skin pre-  vents many harmful substances, as well as microorganisms, from  entering the body. Skin also retards water loss by diffusion from  deeper tissues. It houses sensory receptors; contains epidermal  dendritic (den-drit’ik) cells, also known as Langerhans cells, that  play a role in initiating the immune response by phagocytizing  harmful microorganisms; and excretes small quantities of wastes.   The skin plays a role in the production of vitamin D, which  is necessary for normal bone and tooth development. Some skin  cells produce vitamin D precursor (dehydrocholesterol), which  when exposed to sunlight changes to an inactive form of vitamin  D (cholecalciferol). In the liver and kidneys the inactive form is  modified and becomes active vitamin D (calcitriol). The skin also  helps regulate body temperature.    The regulation of body temperature is vitally important because  even slight shifts can disrupt the rates of metabolic reactions.  Normally, the temperature of deeper body parts remains close to a  set point of 37°C (98.6°F). The maintenance of a stable tempera-  ture requires that the amount of heat the body loses be balanced by  the amount it produces. The skin plays a key role in the homeo-  static mechanism that regulates body temperature.    Heat is a product of cellular metabolism. The major heat produc-  ers are the more active cells of the body, such as skeletal and car-  diac muscle cells and cells of the liver.   When body temperature rises above the set point, the nervous  system stimulates structures in the skin and other organs to release  heat. For example, during physical exercise, active muscles release  heat, which the blood carries away. The warmed blood reaches the  part of the brain (the hypothalamus) that controls the body’s tempera-  ture set point, which signals muscles in the walls of dermal blood ves-  sels to relax. As these vessels dilate (vasodilation), more blood enters  them, and some of the heat the blood carries escapes to the outside.  At the same time, deeper blood vessels contract (vasoconstriction),  diverting blood to the surface, and the skin reddens. The heart is stim-  ulated to beat faster, moving more blood out of the deeper regions.   The primary means of body heat loss is radiation (ra-de-  a’shun), by which infrared heat rays escape from warmer surfaces to  cooler surroundings. These rays radiate in all directions, much like  those from the bulb of a heat lamp.   Conduction and convection release less heat than does radiation.  In conduction (kon-duk’shun), heat moves from the body directly  into the molecules of cooler objects in contact with its surface. For  example, heat is lost by conduction into the seat of a chair when a  person sits down. The heat loss continues as long as the chair is cooler  than the body surface touching it. Heat is also lost by conduction to  the air molecules that contact the body. As air becomes heated, it  moves away from the body, carrying heat with it, and is replaced by    cooler air moving toward the body. This type of continuous circula-  tion of air over a warm surface is convection (kon-vek’shun).   Still another means of body heat loss is evaporation (e-vap”o-  ra’shun). When the body temperature rises above normal, the nervous  system stimulates merocrine sweat glands to release sweat onto the  surface of the skin. As this fluid evaporates (changes from a liquid to  a gas), it carries heat away from the surface, cooling the skin.   When body temperature drops below the set point, as may  occur in a very cold environment, the brain triggers different  responses in the skin structures. Muscles in the walls of dermal  blood vessels are stimulated to contract. This action decreases the  flow of heat-carrying blood through the skin, which loses color, and  helps reduce heat loss by radiation, conduction, and convection. At  the same time, merocrine sweat glands remain inactive, decreasing  heat loss by evaporation. If body temperature continues to drop, the  nervous system may stimulate muscle cells in the skeletal muscles  throughout the body to contract slightly. This action requires an  increase in the rate of cellular respiration, which releases heat as a  by-product. If this response does not raise the body temperature to  normal, small groups of muscles may rhythmically contract with  greater force, causing the person to shiver, generating more heat.  Figure 6.12 summarizes the body’s temperature-regulating mecha-  nism, and Clinical Application 6.4 examines two causes of elevated  body temperature.   The body’s temperature-regulating mechanism does not always  operate satisfactorily, and the consequences may be dangerous.  For example, air can hold only a limited volume of water vapor,  so on a hot, humid day, the air may become nearly saturated  with water. At such times, the sweat glands may be activated, but  the sweat cannot quickly evaporate. The skin becomes wet, but the  person remains hot and uncomfortable. In addition, if the air tem-  perature is high, heat loss by radiation is less effective. If the air  temperature exceeds body temperature, the person may gain heat  from the surroundings, elevating body temperature even more.  Body temperature may rise high enough to cause a condition called  hyperthermia. The skin becomes dry, hot, and flushed. The person  becomes weak, dizzy, and nauseous, with headache and a rapid,  irregular pulse.   Hypothermia, or lowered body temperature, can result  from prolonged exposure to cold or as part of an illness. It can be  extremely dangerous. Hypothermia begins with shivering and a  feeling of coldness. If not treated, it progresses to mental confu-  sion, lethargy, loss of reflexes and consciousness, and, eventually,  the shutdown of major organs. If the temperature in the body’s  core drops just a few degrees, fatal respiratory failure or heart  arrhythmia may result. However, the extremities can withstand  drops of 20°F to 30°F below normal.   Certain people are at higher risk for developing hypothermia  due to less adipose tissue in the subcutaneous layer beneath the skin  (less insulation). These include the very old, very thin individuals,  and the homeless. The very young with undeveloped nervous sys-  tems have difficulty regulating their body temperature. Dressing  appropriately and staying active in the cold can prevent hypother-  mia. A person suffering from hypothermia must be warmed gradu-  ally so that respiratory and cardiovascular functioning remain stable.   The hypothalamus  detects the deviation  from the set point and  signals effector organs.    Hypothermia is intentionally induced during certain surgi-  cal procedures to protect vital organs from decreased oxygen  supply that may occur during the operations. For example, in  heart surgery, body temperature may be lowered to between  78°F (26°C) and 89°F (32°C), which lowers the body’s metabolic  rate so that cells require less oxygen. Hypothermia for surgery  is accomplished by packing the patient in ice or by removing    18 What, besides body temperature regulation, are some functions  of the skin?    19 How is body heat produced?  20 How does the body lose excess heat?    Inflammation is a normal response to injury or stress. Blood ves-  sels in affected tissues dilate and become more permeable, allow-  ing fluids to leak into the damaged tissues. Inflamed skin may  become reddened, swollen, warm, and painful to touch. However,  the dilated blood vessels provide the tissues with more nutrients  and oxygen, which aids healing. The specific events in the healing  process depend on the nature and extent of the injury.    R A GLIMPSE AHEAD | To Chapters 14, 15, and 16    Vasodilation increases blood flow to an inflamed area. Cells  in the blood help to eliminate dangerous microorganisms.    Breaks in the skin must heal to prevent infection and loss of blood.  If a break in the skin is shallow, epithelial cells of the epidermis  along its margin are stimulated to divide more rapidly than usual.  The newly formed cells fill the gap.   If an injury extends into the dermis or subcutaneous layer,  blood vessels break and the released blood forms a clot in the  wound. A clot consists mainly of a fibrous protein (fibrin) that  forms from another protein in the plasma, blood cells, and plate-  lets trapped in the protein fibers. Tissue fluids seep into the area  and dry. The blood clot and the dried tissue fluids form a scab that  covers and protects underlying tissues. Epithelial cells prolifer-  ate beneath the scab, bridging the wound. Before long, fibroblasts  migrate into the injured region and begin secreting collagen fibers  that bind the edges of the wound. Suturing (stitching) or otherwise  closing a large break in the skin speeds this process. In addition,  the connective tissue matrix releases growth factors that stimulate  certain cells to divide and regenerate the damaged tissue.   As healing continues, blood vessels extend beneath the scab.  Phagocytic cells remove dead cells and other debris. Eventually,  the damaged tissues are replaced, and the scab sloughs off. In  some cases, extensive production of collagen fibers may form an  elevation above the normal epidermal surface, called a scar.   In large, open wounds, healing may be accompanied by forma-  tion of small, rounded masses called granulations that develop in the  exposed tissues. A granulation consists of a new branch of a blood  vessel and a cluster of collagen-secreting fibroblasts that the vessel  nourishes. In time, some of the blood vessels are resorbed, and the  fibroblasts move away, leaving a scar largely composed of collagen  fibers. Figure 6.13 shows the stages in the healing of a wound.    It was a warm June morning when the harried and hurried father  strapped his five-month-old son Bryan into the backseat of his car and  headed for work. Tragically, the father forgot to drop his son off at the  babysitter’s. When his wife called him at work late that afternoon to  inquire why the child was not at the sitter’s, the shocked father realized  his mistake and hurried down to his parked car. But it was too late—  Bryan had died. Left for ten hours in the car in the sun, all windows  shut, the baby’s temperature had quickly soared. Two hours after he  was discovered, the child’s temperature still exceeded 41°C (106°F).   Sarah L.’s case of elevated body temperature was more typi-  cal. She awoke with a fever of 40°C (104°F) and a sore throat. At  the doctor's office, a test revealed that Sarah had a Streptococcus  infection. The fever was her body’s attempt to fight the infection.   The true cases of Bryan and Sarah illustrate two reasons  why body temperature may rise—inability of the temperature  homeostatic mechanism to handle an extreme environment and  an immune system response to infection. In Bryan's case, sus-  tained exposure to very high heat overwhelmed his temperature-  regulating mechanism, resulting in hyperthermia. Body heat built  up faster than it could dissipate, and body temperature rose, even  though the set point of the thermostat was normal. His blood ves-  sels dilated so greatly in an attempt to dissipate the excess heat  that after a few hours, his cardiovascular system collapsed.    Fever is a special case of hyperthermia in which temperature  rises in response to an elevated set point. In fever, molecules on the  surfaces of the infectious agents (usually bacteria or viruses) stimu-  late phagocytes to release a substance called interleukin-1 (also  called endogenous pyrogen, meaning “fire maker from within”).  The bloodstream carries interleukin-1 to the hypothalamus, where  it raises the set point controlling temperature. In response, the brain  signals skeletal muscles to contract (shivering) and increase heat  production, blood flow to the skin to decrease, and sweat glands  to decrease secretion. As a result, body temperature rises to the  new set point, and fever develops. The increased body temperature  helps the immune system kill the pathogens.   Rising body temperature requires different treatments,  depending on the degree of elevation. Hyperthermia in response  to exposure to intense, sustained heat should be rapidly treated by  administering liquids to replace lost body fluids and electrolytes,  sponging the skin with water to increase cooling by evaporation,  and covering the person with a refrigerated blanket. Fever can  be lowered with ibuprofen or acetaminophen, or aspirin in adults.  Some health-care professionals believe that a slightly elevated  temperature should not be reduced (with medication or cold baths)  because it may be part of a normal immune response. A high or  prolonged fever, however, requires medical attention.    Regenerated skin is injured, blood escapes from dermal  epidermis blood vessels, and (b) a blood clot soon forms.  ; (c) Blood vessels send out branches, and  Scar tissue : : ; :  (fibrosis) fibroblasts migrate into the area. The fibroblasts  produce new collagen fibers. (d) The scab  Fibroblast formed by the blood clot and dried tissue fluid    protects the damaged region until the skin is  mostly repaired. Then, the scab sloughs off.  Scar tissue continues to form, elevating the  epidermal surface. (Note: Cells are not drawn  to scale.)    Burns are classified by the extent of tissue damage. Slightly burned  skin, such as from a minor sunburn, becomes inflamed, warms and  reddens (erythema) as dermal blood vessels dilate. Mild edema  may swell the exposed tender skin, and a few days later the surface  layer of skin may peel. Any burn injuring only the epidermis is  a superficial partial-thickness (first-degree) burn. Healing usually  takes a few days to two weeks, with no scarring.   A burn that destroys some epidermis as well as some underly-  ing dermis is a deep partial-thickness (second-degree) burn. Fluid  escapes from damaged dermal capillaries, accumulating beneath  the outer layer of epidermal cells, forming blisters. The injured  region becomes moist and firm and may vary in color from dark  red to waxy white. Such a burn most commonly occurs as a result  of exposure to hot objects, hot liquids, flames, or burning clothing.    Acute sunburn (solar erythema) is an inflammatory reaction  of the skin to excessive exposure to ultraviolet radiation in  sunlight. The skin becomes very red, swollen, and painful.  Microscopic skin changes begin within a half hour of intense  sun exposure, including damage to cells in the upper, epidermal    layer of the skin, and swelling of blood vessels in the deeper,  dermal layer. Discomfort peaks 6 to 48 hours after exposure.  Within a few days the skin may peel, as surface cells die and  are shed. Peeling, an example of apoptosis (programmed cell  death), prevents cancer from developing by ridding the body of  susceptible cells.    The extent of healing of a deep partial-thickness burn depends  upon stem cells that are associated with accessory structures of  the skin. These structures include hair follicles, sweat glands,  and sebaceous glands. They survive the injury because although  they are derived from the epidermis, they extend into the dermis.  During healing, the stem cells divide, and their daughter cells  grow out onto the surface of the exposed dermis, spread over it,  and differentiate as new epidermis. In time, the skin usually com-  pletely recovers, and scar tissue does not develop unless an infec-  tion occurs.   A burn that destroys the epidermis, dermis, and the acces-  sory structures of the skin is called a full-thickness (third-degree)  burn. The injured skin becomes dry and leathery, and it may vary  in color from red to black to white.   A full-thickness burn usually results from immersion in hot  liquids or prolonged exposure to hot objects, flames, or corrosive  chemicals. Because most of the epithelial cells in the affected  region are destroyed, spontaneous healing occurs by growth of  epithelial cells inward from the margin of the burn. If the injured  area is extensive, treatment may require removing a thin layer of  skin from an unburned region of the body and transplanting it to  the injured area. This procedure is an example of an autograft, a  transplant within the same individual.   If the injured area is too extensive to replace with skin from  other parts of the body, cadaveric skin from a skin bank may be used  to cover the injury. Such an allograft (from person to person) is a  temporary covering that shrinks the wound, helps prevent infection,    and preserves deeper tissues. In time, after healing begins, an auto-  graft may replace the temporary covering, as skin becomes available  from healed areas. Skin grafts can leave extensive scars.   Various skin substitutes may also be used to cover the injured  area. Artificial skin typically consists of a collagen framework  seeded with a patient’s own skin cells (fig. 6.14).   The treatment of a burn patient requires estimating the extent  of the body’s affected surface. Physicians use the “rule of nines,”  subdividing the skin’s surface into regions, each accounting for 9%  (or some multiple of 9%) of the total surface area (fig. 6.15). This  estimate is important in planning to replace body fluids and electro-  lytes lost from injured tissues and for covering the burned area with  skin or skin substitutes.    »>  R ) -PRACTICE  22 What is the tissue response to inflammation?  23 How does a scab slough off?  24 Which type of burn is most likely to leave a scar? Why?    We are more aware of aging-related changes in skin than in other  organ systems, because we can easily see them. Aging skin affects  appearance, temperature regulation, and vitamin D formation.   The epidermis thins as the decades pass. As the cell cycle  slows, epidermal cells grow larger and more irregular in shape,    FIGURE 6.15 Asan aid for estimating the extent of damage burns cause, the body is subdivided into regions, each representing 9% (or some multiple    but are fewer. Skin may appear scaly because, at the microscopic  level, more sulfur—sulfur bonds form within keratin molecules.  Patches of pigment commonly called “age spots” or “liver spots”  appear and grow (fig. 6.16). These are sites of oxidation of fats  in the secretory cells of apocrine and eccrine glands and reflect  formation of oxygen free radicals.   The dermis becomes reduced as synthesis of the connective  tissue proteins collagen and elastin slows. The combination of a  shrinking dermis and loss of some fat from the subcutaneous layer  results in wrinkling and sagging of the skin. Wound healing slows  because the skin has fewer fibroblasts. Some of the changes in the  skin’s appearance result from specific deficits. The decrease in oil  from sebaceous glands dries the skin.    Various treatments temporarily smooth facial wrinkles. “Botox”  is an injection of a very dilute solution of botulinum toxin.  Produced by the bacterium Clostridium botulinum, the toxin  causes food poisoning. It also blocks nerve activation of certain  muscle cells, including the facial muscles that control smiling,  frowning, and squinting. After three months, though, the facial    nerves contact the muscles at different points, and the wrinkles  return. (Botox used at higher doses to treat neuromuscular con-  ditions can cause adverse effects.) Other anti-wrinkle treatments  include chemical peels and dermabrasion to reveal new skin  surface; collagen injections; and transplants of subcutaneous fat  from the buttocks to the face.    The skin provides protection, contains sensory  organs, and helps control body temperature.    Vitamin D,  production of which  begins in the skin,  helps provide  calcium needed for  bone matrix.   with the skin to control  body temperature.  Muscles act on facial  skin to create  expressions.    Sensory receptors  provide information  about the outside  world to the nervous  system. Nerves  control the activity  of sweat glands.    Hormones help to  increase skin blood  flow during exercise.  Other hormones  stimulate either the  synthesis or the  decomposition of  subcutaneous fat.   as a barrier, provides  an important first line  of defense for the  immune system.   may be stored as  subcutaneous fat.  Vitamin D, production  of which begins in the  skin, stimulates  dietary calcium  absorption.    The kidneys help  compensate for water  and electrolytes lost  in sweat.    Sensory receptors  play an important  role in sexual activity  and in the suckling  reflex.    The skin’s accessory structures also show signs of aging.  Slowed melanin production whitens hair as the hair shafts become  increasingly transparent. Hair growth slows, the hairs thin, and the  number of follicles decreases. Males may develop pattern bald-  ness. A diminished blood supply to the nail beds impairs their  growth, dulling and hardening them. Sensitivity to pain and pres-  sure diminishes with age as the number of sensory receptors falls.  A ninety-year-old’s skin has only one-third the number of such  sensory receptors as the skin of a young adult.   The ability to control temperature falters as the number of  sweat glands in the skin falls, as the capillary beds that surround    Skin is composed of an epidermis and a dermis separated by a  basement membrane. A subcutaneous layer, not part of the skin,  lies beneath the dermis. The subcutaneous layer is composed of  areolar tissue and adipose tissue that helps conserve body heat.  This layer contains blood vessels that supply the skin.   a. The epidermis is stratified squamous epithelium that  lacks blood vessels.   b. The deepest layer, called the stratum basale, contains  cells that divide and grow.   c. Epidermal cells undergo keratinization as they are  pushed toward the surface.   d. The outermost layer, called the stratum corneum, is  composed of dead epidermal cells.   e. Production of epidermal cells in the stratum basale  balances the rate at which they are lost at the surface.   f. The epidermis protects underlying tissues against water  loss, mechanical injury, and the effects of harmful  chemicals.   g. Melanin, a pigment produced from the amino acid  tyrosine, provides skin color and protects underlying  cells from the effects of ultraviolet light.    sweat glands and hair follicles shrink, and as the ability to shiver  declines. In addition, the number of blood vessels in the deeper  layers decreases, as does the ability to shunt blood toward the  body’s interior to conserve heat. As a result, an older person is  less able to tolerate the cold and cannot regulate heat. In the win-  ter, an older person might set the thermostat ten to fifteen degrees  higher than a younger person would. Fewer blood vessels in and  underlying the skin account for the pale complexions of some  older individuals. Changes in the distribution of blood vessels also  contribute to development of pressure sores in a bedridden person  whose skin does not receive adequate circulation.   Aging of the skin is also related to skeletal health. The skin is  the site of formation of vitamin D from its precursor, which requires  exposure to the sun. Vitamin D is necessary for absorption of cal-  cium, needed for bone structure. Many older people do not get  outdoors much, and the wavelengths of light that are important for  vitamin D formation do not readily penetrate glass windows. In  addition, older skin has a diminished ability to activate the vitamin.  Therefore, homebound seniors can benefit from vitamin D supple-  ments to help maintain bone structure.    25 What changes occur with age in the epidermis and dermis?  26 How do the skin’s accessory structures change over time?    27 Why do older people have more difficulty controlling body  temperature than do younger people? Hf    i. All humans have about the same number of  melanocytes. Skin color is largely due to the amount of  melanin in the epidermis.   (a) Dark skin is due to genes that cause large  amounts of melanin to be produced; lighter  skin is due to genes that cause lesser amounts  of melanin to form.   (b) Mutant genes may cause a lack of melanin in  the skin.   (2) Environmental factors that influence skin color  include sunlight, ultraviolet light, and X rays.   (a) The oxygen content of the blood in dermal  vessels may cause the skin of light-  complexioned persons to appear pinkish or  bluish.   (b) Carotene in the subcutaneous layer may cause  the skin to appear yellowish.   a. Cone-shaped dermal papillae contain blood capillaries  that provide epidermal cells with oxygen and nutrients.   b. Dermal papillae create friction ridges that leave a  fingerprint when a finger presses against a surface.   (2) The lower reticular layer is dense irregular  connective tissue that binds the epidermis to  underlying tissues.   e. Dermal blood vessels supply nutrients to skin cells and  help regulate body temperature.   (1) Some dermal nerve cell processes conduct  impulses to muscles and glands of the skin.   (2) Other dermal nerve cell processes are associated  with sensory receptors in the skin.   a. Nails are protective covers on the ends of fingers and  toes.  b. They consist of keratinized epidermal cells.   2. Hair follicles  a. Hair covers nearly all regions of the skin.   b. Each hair develops from epidermal cells at the base of a  tubelike hair follicle.   c. As newly formed cells develop and grow, older cells are  pushed toward the surface and undergo keratinization.   d. A hair usually grows for a while, rests, and then is  replaced by a new hair.   e. Hair color is determined by genes that direct the type  and amount of pigment in hair cells.   f. A bundle of smooth muscle cells and one or more  sebaceous glands are attached to each hair follicle.   3. Skin glands  a. Sebaceous glands secrete sebum, which softens and   waterproofs both the skin and hair.  b. Sebaceous glands are usually associated with hair  follicles.   Sweat glands are located in nearly all regions of the skin.   e. Merocrine sweat glands, located on the forehead,  neck, back, palms, and soles, respond to elevated body  temperature and produce sweat that is primarily water,  but also contains salts and waste products.   f. Apocrine sweat glands, located in the axillary  regions and groin, moisten the skin when a person is  emotionally upset, scared, in pain, or sexually aroused  and produce sweat containing proteins and lipids.    The skin is vital in maintaining homeostasis. Regulation of  body temperature is vital because heat affects the rates of  metabolic reactions. Normal temperature of deeper body parts  is close to a set point of 37°C (98.6°F).  1. The skin is a protective covering, retards water loss, and  houses sensory receptors.  2. The skin produces vitamin D precursor.    3. The skin helps regulate body temperature.  a. Heat production and loss   (2) When body temperature rises above normal, more  blood enters dermal blood vessels and the skin  reddens.   (3) Heat is lost to the outside by radiation,  conduction, convection, and evaporation.   (5) When body temperature drops below normal,  dermal blood vessels constrict, causing the skin  to lose color, and merocrine sweat glands to  become inactive.   (6) If body temperature continues to drop, skeletal  muscles involuntarily contract; this increases  cellular respiration, which produces additional heat.   (2) When the air is saturated with water, sweat may fail to  evaporate and body temperature may remain elevated.   (3) Hyperthermia is a body temperature above 101°F.  It causes weakness, dizziness, nausea, headache,  and a rapid, irregular pulse.   (4) Hypothermia is lowered body temperature. It  causes shivering, mental confusion, lethargy, loss  of reflexes and consciousness, and eventually  major organ failure.    Skin injuries trigger inflammation. The affected area becomes  red, warm, swollen, and tender.  1. Accutin the epidermis is filled in by dividing epithelial  cells. Clots close deeper cuts, sometimes leaving a  scar where connective tissue produces collagen fibers,  forming an elevation above the normal epidermal surface.  Granulations form as part of the healing process in large,  open wounds.  2. A superficial partial-thickness burn heals quickly with no  scarring. The area is warm and red. A burn penetrating  to the dermis is a deep partial-thickness burn. It blisters.  Deeper skin structures help heal this more serious type  of burn. A full-thickness burn is the most severe and may  require a skin graft.  3. The “rule of nines” is used to estimate the extent of the  body’s affected surface in determining burn treatment.   2. Due to changes in the number of sweat glands and  shrinking capillary beds in the skin, elderly people are less  able to tolerate the cold and cannot regulate heat well.   3. Older skin has a diminished ability to produce vitamin D,  which is necessary for skeletal health.    The epidermis on the soles of the feet is composed of layers  of tissue. (p. 178)   Distinguish between the epidermis and the dermis. (p.178)  Explain the functions of the subcutaneous layer. (p. 178)  Explain what happens to epidermal cells as they undergo  keratinization. (p. 179)   Place the layers of the epidermis in order (1-5) from the  outermost layer to the layer attached to the dermis by the  basement membrane. (p. 179)    Describe the function of melanocytes. (pp. 180 and 183)  Discuss the function of melanin, other than providing color to  the skin. (pp. 180)   Explain how environmental factors affect skin color. (fp. 183)  Describe three physiological factors that affect skin color.   Name the tissue(s) in each of the two layers of the dermis  and describe their functions. (p. 183)   The sweat glands that respond to elevated body  temperature and are commonly found on the forehead, neck,  and back are sweat glands. (pp. 185-187)   Describe the role of the skin in promoting the loss of excess  body heat. (p. 189)    Explain how air saturated with water vapor may interfere  with body temperature regulation. (p. 189)    Distinguish between the healing of shallow and deeper  breaks in the skin. (p. 190)    Life-Span Changes  Discuss three effects of aging on skin. (pp. 192-195)    1. What methods might be used to cool the skin of a child  experiencing a high fever? For each method you list, identify the  means by which it promotes heat loss—radiation, conduction,  convection, or evaporation.    2. Why would collagen and elastin added to skin creams be unlikely  to penetrate the skin—as some advertisements imply they do?    3. A premature infant typically lacks subcutaneous adipose tissue.  Also, the surface area of an infant's body is relatively large  compared to its volume. How do these factors affect the ability  of an infant to regulate its body temperature?    4. Which of the following would result in the more rapid absorption of  a drug: a subcutaneous injection or an intradermal injection? Why?    5. Everyone's skin contains about the same number of  melanocytes even though people come in many different  colors. How is this possible?    6. Using the rule of nines, estimate the extent of damage for an  individual whose body, clad only in a short nightgown, was  burned when the nightgown caught fire as she was escaping  from a burning room. What special problems might result  from the loss of the individual’s functional skin surface? How  might this individual's environment be modified to compensate  partially for such a loss?    7. Asarule, a superficial partial-thickness burn is more painful  than one involving deeper tissues. How would you explain  this observation?    Connect Interactive Questions Reinforce your knowledge using  assigned interactive questions covering the structure of skin and  its accessory organs.    Connect Integrated Activity Practice your understanding of skin  as you look at the process of wound healing.    Anatomy & Physiology Revealed Go more in depth into the  human body by exploring the skin and its histology.    A bone may appear to be inert because of nonliving material  in the extracellular matrix of bone tissue. However, bone also  includes active, living tissues: bone tissue, cartilage, dense con-  nective tissue, blood, and nervous tissue. Bones are not only  alive, but also multifunctional. Bones, the organs of the skeletal  system, support and protect softer tissues, provide points of  attachment for muscles, house blood-producing cells, and store  inorganic salts.    After you have studied this chapter, you should be able to:    Classify bones according to their shapes, and name an  example from each group. (p. 200)    Describe the macroscopic and microscopic structure  of a long bone, and list the functions of these parts.  (pp. 200-202)    Distinguish between intramembranous and  endochondral bones, and explain how such bones  develop and grow. (pp. 202-207)    Describe the effects of sunlight, nutrition, hormonal  secretions, and exercise on bone development and  growth. (pp. 207-210)    Distinguish between the axial and appendicular skeletons,  and name the major parts of each. (pp. 212-215)   Locate and identify the bones and the major features  of the bones that comprise the skull, vertebral column,  thoracic cage, pectoral girdle, upper limb, pelvic girdle,  and lower limb. (pp. 215-245)    acetabul-, vinegar cup: acetabulum—depres-  sion of the hip bone that articulates with  the head of the femur.   ax-, axis: axial skeleton—upright portion  of the skeleton that supports the head,  neck, and trunk.   cribr-, sieve: cribriform plate—portion of the  ethmoid bone with many small openings.   glen-, joint socket: glenoid cavity—depres-  sion in the scapula that articulates with  the head of a humerus.   meat-, passage: external acoustic meatus—  canal of the temporal bone that leads  inward to parts of the ear.    The bones of the skeletal system vary greatly in size and shape.  However, bones are similar in structure, development, and function.    Bones are classified according to their shapes—long, short, flat, or  irregular (fig. 7.1).    ¢ Long bones have long longitudinal axes and expanded ends.  Examples of long bones are the forearm and thigh bones.   e Short bones are cubelike, with roughly equal lengths and  widths. The bones of the wrists and ankles are this type. A  special type of short bone is a sesamoid bone, or round  bone. This type of bone is usually small and nodular and  embedded in a tendon adjacent to a joint, where the tendon is  compressed. The kneecap (patella) is a sesamoid bone.   e Flat bones are platelike structures with broad surfaces, such  as the ribs, the scapulae, and some bones of the skull.   ¢ Irregular bones have a variety of shapes, and most are con-  nected to several other bones. Irregular bones include the ver-  tebrae that compose the backbone, and many facial bones.    The femur, the long bone in the thigh, illustrates the structure of  a bone (fig. 7.2). At each end of a long bone is an expanded por-  tion called an epiphysis (e-pif’i-sis) (pl., epiphyses), which articu-  lates (or forms a joint) with another bone. One epiphysis, called  the proximal epiphysis, is nearest to the torso. The other, called the  distal epiphysis, is farthest from the torso. On its outer surface, the  articulating portion of the epiphysis is coated with a layer of hya-  line cartilage called articular cartilage (ar-tik’u-lar kar’ti-lij). The  shaft of the bone is called the diaphysis (di-af’i-sis). The metaph-  ysis (met”ah-fi’-sis) is the widening part of the bone between the  diaphysis and the epiphysis.   A bone is enclosed by a tough, vascular covering of dense  connective tissue called the periosteum (per”e-os’te-um), except    for the articular cartilage on its ends. The periosteum is firmly  attached to the bone, and the periosteal fibers are continuous with  connected ligaments and tendons. The periosteum also helps form  and repair bone tissue.    FIGURE 7.1 Bones are classified by shape. (a) The femur of the thigh is  along bone, (b) the talus of the ankle is a short bone, (c) a parietal bone of  the skull is a flat bone, (d) a vertebra of the backbone is an irregular bone,  and (e) the patella of the knee is a sesamoid bone. The location icon of the  whole skeleton highlights the bones used as examples for classification.    of ligaments and tendons; grooves and openings are passageways  for blood vessels and nerves; and a depression of one bone might  articulate with a process of another.   The wall of the diaphysis is mainly composed of tightly packed  tissue called compact bone, or cortical bone. This type of bone  has a continuous extracellular matrix with no gaps (fig. 7.3a). The  epiphyses, on the other hand, are largely composed of spongy  bone, or cancellous bone, with thin layers of compact bone on  their surfaces (fig. 7.3b). Spongy bone consists of many branching  bony plates called trabeculae (trah-bek’u-le). Irregular connecting  spaces between these plates help reduce the bone’s weight. The  bony plates are most highly developed in the regions of the epiph-  yses subjected to compressive forces. Both compact and spongy  bone are strong and resist bending.   Most bones have compact bone overlying spongy bone, with  the relative amounts of each varying in the differently shaped  bones. Short, flat, and irregular bones typically consist of a mass  of spongy bone either covered by a layer of compact bone or sand-  wiched between plates of compact bone (fig. 7.3c).    Compact bone in the diaphysis of a long bone forms a tube  with a hollow chamber called the medullary cavity (med’u-lar’e  kav’i-te) that is continuous with the spaces of the spongy bone. A  thin membrane containing bone-forming cells, called endosteum  (en-dos’té-um), lines these spaces and the medullary cavity. A spe-  cialized type of soft connective tissue called marrow (mar’o) fills  the spongy bone spaces and the medullary cavity. The two forms  of marrow, red and yellow, are described later in this chapter (see  also fig. 7.2).    Recall from chapter 5 (p. 167) that bone cells called osteocytes  (os’te-o-sitz) are in tiny, bony chambers called lacunae. Osteocytes  exchange substances with nearby cells by means of cellular pro-  cesses passing through canaliculi. The extracellular matrix of  bone tissue is largely collagen and inorganic salts. Collagen gives  bone its strength and resilience, and inorganic salts make it hard  and resistant to crushing.    In compact bone, the osteocytes and layers of extracellular matrix  called lamellae are concentrically clustered around a central canal  (Haversian canal) forming a cylinder-shaped unit called an osteon  (os’te-on), also called an Haversian system (figs. 7.4 and 7.5).  Many of these units together form the substance of compact bone.  The osteons run longitudinally with the axis of the bone, function-  ing as weight-bearing pillars, resisting compression.   Each central canal contains blood vessels and nerves sur-  rounded by loose connective tissue. Blood in these vessels nourishes    At age fifty-two the woman is younger than most of the  others having their bone mineral density measured. The  gynecologist advised a baseline test to assess the health of  the patient’s skeleton because her parents had osteoporosis.   A radiology technologist conducts the test. She explains  the procedure to the patient, then positions her on her  back on a padded table, fully clothed. The scanner passes  painlessly over the patient's hip and lower spine, emitting  low-dose X rays that form images of the bones. Spaces on the  scan indicate osteopenia, the low bone mineral density that  may be a prelude to osteoporosis.   Radiology technologists administer medical imaging  tests, such as ultrasound and magnetic resonance imaging  (MRI), as well as mammography and the three-dimensional  X-ray cross sections of computerized tomography (CT). The  technologists protect patients from radiation with drapes  and positioning, and operate scanning devices to produce  the highest-quality images from which a radiologist can  accurately diagnose an illness or injury.   A registered radiologic technologist completes  two years of training at a hospital or a two- or four-year  program at a college or university, and must pass a national  certification exam.    FIGURE 7.3 (§AP|F) Compact bone and spongy bone. (a) Ina femur,  the wall of the diaphysis consists mostly of compact bone. (b) The epiphyses    of the femur contain spongy bone enclosed by a thin layer of compact bone.    (c) This skull bone contains a layer of spongy bone sandwiched between  plates of compact bone.    @ What type of section has been cut from a long bone in (a)?    bone cells associated with the central canal via gap junctions  between osteocytes.   Central canals extend longitudinally through bone tissue, and  transverse perforating canals (Volkmann’s canals) connect the  central canals. Perforating canals contain larger blood vessels and  nerves by which the smaller blood vessels and nerve fibers in cen-  tral canals communicate with the surface of the bone and the med-  ullary cavity (see fig. 7.4).   Spongy bone, like compact bone, is composed of osteocytes and  extracellular matrix, but the bone cells do not aggregate around  central canals. Instead, the cells lie in the trabeculae and get nutri-  ents from substances diffusing into the canaliculi that lead to the  surfaces of these thin, bony plates.    Severe bone pain is one symptom of sickle cell disease, which is  inherited. Under low oxygen conditions, abnormal hemoglobin  (an oxygen-carrying protein) bends the red blood cells that con-    tain it into sickle shapes, obstructing circulation. Radiographs  can reveal blocked arterial blood flow in bones of sickle cell  disease patients.    R r] PRACTICE  1 Explain how bones are classified by shape.  2. List five major parts of a long bone.  3 Describe the microscopic structure of compact bone.  4 How do compact and spongy bone differ in structure?    Parts of the skeletal system begin to form during the first few weeks  of prenatal development, and bony structures continue to grow and  develop into adulthood. Bones form when bone tissue, including a  bony matrix mostly of calcium phosphate, replaces existing connec-  tive tissue in one of two ways. Bones that originate within sheet-  like layers of connective tissues are called intramembranous bones.  Bones that begin as masses of hyaline cartilage later replaced by  bone tissue are called endochondral bones (fig. 7.6).    The flat bones of the skull, clavicles, sternum, and some facial  bones, including the mandible, maxillae, and zygomatic bones, are  intramembranous (in’trah-mem’brah-nus) bones. During their  development (osteogenesis), membranelike layers of embryonic con-  nective tissue (mesenchyme) appear at the sites of the future bones.  Mesenchymal cells that are part of the connective tissues enlarge  and further differentiate into bone-forming cells called osteoblasts  (os’te-o-blasts), which, in turn, deposit bony matrix around them-  selves. Dense networks of blood vessels supply these connective tis-  sues. Spongy bone forms in all directions along the blood vessels.    FIGURE 7.4 (AP|R) Compact bone is composed of osteons cemented together by bone matrix. Extensions from osteocytes communicate through  tunnel-like canaliculi. (Note: Drawings are not to scale.)    FIGURE 7.5 (AP|RJ Scanning electron micrograph of a single osteon in compact bone (395x).    As development continues, the osteoblasts may become com-  pletely surrounded by extracellular matrix, and in this manner,  they become secluded within lacunae. At the same time, extra-  cellular matrix enclosing the cellular processes of the osteoblasts  gives rise to canaliculi. Once isolated in lacunae, these cells are  called osteocytes (fig. 7.7).    FIGURE 7.6 Fetal skeleton. (a) Note the stained developing bones of  this fourteen-week fetus. (b) Bones can fracture even before birth. This  fetus has numerous broken bones (arrows) because of an inherited defect in  collagen called osteogenesis imperfecta, which causes brittle bones.    Mesenchyme that persists outside the developing bone gives  rise to the periosteum. Osteoblasts on the inside of the periosteum  form a layer of compact bone over the surface of the newly formed  spongy bone.   This process of replacing embryonic connective tissue to form  an intramembranous bone is called intramembranous ossification.  Figure 7.8 illustrates the process of intramembranous ossification,  and table 7.1 lists the major steps of the process.    Most of the bones of the skeleton are endochondral (en’do-  kon’dral) bones. They develop from masses of hyaline cartilage  shaped like future bony structures. These cartilaginous models grow  rapidly for a time and then begin to change extensively. Cartilage  cells enlarge and their lacunae grow. The surrounding matrix breaks  down, and soon the cartilage cells die and degenerate.   As the cartilage decomposes, a periosteum forms from con-  nective tissue that encircles the developing structure. Blood ves-  sels and partially differentiated connective tissue cells invade the  disintegrating tissue. Some of the invading cells further differenti-  ate into osteoblasts and begin to form spongy bone in the spaces  previously housing the cartilage. Once completely surrounded by  the bony matrix, osteoblasts are called osteocytes. As ossification  continues, osteoblasts beneath the periosteum deposit compact  bone around the spongy bone.   The process of forming an endochondral bone by the replace-  ment of hyaline cartilage is called endochondral ossification. Its  major steps are listed in table 7.1 and illustrated in figure 7.9.   In a long bone, bone tissue begins to replace hyaline cartilage  in the center of the diaphysis. This region is called the primary ossi-  fication center, and bone develops from it toward the ends of the  cartilaginous structure. Meanwhile, osteoblasts from the periosteum  deposit compact bone around the primary ossification center. The  epiphyses of the developing bone remain cartilaginous and continue  to grow. Later, secondary ossification centers appear in the epiphy-  ses, and spongy bone forms in all directions from them. As spongy  bone is deposited in the diaphysis and in the epiphysis, a band of  cartilage called the epiphyseal plate (ep”i-fiz’e-al plat) remains  between the two ossification centers (see figs. 7.2, 7.3b, and 7.9).    FIGURE 7.7 Scanning electron micrograph (falsely colored) of an  osteocyte isolated in a lacuna (4,700x).    . Sheets of embryonic connective tissue (mesenchyme) appear  at the sites of future bones.    . Dense networks of blood vessels supply the developing  spongy bone.    . Mesenchyme on the surface of each developing structure  condenses to form periosteum.    . Osteoblasts on the inside of the periosteum deposit compact  bone over the spongy bone.    In a long bone, the diaphysis is separated from the epiphysis by  an epiphyseal plate. The cartilaginous cells of the epiphyseal plate  form four layers, each of which may be several cells thick, as  shown in figure 7.10. The first layer, or zone of resting cartilage, is  closest to the end of the epiphysis. It is composed of resting cells  that do not actively participate in growth. This layer anchors the  epiphyseal plate to the bony tissue of the epiphysis.   The second layer of the epiphyseal plate, or zone of proliferat-  ing cartilage, includes rows of many young cells undergoing mito-    . Blood vessels and differentiating osteoblasts from the  periosteum invade the disintegrating tissue.    . Osteoblasts form spongy bone in the space occupied by  cartilage.    sis. As new cells appear and as extracellular matrix forms around  them, the cartilaginous plate thickens.   The rows of older cells, left behind when new cells appear,  form the third layer, or zone of hypertrophic cartilage, enlarging  and thickening the epiphyseal plate still more. Consequently, the  entire bone lengthens. At the same time, invading osteoblasts,  which secrete calcium salts, accumulate in the extracellular matrix  adjacent to the oldest cartilage cells, and as the extracellular  matrix calcifies, the cartilage cells begin to die.    cartilage ossification Secondary Spongy  center ossification bone  center Articular  cartilage  (a) (b) (c) (d) (e) (f)    FIGURE 7.9 Major stages (a-—d fetal, e child) in the development of an endochondral bone. In an (f) adult, when bone growth ceases, an epiphyseal line  is what remains of the epiphyseal plate. (Relative bone sizes are not to scale.)    FIGURE 7.10 Epiphyseal plate. (a) The cartilaginous cells of an epiphyseal plate lie in four layers, each of which may be several cells thick.  (b) A micrograph of an epiphyseal plate (100x).    The fourth layer of the epiphyseal plate, or zone of calcified  cartilage, is thin. It is composed of dead cartilage cells and calcified  extracellular matrix.   In time, large, multinucleated cells called osteoclasts (os’te-o-  klasts) break down the calcified matrix. These large cells originate  from the fusion of single-nucleated white blood cells called mono-  cytes (see chapter 14, p. 537). Osteoclasts secrete an acid that dis-  solves the inorganic component of the calcified matrix, and their  lysosomal enzymes digest the organic components. Osteoclasts  also phagocytize components of the bony matrix. After osteoclasts  remove the extracellular matrix, bone-building osteoblasts invade  the region and deposit bone tissue in place of the calcified cartilage.   A long bone continues to lengthen while the cartilaginous cells  of the epiphyseal plates are active. However, once the ossification  centers of the diaphysis and epiphyses meet and the epiphyseal plates  ossify, lengthening is no longer possible in that end of the bone.   A developing bone thickens as compact bone is deposited on  the outside, just beneath the periosteum. As this compact bone  forms on the surface, osteoclasts erode other bone tissue on the  inside (fig. 7.11). The resulting space becomes the medullary cavity  of the diaphysis, which later fills with marrow.   The bone in the central regions of the epiphyses and diaphysis  remains spongy, and hyaline cartilage on the ends of the epiphy-  ses persists throughout life as articular cartilage. Table 7.2 lists the  ages at which various bones ossify.    If a child’s long bones are still growing, a radiograph will reveal  epiphyseal plates (fig. 7.12). If an epiphyseal plate is damaged  as a result of a fracture before it ossifies, elongation of that long  bone may prematurely cease, or if growth continues, it may be    uneven. For this reason, injuries to the epiphyses of a young  person's bones are of special concern. Surgery may be used on  an epiphysis to equalize growth of bones developing at very  different rates.    Most primary ossification centers have  appeared in the diaphyses of long bones.    FIGURE 7.12 Radiograph of the right hand. Epiphyseal plates  (arrows) in a child's bones indicate that the bones are still lengthening.    After the intramembranous and endochondral bones form, the  actions of osteoclasts and osteoblasts continually remodel them.  Bone remodeling occurs throughout life as osteoclasts resorb bone  tissue and osteoblasts replace the bone. These opposing processes  of resorption and deposition occur on the surfaces of the endosteum  and periosteum. The rate of bone remodeling is not uniform among  the types of bones; remodeling of spongy bone is faster than that    When seven-year-old Jacob fell from the tree limb,  he had been hanging about eight feet from the  ground. He landed in a crumpled heap, crying, with  his right leg at an abnormal angle. Emergency medi-  cal technicians immobilized the leg and took Jacob  to the emergency department at the nearest hos-  pital, where an X ray indicated a broken tibia. He  spent the next six weeks with his leg in a cast, and  the bone continued to heal over several months. By  the next summer, Jacob was again climbing trees—  but more carefully.   Many of us have had fractured, or broken, bones.  A fracture is classified by its cause and the nature of  the break. For example, a break due to injury is a trau-  matic fracture, whereas one resulting from disease  is a spontaneous, or pathologic, fracture. A broken  bone exposed to the outside by an opening in the  skin is termed a compound (open) fracture. It has the  added danger of infection, because microorganisms  can enter through the broken skin. A break protected  by uninjured skin is a closed fracture. Figure 7A shows  several types of traumatic fractures.    When a bone breaks, blood vessels in it also break,  and the periosteum is likely to tear. Blood from the  broken vessels spreads through the damaged area  and soon forms a hematoma, which is a localized col-  lection of blood that usually is clotted. Vessels in sur-  rounding tissues dilate, swelling and inflaming tissues.   Within days or weeks, developing blood vessels  and large numbers of osteoblasts originating from  the periosteum invade the hematoma. The osteo-  blasts rapidly divide in the regions close to the new blood ves-  sels, building spongy bone nearby. Granulation tissue develops,  and in regions farther from a blood supply, fibroblasts produce  masses of fibrocartilage. Meanwhile, phagocytic cells begin to  remove the blood clot as well as any dead or damaged cells in    of compact bone. The total mass of bone tissue in an adult skeleton  normally remains nearly constant because of the tight regulation of  bone remodeling. These ongoing processes replace 10% to 20%  of the skeleton each year. Clinical Application 7.1 describes what  happens when a bone breaks.    A number of factors influence bone development, growth, and  repair. These include nutrition, exposure to sunlight, hormonal    A greenstick fracture is  incomplete, and the  break occurs on the  convex surface of the  bend in the bone.    A transverse fracture is  complete, and the break  occurs at a right angle to  the axis of the bone.    An oblique fracture  occurs at an angle  other than a right angle  to the axis of the bone.   In time, fibrocartilage fills the gap between the ends of the bro-  ken bone. This mass, a soft (cartilaginous) callus, is later replaced  by bone tissue in much the same way that the hyaline cartilage of    secretions, and physical exercise. For example, vitamin D is neces-  sary for proper absorption of dietary calcium in the small intestine.  Without this vitamin, dietary calcium is poorly absorbed and the  inorganic salt portion of bone matrix will lack calcium, softening  and thereby deforming bones. In children, this condition is called  rickets, and in adults, it is called osteomalacia.   Vitamin D is scarce in natural foods, except for eggs, but it  is readily available in milk and other dairy products fortified with  vitamin D. An inactive form of vitamin D also forms when dehy-  drocholesterol, produced by skin cells or obtained in the diet and  carried by the blood to the skin, is exposed to ultraviolet light.    a developing endochondral bone is  replaced. That is, the cartilaginous cal-  lus breaks down, blood vessels and  osteoblasts invade the area, and a hard  (bony) callus fills the space.   Typically, more bone is produced  at the site of a healing fracture than is  necessary to replace the damaged tis-  sues. Osteoclasts remove the excess,  and the result is a bone shaped much  like the original. Figure 7B shows the  steps in the healing of a fracture.   If the ends of a broken bone are  close together, healing is faster than if  they are far apart. Physicians can help  the bone-healing process. The first  casts to immobilize fractured bones  were introduced in Philadelphia in  1876, and soon after, doctors began  using screws and plates internally  to align healing bone parts. Today,  orthopedic surgeons also use rods,  wires, and nails. These devices have  become lighter and smaller; many  are built of titanium. A device called  a hybrid fixator treats a broken leg  using metal pins internally to align  bone pieces. The pins are anchored  to a metal ring device worn outside  the leg.   Some bones naturally heal more  rapidly than others. The long bones  of the upper limbs, for example,  may heal in half the time required by  the long bones of the lower limbs,  as Jacob was unhappy to discover.  However, his young age would favor  quicker healing.    This inactive form of vitamin D is then processed in the liver and  kidneys to become the active form of vitamin D.  Vitamins A and C are also required for normal bone develop-    (a) Blood escapes from ruptured blood  vessels and forms a hematoma.    (b) Spongy bone forms in regions close to  developing blood vessels, and fibrocartilage  forms in more distant regions.    (d) Osteoclasts remove excess bony tissue,  restoring new bone structure much like  the original.    ment and growth. Vitamin A is necessary for osteoblast and osteo-  clast activity during normal development. This is why deficiency  of vitamin A may retard bone development. Vitamin C is required  for collagen synthesis. Deficiency inhibits bone development.  Osteoblasts cannot produce enough collagen in the extracellular  matrix of the bone tissue, and as a result, bones are abnormally  slender and fragile.    About 90% of the protein that is part of bone is collagen. Less    e Osteocalcin is activated by vitamin K to bind calcium, which    Osteonectin binds hydroxyapatite and collagen and stimu-  lates mineral crystal deposition in bone.  Osteopontin speeds bone remodeling.  Bone morphogenetic proteins include growth factors that   induce bone and cartilage formation. They are used in spinal  fusion procedures.    Hormones secreted by the pituitary gland, thyroid gland,  parathyroid glands, and ovaries or testes affect bone growth and  development. The pituitary gland secretes growth hormone,  which stimulates division of cartilage cells in the epiphyseal  plates. If too little growth hormone is secreted, the long bones  of the limbs fail to develop normally, and the child has pituitary  dwarfism. He or she is very short but has normal body propor-  tions. If excess growth hormone is released before the epiphy-  seal plates ossify, height may exceed 8 feet—a condition called  pituitary gigantism. In an adult, secretion of excess growth  hormone causes acromegaly, in which the hands, feet, and jaw  enlarge (see chapter 13, p. 500).   The thyroid hormone thyroxine stimulates replacement of  cartilage in the epiphyseal plates of long bones with bone tissue.  This hormone increases cellular metabolism, including stimulat-  ing osteoblast activity. In contrast to the bone-forming activity of  thyroid hormone, parathyroid hormone stimulates an increase in  the number and activity of osteoclasts, which break down bone  (see chapter 13, pp. 505-507).    Abnormal swings in blood sugar are less likely in individu-  als who exercise regularly. Part of the reason may be that the  bone protein osteocalcin appears to act as a hormone, released    from bones after the stress of exercise. Osteocalcin works with  another hormone, insulin, to help the body regulate blood  sugar levels more precisely.    Both male and female sex hormones (called testosterone  and estrogens, respectively) from the testes and ovaries promote  formation of bone tissue. Beginning at puberty, these hormones  are abundant, causing the long bones to grow considerably (see  chapter 22, pp. 838-839 and 849). However, sex hormones also  stimulate ossification of the epiphyseal plates, and consequently  they stop bone lengthening at a relatively early age. The effect  of estrogens on the epiphyseal plates is somewhat stronger than  that of testosterone. For this reason, females typically reach their  maximum heights earlier than males.   Physical stress also stimulates bone growth. For example,  when skeletal muscles contract, they pull at their attachments on  bones, and the resulting stress stimulates the bone tissue to thicken  and strengthen (hypertrophy). Conversely, with lack of exercise,  the same bone tissue becomes thinner and weaker. This condition,  called atrophy, is why the bones of athletes are usually stronger  and heavier than those of nonathletes (fig. 7.13). Atrophy is also  why fractured bones immobilized in casts may shorten. Clinical  Application 7.2 describes the importance of calcium, vitamin D,  and exercise for maintaining healthy bones.    8 Explain how nutritional factors affect bone development.  9 What effects do hormones have on bone growth?    FIGURE 7.13 Note the increased amount of bone at the sites of  muscle attachments in the femur on the left. The thickened bone is better  able to withstand the forces resulting from muscle contraction.    Bones shape, support, and protect body structures, as well as aid  body movements. They house tissue that produces blood cells, and  store various inorganic salts.    Bones give shape to structures such as the head, face, thorax, and  limbs. They also support and protect. For example, the bones of  the lower limbs, pelvis, and vertebral column support the body’s  weight. The bones of the skull protect the eyes, ears, and brain.  Bones of the rib cage and shoulder girdle protect the heart and  lungs, whereas bones of the pelvic girdle protect the lower abdom-  inal and internal reproductive organs. Whenever limbs or other  body parts move, bones and muscles interact.    The process of blood cell formation, called hematopoiesis  (hem”ah-to-poi-e’sis), or hemopoiesis, begins in the yolk sac,  which lies outside the embryo (see chapter 23, p. 874). Later in  development, blood cells are manufactured in the liver and spleen,  and still later, they form in bone marrow.   Marrow is a soft, netlike mass of connective tissue in the med-  ullary cavities of long bones, in the irregular spaces of spongy  bone, and in the larger central canals of compact bone tissue. The  two types of marrow are red and yellow. In red marrow, red blood  cells (erythrocytes), white blood cells (leukocytes), and blood plate-  lets form. The color comes from the red, oxygen-carrying pigment  hemoglobin in red blood cells.   The distribution of the two types of marrow changes with age.  In an infant, the cavities of most bones house red marrow, but with  time, yellow marrow replaces much of it. Yellow marrow stores fat  and does not produce blood cells. In an adult, red marrow is primar-  ily found in the spongy bone of the skull, ribs, sternum, clavicles,  vertebrae, and hip bones. If the blood cell supply is deficient, some    yellow marrow may become red marrow and produce blood cells.  Then, the red marrow reverts to yellow marrow when the deficiency  is corrected. Chapter 14 (pp. 531, 533, 536, and 539) discusses  blood cell formation in more detail.    Bone marrow transplants have been used for more than half  a century to enable people with certain cancers to tolerate  high levels of chemotherapy drugs. Replacing bone marrow  is also a way to treat an inherited disorder of blood cells (such  as sickle cell disease) or a disease of the descendants of these  cells that function outside the circulation (such as the brain  disease adrenoleukodystrophy).   In a bone marrow transplant, a hollow needle and syringe  remove normal red marrow cells from the spongy bone of a  donor, or stem cells (which can give rise to specialized blood  cells) are separated out from the donor's bloodstream. Stem  cells from the umbilical cord of a newborn can be used in place  of bone marrow and are less likely to stimulate an immune  response in the recipient.   Donors are selected based on their cells having a pat-  tern of molecules on their surfaces that closely matches that of  the recipient's cells. In 30% of bone marrow transplants from  donors, the donor is a blood relative. The cells are injected into  the bloodstream of the recipient, whose own marrow has been  intentionally destroyed with radiation or chemotherapy. If all  goes well, the donor cells travel to the spaces within bones that  red marrow normally occupies, where they replenish the blood  supply with healthy cells. About 5% of patients die from infection  because their immune systems reject the transplant, or because  the transplanted tissue attacks the recipient, a condition called  graft-versus-host disease.   Safer than a bone marrow transplant for some conditions is  an autologous (“self”) stem cell transplant. Stem cells are taken  from a patient's bloodstream, and a mutation is corrected or  healthy cells are separated and cultured. Or the bone marrow  is stimulated to make stem cells, which are isolated. Then high  doses of chemotherapy or radiation are used to destroy the rest  of the bone marrow in the patient's body, and the patient's stem  cells are infused. They migrate to the bone marrow and recon-  stitute a disease-free blood-forming system that the patient's  immune system does not reject.    Recall that the extracellular matrix of bone tissue includes collagen  and inorganic mineral salts. The salts account for about 70% of the  extracellular matrix by weight and are mostly small crystals of a  type of calcium phosphate called hydroxyapatite.   The human body requires calcium for a number of vital meta-  bolic processes, including muscle cell contraction, nerve cell con-  duction, and blood clot formation. When the blood is low in calcium,  parathyroid hormone stimulates osteoclasts to break down bone tis-  sue, releasing calcium salts from the extracellular matrix into the  blood. Very high blood calcium inhibits osteoclast activity, and cal-  citonin from the thyroid gland stimulates osteoblasts to form bone  tissue, storing excess calcium in the extracellular matrix (fig. 7.14).    This response is particularly important in developing bone matrix in  children. The details of the homeostatic mechanism that controls cal-  cium levels in the blood are in chapter 13, pp. 505-508.   In addition to storing calcium and phosphorus (as calcium  phosphate), bone tissue contains smaller amounts of magnesium,  sodium, potassium, and carbonate ions. Bones also accumulate  certain harmful metallic elements such as lead, radium, and stron-  tium, which are not normally present in the body but are some-  times accidentally ingested.    Cells in the thyroid  gland sense the  increase in blood  calcium.    Skeletal health is a matter of balance. Before age thirty, cells that  form new bone counter cells that degrade it, so that living bone is  in a constant state of remodeling. Then the balance shifts so that  bone is lost, especially in women past menopause, due to hor-  monal changes. This imbalance may progress to osteopenia or the  more severe osteoporosis (fig. 7C).   A "fragility fracture” is a telltale sign of dangerously low bone  density. This is a fracture that happens after a fall from less than  standing height, which a strong, healthy skeleton could resist.  Fragility fractures occur in more than 2 million people in the  United States each year, yet despite this warning sign, only one-  fourth to one-third of them are followed up with bone scans and  treatment to build new bone tissue. Since 1995, five new drugs  have become available to treat osteoporosis. One class, the  bisphosphonates, actually builds new bone.   Osteopenia and osteoporosis are common. The surgeon gen-  eral estimates that half of all people over age fifty have one of  these conditions, which amounts to 10 million with osteoporosis  and another 35 million with osteopenia. Screening is advised for all  individuals over age sixty-five, as well as for those with risk factors.  The most telling predictor is a previous fragility fracture. Other risk  factors include a family history of osteoporosis, recent height loss,  and older age.   Osteopenia and osteoporosis are not just concerns of older  people approaching retirement age. People of all ages can  take steps to avoid developing these preventable conditions.  Researchers think that what puts people at risk is failure to attain  maximal possible bone density by age thirty. To keep bones as    12 Distinguish between the functions of red marrow and yellow  marrow.    The number of bones in an adult human skeleton is often reported  to be 206 (table 7.3), but the number varies because people may  lack certain bones or have extra ones. For example, the flat bones of  the skull usually grow together and tightly join along irregular lines  called sutures. In some people, extra bones called sutural bones  (wormian bones) develop in these sutures (fig. 7.15). Extra small,  round sesamoid bones may develop in tendons, where they reduce  friction in places where tendons pass over bony prominences.    FIGURE 7C Spaces in bones enlarge when a person has osteoporosis.  The portion of a vertebra on the left is normal; the one on the right  has been weakened by osteoporosis.    strong as possible for as long as possible, it is essential to get  at least 30 minutes of exercise daily (some of which should be  weight-bearing), consume enough daily calcium (1,000-1,200 mg)  and vitamin D (600-4,000 IU), and not smoke. There is much you  can do to promote skeletal health—at any age.    For purposes of study, it is convenient to divide the skeleton into  two major portions—an axial skeleton and an appendicular skeleton  (fig. 7.16). The axial skeleton consists of the bony and cartilaginous  parts that support and protect the organs of the head, neck, and trunk.  These parts include the following:    1. The skull is composed of the cranium (brain case) and the  facial bones.   2. The middle ear bones transfer sound vibrations to the hearing  receptors.   3. The hyoid (hi’oid) bone is located in the neck between the  lower jaw and the larynx (fig. 7.17). It does not articulate  with any other bones but is fixed in position by muscles and  ligaments. The hyoid bone supports the tongue and is an  attachment for certain muscles that help move the tongue  during swallowing. It can be felt approximately a finger’s  width above the anterior prominence of the larynx.   4. The vertebral column, or spinal column, consists of many  vertebrae separated by cartilaginous intervertebral discs.  This column forms the central axis of the skeleton. Near its  distal end, five vertebrae fuse to form the sacrum (sa’krum),    8 cranial bones  frontal 1  parietal 2  occipital 1  temporal 2  sphenoid 1  ethmoid 1   . Vertebral column  cervical vertebra 7  thoracic vertebra 12  lumbar vertebra 5  sacrum 1    part of the pelvis. A small tailbone formed by the fusion of  four vertebrae and called the coccyx (kok’siks) is attached to  the end of the sacrum.   . The thoracic cage protects the organs of the thoracic cavity  and the upper abdominal cavity. It is composed of twelve  pairs of ribs, which articulate posteriorly with the thoracic  vertebrae. It also includes the sternum (ster’num), or  breastbone, to which most of the ribs are attached anteriorly.    and lower limbs and the bones that anchor the limbs to the axial  skeleton. It includes the following:    1. The pectoral girdle is formed by a scapula (scap’u-lah), or  shoulder blade, and a clavicle (klav’i-k’1), or collarbone, on  both sides of the body. The pectoral girdle connects the bones  of the upper limbs to the axial skeleton and aids in upper limb  movements.   2. Each upper limb consists of a humerus (hu’mer-us), or arm  bone; two forearm bones—a radius (ra’de-us) and an ulna  (ul’nah)—and a hand. The humerus, radius, and ulna articulate  with each other at the elbow joint. At the distal end of the radius  and ulna is the hand. There are eight carpals (kar’palz), or  wrist bones. The five bones of the palm are called metacarpals  (met”ah-kar’palz), and the fourteen finger bones are called  phalanges (fah-lan’jéz; sing., phalanx, fa’lanks).    FIGURE 7.15 Sutural (wormian) bones are extra bones that  sometimes develop in sutures between the flat bones of the skull.    FIGURE 7.16 (AP|R) Major bones of the skeleton. (a) Anterior view. (b) Posterior view. The axial portion is shown in orange, and the appendicular    FIGURE 7.17 (AP|R} The hyoid bone supports the  tongue and serves as an attachment for muscles that move  the tongue and function in swallowing.    3. The pelvic girdle is formed by two hip bones attached to each  other anteriorly and to the sacrum posteriorly. They connect  the bones of the lower limbs to the axial skeleton and, with  the sacrum and coccyx, form the pelvis, which protects the  lower abdominal and internal reproductive organs.   4. Each lower limb consists of a femur (fe’mur), or thigh bone;  two leg bones—a large tibia (tib’e-ah), or shin bone, and a  slender fibula (fib’u-lah)—and a foot. The femur and tibia  articulate with each other at the knee joint, where the patella  (pah-tel’ah), or kneecap, covers the anterior surface. At the  distal ends of the tibia and fibula is the foot. There are seven  tarsals (tahr’salz), or ankle bones. The five bones of the instep  are called metatarsals (met’ah-tar’salz), and the fourteen  bones of the toes (like those of the fingers) are called phalanges.  Table 7.4 defines some terms used to describe skeletal structures.    16 List the bones of the axial skeleton and of the appendicular skeleton.    A human skull usually consists of twenty-two bones that, except  for the lower jaw, are firmly interlocked along immovable joints  called sutures. Eight of these interlocked bones make up the  cranium and fourteen form the facial skeleton. The mandible  (man’di-b’1), or lower jawbone, is a movable bone held to the cra-  nium by ligaments (figs. 7.18 and 7.19). Some facial and cranial  bones together form the orbit of the eye (fig. 7.20). Plates 26-54  on pages 252-266 show a set of photographs of the human skull  and its parts.    The cranium (kra’ne-um) encloses and protects the brain, and its  surface provides attachments for muscles that make chewing and  head movements possible. Some of the cranial bones contain air-  filled cavities called paranasal sinuses, lined with mucous mem-  branes and connected by passageways to the nasal cavity (fig. 7.21).  Sinuses reduce the weight of the skull and increase the intensity of  the voice by serving as resonant sound chambers.    Fossa (fos’ah)  Fovea (fo’ve-ah)  Head (hed)  Linea (lin’e-ah)  Meatus (me-a’tus)  Process (pros’es)  Ramus (ra’mus)  Sinus (si’nus)  Spine (spin)  Sulcus (sul’kus)  Suture (soo’cher)    Soft spot in the skull where membranes cover the  space between bones    Opening through a bone that usually serves as a  passageway for blood vessels, nerves, or ligaments   Tubelike passageway within a bone  Prominent projection on a bone  Branch or similar extension    lliac crest of the ilium (fig. 7.49)  Medial epicondyle of the humerus (fig. 7.44)  Rib facet of a thoracic vertebra (fig. 7.376)    Inferior orbital fissure in the orbit of the eye (fig. 7.19)    Olecranon fossa of the humerus (fig. 7.44b)  Fovea capitis of the femur (fig. 7.52b)  Head of the humerus (fig. 7.44)    Mastoid process of the temporal bone (fig. 7.19)  Ramus of the mandible (fig. 7.30a)    Greater trochanter of the femur (fig. 7.52a)  Tubercle of a rib (fig. 7.40)  Radial tuberosity of the radius (fig. 7.45a)    skull above the eyes, including the forehead, the roof of the  nasal cavity, and the roofs of the orbits (bony sockets) of the  eyes. On the upper margin of each orbit, the frontal bone is  marked by a supraorbital foramen (or supraorbital notch in  some skulls) through which blood vessels and nerves pass to  the tissues of the forehead. Within the frontal bone are two  frontal sinuses, one above each eye near the midline (fig. 7.21).  The frontal bone is a single bone in adults, but it develops in  two parts (see fig. 7.32). These halves grow together and usu-  ally completely fuse by the fifth or sixth year of life.    . One parietal (pah-ri’é-tal) bone is located on each side of the    skull just behind the frontal bone. Each is shaped like a curved  plate and has four borders. Together, the parietal bones form  the bulging sides and roof of the cranium. They are fused at  the midline along the sagittal suture, and they meet the frontal  bone along the coronal suture.    the lambdoid (lam’doid) suture. It forms the back of the skull  and the base of the cranium. A large opening on its lower  surface is the foramen magnum, where the inferior part of the  brainstem connects with the spinal cord. Rounded processes  called occipital condyles, located on each side of the foramen  magnum, articulate with the first vertebra (atlas) of the verte-  bral column.    the parietal bone along a squamous suture. The temporal  bones form parts of the sides and the base of the cranium.  Located near the inferior margin is an opening, the exter-   nal acoustic (auditory) meatus, which leads inward to parts  of the ear. The temporal bones also house the internal ear  structures and have depressions called the mandibular fossae  (glenoid fossae) that articulate with condyles of the mandible.  Below each external acoustic meatus are two projections—a  rounded mastoid process and a long, pointed styloid process  (see fig. 7.20). The mastoid process provides an attachment  for certain muscles of the neck, whereas the styloid process  anchors muscles associated with the tongue and pharynx. An    Sphenoid (1) Forms parts of base of cranium, sides of skull,    Ethmoid (1) Forms parts of roof and walls of nasal cavity,  floor of cranium, and walls of orbits    opening near the mastoid process, the carotid canal, transmits  the internal carotid artery. An opening between the temporal and  occipital bones, the jugular foramen, accommodates the inter-  nal jugular vein (fig. 7.22).    The mastoid process may become infected. The tissues in this  region of the temporal bone contain a number of interconnected  spaces known as air cells that are lined with mucous membranes  that communicate with the middle ear. Microorganisms from an    infected middle ear (otitis media) can spread into the air cells,  causing infection and inflammation, called mastoiditis.The dan-  ger is that the infection may spread to nearby membranes that  surround the brain.    A zygomatic process projects anteriorly from the tempo-  ral bone in the region of the external acoustic meatus. It joins  the temporal process of the zygomatic bone and helps form the  prominence of the cheek, the zygomatic arch (fig. 7.22).   5. The sphenoid (sfe’noid) bone is wedged between several  other bones in the anterior portion of the cranium (fig. 7.23).  It consists of a central part and two winglike structures that  extend laterally toward each side of the skull. This bone helps  form the base of the cranium, the sides of the skull, and the  floors and sides of the orbits. Along the midline within the  cranial cavity, a portion of the sphenoid bone indents to form  the saddle-shaped sella turcica (sel’ah tur’si-ka) (Turk’s  saddle). In this depression lies the pituitary gland, which  hangs from the base of the brain by a stalk.   The sphenoid bone also contains two sphenoidal sinuses  (see fig. 7.21). These lie side by side and are separated by a  bony septum that projects downward into the nasal cavity.   6. The ethmoid (eth’moid) bone is located in front of the  sphenoid bone (fig. 7.24). It consists of two masses, one  on each side of the nasal cavity, joined horizontally by thin  cribriform (krib’ri-form) plates. These plates form part of the  roof of the nasal cavity, and nerves associated with the sense  of smell pass through tiny openings (olfactory foramina) in  them. Portions of the ethmoid bone also form sections of the    External acoustic meatus, mandibular fossa, mastoid process, styloid  process, zygomatic process    Cribriform plates, perpendicular plate, superior and middle nasal  conchae, ethmoidal air cells, crista galli    External acoustic meatus  : Jugular foramen  Mastoid process  Stylomastoid foramen  Occipital condyle  Foramen magnum  Temporal bone  Lambdoid suture    FIGURE 7.23 fAP|R) The sphenoid bone. (a) Superior view. (b) Posterior view.    FIGURE 7.24 fAP|R) The ethmoid bone. (a) Superior view. (b) Posterior view.    cranial floor, orbital walls, and nasal cavity walls. A perpen-  dicular plate projects downward in the midline from the  cribriform plates to form most of the nasal septum.   Delicate, scroll-shaped plates called the superior nasal  concha (kong’kah) and the middle nasal concha project  inward from the lateral portions of the ethmoid bone toward  the perpendicular plate. These bony plates support mucous  membranes that line the nasal cavity. The mucous mem-  branes, in turn, begin moistening, warming, and filtering air  as it enters the respiratory tract. The lateral portions of the  ethmoid bone contain many small spaces, the ethmoidal air  cells, that together form the ethmoidal sinus (see fig. 7.21).  Figure 7.25 shows various structures in the nasal cavity.   Projecting upward into the cranial cavity between the crib-  riform plates is a triangular process of the ethmoid bone called    The facial skeleton consists of thirteen immovable bones and a  movable lower jawbone. In addition to forming the basic shape of  the face, these bones provide attachments for muscles that move  the jaw and control facial expressions.    1. The maxillae (mak-sil’e; sing., maxilla, mak-sil’ah)  form the upper jaw; together they form the keystone of the  face, because the other immovable facial bones articulate  with them.    Portions of the maxillary bones compose the anterior 2. The L-shaped palatine (pal’ah-tin) bones are located behind  roof of the mouth (hard palate), the floors of the orbits, and the maxillae (fig. 7.27). The horizontal portions of these  the sides and floor of the nasal cavity. They also contain the bones form the posterior section of the hard palate and the  sockets of the upper teeth. Inside the maxillae, lateral to floor of the nasal cavity. The perpendicular portions of the  the nasal cavity, are maxillary sinuses (see fig. 7.21). These bones help form the lateral walls of the nasal cavity.  spaces are the largest of the sinuses, and they extend from 3. The zygomatic (zi”go-mat’ik) bones are responsible for the  the floor of the orbits to the roots of the upper teeth. During prominences of the cheeks below and to the sides of the eyes.  development, portions of the maxillary bones called palatine These bones also help form the lateral walls and the floors of  processes grow together and fuse along the midline, or the orbits. Each bone has a temporal process, which extends  median palatine suture. This structure forms the anterior posteriorly to join the zygomatic process of a temporal bone  section of the hard palate (see fig. 7.22). (see fig. 7.20).    A cleft palate results from incomplete fusion of the palatine  processes of the maxillae by the time of birth. An infant with a  cleft palate may have trouble sucking a bottle due to the open-  ing between the oral and nasal cavities. A temporary prosthetic    device (artificial palate) worn in the mouth, or a special type  of nipple placed on a bottle, can help the child eat and drink  until surgery corrects the cleft. This surgery is best performed  between the ages of twelve and eighteen months.    The inferior border of each maxillary bone projects  downward, forming an alveolar (al-ve’o-lar) process.  Together these processes form a horseshoe-shaped alveolar  arch (dental arch). Teeth occupy cavities (dental alveoli) in FIGURE 7.27 The horizontal portions of the palatine bones form the    this arch (see chapter 17, p. 655). Dense connective tissue posterior section of the hard palate, and the perpendicular portions help  binds teeth to the bony sockets. form the lateral walls of the nasal cavity.    in the medial wall of each orbit between the ethmoid bone and  the maxilla (see fig. 7.20). A groove in its anterior portion leads  from the orbit to the nasal cavity, providing a pathway for a  channel that carries tears from the eye to the nasal cavity.    lar (see fig. 7.18). They lie side by side and are fused at the  midline, where they form the bridge of the nose. These bones  are attachments for the cartilaginous tissues that form the  shape of the nose.   The thin, flat vomer (vo’mer) bone is located along the mid-  line within the nasal cavity. Posteriorly, the vomer bone joins  the perpendicular plate of the ethmoid bone, and together the  two bones form the nasal septum (figs. 7.28 and 7.29).    shaped bones attached to the lateral walls of the nasal cavity.  They are the largest of the conchae and are below the superior  and middle nasal conchae of the ethmoid bone (see figs. 7.18  and 7.25). Like the ethmoidal conchae, the inferior conchae  support mucous membranes in the nasal cavity.   The mandible (man’di-bl), or lower jawbone, is a horizontal,  horseshoe-shaped body with a vertical, flat ramus project-  ing upward at each end. The rami are divided into a posterior    mandibular condyle and an anterior coronoid (kor’o-noid)  process (fig. 7.30). The mandibular condyles articulate with  the mandibular fossae of the temporal bones, whereas the  coronoid processes provide attachments for muscles used in  chewing. Other large chewing muscles are inserted on the  lateral surfaces of the rami. On the superior border of the  mandible, the alveolar processes contain the hollow sockets  (dental alveoli) that bear the lower teeth.   On the medial side of the mandible, near the center of  each ramus, is a mandibular foramen. This opening admits  blood vessels and a nerve, which supply the roots of the  lower teeth. Dentists inject anesthetic into the tissues near  this foramen to temporarily block impulse conduction and  desensitize teeth on that side of the jaw. Branches of the  blood vessels and the nerve emerge from the mandible  through the mental foramen, which opens on the outside  near the point of the jaw. They supply the tissues of the  chin and lower lip.    Table 7.6 describes the fourteen facial bones. Figure 7.31  shows features of these bones on radiographs. Table 7.7 lists the  major openings (foramina) and passageways through bones of the  skull, as well as their general locations and the structures that pass  through them.    FIGURE 7.30 (AP|R} Mandible. (a) Left lateral view. (b) Inferior view.    Name and  Number Description Special Features  Maxilla (2) Form upper jaw, anterior Alveolar processes, maxillary  roof of mouth, floors of sinuses, palatine process  orbits, and sides and floor  of nasal cavity  Palatine (2) Form posterior roof of  mouth and floor and lateral  walls of nasal cavity  Zygomatic (2) Form prominences of Temporal process  cheeks and lateral walls  and floors of orbits  Lacrimal (2) Form part of medial walls Groove that leads from orbit to  of orbits nasal cavity  Nasal (2) Form bridge of nose  Vomer (1) Forms inferior portion of  nasal septum  Inferior nasal — Extend into nasal cavity  concha (2) from its lateral walls  Mandible (1) Forms lower jaw Body, ramus, mandibular  condyle, coronoid process,  alveolar process, mandibular  foramen mente Wforamen FIGURE 7.31 (AP|R) Radiograph of the skull. Anterior view.  TABLE 7.7 Passageways Through Bones of the Skull  Passageway Location Major Structures Passing Through  Carotid canal (fig. 7.22) Inferior surface of the temporal bone Internal carotid artery, veins, and nerves  Foramen lacerum (fig. 7.22) Floor of cranial cavity between temporal and Branch of pharyngeal artery (in life, opening is largely  sphenoid bones covered by fibrocartilage)  Foramen magnum (fig. 7.26) Base of skull in occipital bone Inferior part of brainstem connecting to spinal cord, also  certain arteries  Foramen ovale (fig. 7.22) Floor of cranial cavity in sphenoid bone Mandibular division of trigeminal nerve and veins  Foramen rotundum (fig. 7.26) Floor of cranial cavity in sphenoid bone Maxillary division of trigeminal nerve  Foramen spinosum (fig. 7.26) Floor of cranial cavity in sphenoid bone Middle meningeal blood vessels and branch of mandibular nerve    Greater palatine foramen (fig. 7.22) Posterior portion of hard palate in palatine bone _ Palatine blood vessels and nerves    Hypoglossal canal (fig. 7.28) Near margin of foramen magnum in occipital bone Hypoglossal nerve   Incisive foramen (fig. 7.22) Incisive fossa in anterior portion of hard palate Nasopalatine nerves, openings of vomeronasal organ   Inferior orbital fissure (fig. 7.20) Floor of the orbit Maxillary nerve and blood vessels   Infraorbital foramen (fig. 7.20) Below the orbit in maxillary bone Infraorbital blood vessels and nerves   Internal acoustic meatus (fig. 7.26) Floor of cranial cavity in temporal bone Branches of facial and vestibulocochlear nerves and   Jugular foramen (fig. 7.26) Base of the skull between temporal and Glossopharyngeal, vagus and accessory nerves, and  occipital bones blood vessels   Mandibular foramen (fig. 7.30) Inner surface of ramus of mandible Inferior alveolar blood vessels and nerves   Mental foramen (fig. 7.30) Near point of jaw in mandible Mental nerve and blood vessels   Stylomastoid foramen (fig. 7.22) Between styloid and mastoid processes Facial nerve and blood vessels   Superior orbital fissure (fig. 7.20) Posterior wall of orbit Oculomotor, trochlear, and abducens nerves and ophthalmic    Supraorbital foramen (fig. 7.18) Upper margin or orbit in frontal bone Supraorbital blood vessels and nerves    FIGURE 7.32 Fontanels. (a) Right lateral view and (b) superior view of the infantile skull.    At birth, the skull is incompletely developed, with fibrous mem-  branes connecting the cranial bones. These membranous areas  of incomplete intramembranous ossification are called fontanels  (fon”tah-nel’z), or, more commonly, soft spots (fig. 7.32). They  permit some movement between the bones so that the developing  skull is partially compressible and can slightly change shape. This  action, called molding, eases passage of an infant’s skull through  the birth canal. Eventually, the fontanels close as the cranial bones  grow together. The posterior fontanel usually closes about two  months after birth; the sphenoidal fontanel closes at about three  months; the mastoid fontanel closes near the end of the first year;  and the anterior fontanel may not close until the middle or end of  the second year.    Other characteristics of an infantile skull include a small face  with a prominent forehead and large orbits. The jaw and nasal cav-  ity are small, the sinuses are incompletely formed, and the frontal  bone is in two parts (reference plate 51, p. 265). The skull bones  are thin, but they are also somewhat flexible and thus are less easily  fractured than adult bones.    17 Locate and name each of the bones of the cranium.    19 Explain how an adult skull differs from that of an infant.    The vertebral column extends from the skull to the pelvis and  forms the vertical axis of the skeleton (fig. 7.33). It is composed  of many bony parts called vertebrae (ver’té-bre) separated by  masses of fibrocartilage called intervertebral discs and connected  to one another by ligaments. The vertebral column supports the  head and the trunk of the body, yet is flexible enough to permit    movements, such as bending forward, backward, or to the side and  turning or rotating on the central axis. It also protects the spinal  cord, which passes through a vertebral canal formed by openings  in the vertebrae.   An infant has thirty-three separate bones in the vertebral col-  umn. Five of these bones eventually fuse to form the sacrum, and  four others join to become the coccyx. As a result, an adult verte-  bral column has twenty-six bones.    FIGURE 7.33 (AP|R) The curved vertebral column consists of many vertebrae separated by intervertebral discs. (a) Right lateral view. (b) Posterior view.    Normally, the vertebral column has four curvatures, which  give it a degree of resiliency. The names of the curves correspond  to the regions where they are located, as figure 7.33 shows. The  thoracic and sacral curvatures are concave anteriorly and are  called primary curves. The cervical curvature in the neck and the  lumbar curvature in the lower back are convex anteriorly and are  called secondary curves. The cervical curvature develops when a  baby begins to hold up its head, and the lumbar curvature develops  when the child begins to stand.    The vertebrae in different regions of the vertebral column have spe-  cial characteristics, but they also have features in common. A typical  vertebra has a drum-shaped body, which forms the thick, anterior  portion of the bone (fig. 7.34). A longitudinal row of these verte-  bral bodies supports the weight of the head and trunk. The interver-  tebral discs, which separate adjacent vertebrae, are fastened to the  roughened upper and lower surfaces of the vertebral bodies. These  discs cushion and soften the forces generated by such movements  as walking and jumping, which might otherwise fracture vertebrae  or jar the brain. The bodies of adjacent vertebrae are joined on their  anterior surfaces by anterior longitudinal ligaments and on their  posterior surfaces by posterior longitudinal ligaments.   Projecting posteriorly from each vertebral body are two short  stalks called pedicles (ped’i-k’1z). They form the sides of the vertebral    foramen. Two plates called laminae (lam’i-ne) arise from the pedicles  and fuse in the back to become a spinous process. The pedicles, lami-  nae, and spinous process together complete a bony vertebral arch  around the vertebral foramen, through which the spinal cord passes.    If the laminae of the vertebrae fail to unite during development,  the vertebral arch remains incomplete, causing a condition call  spina bifida. The contents of the vertebral canal protrude. This    problem occurs most frequently in the lumbrosacral region.  Spina bifida is associated with folic acid deficiency in certain  genetically susceptible individuals.    Between the pedicles and laminae of a typical vertebra is a  transverse process, which projects laterally and posteriorly. Various  ligaments and muscles are attached to the dorsal spinous process  and the transverse processes. Projecting upward and downward  from each vertebral arch are superior and inferior articular pro-  cesses. These processes bear cartilage-covered facets by which each  vertebra is joined to the one above and the one below it.   On the lower surfaces of the vertebral pedicles are notches  that align with adjacent vertebrae to help form openings called  intervertebral foramina (in’ter-ver’té-bral fo-ram’i-nah). These  openings provide passageways for spinal nerves (see fig. 7.33).    FIGURE 7.34 Typical thoracic vertebra. (a) Right lateral view. (b) Adjacent vertebrae join at their articular processes. (c) Superior view.    Posterior : a  with occipital condyle Vertebral  foramen  Transverse  process  Facet that articulates Transverse  Anterior with dens (odontoid process) foramen  of axis  (a)  . Anterior articular :  Superior ic facet for atlas Spi POstenor  Spinous Dens — i pinous process  process Superior  articular facet  Transverse  foramen  Inferior Body  Inferior articular  process Transverse vo  process . Anterior  Dens (odontoid  (b) (c) process)    FIGURE 7.35 fAP|R) Atlas and axis. (a) Superior view of the atlas. (b) Right lateral view and (c) superior view of the axis.    Seven cervical vertebrae comprise the bony axis of the neck.  These are the smallest vertebrae, but their bone tissues are denser  than those in any other region of the vertebral column.   The transverse processes of the cervical vertebrae are distinc-  tive because they have transverse foramina, which are passage-  ways for arteries leading to the brain. Also, the spinous processes  of the second through the sixth cervical vertebrae are uniquely  forked (bifid). These processes provide attachments for muscles.   The spinous process of the seventh vertebra is longer and pro-  trudes beyond the other cervical spines. It is called the vertebra  prominens, and because it can be felt through the skin, it is a useful  landmark for locating other vertebral parts (see fig. 7.33).   Two of the cervical vertebrae, shown in figure 7.35, are of spe-  cial interest. The first vertebra, or atlas (at’las), supports the head.  It has practically no body or spine and appears as a bony ring with  two transverse processes. On its superior surface, the atlas has two  kidney-shaped facets, which articulate with the occipital condyles.   The second cervical vertebra, or axis (ak’sis), bears a toothlike  dens (odontoid process) on its body. This process projects upward  and lies in the ring of the atlas. As the head is turned from side  to side, the atlas pivots around the dens (fig. 7.35). Figure 7.36 is  a radiograph showing the cervical vertebrae.    The twelve thoracic vertebrae are larger than those in the cervi-  cal region. Their transverse processes project posteriorly at sharp  angles. Each vertebra has a long, pointed spinous process, which    slopes downward, and a facet on each side of its body which artic-  ulates with a rib head.   Beginning with the third thoracic vertebra and moving inferi-  orly, the bodies of these bones increase in size. This adapts them to  bear increasing loads of body weight.    The five lumbar vertebrae in the small of the back (loin) sup-  port more weight than the superior vertebrae and have larger and  stronger bodies. Compared to other types of vertebrae, the thinner  transverse processes of these vertebrae project laterally, whereas  their short, thick spinous processes are nearly horizontal where  they project posteriorly. Figure 7.37 compares the structures of  the cervical, thoracic, and lumbar vertebrae.    The sacrum (sa’krum) is a triangular structure at the base of the ver-  tebral column. It is composed of five vertebrae that develop separately  but gradually fuse between ages eighteen and thirty (fig. 7.38). In some  individuals only four vertebrae fuse to form the sacrum, and the fifth  vertebra becomes a sixth lumbar vertebra. The spinous processes of  these fused bones form a ridge of tubercles, called the median sacral  crest. Nerves and blood vessels pass through rows of openings, called  the posterior sacral foramina, located to the sides of the tubercles.   The sacrum is wedged between the hip bones of the pelvis  and joins them at its auricular surfaces by the fibrocartilage of the  sacroiliac (sa”kro-il’e-ak) joints. The pelvic girdle transmits the  body’s weight to the legs at these joints (see fig. 7.16).   The sacrum forms the posterior wall of the pelvic cavity. The  upper anterior margin of the sacrum, which represents the body  of the first sacral vertebra, is called the sacral promontory (sa’kral  prom’on-to’re). A physician performing a vaginal examination can  feel this projection and use it as a guide in determining the size of  the pelvis. This measurement is helpful in estimating how easily an  infant may be able to pass through a woman’s pelvic cavity.   The vertebral foramina of the sacral vertebrae form the sacral  canal, which continues through the sacrum to an opening of vari-  able size at the tip, called the sacral hiatus (hi-a’tus). This foramen  exists because the laminae of the last sacral vertebra are not fused.  On the ventral surface of the sacrum, four pairs of anterior sacral  foramina provide passageways for nerves and blood vessels.    The painful condition spondylolisthesis results from a vertebra  that slips out of place over the vertebra beneath it. Most com-  monly the fifth lumbar vertebra slides forward over the body  of the sacrum. Spondylolisthesis may be present at birth, be a  consequence of small stress fractures of the vertebra between  the superior and inferior articular processes (spondylolysis),  or, most commonly, be associated with the loss of moisture in  intervertebral discs that accompanies aging. Gymnasts, foot-  ball players, and other athletes and dancers who flex, extend,  or rotate their vertebral columns excessively and forcefully are  at elevated risk of developing spondylolisthesis.    The coccyx (kok’siks), or tailbone, is the lowest part of the vertebral  column and is usually composed of four vertebrae that fuse between  the ages of twenty-five and thirty (fig. 7.38).   Variations in individuals include three to five coccygeal ver-  tebrae with typically the last three fused. In the elderly, the coccyx  may fuse to the sacrum. Ligaments attach the coccyx to the margins    of the sacral hiatus. Sitting presses on the coccyx, and it moves for-  ward, acting like a shock absorber. Sitting down with great force, as  when slipping and falling on ice, can fracture or dislocate the coc-  cyx. The coccyx is also an attachment for the muscles of the pelvic  floor. Table 7.8 summarizes the bones of the vertebral column, and  Clinical Application 7.3 discusses disorders of the vertebral column.    21 Explain the difference between the vertebral column of an  adult and that of an infant.    23 Explain how the structures of cervical, thoracic, and lumbar  vertebrae differ.    Changes in the intervertebral discs may cause painful problems.  Each disc is composed of a tough, outer layer of fibrocartilage  (annulus fibrosus) and an elastic central mass (nucleus pulposus).  With age, these discs degenerate. The central masses lose firm-  ness, and the outer layers thin, weaken, and crack. Taking a fall  or lifting a heavy object can exert enough pressure to break the  outer layers of the discs and squeeze out the central masses.  Such a rupture may press on the spinal cord or on spinal nerves  that branch from it. This condition, called a ruptured, or herniated  disc, may cause inflammation with back pain and numbness, or  loss of muscular function in the parts innervated by the affected  spinal nerves.   The pain of a herniated disc in the lower back decreases in  about one month for half of affected individuals and for most  others within six months. Pain medications and physical ther-  apy may be very helpful to strengthen muscles surrounding the  injured area.   For about 10% of people with herniated discs, a surgical pro-  cedure called a laminectomy may relieve the pain by removing a  portion of the posterior arch of a vertebra, which reduces pres-    sure on nerve tissues. Then a surgeon may perform a microdiscec-  tomy to remove the herniated disc material.   Poor posture, injury, or disease can affect the curvatures of  the vertebral column. An exaggerated thoracic curvature causes  rounded shoulders and a hunchback. This condition, called  kyphosis, is seen in adolescents who undertake strenuous athletic  activities. Unless corrected before bone growth completes, the  condition can permanently deform the vertebral column.   The vertebral column may develop an abnormal lateral cur-  vature, placing one hip or shoulder lower than the other, which  may displace or compress the thoracic and abdominal organs.  This condition, called scoliosis, is most common in adolescent  females. It may accompany poliomyelitis, rickets, or tuberculosis,  or have an unknown cause. An accentuated lumbar curvature is  called lordosis, or swayback.   As a person ages, the intervertebral discs shrink and become  more rigid, and compression is more likely to fracture the verte-  bral bodies. Consequently, height may decrease, and the thoracic  curvature of the vertebral column may become accentuated,  bowing the back.    FIGURE 7.38 (AP|R) Sacrum and coccyx. (a) Anterior view. (b) Posterior view.    ones Number Special Features  Transverse foramina; facets of atlas that  articulate with occipital condyles of skull;  dens of axis that articulates with atlas;  spinous processes of second through  sixth vertebrae are bifid    The thoracic cage includes the ribs, the thoracic vertebrae, the  sternum, and the costal cartilages that attach the ribs to the ster-  num (fig. 7.39). These bones support the pectoral girdle and upper  limbs, protect the viscera in the thoracic and upper abdominal  cavities, and play a role in breathing.   The usual number of ribs is twenty-four—one pair attached to each  of the twelve thoracic vertebrae. Some individuals have extra ribs  associated with their cervical or lumbar vertebrae.   The first seven rib pairs, called the true ribs (vertebroster-  nal ribs), join the sternum directly by their costal cartilages. The  remaining five pairs are called false ribs because their cartilages  do not reach the sternum directly. Instead, the cartilages of the  upper three false ribs (vertebrochondral ribs) join the cartilages of  the seventh rib, whereas the lower two rib pairs do not attach to the  sternum. These lower two pairs (or in some individuals, the lower  three pairs) are called floating ribs (vertebral ribs).   A typical rib has a long, slender shaft that curves around the  chest and slopes downward (fig. 7.40). On the posterior end is an  enlarged head by which the rib articulates with a facet on the body  of its own vertebra and with the body of the next higher vertebra.  The neck of the rib is flattened, lateral to the head, where liga-  ments attach. A tubercle, close to the head of the rib, articulates  with the transverse process of the vertebra.   The costal cartilages are composed of hyaline cartilage. They  are attached to the anterior ends of the ribs and continue in line  with them toward the sternum.    The sternum (ster’num), or breastbone, is located along the mid-  line in the anterior portion of the thoracic cage. It is a flat, elon-  gated bone that develops in three parts—an upper manubrium    Transverse processes that project posteriorly Sacrum  at sharp angles; pointed spinous processes    Large bodies; thinner transverse  processes that project laterally; short,  thick spinous processes that project  posteriorly nearly horizontal   fused surfaces, sacral promontory, sacral  canal, sacral hiatus, anterior sacral  foramina    (mah-nu’bre-um), a middle body, and a lower xiphoid (zif’oid)  process that projects downward (see fig. 7.39).   The sides of the manubrium and the body are notched where  they articulate with costal cartilages. The manubrium also articu-  lates with the clavicles by facets on its superior border. It usually  remains as a separate bone until middle age or later, when it fuses  to the body of the sternum.    The manubrium and body of the sternum lie in different planes,  so their line of union projects slightly forward. This projection,  at the level of the second costal cartilage, is called the sternal    angle (angle of Louis). It is commonly used as a clinical land-  mark (see fig. 7.39a).    The xiphoid process begins as a piece of cartilage. It slowly ossi-  fies, and by middle age it usually fuses to the body of the sternum.    >  R y PRACTICE  24 Which bones compose the thoracic cage?  25 Describe a typical rib.  26 What are the differences among true, false, and floating ribs?    The pectoral (pek’tor-al) girdle, or shoulder girdle, is composed  of four parts—two clavicles (collarbones) and two scapulae  (shoulder blades) (fig. 7.41). Although the word girdle suggests a  ring-shaped structure, the pectoral girdle is an incomplete ring. It  is open in the back between the scapulae, and the sternum sepa-  rates its bones in front. The pectoral girdle supports the upper  limbs and is an attachment for several muscles that move them.    FIGURE 7.39 fAP|R) The thoracic cage includes (a) the thoracic vertebrae, the sternum, the ribs, and the costal cartilages that attach the ribs to the  sternum. (b) Radiograph of the thoracic cage, anterior view. The light region behind the sternum and above the diaphragm is the heart.    FIGURE 7.40 A typical rib. (a) Posterior view. (b) Articulations of a rib  with a thoracic vertebra (superior view).    The clavicles (klav’i-k’1z) are slender, rodlike bones with elongated  S-shapes (fig. 7.41). Located at the base of the neck, they run hori-  zontally between the manubrium and the scapulae. The sternal (or  medial) ends of the clavicles articulate with the manubrium, and the  acromial (or lateral) ends join processes of the scapulae.   The clavicles brace the freely movable scapulae, helping to hold  the shoulders in place. They also provide attachments for muscles of  the upper limbs, chest, and back. The clavicle is structurally weak  because of its elongated double curve. If compressed lengthwise due  to abnormal pressure on the shoulder, it is likely to fracture.    The scapulae (skap’u-le) are broad, somewhat triangular bones  located on either side of the upper back. They have flat bodies with    concave anterior surfaces (fig. 7.42). The posterior surface of each  scapula is divided into unequal portions by a spine. Above the spine  is the supraspinous fossa, and below the spine is the infraspinous  fossa. This spine leads to an acromion (ah-kro’me-on) process that  forms the tip of the shoulder. The acromion process articulates with  the clavicle and provides attachments for muscles of the upper limb  and chest. A coracoid (kor’ah-koid) process curves anteriorly and  inferiorly to the acromion process. The coracoid process also pro-  vides attachments for upper limb and chest muscles. On the lateral  surface of the scapula between these processes is a depression called  the glenoid cavity (glenoid fossa of the scapula). It articulates with  the head of the arm bone (humerus).   The scapula has three borders. The superior border is on the  superior edge. The axillary, or lateral border, is directed toward  the upper limb. The vertebral, or medial border, is closest to the  vertebral column, about 5 cm away.    28 Which bones form the pectoral girdle?  29 What is the function of the pectoral girdle?    The bones of the upper limb form the framework of the arm, fore-  arm, and hand. They also provide attachments for muscles and inter-  act with muscles to move limb parts. These bones include a humerus,  aradius, an ulna, carpals, metacarpals, and phalanges (fig. 7.43).    The humerus is a long bone that extends from the scapula to the  elbow. At its upper end is a smooth, rounded head that fits into the  glenoid cavity of the scapula (fig. 7.44). Just below the head are  two processes—a greater tubercle on the lateral side and a lesser  tubercle on the anterior side. These tubercles provide attachments  for muscles that move the upper limb at the shoulder. Between  them is a narrow furrow, the intertubercular sulcus (intertubercular  groove), through which a tendon passes from a muscle in the arm  (biceps brachii) to the shoulder.   The narrow depression along the lower margin of the head  that separates it from the tubercles is called the anatomical neck.  Just below the head and the tubercles of the humerus is a tapering  region called the surgical neck, so named because fractures com-  monly occur there. Near the middle of the bony shaft on the lateral  side is a rough V-shaped area called the deltoid tuberosity. It pro-  vides an attachment for the muscle (deltoid) that raises the upper  limb horizontally to the side.   At the lower end of the humerus are two smooth  condyles—a knoblike capitulum (kah-pit’u-lum) on the lateral  side and a pulley-shaped trochlea (trok’le-ah) on the medial side.  The capitulum articulates with the radius at the elbow, whereas  the trochlea joins the ulna.   Above the condyles on either side are epicondyles, which  provide attachments for muscles and ligaments of the elbow.    FIGURE 7.41 (AP|R) Right portion of the pectoral girdle. (a) The  pectoral girdle, to which the upper limbs are attached, consists of a  clavicle and a scapula on each side. (b) Radiograph of the right shoulder  (a) region, anterior view.    FIGURE 7.42 (AP|R) Right scapula. (a) Posterior surface. (b) Lateral view showing the glenoid cavity that articulates with the head of the humerus.  (c) Anterior surface.    FIGURE 7.43 fAP|R) Right upper limb. (a) Anterior view with the hand, palm anterior and (b) with the hand, palm posterior. (c) Posterior view of the    right elbow. (d) Radiograph of the right elbow and forearm, anterior view.    Between the epicondyles anteriorly is a depression, the coronoid  fossa, that receives a process of the ulna (coronoid process) when  the elbow bends. Another depression on the posterior surface, the  olecranon (o0"lek’ra-non) fossa, receives a different ulnar process  (olecranon process) when the elbow straightens.    The radius, located on the thumb side of the forearm, is somewhat  shorter than its companion, the ulna (fig. 7.45). The radius extends    from the elbow to the wrist and crosses over the ulna when the  hand is turned so that the palm faces backward.   A thick, disclike head at the upper end of the radius articu-  lates with the capitulum of the humerus and a notch of the ulna  (radial notch). This arrangement allows the radius to rotate.   On the radial shaft just below the head is a process called the  radial tuberosity. It is an attachment for a muscle (biceps brachii)  that bends the upper limb at the elbow. At the distal end of the  radius, a lateral styloid (sti’loid) process provides attachments for  ligaments of the wrist.    The ulna, located on the medial side of the forearm, is longer than  the radius and overlaps the end of the humerus posteriorly. At its  proximal end, the ulna has a wrenchlike opening, the trochlear  notch (semilunar notch), that articulates with the trochlea of the  humerus. A process lies on either side of this notch. The olecranon  process, located above the trochlear notch, provides an attachment  for the muscle (triceps brachii) that straightens the upper limb at  the elbow. During this movement, the olecranon process of the  ulna fits into the olecranon fossa of the humerus. Similarly, the  coronoid process, just below the trochlear notch, fits into the coro-  noid fossa of the humerus when the elbow bends.   At the distal end of the ulna, its knoblike head articulates lat-  erally with a notch of the radius (ulnar notch) and with a disc of  fibrocartilage inferiorly (fig. 7.45). This disc, in turn, joins a wrist  bone (triquetrum). A medial styloid process at the distal end of the  ulna provides attachments for ligaments of the wrist.    Many a thirtyish parent of a young little leaguer or softball  player becomes tempted to join in. But if he or she has not  pitched in many years, sudden activity may break the forearm.  Forearm pain while pitching is a signal that a fracture could hap-  pen. Medical specialists advise returning to the pitching mound  gradually. Start with twenty pitches, five days a week, for two to  three months before regular games begin. By the season’s start,  120 pitches per daily practice session should be painless.    The hand is made up of the wrist, palm, and fingers. The skeleton  of the wrist consists of eight small carpal bones in two rows of  four bones each. The resulting compact mass is called a carpus  (kar’pus). The carpus is rounded on its proximal surface, where it  articulates with the radius and with the fibrocartilaginous disc on  the ulnar side. The carpus is concave anteriorly, forming a canal  through which tendons and nerves extend to the palm. Its distal  surface articulates with the metacarpal bones. Figure 7.46 names  the individual bones of the carpus.   Five metacarpal bones, one in line with each finger, form  the framework of the palm or metacarpus (met”ah-kar’ pus) of the  hand. These bones are cylindrical, with rounded distal ends that  form the knuckles of a clenched fist. The metacarpals articulate  proximally with the carpals and distally with the phalanges. The  metacarpal on the lateral side is the most freely movable; it per-  mits the thumb to oppose the fingers when grasping something.  These bones are numbered | to 5, beginning with the metacarpal  of the thumb (fig. 7.46).   The phalanges are the finger bones. Three are in each fin-  ger—a proximal, a middle, and a distal phalanx—and two are in  the thumb. (The thumb lacks a middle phalanx.) Thus, each hand  has fourteen finger bones. Figure 7.47 depicts a rare inherited con-  dition in which extra toes and/or fingers develop. Table 7.9 sum-  marizes the bones of the pectoral girdle and upper limbs.    FIGURE 7.45 (AP|R} Right radius and ulna. (a) The head of the radius articulates with the radial notch of the ulna, and the head of the ulna articulates  with the ulnar notch of the radius. (b) Lateral view of the proximal end of the ulna.    Scapula (2) Upper back, forming part of shoulder Body, spine, acromion process, coracoid process, glenoid cavity    Radius (2) Lateral side of forearm, between elbow and Head, radial tuberosity, styloid process, ulnar notch  wrist    Phalanx (28) Finger Three phalanges in each finger; two phalanges in each thumb    FIGURE 7.46 (AP|R) Right hand.  (a) Anterior view. (b) Posterior view.   (Note: The arrow points to a sesamoid  bone associated with the first metacarpal  in the radiograph.)    30 Locate and name each of the bones of the upper limb.    The pelvic girdle consists of the two hip bones, also known as  coxal bones (ossa coxae), pelvic bones or innominate bones,  which articulate with each other anteriorly and with the sacrum  posteriorly (fig. 7.48). The sacrum, coccyx, and pelvic girdle form    FIGURE 7.47 Polydactyly (“extra digits”) is an inherited trait. Hands  like these are rarely seen, because in many cases of polydactyly the extra  fingers and/or toes are surgically removed shortly after birth.    the bowl-shaped pelvis. The pelvic girdle supports the trunk of the  body; provides attachments for the lower limbs; and protects the  urinary bladder, the distal end of the large intestine, and the inter-  nal reproductive organs. The body’s weight is transmitted through  the pelvic girdle to the lower limbs and then onto the ground.   Each hip bone develops from three parts—an ilium, an ischium, and  a pubis (fig. 7.49). These parts fuse in the region of a cup-shaped  cavity called the acetabulum (as”é-tab’u-lum). This depression, on  the lateral surface of the hip bone, receives the rounded head of the  femur or thigh bone.   The ilium (il’e-um), the largest and most superior portion of the  hip bone, flares outward, forming the prominence of the hip. The  margin of this prominence is called the iliac crest. The smooth, con-  cave surface on the anterior aspect of the ilium is the iliac fossa.   Posteriorly, the ilium joins the sacrum at the sacroiliac joint.  Anteriorly, a projection of the ilium, the anterior superior iliac spine,  can be felt lateral to the groin. This spine provides attachments for lig-  aments and muscles and is an important surgical landmark.    A common injury in contact sports such as football is bruising  the soft tissues and bone associated with the anterior superior    iliac spine. Wearing protective padding can prevent this painful  injury, called a hip pointer.    On the posterior border of the ilium is a posterior superior iliac  spine. Below this spine is a deep indentation, the greater sciatic  notch, through which a number of nerves and blood vessels pass.   The ischium (is’ke-um), which forms the lowest portion of the  hip bone, is L-shaped, with its angle, the ischial tuberosity, point-  ing posteriorly and downward. This tuberosity has a rough surface  that provides attachments for ligaments and lower limb muscles.  It also supports the weight of the body during sitting. Above the  ischial tuberosity, near the junction of the ilium and ischium, is a  sharp projection called the ischial spine. Like the sacral promon-  tory, this spine, which can be felt during a vaginal examination, is  used as a guide for determining pelvis size. The distance between  the ischial spines is the shortest diameter of the pelvic outlet.    Sacrum  Acetabulum  Pubis Pubic  : tubercle  Pubic  symphysis Ischium  Pubic arch  (a)  Sacral  canal  llium  Sacrum  Sacral  hiatus  Coccyx    (c)  FIGURE 7.48 fAP|R) Pelvic girdle. (a) Anterior view. (b) Posterior view.    The pelvic girdle provides an attachment for the lower limbs and together  with the sacrum and coccyx forms the pelvis. (c) Radiograph of the pelvic  girdle, anterior view.    The pubis (pu’bis) constitutes the anterior portion of the hip  bone. The two pubic bones come together at the midline to form  a joint called the pubic symphysis (pu’bik sim’fi-sis). The angle  these bones form below the symphysis is the pubic arch (fig. 7.50).    (a) (b)  FIGURE 7.49 (AP|R} Right hip bone. (a) Medial surface. (b) Lateral view.    FIGURE 7.50 fAP|R} The female pelvis is usually wider in all diameters and roomier than that of the male. (a) Female pelvis. (b) Male pelvis.  Co) Is the radiograph in fig. 7.48c taken of a male or female?    A portion of each pubis passes posteriorly and downward  to join an ischium. Between the bodies of these bones on either  side is a large opening, the obturator foramen, which is the largest  foramen in the skeleton. An obturator membrane covers and nearly  closes this foramen (see figs. 7.48 and 7.49).    If a line were drawn along each side of the pelvis from the sacral  promontory downward and anteriorly to the upper margin of the  symphysis pubis, it would mark the pelvic brim (linea terminalis).  This margin separates the lower, or lesser (true), pelvis from the  upper, or greater (false), pelvis (fig. 7.50).   Superior to the pelvic brim, the false pelvis is bounded pos-  teriorly by the lumbar vertebrae, laterally by the flared parts of the  iliac bones, and anteriorly by the abdominal wall. The false pelvis  helps support the abdominal organs.   Inferior to the pelvic brim, the true pelvis is bounded pos-  teriorly by the sacrum and coccyx and laterally and anteriorly by  the lower ilium, ischium, and pubis bones. This portion of the pel-  vis surrounds a short, canal-like cavity. The superior opening of  the cavity, the pelvic inlet, is at the boundary between the true and  false pelves. The inferior opening of the cavity is the pelvic outlet.  An infant passes through this cavity during childbirth.    Some basic structural differences distinguish the male and the female  pelves, even though it may be difficult to find all of the “typical”  characteristics in any one individual. These differences arise from  the function of the female pelvis as a birth canal. In most females  the iliac bones are more flared than those in males. Consequently, the    female hips are typically broader than the male hips. The angle of the  female pubic arch is usually greater, the distance between the ischial  spines and the ischial tuberosities is greater, and the sacral curvature  is shorter and flatter. Thus, the female pelvic cavity is usually wider  in all diameters than that of the male. Also, the bones of the female  pelvis are typically lighter, more delicate, and show less evidence of  muscle attachments although the attachments are the same in both  sexes (fig. 7.50). Table 7.10 summarizes some of the differences  between the male and female skeletons.    R y -PRACTICE  32 Locate and name each bone that forms the pelvis.  33 Name the bones that fuse to form a hip bone.  34 Distinguish between the false pelvis and the true pelvis.    The bones of the lower limb form the frameworks of the thigh, leg,  and foot. They include a femur, a tibia, a fibula, tarsals, metatar-  sals, and phalanges (fig. 7.51).    The femur, or thigh bone, is the longest bone in the body and  extends from the hip to the knee. A large, rounded head at its prox-  imal end projects medially into the acetabulum of the hip bone  (fig. 7.52). On the head, a pit called the fovea capitis marks the  attachment of a ligament. Just below the head are a constriction,  or neck, and two large processes—a superior, lateral greater    Fibula Famu  Tibia  Lateral (d)  Medial condyle  condyle  Fibula  Tibia  . [- Tarsals (c) Posterior view  Metatarsals + ——_  FIGURE 7.51 fAP|R) Right lower limb. (a) Anterior view of the  lower limb. (b) Lateral view of the knee. (c) Posterior view of the knee.  if LP I Phalanges (d) Radiograph of the knee (anterior view), showing the ends of the femur,  f tibia, and fibula. Thinner areas of bone, such as part of the head of the  (a) fibula and the patella, barely show in this radiograph.    cesses provide attachments for muscles of the lower limbs and but- The patella can slip to one side as a result of a blow to the  tocks. On the posterior surface in the middle third of the shaft is knee or a forceful unnatural movement of the leg. This painful  a longitudinal crest called the linea aspera. This rough strip is an condition is called a patellar dislocation. Doing exercises that  attachment for several muscles. strengthen muscles associated with the knee and wearing pro-   At the distal end of the femur, two rounded processes, the tective padding can prevent knee displacement. Unfortunately,  lateral and medial condyles, articulate with the tibia of the leg. A once the soft tissues that hold the patella in place are stretched,  patella also articulates with the femur on its distal anterior surface. patellar dislocation tends to recur.    On the medial surface at its distal end is a prominent medial  epicondyle, and on the lateral surface is a lateral epicondyle. These  projections provide attachments for muscles and ligaments.    Patella The tibia, or shin bone, is the larger of the two leg bones and  The patella, or kneecap, is a flat sesamoid bone located in a ten- is located on the medial side. Its proximal end is expanded into  don that passes anteriorly over the knee (see fig. 7.51). The patella, medial and lateral condyles, which have concave surfaces and  because of its position, controls the angle at which this tendon articulate with the condyles of the femur (fig. 7.53). Below the  continues toward the tibia. Therefore it functions in lever actions condyles, on the anterior surface, is a process called the tibial  associated with lower limb movements. tuberosity, which provides an attachment for the patellar ligament    (a continuation of the patella-bearing tendon). A prominent ante-  rior crest extends downward from the tuberosity and attaches con-  nective tissues in the leg.   At its distal end, the tibia expands to form a prominence on the  medial side of the ankle called the medial malleolus (mah-le’o-lus),  which is an attachment for ligaments. On its lateral side is a depres-  sion that articulates with the fibula. The inferior surface of the tibia’s  distal end articulates with a large bone (the talus) in the ankle.    The fibula is a long, slender bone located on the lateral side of  the tibia. Its ends are slightly enlarged into a proximal head and  a distal lateral malleolus (fig. 7.53). The head articulates with the  tibia just below the lateral condyle, but it does not enter into the  knee joint and does not bear any body weight. The lateral malleo-  lus articulates with the ankle and protrudes on the lateral side.    The foot is made up of the ankle, the instep, and the toes. The  ankle or tarsus (tahr’sus) is composed of seven tarsal bones. One  of these bones, the talus (ta’lus), can move freely where it joins  the tibia and fibula, forming the ankle. The largest of the tarsals,  the calcaneus (kal-ka’ne-us), or heel bone, is below the talus  where it projects backward to form the base of the heel. The cal-  caneus helps support body weight and provides an attachment, the  calcaneal tuberosity, for muscles that move the foot. Figures 7.54  and 7.55 name the bones of the tarsus.   The instep or metatarsus (met’ah-tahr’sus) consists of five elon-  gated metatarsal bones, which articulate with the tarsus. They are  numbered | to 5, beginning on the medial side (fig. 7.55). The heads  at the distal ends of these bones form the ball of the foot. The tarsals  and metatarsals are bound by ligaments, forming the arches of the  foot. A longitudinal arch extends from the heel to the toe, and a trans-  verse arch stretches across the foot. These arches provide a stable,  springy base for the body. Sometimes, however, the tissues that bind  the metatarsals weaken, producing fallen arches, or flat feet.    FIGURE 7.54 (AP|RJ Right  foot. (a) Radiograph view from the  medial side. (b) The talus moves  freely where it articulates with the  tibia and fibula.    Hip bone (2) llium, iliac crest, anterior superior iliac spine, ischium, ischial tuberosity, ischial    Hip, articulating with the other hip bone  anteriorly and with the sacrum posteriorly    Head, fovea capitis, neck, greater trochanter, lesser trochanter, linea aspera,  lateral condyle, medial condyle, gluteal tuberosity, intercondylar fossa    Anterior surface of knee A flat sesamoid bone located within a tendon    Medial condyle, lateral condyle, tibial tuberosity, anterior crest, medial  malleolus, intercondylar eminence    Lateral side of leg, between knee and ankle Head, lateral malleolus    Ankle Freely movable talus that articulates with leg bones; calcaneus that forms the    base of the heel; five other tarsal bones bound firmly together  Metatarsal (10)    Phalanx (28) Toe Three phalanges in each toe, two phalanges in great toe    The phalanges of the toes are shorter but otherwise similar to  those of the fingers and align and articulate with the metatarsals.  Each toe has three phalanges—a proximal, a middle, and a distal  phalanx—except the great toe, which has only two because it lacks  the middle phalanx (fig. 7.55). Table 7.11 summarizes the bones  of the pelvic girdle and lower limbs.    An infant with two casts on her feet is probably being treated  for clubfoot, a common birth defect in which the foot twists out    of its normal position. Clubfoot probably results from arrested  development during fetal existence, but the precise cause is  not known.    36 Locate and name each of the bones of the lower limb.  37 Explain how the bones of the lower limb articulate.    38 Describe how the foot is adapted to support the body.    Aging-associated changes in the skeletal system are apparent at the  cellular and whole-body levels. Most obvious is the incremental  decrease in height that begins at about age thirty, with a loss of about  1/16 of an inch a year. In the later years, compression fractures in  the vertebrae may contribute significantly to loss of height (fig. 7.56).  Overall, as calcium levels fall and bone material gradually vanishes,  the skeleton loses strength, and the bones become brittle and increas-  ingly prone to fracture. However, the continued ability of fractures to  heal reveals that the bone tissue is still alive and functional.  Components of the skeletal system and individual bones change  to different degrees and at different rates over a lifetime. Gradually,  osteoclasts come to outnumber osteoblasts, which means that bone  is eaten away in the remodeling process at a faster rate than it is    FIGURE 7.56 The bones change to different degrees and at different  rates over a lifetime.    replaced. The result is more spaces in bones. The bone thins, its  strength waning. Bone matrix changes, with the ratio of mineral to  protein increasing, making bones more brittle and prone to fracture.  Beginning in the third decade of life, bone matrix is removed faster  than it is laid down. By age thirty-five, we start to lose bone mass.   Trabecular bone, due to its spongy, less compact nature,  shows the changes of aging first. It thins, increasing in porosity  and weakening the overall structure. The vertebrae consist mostly  of trabecular bone. It is also found in the upper part of the femur,  whereas the shaft is more compact bone. The fact that trabecular  bone weakens sooner than compact bone destabilizes the upper  part of the femur, which is why it is a commonly broken bone  among the elderly.    Compact bone loss begins at around age forty and continues  at about half the rate of loss of trabecular bone. As remodeling  continues throughout life, older osteons disappear as new ones  are built next to them. With age, the osteons may coalesce, further  weakening the overall structures as gaps form.   Bone loss is slow and steady in men, but in women it is clearly  linked to changing hormone levels. In the first decade following  menopause, women lose 15% to 20% of trabecular bone, which  is two to three times the rate of loss in men and in premenopausal  women. During the same time, compact bone loss is 10% to 15%,  which is three to four times the rate of loss in men and premeno-  pausal women. By about age seventy, both sexes are losing bone at  about the same rate. By very old age, a woman may have only half  the trabecular and compact bone mass as she did in her twenties,  whereas a very elderly man may have one-third less bone mass.   Falls among the elderly are common and have many causes  (table 7.12). The most common fractures, after vertebral com-  pression and hip fracture, are of the wrist, leg, and pelvis. Aging-  related increased risk of fracture usually begins at about age  fifty. Healing slows, and pain from a broken bone may persist for  months. Recommendations for preserving skeletal health include   Slowed reaction time due to stiffening joints  Poor vision and/or hearing    avoiding falls, taking calcium supplements, getting enough vita-  min D, avoiding carbonated beverages (phosphates deplete bone),  and getting regular exercise.    Bones are grouped according to their shapes—long, short, flat,  or irregular.  1. Parts of a long bone   a. Epiphyses at each end are covered with articular  cartilage and articulate with other bones.   c. The region between the epiphysis and diaphysis is the  metaphysis.   d. Except for the articular cartilage, a bone is covered  by a periosteum.   e. Compact bone has a continuous extracellular matrix  with no gaps.   f. Spongy bone has irregular interconnecting spaces  between bony plates called trabeculae.   g. Both compact and spongy bone are strong and resist  bending.   c. Central canals in compact bone contain blood vessels  that nourish the cells of osteons.   d. Perforating canals in compact bone connect central  canals transversely and communicate with the bone’s  surface and the medullary cavity.   e. Diffusion from the surface of thin bony plates nourishes  cells of spongy bones.    a. Flat bones of the skull, the clavicles, the sternum, and  some facial bones are intramembranous bones.    b. They develop from sheetlike layers of embryonic  connective tissues (mesenchyme).   e. Mesenchyme outside the developing bone gives rise to  the periosteum.   b. They develop as hyaline cartilage that bone tissue later  replaces.   c. The primary ossification center appears in the  diaphysis, whereas secondary ossification centers  appear in the epiphyses.   d. An epiphyseal plate remains between the primary and  secondary ossification centers.   a. An epiphyseal plate consists of layers of cells: zone of  resting cartilage, zone of proliferating cartilage, zone of  hypertrophic cartilage, and zone of calcified cartilage.   c. Long bones continue to lengthen until the epiphyseal  plates are ossified.   d. Growth in bone thickness is due to ossification beneath  the periosteum.   a. Deficiencies of vitamin A, C, or D result in abnormal  bone development.   b. Insufficient secretion of pituitary growth hormone may  result in dwarfism; excessive secretion may result in  gigantism.    Vitamin D,  production of which  “=, begins in the skin,  plays a role in  calcium absorption  and availability for  bone matrix.    Proprioceptors  sense the position of  body parts. Pain  receptors warn of  trauma to bone.  Bones protect the    Some hormones  act on bone to help  regulate blood  calcium levels.    Blood transports  nutrients to bone  cells. Bone helps  regulate plasma  calcium levels,  important to heart  function.    Bones provide support, protection,  and movement and also play a role  in calcium balance.    The kidneys and  bones work together  to help regulate blood  calcium levels.    The pelvis helps  support the uterus  during pregnancy.  Bones provide a  source of calcium  during lactation.    c. Thyroxine stimulates replacement of cartilage in the  epiphyseal plates with bone.   d. Male and female sex hormones promote bone formation  and stimulate ossification of the epiphyseal plates.    7.3. Bone Function (page 210)  1. Support, protection, and movement  a. Bones shape and form body structures.  b. Bones support and protect softer, underlying tissues.  c. Bones and muscles interact, producing movement.  2. Blood cell formation  a. At different stages in life, hematopoiesis occurs in the  yolk sac, the liver, the spleen, and the red bone marrow.  b. Red marrow houses developing red blood cells, white  blood cells, and blood platelets.  3. Inorganic salt storage  a. The extracellular matrix of bone tissue contains  abundant calcium phosphate in the form of  hydroxyapatite.  b. When blood calcium ion concentration is low,  osteoclasts resorb bone, releasing calcium salts.  c. When blood calcium ion concentration is high,  osteoblasts are stimulated to form bone tissue and  store calcium salts.  d. Bone stores small amounts of sodium, magnesium,  potassium, and carbonate ions.  e. Bone tissues may accumulate lead, radium, or strontium.    7.4 Skeletal Organization (page 212)  1. Number of bones  a. Usually an adult human skeleton has 206 bones, but the  number may vary.  b. Extra bones include sutural bones and sesamoid bones.  2. Divisions of the skeleton  a. The skeleton can be divided into axial and appendicular  portions.  b. The axial skeleton consists of the skull, hyoid bone,  vertebral column, and thoracic cage.  c. The appendicular skeleton consists of the pectoral  girdle, upper limbs, pelvic girdle, and lower limbs.    The skull consists of twenty-two bones, which include eight  cranial bones and fourteen facial bones.   a. The cranium encloses and protects the brain and  provides attachments for muscles.   b. Some cranial bones contain air-filled paranasal sinuses  that help reduce the weight of the skull.   c. Cranial bones include the frontal bone, parietal  bones, occipital bone, temporal bones, sphenoid  bone, and ethmoid bone.   a. Facial bones form the basic shape of the face and  provide attachments for muscles.   b. Facial bones include the maxillae, palatine bones,  zygomatic bones, lacrimal bones, nasal bones,  vomer bone, inferior nasal conchae, and mandible.    b. Infantile skull bones are thin, somewhat flexible, and  less easily fractured.    The vertebral column extends from the skull to the pelvis and  protects the spinal cord. It is composed of vertebrae separated  by intervertebral discs. An infant has thirty-three vertebral  bones and an adult has twenty-six. The vertebral column has  four curvatures—cervical, thoracic, lumbar, and sacral.   a. A typical vertebra consists of a body, pedicles, laminae,  spinous process, transverse processes, and superior and  inferior articular processes.   b. Notches on the upper and lower surfaces of the pedicles  on adjacent vertebrae form intervertebral foramina  through which spinal nerves pass.   d. The dens of the axis (second vertebra) provides a  pivot for the atlas that allows the head to turn from  side to side.   c. Their long spinous processes slope downward, and facets  on the sides of the vertebral bodies articulate with the  heads of ribs.   b. Their transverse processes project laterally, and their  spinous processes project posteriorly nearly horizontally.   a. The sacrum, formed of five fused vertebrae, is a  triangular structure that has rows of dorsal sacral  foramina.   b. It is united with the hip bones at the sacroiliac joints.   c. The sacral promontory provides a guide for  determining the size of the pelvis.   a. The coccyx, composed of four fused vertebrae, forms  the lowest part of the vertebral column.   b. It acts as a shock absorber when a person sits and is an  attachment for muscles of the pelvic floor.    The thoracic cage includes the ribs, thoracic vertebrae, sternum,  and costal cartilages that attach the ribs to the sternum. It supports  the pectoral girdle and upper limbs, protects viscera, and  functions in breathing.  1. Ribs  a. Twelve pairs of ribs are attached to the twelve thoracic  vertebrae.  b. Costal cartilages of the true ribs join the sternum directly;  those of the false ribs join indirectly or not at all.  c. A typical rib has a shaft, head, and tubercles that  articulate with the thoracic vertebrae.  2. Sternum  a. The sternum consists of a manubrium, body, and  xiphoid process.    b. It articulates with costal cartilages of the ribs and the  clavicles.    The pectoral girdle is composed of two clavicles and two  scapulae. It forms an incomplete ring that supports the upper limbs  and provides attachments for muscles that move the upper limbs.    1. Clavicles  a. Clavicles are rodlike bones that run horizontally  between the sternum and shoulders.  b. They help hold the shoulders in place and provide  attachments for muscles.  2. Scapulae  a. The scapulae are broad, triangular bones each with  a body, spine, acromion process, coracoid process,  glenoid cavity, supraspinous and infraspinous fossae,  superior border, axillary border, and vertebral border.  b. Each articulates with the humerus of each upper limb  and provides attachments for muscles of the upper  limbs and chest.    Bones of the upper limb provide the framework for the limb  and provide the attachments for muscles that move the limb.    1. Humerus  a. The humerus extends from the scapula to the elbow.  b. It has a head, greater tubercle, lesser tubercle,  intertubercular sulcus, anatomical neck, surgical neck,  deltoid tuberosity, capitulum, trochlea, epicondyles,  coronoid fossa, and olecranon fossa.  2. Radius  a. The radius is on the thumb side of the forearm between  the elbow and wrist.  b. It has a head, radial tuberosity, styloid process, and  ulnar notch.  3. Ulna  a. The ulna, on the medial side of the forearm, is longer  than the radius and overlaps the humerus posteriorly.  b. It has a trochlear notch, olecranon process, coronoid  process, head, styloid process, and radial notch.  4. Hand  a. The wrist has eight carpals.  b. The palm has five metacarpals.  c. The five fingers have fourteen phalanges.    The pelvic girdle consists of two hip bones that articulate with  each other anteriorly and with the sacrum posteriorly. The  sacrum, coccyx, and pelvic girdle form the pelvis. The girdle  provides support for body weight and attachments for muscles  and protects visceral organs.  1. Hip bones  Each hip bone consists of an ilium, ischium, and pubis,  fused in the region of the acetabulum.  a. Ilium  (1) The ilium, the largest portion of the hip bone, joins  the sacrum at the sacroiliac joint.  (2) It has an iliac crest with anterior and posterior  superior iliac spines and iliac fossae.    b. Ischium  (1) The ischium is the lowest portion of the hip bone.  (2) It has an ischial tuberosity and ischial spine.  c. Pubis  (1) The pubis is the anterior portion of the hip bone.  (2) Pubic bones are joined anteriorly at the pubic  symphysis.  2. True and false pelves  a. The false pelvis is superior to the pelvic brim; the true  pelvis is inferior to the pelvic brim.  b. The false pelvis helps support abdominal organs; the  true pelvis functions as a birth canal.  3. Differences between male and female pelves  a. Differences between male and female pelves reflect the  function of the female pelvis as a birth canal.  b. Usually the female pelvis is more flared; pubic arch  is broader; distance between the ischial spines and  the ischial tuberosities is greater; and sacral curvature  is shorter.    Bones of the lower limb provide the framework for the limb  and provide the attachments for muscles that move the limb.  1. Femur   b. It has a head, fovea capitis, neck, greater trochanter,  lesser trochanter, linea aspera, lateral condyle, and  medial condyle.   a. The patella is a sesamoid bone in the tendon that passes  anteriorly over the knee.   b. It controls the angle of this tendon and functions in lever  actions associated with lower limb movements.   a. The tibia is located on the medial side of the leg.   b. It has medial and lateral condyles, tibial tuberosity,  anterior crest, and medial malleolus.   a. The fibula is located on the lateral side of the tibia.   b. It has a head that proximally articulates with the tibia  and distally the lateral malleolus articulates with the  ankle, but the fibula does not bear body weight.   a. The ankle includes the talus, the calcaneus, and five  other tarsals.    7.12 Life-Span Changes (page 245)  Aging-associated changes in the skeleton are apparent at the  cellular and whole-body levels.  1. Incremental decrease in height begins at about age thirty.  2. Gradually, bone loss exceeds bone replacement.  a. In the first decade following menopause, bone  loss occurs more rapidly in women than in men or  premenopausal women. By age seventy, both sexes  are losing bone at about the same rate.  b. Aging increases risk of bone fractures.    List four groups of bones based on their shapes, and give an  example from each group. (p. 200)   Sketch a typical long bone, and label its epiphyses, diaphysis,  medullary cavity, periosteum, and articular cartilages.  Designate the locations of compact and spongy bone.   Discuss the functions of the parts labeled in the sketch you  made for question 2. (pp. 200-201)   Distinguish between the microscopic structure of compact  bone and spongy bone. (pp. 201-202)    Explain how the development of intramembranous bone  differs from that of endochondral bone. (pp. 202-204)  are bone cells in lacunae, whereas  are bone-forming cells and  are bone-resorbing cells. (pp. 202-207)  Explain the function of an epiphyseal plate. (pp. 205-207)  Place the zones of cartilage in an epiphyseal plate in order  (1-4), with the first zone attached to the epiphysis. (jp. 205)  zone of hypertrophic cartilage  zone of calcified cartilage  zone of resting cartilage  zone of perforating cartilage  Explain how osteoblasts and osteoclasts regulate bone mass.  (p. 207)  Describe the effects of vitamin deficiencies on bone  development and growth. (pp. 207-209)  Explain the causes of pituitary dwarfism and gigantism. (p. 210)  Describe the effects of thyroid and sex hormones on bone  development and growth. (p. 210)  Physical exercise pulling on muscular attachments to bone  stimulates . (p. 210)    Provide several examples to illustrate how bones support  and protect body parts. (p. 210)   Explain the mechanism that regulates the concentration of  blood calcium ions. (p. 211)   List three metallic elements that may be abnormally stored in  bone. (p. 211)   skeleton; bones of the limbs and their  attachments compose the skeleton.  (pp. 212-213)    Name the bones of the cranium and the facial skeleton.  (pp. 218-222)   Describe a typical vertebra, and distinguish among the  cervical, thoracic, and lumbar vertebrae. (pp. 227-229)  Describe the locations of the sacroiliac joint, the sacral  promontory, and the sacral hiatus. (p. 229)   Name the bones that comprise the thoracic cage. (p. 231)  The clavicle and scapula form the   Name the bones of the upper limb, and describe their  locations. (pp. 233-236)   Name the bones that comprise the hip bone. (p. 239)  Explain the major differences between the male and female  skeletons. (p. 241)   Name the bones of the lower limb, and describe their  locations. (pp. 241-245)   Match the parts listed on the left with the bones listed on the  right. (pp. 218-243)    (1) coronoid process A. ethmoid bone  (2) cribriform plate B. frontal bone  (3) foramen magnum C. mandible   (5) palatine process E. occipital bone  (6) sella turcica F. temporal bone  (7) supraorbital notch G. sphenoid bone  (8) temporal process H. zygomatic bone  (9) acromion process |. femur    Life-Span Changes  Describe the changes brought about by aging in trabecular  bone. (p. 245)    1. How might the condition of an infant's fontanels be used to  evaluate skeletal development? How might the fontanels be used  to estimate intracranial pressure (pressure in the cranial cavity)?    2. Why are incomplete, longitudinal fractures of bone shafts  (greenstick fractures) more common in children than in adults?    3. How does the structure of a bone make it strong yet lightweight?    4. If ayoung patient’s forearm and elbow are immobilized by a cast  for several weeks, what changes would you expect to occur in the  bones of the upper limb?    5. When a child's bone is fractured, growth may be stimulated at  the epiphyseal plate. What problems might this extra growth  cause in an upper or lower limb before the growth of the other  limb compensates for the difference in length?    6. Suppose archeologists discover human skeletal remains in  Ethiopia. Examination of the bones suggests that the remains  represent four types of individuals. Two of the skeletons have  bone densities that are 30% less than those of the other two  skeletons. The skeletons with the lower bone mass also have  broader front pelvic bones. Within the two groups defined  by bone mass, smaller skeletons have bones with evidence  of epiphyseal plates, but larger bones have only a thin line  where the epiphyseal plates should be. Give the age group  and gender of the individuals in this find.    7. Why do elderly persons often develop bowed backs and appear  to lose height?    Connect Interactive Questions Reinforce your knowledge  using assigned interactive questions covering skeletal tissue,  ossification, and parts of the skeleton.    Connect Integrated Activity Can you help a forensic investigator  identify and assemble a skeleton from scattered bones at a crime  scene or identify bones on an X ray?    Anatomy & Physiology Revealed Go more in depth into the  human body by viewing X rays and CT scans of the skeleton.    The following set of reference plates will help you locate some of the more prominent features of the  human skull. As you study these photographs, it is important to remember that individual human skulls    vary in every characteristic. Also, the photographs in this set depict bones from several different skulls.    process  Mandibular  condyle  Mandibular  ramus Alveolar arch  Body Mental  foramen  PLATE THIRTY-SEVEN Mandible, right lateral view.  Coronoid  process  Mandibular  condyle  Mandibular  ramus    PLATE THIRTY-NINE Frontal bone, anterior view.  PLATE FORTY Occipital bone, inferior view.    Frontal  bone  Parietal bone  Frontal  sinus  Sphenoidal  sinus  Occipital bone  : Internal  ee acoustic  meatus  Occipital  condyle  Mandible  PLATE FORTY-FIVE The skull, sagittal section.  bone  Frontal  sinus  Ethmoidal  air cells  Ethmoid  bone  Maxillary :  sinus Sphenoid  bone    PLATE FIFTY-FOUR Skull of an aged person, left lateral view. (This skull has been cut postmortem to allow the removal of the cranium.)    Arthritis has inflamed the joints in these fingers. Drugs and replacement  joints are used to treat this painful condition.    Joints, or articulations, are functional junctions between bones.  They bond parts of the skeletal system, make possible bone  growth, permit parts of the skeleton to change shape during  childbirth, and enable the body to move in response to skeletal  muscle contractions.    After you have studied this chapter, you should be able to:    1 Explain how joints can be classified according to the type    of tissue that binds the bones together and the degree  of movement possible at the joint. (p. 268)    name an example of each type of fibrous joint. (1p. 268)  Describe how bones of cartilaginous joints are held  together, and name an example of each type of  cartilaginous joint. (pp. 269)    Distinguish among the six types of synovial joints, and  name an example of each type. (p. 272)   Explain how skeletal muscles produce movements at  joints, and identify several types of joint movements.  (pp. 274-277)    Describe the shoulder joint, and explain how its  articulating parts are held together. (pp. 277 and 279)    Describe the elbow, hip, and knee joints, and explain  how their articulating parts are held together.    anul-, ring: anular ligament—ring-shaped  band of connective tissue below the  elbow joint that encircles the head of  the radius.    glen-, joint socket: glenoid cavity—depres-  sion in the scapula that articulates with  the head of the humerus.   syn-, with, together: synchondrosis—type  of joint in which the bones are held  together by cartilage.   syndesm-, band, ligament: syndesmosis—  type of joint in which the bones are  held together by long fibers of connec-  tive tissue.    Joints, which are structures that connect bones, vary considerably  in structure and function. However, they can be classified struc-  turally by the type of tissue that binds the bones at each junction.  Three general groups are fibrous joints, cartilaginous joints, and  synovial joints.   Joints can also be grouped functionally according to the  degree of movement possible at the bony junctions. In this scheme,  joints are classified as immovable (synarthrotic), slightly movable  (amphiarthrotic), and freely movable (diarthrotic). At some diar-  throtic joints, movement can occur over considerable distances,  such as flexion and extension of the elbow. In contrast, certain  other joints, such as the joint between the sacrum and the ilium,  move freely, but only for short distances. The structural and func-  tional classification schemes overlap somewhat. Currently, struc-  tural classification is the one most commonly used.    Fibrous (fi’brus) joints are so named because the dense connec-  tive tissue holding them together includes many collagen fibers.  These joints are between bones in close contact. The three types of  fibrous joints are:    1. In asyndesmosis (sin’des-mo’sis), the bones are bound by a  sheet (interosseous membrane) or bundle of dense connective  tissue (interosseous ligament). This junction is flexible and  may be twisted, so the joint may permit slight movement and  thus is amphiarthrotic (am”fe-ar-thro’tik). A syndesmosis lies  between the tibia and fibula (fig. 8.1).   2. Sutures (soo’cherz) are only between flat bones of the skull,  where the broad margins of adjacent bones grow together  and unite by a thin layer of dense connective tissue called  a sutural ligament. Recall from chapter 7 (p. 225) that the  infantile skull is incompletely developed, with several of the    bones connected by membranous areas called fontanels (see  fig. 7.32, p. 225). These areas allow the skull to change shape  slightly during childbirth, but as the bones continue to grow,  the fontanels close, and sutures replace them. With time, some  of the bones at sutures interlock by tiny bony processes. Such  a suture is in the adult human skull where the parietal and  occipital bones meet to form the lambdoid suture. Sutures are  immovable, and therefore they are synarthrotic (sin’ar-thro’tik)  joints (figs. 8.2 and 8.3).   3. A gomphosis (gom-fo’sis) is a joint formed by the union of a  cone-shaped bony process in a bony socket. The peglike root of  a tooth fastened to a maxilla or the mandible by a periodontal  ligament is such a joint. This ligament surrounds the tooth root  and firmly attaches it to the bone with bundles of thick collagen  fibers. A gomphosis is a synarthrotic joint (fig. 8.4).   R r] PRACTICE  2 Describe three types of fibrous joints.  3 What is the function of the fontanels?    FIGURE 8.1 The articulation between the tibia and fibula is an  example of a syndesmosis.    FIGURE 8.2 Fibrous joints. (a) The fibrous joints between the bones  of the skull are immovable and are called sutures. (b) A thin layer of  connective tissue connects the bones at the suture.    Hyaline cartilage or fibrocartilage connects the bones of cartilagi-  nous (kar”ti-laj’inus) joints. The two types are:    1. In asynchondrosis (sin”kon-dro’sis), bands of hyaline car-  tilage unite the bones. Many of these joints are temporary  structures that disappear during growth. An example of a  synchondrosis is that part of an immature long bone where a  band of hyaline cartilage (the epiphyseal plate) connects an  epiphysis to a diaphysis. This cartilage band participates in  bone lengthening and, in time, is replaced with bone. When  ossification completes, and the epiphyseal plate becomes an  epiphyseal line, usually before the age of twenty-five years,  the joint becomes a synostosis, a bony joint. The synostosis  is synarthrotic (see fig. 7.9, p. 206).   Another synchondrosis lies between the manubrium and the  first rib, directly united by costal cartilage (fig. 8.5). This joint is  also synarthrotic, but permanent. Most of the joints between the  sternum and the costal cartilages of ribs 2 through 7 are synovial.   2. The articular surfaces of the bones at a symphysis (sim’fi-sis)  are covered by a thin layer of hyaline cartilage, and the bones  are connected by a pad of fibrocartilage. Limited movement  occurs at such a joint whenever forces compress or deform  the fibrocartilage pad. An example of this type of joint is  the pubic symphysis between the pubic bones of the pelvis,  which allows maternal pelvic bones to shift, as a result of  hormone changes affecting the fibrocartilage pad during preg-  nancy, when an infant passes through the birth canal (fig. 8.6a).    The joint formed by the bodies of two adjacent vertebrae  separated and connected by an intervertebral disc is also a  symphysis (fig. 8.6b and reference plate 11, p. 47). Each inter-  vertebral disc is composed of a band of fibrocartilage (annulus  fibrosus) that surrounds a gelatinous core (nucleus pulposus).  The disc absorbs shocks and helps equalize pressure between  the vertebrae when the body moves. Because each disc is  slightly flexible, the combined movement of many of the joints  in the vertebral column allows the back to bend forward or to  the side or to twist. The intervertebral discs are amphiarthrotic  joints because they allow slight movements.    Most joints of the skeletal system are synovial (si-no’ve-al) joints,  and because they allow free movement, they are diarthrotic (di”ar-  thro’tik). These joints are more complex structurally than fibrous  or cartilaginous joints. They consist of articular cartilage; a joint  capsule; and a synovial membrane, which secretes synovial fluid.   The articular ends of the bones in a synovial joint are covered with  a thin layer of hyaline cartilage. This layer, the articular cartilage,  resists wear and minimizes friction when it is compressed as the  joint moves (fig. 8.7).    The forty-eight-year-old man joined an over-thirty basketball  league, and now he regrets his enthusiasm. He lies on the gym  floor, in pain, thanks to an overambitious jump shot. He had felt  a sudden twinge in his knee, and now it is red and swelling.   In the emergency department of the nearest hospital, an  orthopedist sends the man for an MRI scan, which reveals a  small tear in the anterior cruciate ligament (ACL). The patient  is willing to give up basketball and doesn’t want surgery, so he  goes for physical therapy twice a week for a month. A physical  therapy assistant leads him through a series of exercises that  will restore full mobility.   The therapy, under the supervision of a physical  therapist, begins with deep knee bends and progresses  to lifting weights, stepping, squats, and using a single-leg  bicycle that isolates and builds up the injured leg. The physical  therapy assistant gives her patient exercises to do daily, at  home. The therapy builds the muscles around the knee to  compensate for the hurt ACL, restoring full range of motion.   A physical therapy assistant must complete a two-year  college program and pass a certification exam. Physical  therapy assistants work in hospitals, skilled nursing facilities,  private homes, schools, fitness centers, and workplaces.    FIGURE 8.3 Cranial sutures. (a) Sutures between the parietal and occipital bones of the skull. (b) The inner margin of a suture (parietal bone).  The grooves on the inside of this parietal bone mark the paths of blood vessels near the brain's surface.    FIGURE 8.4 The articulation between the root of a tooth and the  mandible is a gomphosis.    A tubular joint capsule (articular capsule) that has two dis-  tinct layers holds together the bones of a synovial joint. The outer  layer largely consists of dense connective tissue, whose fibers  attach to the periosteum around the circumference of each bone  of the joint near its articular end. Thus, the outer fibrous layer of  the capsule completely encloses the other parts of the joint. It is,    FIGURE 8.5 The articulation between the first rib and the manubrium  is a synchondrosis.    @ Is the joint between the first rib and the manubrium an  example of a fibrous, cartilaginous, or synovial joint?    however, flexible enough to permit movement and strong enough  to help prevent the bones from being pulled apart.   Bundles of strong, tough collagen fibers called ligaments  (lig’ah-mentz) reinforce the joint capsule and help bind the articu-  lar ends of the bones. Some ligaments appear as thickenings in the  fibrous layer of the capsule, whereas others are accessory structures    FIGURE 8.6 Fibrocartilage composes (a) the pubic symphysis and (b) the intervertebral discs of the vertebrae.    located outside the capsule. In either case, these structures help  prevent excessive movement at the joint. That is, the ligament is  relatively inelastic, and it tightens when the joint is stressed.   The inner layer of the joint capsule consists of a shiny, vas-  cular lining of loose connective tissue called the synovial mem-  brane. This membrane, only a few cells thick, covers all of the  surfaces within the joint capsule, except the areas the articular  cartilage covers. The synovial membrane surrounds a closed sac    called the synovial cavity, into which the synovial membrane  secretes a clear, viscous fluid called synovial fluid. In some  regions, the surface of the synovial membrane has villi as well as  larger folds and projections that extend into the cavity. Besides  filling spaces and irregularities of the joint cavity, these extensions  increase the surface area of the synovial membrane. The synovial  membrane may also store adipose tissue and form movable fatty  pads in the joint. This multifunctional membrane also reabsorbs  fluid, which is important when a joint cavity is injured or infected.  Synovial fluid contains stem cells, which may function in ligament  regeneration following injury.   Synovial fluid has a consistency similar to uncooked egg  white, and it moistens and lubricates the smooth cartilaginous sur-  faces of the joint. It also helps supply articular cartilage with nutri-  ents obtained from blood vessels of the synovial membrane. The  volume of synovial fluid in a joint cavity is usually just enough to  cover the articulating surfaces with a thin film of fluid. The volume  of synovial fluid in the cavity of the knee is 0.5 mL or less.    A physician can determine the cause of joint inflammation or  degeneration (arthritis) by aspirating a sample of synovial fluid  from the affected joint using a procedure called arthrocentesis.  Bloody fluid may indicate trauma to the joint. Cloudy, yellowish  fluid may indicate rheumatoid arthritis, and crystals in the syno-    vial fluid may signal gout. If the fluid is cloudy but red-tinged  and containing pus, a bacterial infection may be present that  requires prompt treatment. Normal synovial fluid has 180 or  fewer leukocytes (white blood cells) per mL. If the leukocyte  count exceeds 2,000, the fluid is infected.    Some synovial joints are partially or completely divided  into two compartments by discs of fibrocartilage called menisci  (me-nis’ke) (sing., meniscus) between the articular surfaces. Each  meniscus attaches to the fibrous layer of the joint capsule peripher-  ally, and its free surface projects into the joint cavity. In the knee  joint, crescent-shaped menisci cushion the articulating surfaces  and help distribute body weight onto these surfaces (fig. 8.8).   Fluid-filled sacs called bursae (ber’se) are associated with  certain synovial joints. Each bursa has an inner lining of synovial  membrane, which may be continuous with the synovial membrane  of a nearby joint cavity. These sacs contain synovial fluid and are  commonly located between the skin and underlying bony promi-  nences, as in the case of the patella of the knee or the olecranon  process of the elbow. Bursae cushion and aid the movement of ten-  dons that glide over bony parts or over other tendons. The names  of bursae indicate their locations. Figure 8.8 shows a suprapatellar  bursa, a prepatellar bursa, and an infrapatellar bursa.    The articulating bones of synovial joints have a variety of shapes  that allow different types of movement. Based upon their shapes  and the movements they permit, these joints can be classified into  six major types—ball-and-socket joints, condylar joints, plane  joints, hinge joints, pivot joints, and saddle joints.    1. A ball-and-socket joint, or spheroidal joint, consists of a  bone with a globular or slightly egg-shaped head that articu-  lates with the cup-shaped cavity of another bone. Such a joint  allows a wider range of motion than does any other type,  permitting movements in all planes (multiaxial movement),  as well as rotational movement around a central axis. The hip  and shoulder have joints of this type (fig. 8.9a).   2. Ina condylar joint, or ellipsoidal joint, the ovoid condyle of  one bone fits into the elliptical cavity of another bone, as in  the joints between the metacarpals and phalanges (fig. 8.9b).  This type of joint permits back-and-forth and side-to-side  movement in two planes (biaxial movement), but not rotation.   3. The articulating surfaces of plane joints, or gliding joints,  are nearly flat or slightly curved. These joints allow sliding  or back-and-forth motion and twisting movements (nonaxial  movement). Most of the joints in the wrist and ankle, as well  as those between the articular processes of vertebrae, belong  to this group (fig. 8.9c). The sacroiliac joints and the joints  formed by ribs 2 through 7 connecting with the sternum are  also plane joints.   4. Ina hinge joint, the convex surface of one bone fits into the  concave surface of another, as in the elbow and the joints of  the phalanges (fig. 8.9d). Such a joint resembles the hinge    FIGURE 8.8 Menisci separate the articulating surfaces of the femur  and tibia. Several bursae are associated with the knee joint. Synovial  spaces in this and other line drawings in this chapter are exaggerated. In  actuality, articulating cartilages are essentially in contact with one another.    of a door in that it permits movement in one plane only (uni-  axial movement).   5. Ina pivot joint, or trochoid joint, the cylindrical surface  of one bone rotates in a ring formed of bone and a ligament.  Movement at such a joint is limited to rotation around a cen-  tral axis (uniaxial movement). The joint between the proximal  ends of the radius and the ulna, where the head of the radius  rotates in a ring formed by the radial notch of the ulna and a  ligament (anular ligament), is of this type. Similarly, a pivot  joint functions in the neck as the head turns from side to side.  In this case, the ring formed by a ligament (transverse liga-  ment) and the anterior arch of the atlas rotates around the  dens of the axis (fig. 8.9e).   6. A saddle joint, or sellar joint, forms between bones whose  articulating surfaces have both concave and convex regions.  The surface of one bone fits the complementary surface of  the other. This physical relationship permits a variety of  movements, mainly in two planes (biaxial movement), as in  the case of the joint between the carpal (trapezium) and the  metacarpal of the thumb (fig. 8.9f).    FIGURE 8.9 Types and examples of synovial (freely movable) joints (a-f).    Skeletal muscle action produces movements at synovial joints.  Typically, one end of a muscle is attached to a less movable or  relatively fixed part on one side of a joint, and the other end of the  muscle is fastened to a more movable part on the other side. When  the muscle contracts, its fibers pull its movable end (insertion)    Articulating bones fastened together by a thin layer of  dense connective tissue containing many collagen fibers    Bones bound by interosseous ligament  Flat bones united by sutural ligament  Cone-shaped process fastened in bony socket by   Articular surfaces of bones are covered by hyaline cartilage  and the bones are connected by a pad of fibrocartilage  Articulating ends of bones surrounded by a joint capsule;  articular bone ends covered by hyaline cartilage and  separated by synovial fluid    Oval-shaped condyle of one bone articulates with elliptical  cavity of another    Articulating surfaces are nearly flat or slightly curved  Convex surface of one bone articulates with concave    Cylindrical surface of one bone articulates with ring of  bone and ligament    Articulating surfaces have both concave and convex  regions; surface of one bone fits the complementary  surface of another    toward its fixed end (origin), and a movement occurs at the joint.    The following terms describe movements at joints that occur in  different directions and in different planes (figs. 8.10, 8.11, and 8.12):    flexion (flek’shun) Bending parts at a joint so that the angle  between them decreases and the parts come closer together  (bending the knee).   extension (ek-sten’shun) Moving parts at a joint so that the  angle between them increases and the parts move farther  apart (straightening the knee).    hyperextension (hi” per-ek-sten’shun) A term sometimes used  to describe the extension of the parts at a joint beyond the  anatomical position (bending the head back beyond the upright  position); often used to describe an abnormal extension  beyond the normal range of motion, resulting in injury.    angle with the side of the body) or from the axial line of the    limb (spreading the fingers or toes). Abduction of the head  and neck and bending of the trunk to the side may be termed  lateral flexion.    FIGURE 8.10 (AP|R) Joint movements illustrating abduction, adduction, lateral flexion, extension, and flexion.    adduction (ah-duk’shun) Moving a part toward the midline  (returning the upper limb from the horizontal position to the  side of the body) or toward the axial line of the limb (moving  the fingers or toes closer together).   rotation (ro-ta’shun) Moving a part around an axis (twisting  the head from side to side). Medial (internal) rotation is   the turning of a limb on its longitudinal axis so its anterior  surface moves toward the midline, whereas lateral (external)  rotation is the turning of a limb on its longitudinal axis in the  opposite direction.    circumduction (ser”kum-duk’shun) Moving a part so that its  end follows a circular path (moving the finger in a circular  motion without moving the hand).   pronation (pro-na’shun) Rotation of the forearm so the palm  is downward or facing posteriorly (in anatomical position).  Prone refers to the body lying face down.    FIGURE 8.12 (AP|R} Joint movements illustrating inversion, eversion, protraction, retraction, elevation, and depression.    Description of movements of body parts is complex. At times,  it will suffice to include the descriptive term of the movement fol-  lowed by the part that is moving. For example, the deltoid muscle  “abducts arm.” Because the action of a muscle is at the insertion,  the action of the biceps brachii muscle, for example, is sometimes  described as “flexes forearm at the elbow.” We have elected to use    The shoulder, elbow, hip, and knee are large, freely movable joints.  Although these joints have much in common, each has a unique  structure that makes possible its specific function.    The shoulder joint is a ball-and-socket joint that consists of the  rounded head of the humerus and the shallow glenoid cavity of  the scapula. The coracoid and acromion processes of the scapula  protect these parts, and dense connective tissue and muscle hold  them together.   The joint capsule of the shoulder is attached along the cir-  cumference of the glenoid cavity and the anatomical neck of the  humerus. Although it completely envelops the joint, the capsule is    very loose, and by itself is unable to keep the bones of the joint in  close contact. However, muscles and tendons surround and rein-  force the capsule, keeping together the articulating parts of the  shoulder (fig. 8.13).    The tendons of several muscles intimately blend with the fibrous  layer of the shoulder joint capsule, forming the rotator cuff,  which reinforces and supports the shoulder joint. Some sports-    related movements can injure the rotator cuff. Injury to this area  can make activities of daily living difficult. If rest, pain medication,  and physical therapy do not help, surgery may be necessary.    The ligaments of the shoulder joint, some of which help pre-  vent displacement of the articulating surfaces, include the follow-  ing (fig. 8.14):    1. The coracohumeral (kor’ah-ko-hu’mer-al) ligament is  composed of a broad band of connective tissue that con-  nects the coracoid process of the scapula to the greater  tubercle of the humerus. It strengthens the superior portion  of the joint capsule.   2. The glenohumeral (gle”no-hu’mer-al) ligaments include  three bands of fibers that appear as thickenings in the ventral  wall of the joint capsule. They extend from the edge of the gle-  noid cavity to the lesser tubercle and the anatomical neck of  the humerus.    FIGURE 8.13 fAP|R) Left shoulder joint. (a) The shoulder joint allows movements in all directions. A bursa is associated with this joint.    @ The photograph (fig. 8.13b) is of what type of section (sagittal, transverse, or frontal)?    Knee (tibiofemoral)  Knee (femoropatellar)  Proximal tibiofibular  Distal tibiofibular  Ankle (talocrural)  Intertarsal  Tarsometatarsal    Carpal and metacarpal 1  Carpals and metacarpals 2-5  Metacarpal and proximal  phalanx   Slight rotation during dorsiflexion; amphiarthrotic  Dorsiflexion, plantar flexion, slight circumduction; diarthrotic  Inversion, eversion; diarthrotic    FIGURE 8.14 Ligaments associated with the right shoulder joint. (a) Ligaments hold together the articulating surfaces of the shoulder (frontal view).  (b) The glenoid labrum is composed of fibrocartilage (lateral view of the shoulder joint with the humerus removed).    3. The transverse humeral ligament consists of a narrow  sheet of connective tissue fibers that runs between the lesser  and the greater tubercles of the humerus. Together with the  intertubercular sulcus of the humerus, the ligament forms  a canal (retinaculum) through which the long head of the  biceps brachii muscle passes.    The glenoid labrum (gle’noid la’brum) is composed of fibro-  cartilage. It is attached along the margin of the glenoid cavity and  forms a rim with a thin, free edge that deepens the cavity.   Several bursae are associated with the shoulder joint. The  major ones include the subscapular bursa between the joint cap-  sule and the tendon of the subscapularis muscle, the subdeltoid  bursa between the joint capsule and the deep surface of the del-  toid muscle, the subacromial bursa between the joint capsule  and the undersurface of the acromion process of the scapula, and  the subcoracoid bursa between the joint capsule and the cora-  coid process of the scapula (see figs. 8.13 and 8.14). Of these, the  subscapular bursa is usually continuous with the synovial cavity  of the joint cavity, and although the others do not communicate  with the joint cavity, they may be connected to each other.   The shoulder joint is capable of a wide range of movement,  due to the looseness of its attachments and the large articular sur-  face of the humerus compared to the shallow depth of the glenoid  cavity. These movements include flexion, extension, adduction,  abduction, rotation, and circumduction. Motion occurring simul-  taneously in the joint formed between the scapula and the clavicle  may also aid such movements.    The shoulder joint is somewhat weak because the bones are  mainly held together by supporting muscles rather than by bony  structures and strong ligaments. Consequently, the articulating  surfaces may become displaced or dislocated easily. Such a dis-  location can occur with a forceful impact, as when a person falls  on an outstretched arm. This movement may press the head of  the humerus against the lower part of the joint capsule where its  wall is thin and poorly supported by ligaments. Dislocations most  commonly affect joints of the shoulders, knees, fingers, and jaw.    The elbow joint is a complex structure that includes two articula-  tions—a hinge joint between the trochlea of the humerus and the  trochlear notch of the ulna and a plane joint between the capitulum  of the humerus and a shallow depression (fovea) on the head of  the radius. A joint capsule completely encloses and holds together  these unions (fig. 8.15). Ulnar and radial collateral ligaments  thicken the two joints, and fibers from a muscle (brachialis) in the  arm reinforce its anterior surface.   The ulnar collateral ligament, a thick band of dense connec-  tive tissue, is located in the medial wall of the capsule. The ante-  rior portion of this ligament connects the medial epicondyle of  the humerus to the medial margin of the coronoid process of the  ulna. Its posterior part is attached to the medial epicondyle of the  humerus and to the olecranon process of the ulna (fig. 8.16a).    FIGURE 8.15 (AP|R) Left elbow joint. (a) The elbow joint allows hinge movements, as well as pronation and supination of the hand.    FIGURE 8.16 Ligaments associated with the right elbow joint. (a) The ulnar collateral ligament, medial view, and (b) the radial collateral ligament    The radial collateral ligament, which strengthens the lateral  wall of the joint capsule, is a fibrous band extending between the  lateral epicondyle of the humerus and the anular ligament of the  radius. The anular ligament, in turn, attaches to the margin of the  trochlear notch of the ulna, and it encircles the head of the radius,  keeping the head in contact with the radial notch of the ulna  (fig. 8.16b). The elbow joint capsule encloses the resulting radio-  ulnar joint so that its function is closely associated with the elbow.   The synovial membrane that forms the inner lining of the  elbow capsule projects into the joint cavity between the radius    and ulna and partially divides the joint into humerus—ulnar and  humerus-radial portions. Also, varying amounts of adipose tissue  form fatty pads between the synovial membrane and the fibrous  layer of the joint capsule. These pads help protect nonarticular  bony areas during joint movements.   The only movements that can occur at the elbow between  the humerus and ulna are hinge-type movements—flexion and  extension. The head of the radius, however, is free to rotate in the  anular ligament. This movement allows pronation and supination  of the forearm.    12 Which parts help keep together the articulating surfaces of the  shoulder joint?    13. What factors allow an especially wide range of motion in the  shoulder?  14 Which structures form the hinge joint of the elbow?    15 Which parts of the elbow permit pronation and supination of  the hand?    A procedure called arthroscopy is commonly used to diag-  nose and treat injuries to the shoulder, elbow, and knee. The  technique enables a surgeon to visualize the interior of a joint  and perform procedures, guided by the image on a video  screen. An arthroscope is a thin, tubular instrument about  25 cm long containing optical fibers that transmit an image. The  surgeon inserts the device through a small incision in the joint  capsule that is first filled with saline to provide a good view.  Arthroscopy is much less invasive than conventional surgery.  Some runners have undergone uncomplicated arthroscopy and  raced several weeks later.   Arthroscopy can also help to rapidly diagnose infection.  Guided by an arthroscope, the surgeon samples a small piece  of the synovial membrane and extracts and examines DNA for  bacterial sequences, such as from the bacterium that causes  Lyme disease (Borrelia burgdorferi). Sampling the synovial  membrane may provide valuable information because a variety  of bacteria can infect joints, and choosing the appropriate anti-  biotic, based on knowing the type of bacterium, is crucial for  fast and complete recovery.    Hip Joint  The hip joint is a ball-and-socket joint that consists of the head of    the femur and the cup-shaped acetabulum of the hip bone (fig. 8.17).  A ligament (ligamentum capitis) attaches to a pit (fovea capitis) on    the head of the femur and to connective tissue in the acetabulum.  This attachment, however, seems to have little importance in hold-  ing the articulating bones together, but rather carries blood vessels  to the head of the femur.   A horseshoe-shaped ring of fibrocartilage (acetabular labrum)  at the rim of the acetabulum deepens the cavity of the acetabulum.  It encloses the head of the femur and helps hold it securely in place.  In addition, a heavy, cylindrical joint capsule reinforced with still  other ligaments surrounds the articulating structures and connects  the neck of the femur to the margin of the acetabulum (fig. 8.18).   The major ligaments of the hip joint include the following  (fig. 8.19):    1. The iliofemoral (il”e-o-fem’o-ral) ligament consists of a  Y-shaped band of strong fibers that connects the anterior  inferior iliac spine of the hip bone to a bony line (intertro-  chanteric line) extending between the greater and lesser  trochanters of the femur. The iliofemoral ligament is the  strongest ligament in the body.   2. The pubofemoral (pu”bo-fem’o-ral) ligament extends between  the superior portion of the pubis and the iliofemoral ligament.  Its fibers also blend with the fibers of the joint capsule.   3. The ischiofemoral (is”ke-o-fem’o-ral) ligament consists  of a band of strong fibers that originates on the ischium just  posterior to the acetabulum and blends with the fibers of the  joint capsule.    Muscles surround the joint capsule of the hip. The articulating  parts of the hip are held more closely together than those of the  shoulder, allowing considerably less freedom of movement. The  structure of the hip joint, however, still permits a wide variety of  movements, including flexion, extension, adduction, abduction,  rotation, and circumduction. The hip is one of the joints most fre-  quently replaced (Clinical Application 8.1).    The knee joint is the largest and most complex of the synovial  joints. It consists of the medial and lateral condyles at the distal end  of the femur and the medial and lateral condyles at the proximal    (b)  FIGURE 8.17 Hip joint. (a) The ball-like head of the femur. (b) The acetabulum provides the socket for the head of the femur in the hip joint.    Surgeons use synthetic materials to replace joints severely dam-  aged by arthritis or injury. Metals such as steel and titanium are used  to replace larger joints, whereas flexible silicone polymers are often  used to replace smaller joints. Such artificial joints must be durable  yet not provoke immune system rejection. They must also allow nor-  mal healing to occur and not move surrounding structures out of  their normal positions. Ceramic materials are used in about 5% of  hip replacements. More than two dozen joint replacement models  are in use by more than a million people, mostly in the hip.   A surgeon inserts a joint implant in a procedure called implant  resection arthroplasty. The surgeon first removes the surface of  the joint bones and excess cartilage. Next, the centers of the tips  of abutting bones are hollowed out, and the stems of the implant  inserted. The movable part of the implant lies between the bones,  aligning them yet allowing them to move. Bone cement fixes the    end of the tibia. In addition, the femur articulates anteriorly with  the patella. Although the knee articulations between the condyles  of the femur and tibia function largely as a modified hinge joint  (allowing flexion and extension), they allow some rotation when  the knee is flexed. The joint between the femur and patella is a  plane joint.    implant in place. Finally, the surgeon repairs the tendons, muscles,  and ligaments. A year of physical therapy may be necessary to fully  benefit from replacement joints.   Newer joint replacements use materials that resemble natu-  ral body chemicals. Hip implants, for example, may bear a coat of  hydroxyapatite, which interacts with natural bone. Instead of filling in  spaces with bone cement, some investigators are testing a variety of  porous coatings that allow bone tissue to grow into the implant area.   Three-dimensional (3D) printing technology is useful in creating  a replacement joint that closely matches an individual’s anatomy.  A biomedical engineer applies the technology to CT or MRI scans  to create and customize a 3D model to guide surgeons in perform-  ing the replacement. The precision that the technology offers can  decrease surgical time, speed recovery, lengthen the lifetime of the  part, and increase range of motion.    The joint capsule of the knee is relatively thin, but ligaments  and the tendons of several muscles greatly strengthen it. For  example, the fused tendons of several muscles in the thigh cover  the capsule anteriorly. Fibers from these tendons descend to the  patella, partially enclose it, and continue downward to the tibia.  The capsule attaches to the margins of the femoral and tibial con-  dyles as well as between these condyles (fig. 8.20).    FIGURE 8.18 Right hip joint. (a) A ring of cartilage in the acetabulum and a ligament-reinforced joint capsule hold together the hip joint.    FIGURE 8.19 The major ligaments of the right hip joint. (a) Anterior view. (b) Posterior view.    FIGURE 8.20 fAP|R} Knee joint. (a) The knee joint is the most complex of the synovial joints (sagittal section). (b) Photograph of the left knee joint  (frontal section).    FIGURE 8.21 Ligaments within the knee joint help to strengthen it. (a) Anterior view of right bent knee (patella removed). (b) Posterior view of left knee.    The ligaments associated with the joint capsule that help keep  the articulating surfaces of the knee joint in contact include the  following (fig. 8.21):    1. The patellar (pah-tel’ar) ligament is a continuation of a  tendon from a large muscle group in the thigh (quadriceps  femoris). It consists of a strong, flat band that extends from  the margin of the patella to the tibial tuberosity.   2. The oblique popliteal (6’blék pop-lit’e-al) ligament connects  the lateral condyle of the femur to the margin of the head of  the tibia.   3. The arcuate (ar’ku-at) popliteal ligament appears as a  Y-shaped system of fibers that extends from the lateral con-  dyle of the femur to the head of the fibula.   4. The tibial collateral (tib’e-al k6-lat’er-al) ligament (medial col-  lateral ligament) is a broad, flat band of tissue that connects the  medial condyle of the femur to the medial condyle of the tibia.   5. The fibular (fib’u-lar) collateral ligament (lateral collateral  ligament) consists of a strong, round cord located between the  lateral condyle of the femur and the head of the fibula.    In addition to the ligaments that strengthen the joint capsule,  two ligaments in the joint, called cruciate (kroo’she-at) ligaments,  help prevent displacement of the articulating surfaces. These strong  bands of fibrous tissue stretch upward and cross between the tibia  and the femur. They are named according to their positions of  attachment to the tibia. For example, the anterior cruciate liga-  ment originates from the anterior intercondylar area of the tibia and  extends to the lateral condyle of the femur. The posterior cruciate  ligament connects the posterior intercondylar area of the tibia to the  medial condyle of the femur.    Two fibrocartilaginous menisci separate the articulating sur-  faces of the femur and tibia and help align them. Each meniscus  is roughly C-shaped, with a thick rim and a thinner center, and  attaches to the head of the tibia. The medial and lateral menisci  form depressions that fit the corresponding condyles of the femur  (fig. 8.21).   Several bursae are associated with the knee joint. These  include a large extension of the knee joint cavity called the supra-  patellar bursa, located between the anterior surface of the distal  end of the femur and the muscle group (quadriceps femoris) above  it; a large prepatellar bursa between the patella and the skin; and a  smaller infrapatellar bursa between the proximal end of the tibia  and the patellar ligament (see fig. 8.8).   The basic structure of the knee joint permits flexion and exten-  sion, as is the case for a hinge joint. However, when the knee is  flexed, rotation is also possible. Clinical Application 8.2 discusses  some common joint disorders.    Tearing or displacing a meniscus is a common knee injury, usu-  ally resulting from forcefully twisting the knee when the leg  is flexed (fig. 8.22). Because the meniscus is composed of  fibrocartilage, this type of injury heals slowly. Also, a torn and  displaced portion of cartilage jammed between the articulat-  ing surfaces impedes movement of the joint. Following such  a knee injury, the synovial membrane may become inflamed  (acute synovitis) and secrete excess fluid, distending the joint  capsule so that the knee swells above and on the sides of  the patella.    FIGURE 8.22 Arthroscopic view of a torn meniscus in the knee and  arthroscopic scissors. Fibrocartilage does not heal well, so in many cases of  torn meniscus the only treatment option is to cut out the damaged portion.    17 What types of movement does the hip joint permit?  18 What types of joints are in the knee?    19 Which parts help hold together the articulating surfaces of  the knee?    Joint stiffness is an early sign of aging. By the fourth decade, a  person may notice that the first steps each morning become dif-  ficult. Changes in collagen structure lie behind the increasing stiff-  ness (fig. 8.23). Range of motion may diminish. However, joints  age slowly, and exercise can lessen or forestall stiffness.   The fibrous joints are the first to change, as the four types of  fontanels close the bony plates of the skull at two, three, twelve, and  eighteen to twenty-four months of age. Other fibrous joints may  accumulate bone matrix over time, bringing bones closer together,  even fusing them. Fibrous joints strengthen over a lifetime.   Synchondroses that connect epiphyses to diaphyses in long  bones disappear as the skeleton grows and develops. Another  synchondrosis is the joint that links the first rib to the manubrium  (sternum). As water content decreases and deposition of calcium  salts increases, this cartilage stiffens. Ligaments lose their elas-    FIGURE 8.23 Nuclear scan of (a) a healthy knee and (b) an arthritic  knee. The different colors in (b) indicate changes within the tissues  associated with degeneration.    ticity as the collagen fibers become more tightly cross-linked.  Breathing may become labored, and movement more restrained.   Aging also affects symphysis joints, which consist of a pad of  fibrocartilage sandwiched between thin layers of hyaline cartilage.  In the intervertebral discs, less water diminishes the flexibility of  the vertebral column and impairs the ability of the soft centers of  the discs to absorb shocks. The discs may even collapse on them-  selves slightly, contributing to the loss of height in the elderly. The  stiffening spine gradually restricts the range of motion.   Loss of function in synovial joints begins in the third decade  of life, but progresses slowly. Fewer capillaries serving the synovial  membrane slows the circulation of synovial fluid, and the membrane  may become infiltrated with fibrous material and cartilage. As a  result, the joint may lose elasticity, stiffening. More collagen cross-  links shorten and stiffen ligaments, affecting the range of motion.  This may, in turn, upset balance and retard the ability to respond in  a protective way to falling, which may explain why older people are  more likely to be injured in falls than younger individuals.   Using joints, through activity and exercise, can keep them  functional longer. Disuse hampers the nutrient supply to joints,  which hastens stiffening. Paradoxically, this can keep people from  exercising, when this is exactly what they should be doing.    v PRACTICE  20 Describe the loss of function in synovial joints as a progressive  process.  CHAPTER 8 | Joints of the Skeletal System 285    Joints must support weight, provide a variety of body movements,  and are used frequently. Trauma, overuse, infection, a misdirected  immune system attack, and degeneration can injure joints. Here is  a look at some common joint problems.   Sprains result from overstretching or tearing the connective tis-  sues, including cartilage, ligaments, and tendons associated with a  joint, but they do not dislocate the articular bones. Usually forceful  wrenching or twisting sprains a wrist or ankle. For example, invert-  ing an ankle too far can sprain it by stretching the ligaments on its  lateral side. Severe injuries may pull these structures loose from  their attachments.   A sprained joint is painful and swollen, restricting move-  ment. Immediate treatment of a sprain is rest; more serious cases  require medical attention. However, immobilization of a joint,  even for a brief period, causes bone resorption and weakens liga-  ments. Exercise may strengthen a joint.    Overuse of a joint or stress on a bursa may cause bursitis, an inflam-  mation of a bursa. The bursa between the heel bone (calcaneus) and  the Achilles tendon may become inflamed as a result of a sudden  increase in physical activity using the feet. Bursitis is treated with  rest. Medical attention may be necessary.    Arthritis causes inflamed, swollen, and painful joints. More than a  hundred different types of arthritis affect 50 million people in the  United States. Arthritis can also be part of other syndromes (table  8A). The most common types of arthritis are rheumatoid arthritis  (RA), osteoarthritis, and Lyme arthritis.    Rheumatoid Arthritis (RA)  Rheumatoid arthritis, an autoimmune disorder (a condition in  which the immune system attacks the body’s healthy tissues), is  painful and debilitating. The synovial membrane of a joint becomes  inflamed and thickens, forming a mass called a pannus. Then, the  articular cartilage is damaged, and fibrous tissue infiltrates, inter-  fering with joint movements. In time, the joint may ossify, fusing  the articulating bones (bony ankylosis). Joints severely damaged  by RA may be surgically replaced.   RA may affect many joints or only a few. It is usually a sys-  temic illness, accompanied by fatigue, muscular atrophy, anemia,    and osteoporosis, as well as changes in the skin, eyes, lungs,  blood vessels, and heart. RA usually affects adults, but there is a  juvenile form.   Osteoarthritis, a degenerative disorder, is the most common type  of arthritis (fig. 8A). It usually occurs with aging, and its prevalence  is expected to greatly increase by 2020 due to the aging of the  population. An inherited form of osteoarthritis may appear as early  as one’s thirties. A person may first become aware of osteoarthritis  when a blow to the affected joint produces intense pain. Gradu-  ally the area of the affected joint deforms. Arthritic fingers become  gnarled, or a knee may bulge.   In osteoarthritis, articular cartilage softens and disintegrates  gradually, roughening the articular surfaces. Joints become pain-  ful, with restricted movement. For example, arthritic fingers may  lock into place while a person is playing the guitar or tying a shoe-  lace. Osteoarthritis most often affects joints used the most, such  as those of the fingers, hips, knees, and lower vertebral column.   If a person with osteoarthritis is overweight or obese, the  first treatment is usually an exercise and dietary program to lose  weight. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been  used for many years to control osteoarthritis symptoms. NSAIDs  called COX-2 inhibitors relieve inflammation without the gastroin-  testinal side effects of older drugs, but they are prescribed only to  people who do not have risk factors for cardiovascular disease, to  which some of these drugs are linked.   Lyme disease, a bacterial infection passed in a tick bite, causes  intermittent arthritis of several joints, usually weeks after the  initial symptoms of rash, fatigue, and flulike aches and pains.  Lyme arthritis was first observed by a resident of Lyme, Connect-  icut, who noticed that many of her young neighbors had what  appeared to be the very rare juvenile form of rheumatoid arthri-  tis. She contacted Yale University rheumatologist Allen Steere,  who traced the illness to bacteria-bearing ticks. Antibiotic treat-  ment that begins as soon as the early symptoms are recognized  may prevent Lyme arthritis.   Other types of bacteria that cause arthritis include common  Staphylococcus and Streptococcus species, Neisseria gonorrhoeae  (which causes the sexually transmitted infection gonorrhea), and  Mycobacterium (which causes tuberculosis). Arthritis may also be  associated with AIDS, because the immune system breakdown  raises the risk of infection by bacteria that can cause arthritis.    Gout 1.6 million (85% male) >40 Sudden onset of extreme pain and swelling of a large joint    ~ Scleroderma 300,000 30-50 Skin hardens and thickens  Systemic lupus 500,000 (>90% female) teens—50s Fever, weakness, upper body rash, joint pain  erythematosus  Kawasaki disease Hundreds of cases in local 6 months-11 Fever, joint pain, red rash on palms and soles, heart  outbreaks years complications  Strep A infection 100,000 any age Confusion, body aches, shock, low blood pressure,  dizziness, arthritis, pneumonia    FIGURE 8A In osteoarthritis, an inherited defect in collagen, trauma, or prolonged wear and tear destroys joints.  The (a) normal knee as compared to the (b) osteoarthritic knee, in which articular cartilage is breaking down.    Joints are classified according to structure (the type of tissue that  binds the bones) and function (the degree of movement possible).    Bones at fibrous joints are tightly fastened to each  other by a layer of dense connective tissue with many  collagen fibers.   (2) A suture is where flat bones are united by a thin  layer of connective tissue and are interlocked by a  set of bony processes.   (3) A gomphosis is formed by the union of a cone-  shaped bony process with a bony socket.   (1) Asynchondrosis occurs where bones are united by  hyaline cartilage that may disappear as a result of  bone growth.   (2) Asymphysis is found where articular surfaces of  the bones are covered by hyaline cartilage and the  bones are connected by a pad of fibrocartilage.   (1) Most bursae are located between the skin and  underlying bony prominences.   (2) Bursae cushion and aid movements of tendons over  bony parts.    (1) Inaball-and-socket joint, the globular head of a  bone fits into the cup-shaped cavity of another bone.  a. These joints permit a wide variety of  movements.  b. The hip and shoulder are ball-and-socket joints.  (2) A condylar joint consists of an ovoid condyle  of one bone fitting into an elliptical cavity of  another bone.  a. This joint permits movement in two planes.  b. The joints between the metacarpals and  phalanges are condylar.  (3) Articular surfaces of plane joints are nearly flat.  a. These joints permit the articular surfaces to  slide back and forth.  b. Most of the joints of the wrist and ankle are  plane joints.    (4) Ina hinge joint, the convex surface of one bone  fits into the concave surface of another bone.   a. This joint permits movement in one plane only.  b. The elbow and the joints of the phalanges are  the hinge type.   (5) Ina pivot joint, a cylindrical surface of one bone  rotates within a ring of bone and ligament.   a. This joint permits rotational movement.  b. The articulation between the proximal ends of  the radius and the ulna is a pivot joint.   (6) A saddle joint forms between bones that have  complementary surfaces with both concave and  convex regions.   a. This joint permits a variety of movements.  b. The articulation between the carpal and  metacarpal of the thumb is a saddle joint.    1. Muscles acting at synovial joints produce movements in  different directions and in different planes.    2. Joint movements include flexion, extension,  dorsiflexion, plantar flexion, abduction, adduction,  rotation, circumduction, supination, pronation,  eversion, inversion, protraction, retraction, elevation,  and depression.   (1) The capsule is loose and by itself cannot keep the  articular surfaces together.    Its parts are loosely attached, so the shoulder joint  permits a wide range of movements.    The elbow has a hinge joint between the humerus and the  ulna and a plane joint between the humerus and the radius.    A synovial membrane partially divides the joint cavity  into two portions.   The joint between the humerus and the ulna permits  flexion and extension only.    The hip joint is a ball-and-socket joint between the  femur and the hip bone.   The articular surfaces are held together by a heavy joint  capsule reinforced by ligaments.    The knee joint includes a modified hinge joint between  the femur and the tibia and a plane joint between the  femur and the patella.   c. Several ligaments, some in the joint capsule, bind the  articular surfaces of the joint bones.   d. Two menisci separate the articulating surfaces of the  femur and the tibia.   f. The knee joint permits flexion and extension; when the  knee is flexed, some lower limb rotation is possible.    1. Joint stiffness is often the earliest sign of aging.  a. Collagen changes cause the feeling of stiffness.  b. Regular exercise can lessen the effects.    1 Describe how joints are classified. (p. 268)  2A is a fibrous joint with bones bound by  long connective tissue fibers, whereas a is  a fibrous joint where flat bones are united by a thin layer of  connective tissue. (p. 268)  3 Describe a gomphosis, and name an example. (p. 268)  4 Compare the structures of a synchondrosis and a symphysis.  (p. 269)  5 Explain how the joints between vertebrae permit movement.  (p. 269)  6 Draw the general structure of a synovial joint, labeling all the  main parts. (pp. 269-272)  7 Describe how a joint capsule may be reinforced. (p. 270)  8 Explain the function of a synovial membrane. (p. 271)  9 Explain the function of synovial fluid. (p. 271)  10 Define meniscus. (p. 272)  11 Define bursa. (p. 272)  12 Describe the six types of synovial joints, and name an  example of each type. (p. 272)  13 Describe the movements permitted by each type of synovial  joint. (p. 272)  8.2 Types of Joint Movements  14 Joint movements occur when a muscle contracts and the  muscle fibers pull the muscle’s more movable end of   (2) supination B. decreasing the angle between parts  (3) extension C. moving a part forward    2. Fibrous joints are the first to begin to change and  strengthen over a lifetime.   3. Synchondroses of the long bones disappear with growth  and development.   4. Changes in symphysis joints of the vertebral column  diminish flexibility and decrease height.    Name the parts that compose the shoulder joint. (p. 277)  Name the major ligaments associated with the shoulder joint.  (pp. 277 and 279)   Explain why the shoulder joint permits a wide range of  movements. (p. 279)   Name the parts that comprise the elbow joint. (p. 279)  Name the major ligaments associated with the elbow joint.  (pp. 279-280)   Name the parts that comprise the hip joint. (p. 281)  Describe how the articular surfaces of the hip joint are held  together. (p. 281)   Explain why there is less freedom of movement in the hip  joint than in the shoulder joint. (p. 281)   Name the parts that comprise the knee joint. (pp. 281-282)  Describe the major ligaments associated with the knee joint.  (p. 284)   Explain the function of the menisci of the knee. (p. 284)  Describe the locations of the bursae associated with the  knee joint. (p. 284)    Life-Span Changes  Describe the process of aging as it contributes to the  stiffening of fibrous, cartilaginous, and synovial joints. (p. 285)    Outcomes 5.3, 8.1, 8.3, 8.4 Outcomes 8.1, 8.3  1. How would you explain to an athlete why damaged joint 3. Based upon your knowledge of joint structures, which do you  ligaments and cartilages are so slow to heal following an injury? think could be more satisfactorily replaced by a prosthetic    Outcomes 8.1, 8.3, 8.4 4. Compared to the shoulder and hip joints, in what ways is the    . . : knee joint especially vulnerable to injuries?  2. How would you explain to a person with a dislocated shoulder    that the shoulder is likely to become more easily dislocated in  the future?    pick activities for a patient based on specific desired joint Anatomy & Physiology Revealed Go more in depth into the  movements? human body as you view the anatomy of specific joints. Also view  animations of the movement that occurs at various joints.    Falsely colored scanning electron micrograph (SEM) of a normal human  skeletal muscle fiber reveals the characteristic banding pattern of the  myofibrils (3,000x).    Everything we do to express ourselves uses muscles. Consciously  controlled skeletal muscles are necessary for talking, smiling  or frowning, raising a hand in class to ask a question, and even  raising an eyebrow.   Behind the scenes, the involuntary, non-consciously-controlled  smooth muscle and cardiac muscle are active too. All muscle  requires energy from food, and it is smooth muscle that moves  that food through the digestive tract. Cardiac muscle continu-  ously pumps blood so that all cells, including muscle cells, can  access the absorbed nutrients.   All of the force that muscles provide, whether it is moving your  eyes in their sockets as you read this page or climbing up a flight of  stairs, comes from one set of muscle proteins pulling on another  set of muscle proteins. Individually these proteins do not generate  much force, but collectively they are strong—as strong as you!    After you have studied this chapter, you should be able to:   Describe the structure of a skeletal muscle. (pp. 292-293)  Name the major parts of a skeletal muscle fiber and  describe the functions of each. (pp. 293-296)   Identify the major events of skeletal muscle fiber  contraction. (pp. 298-299)   List the energy sources for skeletal muscle fiber  contraction. (pp. 299-302)   Explain how various types of muscular contractions produce  body movements and help maintain posture. (p. 306)  Distinguish between fast and slow twitch muscle fibers.  (pp. 306-307)   Distinguish between the structures and functions of  multiunit smooth muscle and visceral smooth muscle.  (p. 307)   Compare the contraction mechanisms of skeletal and  smooth muscle cells. (p. 308)    Cardiac Muscle  Compare the contraction mechanisms of skeletal and  cardiac muscle cells. (pp. 308-309)   Explain how the attachments, locations, and interactions  of skeletal muscles make possible certain movements.  (pp. 311-312)    Major Skeletal Muscles  Identify and locate the skeletal muscles of each body region  and describe the action(s) of each muscle. (pp. 312-340)   Discuss how exercise can help maintain a healthy  muscular system as the body ages. (p. 340)   laten-, hidden: latent period—period be-  tween a stimulus and the beginning of a  muscle contraction.    This chapter focuses mostly on skeletal muscles, which attach to  bones and to the skin of the face and are under conscious control.  A skeletal muscle is an organ of the muscular system. It is com-  posed primarily of skeletal muscle tissue, nervous tissue, blood,  and other connective tissues.    An individual skeletal muscle is separated from adjacent muscles  and held in position by layers of dense connective tissue called  fascia (fash’e-ah). This connective tissue surrounds each muscle  and may project beyond the ends of its muscle fibers, forming a  cordlike tendon. Fibers in a tendon may intertwine with those in  the periosteum of a bone, attaching the muscle to the bone. Or, the  connective tissues associated with a muscle form broad, fibrous  sheets called aponeuroses (ap”o-nu-ro’séz), which may attach to  bone or the coverings of adjacent muscles (figs. 9.1 and 9.2).    A tendon or the connective tissue sheath of a tendon (tenosy-  novium) may become painfully inflamed and swollen following  an injury or the repeated stress of athletic activity. Tendinitis  affects the tendon and tenosynovitis affects the connective    tissue sheath of the tendon. Most commonly affected are the  tendons associated with the joint capsules of the shoulder,  elbow, hip, and knee and those involved with moving the wrist,  hand, thigh, and foot.    The layer of connective tissue that closely surrounds a skel-  etal muscle is called the epimysium, which in some areas of the  body may merge with the surrounding deep fascia. Another layer  of connective tissue, called the perimysium, extends inward from  the epimysium and separates the muscle tissue into small sections.  These sections contain bundles of skeletal muscle fibers called fas-  cicles (fasciculi). Each muscle fiber within a fascicle (fasciculus)    FIGURE 9.1 Tendons attach muscles to bones, whereas aponeuroses  attach muscles to other muscles or to bone.    Thick and thin filaments Structures containing the contractile proteins actin Intracellular  and myosin  Myofibril Overlapping parallel groups of thick and thin Intracellular    filaments in a repeating pattern; the underlying  basis for the striation pattern    Muscle fiber A single muscle cell, multinucleated and may be  many centimeters long    Within a muscle, surrounded by a layer of connective tissue  called endomysium    Within a muscle, surrounded by a layer of connective tissue  called perimysium    Surrounded by a layer of connective tissue called epimysium  and in some cases an additional layer called muscle fascia    lies within a layer of connective tissue in the form of a thin cover-  ing called endomysium (fig. 9.2, fig. 9.3, and table 9.1). Layers  of connective tissue, therefore, enclose and separate all parts of a  skeletal muscle. This organization allows the parts to move some-  what independently. Many blood vessels and nerves pass through  these layers.    A compartment is the space that contains a particular group  of muscles, blood vessels, and nerves, all tightly enclosed by  fascia. The limbs have many such compartments. If an injury  causes fluid, such as blood from an internal hemorrhage, to  accumulate in a compartment, the pressure inside will rise. The  increased pressure, in turn, may interfere with blood flow into    the region, reducing the supply of oxygen and nutrients to the  affected tissues. This condition, called compartment syndrome,  often produces severe, unrelenting pain. Persistently elevated  compartmental pressure may irreversibly damage the enclosed  muscles and nerves. Treatment for compartment syndrome  may require an immediate surgical incision through the fascia  (fasciotomy) to relieve the pressure and restore circulation.    The fascia associated with each individual organ of the mus-  cular system is part of a complex network of fasciae that extends  throughout the body. The portion of the network that surrounds the  muscles is called deep fascia. It is continuous with the subcutaneous  fascia that lies just beneath the skin, forming the subcutaneous  layer described in chapter 6 (p. 178). The network is also con-  tinuous with the subserous fascia that forms the connective tissue  layer of the serous membranes covering organs in various body  cavities and lining those cavities (see chapter 5, p. 168).    Recall from chapter 5 (p. 170) that a skeletal muscle fiber is a sin-  gle muscle cell (see fig. 5.29, p. 170). Each fiber forms from many  undifferentiated cells that fuse during development. The result-  ing multinucleated muscle fiber is a thin, elongated cylinder with    rounded ends that attach to the connective tissues associated with  a muscle. Just beneath the muscle cell membrane (sarcolemma),  the cytoplasm (sarcoplasm) of the fiber contains many small, oval  nuclei and mitochondria. The sarcoplasm also has abundant long,  parallel structures called myofibrils (mi”o-fi’-brilz) (fig. 9.4a).  The myofibrils play a fundamental role in the muscle contrac-  tion mechanism. They consist of two types of protein filaments:  thick filaments composed of the protein myosin (mi’o-sin), and  thin filaments composed primarily of the protein actin (ak’tin).  (Two other thin filament proteins, troponin and tropomyosin, will    The middle-aged woman feels something give way in her  left knee as she comes down from a jump in her dance class.  She limps away between her much younger classmates, in  great pain.   Over the next few weeks, the massage therapist  helped by applying light pressure to the injured area, which  stimulated circulation, and applied friction in a transverse  pattern to break up scar tissue and relax the muscles. She  also massaged the quadriceps to improve flexibility.   A massage therapist manipulates soft tissues, using  combinations of pressing, stroking, kneading, compressing,  and vibrating, to relieve pain and reduce stress. Many  cultures have practiced massage therapy, dating back  5,000 years. Modern massage therapists complete  programs that include 300 to 1,000 hours of class time,  hands-on practice, and continuing education. A massage  therapist may work in a pediatrics or orthopedics practice,  a spa, a hospital, or a fitness center.    FIGURE 9.2 (AP|R) A skeletal  muscle is composed of a variety of  tissues, including layers of connective  tissue. Fascia covers the surface of  the muscle, epimysium lies beneath  the fascia, and perimysium extends  into the structure of the muscle where  it separates fascicles. Endomysium  separates individual muscle fibers.    FIGURE 9.3 Light micrograph of a fascicle (fasciculus) surrounded by its connective tissue sheath, the perimysium. Muscle fibers within the fascicle are    FIGURE 9.4 Skeletal muscle fiber. (a) A skeletal muscle fiber contains numerous myofibrils, each consisting of (b) repeating units called sarcomeres.  The characteristic striations of a sarcomere reflect the organization of actin and myosin filaments.    be discussed later.) The organization of these filaments produces  the alternating light and dark striations characteristic of skeletal  muscle (and cardiac muscle) fibers. The striations form a repeating  pattern of units called sarcomeres (sar’ko-mérz) along each mus-  cle fiber. The myofibrils may be thought of as sarcomeres joined  end to end (fig. 9.4a). Muscle fibers, and in a way muscles them-  selves, are basically collections of sarcomeres, discussed later in  this chapter as the functional units of muscle contraction.   The striation pattern of skeletal muscle has two main parts.  The first, the J bands (the light bands), are composed of thin actin  filaments held by direct attachments to structures called Z lines, sei iil  which appear in the center of the I bands. The second part of the  striation pattern consists of the A bands (the dark bands), which  are composed of thick myosin filaments overlapping thin actin  filaments (fig. 9.4D).   The A band consists not only of a region where thick and thin  filaments overlap, but also a slightly lighter central region (H zone)  consisting only of thick filaments. The A band includes a thicken-  ing known as the M line, which consists of proteins that help hold  the thick filaments in place (fig. 9.4b). The myosin filaments are  also held in place by the Z lines and are attached to them by a large  protein called titin (connectin) (fig. 9.5). A sarcomere extends  from one Z line to the next.   Thick filaments are composed of many molecules of myo-  sin. Each myosin molecule consists of two twisted protein strands Thin filaments Thick filaments  with globular parts called heads that project outward along their (c)  lengths. Thin filaments consist of double strands of actin twisted  into a helix. Actin molecules are globular, and each has a binding FIGURE 9.5 (AP|RJ A sarcomere. (a) Micrograph (16,000).  site to which the heads of a myosin molecule can attach (fig. 9.6). (b—c) The relationship of thin and thick filaments in a sarcomere.    FIGURE 9.6 Thick filaments are composed of the protein myosin,  and thin filaments are primarily composed of the protein actin. Myosin  molecules have heads that extend toward nearby actin filaments.    Two other types of protein, troponin and tropomyosin, asso-  ciate with actin filaments. Troponin molecules have three protein  subunits and are attached to actin. Tropomyosin molecules are rod-  shaped and occupy the longitudinal grooves of the actin helix. Each  tropomyosin is held in place by a troponin molecule, forming a  troponin-tropomyosin complex (fig. 9.6).   Within the sarcoplasm of a muscle fiber is a network of mem-  branous channels that surrounds each myofibril and runs parallel  to it. These channels form the sarcoplasmic reticulum, which  corresponds to the endoplasmic reticulum of other cells (see  figs. 9.2 and 9.4). A set of membranous channels, the transverse    tubules (T tubules), extends into the sarcoplasm as invaginations  continuous with the sarcolemma and contains extracellular fluid.  Each transverse tubule lies between two enlarged portions of the  sarcoplasmic reticulum called cisternae. These three structures  form a triad near the region where the actin and myosin filaments  overlap (fig. 9.7).    Muscle fibers and the connective tissues associated with them  are flexible, but they can tear if overstretched. This type of  injury, common in athletes, is called a muscle strain. The sever-  ity of the injury depends on the degree of damage the tissues  sustain. In a mild strain, only a few muscle fibers are injured, the  fascia remains intact, and little function is lost. In a severe strain,    many muscle fibers as well as fascia tear, and muscle function  may be lost completely. A severe strain is very painful and is  accompanied by discoloration and swelling of tissues due to  torn blood vessels. Surgery may be required to reconnect the  separated tissues.    1 Describe how connective tissue is associated with a skeletal  muscle.    2 Describe the general structure of a skeletal muscle fiber.  3 Explain why skeletal muscle fibers appear striated.    4 Explain the physical relationship between the sarcoplasmic  reticulum and the transverse tubules.    FIGURE 9.7 Within the sarcoplasm of a skeletal muscle fiber is a network of sarcoplasmic reticulum and a system of transverse tubules.    A muscle fiber contraction is a complex interaction of several cel-  lular and chemical constituents. The result is a movement within  the myofibrils in which the filaments of actin and myosin slide  past one another, shortening the sarcomeres. When this happens,  the muscle fiber shortens and pulls on its attachments.    Actin, myosin, troponin, and tropomyosin are abundant in  muscle cells. Scarcer proteins are also vital to muscle function.  A rod-shaped muscle protein called dystrophin, for example,  accounts for only 0.002% of total muscle protein in skeletal  muscle, but its absence causes the devastating inherited dis-  order Duchenne muscular dystrophy, which only affects males.  Dystrophin binds to the inside face of muscle cell membranes,  supporting them against the powerful force of contraction.  Without dystrophin, muscle cells lose their normal structure  and die. Abnormalities in several other types of proteins that  bind to dystrophin cause other inherited muscle diseases.    Recall from chapter 5 (p. 170) that neurons establish communica-  tion networks throughout the body based on their specialized struc-  tures and functions. Each neuron has a process called an axon, which  extends from the cell body and can conduct electrical impulses called  action potentials (described in chapter 10, pp. 375-377).   Each cell that a neuron controls is connected functionally (but  not physically) to the end of an axon, in much the same way that  you can talk into a cell phone although your mouth is not in direct  physical contact with it. The site of this functional connection is  called a synapse. Neurons communicate with the cells that they  control by releasing chemicals, called neurotransmitters (nu”ro-  trans-mit-erz), at a synapse. The neurotransmitter molecules then  diffuse a very short distance to the cell being controlled, where  they have a specific effect.   Neurons that control effectors, including skeletal muscle  fibers, are called motor neurons. Normally a skeletal muscle fiber  contracts only upon stimulation by its motor neuron.   The synapse where a motor neuron axon and a skeletal mus-  cle fiber meet is called a neuromuscular junction (myoneural  junction). Here, the muscle fiber membrane is specialized to form  a motor end plate, where nuclei and mitochondria are abundant  and the sarcolemma is extensively folded (fig. 9.8).   A small gap called the synaptic cleft separates the membrane  of the neuron and the membrane of the muscle fiber. The cytoplasm  at the distal end of the axon is rich in mitochondria and contains  many tiny vesicles (synaptic vesicles) that store neurotransmitters.    Acetylcholine (ACh) is the neurotransmitter that motor neurons  use to control skeletal muscle contraction. ACh is synthesized  in the cytoplasm of the motor neuron and is stored in synaptic  vesicles near the distal end of its axon. When an action potential    junction includes the end of a motor neuron and the motor end plate of  a muscle fiber. (b) Micrograph of a neuromuscular junction (500x).    reaches the end of the axon, some of these vesicles release acetyl-  choline into the synaptic cleft (fig. 9.8).   Acetylcholine diffuses rapidly across the synaptic cleft and  binds to specific protein molecules (receptors) in the muscle fiber  membrane, increasing the membrane permeability to sodium and  potassium ions. Recall from chapter 3 (p. 103) that active trans-  port of sodium and potassium ions across the cell membrane cre-  ates a condition in which the sodium ion concentration is higher  outside the cell and the potassium ion concentration is higher    In an autoimmune disorder, the immune system attacks part of the  body. In myasthenia gravis (MG), the part attacked is the muscular  system. The name means “grave muscular weakness.” The body  produces antibodies that target receptors for the neurotransmitter  acetylcholine on skeletal muscle cells at neuromuscular junctions.  People with MG have one-third the normal number of acetylcho-  line receptors on their skeletal muscle cells. On a whole-body  level, this causes weak and easily fatigued muscles.   MG affects hundreds of thousands of people worldwide,  mostly women beginning in their twenties or thirties, and men in  their sixties and seventies. The specific symptoms depend upon  the site of attack. For 85% of patients, the disease causes gen-  eralized muscle weakness. Many people develop a characteristic  flat smile and nasal voice and have difficulty chewing and swal-  lowing due to affected facial and neck muscles. Limb weakness is  common. About 15% of patients experience the illness only in the    inside the cell. Also remember that an ion will diffuse across a  cell membrane only if two conditions are met: there is a concen-  tration gradient and the membrane is permeable to that ion. The  sodium/potassium pump maintains the concentration gradients  for these two ions, but membrane permeability is normally very  low, so in the non-stimulated state the extent of diffusion of these  ions across the membrane is very low.   When a motor neuron stimulates a muscle cell, the situation  changes. Membrane permeability to both sodium and potassium  ions increases temporarily in a pattern that results in positively  charged ions (sodium) entering the muscle cell faster than other  positively charged ions (potassium) leave. This net movement of  positive charges into the muscle cell at the motor end plate opens  nearby sodium channels on the sarcolemma.   The result of this second set of channels opening is an  impulse, an action potential. In much the same way that an impulse    When the bacterium Clostridium botulinum grows in an anaer-  obic (oxygen-poor) environment, such as in a can of unrefrig-  erated food, it produces a toxin. If a person ingests the toxin,  the release of acetylcholine from axon terminals at neuromus-  cular junctions is prevented. Symptoms of such food poisoning  include nausea, vomiting, and diarrhea; headache, dizziness,  and blurred or double vision; and finally, weakness, hoarseness,  and difficulty swallowing and, eventually, inability to breathe.  Physicians can administer an antitoxin substance that binds to  and inactivates botulinum toxin in the bloodstream, stemming  further symptoms, although not correcting damage already  done. Small amounts of botulinum toxin are used to treat  migraine headaches and to temporarily paralyze selected facial  muscles, smoothing wrinkles (Botox).    muscles surrounding their eyes. The disease reaches crisis level  when respiratory muscles are affected, requiring a ventilator to  support breathing. MG does not affect sensation or reflexes.  Most people with MG live a normal life span, with symptoms  that are controlled with a combination of treatments that include  the following:  ¢ Drugs that inhibit acetylcholinesterase, the enzyme that  normally breaks down acetylcholine, thus increasing levels  of the neurotransmitter.  e Immunosuppressant drugs, such as corticosteroids,  cyclosporine, and rituximab, that decrease production  of antibodies.  e Intravenous antibodies that bind and inactivate the  antibodies causing the damage.  e Plasma exchange that rapidly removes the damaging  antibodies from the bloodstream, helping people in crisis.    is conducted along the axon of a neuron, an impulse now spreads  throughout the muscle cell. This electrical impulse is what trig-  gers the release of calcium ions from the sarcoplasmic reticulum,  leading to muscle contraction. Clinical Application 9.1 discusses  myasthenia gravis, in which the immune system attacks certain  neuromuscular junctions.    The connection between stimulation of a muscle fiber and contrac-  tion is called excitation-contraction coupling, and it involves an  increase in calcium ions in the cytosol. At rest, the sarcoplasmic  reticulum has a high concentration of calcium ions compared to  the cytosol. This is due to active transport of calcium ions (cal-  cium pump) in the membrane of the sarcoplasmic reticulum. In  response to stimulation, the membranes of the cisternae become  more permeable to these ions, and the calcium ions diffuse out of  the cisternae into the cytosol of the muscle fiber (see fig. 9.7).    When a muscle fiber is at rest, the troponin-tropomyosin com-  plexes block the binding sites on the actin molecules and thus pre-  vent the formation of linkages with myosin heads (fig. 9.9 @). As  the concentration of calcium ions in the cytosol rises, however, the  calcium ions bind to the troponin, changing its shape (conforma-  tion) and altering the position of the tropomyosin. The movement  of the tropomyosin molecules exposes the binding sites on the  actin filaments, allowing linkages to form between myosin heads  and actin, forming cross-bridges (fig. 9.9 @ and @).    Muscle relaxation  Active transport of Ca‘? into  sarcoplasmic reticulum, which  requires ATP, makes myosin  binding sites unavailable.    @ Exposed binding sites on actin allow the muscle  contraction cycle to occur    8) Myosin heads bind to actin, forming cross-bridges,  connecting myosin to actin    FIGURE 9.9 (AP|R) The sliding filament model. (1) Relaxed muscle. (2) and (3) When calcium ion concentration rises, binding sites on  actin filaments open and myosin heads bind to the actin, forming cross-bridges. (4) Upon binding to actin, myosin heads spring from the  cocked position and pull on actin filaments. (5) ATP binds (but is not yet broken down), causing the myosin heads to release from the actin  filament. (6) ATP breakdown provides energy to “cock” the unattached myosin heads. As long as ATP and calcium ions are present, the cycle    continues. When the calcium ion concentration in the cytosol is low, the muscle is relaxed.    The sarcomere is considered the functional unit of skeletal muscles  because contraction of an entire skeletal muscle can be described  in terms of the shortening of the sarcomeres of its muscle fibers.  According to the sliding filament model, when sarcomeres shorten,  the thick and thin filaments do not change length. Rather, they slide  past one another, with the thin filaments moving toward the center  of the sarcomere from both ends. As this occurs, the H zones and the  I bands narrow; the regions of overlap widen; and the Z lines move  closer together, shortening the sarcomere (fig. 9.10).   The force that shortens the sarcomeres comes from cross-bridges  pulling on the thin filaments. A myosin head can attach to an actin  binding site forming a cross-bridge, and bend slightly, pulling on  the actin filament. Then the head can release, straighten, combine  with another binding site further down the actin filament, and pull  again (see fig. 9.9 @-@).   Myosin heads contain the enzyme ATPase, which catalyzes  the breakdown of ATP to ADP and phosphate. This reaction trans-  fers energy (see chapter 4, p. 126) that provides the force for muscle  contraction. Breakdown of ATP puts the myosin head in a “cocked”  position (see fig. 9.9 @). When a muscle is stimulated to contract,  a cocked myosin head attaches to actin (see fig. 9.9 @), forming a  cross-bridge that pulls the actin filament toward the center of the  sarcomere (see fig. 9.9 @). This movement causes a greater overlap  of the actin and myosin filaments, shortens the sarcomere and thus  shortens the muscle (fig. 9.10). When another ATP binds, the myosin  head first detaches from the actin binding site (see fig. 9.9 ®), then  breaks down the ATP to return to the cocked position (see fig. 9.9 @).  This cross-bridge cycle may repeat as long as ATP is present and  action potentials release ACh at that neuromuscular junction.    When nervous stimulation of the muscle fiber ceases (when action  potentials no longer reach the axon terminal), two events relax the  muscle fiber. First, an enzyme called acetylcholinesterase rapidly  decomposes acetylcholine remaining in the synapse. This enzyme,  which is also on the membranes of the motor end plate, prevents  a single action potential from continuously stimulating a muscle  fiber. Second, when ACh breaks down, the stimulus to the sarco-  lemma and the membranes of the muscle fiber ceases. The calcium  pump (which requires ATP) quickly moves calcium ions back  into the sarcoplasmic reticulum, decreasing the calcium ion con-  centration of the cytosol. The cross-bridge linkages break (see  fig. 9.9 @—this also requires ATP, although it is not broken down  in this step), and tropomyosin rolls back into its groove, prevent-  ing cross-bridge attachment (see fig. 9.9 @). Consequently, the  muscle fiber relaxes. Table 9.2 summarizes the major events lead-  ing to muscle contraction and relaxation.   It is important to remember that ATP is necessary for both  muscle contraction and for muscle relaxation. The trigger for con-  traction is the increase in cytosolic calcium in response to stimula-  tion by ACh from a motor neuron.    FIGURE 9.10 (AP|R) When a skeletal muscle contracts (a),  individual sarcomeres shorten as thick and thin filaments slide past one  another. (b) Transmission electron micrograph showing a sarcomere  shortening during muscle contraction (23,000x).    Q) What happens to the length of the thick and thin filaments  during contraction?    . An action potential is conducted down a motor neuron axon.    . The sarcolemma is stimulated, an action potential is generated,  and the impulse is conducted over the surface of the muscle  fiber and deep into the fiber through the transverse tubules.    . The impulse reaches the sarcoplasmic reticulum, and calcium  channels open.    . Calcium ions diffuse from the sarcoplasmic reticulum into the  cytosol and bind to troponin molecules.    . Tropomyosin molecules move and expose specific sites on  actin where myosin heads can bind.    . Thin (actin) filaments are pulled toward the center of the  sarcomere by pulling of the cross-bridges, increasing the  overlap of the thin and thick filaments.    A few hours after death, the skeletal muscles partially contract,  fixing the joints. This condition, called rigor mortis, may con-  tinue for seventy-two hours or more. It results from an increase  in membrane permeability to calcium ions, which promotes    cross-bridge formation, and a decrease in availability of ATP  in the muscle fibers, which prevents myosin release from actin.  Thus, the actin and myosin filaments of the muscle fibers remain  linked until the proteins begin to decompose.    Explain how a motor neuron action potential can trigger a  skeletal muscle fiber contraction.    7 List four proteins associated with myofibrils, and explain their  structural and functional relationships.    8 Explain how the filaments of a myofibril interact during muscle  contraction.    The energy that powers the interaction between actin and myosin  filaments as muscle fibers contract comes from ATP molecules.  However, a muscle fiber has only enough ATP to contract briefly,  and must regenerate ATP.    . Acetylcholinesterase decomposes acetylcholine, and the  muscle fiber membrane is no longer stimulated.    . ATP breaks cross-bridge linkages between actin and myosin  filaments without breakdown of the ATP itself.    . Troponin and tropomyosin molecules block the interaction  between myosin and actin filaments.    The initial source of energy available to regenerate ATP from  ADP and phosphate is creatine phosphate. Like ATP, creatine phos-  phate includes a high-energy phosphate bond. Whenever sufficient  ATP is present, an enzyme in the mitochondria (creatine phospho-  kinase) promotes the synthesis of creatine phosphate, which stores  excess energy in its phosphate bond (fig. 9.11).   Creatine phosphate is four to six times more abundant in muscle  fibers than ATP, but it cannot directly supply energy to a cell’s energy-  utilizing reactions. Instead, as ATP is decomposed to ADP, the phos-  phate from creatine phosphate molecules is transferred to these ADP  molecules, quickly converting them back into ATP. The amount of  ATP and creatine phosphate in a skeletal muscle, however, is usually  not sufficient to support maximal muscle activity for more than about  ten seconds during an intense contraction. As a result, the muscle fibers  in an active muscle soon use cellular respiration of glucose to synthe-  size ATP. Typically, a muscle stores glucose in the form of glycogen.    FIGURE 9.11 Creatine phosphate may be used to replenish ATP  stores when ATP levels in a muscle cell are low.    Recall from chapter 4 (pp. 127-128) that glycolysis, the early  phase of cellular respiration, occurs in the cytosol and is anaero-  bic, not requiring oxygen. This phase only partially breaks down  energy-supplying glucose and yields only two ATP molecules for  each molecule of glucose. The complete breakdown of glucose  occurs in the mitochondria and is aerobic, requiring oxygen. This  process, which includes the complex series of reactions of the cit-  ric acid cycle and electron transport chain, produces many ATP  molecules (see chapter 4, pp.129-131).   Blood carries the oxygen necessary to support the aero-  bic reactions of cellular respiration from the lungs to body cells.  Oxygen is carried in red blood cells, where it is loosely bound  to molecules of hemoglobin, the pigment responsible for the red  color of blood. In regions of the body where the oxygen concen-  tration is low, oxygen is released from hemoglobin and becomes  available for the aerobic reactions of cellular respiration.   Another pigment, myoglobin, is synthesized in muscle  cells and imparts the reddish brown color of skeletal muscle tis-  sue. Like hemoglobin, myoglobin can loosely bind oxygen and,  in fact, has a greater attraction for oxygen than does hemoglobin.  Myoglobin’s ability to temporarily store oxygen increases the  amount of oxygen available in the muscle cells to support aerobic  respiration (fig. 9.12). Oxygen storage in myoglobin is important  because blood flow may decrease when contracting muscle fibers  compress blood vessels.    @ In the absence of  sufficient oxygen,  aerobic respiration  cannot continue,  and glycolysis  leads to lactic acid  formation.    @ Oxygen carried from  lungs by hemoglobin  in red blood cells is  temporarily stored in  muscle cells by  myoglobin, increasing  the amount of oxygen  available to support  aerobic respiration.    When a person is resting or moderately active, the respiratory and  cardiovascular systems can usually supply sufficient oxygen to the  skeletal muscles to support the aerobic reactions of cellular res-  piration. However, when skeletal muscles are used more strenu-  ously, these systems may not be able to supply enough oxygen to  sustain the aerobic reactions of cellular respiration. Under these  conditions muscles may be limited to the anaerobic reactions to  produce ATP. This shift in metabolism is referred to as the anaerobic  threshold, or the lactic acid threshold.   In the anaerobic reactions, glycolysis breaks down glucose  molecules to yield pyruvic acid, which would normally enter the  citric acid cycle. When the oxygen supply is low, however, the  pyruvic acid reacts to produce lactic acid, which enters the blood-  stream and eventually reaches the liver (see chapter 4, p. 129). In  liver cells, reactions requiring ATP synthesize glucose from lactic  acid (fig. 9.13). In the body, lactic acid dissociates rapidly to form  lactate ion (lactate) and hydrogen ion, both of which leave muscle  cells by facilitated diffusion. For simplicity we refer only to lactic  acid in this discussion.   During strenuous exercise, available oxygen is primarily used  to synthesize ATP for muscle contraction rather than to make ATP  for reacting lactic acid to yield glucose. Consequently, as lactic acid  accumulates, a person develops an oxygen debt or excess post-  exercise oxygen consumption (EPOC) that must be repaid at a later  time. The degree of oxygen debt includes the amount of oxygen that    FIGURE 9.12 The oxygen required to support the aerobic reactions of cellular respiration is carried in the blood and stored in myoglobin.  The maximum number of ATPs generated per glucose molecule varies with cell type; in skeletal muscle, it is 36 (2 + 34). In the absence of  sufficient oxygen, anaerobic reactions generate only 2 ATP per glucose molecule and use pyruvic acid to produce lactic acid.    Lactic acid  | | | |  Glycolysis and Synthesis of glucose  lactic acid formation from lactic acid  (in muscle) (in liver)    FIGURE 9.13 Liver cells can synthesize glucose from lactic acid  produced anaerobically by muscles.    liver cells require to convert the accumulated lactic acid to glucose, as  well as the amount that the muscle cells require to resynthesize suffi-  cient ATP and creatine phosphate to restore their original concentra-  tions. The degree of oxygen debt also reflects the oxygen required to  restore blood and tissue oxygen levels to preexercise levels.   The metabolic capacity of a muscle may change with ath-  letic training. With high-intensity exercise, which depends more  on glycolysis for ATP, a muscle will synthesize more glycolytic  enzymes, and its capacity for glycolysis will increase. With aerobic  exercise, the muscles’ capacity for the aerobic reactions of cellular  respiration increases.    The runners are on the starting line, their muscles primed for  a sprint. The starting horn sounds. Energy comes first from  residual ATP, but almost instantly, creatine phosphate begins  donating high-energy phosphates to ADP, regenerating ATP.  Meanwhile, oxidation of glucose potentially produces more  ATP, but because the runner cannot take in enough oxygen to  meet the high demand, most ATP is generated in glycolysis.  Lactic acid forms, and as the runner crosses the finish line, her  liver is actively converting lactic acid back to pyruvic acid. In her  muscles, creatine phosphate levels begin to return to normal.    A muscle exercised persistently for a prolonged period may lose  its ability to contract, which is a condition called fatigue. It has a  number of potential causes, including decreased blood flow, ion  imbalances across the sarcolemma from repeated stimulation, and  psychological loss of the desire to continue the exercise.   For many years fatigue associated with anaerobic exercise  has been attributed to increased lactic acid production. As mus-  cle metabolism shifts from aerobic to anaerobic ATP production,    lactic acid begins to accumulate in muscles and to appear in the  bloodstream (lactic acid threshold). In the body, lactic acid disso-  ciates rapidly into lactate ion (lactate) and hydrogen ion. Recent  studies on the effect of both hydrogen ion and lactate suggest that  the relationship between lactic acid and muscle fatigue may not be  as clear-cut as once thought. Research in this area is ongoing.   The strenuous exercise of aerobic training stimulates new  capillaries to extend into muscles, supplying more oxygen and  nutrients to the muscle fibers. Such physical training also adds  mitochondria, which split and enlarge to increase their abundance.  Both the adaptations of increased blood supply and more mitochon-  dria boost the ability of muscle fibers to produce ATP aerobically.   Occasionally a muscle fatigues and cramps at the same time.  A cramp is a sustained, painful, involuntary muscle contraction.  The cause of muscle cramps is not fully understood. One hypoth-  esis suggests that cramps may result from changes in electrolyte  concentration in the extracellular fluid surrounding the muscle  fibers and their motor neurons, triggering uncontrolled stimulation  of the muscle.    All active cells generate heat, which is a by-product of cellular res-  piration. Muscle tissue constitutes such a large proportion of total  body mass that it is a major source of heat.   Less than half of the energy released in cellular respiration  is transferred to ATP; the rest becomes heat. Blood transports the  heat from muscle contraction throughout the body, which helps  to maintain body temperature. Homeostatic mechanisms promote  heat loss when the temperature of the internal environment begins  to rise (see chapters | and 6, p. 16 and 189, respectively).    9 What are the sources of energy used to regenerate ATP?    10 What are the sources of oxygen required for the aerobic reactions  of cellular respiration?    11. How do lactic acid and oxygen debt relate to muscle fatigue?    12 What is the relationship between cellular respiration and heat  production?    One way to observe muscle contraction is to remove a single mus-  cle fiber from a skeletal muscle of a small animal, such as a frog,  and connect it to a device that senses and records changes in the  fiber’s length. An electrical stimulator is usually used to promote  muscle contraction.    In the laboratory, when an isolated muscle fiber is exposed to a series  of electrical stimuli of increasing strength, the fiber remains unre-  sponsive until a certain strength of stimulation called the thresh-  old stimulus (thresh’old stim’u-lus) is applied. Once threshold is  reached, an action potential is generated, resulting in an impulse that  spreads throughout the muscle fiber, releasing enough calcium ions  from the sarcoplasmic reticulum to activate cross-bridge formation    and contract the fiber. A single action potential conducted down a  motor neuron normally releases enough ACh to bring the muscle  fibers to threshold, generating an impulse.    The contractile response of a single muscle fiber to a single impulse  is called a twitch. A twitch consists of a period of contraction, dur-  ing which the fiber pulls at its attachments, followed by a period of  relaxation, during which the pulling force declines. These events  can be recorded in a pattern called a myogram (fig. 9.14). A twitch  has a brief delay between the time of stimulation and the begin-  ning of contraction. This is the latent period, which in human  muscle may be less than 2 milliseconds.   The length to which a muscle fiber is stretched before stimu-  lation affects the force it will develop. If a skeletal muscle fiber  is stretched well beyond its normal resting length, the force will  decrease. This is because sarcomeres of that fiber become so  extended that some myosin heads cannot reach binding sites on the  thin filaments and cannot contribute to contraction. Conversely, at  very short fiber lengths, the sarcomeres become compressed, and  further shortening is not possible (fig. 9.15). During normal activi-  ties, muscle fibers contract at their optimal lengths. Some activities,  such as walking up stairs two at a time or lifting something from  an awkward position, put fibers at a disadvantageous length and  compromise muscle performance.    Cardiac muscle does not normally decrease its force  of contraction when stretched. This ability allows the heart to  respond to conditions of greater demand, such as exercise.    Increasing the stimulus above threshold will not result in a  stronger twitch in a muscle fiber. However, twitches from  a given fiber may vary in strength for a number of reasons,  including the length to which the fiber is stretched and the  development of fatigue.    Understanding how individual muscle fibers contract is  important for understanding how muscles work, but such contrac-  tions by themselves are of little significance in day-to-day activi-  ties. Rather, the actions we need to perform usually require the  contribution of multiple muscle fibers simultaneously. To record  how a whole muscle responds to stimulation, a skeletal muscle can  be removed from a small animal, such as a frog, and mounted on  a special device. The muscle is then electrically stimulated, and  when it contracts, it pulls on a lever. The lever’s movement is  recorded as a myogram, which reflects the combined twitches of  muscle fibers contracting, so it looks like the twitch contraction  depicted in figure 9.14.   Sustained contractions of whole muscles enable us to perform  everyday activities, but the force generated by those contractions  must be controlled. For example, holding a styrofoam cup of cof-  fee firmly enough to keep it from slipping through our fingers, but  not so forcefully as to crush it, requires precise control of contractile    force. In the whole muscle, the force developed reflects (1) the fre-  quency at which individual muscle fibers are stimulated and (2) how  many fibers take part in the overall contraction of the muscle.    The force that a muscle fiber can generate is not limited to the  maximum force of a single twitch (fig. 9.16a). A muscle fiber  exposed to a series of stimuli of increasing frequency reaches a  point when it is unable to completely relax before the next stimu-  lus in the series arrives. When this happens, the individual twitches  begin to combine, and the contraction becomes sustained. In such  a sustained contraction, the force of individual twitches combines  by the process of summation (fig. 9.16b). At higher frequen-  cies of stimulation, as the time spent in relaxation becomes very  brief, a condition called partial tetany results. When the resulting  forceful, sustained contraction lacks even partial relaxation, it is  called a complete (fused) tetanic (té-tan’ik) contraction (tetanus)  (fig. 9.16c). Complete tetany does not occur in the body, but can be  demonstrated in the laboratory.    While summation increases the force of contraction of a single mus-  cle fiber, a whole muscle can generate more force if more muscle  fibers are involved in the contraction. Most muscle fibers have only  one motor end plate. Motor neuron axons, however, are densely  branched, which enables one such axon to connect to many mus-  cle fibers. Together, a motor neuron and the muscle fibers it con-  trols constitute a motor unit (mo’tor u’nit) (fig. 9.17). The number of  muscle fibers in a motor unit varies considerably. The fewer muscle  fibers in the motor units, however, the more precise the movements  that can be produced in a particular muscle. For example, the motor  units of the muscles that move the eyes may include fewer than ten  muscle fibers per motor unit and can produce very slight move-  ments. Conversely, the motor units of the large muscles in the back  may include a hundred or more muscle fibers. Movements of these  motor units are larger-scale than those of the eye.    FIGURE 9.15 The force a muscle fiber can generate depends on the length to which it is stretched when stimulated.    FIGURE 9.16 Myograms of (a) a series of twitches, (b) summation,  and (c) a tetanic contraction. Stimulation frequency increases from one  myogram to the next.    Each motor unit is a functional unit, because an impulse in  its motor neuron will contract all of the fibers in that motor unit  simultaneously. A whole muscle is composed of many such motor  units controlled by different motor neurons. Like muscle fibers,  motor neurons must be brought to threshold before an impulse is  generated. Some motor neurons are more easily brought to thresh-  old than others. If only the more easily stimulated motor neurons    are involved, few motor units contract. At higher intensities of  stimulation, other motor neurons respond, and more motor units  are activated. Such an increase in the number of activated motor  units is called multiple motor unit summation, or recruitment  (re-kroo-t’ment). As the intensity of stimulation increases, recruit-  ment of motor units continues until finally all motor units are acti-  vated in that muscle.    During sustained contractions smaller motor units, whose neurons  have smaller-diameter axons, are more easily stimulated and are  recruited first. Larger motor units, whose neurons have larger-  diameter axons, respond later and with greater force. Summation  and recruitment together can produce a sustained contraction of  increasing strength.   Typically, many action potentials are triggered in a motor  neuron, and so individual twitches do not normally occur. Partial    FIGURE 9.17 Two motor units. The muscle fibers of a motor unit are  innervated by a single motor neuron and may be distributed throughout  the muscle.    tetanic contractions of muscle fibers are common. On the whole-  muscle level, contractions are smooth rather than irregular or jerky  because the spinal cord stimulates contractions in different sets of  motor units at different moments.   Partial tetanic contractions occur frequently in skeletal mus-  cles during everyday activities, often in only a portion of a muscle.  For example, when a person lifts a weight or walks, sustained con-  tractions are maintained in the upper limb or lower limb muscles  for varying lengths of time. These contractions are responses to a  rapid series of action potentials from the brain and spinal cord on  motor neurons.   Even when a muscle appears to be at rest, its fibers undergo  a certain degree of sustained contraction. This continuous state  of partial contraction is called muscle tone (tonus), and it is a  response to impulses originating repeatedly in the spinal cord and  conducted along axons to a few muscle fibers.   Muscle tone is particularly important in maintaining posture.  Tautness in the muscles of the neck, trunk, and lower limbs enables  a person to hold the head upright, stand, or sit. If tone is suddenly  lost, such as when a person loses consciousness, the body collapses.  Muscle tone is maintained in health but is lost if motor nerve axons  are cut or if diseases interfere with impulse conduction.    Skeletal muscles contracting forcefully may generate up to  50 pounds of pull for each square inch of muscle cross section.  Consequently, large muscles such as those in the thigh can pull  with several hundred pounds of force. Occasionally, this force  is so great that the tendons of muscles pull away from their  attachments to the bones.    Sometimes muscles shorten when they contract. For example, if a  person lifts an object, the muscles remain taut, their attached ends  pull closer together, and the object is moved. This type of con-    (a) Muscle contracts with  force greater than  resistance and  shortens (concentric  contraction)    (b) Muscle contracts  with force less than  resistance and  lengthens (eccentric  contraction)    traction is termed isotonic (equal force—change in length), and  because shortening occurs, it is called concentric.   Another type of isotonic contraction, called a lengthening or an  eccentric contraction, occurs when the force a muscle generates is  less than that required to move or lift an object, as in laying a book  down on a table. Even in such a contraction, cross-bridges are work-  ing but not generating enough force to shorten the muscle.   At other times, a skeletal muscle contracts, but the parts to  which it is attached do not move. This happens, for instance, when  a person pushes against a wall or holds a yoga pose but does not  move. Tension within the muscles increases, but the wall does not  move, and the muscles remain the same length. Contractions of this  type are called isometric (equal length—change in force). Isometric  contractions occur continuously in postural muscles that stabilize  skeletal parts and hold the body upright. Figure 9.18 illustrates  isotonic and isometric contractions.   Most body actions require both isotonic and isometric con-  tractions. In walking, for instance, certain leg and thigh muscles  contract isometrically and keep the limb stiff as it touches the  ground, while other muscles contract isotonically, bending and  lifting the opposite limb. Similarly, walking down stairs requires  eccentric contraction of certain thigh muscles. Isometric contrac-  tions of muscles around a joint can maintain a fixed position, such  as holding out a printed page to read.    Muscle fibers vary in contraction speed (slow-twitch or fast-  twitch) and in whether they produce ATP oxidatively or glycolyti-  cally. At least three combinations of these characteristics are found  in humans. Slow-twitch fibers (type I) are always oxidative and are  therefore resistant to fatigue. Fast-twitch fibers (type II) may be pri-  marily glycolytic (fatigable) or primarily oxidative (fatigue resistant).   Slow-twitch (type I) fibers, such as those in the long muscles  of the back, are also called red fibers because they contain the red,  oxygen-storing pigment myoglobin. These fibers are well supplied  with oxygen-carrying blood. In addition, red fibers contain many  mitochondria, which is an adaptation for the aerobic reactions of    FIGURE 9.18 Types of muscle contractions. (a and b) lsotonic contractions include concentric and eccentric contractions.  (c) lsometric contractions occur when a muscle contracts but does not shorten or lengthen.    cellular respiration. Red fibers have a high respiratory capacity and  can generate ATP fast enough to keep up with the ATP breakdown  that occurs when they contract. Because of the high ATP produc-  tion, red fibers can function for long periods without fatiguing.   Fast-twitch glycolytic fibers (type Ib) are also called white  jibers because they have less myoglobin and have a poorer blood  supply than red fibers. White fibers are in certain hand muscles as  well as in muscles that move the eye. These fibers have fewer mito-  chondria and thus have a reduced respiratory capacity. However,  they have a more extensive sarcoplasmic reticulum to store and  reabsorb calcium ions, and their ATPase is faster than that of red  fibers. White muscle fibers can contract rapidly because of these  factors, although they are more susceptible to fatigue.   A type of white fiber, the fast-twitch fatigue-resistant fibers  (type Ila), are also called intermediate fibers. These fibers have the  fast-twitch speed associated with white fibers with an intermediate  oxidative capacity.   All muscles include a combination of fiber types, although  some muscles may have mostly one fiber type. The speed of con-  traction and aerobic capacities of the fibers reflect the specialized  functions of the muscle. For example, muscles that move the eyes  contract about ten times faster than those that maintain posture,  and the muscles that move the limbs contract at intermediate rates.  Slowing of eye movements may be an early sign of certain neu-  rological diseases. Clinical Application 9.2 discusses noticeable  effects of muscle use and disuse.    The contractile mechanisms of smooth and cardiac muscle are  similar to those of skeletal muscles. However, the cells of these tis-  sues have important structural and functional distinctions.    Recall from chapter 5 (p. 170) that smooth muscle cells are shorter  than the fibers of skeletal muscle, and they have single, centrally  located nuclei. Smooth muscle cells are elongated with tapering  ends and contain filaments of actin and myosin in myofibrils that  extend throughout their lengths, but these filaments are thin and  more randomly distributed than those in skeletal muscle fibers.  Therefore, smooth muscle cells lack striations and appear “smooth”  under the microscope. Smooth muscle cells do not have transverse  tubules, and their sarcoplasmic reticula are not well developed.   The two major types of smooth muscle are multiunit and vis-  ceral. In multiunit smooth muscle, the muscle cells are less well  organized and function as separate units, independent of neigh-  boring cells. Smooth muscle of this type is found in the irises of  the eyes and in the walls of large blood vessels. Typically, multi-    unit smooth muscle contracts only after stimulation by neurons or  certain hormones.   Visceral smooth muscle (single-unit smooth muscle) is com-  posed of sheets of spindle-shaped cells held in close contact by  gap junctions. The thick portion of each cell lies next to the thin  parts of adjacent cells. Cells of visceral smooth muscle respond as  a single unit. When one cell is stimulated, the impulse conducted  over its surface may excite adjacent cells that, in turn, stimulate  others. Some visceral smooth muscle also displays rhythmicity—a  pattern of spontaneous repeated contractions.   These two features of visceral smooth muscle—conduction of  impulses from cell to cell and rhythmicity—are largely responsible  for the wavelike motion called peristalsis of certain tubular organs  (see chapter 17, p. 651). Peristalsis consists of alternate contrac-  tions and relaxations of the longitudinal and circular muscles.  These movements help mix the contents of a tube and push them  along its length. In the intestines, for example, peristaltic waves  move masses of partially digested food and help to mix them with  digestive fluids. Peristalsis in the ureters moves urine from the kid-  neys to the urinary bladder.   Visceral smooth muscle is the more common type of smooth  muscle. It is found in the walls of hollow organs, such as the stom-  ach, intestines, urinary bladder, and uterus. Most of the smooth  muscle in the walls of these organs is of two thicknesses. The cells  of the outer coats are oriented longitudinally, whereas those of the  inner coats are circular. The muscular layers change the sizes and  shapes of the organs as they contract and relax.   Vascular smooth muscle, which is a form of visceral smooth  muscle, is found in the walls of many of the smaller blood vessels,  where it plays a role in controlling blood flow and blood pressure.  The function of vascular smooth muscle will be discussed further  in chapter 15 (pp. 580-581 and 586).    Smooth muscle contraction resembles skeletal muscle contrac-  tion in a number of ways. Both mechanisms reflect reactions of  actin and myosin. Both are triggered by membrane impulses and  release of calcium ions. Finally, both use energy from ATP mole-  cules. However, smooth muscle and skeletal muscle also differ in  their actions. Smooth muscle cells do not have troponin, the protein  that binds to calcium ions in skeletal muscle. Instead, smooth mus-  cle uses a protein called calmodulin, which binds to calcium ions  released when its cells are stimulated, activating contraction. In  addition, much of the calcium necessary for smooth muscle con-  traction diffuses into the cell from the extracellular fluid.   Acetylcholine, the neurotransmitter in skeletal muscle, as well  as norepinephrine, affect smooth muscle. Each of these neurotrans-  mitters stimulates contraction in some smooth muscle and inhibits  contraction in other smooth muscle. The discussion of the auto-  nomic nervous system in chapter 11 (pp. 431-438) describes these  actions in greater detail.   Hormones affect smooth muscle by stimulating or inhibiting  contraction in some cases and altering the degree of response to  neurotransmitters in others. For example, during the later stages of  childbirth, the hormone oxytocin stimulates smooth muscle in the  wall of the uterus to contract (see chapter 23, p. 890).    Skeletal muscles respond to use and disuse. Forcefully exer-  cised muscles enlarge, or hypertrophy. Unused muscles atrophy,  decreasing in size and strength.   The way a muscle responds to use also depends on the type  of exercise. Aerobic activity, such as in swimming and running,  activates slow-twitch, fatigue-resistant red fibers. In response,  these fibers develop more mitochondria and the muscles that  they comprise develop more extensive capillary networks, both of  which increase fatigue-resistance during prolonged exercise.   In forceful exercise, such as weightlifting, a muscle may exert  more than 75% of its maximum tension, using predominantly the  muscle’s fast-twitch, fatigable white fibers. In response, existing  muscle fibers synthesize new filaments of actin and myosin, and  as muscle fiber diameters increase, the entire muscle enlarges.   The strength of a contraction is directly proportional to the  diameter of the muscle fibers. Therefore, an enlarged muscle  can contract more strongly than before. However, such a change  in response to forceful exercise does not increase the muscle’s  ability to resist fatigue during aerobic activities such as running  or swimming.   If regular muscle use stops, capillary networks shrink, and  muscle fibers lose some mitochondria. Actin and myosin filaments  diminish, and the entire muscle atrophies. Injured limbs immobi-    Stretching of smooth muscle can also trigger contractions.  This response is particularly important to the function of visceral  smooth muscle in the walls of certain hollow organs, such as the  urinary bladder and the intestines. For example, when partially  digested food stretches the wall of the intestine, contractions move  the contents further along the intestine.   Smooth muscle is slower to contract and relax than skeletal  muscle, yet smooth muscle can forcefully contract longer with the  same amount of ATP. Unlike skeletal muscle, smooth muscle cells  can change length without changing tautness. This ability enables  smooth muscle in the stomach and intestinal walls to stretch as these  organs fill, yet maintain a constant pressure inside the organs.    20 How is smooth muscle contraction similar to skeletal muscle  contraction?    21 How do the contraction mechanisms of smooth and skeletal  muscles differ?    Cardiac muscle is found only in the heart. It is composed of stri-  ated cells joined end to end, forming interconnected, branching,    lized in casts, or accidents or diseases that interfere with nervous  stimulation, also cause muscle atrophy. An unexercised muscle  may shrink to less than one-half its usual size in a few months.   In functional electrical stimulation, physical therapists apply  electrodes to the skin over an injured muscle. The electrical cur-  rent triggers action potentials in motor neurons controlling nearby  muscle fibers, contracting those muscle fibers. This technique can  prevent tissue atrophy, increase muscle strength, reduce pain, and  promote healing by increasing blood supply.   Muscle fibers whose motor neurons are severed not only  shrink but also may fragment, and in time fat or fibrous tissue  replaces them. However, reinnervation of such a muscle within the  first few months following an injury can restore function.   New technologies can compensate for some muscle loss.  “Targeted muscle reinnervation,” for example, can tap into the  neuromuscular system to assist a person who has lost an upper  limb. A surgeon reattaches muscles from a severed arm to the  patient’s chest wall, then uses electromyography to detect the  electrical activity that still reaches those muscles. The information  is sent to a microprocessor built into an attached prosthetic arm,  where a “neural-machine interface” enables the patient to move  the “myoelectric prosthetic” arm at will, just as he or she would  consciously direct the movement of the missing part.    three-dimensional networks. Each cell contains a single nucleus and  many filaments of actin and myosin similar to those in skeletal mus-  cle. A cardiac muscle cell also has a well-developed sarcoplasmic  reticulum, a system of transverse tubules, and many mitochondria.  However, the cisternae of the sarcoplasmic reticulum of a cardiac  muscle cell are less developed and store less calcium than those of  a skeletal muscle cell. On the other hand, the transverse tubules of  cardiac muscle cells are larger than those in skeletal muscle cells,  and they release many calcium ions into the sarcoplasm in response  to a single impulse.   The calcium ions in transverse tubules come from the fluid  outside the cardiac muscle cell. In this way, extracellular calcium  partially controls the strength of cardiac muscle contraction and  enables cardiac muscle cells to contract longer than skeletal muscle  fibers can.   The opposing ends of cardiac muscle cells are connected by  cross-bands called intercalated discs. These bands are complex  intercellular junctions that include components of desmosomes and  gap junctions.    Drugs called calcium channel blockers are used to treat irregular  heart rhythms. They do this by blocking ion channels that admit  extracellular calcium into cardiac muscle cells.    intercalated discs of cardiac muscle,  shown in this transmission electron  micrograph, bind cells and allow ions  to move between the cells (12,500x).    Network of cells contracts as a unit;  self-exciting; rhythmic; remains  refractory until contraction ends    Intercalated discs help join cells and transmit the force of con-  traction from cell to cell, and also allow ions to diffuse between  the cells. This ion movement allows action potentials to travel  from cell to cell (see fig. 5.31, p. 171, and fig. 9.19). In this way,  when one portion of the cardiac muscle network is stimulated, the  impulse passes rapidly to other cells of the network, and the whole  structure contracts as a unit or syncytium (sin-sish’e-um); that is, the  network responds to stimulation in an all-or-none manner.   Cardiac muscle is self-exciting and rhythmic. A pattern  of contraction and relaxation repeats, generating the rhyth-  mic contraction of the heart. Also, cardiac muscle becomes non-  responsive (refractory) after stimulation until the contraction ends.  Therefore, sustained or tetanic contractions do not occur in the    heart muscle. Table 9.3 summarizes characteristics of the three  types of muscles.    ® RECONNECT  ~< To Chapter 5, Figure 5.1, Intercellular Junctions, page 150.    22 How is cardiac muscle similar to skeletal muscle?  23 How does cardiac muscle differ from skeletal muscle?  24 What is the function of intercalated discs?    25 What characteristic of cardiac muscle causes the heart to  contract as a unit?    Skeletal muscles generate a great variety of body movements. The  action of each muscle mostly depends upon the type of joint it is  associated with and the way the muscle is attached on either side  of that joint.    Whenever limbs or other body parts move, bones and muscles  interact as simple mechanical devices called levers (lev’erz). A  lever has four basic components: (1) a rigid bar or rod, (2) a ful-  crum or pivot on which the bar turns, (3) an object moved against  resistance, and (4) a force that supplies energy to move the bar.   A pair of scissors is a lever. The handle and blade form a rigid  bar that rocks on a fulcrum near the center (the screw). The mate-  rial the blades cut represents the resistance, while the person on the  handle end supplies the force to cut the material.    Fulcrum  (a) First-class lever  Resistance  Fulcrum Force  (b) Second-class lever  Resistance Force    Figure 9.20 shows the three types of levers, which differ in  their component arrangements. A first-class lever’s parts are like  those of a pair of scissors. Its fulcrum is located between the resistance  and the force, making the sequence of components resistance—  fulcrum-—force. Other examples of first-class levers are seesaws  and hemostats (devices used to clamp blood vessels).   The parts of a second-class lever are in the sequence fulcrum—  resistance—force, as in a wheelbarrow. The parts of a third-class  lever are in the sequence resistance—-force—fulcrum. Eyebrow twee-  zers or forceps used to grasp an object illustrate this type of lever.   The actions of bending and straightening the upper limb at the  elbow illustrate bones and muscles functioning as levers. When  the upper limb bends, the forearm bones represent the rigid bar,  the elbow joint is the fulcrum, the hand is moved against the resis-  tance provided by the weight, and the force is supplied by muscles  on the anterior side of the arm (fig. 9.21a). One of these muscles,  the biceps brachii, is attached by a tendon to a projection (radial  tuberosity) on the radius bone in the forearm, a short distance    FIGURE 9.20 Three types of levers. (a) A first-class lever is used in a pair of scissors, (b) a second-class lever is used in a wheelbarrow, and    (c) a third-class lever is used in a pair of forceps.   (a) When the forearm bends at the elbow or  (b) when the forearm straightens at the elbow,  the bones and muscles function as a lever. (b)    below the elbow. Because the parts of this lever are arranged in the  sequence resistance—force—fulcrum, it is a third-class lever.   When the upper limb straightens at the elbow, the forearm bones  again serve as the rigid bar, the hand moves against the resistance  by pulling on the rope to raise the weight (fig. 9.215), and the elbow  joint serves as the fulcrum. However, in this case the triceps brachii, a  muscle located on the posterior side of the arm, supplies the force. A  tendon of this muscle attaches to a projection (olecranon process) of  the ulna bone at the point of the elbow. Because the parts of the lever  are arranged resistance—fulcrum-force, it is a first-class lever.   The human body also has a second-class lever (fulcrum—  resistance—force). The fulcrum is the temporomandibular joint.  Muscles supply the resistance, attaching to a projection (coronoid  process) and body of the mandible. These muscles resist or oppose  opening the mouth. The muscles attached to the chin area of the  mandible provide the force that opens the mouth.   Levers provide a range of movements. Levers that move limbs,  for example, produce rapid motions, whereas others, such as those  that move the head, help maintain posture with minimal effort.    Recall from chapter 8 (p. 274) that one end of a skeletal muscle is typ-  ically fastened to a relatively immovable or fixed part on one side of  a joint, and the other end is connected to a movable part on the other  side of that joint. The less movable end is called the origin of the mus-  cle, and the more movable end is called its insertion. When a muscle  contracts, its insertion is pulled toward its origin (fig. 9.22).   Some muscles have more than one origin or insertion. The  biceps brachii in the arm, for example, has two origins. This is  reflected in its name biceps, meaning “two heads.” The head of a    FIGURE 9.22 The biceps brachii has two heads that originate on the  scapula. A tendon inserts this muscle on the radius.    muscle is the part nearest its origin. As figure 9.22 shows, one head  of the muscle is attached to the coracoid process of the scapula,  and the other head arises from a tubercle above the glenoid cavity  of the scapula. The muscle runs along the anterior surface of the  humerus and is inserted by a single tendon on the radial tuberos-  ity of the radius. When the biceps brachii contracts, its insertion is  pulled toward its origin, and the elbow flexes.    Most skeletal muscles function in groups. Consequently, a particu-  lar body movement requires contracting more than a single muscle.  After learning to make a particular movement, the person initiates  the movement consciously, and the nervous system stimulates the  appropriate group of muscles. It is possible to determine the roles of  particular muscles by carefully observing the resulting movement.   A number of terms describe the roles of muscles in perform-  ing particular actions. An agonist (ag’o-nist) causes an action,  and an antagonist (an-tag’o-nist) works against the action. In the  example of elbow flexion, the biceps brachii is the agonist for flex-  ion and the triceps brachii is the antagonist to that movement. Note  that the role of a muscle is dependent on the movement, because  in the opposite example of elbow extension, the triceps brachii  is the agonist and the biceps brachii is the antagonist. The term  agonist is often used interchangeably with prime mover, but in  many applications the term prime mover refers to an agonist that  provides most of the force for a movement when more than one  muscle contributes to that movement.   In most cases other muscles, called synergists, contribute  to an action by helping the agonist. Again, however, the relation-  ship between muscles depends on the action. For example, pecto-  ralis major, a chest muscle, and latissimus dorsi, a back muscle,  are synergistic for medial rotation of the arm. However, they are  antagonistic for flexion and extension of the shoulder. Similarly,  two muscles on the lateral forearm, the flexor carpi radialis and  the extensor carpi radialis longus, are synergistic for abduction of  the hand, yet they are antagonistic for flexion and extension of the  wrist. Thus, any role of a muscle must be learned in the context of  a particular movement.    26 Explain how parts of the upper limb form a first-class lever and a  third-class lever.    27 Distinguish between the origin and the insertion of a muscle.  28 Define agonist.    This section discusses the locations, actions, origins, and inser-  tions of some of the major skeletal muscles. The tables that sum-  marize the information concerning groups of these muscles also  include the names of nerves that supply (innervate) the individual  muscles. Chapter 11 (pp. 420-421) presents the origins and path-  ways of these nerves.   Figures 9.23 and 9.24 show the locations of superficial skele-  tal muscles—that is, those near the surface. The names of muscles  often describe them. A name may indicate a muscle’s size, shape,  location, action, number of attachments, or the direction of its  fibers, as in the following examples:    pectoralis major A muscle of large size (major) in the  pectoral region (chest).  deltoid Shaped like a delta or triangle.    At times, there are discrepancies between anatomical terminol-  ogy and the terms the general public uses when referring to  body parts. For example, someone with a bruised thigh may  complain of a sore leg, instead of correctly referring to the  thigh. Similarly, someone may describe an action as flexing a  muscle, when really the muscle is contracting and the corre-  sponding joint, such as the elbow, is flexing.    extensor digitorum Extends the digits (fingers or toes).  biceps brachii A muscle with two heads (biceps), or points  of origin, in the brachium (arm).   external oblique Located near the outside, with fibers that  run obliquely or in a slanting direction.    In this book we have tried to adhere to accepted anatomical ter-  minology when referring to body parts or to body movements. On  the other hand, you will likely be dealing not only with colleagues  (who rely on the precision of correct terminology when communi-  cating) but also with patients (who simply, sometimes desperately,  want to communicate). You must become a master of both ways  of communicating. The bottom line is being able to communicate  accurately with colleagues and effectively with patients.   Note that in the anatomical position some actions have  already occurred, such as supination of the forearm and hand,  extension of the elbow, and extension of the knee. The muscle  actions described in the following section consider the entire range  of movement at each joint, and do not presume that the starting  point is the anatomical position.   Some muscles have more than one origin or more than one  insertion. The wide range of attachments of some of the larger  muscles has the effect of giving those muscles different, some-  times opposing, actions, depending on which portion of the mus-  cle is active. These cases are described in the appropriate sections  and tables.    A number of small muscles beneath the skin of the face and scalp  enable us to communicate feelings through facial expression.  Many of these muscles are located around the eyes and mouth, and  they make possible such expressions as surprise, sadness, anger,  fear, disgust, and pain. As a group, the muscles of facial expres-  sion connect the bones of the skull to connective tissue in regions  of the overlying skin. Figure 9.25 and reference plate 66 (p. 352)  show these muscles, and table 9.4 lists them. The muscles of facial  expression include the following:    The epicranius (ep”i-kra’ne-us) covers the upper part of  the cranium and includes two muscular parts—the frontalis    Zygomaticus Zygomatic bone Skin and muscle at Elevates corner of mouth as when smiling Facial nerve    Zygomaticus Zygomatic bone Skin and muscle at Elevates corner of mouth as when smiling Facial nerve    (a) Muscles of facial expression [Frontalis  and mastication; isolated  views of (b) the temporalis  and buccinator muscles and  (c) the lateral and medial    (frun-ta’lis), which lies over the frontal bone, and the occipitalis  (ok-sip”i-ta’lis), which lies over the occipital bone. These muscles  are united by a broad, tendinous membrane called the epicranial  aponeurosis, which covers the cranium like a cap. Contraction  of the epicranius raises the eyebrows and horizontally wrinkles  the skin of the forehead, as when a person expresses surprise.  Headaches often result from sustained contraction of this muscle.  The orbicularis oculi (or-bik’u-la-rus ok’u-li) is a ringlike  band of muscle, called a sphincter muscle, that surrounds the eye.  It lies in the subcutaneous tissue of the eyelid and closes or blinks  the eye. At the same time, it compresses the nearby tear gland, or  lacrimal gland, aiding the flow of tears over the surface of the eye.  Contraction of the orbicularis oculi also causes the folds, or crow’s    feet, that radiate laterally from the corner of the eye. Chapter 12  (pp. 469-470) describes the muscles that move the eye.   The orbicularis oris (or-bik’u-la-rus o’ris) encircles the  mouth. It lies between the skin and the mucous membranes of the  lips, extending upward to the nose and downward to the region  between the lower lip and chin. The orbicularis oris is also called  the kissing muscle because it closes and puckers the lips.   The buccinator (buk’si-na”tor) is located in the wall of the  cheek. Its fibers are directed forward from the bones of the jaws to  the angle of the mouth, and when they contract, the cheek is pulled  inward. This action helps hold food in contact with the teeth when  a person is chewing. The buccinator also aids in blowing air out of  the mouth, and for this reason, it is also called the trumpeter muscle.    Temporomandibular joint (TMJ) syndrome causes facial pain,  headache, ringing in the ears, a clicking jaw, insomnia, teeth sen-  sitive to heat or cold, backache, dizziness, and pain in front of  the ears. A misaligned jaw or grinding or clenching the teeth can  cause TMJ by stressing the temporomandibular joint, which is the  articulation between the mandibular condyle of the mandible and  the mandibular fossa of the temporal bone. Loss of coordination  of these structures affects the nerves that pass through the neck  and jaw region, causing the symptoms.   Getting enough sleep and drinking enough water can help  prevent symptoms of TMJ, and eating soft foods, applying ice  packs, using relaxation techniques, and massaging affected mus-  cles can alleviate symptoms. A physical therapist can recommend  exercises that stretch and relax the jaw, which may help some peo-  ple. Sitting for long hours in one position can cause or worsen TMJ.    Doctors diagnose TMJ syndrome using an electromyograph,  in which electrodes record muscle activity in four pairs of head  and neck muscle groups. Several treatments are available. The  National Institute of Dental and Craniofacial Research recom-  mends that treatments not permanently alter the teeth or jaw.  Low doses of certain antidepressants, or injections of botulinum  toxin or corticosteroids, may help. Using a procedure called  arthrocentesis, a physician might remove fluid accumulating in  the affected joint. Another treatment is an oral appliance fitted by  a dentist that fine-tunes the action of jaw muscles to form a more  comfortable bite. An oral appliance, also known as a bite guard  or stabilization splint, is a piece of plastic that fits over the top or  bottom teeth. Very rarely, surgery may be required to repair or  replace a joint.    The zygomaticus (zi”go-mat’ik-us) major and minor run  from the zygomatic arch downward to the corner of the mouth.  When they contract, the corner of the mouth is drawn upward,  such as in smiling or laughing.   The platysma (plah-tiz’mah) is a thin, sheetlike muscle whose  fibers run from the chest upward over the neck to the face. It pulls  the angle of the mouth downward, as in pouting. The platysma also  helps open the mouth.    Four pairs of muscles attached to the mandible produce chew-  ing movements. Three pairs of these muscles close the lower jaw,  which happens in biting. The fourth pair of muscles of mastication  can lower the jaw, cause side-to-side grinding motions of the man-  dible, and pull the mandible forward so that it protrudes. Figure  9.25 and reference plate 66 (p. 352) show the muscles of mastica-  tion, and table 9.5 lists them. They include the following:    Lateral surface of ramus of  Coronoid process and anterior  ramus of mandible    Depresses and protracts mandible  and moves it from side to side    The masseter (mas-se’ter) is a thick, flattened muscle that can  be felt just in front of the ear when the teeth are clenched. Its fibers  run downward from the zygomatic arch to the mandible. The mas-  seter raises the jaw, but it can also control the rate at which the jaw  falls open in response to gravity (fig. 9.25a).   The temporalis (tem-po-ra’lis) is a fan-shaped muscle located  on the side of the skull above and in front of the ear. Its fibers,  which also raise the jaw, pass downward beneath the zygomatic  arch to the mandible (fig. 9.25a and b). Tensing this muscle is  associated with temporomandibular joint syndrome, discussed in  Clinical Application 9.3.   The medial pterygoid (ter’i-goid) runs back and down-  ward from the sphenoid, palatine, and maxillary bones to the  ramus of the mandible. It closes the jaw (fig. 9.25c) and moves  it from side to side.   The fibers of the lateral pterygoid run from the region just  below the mandibular condyle forward to the sphenoid bone. This  muscle can open the mouth, pull the mandible forward to make it  protrude, and move the mandible from side to side (fig. 9.25c).    Ligamentum nuchae and spinous  processes of seventh cervical  and upper thoracic vertebrae    Each laterally flexes neck to  the same side, rotates head  to the opposite side. Together  they flex neck forward; also  aid in forceful inhalation.    Quadratus lumborum lliac crest  Erector spinae  (divides into three groups)  lliocostalis (lateral) group  lliocostalis lumborum Iliac crest    Paired muscles in the neck and back flex and extend the neck, and  rotate the head and hold the torso erect (figs. 9.26 and see fig. 9.28,  table 9.6). They include the following:    The sternocleidomastoid (ster”no-kli”do-mas’toid) is a long  muscle in the side of the neck that runs upward from the thorax  to the base of the skull behind the ear. When the sternocleido-  mastoid on one side contracts, the face turns to the opposite side.    When both muscles contract, the head is pulled toward the chest.  If other muscles fix the head in position, the sternocleidomastoids  can raise the sternum, aiding forceful inhalation (see fig. 9.28 and  table 9.6).   The splenius capitis (sple’ne-us kap’i-tis) is a broad, straplike  muscle in the back of the neck. It connects the base of the skull  to the vertebrae in the neck and upper thorax. A splenius capitis  acting singly rotates the head and laterally flexes the neck. Acting  together, these muscles bring the head into an upright position  (fig. 9.26 and table 9.6).   The semispinalis capitis (sem”e-spi-na’lis kap’itis) is a broad,  sheetlike muscle running upward from the vertebrae in the neck and  thorax to the occipital bone and mastoid processes of the temporal  bones. It extends and laterally flexes the neck or rotates the head  (fig. 9.26 and table 9.6).    FIGURE 9.26 {AP|R] Deep muscles of the back and the neck help move the head (posterior view) and hold the torso erect. The splenius capitis and    Three scalene (ska’len) muscles (anterior, middle, and poste-  rior) are synergistic with the sternocleidomastoid for flexion of the  neck. They also assist with forceful breathing by elevating the first  two ribs (figs. 9.27 and 9.28).   The quadratus lumborum (kwod-ra’tus lum-bo’rum) is  located in the lumbar region. When the quadratus lumborum  muscles on both sides contract, the vertebral column is extended.  When the muscle on only one side contracts, the vertebral column  is flexed laterally.   Erector spinae (é-rek’tor spi’ne) muscles run longitudinally  along the back, with origins and insertions at many places on the  axial skeleton. These muscles extend the neck and rotate the head  and maintain the erect position of the vertebral column. In the neck  region they are aided by an elastic ligament (/igamentum nuchae),  which limits flexion of the neck and helps to hold the head upright.  Erector spinae can be subdivided into lateral, intermediate, and  medial groups (table 9.6).    The muscles that move the pectoral girdle are closely associated  with those that move the arm. A number of these chest and shoulder  muscles connect the scapula to nearby bones and move the scapula  upward, downward, forward, and backward (figs. 9.27, 9.28, and  fig. 9.29; reference plates 68, 69, pp. 354-355; table 9.7). Muscles  that move the pectoral girdle include the following:    The trapezius (trah-pe’ze-us) is a large, triangular muscle in the  upper back that runs horizontally from the base of the skull and the  cervical and thoracic vertebrae to the shoulder. Its fibers are organized  into three groups—upper, middle, and lower. Together these fibers  rotate the scapula. The upper fibers acting alone raise the scapula and  shoulder, such as when shrugging the shoulders to express a feeling of  indifference. The middle fibers pull the scapula toward the vertebral  column, and the lower fibers draw the scapula and shoulder down-  ward. When other muscles fix the shoulder in position, the trapezius  can pull the head backward or to one side (see fig. 9.24).   Rhomboid (rom-boid’) major and minor connect the vertebral  column to the scapula. Both retract and elevate the scapula. Rhomboid  major can also rotate the scapula downward (see fig. 9.27).    A small, triangular region, called the triangle of auscultation,  is located in the back where the trapezius overlaps the supe-  rior border of the latissimus dorsi and the underlying rhomboid  major. This area, near the medial border of the scapula, enlarges  when a person bends forward with the arms folded across  the chest. By placing the bell of a stethoscope in the triangle of  auscultation, a physician can usually clearly hear the sounds of  the respiratory organs.    The levator scapulae (le-va’tor scap’u-le) is a straplike muscle  that runs almost vertically through the neck, connecting the cervi-  cal vertebrae to the scapula. It elevates the scapula (see figs. 9.27  and 9.29).    The serratus anterior (ser-ra’tus an-te’re-or) is a broad,  curved muscle located on the side of the chest. It arises as fleshy,  narrow strips on the upper ribs and continues along the medial  wall of the axilla to the ventral surface of the scapula. It pulls the  scapula downward and anteriorly and is used to thrust the shoulder  forward, as when pushing something (see fig. 9.28).   The pectoralis (pek’tor-a’lis) minor is a thin, flat muscle that lies  beneath the larger pectoralis major. It runs laterally and upward from  the ribs to the scapula and pulls the scapula forward and downward.  When other muscles fix the scapula in position, the pectoralis minor  can raise the ribs and thus aid forceful inhalation (see fig. 9.28).    The arm is one of the more freely movable parts of the body because  muscles connect the humerus to regions of the pectoral girdle, ribs,  and vertebral column. These muscles can be grouped according to  their primary actions—flexion, extension, abduction, and rotation  (figs. 9.29, 9.30, 9.31; reference plates 67, 68, 69, pp. 353-355;  table 9.8). Muscles that move the arm include the following:    Flexors Abductors  Coracobrachialis Supraspinatus  Pectoralis major Deltoid  Extensors Rotators  Teres major Subscapularis  Latissimus dorsi Infraspinatus   The movement of flexion of the shoulder may be less obvious than  at other joints. Movements of the humerus forward and upward flex  the shoulder. The coracobrachialis (kor”ah-ko-bra’ke-al-is) runs  from the scapula to the middle of the humerus along its medial sur-  face. It flexes and adducts the arm (see figs. 9.30 and 9.31).   The pectoralis major is a thick, fan-shaped muscle in the  upper chest. Its fibers run from the center of the thorax through the  armpit to the humerus. This muscle primarily pulls the arm for-  ward and across the chest. It can also rotate the humerus medially  and adduct the arm from a raised position (see fig. 9.28).   The movement of extension of the shoulder may be less obvious  than at other joints. Movements of the humerus backward and  upward extend the shoulder. The shoulder is already extended  in the anatomical position. The teres (te’réz) major connects  the scapula to the humerus. It extends the shoulder and can also  adduct and rotate the arm medially (see figs. 9.27 and 9.29).   The latissimus dorsi (lah-tis’i-mus dor’si) is a wide, triangular  muscle that curves upward from the lower back, around the side, and  to the armpit. It can extend the shoulder and adduct the arm and rotate  the humerus medially. It also pulls the shoulder downward and back.  The actions of pulling the arm back in swimming, climbing, and row-  ing use this muscle (see figs. 9.27 and 9.30).    The supraspinatus (su” prah-spi’na-tus) is located in the depres-  sion above the spine of the scapula on its posterior surface. It    FIGURE 9.27 fAP|R) Muscles of the shoulder and back. (a) Muscles of the posterior shoulder. The right trapezius is removed to show underlying  muscles. Isolated views of (b) trapezius, (c) deltoid, and (d) rhomboid and latissimus dorsi muscles.    connects the scapula to the greater tubercle of the humerus and  abducts the arm (see figs. 9.27 and 9.29).   The deltoid (del’toid) is a thick, triangular muscle that cov-  ers the shoulder joint. It connects the clavicle and scapula to the  lateral side of the humerus and abducts the arm. The deltoid’s pos-  terior fibers can extend the shoulder, and its anterior fibers can flex  the shoulder (see fig. 9.27).    A humerus fractured at its surgical neck may damage the axil-  lary nerve that supplies the deltoid muscle (see fig. 7.44, p. 236).  If this occurs, the muscle is likely to shrink and weaken. To test    the deltoid for such weakness, a physician may ask a patient to  abduct the arm against some resistance and maintain that posi-  tion for a time.    FIGURE 9.28 (AP|R} Muscles of the  anterior chest and abdominal wall. The right  pectoralis major and external oblique are  removed to show underlying muscles.    Occipital bone, ligamentum  nuchae, and spinous processes  of seventh cervical and all  thoracic vertebrae   The subscapularis (sub-scap’u-lar-is) is a large, triangular muscle  that covers the anterior surface of the scapula. It connects the scap-  ula to the humerus and rotates the arm medially (fig. 9.31).   The infraspinatus (in’frah-spi’na-tus) occupies the depres-  sion below the spine of the scapula on its posterior surface. The  fibers of this muscle attach the scapula to the humerus and rotate  the arm laterally (see fig. 9.29).    Rotates and retracts scapula Accessory nerve  Superior portion elevates scapula  Inferior portion depresses scapula    The teres minor is a small muscle connecting the scapula to  the humerus. It rotates the arm laterally (see figs. 9.27 and 9.29).    Most forearm movements are produced by muscles that connect  the radius or ulna to the humerus or pectoral girdle. A group of  muscles located along the anterior surface of the humerus flexes  the forearm at the elbow, whereas a single posterior muscle    FIGURE 9.29 (AP|R) Muscles of the shoulder and arm. (a) Muscles of the posterior surface of the scapula  and the arm. (b and c) Muscles associated with the scapula. (d) Isolated view of the triceps brachii.    extends this joint. Other muscles cause movements at the radioulnar  joint and rotate the forearm.   The muscles that move the forearm are shown in figures 9.31,  9.32, 9.33, and 9.34, in reference plates 68, 69, and 70 (pp. 354-356),  and are listed in table 9.9, grouped according to their primary  actions. They include the following:    Flexors Extensor Rotators  Biceps brachii Triceps brachii Supinator  Brachialis Pronator teres  Brachioradialis Pronator  quadratus    The biceps brachii (bi’seps bra’ke-i) is a fleshy muscle that forms  a long, rounded mass on the anterior side of the arm. It connects  the scapula to the radius and flexes the elbow and rotates the hand  laterally (supination), as when a person turns a doorknob or screw-  driver (see fig. 9.31).   The brachialis (bra’ke-al-is) is a large muscle beneath the  biceps brachii. It connects the shaft of the humerus to the ulna and  is the strongest flexor of the elbow (see fig. 9.31).   The brachioradialis (bra”ke-o-ra”de-a’lis) connects the  humerus to the radius. It aids in flexing the elbow (see fig. 9.32).    Coracobrachialis Coracoid process of scapula Medial mid-shaft of humerus Flexes shoulder and adducts arm Musculocutaneus  nerve  Pectoralis major Clavicle, sternum, and costal Intertubercular sulcus of Flexes shoulder, adducts, and Pectoral nerve  cartilages of upper ribs humerus rotates arm medially  Teres major Lateral border of scapula Intertubercular sulcus of Extends shoulder, adducts, and Lower subscapular  humerus rotates arm medially nerve  Latissimus dorsi Spines of sacral, lumbar, and lower Intertubercular sulcus of Extends shoulder, adducts, Thoracodorsal  thoracic vertebrae, iliac crest, and humerus and rotates arm medially, or nerve  lower ribs depresses and retracts shoulder  Supraspinatus Supraspinous fossa of scapula Greater tubercle of humerus Abducts arm Suprascapular  nerve  Deltoid Acromion process, spine of the Deltoid tuberosity of humerus Lateral portion abducts arm Axillary nerve    Subscapularis Anterior surface of scapula Lesser tubercle of humerus Rotates arm medially Subscapular  nerve   Infraspinatus Infraspinous fossa of scapula Greater tubercle of humerus Rotates arm laterally Upper and lower  suprascapular  nerves   Teres minor Lateral border of scapula Greater tubercle of humerus Rotates arm laterally Axillary nerve    FIGURE 9.31 (AP|R} Muscles of the shoulder and arm. (a) Muscles of the anterior shoulder and the arm, with the rib cage removed.    (b, c, and d) Isolated views of muscles associated with the arm.    Extensor  The triceps brachii (tri’seps bra’ke-i) has three heads and is the  only muscle on the back of the arm. It connects the humerus and    scapula to the ulna and is the primary extensor of the elbow (see  figs. 9.29 and 9.30).    The supinator (su’pi-na-tor) is a short muscle whose fibers run  from the ulna and the lateral end of the humerus to the radius. It  assists the biceps brachii in rotating the forearm laterally, such as  when turning the hand so the palm faces upward (supination) (see  fig. 9.32).    The pronator teres (pro-na’tor te’réz) is a short muscle con-  necting the ends of the humerus and ulna to the radius. It rotates  the arm medially, such as when turning the hand so the palm faces  downward (pronation) (see fig. 9.32).   The pronator quadratus (pro-na’tor kwod-ra’tus) runs from  the distal end of the ulna to the distal end of the radius. It assists  the pronator teres in rotating the arm medially (see fig. 9.32).    Movements of the hand include movements of the wrist and fin-  gers. Many of the implicated muscles originate from the distal  end of the humerus and from the radius and ulna. The two major    Tubercle below glenoid cavity  and lateral and posterior surfaces  of humerus    Radial tuberosity of radius  Coronoid process of ulna  Lateral surface of radius    Medial epicondyle of humerus  Medial epicondyle of humerus  and olecranon process of ulna  Medial epicondyle of humerus    groups of these muscles are flexors on the anterior side of the fore-  arm and extensors on the posterior side. Figures 9.32, 9.33, 9.34,  and reference plate 70 (p. 356) show these muscles, and table 9.10  lists them. The muscles that move the hand include the following:   Extensor carpi radialis longus  Extensor carpi radialis brevis  Extensor carpi ulnaris  Extensor digitorum   The flexor carpi radialis (flek’sor kar-pi’ ra”de-a’lis) is a fleshy  muscle located medially on the anterior side of the forearm. It  runs from the distal end of the humerus into the hand, where it is  attached to metacarpal bones. The flexor carpi radialis flexes the  wrist and abducts the hand (see fig. 9.32).   The flexor carpi ulnaris (flek’sor kar-pi’ ul-na’ris) is located  along the medial border of the forearm. It connects the distal end of  the humerus and the proximal end of the ulna to carpal and meta-  carpal bones. It flexes the wrist and adducts the hand (see fig. 9.32).    The palmaris longus (pal-ma’ris long’ gus) is a slender muscle  located on the medial side of the forearm between the flexor carpi  radialis and the flexor carpi ulnaris. It connects the distal end of the  humerus to fascia of the palm and flexes the wrist (see fig. 9.32).   The flexor digitorum profundus (flek’sor dij”i-to’rum pro-  fun’dus) is a large muscle that connects the ulna to the distal  phalanges. It flexes the distal joints of the fingers, such as when  making a fist (see fig. 9.34).   The flexor digitorum superficialis (flek’sor dij  su’ per-fish”e-a’lis) is a large muscle located beneath the flexor  carpi ulnaris. It arises by three heads—one from the medial epi-  condyle of the humerus, one from the medial side of the ulna,  and one from the radius. It is inserted in the tendons of the fin-  gers and flexes the fingers and, by a combined action, flexes the  wrist (see fig. 9.32).    More than thirty muscles provide fingertip dexterity and hand  movements. To track the movements required to send a text  message, researchers recorded the electrical activity and  fingertip force in seven muscles of the index fingers of vol-  unteers as they pushed their fingers against a surface. The  researchers observed two patterns of muscle activation, indi-  cating two types of movement—light tapping from an angle  versus direct downward pressure on one key. The act of texting  entails a key-locating “tap” followed by a more direct push.  The switch from one type of movement to another is so fast  and fluid that we are not aware of it.   The extensor carpi radialis longus (eks-ten’sor kar-pi’ra”de-a’lis  long’gus) runs along the lateral side of the forearm, connecting the  humerus to the hand. It extends the wrist and assists in abducting  the hand (see figs. 9.33 and 9.34).   The extensor carpi radialis brevis (eks-ten’sor kar-pi’ ra”de-  a’lis brev’is) is a companion of the extensor carpi radialis longus and  is located medially to it. This muscle runs from the humerus to the  metacarpal bones and extends the wrist. It also assists in abducting  the hand (see figs. 9.33 and 9.34).   The extensor carpi ulnaris (eks-ten’sor kar-pi’ ul-na’ris) is  located along the posterior surface of the ulna and connects the  humerus to the hand. It extends the wrist and assists in adducting  the hand (see figs. 9.33 and 9.34).   The extensor digitorum (eks-ten’sor dij”i-to’rum) runs medi-  ally along the back of the forearm. It connects the humerus to the  posterior surface of the phalanges and extends the fingers (see figs.  9.33 and 9.34).   A structure called the extensor retinaculum consists of a  group of heavy connective tissue fibers in the fascia of the wrist  (see fig. 9.33). It connects the lateral margin of the radius with the  medial border of the styloid process of the ulna and certain bones  of the wrist. The retinaculum gives off branches of connective tis-  sue to the underlying wrist bones, creating a series of sheathlike  compartments through which the tendons of the extensor muscles  pass to the wrist and fingers.    The walls of the chest and pelvic regions are supported directly by  bone, but those of the abdomen are not. Instead, the anterior and  lateral walls of the abdomen are composed of layers of broad, flat-  tened muscles. These muscles connect the rib cage and vertebral  column to the pelvic girdle. A band of tough connective tissue,  called the linea alba (lin’e-ah al’bah), extends from the xiphoid  process of the sternum to the pubic symphysis. It is an attachment  for some of the abdominal wall muscles.   Contraction of the abdominal muscles decreases the volume  of the abdominal cavity and increases the pressure inside, which is  transferred upwards to the thoracic cavity. This action helps move  air out of the lungs during forceful exhalation and also aids in def-  ecation, urination, vomiting, and childbirth.   The abdominal wall muscles are shown in figure 9.35, refer-  ence plate 67 (p. 353), and are listed in table 9.11. They include  the following:    The external oblique (eks-ter’nal 6-blék), is a broad, thin  sheet of muscle whose fibers slant downward from the lower ribs  to the pelvic girdle and the linea alba. When this muscle contracts,  it tenses the abdominal wall and compresses the contents of the  abdominal cavity. Similar in structure and function is the internal  oblique (in-ter’nal 6-blék) which is a broad, thin sheet of muscle  beneath the external oblique. Its fibers run up and forward from the  pelvic girdle to the lower ribs.   The transversus abdominis (trans-ver’sus ab-dom’‘i-nis) forms  a third layer of muscle beneath the external and internal obliques.  Its fibers run horizontally from the lower ribs, lumbar vertebrae,  and ilium to the linea alba and pubic bones. It functions in the  same manner as the external and internal obliques.   The rectus abdominis (rek’tus ab-dom’i-nis) is a long, strap-  like muscle that connects the pubic bones to the ribs and sternum.  Three or more fibrous bands cross the muscle transversely, giv-  ing it a segmented appearance. The muscle functions with other  abdominal wall muscles to compress the contents of the abdomi-  nal cavity, and it also helps to flex the vertebral column.    Two muscular sheets form the floor of the pelvis—a deeper pel-  vic diaphragm and a more superficial urogenital diaphragm.  The pelvic diaphragm forms the floor of the pelvic cavity, and  the urogenital diaphragm fills the space within the pubic arch.  Figure 9.36 and table 9.12 show the muscles of the male and  female pelvic floors. They include the following:    FIGURE 9.32 Muscles of the arm and forearm. (a) Muscles of the anterior forearm. (b—e) Isolated views of muscles associated with the    FIGURE 9.33 fAP|R) Muscles of the arm and forearm. (a) Muscles of the posterior forearm. (b and c) Isolated views of muscles associated with the    a central tendon that extends from the tip of the coccyx to the anal  canal. Anteriorly, they are separated in the male by the urethra and  the anal canal, and in the female by the urethra, vagina, and anal  canal. These muscles help support the pelvic viscera and provide  sphincterlike action in the anal canal and vagina.   An external anal sphincter under voluntary control and an  internal anal sphincter formed of involuntary muscle fibers of the  intestine encircle the anal canal and keep it closed.   The coccygeus (kok-sij’e-us) is a fan-shaped muscle that spans  from the ischial spine to the coccyx and sacrum. It aids the levator ani.   The superficial transversus perinei (soo’per-fish’al trans-ver’sus  per’ i-ne’i) consists of a small bundle of muscle fibers that passes  medially from the ischial tuberosity along the posterior border of  the urogenital diaphragm. It assists other muscles in supporting  the pelvic viscera.   In the male, the bulbospongiosus (bul”bo-spon”je-o’sus)  muscles are united surrounding the base of the penis and assist in  emptying the urethra. In the female, these muscles are separated  by the vagina medially, and constrict the vaginal opening. These    Costal cartilages of lower 6 ribs,  processes of lumbar vertebrae, lip  of iliac crest, and inguinal ligament    muscles can also slow the flow of blood in veins, which helps  maintain an erection of the penis in the male and of the clitoris in  the female.   The ischiocavernosus (is”ke-o-kav”er-no’sus) muscle is a  tendinous structure that runs from the ischial tuberosity to the mar-  gin of the pubic arch. It assists erection of the penis in males and  the clitoris in females.   The sphincter urethrae (sfingk’ter u-re’thré) are muscles  that arise from the margins of the pubic and ischial bones. Each  arches around the urethra and unites with the one on the other side.  Together they act as a sphincter that closes the urethra by compres-  sion and opens it by relaxation, helping control the flow of urine.    The muscles that move the thigh are attached to the femur and to  part of the pelvic girdle. (Important exceptions are the sartorius  and rectus femoris, described later.) The muscles can be separated  into an anterior group that primarily flexes the hip and a posterior  group that extends the hip and abducts or rotates the thigh.   The movement of flexion and extension of the hip may be  less obvious than at other joints. Movements of the femur forward    and upward flex the hip. Movement of the femur down or to the  back extend the hip. The hip is extended in the anatomical posi-  tion. Figures 9.37, 9.38, 9.39, 9.40 and reference plates 71 and 72  (pp. 356-357) show the muscles in these groups, and table 9.13  lists them. Muscles that move the thigh include the following:    Posterior Group  Gluteus maximus  Gluteus medius  Gluteus minimus  Piriformis  Tensor fasciae latae  Another group of muscles, attached to the femur and pelvic  girdle, adducts the thigh. This group includes the following:    The psoas (so’as) major is a long, thick muscle that connects the  lumbar vertebrae to the femur. It flexes the hip (see fig. 9.37).    FIGURE 9.35 (AP|R) Muscles of the abdominal wall. (a—-d) Isolated muscles of the abdominal wall. (e) Transverse section through the abdominal wall.    FIGURE 9.36 (AP|R) External view of muscles of (a) the male pelvic floor and (b) the female pelvic floor. (c) Internal view of female pelvic and  urogenital diaphragms.    Levator ani Pubis and ischial Coccyx Supports pelvic viscera and compresses Pudendal nerve  spine anal canal    Coccygeus Ischial spine Sacrum and coccyx Supports pelvic viscera and provides S4 and S5 nerves  sphincterlike action in anal canal and vagina    Superficial transversus Ischial tuberosity | Central tendon Supports pelvic viscera Pudendal nerve   Bulbospongiosus Central tendon Males: Corpus cavernosa of penis Males: Assists emptying of urethra and Pudendal nerve  assists in erection of penis    Females: Corpus cavernosa Females: Constricts vagina and assists in  of clitoris erection of clitoris    Ischiocavernosus Ischial tuberosity | Males: Corpus cavernosa of Males: Contributes to erection of the penis | Pudendal nerve  penis    Females: Corpus cavernosa Females: Contributes to erection of the  of clitoris clitoris    Sphincter urethrae Margins of pubis Fibers of each unite with those Closes urethra Pudendal nerve  and ischium from other side    Pectineus  Sartorius  Adductor longus  Sartorius  Rectus femoris  AGRUCLOR magnes Vastus intermedius    FIGURE 9.37 Muscles of the thigh and leg. (a) Muscles of the anterior right thigh. Isolated views of (b) the vastus intermedius,  (c-e) adductors of the thigh, (fg) flexors of the hip.    FIGURE 9.38 Muscles of the thigh and leg. (a) Muscles of the lateral right thigh. (b-d) Isolated views of the gluteal muscles.    The iliacus (il’e-ak-us), a large, fan-shaped muscle, lies along  the lateral side of the psoas major. The iliacus and the psoas major  are the primary flexors of the hip, and they advance the lower limb  in walking movements (see fig. 9.37).   The gluteus maximus (gloo’te-us mak’si-mus) is the largest mus-  cle in the body and covers a large part of each buttock. It connects  the ilium, sacrum, and coccyx to the femur by fascia of the thigh    and extends the hip. The gluteus maximus helps to straighten the  lower limb at the hip when a person walks, runs, or climbs. It is  also used to raise the body from a sitting position (see fig. 9.38).   The gluteus medius (gloo’te-us me’de-us) is partly covered  by the gluteus maximus. Its fibers run from the ilium to the femur,  and they abduct the thigh and rotate it medially (see fig. 9.38).   The gluteus minimus (gloo’te-us min’i-mus) lies beneath the  gluteus medius and is its companion in attachments and functions  (see fig. 9.38).    FIGURE 9.39 fAP|R) Muscles of the thigh and leg.  (a) Muscles of the posterior right thigh. (b and c) Isolated  views of muscles that flex the knee.    The piriformis (pir-i-for’mis) is shaped like a pyramid and  located inferior to the gluteus minimus. It abducts and laterally  rotates the thigh and is part of the posterior group of muscles that  stabilizes the hip.   The tensor fasciae latae (ten’sor fash’e-e lah-té) connects the  ilium to the iliotibial tract (fascia of the thigh), which continues  downward to the tibia. This muscle flexes the hip and abducts and  rotates the thigh medially (see fig. 9.38).    The gluteus medius and gluteus minimus help support and  maintain the normal position of the pelvis. If these muscles are  paralyzed on one side as a result of injury or disease, the pelvis  tends to drop on the contralateral side when that foot is raised.  Consequently, the person walks with a waddling movement  called the gluteal gait.    Thigh Adductors  The pectineus (pek-tin’e-us) muscle runs from the spine of the pubis  to the femur. It flexes the hip and adducts the thigh (see fig. 9.37).   The adductor brevis (ah-duk’tor brev’is) is a short, triangular  muscle that runs from the pubic bone to the femur. It adducts the  thigh and assists in flexing the hip (see fig. 9.37).   The adductor longus (ah-duk’tor long’ gus) is a long, triangu-  lar muscle that runs from the pubic bone to the femur. It adducts  the thigh and assists in flexing the hip and rotating the thigh later-  ally (see fig. 9.37).   The adductor magnus (ah-duk’tor mag’nus) is the largest  adductor of the thigh. It is a triangular muscle that connects the  ischium to the femur. It adducts the thigh and portions assist in  flexing or extending the hip (see fig. 9.37).   The gracilis (gras’il-is) is a long, straplike muscle that passes  from the pubic bone to the tibia. It adducts the thigh and flexes the  knee (see fig. 9.37).   Ss ° ~ Shaft of femur i; Femoral v. and a.  Plane : / Sartorius m.  of Vastus lateralis m. ; Vastus medialis m.  section \ \ ,  Vastus intermedius m. > f    FIGURE 9.40 Across section of the thigh (superior view). (a. stands for artery, m. stands for muscle,  n. stands for nerve, and v. stands for vein.)   Gluteus maximus Sacrum, coccyx, and posterior Posterior surface of Extends hip Inferior gluteal nerve   Gluteus medius Lateral surface of ilium Greater trochanter Abducts and rotates thigh medially Superior gluteal nerve  of femur   Gluteus minimus Lateral surface of ilium Greater trochanter Abducts and rotates thigh medially Superior gluteal nerve  of femur    Patella by tendon, which continues as  patellar ligament to tibial tuberosity    Patella by tendon, which continues as  patellar ligament to tibial tuberosity    The muscles that move the leg connect the tibia or fibula to the  femur or to the pelvic girdle. They fall into two major groups—  those that flex the knee and those that extend it. The muscles of  these groups are shown in figures 9.37, 9.38, 9.39, 9.40, in reference  plates 71 and 72 (pp. 356-357), and are listed in table 9.14. Muscles  that move the leg include the following:   As its name implies, the biceps femoris (bi’seps fem’or-is) has two  heads, one attached to the ischium and the other attached to the  femur. This muscle passes along the back of the thigh on the lateral  side and connects to the proximal ends of the fibula and tibia. The  biceps femoris is one of the hamstring muscles, and its tendon (ham-  string) feels like a lateral ridge behind the knee. This muscle flexes  the knee, rotates the leg laterally, and extends the hip (see figs. 9.38  and 9.39).   The semitendinosus (sem”e-ten’di-no-sus) is another ham-  string muscle. It is a long, bandlike muscle on the back of the  thigh toward the medial side, connecting the ischium to the proxi-  mal end of the tibia. The semitendinosus is so named because it  becomes tendinous in the middle of the thigh, continuing to its    Patella by tendon, which continues as  patellar ligament to tibial tuberosity    | Strenuous running or kicking motions can tear the tendinous |  attachments of the hamstring muscles to the ischial tuberosity.  Internal bleeding from damaged blood vessels that supply the  muscles usually occurs with this painful injury, commonly called  a pulled hamstring. |    insertion as a long, cordlike tendon. It flexes the knee, rotates the  leg medially, and extends the hip (see fig. 9.39).   The semimembranosus (sem”e-mem’brah-no-sus) is the third  hamstring muscle and is the most medially located muscle in the  back of the thigh. It connects the ischium to the tibia and flexes the  knee, rotates the leg medially, and extends the hip (see fig. 9.39).   The sartorius (sar-to’re-us) is an elongated, straplike muscle  that passes obliquely across the front of the thigh and then descends  over the medial side of the knee. It connects the ilium to the tibia and  flexes the knee and the hip. It can also abduct the thigh, rotate the  thigh laterally, and rotate the leg medially (see figs. 9.37 and 9.38).    The large muscle group called the quadriceps femoris (kwod’ri-  seps fem’or-is) occupies the front and sides of the thigh and is the  primary extensor of the knee. It is composed of four parts—rectus  femoris, vastus lateralis, vastus medialis, and vastus intermedius  (see figs. 9.38 and 9.40). These parts connect the illum and femur  to a common patellar tendon, which passes over the front of the  knee and attaches to the patella. This tendon then continues as the  patellar ligament to the tibia. Because the rectus femoris origi-  nates on the ilium, it can flex the hip.    FIGURE 9.41 (AP|R) Muscles of the leg. (a) Muscles  of the anterior right leg. (b-d) Isolated views of muscles  associated with the anterior right leg.    Movements of the foot include movements of the ankle and toes.  A number of muscles that move the foot are in the leg. They attach  the femur, tibia, and fibula to bones of the foot and move the foot  upward (dorsiflexion) or downward (plantar flexion) and turn the  foot so the plantar surface faces medially (inversion) or laterally  (eversion). These muscles are shown in figures 9.41, 9.42, 9.43, and    9.44, in reference plates 73, 74, 75 (pp. 357-358), and are listed in  table 9.15. Muscles that move the foot include the following:    FIGURE 9.42 Muscles of the leg.  (a) Muscles of the lateral right leg.  Isolated views of (b) fibularis longus    The tibialis anterior (tib’e-a’lis ante’re-or) is an elongated, spindle-  shaped muscle located on the front of the leg. It arises from the  surface of the tibia, passes medially over the distal end of the tibia,  and attaches to bones of the foot. Contraction of the tibialis ante-  rior causes dorsiflexion and inversion of the foot (see fig. 9.41).  The fibularis (peroneus) tertius (fib’u-la’ris ter’shus) is a  muscle of variable size that connects the fibula to the lateral side    of the foot. It functions in dorsiflexion and eversion of the foot  (see fig. 9.41).   The extensor digitorum longus (eks-ten’sor dij” i-to’rum  long’ gus) is situated along the lateral side of the leg just behind  the tibialis anterior. It arises from the proximal end of the tibia  and the shaft of the fibula. Its tendon divides into four parts as it  passes over the front of the ankle. These parts continue over the  surface of the foot and attach to the four lateral toes. The actions  of the extensor digitorum longus include dorsiflexion of the foot,  eversion of the foot, and extension of the toes (see figs. 9.41  and 9.42).   The extensor hallucis longus (eks-ten’sor hal’lu-sis long’ gus)  connects the anterior fibula with the great toe. Actions include  extension of the great toe, dorsiflexion and inversion of the foot  (see fig. 9.41).    FIGURE 9.43 (AP|R) Muscles of the leg. (a) Muscles of the  posterior right leg. (b-e) Isolated views of muscles associated with  the posterior right leg.   The gastrocnemius (gas”trok-ne’me-us) on the back of the leg  forms part of the calf. It arises by two heads from the femur.  The distal end of this muscle joins the strong calcaneal tendon  (Achilles tendon), which descends to the heel and attaches to the  calcaneus. The gastrocnemius is a powerful plantar flexor of the  foot that aids in pushing the body forward when a person walks or  runs. It also flexes the knee (see figs. 9.42 and 9.43).    Strenuous athletic activity may partially or completely tear the  calcaneal (Achilles) tendon. This injury occurs most frequently in    middle-aged athletes who run or play sports that involve quick  movements and directional changes. A torn calcaneal tendon  usually requires surgical treatment.   Great saphenous v.  Flexor digitorum longus m.  Tibialis posterior m.  Tibialis anterior m.    FIGURE 9.44 A cross section of the leg  (superior view). (a. stands for artery, m. stands for  muscle, n. stands for nerve, and v. stands for vein.)    Lateral condyle and posterior  surface of tibia and posterior  surface of fibula    Dorsal surfaces of middle  and distal phalanges of four  lateral toes    The plantaris (plan-ta’ris) connects the femur to the heel,  where it inserts with the gastrocnemius and soleus via the calca-  neal tendon. When the plantaris contracts it plantar flexes the foot,  and because it crosses the knee joint, it also flexes the knee.    The soleus (so’le-us) is a thick, flat muscle located beneath  the gastrocnemius, and together these two muscles form the  calf of the leg. The soleus arises from the tibia and fibula, and it  inserts at the heel by way of the calcaneal tendon. It acts with the  gastrocnemius to cause plantar flexion of the foot (see figs. 9.42  and 9.43).    passes along the plantar surface of the foot. There the tendon  divides into four parts that attach to the distal phalanges of the four  lateral toes. This muscle assists in plantar flexion of the foot, flex-  ion of the four lateral toes, and inversion of the foot (see fig. 9.43).   The tibialis posterior (tib”’e-a’lis pos-tér’e-or) is the deepest of the  muscles on the back of the leg. It connects the fibula and tibia to  the ankle bones by means of a tendon that curves under the medial  malleolus. This muscle assists in inversion and plantar flexion of  the foot (see fig. 9.43). Extensor hallucis longus also inverts the  foot, because it pulls up on the medial portion (see fig. 9.41).    The fibularis (peroneus) longus (fib’u-la’ris long’gus) is a long,  straplike muscle located on the lateral side of the leg. It connects the  tibia and the fibula to the foot by means of a stout tendon that passes  behind the lateral malleolus. It everts the foot, assists in plantar flex-  ion, and helps support the arch of the foot (see figs. 9.42 and 9.44).   Fascia in various regions of the ankle thicken to form retinac-  ula, as in the wrist. Anteriorly, for example, extensor retinacula  connect the tibia and fibula as well as the calcaneus and fascia of  the sole. These retinacula form sheaths for tendons crossing the  front of the ankle (see figs. 9.41 and 9.42).   Posteriorly, on the inside, a flexor retinaculum runs between  the medial malleolus and the calcaneus and forms sheaths for ten-  dons passing beneath the foot (see fig. 9.43). Fibular retinacula  connect the lateral malleolus and the calcaneus, providing sheaths  for tendons on the lateral side of the ankle (see fig. 9.42).    31 Which muscles move the pectoral girdle? the arm, forearm, and hand?    Skeletal muscles are composed of nervous, vascular, and various  other connective tissues, as well as skeletal muscle tissue.   b. Other connective tissues surround cells and groups  of cells within the muscle’s structure (epimysium,  perimysium, endomysium).   c. Fascia is part of a complex network of connective tissue  that extends throughout the body.   a. Each skeletal muscle fiber is a single muscle cell, the  unit of contraction.   c. The cytoplasm contains mitochondria, sarcoplasmic  reticulum, and myofibrils of actin and myosin.    Signs of aging in the muscular system begin to appear in one’s for-  ties, although a person can still be active. At a microscopic level,  supplies of the molecules that enable muscles to function—myo-  globin, ATP, and creatine phosphate—decline. Gradually, the mus-  cles become smaller, drier, and capable of less forceful contraction.  Connective tissue and adipose cells begin to replace some muscle  tissue. By age eighty, nearly half the muscle mass has atrophied, due  to a decline in motor neuron activity. Diminishing muscular strength  slows reflexes.   Exercise can help maintain a healthy muscular system  throughout life, countering the less effective oxygen delivery that  results from the decreased muscle mass that accompanies aging.  Exercise can even lead to formation of new muscle by stimulating  skeletal muscle cells to release interleukin-6 (IL-6), a type of pro-  inflammatory molecule called a cytokine. The IL-6 stimulates sat-  ellite cells, which function as muscle stem cells. They divide and  migrate, becoming incorporated into the muscle fiber. Exercise  also maintains the flexibility of blood vessels, which helps to keep  blood pressure at healthy levels. A physician should be consulted  before starting any exercise program.   According to the National Institute on Aging, exercise should  include strength training and aerobics. Strength training consists  of weight lifting or using a machine that works specific muscles  against a resistance, performed so that the same muscle is not  exercised on consecutive days. Strength training increases muscle  mass, and the resulting stronger muscles can alleviate pressure  on the joints, which may lessen arthritis pain. Aerobic exercise  improves oxygen use by muscles and increases endurance.    d. The arrangement of the actin and myosin filaments causes  striations forming repeating patterns of sarcomeres.  (I bands, Z lines, A bands, H zone, and M line)   f. Transverse tubules extend from the cell membrane  into the cytoplasm and are associated with the cisternae  of the sarcoplasmic reticulum.    Muscle fiber contraction results from a sliding movement of actin  and myosin filaments overlapping that shortens the muscle fiber.  1. Neuromuscular junction  a. The functional connection between a neuron and    another cell is a synapse. The neuromuscular junction  is a synapse.    The heart pumps as  a result of cardiac  muscle contraction.  Blood flow delivers  oxygen and nutrients  and removes wastes.    Skeletal muscles  are important in  swallowing. The  digestive system  absorbs nutrients  needed for muscle  contraction.    Breathing depends  on skeletal muscles.  The lungs provide  oxygen for muscle  cells and excrete  carbon dioxide.    Skeletal muscles  help control expulsion  of urine from the  urinary bladder.   c. The motor end plate of a muscle fiber lies on one side  of a neuromuscular junction.   d. In response to an action potential, the end of a motor  neuron axon releases a neurotransmitter, which diffuses  across the junction and stimulates the muscle fiber.   a. Acetylcholine released from the end of a motor neuron  axon stimulates a muscle fiber.   b. Stimulation causes a muscle fiber to conduct an  impulse that travels over the surface of the sarcolemma  and reaches the deep parts of the fiber by means of the  transverse tubules.   a. In response to stimulation the sarcoplasmic reticulum  releases calcium ions.    actin filaments move inward, shortening the sarcomere.  4. The sliding filament model of muscle contraction  a. The sarcomere is the functional unit of skeletal muscle.  b. When the overlapping thick and thin myofilaments  slide past one another, the sarcomeres shorten. The  muscle contracts.  5. Cross-bridge cycling  a. A myosin head can attach to an actin binding site to  form a cross-bridge which pulls on the actin filament.  The myosin head can then release the actin and attach  to another active binding site farther down the actin  filament and pull again.    the repetition of the cross-bridge cycle.  6. Relaxation  a. Acetylcholinesterase rapidly decomposes  acetylcholine remaining in the synapse, preventing  continuous stimulation of a muscle fiber.  b. The muscle fiber relaxes when calcium ions are    c. Cross-bridge linkages break and do not re-form—the  muscle fiber relaxes.  7. Energy sources for contraction  a. ATP supplies the energy for muscle fiber contraction.  b. Creatine phosphate stores energy that can be used to  synthesize ATP as it is decomposed.  c. Active muscles require cellular respiration for energy.  8. Oxygen supply and cellular respiration  a. Anaerobic reactions of cellular respiration yield few  ATP molecules, whereas aerobic reactions of cellular    b. Hemoglobin in red blood cells carries oxygen from the  lungs to body cells.  c. Myoglobin in muscle cells temporarily stores some  oxygen.  9. Oxygen debt    a. During rest or moderate exercise, oxygen is sufficient to 6.   b. During strenuous exercise, oxygen deficiency may  develop, and lactic acid may accumulate as a result of  the anaerobic reactions of cellular respiration.    c. The oxygen debt includes the amount of oxygen required  to react accumulated lactic acid to form glucose and to  restore supplies of ATP and creatine phosphate.   b. Muscle fatigue may be due in part to the effects of  accumulation of lactic acid.   c. Athletes usually produce less lactic acid than  nonathletes because of their increased ability to  supply oxygen and nutrients to muscles.    a. Muscular contraction generates body heat.  b. Most of the energy released by cellular respiration is  lost as heat.    tropomyosin to shift and expose active sites on the actin iF   a. A twitch is a single, short contraction of a muscle  fiber.   b. A myogram is a recording of the contraction of an  electrically stimulated isolated muscle or muscle fiber.   c. The latent period is the time between stimulus and  responding contraction.   d. The length to which a muscle is stretched before  stimulation affects the force it will develop.   (1) Normal activities occur at optimal length.  (2) Too long or too short decreases force.   e. Sustained contractions are more important than twitch  contractions in everyday activities.   a. A rapid series of stimuli may produce summation of  twitches and sustained contraction.   b. At higher frequencies of stimulation, contraction with  little time for relaxation is called partial tetany.   c. Forceful, sustained contraction without any  relaxation is a complete (fused) tetanic contraction.   a. One motor neuron and the muscle fibers associated with  it constitute a motor unit.   d. At low intensity of stimulation, relatively few motor  units contract.   e. At increasing intensities of stimulation, other motor  units are recruited until the muscle contracts with  maximal tension.   b. Even when a whole muscle appears at rest, some of  its fibers undergo sustained contraction. This is called  muscle tone.   a. One type of contraction called isotonic occurs when a  muscle contracts and its ends are pulled closer together.  Because the muscle shortens, it is called a concentric  contraction.    b. In another type of isotonic contraction, the force a b. A lever consists of a rod, a fulcrum (pivot), a resistance,  muscle generates is less than that required to move and a force that supplies energy.  or lift an object. This lengthening contraction is an c. Parts of a first-class lever are arranged resistance—fulcrum—  eccentric contraction. force; of a second-class lever, fulcrum—resistance—force;   d. Most body movements involve both isometric and a. The less movable end of attachment of a skeletal  isotonic contractions. muscle to a bone is its origin, and the more movable   a. The speed of contraction is related to a muscle’s b. Some muscles have more than one origin or insertion.  specific function. 3. Interaction of skeletal muscles   b. Slow-contracting, or red, muscles can generate ATP a. Skeletal muscles function in groups.  fast enough to keep up with ATP breakdown and can b. A muscle that causes a specific movement is an agonist  contract for long periods. for that movement; antagonists can resist a movement;   c. Fast-contracting, or white, muscles have reduced ability synergists work together to perform a specific movement.  to carry on the aerobic reactions of cellular respiration c. Smooth movements depend upon antagonists giving  and tend to fatigue rapidly. way to the actions of agonists.    The contractile mechanisms of smooth and cardiac muscle are  similar to those of skeletal muscle.    9.7 Major Skeletal Muscles (page 312)  Muscle names often describe sizes, shapes, locations, actions,  number of attachments, or direction of fibers.   b. They lack transverse tubules, and the sarcoplasmic  reticula are not well developed.   a. In smooth muscle, calmodulin binds to calcium ions  and activates the contraction mechanism.   d. With a given amount of energy, smooth muscle can  maintain a contraction longer than skeletal muscle.    a. These muscles lie beneath the skin of the face and  scalp and are used to communicate feelings through  facial expression.   b. They include the epicranius, orbicularis oculi,  orbicularis oris, buccinator, zygomaticus major,  zygomaticus minor, and platysma.   a. These muscles are attached to the mandible and are  used in chewing.   b. They include the masseter, temporalis, medial  pterygoid, and lateral pterygoid.   b. They include the sternocleidomastoid, splenius  capitis, semispinalis capitis, scalenes, quadratus  lumborum, and erector spinae.   a. Most of these muscles connect the scapula to nearby  bones and are closely associated with muscles that  move the arm.   b. They include the trapezius, rhomboid major,  rhomboid minor, levator scapulae, serratus anterior,  and pectoralis minor.    1. Cardiac muscle contracts for a longer time than  Muscles that move the arm  skeletal muscle because transverse tubules supply . :  ae a. These muscles connect the humerus to various regions  extra calcium ions. . :  . . of the pectoral girdle, ribs, and vertebral column.  2. Intercalated discs connect the ends of cardiac muscle cells b. They include the coracobrachialis, pectoralis major,  and hold the cells together. teres major, latissimus dorsi, supraspinatus, deltoid,  3. A network of cells contracts as a unit and responds to subscapularis, infraspinatus, and teres minor.  stimulation in an all-or-none manner. Muscles that move the forearm  4. Cardiac muscle is self-exciting, rhythmic, and remains a. These muscles connect the radius and ulna to the   b. They include the biceps brachii, brachialis,  brachioradialis, triceps brachii, supinator, pronator  teres, and pronator quadratus.   a. These muscles arise from the distal end of the humerus  and from the radius and ulna.    b. They include the flexor carpi radialis, flexor  carpi ulnaris, palmaris longus, flexor digitorum  profundus, flexor digitorum superficialis, extensor  carpi radialis longus, extensor carpi radialis brevis,  extensor carpi ulnaris, and extensor digitorum.   c. An extensor retinaculum forms sheaths for tendons of  the extensor muscles.   a. These muscles connect the rib cage and vertebral  column to the pelvic girdle.   b. They include the external oblique, internal oblique,  transversus abdominis, and rectus abdominis.   a. These muscles form the floor of the pelvic cavity and  fill the space of the pubic arch.   b. They include the levator ani, coccygeus,  superficial transversus perinei, bulbospongiosus,  ischiocavernosus, and sphincter urethrae.   a. These muscles are attached to the femur and to some  part of the pelvic girdle.   b. They include the psoas major, iliacus, gluteus  maximus, gluteus medius, gluteus minimus,  piriformis, tensor fasciae latae, pectineus,  adductor brevis, adductor longus, adductor  magnus, and gracilis.    Structure of a Skeletal Muscle 9.3  Describe the difference between a tendon and an 13  aponeurosis. (p. 292) 14  Describe how connective tissue is part of the structure of a  skeletal muscle. (p. 293) 15  Distinguish among deep fascia, subcutaneous fascia, and  subserous fascia. (p. 293) 16  Identify the major parts of a skeletal muscle fiber and  describe the functions of each. (pp. 293-296)  Skeletal Muscle Contraction  A neurotransmitter . (p. 297)  a. binds actin filaments, causing them to slide 17  b. diffuses across a synaptic cleft from a neuron to a   muscle cell 18  c. transports ATP across the synaptic cleft  d. breaks down acetylcholine at the synapse 19  Describe the neuromuscular junction. (p. 297)  Describe the neural control of skeletal muscle contraction. 20  (p. 297)  Identify the major events that occur during skeletal muscle  fiber contraction. (pp. 298-299) 9.4  Explain how ATP and creatine phosphate function in skeletal 21  muscle fiber contraction. (pp. 299-302)  Describe how oxygen is supplied to skeletal muscle. (p. 302) 22  Describe how oxygen debt may develop. (pp. 302-303) 23  Explain how a muscle may become fatigued, and how a  person's physical condition may affect tolerance to fatigue. 9.5  (p. 303) a   a. These muscles connect the tibia or fibula to the femur  or pelvic girdle.   b. They include the biceps femoris, semitendinosus,  semimembranosus, sartorius, rectus femoris, vastus  lateralis, vastus medialis, and vastus intermedius.   a. These muscles attach the femur, tibia, and fibula to  various bones of the foot.   b. They include the tibialis anterior, fibularis tertius,  extensor digitorum longus, extensor hallucis longus,  gastrocnemius, soleus, plantaris, flexor digitorum  longus, tibialis posterior, and fibularis longus.    1. Beginning in one’s forties, supplies of ATP, myoglobin,  and creatine phosphate begin to decline.   2. By age eighty, muscle mass may be halved. Reflexes  slow. Adipose cells and connective tissue replace some  muscle tissue.   Define motor unit and explain how the number of fibers in a  unit affects muscular contractions. (p. 305)   Which of the following describes addition of muscle fibers to  take part in a contraction? (p. 305)   Explain how a skeletal muscle can be stimulated to produce  a sustained contraction. (p. 306)   Distinguish between a complete tetanic contraction and  muscle tone. (pp. 304-306)   Distinguish between concentric and eccentric contractions,  and explain how each is used in body movements. (pp. 306)  Distinguish between fast- and slow-twitch muscle fibers.  (pp. 306-307)    Distinguish between multiunit smooth muscle and visceral  smooth muscle. (p. 307)   Define peristalsis and explain its function. (p. 307)  Compare the characteristics of skeletal and smooth muscle  cell contractions. (pp. 307-308)    Compare the characteristics of skeletal and cardiac muscle  cell contractions. (pp. 308-309)    Describe a lever, and explain how its parts may be arranged  to form first-class, second-class, and third-class levers.    Explain how limb movements function as levers. (pp. 310-311)  Distinguish between a muscle’s origin and its insertion.   2) latissimus dorsi  3) pectoralis major  4) pronator teres  5) teres minor   6) triceps brachii  7) biceps femoris  8) external oblique  9) gastrocnemius  0) gluteus maximus  1) gluteus medius  2) gracilis    inserted on the coronoid  process of the mandible  elevates the corner of the  mouth   can extend the neck  consists of two parts—the  frontalis and the occipitalis   pulls the jaw from side to side  primary extensor of the elbow  depresses and retracts   a plantar flexor of the foot  compresses the contents of  the abdominal cavity    30 Label as many muscles as you can identify in these photos of  a model whose muscles are enlarged by exercise. Describe  the action of each muscle identified. (pp. 312-340)    31 Describe three aging-related changes in the muscular  system. (p. 340)  32 Explain the benefits of exercise for maintaining muscular  health while aging. (p. 340)    1. Several important nerves and blood vessels course through  the muscles of the gluteal region. To avoid the possibility of  damaging such parts, intramuscular injections are usually made  into the lateral, superior portion of the gluteus medius. What  landmarks would help you locate this muscle in a patient?    2. Millions of people take drugs called statins to lower serum  cholesterol levels. In a small percentage of people taking these  drugs, muscle pain, termed myopathy, is an adverse effect. Ina  small percentage of these individuals, the condition progresses  to rhabdomyolysis, in which the sarcolemma breaks down.    a. Describe the structure and state the function of the  sarcolemma.   b. Physicians can measure a patient's levels of creatine  phosphokinase to track the safety of using a statin. Enzyme  levels that exceed 10 times normal indicate possible  rhabdomyolysis. Explain what this elevated enzyme  level indicates about the physiology of the muscle cell.   c. Explain why a dusky, dark color in the urine, resulting from    3. What steps might be taken to minimize atrophy of skeletal  muscles in patients confined to bed for prolonged times?    4. As lactic acid and other substances accumulate in an active  muscle, they stimulate pain receptors, and the muscle may feel  sore. How might the application of heat or substances that dilate  blood vessels help relieve such soreness?    5. Why do you think athletes generally perform better if they warm  up by exercising lightly before a competitive event?    6. Following an injury to a nerve, the muscles it supplies with motor  nerve fibers may become paralyzed. How would you explain to a  patient the importance of moving the disabled muscles passively  or contracting them with electrical stimulation?    7. Following childbirth, a woman may lose urinary control  (incontinence) when sneezing or coughing. Which muscles of  the pelvic floor should be strengthened by exercise to help  control this problem?    Connect Interactive Questions Reinforce your knowledge  using assigned interactive questions covering muscle structure,  the process of muscle contraction, and identification of  skeletal muscles.    Connect Integrated Activity Can you predict the effects on  muscle function of different drugs, toxins, and neuromuscular  diseases?    Anatomy & Physiology Revealed Go more in depth into the  human body by exploring cadaver dissections of assigned skeletal  muscles and viewing animations of their actions.    The following set of reference plates, made up of surface anatomy photos and cadaver dissection photos,  is presented to help you locate some of the more prominent surface features in various regions of the  body. For the most part, the labeled structures on the surface anatomy photos are easily seen or palpated  (felt) through the skin. As a review, you may want to locate as many of these features as possible on your    own body. The cadaver dissection photos reveal the structures located beneath the skin.    PLATE FIFTY-FIVE Surface anatomy of head and neck, lateral view. (m. stands for muscle.)    Tendon of palmaris longus m.  Tendon of flexor carpi radialis m.  Tendon of superficial digital flexor m.  Site for palpation of radial a.    PLATE SIXTY-EIGHT Posterior view of the trunk, with deep thoracic muscles exposed on the left. (m. stands for muscle.)    PLATE SEVENTY Posterior view of the right forearm and hand. (m.  stands for muscle.) PLATE SEVENTY-ONE Anterior view of the right thigh. (m. stands    PLATE SEVENTY-FOUR Lateral view of the right leg. (m. stands for PLATE SEVENTY-FIVE Posterior view of the right leg. (m. stands for    These progenitor cells will give rise to astrocytes (green) that supply  neurons with nutrients. In this immunofluorescent light micrograph,  cell nuclei are stained blue (1,150x).    Snap your fingers! In the time it took to do that, a decision made  in a part of your brain that controls skeletal muscles resulted in  impulses along motor neuron axons to the muscles in your hand,  releasing acetylcholine (ACh) at neuromuscular junctions. As  soon as the muscles contracted during the “snap,” a decision in  the brain stopped the action. Impulses ceased, enzymes broke  down the ACh, active transport carried calcium back into storage  in the muscle cells, and your hand relaxed.   Think about how quickly these events unfolded. Then focus  on all of the activities going on in your body while reading this  passage. Your nervous system exerts precise control over many  of the body’s functions, and is responsible for your awareness of  some of what is happening.    After you have studied this chapter, you should be able to:    10.1 Overview of the Nervous System  1 Describe the general functions of the nervous system. (p. 360)  2 Identify the two types of cells that comprise nervous tissue.  (p. 360)  3 Identify the two major groups of nervous system organs. (p. 361)    10.2 General Functions of the Nervous System  4 List the functions of sensory receptors. (p. 361)  5 Describe how the nervous system responds to stimuli. (1p. 361)    10.3 Description of Cells of the Nervous System  6 Describe the parts of a neuron. (p. 363)  7 Describe the relationships among myelin, the neurilemma,  and nodes of Ranvier. (p. 363)  8 Distinguish between the sources of white matter and gray  matter. (p. 363)    10.4 Classification of Cells of the Nervous System  9 Identify structural and functional differences among neurons.  (pp. 363-368)  10 Identify the types of neuroglia in the central nervous system  and their functions. (pp. 368-369)  11 Describe the role of Schwann cells in the peripheral nervous  system. (jp. 370)    12 Explain how information passes from a presynaptic neuron  to a postsynaptic cell. (pp. 371-372)   14 Describe the events leading to the generation of an action  potential. (p. 375)   15 Explain how action potentials move down an axon.  (pp. 375-377)    10.7 Synaptic Transmission  17 Identify the changes in membrane potential associated  with excitatory and inhibitory neurotransmitters. (p. 379)  18 Explain what prevents a postsynaptic cell from being  continuously stimulated. (p. 381)    10.8 Impulse Processing  19 Describe the basic ways in which the nervous system  processes information. (pp. 382-383)   ax-, axle: axon—cylindrical nerve process  that conducts impulses away from a  neuron cell body.   ependym-, tunic: ependyma—neuroglia that  line spaces in the brain and spinal cord.    moto-, moving: motor neuron—neuron  that stimulates a muscle to contract  or a gland to release a secretion.   peri-, all around: peripheral nervous  system—portion of the nervous system  that consists of the nerves branching  from the brain and spinal cord.    saltator-, a dancer: saltatory conduction—  impulse conduction in which the impulse  seems to jump from node to node along  the nerve fiber.   sens-, feeling: sensory neuron—neuron that  can be stimulated by a sensory receptor  and conducts impulses into the brain or  spinal cord.    The nervous system oversees all that we do and determines who we  are. Through a vast communicating network of cells and the infor-  mation that they send and receive, the nervous system can detect  changes affecting the body, make decisions, and stimulate muscles  or glands to respond. Typically, these responses counteract the  effects of the changes, and in this way, the nervous system helps  maintain homeostasis.   The nervous system is composed predominantly of neural tis-  sue, but also includes blood vessels and connective tissue. Neural  tissue consists of two cell types: nerve cells, or neurons (nu’ronz),  and neuroglia (nu-ro’gle-ah) (or neuroglial cells). Clinical  Application 10.1 discusses how environmental changes may trig-  ger migraine headaches, a common medical problem attributed  to the nervous system that may involve its blood supply as well  as neurons.   Neurons are specialized to react to physical and chemical  changes in their surroundings. Small cellular processes called  dendrites (den’dritz) receive the input. A longer process called an  axon (ak’son), or nerve fiber, carries the information away from  the cell in the form of bioelectric signals, called impulses (action  potentials), which allow the neuron to communicate with other  neurons and with cells outside the nervous system (fig. 10.1).  Typically, axons within the nervous system are not isolated, but  bundled in groups. In the peripheral nervous system, such bundles  of axons are called nerves. In the central nervous system (brain  and spinal cord) they are called tracts.   Neuroglia are found throughout the nervous system, and in  the brain they greatly outnumber neurons. It was once thought that  neuroglia only fill spaces and surround or support neurons. Today  we know that they have many other functions, including nourish-  ing neurons and sending and receiving chemical messages.   Neuroglia assemble in a special, protective way in the brain.  The blood-brain barrier offers an example. Most capillaries (the    FIGURE 10.1 fAP|R) Neurons are the structural and functional units  of the nervous system (600x). The dark spots in the area surrounding the  neuron are the nuclei of neuroglia. Note the neuron processes (dendrites  and a single axon).    @ What structure forms the outer portion of the axon and  dendrites of a neuron?    smallest blood vessels) are “leaky,” allowing small molecules to  enter or leave the bloodstream. The cells that form capillaries in the  brain, in contrast, are much more tightly connected, thanks partly  to neuroglia called astrocytes. The barrier that this specialized    architecture provides shields delicate brain tissue from chemical  fluctuations, blocking entry to many substances (see From Science  to Technology 5.1, p. 150). Drug developers must consider the  barrier when formulating drugs that act in the brain, including  chemicals that let the drug through.   An important part of the nervous system at the cellular level  is not a cell at all, but the small space between a neuron and the  cell(s) with which it communicates, called a synapse (sin’aps).  Much of the work of the nervous system is to send and receive  electrochemical messages across synapses. Biological messenger  molecules called neurotransmitters (nu”ro-trans-mit’erz) convey  this neural information.   The organs of the nervous system can be divided into two  groups. One group, consisting of the brain and spinal cord, forms  the central nervous system (CNS). The other group, composed of  the nerves (cranial and spinal nerves) that connect the central ner-  vous system to other body parts, is the peripheral nervous system  (PNS) (fig. 10.2).    The three general functions of the nervous system—receiving  information, deciding what to do, and acting on those decisions—  are termed sensory, integrative, and motor. Structures called  sensory receptors at the ends of neurons in the peripheral nervous  system (peripheral neurons) provide the sensory function of the  nervous system (see chapter 11, p. 411). These receptors gather  information by detecting changes inside and outside the body.  They monitor external environmental factors such as light and  sound intensities as well as the temperature, oxygen concentra-  tion, and other conditions of the body’s internal environment.   Sensory receptors convert (or transduce) their informa-  tion into impulses, which are then conducted along peripheral  nerves to the CNS. There the signals are integrated. That is, they  are brought together, creating sensations, adding to memory, or  helping produce thoughts. Following integration, conscious or  subconscious decisions are made and then acted upon by means of  motor functions.   Neurons that conduct impulses from the CNS to responsive  structures called effectors carry out the motor functions of the ner-  vous system. These effectors are outside the nervous system and  include muscles and glands whose actions are either controlled or  modified by nerve activity. The motor portion of the PNS can be  subdivided into the somatic and the autonomic nervous systems.  The somatic nervous system communicates voluntary (conscious)  instructions originating in the CNS to skeletal muscles, caus-  ing contraction. The autonomic nervous system communicates  instructions from the CNS that control viscera, such as the heart and  various glands, and thus causes involuntary subconscious actions.    An action potential is often referred to as a “nerve impulse.”  This may be misleading, because in anatomy the term nerve  refers to a bundle of axons, not an individual cell. A similar situa-  tion arises when referring to a neuron as a “nerve cell.” We may  sometimes use the terms nerve impulse and nerve cell because  they are familiar, but we feel it is important to point out this  departure from strict anatomical terminology.   care unit of a hospital, a nurse emails prescriptions to the  supermarket pharmacy near the patient’s home. By the  time the man’s daughter arrives at the pharmacy a few  hours later, not only are all five drugs packaged and ready  to go, but the pharmacist explains what each drug does and  how it should be taken. She also answers the daughter’s  questions about potential interactions of the prescription  drugs with over-the-counter medications that her father  sometimes takes.   A pharmacist is a health-care professional who measures  and packages prescription drugs and explains to patients  or their caregivers what each drug is for, how it should be  taken, and possible adverse effects. In many instances a  pharmacist can knowledgeably answer the same questions  about a drug that a doctor might be asked.   In college, a future pharmacist should take a variety  of science and math courses. The profession requires  knowledge of chemistry (especially organic chemistry),  biology, physics, and anatomy and physiology. Attention  to detail is a critical skill—an error in dispensing a drug  can have tragic consequences.   To become a pharmacist, one must earn a doctor of  pharmacy, or “pharmD” degree, and pass state licensure  exams. A pharmD is a graduate degree. Admission to  pharmacy school requires at least two years of college and a  passing score on the pharmacy college admission test. The  four-year program includes 7 to 10 rotations of 4 to 6 weeks  each, during which the student works in various clinical  and pharmaceutical settings. Following graduate school  a pharmacist might acquire training in a specialty, such as  psychopharmaceuticals, chemotherapy, or working with  radioactive drugs, in a one- to two-year residency program.   Pharmacists work in retail drug, grocery, and “big box”  stores; at hospitals as part of a clinical team; and in long-  term care facilities such as rehabilitation centers and nursing  homes. They may work for the government, such as at the  Food and Drug Administration, or as sales representatives  for pharmaceutical companies.    The signs of a migraine are unmistakable—a pounding head,  typically in one area, waves of nausea, shimmering images in the  peripheral visual field called an “aura,” and extreme sensitivity to  light or sound. Inherited susceptibilities and environmental factors  probably cause migraines. Environmental triggers include sudden  exposure to bright light, eating a particular food (chocolate, red  wine, nuts, and processed meats top the list), lack of sleep, stress,  high altitude, stormy weather, and excessive caffeine or alco-  hol intake. Hormonal influences may also be involved, because  about three-quarters of the 300 million people who suffer from  migraines worldwide are women between the ages of 15 and 55.  Many women get migraines just before menstruation.   A migraine attack may last from 4 to 72 hours. It is due to a  phenomenon called “cortical spreading depression,” in which an  intense wave of excitation followed by a brief period of unrespon-  siveness in certain neurons stimulates areas at the base of the brain  to produce pain sensations. The excitation and dampening of the  activity level of these neurons also triggers changes in blood flow in  the brain that were once thought to be the direct cause of migraine.    Drugs called triptans can very effectively halt a migraine attack,  but must be taken as soon as symptoms begin. Triptans block the  release of neurotransmitter from certain neurons. Because triptans  constrict blood vessels throughout the body, making them danger-  ous for some people, newer migraine drugs have been devel-  oped that block the specific neurotransmitter that these neurons  release (calcitonin gene-related peptide), better targeting the  therapeutic effect.   A newer treatment option is “transcranial magnetic stimula-  tion,” which is used to treat migraine among the third of sufferers  who experience aura. A device is held to the back of the head, and  a button is pressed that sends magnetic energy into the brain.   Several drugs developed to treat other conditions are used  on a long-term, daily basis to lessen the frequency of migraines.  These drugs include certain antidepressants, anticonvulsants,  and drugs used to treat high blood pressure (calcium channel  blockers and beta blockers). A physician considers an individual's  family and health history before prescribing these drugs to pre-  vent migraine.    FIGURE 10.2 A diagrammatic representation of the nervous system. (a) The nervous system includes the central nervous system (brain and spinal  cord) and the peripheral nervous system (cranial nerves and spinal nerves). (b) The nervous system receives information from sensory receptors and  initiates responses through effector organs (muscles and glands).    Neurons vary in size and shape. They may differ in the lengths and  sizes of their axons and dendrites and in the number of processes.  Despite this variability, neurons share certain features. Every neu-  ron has a cell body, dendrites, and an axon. Figure 10.3 shows  some of the other structures common to neurons.   A neuron’s cell body (soma or perikaryon) contains granu-  lar cytoplasm, mitochondria, lysosomes, a Golgi apparatus, and  many microtubules. A network of fine threads called neurofila-  ments extends into the axon and supports it. Scattered throughout  the cytoplasm are many membranous packets of chromatophilic  substance (Nissl bodies), which consist mainly of rough endo-  plasmic reticulum. Cytoplasmic inclusions in neurons include  glycogen, lipids, and pigments such as melanin. Near the center  of the neuron cell body is a large, spherical nucleus with a con-  spicuous nucleolus.   Dendrites are typically highly branched, providing receptive  surfaces with which processes from other neurons communicate. (In  some types of neurons, the cell body provides such a receptive sur-  face.) Some dendrites have tiny, thornlike spines (dendritic spines)  on their surfaces, which are contact points for other neurons.   A neuron may have many dendrites, but no more than one  axon. In most neurons the axon arises from the cell body as a  cone-shaped thickening called the axon hillock. The cytoplasm  of the axon includes many mitochondria, microtubules, and neu-  rofibrils (ribosomes are found only in the cell body). The axon  may give off branches, called collaterals. Near its end, an axon  may have many fine extensions, each with a specialized ending  called an axon terminal. The axon terminal ends as a synaptic  knob close to the receptive surface of another cell, separated only  by a space called the synaptic cleft. The general pattern is that  neurons receive input through the dendrites and the cell body,  and send output in the form of an impulse conducted away from  the cell body, down the axon.   An axon, in addition to conducting impulses, conveys bio-  chemicals and organelles, which can be quite a task in these long  cells. In this activity, called axonal transport, movement occurs  in both directions between the cell body and the ends of the  axon. For example, enzymes required for neurotransmitter syn-  thesis are produced in the cell body and transported to the axon  terminals. Old organelles and other cellular components may be  transported in the reverse direction to be recycled. It is a highly  regulated process.   In the PNS, neuroglia called Schwann cells encase the large  axons of peripheral neurons in lipid-rich sheaths. These tight cov-  erings form as Schwann cell membranes wind and wrap around  axons. The layers are composed of myelin (mi’é-lin), which con-  sists of several types of lipids and proteins. Myelin gives the cell  membranes of Schwann cells a higher proportion of lipid than  other cell membranes. This coating is called a myelin sheath. The  parts of the Schwann cells that contain most of the cytoplasm  and the nuclei remain outside the myelin sheath and comprise a  neurilemma (nur’ilem’ah), or neurilemmal sheath, which sur-  rounds the myelin sheath. Narrow gaps in the myelin sheath  between Schwann cells are called nodes of Ranvier (fig. 10.4).    Schwann cells also enclose, but do not wind around, the  smallest axons of peripheral neurons. Consequently, these axons  do not have myelin sheaths. Instead, the axon or a group of axons  may lie partially or completely in a longitudinal groove of a  Schwann cell.   Axons that have myelin sheaths are called myelinated (med-  ullated) axons, and those that do not have these sheaths are unmy-  elinated axons (fig. 10.5). Myelinated axons conduct impulses  rapidly compared to unmyelinated axons. Groups of myelinated  axons appear white. The white matter in the brain and spinal  cord gets its color from masses of myelinated axons. In the CNS,  myelin is produced by a type of neuroglia called an oligodendro-  cyte rather than by a Schwann cell. In the brain and spinal cord,  myelinated axons do not have neurilemmae.   Unmyelinated nerve tissue appears gray. Thus, the gray matter  in the CNS contains many unmyelinated axons and neuron cell bod-  ies. Clinical Application 10.2 discusses multiple sclerosis, a condi-  tion in which neurons in the brain and spinal cord lose their myelin.    5 Explain how an axon in the peripheral nervous system becomes  myelinated.    Myelin begins to form on axons during the fourteenth week of  prenatal development. At the time of birth, many axons are not  completely myelinated. All myelinated axons have begun to  develop sheaths by the time a child starts to walk, and myelina-  tion continues into adolescence.   Excess myelin seriously impairs nervous system functioning.  In Tay-Sachs disease, deficiency of a lysosomal enzyme causes  myelin to accumulate, burying neurons in lipid. An affected child  begins to show symptoms by six months of age, gradually los-  ing sight, hearing, and muscle function until death occurs by  age four. Thanks to genetic screening among people of eastern  European descent and other groups who are most likely to carry  this mutation, Tay-Sachs disease is extremely rare.   Too little myelin is devastating, too. Clinical Application 3.2  (p. 94) describes adrenoleukodystrophy, in which myelin van-  ishes in the brains and spinal cords of boys.    The cells of nervous tissue (neurons and neuroglia) are intimately  related. They descend from the same neural stem cells and remain  associated throughout their existence.    Neurons can be classified into three major groups based on struc-  tural differences, as figure 10.6 shows. Each type of neuron is  specialized to conduct an impulse in one direction.    (Q) The genes in the nucleus of a neuron are the same as the genes in the nuclei of its Schwann cells.  What causes these cells to have such different form and function?    FIGURE 10.4 (AP|R) A myelinated axon. (a) The part of a Schwann cell that winds tightly around an axon forms the myelin sheath. The cytoplasm  and nucleus of the Schwann cell, remaining on the outside, form the neurilemma. (b) Light micrograph of a myelinated axon (longitudinal section) (650x).  (c) An axon lying in a longitudinal groove of a Schwann cell does not have a myelin sheath.    1. A multipolar neuron has many processes arising from its found in specialized parts of the eyes. The neuron illustrated  cell body. Only one is an axon; the rest are dendrites. Most in figure 10.3 is multipolar.  neurons whose cell bodies lie within the brain or spinal 2. The cell body of a bipolar neuron has only two processes,  cord are of this type. Some multipolar neurons associated one arising from either end. Although these processes are  with the autonomic nervous system neurons aggregate in similar in structure, one is an axon and the other is a dendrite.  specialized masses of nerve tissue called ganglia, which Bipolar neurons are found in specialized parts of the eyes,  are located outside the brain and spinal cord. Others are nose, and ears.    Schwan 3. Each unipolar neuron has a single process extending from  cell cytoplasm its cell body. (These are also called pseudounipolar, because  they start out with two processes that merge into one during  development.) A short distance from the cell body, this  Go Myelin process divides into two branches, which really function as  cB nh Mp 3 sheath a single axon: One branch (peripheral process) has dendrites  of. near a peripheral body part. The other branch (central process)  enters the brain or spinal cord. The cell bodies of most unipolar  neurons are found in ganglia.    Neurons can also be classified by functional differences into the  following groups, depending on whether they carry information into  the CNS, completely within the CNS, or out of the CNS (fig. 10.7).    1. Sensory neurons (afferent neurons) conduct impulses from  peripheral body parts into the brain or spinal cord. At their  distal ends, the dendrites of these neurons or specialized  structures associated with them act as sensory receptors,  detecting changes in the outside world (for example, eyes, ears,  or touch receptors in the skin) or in the body (for example,   axon stimulated, sensory receptors trigger impulses that travel  on sensory neuron axons into the brain or spinal cord. Most  sensory neurons are unipolar, as shown in figure 10.7,  although some are bipolar and others are multipolar.   2. Interneurons (also called association or internuncial neurons)  lie within the brain or spinal cord. They are multipolar and  form links with other neurons. Interneurons relay information    FIGURE 10.6 Structural types of neurons include (a) the multipolar neuron, (b) the bipolar neuron, and (c) the unipolar neuron.    Multiple sclerosis (MS) is a disorder of the CNS that affects 2.5 mil-  lion people worldwide, and 400,000 in North America. In addition  to overt nervous system symptoms, affected individuals experience  disability, mood problems such as depression, and great fatigue.  Four subtypes of MS are recognized, based on the pattern of  symptomatic periods over time. The two most common subtypes  are relapsing-remitting (with episodes) and secondary progressive  (when symptoms do not abate).   In MS, the myelin coating in various sites throughout the brain  and spinal cord becomes inflamed due to an immune response and  is eventually destroyed, leaving hard scars, called scleroses, that block  the underlying neurons from conducting impulses. Muscles that no  longer receive input from motor neurons stop contracting, and even-  tually, they atrophy. Symptoms reflect the specific neurons affected.  Short-circuiting in one part of the brain affects fine coordination in one  hand; in another part of the brain, malfunctioning neurons alter vision.   The first symptoms of MS are often blurred or double vision  and weak, numb limbs that can make walking and standing difficult.  Because in many cases these symptoms are intermittent, diagno-  sis may take a while. It is based on symptoms and repeated mag-  netic resonance (MR) scans that track the development of lesions.  A diagnostic workup for MS might also include a lumbar puncture  to rule out infection and an evoked potential test to measure elec-  trical signals sent from the brain. About 70% of affected individuals  first notice symptoms between the ages of twenty and forty; the ear-  liest known age of onset is three years, and the latest, sixty-seven  years. Some affected individuals eventually become permanently  paralyzed. Women are twice as likely to develop MS as men, and  Caucasians are more often affected than people of other races.   MS may develop when particular infections in certain individu-  als stimulate T cells (a type of white blood cell that takes part in  immune responses) in the periphery, which then cross the blood-  brain barrier. Here, these “myelin-reactive” T cells attack myelin-  producing cells through a flood of inflammatory molecules and by  stimulating other cells to produce antibodies against myelin.   A virus may lie behind the misplaced immune attack that is MS.  Evidence includes the observations that viral infection can cause    repeated bouts of symptoms and that MS is much more common in  some geographical regions (the temperate zones of Europe, South  America, and North America) than others, suggesting a pattern  of infection.   Some people have such mild symptoms of MS that no treatment  is required. In others, drugs can help to manage symptoms. Drugs to  decrease bladder spasms can temper problems of urinary urgency  and incontinence. Antidepressants are sometimes prescribed, and  short-term steroid drugs are used to shorten the length of acute  disabling relapses. Muscle relaxants ease stiffness and spasms.   Several drugs are used for long-term treatment of MS. Beta  interferons are immune system biochemicals that diminish the  intensity of flare-ups, but they may cause flulike adverse effects.  Beta interferons are self-injected once to several times a week.   Glatiramer is an alternative to beta interferon that is pre-  scribed if the course of the disease is “relapsing remitting,” with  periodic flare-ups. Glatiramer is self-injected daily and dampens  the immune system's attack on myelin. It consists in part of myelin  basic protein, the most abundant protein of myelin. In response to  the drug, T cells decrease inflammation. Glatiramer also stimulates  increased production of brain-derived neurotrophic factor, which  protects axons.   Mitoxantrone is another drug that halts the immune response  against CNS myelin, but because it can damage the heart, it is  typically used in severe cases of MS and only for up to two years.  Another drug, natalizumab, prevents T cells from binding blood  vessels in the brain, also quelling the abnormal immune response  against myelin. It too may have rare but serious adverse effects.   Experimental approaches attempt to temper the body’s attack  on its own myelin. “Personalized T cell immunotherapy” redirects  a patient's immune response to attack the myelin-reactive T cells.  Autologous bone marrow transplant, in which a person's immune  system is destroyed and then reconstituted, apparently rids the  body of myelin-reactive T cells. It works best for patients with  an inflammatory relapsing-remitting form of the disease. Many  patients treated with bone marrow transplants remain symptom-  free more than a decade later.    Senso Senso  Interneuron Petr se = eerict  Sensory (afferent)  neurons transfer  sensory information  Interneuron to neurons in the CNS  Interneurons  transfer  information  from one  fe FIGURE 10.7 Neurons are classified by function as well  another Motor (efferent) neurons transfer as structure. Sensory (afferent) neurons carry information into  instructions from the CNS to effectors Effector the central nervous system (CNS), interneurons are completely  Motor neuron end (muscle within the CNS, and motor (efferent) neurons carry instructions  or gland) to effectors.    from one part of the brain or spinal cord to another. That is,  they may conduct incoming sensory information to appropri-  ate regions for processing and interpreting. Other instructions  are transferred to motor neurons. The cell bodies of some  interneurons aggregate in specialized masses of nervous tissue  called nuclei (singular, nucleus). Nuclei are similar to ganglia,  but are within the CNS.   3. Motor neurons (efferent neurons) are multipolar and con-  duct impulses out of the brain or spinal cord to effectors. For  example, when motor neurons stimulate muscle cells, the  muscle cells contract; when motor neurons stimulate glands,  the glands release secretions.   Motor neurons of the somatic nervous system (see  fig. 10.2) that control skeletal muscle contraction are under  voluntary (conscious) control. Those that control cardiac and  smooth muscle contraction and the secretions of glands are  part of the autonomic nervous system and are largely under  involuntary control.    7 Indicate the function of sensory neurons, interneurons, and  motor neurons.    Neuroglia were once thought to be mere bystanders to neural func-  tion, providing scaffolding and controlling the sites at which neu-  rons contact one another (figs. 10.8 and 10.9). These important cells  have additional functions. In the embryo, neuroglia guide neurons to  their positions and may stimulate them to specialize. Neuroglia also  produce the growth factors that nourish neurons and remove excess    Cell body with many processes, one of which is an axon,    Cell body with a process arising from each end, one axon    ions and neurotransmitters that accumulate between neurons. In cell  culture experiments, certain types of neuroglia (astrocytes) signal  neurons to form and maintain synapses.    The four types of CNS neuroglia are astrocytes, oligodendrocytes,  microglia, and ependyma:    1. As their name implies, astrocytes are star-shaped cells. They  are commonly found between neurons and blood vessels, where  they provide support and hold structures together with abun-  dant cellular processes. Astrocytes aid metabolism of certain  substances, such as glucose, and they may help regulate the  concentrations of important ions, such as potassium ions, in  the interstitial space of nervous tissue. Astrocytes also respond  to injury of brain tissue and form a special type of scar tissue,  which fills spaces and closes gaps in the CNS. These multifunc-  tional cells also have a nutritive function, regulating movement  of substances from blood vessels to neurons and bathing nearby  neurons in growth factors. Astrocytes play an important role in  the blood-brain barrier, which restricts movement of substances  between the blood and the CNS. Gap junctions link astrocytes  to one another, forming protein-lined channels through which  calcium ions travel, possibly stimulating neurons.   2. Oligodendrocytes resemble astrocytes but are smaller and  have fewer processes. They form in rows along axons (nerve  fibers), and myelinate these axons in the brain and spinal cord.   Unlike the Schwann cells of the PNS, oligodendrocytes  can send out a number of processes, each of which forms a  myelin sheath around a nearby axon. In this way, a single  oligodendrocyte may myelinate many axons. However,  these cells do not form neurilemmae.   3. Microglia are small cells and have fewer processes than  other types of neuroglia. These cells are scattered throughout  the CNS, where they help support neurons and phagocytize    Most common type of neuron in the brain and spinal cord;  also found in ganglia of the autonomic nervous system    FIGURE 10.8 Types of  neuroglia in the central nervous  system include the astrocyte,  oligodendrocyte, microglial :  cell, and ependymal cell. Motile Axon  cilia are on most ependymal  cells during development and  early childhood, but in the adult  are mostly on ependymal cells  in the ventricles of the brain  (spaces where cerebrospinal  fluid forms).    bacterial cells and cellular debris. They usually proliferate  whenever the brain or spinal cord is inflamed because of  injury or disease.   4. Ependyma are cuboidal or columnar cells in shape and may  have cilia. They form the inner lining of the central canal  that extends downward through the spinal cord. Ependymal   cell body that covers the inside of spaces in the brain called ventricles   and the fluid (cerebrospinal fluid) in the ventricles.  Ependymal cells also cover the specialized capillaries    FIGURE 10.9 Ascanning electron micrograph of a neuron cell the brain. Here they help regulate the composition of the  body and some of the neuroglia associated with it (5,000x). cerebrospinal fluid.    Neuroglia, which comprise more than half of the volume of the  brain and outnumber neurons 10 to 1, are critical to neuron func-  tion. Abnormal neuroglia are associated with certain disorders.  Most brain tumors, for example, consist of neuroglia that divide  too often. Neuroglia that produce toxins may lie behind some  neurodegenerative disorders. In one familial form of amyotrophic  lateral sclerosis (ALS, or Lou Gehrig’s disease), astrocytes release a  toxin that destroys motor neurons, causing progressive weakness.  In Huntington disease (HD), which causes uncontrollable move-  ments and cognitive impairment, microglia in the brain release a  toxin that damages neurons. ALS and HD affect specific sets of  neurons. Identifying the roles of neuroglia in nervous system disor-  ders suggests new targets for treatments.    The two types of neuroglia in the peripheral nervous system are  Schwann cells and satellite cells:    1. Schwann cells produce the myelin on peripheral myelinated  neurons, as described earlier.   2. Satellite cells provide nutritional support and help regulate  the concentrations of ions around neuron cell bodies  within ganglia.    Injury to the cell body usually kills the neuron, and because mature  neurons do not divide, the destroyed cell is not replaced unless  neural stem cells are stimulated to proliferate. However, a dam-  aged peripheral axon may regenerate. For example, if injury or  disease separates an axon in a peripheral nerve from its cell body,  the distal portion of the axon and its myelin sheath deteriorate    within a few weeks, although the Schwann cells and neurilemma  remain. Macrophages remove the fragments of myelin and other  cellular debris. The proximal end of the injured axon develops  sprouts shortly after the injury. Influenced by nerve growth factors  that nearby neuroglia secrete, one of these sprouts may grow into  a tube formed by the remaining Schwann cells. At the same time,  Schwann cells along the length of the regenerating portion form  new myelin around the growing axon.   Growth of a regenerating axon is slow (up to 4 millimeters per  day), but eventually the new axon may reestablish the former con-  nection (fig. 10.10). Nerve growth factors, secreted by neuroglia,  may help direct the growing axon. However, the regenerating axon  may still end up in the wrong place, so full function often does  not return.   If an axon of a neuron within the CNS is separated from its  cell body, the distal portion of the axon will degenerate, but more  slowly than a separated axon in the PNS. However, axons in the  CNS lack neurilemmae, and the myelin-producing oligodendro-  cytes do not proliferate following injury. Consequently, the proxi-  mal end of a damaged axon that begins to grow has no tube of  sheath cells to guide it. Therefore, regeneration is unlikely.    If a peripheral nerve is severed, it is important that the two cut  ends be connected as soon as possible so that the regenerating  sprouts of the axons can more easily reach the tubes formed by  the Schwann cells on the distal side of the gap. When the gap  exceeds 3 millimeters, the regenerating axons may not line up  correctly with the distal side of the gap and may form a tangled  mass called a neuroma. A neuroma is composed of sensory  axons and is painfully sensitive to pressure.    Microglia Small cells with few cellular processes and found throughout  the CNS   Ependyma Cuboidal and columnar cells in the lining of the ventricles of  the brain and the central canal of the spinal cord   substances between blood vessels and neurons, communicate  with one another and with neurons, mop up excess ions and  neurotransmitters, induce synapse formation    Form myelin sheaths in the brain and spinal cord, produce  nerve growth factors    Form a porous layer through which substances diffuse  between the interstitial fluid of the brain and spinal cord  and the cerebrospinal fluid    Proximal end of injured axon  regenerates into tube of Schwann cells    FIGURE 10.10 [fa myelinated axon is injured, the following events may occur over several weeks to months: (a) The proximal portion of the  axon may survive, but (b) the portion distal to the injury degenerates. (c and d) In time, the proximal portion may develop extensions that grow  into the tube formed by the remaining Schwann cells and (e) possibly reestablish the former connection. Nerve growth factors that neuroglia    Neurons do not divide. New neural tissue arises from neural  stem cells, which give rise to neural progenitor cells that can  give rise to neurons or neuroglia. In the adult brain, the rare  neural stem cells are in a region called the dentate gyrus and  near the fluid-filled ventricles.   Neural stem cells were discovered in the 1980s, in song-  birds—the cells were inferred to exist because the numbers of  neurons waxed and waned with the seasons, peaking when the  birds learned songs. Moving songbirds far from food, forcing  them to sing longer, resulted in more brain neurons, thanks to  the stem cells. In the 1990s, researchers identified stem cells  in brain slices from marmosets and tree shrews given a drug  that marks dividing cells. Then stem cells were discovered in  humans when a researcher learned of patients taking a drug  to mark their tongue and larynx cancer cells. The drug also  marked neural stem cells. When five of the patients donated  their brains, researchers were able to see human neural stem  cells for the first time. Today, human neural stem and progeni-  tor cells are being used to screen drugs and are being delivered  as implants to experimentally treat a variety of brain disorders.  One day, a person’s neural stem cells may be coaxed to help  heal from within.    Neurons communicate with one another (or with other cells) at syn-  apses (fig. 10.11). When you get a text message, the person texting is  the sender and you are the receiver. Similarly, the neuron conducting  an impulse to the synapse is the sender, or presynaptic neuron. The  neuron receiving input at the synapse is the postsynaptic neuron.  (The postsynaptic cell could also be a muscle or glandular cell.) A  synaptic cleft, or gap, separates the two cells, which are connected  functionally, but not physically. The process by which the impulse in  the presynaptic neuron signals the postsynaptic cell is called synaptic  transmission. As a result of synaptic transmission, the presynaptic  neuron stimulates or inhibits a postsynaptic cell (fig. 10.12).  Synaptic transmission is a one-way process carried out by  neurotransmitters. An impulse travels along the axon of the pre-  synaptic neuron to the axon terminal. Most axons have several  rounded synaptic knobs at their terminals, which dendrites do not  have. These knobs have arrays of membranous sacs, called syn-  aptic vesicles, that contain neurotransmitter molecules. When an  impulse reaches a synaptic knob, voltage-sensitive calcium chan-  nels open and calcium diffuses inward from the extracellular fluid.  The increased calcium concentration inside the cell initiates a  series of events that fuses the synaptic vesicles with the cell mem-  brane, where they release their neurotransmitter by exocytosis.    FIGURE 10.11 fAP|R) For an impulse to continue from one neuron to another, it must cross the synaptic cleft.    A synapse usually separates an axon and a dendrite or an axon and a cell body.    Once the neurotransmitter binds to receptors on a postsyn-  aptic cell, the action is either excitatory (turning a process on)  or inhibitory (turning a process off). The net effect on the post-  synaptic cell depends on the combined effect of the excitatory  and inhibitory inputs from as few as | to 10,000 or more presyn-  aptic neurons.    R r] _PRACTICE  8 Name and describe four types of neuroglia.  9 What are some functions of neuroglia?  10. Explain how an injured peripheral axon might regenerate.    A cell membrane is usually electrically charged, or polarized, so  that the inside is negatively charged with respect to the outside.  This polarization is due to an unequal distribution of positive and  negative ions across the membrane. It is important in the conduc-  tion of impulses in both muscle fibers and neurons.    Potassium ions (K*) are the major intracellular positive ion (cat-  ion), and sodium ions (Na*) are the major extracellular cation.  The distribution is created largely by the sodium/potassium pump  (Na*/K*pump), which actively transports sodium ions out of the  cell and potassium ions into the cell. It is also in part due to chan-  nels in the cell membrane that determine membrane permeability  to these ions. These channels, formed by membrane proteins, can  be selective; that is, a particular channel may allow only one type  of ion to pass through and exclude all other ions of different size  and charge. Thus, even though concentration gradients are pres-  ent for sodium and potassium, the ability of these ions to diffuse  across the cell membrane depends on the presence of channels.    Some channels are always open, whereas others may be either  open or closed, somewhat like a gate. Both chemical and electrical  factors can affect the opening and closing of these gated channels  (fig. 10.13).    FIGURE 10.12 (AP|R) The synapse. (a) When an impulse reaches the synaptic knob at the end of an axon, synaptic vesicles release a neurotransmitter  that diffuses across the synaptic cleft. (b) A transmission electron micrograph of a synaptic knob filled with synaptic vesicles (37,500x).    FIGURE 10.13 A gatelike mechanism can (a) close or (b) open some of the channels in cell membranes through which ions pass.   A resting nerve cell is not being stimulated to send an impulse.  Under resting conditions, non-gated (always open) channels deter-  mine the membrane permeability to sodium and potassium ions.    (a) In a hypothetical neuron before the membrane  potential is established, potassium ions diffuse  out of the cell faster than sodium ions diffuse in.  A net loss of positive charge from the cell results.    (c) The membrane potential, negative on the inside of the  membrane, aids sodium diffusion into the cell, and opposes  potassium diffusion out of the cell. As a result, slightly more  sodium ions enter the cell than potassium ions leave.  However, the sodium/potassium pump balances these  movements, maintaining the concentrations of these ions  and the resting membrane potential.    Sodium and potassium ions follow the rules of diffusion  described in chapter 3 (pp. 98-100) and show a net movement  from areas of high concentration to areas of low concentration  across a membrane as their permeabilities permit. The resting cell  membrane is only slightly permeable to these ions, but the mem-  brane is more permeable to potassium ions than to sodium ions  (fig. 10.14a). Also, the cytoplasm of these cells has many nega-  tively charged ions (anions), which include phosphate (PO, *), sul-  fate (SO en and proteins, that are synthesized inside the cell and  cannot diffuse through cell membranes.    (b) The net loss of positive charges from inside the cell  leaves the inside of the cell membrane slightly negative  compared to the outside, which is slightly positive. This  difference, called an electrical “potential difference,”  measures —70 millivolts (mV) in a typical neuron, and is  called the resting membrane potential.    FIGURE 10.14 The resting potential. (a) Conditions that lead to the  resting potential. (b) In the resting neuron, the inside of the membrane  is negative relative to the outside. (c) The Na*/K* pump maintains the  concentration gradients for Na* and K* ions.    @ Constant activity of the Na*/K* pump requires a constant  supply of which substance?    If we consider a hypothetical neuron, before a membrane  potential has been established, we would expect potassium to dif-  fuse out of the cell more rapidly than sodium could diffuse in. This  means that every millisecond (as the membrane potential is being  established in our hypothetical cell), a few more positive ions leave  the cell than enter it (fig. 10.14a). As a result, the outside of the  membrane gains a slight surplus of positive charges, and the inside  reflects a surplus of the impermeant negatively charged ions. This  situation separates positive and negative electrical charges between  the inside and outside surfaces of the cell membrane (fig. 10.14).  All this time, the cell continues to expend metabolic energy in the  form of ATP to actively transport sodium and potassium ions in  opposite directions, thus maintaining the concentration gradients  for those ions responsible for their diffusion in the first place.   The difference in electrical charge between two points is  measured in units called volts. It is called a potential difference  because it represents stored electrical energy that can be used to  do work at some future time. The potential difference across the  cell membrane is called the membrane potential (transmembrane  potential) and is measured in millivolts.   In the case of a resting neuron, one that is not sending impulses  or responding to other neurons, the membrane potential is termed  the resting potential (resting membrane potential) and has a value  of —70 millivolts (fig. 10.145). The negative sign is relative to the  inside of the cell and is due to the excess negative charges on the  inside of the cell membrane. To understand how the resting potential  provides the energy for sending an impulse down the axon, we must  first understand how neurons respond to signals called stimuli.   With the resting membrane potential established, a few  sodium ions and potassium ions continue to diffuse across the cell  membrane. The negative membrane potential helps sodium ions  enter the cell despite sodium’s low permeability, but it hinders  potassium ions from leaving the cell despite potassium’s higher  permeability. The net effect is that three sodium ions “leak” into  the cell for every two potassium ions that “leak” out. The Na*/K*  pump exactly balances these leaks by pumping three sodium ions  out for every two potassium ions it pumps in (fig. 10.14c).    Recall from chapter | (p. 22) that neurons can conduct electri-  cal signals. The key to understanding how this happens is the action  potential, which is a rapid change in the membrane potential, first  in a positive direction, then in a negative direction, returning to the  resting potential (figure 10.15). When a neuron conducts an electri-  cal current, that current is in the form of a series of action potentials  occurring in sequence along the axon, from the cell body to the axon  terminal. The next sections discuss how all of this happens.    Neurons are excitable; that is, they can respond to changes in their  surroundings. Some neurons, for example, detect changes in tem-  perature, light, or pressure outside the body, whereas others respond  to signals from inside the body, often from other neurons. In either  case, such changes or stimuli usually affect the membrane poten-  tial in the region of the membrane exposed to the stimulus, causing  a local potential change.   Typically, the environmental change affects the membrane poten-  tial by opening a gated ion channel. The effect will depend on the ion  that can pass through the channel. If, as a result, the membrane poten-  tial becomes more negative than the resting potential, the membrane  is hyperpolarized. If the membrane becomes less negative (more posi-  tive) than the resting potential, the membrane is depolarized.   Local potential changes are graded. This means that the  degree of change in the resting potential is directly proportional  to the intensity of the stimulation. For example, if the membrane  is being depolarized, the greater the stimulus, the greater the depo-  larization. If and only if neurons are sufficiently depolarized, the  membrane potential reaches a level called the threshold potential,  which is approximately —55 millivolts in a neuron. If threshold is  reached, an action potential results.   In many cases, a depolarizing stimulus is not sufficient to  bring the postsynaptic cell to threshold (fig. 10.16a). Such a sub-  threshold depolarization will not result in an action potential.    If the presynaptic neurons release more neurotransmitter, or if  other neurons that synapse with the same cell have an additive  effect on depolarization, threshold may be reached, and an action  potential result. The mechanism uses another type of ion chan-  nel, a voltage-gated sodium channel that opens when threshold is  reached (fig. 10.16).   In a multipolar neuron, the first part of the axon, the cone-shaped  axon hillock or initial segment, is often referred to as the trigger  zone because it contains many such voltage-gated sodium channels.  At the resting membrane potential, these sodium channels remain  closed, but when threshold is reached, they open for an instant,  briefly increasing sodium permeability (fig. 10.17a). Sodium ions  diffuse inward through the open sodium channels, down their con-  centration gradient, aided by the attraction of the sodium ions to the  negative electrical state on the inside of the membrane (fig. 10.17b).   As the sodium ions diffuse inward, the membrane potential at  the trigger zone changes from its resting value and momentarily  becomes positive on the inside (still considered depolarization). At  the peak of the action potential, the membrane potential may reach  +30 mV or more (fig. 10.17).    (a) If sodium or potassium channels open, more of that particular ion will cross the cell membrane, altering the resting membrane potential.  This illustration depicts the effect of sodium channels opening in response to a neurotransmitter. As sodium ions enter the cell, the  membrane potential becomes more positive (or less negative), changing from —70 millivolts to -62 millivolts in this example. This change  in a positive direction is called depolarization. Here the depolarization is subthreshold, and does not generate an action potential.    (b) If sufficient sodium ions enter the cell and the membrane potential depolarizes to threshold (here —55 millivolts), another type of sodium channel  opens. These channels are found along the axon, especially near the origin in an area called the “trigger zone.” Opening of these channels    FIGURE 10.16 Action potentials. (a) A subthreshold depolarization will not result in an action potential.  (b) Multiple stimulation by presynaptic neurons may reach threshold, opening voltage-gated channels at the trigger zone.    The voltage-gated sodium channels quickly close, but at almost  the same time, slower voltage-gated potassium channels open and  briefly increase potassium permeability. As potassium ions diffuse  outward through the open potassium channels, the inside becomes  negatively charged once more. The membrane is thus repolarized  (note in fig. 10.17c that it hyperpolarizes for an instant). The voltage-  gated potassium channels then close as well. These actions quickly  reestablish the resting potential, which remains in the resting state  until it is stimulated again (see fig. 10.17a). The number of sodium    and potassium ions crossing the membrane during an action potential  is extremely small, although the bioelectric effect is quite significant.  The active transport mechanism in the membrane restores and main-  tains the original concentrations of sodium and potassium ions.  Axons are capable of action potentials, but the cell body and  dendrites are not. An action potential at the trigger zone causes an  electric current to flow a short distance down the axon, which stimu-  lates the adjacent membrane to reach its threshold level, triggering  another action potential. The second action potential causes another    7 + * ” * kK kK kK kK kK kK    FIGURE 10.17 (AP|R} At rest (a), the axon membrane potential is about —70 millivolts. When the membrane reaches threshold (b),  voltage-sensitive sodium channels open, some Na* diffuses inward, and the membrane is depolarized. Soon afterward (c), voltage-sensitive  potassium channels open, K* diffuses out, and the membrane is repolarized. (Negative ions not shown.)    electric current to flow farther down the axon. This sequence of  events results in a series of action potentials occurring sequentially  all the way to the end of the axon without decreasing in amplitude,  even if the axon branches. The propagation of action potentials (or  impulse conduction) continues along the axon (fig. 10.18).   Conduction of an impulse along an axon is similar to conduction  of an impulse in a muscle fiber mentioned in chapter 9, page 304.  In the muscle fiber, stimulation at the motor end plate triggers an  impulse to travel over the surface of the fiber and down into its trans-  verse tubules. See table 10.3 for a summary of the events leading to  the conduction of a series of action potentials down an axon.    An action potential is an all-or-none response. In other words, if a  neuron responds at all, it responds completely. Thus, an impulse is  conducted whenever a stimulus of threshold intensity or above is  applied to an axon and all impulses conducted on that axon are the  same strength. A greater intensity of stimulation produces more  impulses per second, not a stronger impulse.    of Na* and K* down their concentration gradients as the cell  pumps them up the gradients.    . Sodium channels in the trigger zone of the axon open.    . Action potentials occur sequentially along the length of  the axon.    in one region stimulates the adjacent region, and (b and c) a wave of  action potentials moves along the axon.    The number of impulses per second that an axon can generate is  limited, because during an impulse, that part of the axon becomes  unresponsive to another normal threshold stimulus. This brief period,  called the refractory period, has two parts. During the absolute  refractory period, which lasts about 1/1,000 of a second (1 milli-  second), the axon’s voltage-gated sodium channels are temporarily  not responsive at all, and the axon cannot be stimulated. A relative  refractory period follows, as the membrane reestablishes its resting  potential. During this time, even though repolarization is incomplete,  a stimulus of higher than usual intensity may trigger an impulse.  Rapidly, the intensity of stimulation required to trigger an  impulse decreases until the axon’s original excitability is restored.  This return to the resting state usually takes from | to 3 milliseconds.  The refractory period limits how many action potentials may  be generated in a neuron in a given period. Remembering that the  action potential takes about a millisecond, and adding the time of  the relative refractory period, the maximum theoretical frequency  of impulses in a neuron is about 700 per second. In the body, this  limit is rarely achieved—frequencies of about 100 impulses per sec-    ond are common. The refractory period also ensures that an action  potential is conducted in only one direction, down the axon, because  the area upstream from where the action potential has just occurred  is still in the refractory period from the previous action potential.    An unmyelinated axon conducts an impulse over its entire surface.  A myelinated axon functions differently. Myelin contains a high  proportion of lipid that excludes water and water-soluble sub-  stances. Thus, myelin prevents almost all flow of ions through the  membrane that it encloses and serves as an electrical insulator.   It might seem that the myelin sheath would prevent conduction  of an impulse, and this would be true if the sheath were continuous  along the length of the axon. However, nodes of Ranvier between  Schwann cells or oligodendrocytes interrupt the sheath (see fig. 10.3).  At these nodes, the axon membrane has channels for sodium and  potassium ions that open during a threshold depolarization.   When a myelinated axon is stimulated to threshold, an action  potential occurs at the trigger zone. This causes a bioelectric cur-  rent to flow away from the trigger zone through the cytoplasm of  the axon. As this local current reaches the first node, it stimulates  the membrane to its threshold level, and an action potential occurs  there, sending a bioelectric current to the next node downstream  (the refractory period prevents impulses from going backward  toward the cell body). Consequently, as an impulse is conducted  along a myelinated axon, action potentials occur only at the nodes.  Because the action potentials appear to jump from node to node,  this type of impulse conduction is called saltatory conduction.  Conduction on myelinated axons is many times faster than con-  duction on unmyelinated axons (fig. 10.19).   The diameter of the axon affects the speed of impulse conduc-  tion—the greater the diameter, the faster the impulse. An impulse  on a comparatively thick, myelinated axon, such as that of a motor  neuron associated with a skeletal muscle, might travel 120 meters  per second, whereas an impulse on a thin, unmyelinated axon, such  as that of a sensory neuron associated with the skin, might move  only 0.5 meter per second. Clinical Application 10.3 discusses fac-  tors that influence impulse conduction.   13. Explain how a polarized axon responds to stimulation.  14 List the major events of an action potential.    16 Explain how impulse conduction differs in myelinated and  unmyelinated axons.    Released neurotransmitter molecules diffuse across the synaptic  cleft and bind to receptors on the postsynaptic cell membrane.  When neurotransmitters bind these receptors, they cause ion chan-  nels in the postsynaptic cells to open. Ion channels that respond  to neurotransmitter molecules are called chemically gated, in    Convulsions, paralysis, and anesthesia can each result from  changes in the permeability of axons to particular ions. A number  of substances alter axon membrane permeability to ions.   A small increase in the concentration of extracellular potas-  sium ions reduces the gradient for potassium ions to leave the  cell, causing the resting potential of nerve fibers to be less nega-  tive (partially depolarized). As a result, the threshold potential is  reached with a less intense stimulus than usual. The affected fibers  are excitable, and the person may experience convulsions.    If the extracellular potassium ion concentration is greatly  decreased, the resting potentials of the nerve fibers may become so  negative (hyperpolarized) that action potentials are not generated. In  this case, impulses are not triggered, and muscles become paralyzed.   Certain anesthetic drugs, such as procaine, decrease membrane  permeability to sodium ions. In the tissue fluids surrounding an axon,  these drugs prevent impulses from passing through the affected  region. Consequently, the drugs keep impulses from reaching the  brain, preventing perception of touch and pain.    FIGURE 10.19 On  a myelinated axon, an  impulse appears to jump  from node to node.  (a)-(c) show the action  potential progressing  down the axon.    contrast to the voltage-gated ion channels that participate in action  potentials. Changes in chemically gated ion channels create local  potentials, called synaptic potentials, which enable one neuron to  affect another.   Neurotransmitters that increase postsynaptic membrane per-  meability to sodium ions will bring the postsynaptic membrane  closer to threshold and may trigger impulses. Such neurotransmitters  are excitatory. Neurotransmitters that make reaching threshold  less likely are called inhibitory, because they decrease the chance  that an impulse will occur.    Some relatively uncommon synapses, called electrical synapses,  are in certain parts of the brain and eyes. Electrical synapses  involve direct exchange of ions between neurons through    gap junctions (see chapter 5, p. 149). Synaptic transmission  always occurs, because the postsynaptic cell does not need to  reach threshold.    Synaptic potentials can depolarize or hyperpolarize the receiving  cell membrane. For example, if a neurotransmitter binds to a post-  synaptic receptor and opens sodium ion channels, the ions diffuse  inward, depolarizing the membrane, possibly triggering an action  potential. This type of membrane change is called an excitatory  postsynaptic potential (EPSP), and it lasts for about 15 milliseconds.   If a different neurotransmitter binds other receptors and increases  membrane permeability to potassium ions, these ions diffuse outward,  hyperpolarizing the membrane. Because an action potential is now  less likely to occur, this change is called an inhibitory postsynaptic  potential (IPSP). Some inhibitory neurotransmitters open chloride  ion channels. In this case, if sodium ions enter the cell, negative  chloride ions are free to follow, opposing the depolarization.   In the brain and spinal cord, each neuron may receive the syn-  aptic knobs of a thousand or more axons on its dendrites and cell  body (fig. 10.20). Furthermore, at any moment, some of the post-  synaptic potentials are excitatory on a particular neuron, while  others are inhibitory.    FIGURE 10.20 The synaptic knobs of many axons may communicate  with the cell body of a neuron.    The integrated sum of the EPSPs and IPSPs determines  whether an action potential results. If the net effect is more excit-  atory than inhibitory, threshold may be reached and an action  potential triggered. Conversely, if the net effect is inhibitory, an  action potential does not occur.   Summation of the excitatory and inhibitory effects of the  postsynaptic potentials commonly takes place at the trigger zone.  This is usually in a proximal region of the axon, but in some sen-  sory neurons it may be in the distal peripheral process. This region  has an especially low threshold for triggering an action potential.  In this way, the trigger zone, as its name implies, serves as a decision-  making part of the neuron.    The nervous system produces at least 100 different types of neu-  rotransmitters in the brain alone. Some neurons release only one  type, whereas others produce two or three. Neurotransmitters include  acetylcholine, which stimulates skeletal muscle contractions (see  chapter 9, p. 297); a group of compounds called monoamines (such  as epinephrine, norepinephrine, dopamine, and serotonin), which  are modified amino acids; a group of unmodified amino acids (such  as glycine, glutamic acid, aspartic acid, and gamma-aminobutyric  acid—GABA); and a large group of peptides (such as enkephalins  and substance P), which are short chains of amino acids.   Peptide neurotransmitters are synthesized in the rough endo-  plasmic reticulum of a neuron cell body and transported in vesicles  down the axon to the nerve cell terminal. Other neurotransmitters are  synthesized in the cytoplasm of the nerve cell terminal and stored in  vesicles. When an action potential passes along the membrane of a    synaptic knob, it increases the membrane’s permeability to cal-  cium ions by opening calcium ion channels. Calcium ions diffuse  inward, and in response, some of the synaptic vesicles fuse with  the presynaptic membrane and release their contents by exocytosis  into the synaptic cleft (see fig. 10.12). If multiple action poten-  tials reach the synaptic knob, more calcium will enter. The more  calcium that enters the synaptic knob, the more vesicles release  neurotransmitter. Table 10.4 lists the major neurotransmitters and  their actions. Tables 10.5 and 10.6, respectively, list disorders and  drugs that alter neurotransmitter levels.    Stimulates skeletal muscle  contraction at neuromuscular  junctions; may excite or  inhibit at autonomic nervous  system synapses    Creates a sense of well-  being; low levels may lead to  depression   depending on receptors  Dopamine Creates a sense of well-being;  deficiency in some brain areas  associated with Parkinson  disease    Limited actions in autonomic  nervous system; may excite or  inhibit, depending on receptors    Primarily inhibitory; leads to  sleepiness; action is blocked  by LSD, enhanced by selective  serotonin reuptake inhibitor  antidepressant drugs    Epilepsy Seizures, loss of consciousness Excess GABA leads to excess norepinephrine and dopamine    Huntington disease Cognitive and behavioral changes, loss of coordination, Deficient GABA    Parkinson disease Tremors of hands, slowed movements, muscle rigidity Deficient dopamine    Reserpine Norepinephrine Decreases packaging of neurotransmitter into vesicles Decreases blood pressure    A vesicle becomes part of the cell membrane after it releases  its neurotransmitter. Endocytosis eventually returns the membrane  material to the cytoplasm, where it can provide material to form  new secretory vesicles. Table 10.7 summarizes this process, which  is called vesicle trafficking.   To keep signal duration short, enzymes in synaptic clefts  and on postsynaptic membranes rapidly decompose some neu-  rotransmitters. The enzyme acetylcholinesterase, for example,  decomposes acetylcholine on postsynaptic membranes. Other  neurotransmitters are transported back into the synaptic knob of    the presynaptic neuron or into nearby neurons or neuroglia, in a  process called reuptake. The enzyme monoamine oxidase inac-  tivates the monoamine neurotransmitters epinephrine and norepi-  nephrine after reuptake. This enzyme is found in mitochondria  in the synaptic knob. Destruction or removal of neurotransmitter  prevents continuous stimulation of the postsynaptic neuron.    Neurons in the brain or spinal cord synthesize neuropeptides.  These peptides act as neurotransmitters or as neuromodulators,  which are substances that alter a neuron’s response to a neurotrans-  mitter or block the release of a neurotransmitter.    Opiate drugs, such as morphine, heroin, codeine, and opium, are  potent painkillers derived from the poppy plant. These drugs alter  pain perception making it easier to tolerate, and they elevate mood.   The human body produces opiates, called endorphins (for  “endogenous morphine”), that are peptides. Like the poppy-  derived opiates that they structurally resemble, endorphins influ-  ence mood and perception of pain.   Endorphins were discovered in the 1960s at the University of  California, San Francisco, in dried pituitary glands, but their func-  tions were not described until 1971, when researchers at Stanford  University and the Johns Hopkins School of Medicine exposed  pieces of brain tissue to morphine. The morphine was radio-  actively labeled (some of the atoms were radioactive isotopes) so  researchers could follow its destination in the brain.   The morphine bound receptors on neurons that transmit  pain. Why, the investigators wondered, would an animal's brain  cells have receptors for a plant chemical? One explanation was  that a mammal’s body could manufacture opiates. The opiate  receptors, then, would normally bind the body's opiates (the    1. Action potential passes along an axon and over the surface of  its synaptic knob.    2. Synaptic knob membrane becomes more permeable to  calcium ions, and they diffuse inward.    3. In the presence of calcium ions, synaptic vesicles fuse to  synaptic knob membrane.    4. Synaptic vesicles release their neurotransmitter by exocytosis  into the synaptic cleft.    Among the neuropeptides are the enkephalins, which are  present throughout the brain and spinal cord. Each enkephalin  molecule is a chain of five amino acids. Synthesis of enkepha-  lins increases during periods of painful stress, and they bind to  the same receptors in the brain (opiate receptors) as the narcotic  morphine. Enkephalins relieve pain sensations and probably have  other functions. Another morphinelike peptide, beta endorphin,  is found in the brain and cerebrospinal fluid. It acts longer than  enkephalins and is a much more potent pain reliever. Clinical  Application 10.4 discusses opiates in the human body.   Substance P is a neuropeptide that consists of eleven amino  acids and is widely distributed. It functions as a neurotransmitter    endorphins) but would also bind the chemically similar com-  pounds from poppies. Researchers have since identified several  types of endorphins in the human brain and associated their  release with situations involving pain relief, such as acupuncture,  analgesia to mother and child during childbirth, and the feeling  of well-being that accompanies exercise. PET scans reveal endor-  phins binding opiate receptors after conditioned athletes run for  two hours.   Endorphins explain why some people addicted to opiate  drugs, such as heroin, experience withdrawal pain when they stop  taking the drug. Initially the body interprets the frequent binding  of heroin to its endorphin receptors as an excess of endorphins. To  lower the level, the body slows its own production of endorphins.  Then, when the person stops taking the heroin, the body becomes  short of opiates (heroin and endorphins). The result is pain.   Opiate drugs can be powerfully addicting when they are  taken repeatedly by a person who is not in pain. These same  drugs, however, are extremely useful in dulling severe pain, par-  ticularly in terminal illnesses and after surgery.    (or perhaps as a neuromodulator) in the neurons that conduct  impulses associated with pain into the spinal cord and on to the  brain. Enkephalins and endorphins may relieve pain by inhibiting  the release of substance P from these neurons.    Distinguish between an EPSP and an IPSP.  18 Describe the net effects of EPSPs and IPSPs.  19 Explain the function of a neurotransmitter.    The way the nervous system collects, processes, and responds to  information reflects, in part, the organization of neurons and axons  in the brain and spinal cord.    Interneurons, which are the neurons completely within the CNS,  are organized into neuronal pools. These are groups of neurons  that synapse with each other and perform a common function,  even though their cell bodies may be in different parts of the CNS.  Each neuronal pool receives input from neurons (which may be  part of other pools), and each pool generates output. Neuronal  pools may have excitatory or inhibitory effects on other pools or  on peripheral effectors.    As a result of incoming impulses and neurotransmitter release, a  particular neuron of a neuronal pool may be excited by some presyn-  aptic neurons and inhibited by others. If the net effect is excitatory,  threshold may be reached, and an impulse triggered. If the net effect  is excitatory, but subthreshold, an impulse will not be triggered.   Repeated impulses on excitatory presynaptic neurons may result  in the increased release of neurotransmitter in response to an impulse,  making it more likely to bring the postsynaptic cell to threshold.  This phenomenon is called facilitation (fah-sil” 1-ta’shun).    Any single neuron in a neuronal pool may receive input from two or  more other neurons. Axons originating from different neurons leading  to the same postsynaptic neuron exhibit convergence (kon-ver’jens).   Incoming impulses often represent information from various  sensory receptors that detect changes. Convergence allows the ner-  vous system to collect, process, and respond to information.   Convergence makes it possible for a neuron to sum impulses  from different sources. For example, if a neuron receives what would  be subthreshold stimulation from one input neuron, it may reach  threshold if it receives additional stimulation from a second input  neuron. Thus, impulses on this neuron may reflect summation of  input from two sources (fig. 10.21a). Such output may reach a par-  ticular effector and evoke a response.    A neuron has a single axon, but axons may branch at several  points. Therefore, impulses conducted by a neuron of a neuronal  pool may exhibit divergence (di-ver’jens) by reaching several  other neurons. One neuron stimulates two others, each of which  stimulates several others, and so forth. Such a pattern of diverging  axons allows an impulse to reach increasing numbers of neurons  within the pool (fig. 10.210).   As a result of divergence, an impulse originating from a single  neuron in the CNS may stimulate several motor units in a skeletal  muscle to contract. Similarly, an impulse originating from a sensory    1. The nervous system is a network of cells that sense and  respond to stimuli in ways that maintain homeostasis.   2. The nervous system is composed of neural tissue (neurons  and neuroglia), blood vessels, and connective tissue.   3. Neurons have processes that receive (dendrites) and send  (axons) bioelectric signals (impulses).   4. Biological messenger molecules (neurotransmitters)  convey this neural information across spaces (synapses)  between neurons and the cells they affect.   5. Organs of the nervous system are divided into the central  and peripheral nervous systems.    FIGURE 10.21 Impulse processing in neuronal pools. (a) Axons of  neurons 1 and 2 converge to the cell body of neuron 3. (b) The axon of  neuron 4 diverges to the cell bodies of neurons 5 and 6.    receptor may diverge and reach several different regions of the CNS,  where the information can be processed and evoke a response.   The nervous system enables us to experience the world and to  think and feel emotion. This organ system is also sensitive to out-  side influences. Clinical Application 10.5 discusses one way that  an outside influence can affect the nervous system—drug addiction.    1. Sensory receptors detect changes in internal and external  body conditions.  2. Integrative functions gather sensory information and make  decisions that affect motor functions.  3. Motor impulses stimulate effectors to respond.  a. The motor portion of the PNS that carries out  voluntary activities is the somatic nervous system.  b. The motor portion of the PNS that carries out  involuntary activities is the autonomic nervous system.    Drug abuse and addiction have a long history. A 3,500-year-old  Egyptian document decries reliance on opium. In the 1600s, a  smokable form of opium enslaved many Chinese, and the Japa-  nese and Europeans discovered the addictive nature of nico-  tine. During the American Civil War, morphine was a widely used  painkiller, and soon cocaine was introduced to relieve veterans  addicted to morphine. LSD, originally used in psychotherapy, was  abused in the 1960s as a hallucinogen. PCP was an anesthetic  before being abused in the 1980s. An increasing problem today  is that people who are addicted to opiate-based painkillers may  switch to heroin because it is easier to obtain.   The biology of neurotransmission helps to explain drug addic-  tion. When a drug alters the activity of a neurotransmitter on a  postsynaptic neuron, it either halts or enhances synaptic transmis-  sion. A drug that binds to a receptor, blocking a neurotransmit-  ter from binding, is called an antagonist. A drug that activates the  receptor, triggering an action potential, or that helps a neurotrans-  mitter to bind, is called an agonist. The effect of a drug depends  upon whether it is an antagonist or an agonist; on the particular  behaviors the affected neurotransmitter normally regulates; and  in which parts of the brain the drug affects neurotransmitters and  their binding to receptors. Many addictive substances bind to  receptors for the neurotransmitter dopamine, in a brain region  called the nucleus accumbens.   With repeated use of an addictive substance, the number of  receptors it targets can decline. When this happens, the person  must use more of the drug to feel the same effect. For example,  neural pathways that use the neurotransmitter norepinephrine  control arousal, dreaming, and mood. Amphetamine enhances  norepinephrine activity, thereby heightening alertness and mood.  Amphetamine’s structure is so similar to that of norepinephrine  that it binds to norepinephrine receptors and triggers the same  changes in the postsynaptic membrane.   Cocaine has a complex mechanism of action, both blocking  reuptake of norepinephrine and binding to molecules that transport  dopamine to postsynaptic cells. The drug valium causes relaxation  and inhibits seizures and anxiety by helping GABA, an inhibitory neu-  rotransmitter used in a third of the brain's synapses, bind to recep-  tors on postsynaptic neurons. Valium is therefore a GABA agonist.   Nicotine is highly addictive, and the chemicals in cigarette  smoke can destroy health. An activated form of nicotine binds    postsynaptic nicotinic receptors that normally receive acetylcholine.  When sufficient nicotine binds, a receptor channel opens, allow-  ing positive ions into the cell (fig. 10A). When a certain number of  positive ions enter, the neuron releases dopamine from its other  end, which provides the pleasurable feelings associated with smok-  ing. A drug that helps some people stop smoking (varenicline, or  Chantix) works by partially activating the nicotinic receptors, which  decreases both the enjoyment of smoking and the craving.   When a smoker increases the number of cigarettes smoked, the  number of nicotinic receptors increases. This happens because nico-  tine binding impairs the recycling of receptor proteins, so that recep-  tors are produced faster than they are taken apart. After a period  of steady nicotine exposure, many of the receptors malfunction and  no longer admit the positive ions that trigger dopamine release.  Receptor malfunction may be why as time goes on it takes more  nicotine to produce the same effects—a hallmark of addiction.    FIGURE 10A_ Nicotine binds and transiently alters postsynaptic  receptors that normally bind the neurotransmitter acetylcholine. As  a result, positive ions enter the cell, triggering dopamine release.  With frequent smoking, receptors accumulate and soon become  nonfunctional. Nicotine’s effects on the nervous system are complex.    The nervous  system controls  movement and  processes  information about  the position of  body parts.    The nervous system  alters respiratory  activity to control  oxygen levels and  blood pH.    The nervous  system plays a role  in urine production  and elimination.    Neurons vary in size, shape, sizes and lengths of axons and  dendrites, and number of dendrites.   A neuron includes a cell body, cell processes, and the  organelles usually found in cells.   Chromatophilic substance is mostly rough ER and is  scattered throughout the cytoplasm of neurons.  Dendrites and the cell body provide receptive surfaces.  A single axon arises from the cell body and may be  enclosed in a myelin sheath and a neurilemma.   White matter consists of myelinated axons, and gray  matter consists of unmyelinated axons and cell bodies.   b. Neurons are functionally classified as sensory neurons,  interneurons, or motor neurons.   b. They fill spaces, support neurons, hold nervous tissue  together, help metabolize glucose, help regulate  potassium ion concentration, produce myelin, carry  on phagocytosis, rid synapses of excess ions and  neurotransmitters, nourish neurons, and stimulate  synapse formation.   c. They include astrocytes, oligodendrocytes, microglia,  and ependymal cells in the CNS and Schwann cells  and satellite cells in the PNS.   (1) Ifaneuron cell body is injured, the neuron is  likely to die; neural stem cells may proliferate and  produce replacements.   (2) Ifa peripheral axon is severed, its distal portion  will die, but under the influence of nerve growth  factors, the proximal portion may regenerate and  reestablish connections, if a tube of remaining  Schwann cells guides it.    A synapse is a functional connection between two cells. A  synaptic cleft is the gap between parts of two cells at a synapse.  Synaptic transmission is the process by which the impulse in  the presynaptic neuron signals the postsynaptic cell.    An impulse is conducted along the axon to a synapse.  Axons have synaptic knobs at their distal ends that release  neurotransmitters.   The neurotransmitter is released when an impulse reaches  the end of an axon, and the neurotransmitter diffuses across  the synaptic cleft.   A neurotransmitter reaching a postsynaptic neuron or other  cell may be excitatory or inhibitory.    A cell membrane is usually polarized as a result of an unequal  distribution of ions on either side. Channels in membranes  that allow passage of some ions but not others control ion  distribution.    a. Membrane ion channels, formed by proteins, may be  always open or sometimes open and sometimes closed.   b. Potassium ions pass more readily through resting neuron  cell membranes than do sodium and calcium ions.   c. A high concentration of sodium ions is on the outside of  the membrane, and a high concentration of potassium  ions is on the inside.    a. Large numbers of negatively charged ions, which  cannot diffuse through the cell membrane, are inside  the cell.   b. Inaresting cell, more positive ions leave the cell than  enter it, causing the inside of the cell membrane to  develop a negative charge with respect to the outside.    a. Stimulation of a membrane affects its resting potential  in a local region.   b. The membrane is depolarized if it becomes less negative;  it is hyperpolarized if it becomes more negative.    a. At threshold, sodium channels open and sodium ions  diffuse inward, depolarizing the membrane.   d. Active transport reestablishes and maintains the original  concentrations of ions across the cell membrane.   e. The propagation of action potentials along a nerve fiber  is also called impulse conduction.    a. An action potential is an all-or-none response. An  action potential is generated if a stimulus of threshold  intensity is applied to an axon.   b. All the impulses conducted on an axon are the  same strength.    a. The refractory period is a brief time during the  passage of an impulse when the membrane is  unresponsive to an ordinary stimulus.   b. During the absolute refractory period, the membrane  cannot respond to a stimulus; during the relative  refractory period, the membrane can respond to a  high-intensity stimulus.    a. An unmyelinated axon conducts impulses that travel  over its entire surface.   b. A myelinated axon conducts impulses that travel from  node to node (saltatory conduction).   c. Impulse conduction is more rapid on myelinated axons  with large diameters.    Neurotransmitter molecules diffuse across the synaptic cleft  and react with receptors in the postsynaptic neuron membrane.  1. Synaptic potentials   a. Some neurotransmitters can depolarize the  postsynaptic membrane, possibly triggering an  action potential. This is an excitatory postsynaptic  potential (EPSP).   b. Others hyperpolarize the membrane, inhibiting an  action potential. This is an inhibitory postsynaptic  potential (IPSP).   c. EPSPs and IPSPs are summed in a trigger zone of  the neuron.   a. The nervous system produces at least 100 different  types of neurotransmitters in the brain alone.   b. Calcium ions diffuse into synaptic knobs in response  to action potentials, releasing neurotransmitters.   1 Describe how the nervous system detects change associated  with the body and reacts to that change to maintain  homeostasis. (pp. 360)   3 Which of the following descriptions is accurate? (pp. 360)  a. Aneuron has a single dendrite, which sends information.  b. Aneuron has a single axon, which sends information.  c. A neuron has many axons, which receive information.  d. A neuron has many dendrites, which send information.   4 Explain the difference between the central nervous system  (CNS) and the peripheral nervous system (PNS). (p. 361)   7 Distinguish between the types of activities that the somatic  and autonomic nervous systems control. (p. 361)    8 Match the part of a neuron on the left with the description  on the right (pp. 360-363):    9 Explain how Schwann cells encase large axons, including  the formation of myelin, the neurilemma, and the nodes  of Ranvier. (p. 363)    The way impulses are processed reflects the organization of  neurons in the brain and spinal cord.  1. Neuronal pools  a. Neurons are organized into neuronal pools in the CNS.  b. Each pool receives input, processes the information,  and may generate output.  c. Each neuron in a pool may receive excitatory and  inhibitory stimuli.  d. A neuron is facilitated when it receives subthreshold  stimuli and becomes more excitable.  2. Convergence  a. Impulses from two or more axons may converge on  a single postsynaptic neuron.  b. Convergence enables a neuron to sum input from  different sources.  3. Divergence  a. Impulses from a presynaptic neuron may reach several  postsynaptic neurons.  b. Divergence allows a single neuron reaching threshold  to have potentially widespread effects.    10 What do Schwann cells and oligodendrocytes have in  common, and how do they differ? (p. 363)    12 Describe the three types of neurons classified on the basis of  structure. (pp. 363-366)   13 Describe the three types of neurons classified on the basis of  function (pp. 366-368)    19 The brings the impulse to the synapse,  whereas the on the other side of the  synapse is stimulated or inhibited as a result of the synaptic  transmission. (p. 371)   20 Explain how information is passed from a presynaptic neuron  to a postsynaptic cell. (1p. 372)   21 Diffusion of which of the following ions into the synaptic  knob triggers the release of neurotransmitter? (p. 372)   26 Explain the relationship between an action potential and  impulse conduction down an axon. (pp. 376-377)   28 Explain the importance of the nodes of Ranvier and  conduction in myelinated fibers as opposed to conduction  in unmyelinated fibers. (p. 378)    1. Why are rapidly growing cancers that originate in nervous tissue  more likely to be composed of neuroglia than of neurons?    2. In Tay-Sachs disease, an infant rapidly loses nervous system  functions as neurons in the brain become covered in too much  myelin. In multiple sclerosis, cells in the CNS have too little myelin.    Identify the type of neuroglia implicated in each of these conditions.    a. When motor nerve fibers in the leg are severed, the muscles  they innervate become paralyzed; however, in time, control  over the muscles often returns.    10.7 Synaptic Transmission  29 Distinguish between excitatory and inhibitory postsynaptic  potentials. (p. 379)  30 Explain how enzymes within synaptic clefts and reuptake  of neurotransmitter prevents continuous stimulation of the  postsynaptic cell. (p. 381)    31 Explain what determines the output of a neuronal pool in  terms of input neurons, excitation, and inhibition. (p. 382)    b. When motor nerve fibers in the spinal cord are severed, the  muscles they control become permanently paralyzed.    4. Drugs that improve early symptoms of Alzheimer disease do  so by slowing the breakdown of acetylcholine in synaptic clefts  in certain parts of the brain. From this information, suggest a  neurotransmitter imbalance that lies behind Alzheimer disease.    5. People who inherit familial periodic paralysis often develop very  low blood potassium concentrations. How would you explain  that the paralysis may disappear quickly when potassium ions  are administered intravenously?    Connect Interactive Questions Reinforce your knowledge using  assigned interactive questions covering the structure of nervous  tissue, the generation and conduction of impulses, and the basics  of impulse integration.    Connect Integrated Activity Can you assist a neurology patient  in understanding the actions of drugs that alter neuron function  and impulse conduction?    Anatomy & Physiology Revealed Go more in depth into the  functioning of the human body by viewing animations on synapses    Falsely colored scanning electron micrograph (SEM) of the cell body of a  single neuron of the human cerebral cortex—the outer gray matter of the  brain (7,200x).    All neurons conduct action potentials, and all of theses action  potentials are the same. Yet, the nervous system can process  a wide variety of information from the external environment,  including sight, sounds, and touch on the surface of the skin. The  nervous system can also interpret information from receptors  that sense changes in the internal environment and can activate  effectors to correct those changes. Among the most fascinating  aspects of nervous system function are the abilities of the brain  to store memories and to process conscious thought.   All of these things are accomplished by neurons working in  much the same way, but serving different functions within the  brain, the spinal cord, or the peripheral nerves. This is the chap-  ter in which your brain gets to learn about itself and the other  parts of the nervous system!    After you have studied this chapter, you should be able to:    Overview of Divisions of the Nervous System  Describe the relationship among the brain, brainstem,  and spinal cord. (p. 390)    Meninges  Describe the coverings of the brain and spinal cord.  (pp. 390-391)    Ventricles and Cerebrospinal Fluid  Discuss the formation and function of cerebrospinal fluid.  (pp. 391-395)   Describe the development of the major parts of the brain  and explain the functions of each part. (p. 395)   Distinguish among sensory, association, and motor areas  of the cerebral cortex. (pp. 399-402)   Explain the stages in memory storage. (pp. 402-403)  Explain the functions of the limbic system and the reticular  formation. ( pp. 403, 405, and 407)   Describe the structure of the spinal cord and its major  functions. (pp. 409-410)   Distinguish between the major parts of the peripheral  nervous system. (p. 418)   Describe the structure of a peripheral nerve and how its  fibers are classified. (pp. 418-421)   Identify the cranial nerves and list their major functions.  (pp. 419-424)   Explain how spinal nerves are named and their functions.  (pp. 424-425)   Characterize the autonomic nervous system. (p. 431)  Distinguish between the sympathetic and the parasympathetic  divisions of the autonomic nervous system. (pp. 431-432)  Compare sympathetic and parasympathetic nerve pathways.  (pp. 431-432)    Life-Span Changes  Describe aging-associated changes in the nervous system.  (p. 438)   chiasm-, cross: optic chiasma—X-shaped  structure produced by the crossing over  of optic nerve fibers.   flacc-, flabby: flaccid paralysis—loss of tone  in muscles innervated by damaged axons.    The central nervous system (CNS) consists of the brain and the  spinal cord. The brain is the largest and most complex part of  the nervous system. It oversees many aspects of physiology, such  as sensation and perception, movement, and thinking. The brain  includes the two cerebral hemispheres, the diencephalon, the brain-  stem, and the cerebellum, all described in detail in section 11.4. The  brain contains about one hundred billion (10'') multipolar neurons  as well as countless branches of the axons by which these neurons  communicate with each other and with neurons elsewhere in the  nervous system.   Recall from chapter 10 (p. 363) that areas of the nervous  system containing mostly neuron cell bodies (and unmyelinated  axons) appear gray and are called gray matter, whereas areas con-  taining myelinated axons appear white and are called white mat-  ter. Both the brain and the spinal cord have gray matter and white  matter. In the brain, the outer layers of the cerebral hemispheres  and cerebellum are largely gray matter. White matter, representing  interconnecting axons, is found deeper, with islands of gray matter    located throughout. In the spinal cord, in contrast, gray matter (the  cell bodies of neurons) is found more centrally, with white matter  more peripheral and consisting of axons extending up to the brain  or down from the brain.   The brain connects to the spinal cord through the brainstem.  Axons conducting impulses up to the brain are bundled in ascending  tracts. Those conducting impulses down through the spinal cord are  in descending tracts. Both the brain and the spinal cord connect to  the peripheral nervous system (PNS) via peripheral nerves.   Bones, membranes, and fluid surround the organs of the CNS.  The brain lies in the cranial cavity of the skull, and the spinal cord  occupies the vertebral canal in the vertebral column. Beneath these  bony coverings, membranes called meninges, located between the  bone and the soft tissues of the nervous system, protect the brain  and spinal cord (fig. 11.14).    The meninges (sing., meninx) have three layers—dura mater,  arachnoid mater, and pia mater (fig. 11.1b). The dura mater is the  outermost layer. It is primarily composed of tough, white, dense    FIGURE 11.1 (AP|R) Meninges. (a) Membranes called meninges enclose the brain and spinal cord. (b) The meninges include three layers: dura    connective tissue and contains many blood vessels and nerves. It  attaches to the inside of the cranial cavity and forms the internal peri-  osteum of the surrounding skull bones (see reference plate 13, p. 49).   In some regions, the dura mater extends inward between  lobes of the brain and forms supportive and protective partitions  (table 11.1). In other areas, the dura mater splits into two layers,  forming channels called dural sinuses, shown in figure 11.1b.  Venous blood flows through these channels as it returns from the  brain to vessels leading to the heart.   The dura mater continues into the vertebral canal as a strong,  tubular sheath that surrounds the spinal cord. It is attached to the  cord at regular intervals by a band of pia mater (denticulate liga-  ments) that extends the length of the spinal cord on either side.  The dural sheath terminates as a blind sac at the level of the second  sacral vertebra, below the end of the spinal cord. The sheath around  the spinal cord is not attached directly to the vertebrae but is sepa-  rated by an epidural space, which lies between the dural sheath and  the bony walls (fig. 11.2). This space contains blood vessels, loose  connective tissue, and adipose tissue that pad the spinal cord.    A blow to the head may rupture some blood vessels associated  with the brain, and the escaping blood may collect beneath  the dura mater. This condition, called subdural hematoma,  can increase pressure between the rigid bones of the skull and  the soft tissues of the brain. Unless the accumulating blood is  promptly evacuated, compression of the brain may lead to func-  tional losses or even death.    The arachnoid mater is a thin, weblike membrane that does not  have blood vessels and is located between the dura and pia maters.  It spreads over the brain and spinal cord but generally does not dip  into the grooves and depressions on their surfaces. Many thin strands  extend from its undersurface and attach to the pia mater. A subarach-  noid space between the arachnoid and pia maters contains the clear,  watery cerebrospinal fluid (ser’é-bro-spi’nal floo’id), or CSF.   The subarachnoid space of the meninges completely surrounds  the brain and spinal cord, so these organs in effect float in the CSF.  The fluid protects the brain and spinal cord by absorbing forces  that might otherwise jar and damage their delicate tissues. Clinical  Application 11.1 discusses traumatic brain injury, which vividly  illustrates the importance of the cushioning function of CSF.   The pia mater is thin and contains many nerves, as well as  blood vessels that nourish the underlying cells of the brain and spi-  nal cord. The pia mater is attached to the surfaces of these organs  and follows their irregular contours, passing over the high areas  and dipping into the depressions.    Meningitis, an inflammation of the meninges usually caused by  bacterial or viral infection of the CSF, affects the arachnoid and  pia maters and sometimes the dura mater, mostly in children.  Complications include visual loss, hearing loss, paralysis, and  intellectual disability. It may be fatal. Children are vaccinated  against Haemophilus influenza type b, which was once the most  common bacterial cause of meningitis.    1 Describe the meninges.  2 Name the layers of the meninges.    CSF is formed in four interconnected cavities called ventricles  (ven’tri-klz) that lie in the cerebral hemispheres and brainstem  (fig. 11.3 and reference plates 13 and 14, p. 49). These spaces are  filled with CSF and are continuous with the central canal of the  spinal cord, which extends the full length of the cord (although in  most adults it is at least partially closed).    The man with amyotrophic lateral sclerosis (ALS, or Lou  Gehrig's disease) had been growing frustrated with his  increasing inability to carry out the activities of daily living.  He couldn’t use his hands, and his wrists were growing  weaker. A visit from an occupational therapist greatly  improved both his independence and his spirit.   The occupational therapist showed the man how to  continue to use a bathroom sink by supporting his weight on  his arms, and how to use mirrors to compensate for his neck  stiffness. The therapist was comforting and practical as he  showed the man how to repurpose metal salad tongs to  hold toilet paper to care for his bathroom needs.   An occupational therapist helps a person maintain normal  activities while struggling with a disease, injury, disability, or  other limitation. The therapist evaluates the patient’s situation  and how it is likely to change, sets goals, researches and  presents interventions and adaptive equipment that may help,  and assesses results. The therapist may also instruct family  members and caregivers on how to assist the patient.   Occupational therapists work in health-care facilities,  schools, home health services, and nursing homes. They  must have a master’s degree in occupational therapy and  state licensure.    A traumatic brain injury (TBI) results from mechanical force such as  from a fall, accident, attack, or sports-related injury. According to  the Brain Trauma Foundation, TBI in the United States is the lead-  ing cause of death and disability from ages one to forty-four years,  and is responsible for 52,000 deaths per year. More than 5 million  people have such injuries, which are classified as mild, mild repeti-  tive, or severe.   Mild TBI, also known as a concussion, produces loss of con-  sciousness or altered mental status. Its effects are more psycho-  logical than neurological, and it does not appear to cause lasting  damage. Symptoms include disturbed sleep, ringing in the ears,  memory lapse, balance problems, irritability, and sensitivity to  light and sound. These physical symptoms are heightened if the  person also suffers from depression or post-traumatic stress dis-  order (PTSD). Mild TBI may cause PTSD if, as the brain hits the  skull, the injury generates a shearing force that impairs the pre-  frontal cortex’s control of a region called the amygdala so that  it becomes overactive. As a result, the person cannot let go of  psychological trauma, which is the definition of PTSD.   A sports-related form of mild repetitive TBI is chronic trau-  matic encephalopathy (CTE). It results from many small injuries over  time, rather than a single violent blow. The first report of the condi-  tion in a medical journal appeared in 2005, regarding a player for  the National Football League, but in the 1980s CTE was recognized  in boxers and wrestlers, in whom it was called “punch-drunk syn-  drome” and “dementia pugilistica.” Symptoms typically begin years  after the first of the repetitive head injuries associated with the sport.  They include depression, impulsive and erratic behavior, headaches,  dizziness, memory loss, dementia, and loss of executive function  (ability to process information and make decisions). These difficul-  ties stem from mechanical trauma to the cortex, hematomas (bleed-  ing) in the subcortex, vasospasm, ischemia, and sudden movement  of the skull, which tears axons. The brains of people who have died  with CTE show changes characteristic of Alzheimer disease. Studies  of CTE in football players who wear helmets with sensors to record  the forces applied to their brains show that a college football player  receives on average 950 hits to the head in a season (fig. 11A).   Severe TBI is seen in combat situations, where the cause  and pattern of damage is called “blast-related brain injury.” The  damage results from a change in atmospheric pressure, a vio-  lent release of energy (sound, heat, pressure, or electromagnetic  waves), and sometimes exposure to a neurotoxin released from  the blast. Rocket-propelled grenades, improvised incendiary  devices, and land mines are the primary causes of this most dan-    The two lateral ventricles are the largest. The first ventricle  is in the left cerebral hemisphere and the second ventricle is in the  right cerebral hemisphere. They extend anteriorly and posteriorly  into the cerebral hemispheres.   A narrow space that constitutes the third ventricle is in the mid-  line of the brain beneath the corpus callosum, which is a bridge of    FIGURE 11A Chronic traumatic encephalopathy is a form of mild  repetitive traumatic brain injury seen in football players.    gerous type of TBI. The brain is initially jolted forward at a force  exceeding 1,600 feet per second, and then is hit again as air in  the cranium rushes forward.   A problem in treating blast-related brain injury is recognizing  it swiftly, because symptoms may not appear until hours after the  violent event. Whereas one soldier immediately after the blast  might be blind or deaf or unable to move or speak, another sol-  dier who has suffered similar injuries to the soft tissue of the brain  might not show such effects until later. The effects of blast-related  brain injury are lasting. Studies on veterans of the Vietnam War  indicate injury-related cognitive decline years after the injury.    axons that links the two cerebral hemispheres. This ventricle com-  municates with the lateral ventricles through openings (interventric-  ular foramina) in its anterior end.   The fourth ventricle is in the brainstem, just anterior to the  cerebellum. A narrow canal, the cerebral aqueduct (aqueduct of  Sylvius), connects the third ventricle to the fourth ventricle and    FIGURE 11.2 Meninges of the spinal cord. (a) The dura mater ensheathes the spinal cord. (b) Tissues forming a protective pad around the cord fill the  epidural space between the dural sheath and the bone of the vertebra.    ventricle walls secrete cerebrospinal fluid. Most of the  fluid circulates through the ventricles and enters the  subarachnoid space, and is reabsorbed into the blood  of the dural sinuses through arachnoid granulations.  (Spinal nerves are not shown.)    passes lengthwise through the brainstem. This ventricle is continu-  ous with the central canal of the spinal cord and has openings in its  roof that lead into the subarachnoid space of the meninges.  Structures called choroid plexuses (ko’roid plek’sus-ez) secrete  CSF. Choroid plexuses are tiny, reddish, cauliflower-like masses of  specialized capillaries from the pia mater, covered by a single layer  of specialized ependymal cells (see chapter 10, pp. 368-369). The  ependymal cells are joined closely by tight junctions. Choroid plex-  uses project into the cavities of the ventricles (fig. 11.4). In much  the same way that astrocytes provide a barrier between the blood    and the brain interstitial fluid (blood-brain barrier), ependymal cells  in the choroid plexuses block passage of water-soluble substances  between the blood and the CSF (blood-CSF barrier). At the same  time, these cells selectively transfer certain substances from the  blood into the CSF by facilitated diffusion and transfer other sub-  stances by active transport (see chapter 3, pp. 100-101 and 103),  regulating CSF composition.   CSF is a clear, somewhat viscous liquid that differs in com-  position from the fluid that leaves the capillaries in other parts  of the body. Specifically, it contains a greater concentration of    sodium and lesser concentrations of glucose and potassium than  do other extracellular fluids. Its function is nutritive as well as  protective. CSF helps maintain a stable ionic concentration in  the CNS and provides a pathway to the blood for waste. Clinical  Application 11.2 discusses the pressure that CSF generates.   Most CSF forms in the lateral ventricles, from where it slowly  circulates into the third and fourth ventricles. Small amounts  enter the central canal of the spinal cord, but most CSF circulates  through the subarachnoid space of both the brain and the spinal  cord (fig. 11.4) by passing through the wall of the fourth ventricle  near the cerebellum.   Humans secrete nearly 500 milliliters of CSF daily. However,  only about 140 milliliters are in the nervous system at any time,  because CSF is continuously reabsorbed into the blood through  tiny, fingerlike structures called arachnoid granulations that  project from the subarachnoid space into the blood-filled dural  sinuses (fig. 11.4).    4 Where are the ventricles of the brain located?  5 How does CSF form?  6 Describe the pattern of CSF circulation.    The brain contains neural centers associated with sensory func-  tions and is responsible for sensations and perceptions. It issues  motor commands to skeletal muscles and carries on higher mental  functions, such as memory and reasoning. The brain also contains  neural centers and pathways that coordinate muscular move-  ments, and others that regulate visceral activities. In addition to  overseeing the function of the entire body, the brain is responsible  for characteristics such as personality.    The term “muscle fiber” refers to an entire skeletal muscle  cell, as discussed in chapter 9 (p. 293). The term “fiber” is also  used in discussing the nervous system, but here it does not  refer to an entire cell. A “nerve fiber” is another term for the  axon of a neuron.    The basic structure of the brain reflects the way it forms during  early (embryonic) development. It begins as the neural tube that  gives rise to the central nervous system. The portion that becomes  the brain has three major cavities, or vesicles, at one end—the  forebrain (prosencephalon), midbrain (mesencephalon), and hind-  brain (rhombencephalon) (fig. 11.5). Later, the forebrain divides  into anterior and posterior portions (telencephalon and diencepha-  lon, respectively), and the hindbrain partially divides into two parts  (metencephalon and myelencephalon). The resulting five cavities  persist in the mature brain as the fluid-filled ventricles and the tubes  that connect them. Cells of the tissue surrounding the spaces differ-  entiate into the structural and functional regions of the brain.    The wall of the anterior portion of the forebrain gives rise  to the cerebrum and basal nuclei, whereas the posterior portion  forms a section of the brain called the diencephalon. The region  the midbrain produces continues to be called the midbrain in the  adult structure, and the hindbrain gives rise to the cerebellum,  pons, and medulla oblongata (fig. 11.6 and table 11.2). Together,  the midbrain, pons, and medulla oblongata comprise the brain-  stem (bran’stem), which attaches the brain to the spinal cord.   On a cellular level, the brain develops as specific neurons  attract others by secreting growth factors. In the embryo and fetus,  the brain overgrows, and then apoptosis (programmed cell death)  destroys excess cells.    The cerebrum (ser’é-brum), which develops from the anterior  portion of the forebrain, is the largest part of the mature brain.  It consists of two large masses, or cerebral hemispheres (ser’é-  bral hem’i-sférz), which are essentially mirror images of each   a tubular structure with three cavities. (b) The cavities persist as the  ventricles and their interconnections. (c) The wall of the tube gives rise to  various regions of the brain, brainstem, and spinal cord.    Cerebrospinal fluid (CSF) is secreted and reabsorbed continu-  ously, which keeps the fluid pressure in the ventricles relatively  constant. However, infection, a tumor, or a blood clot can inter-  fere with the fluid’s circulation, increasing pressure in the ven-  tricles (intracranial pressure or ICP). The pressure can collapse  cerebral blood vessels, slowing blood flow. Brain tissues forced  against the skull may be injured.   A lumbar puncture (spinal tap) measures CSF pressure. A  physician inserts a fine, hollow needle into the subarachnoid  space between the third and fourth or between the fourth  and fifth lumbar vertebrae—below the end of the spinal cord  (fig. 11B). An instrument called a manometer measures the pres-  sure of the fluid, which is usually about 130 millimeters of water  (10 millimeters of mercury). At the same time, samples of CSF    may be withdrawn and tested for abnormal constituents. Red  blood cells in the CSF, for example, may indicate a hemorrhage  in the central nervous system. A temporary drain inserted into  the subarachnoid space between the fourth and fifth lumbar ver-  tebrae can relieve pressure.   In a fetus or infant whose cranial sutures have not yet united,  increasing ICP may enlarge the cranium, causing hydrocephalus,  or “water on the brain” (fig. 11C). A shunt to relieve hydrocepha-  lus drains fluid away from the cranial cavity and into the digestive  tract, where it is either reabsorbed into the blood or excreted.    FIGURE 11B A lumbar puncture is performed by inserting a fine needle,  usually below the fourth lumbar vertebra, and withdrawing a sample of CSF  from the subarachnoid space. (For clarity, spinal nerves are not shown.)    Anterior portion Lateral ventricles Cerebrum  (telencephalon) Basal nuclei  Posterior portion Third ventricle Thalamus  (diencephalon) Hypothalamus  Posterior pituitary gland  Pineal gland  Midbrain Cerebral aqueduct  Midbrain  (mesencephalon)  Hindbrain    other (fig. 11.7 and reference plate 9, p. 46). A broad, flat bundle  of axons called the corpus callosum connects the cerebral hemi-  spheres. A layer of dura mater called the falx cerebri separates  them (see fig. 11.1).   Many ridges or convolutions, called gyri (ji’ri) (sing.,  gyrus), separated by grooves, mark the cerebrum’s surface.  Generally, a shallow to somewhat deep groove is called a sul-  cus (sul’kus; pl. sulci, sul’si), and a very deep groove is called a  fissure. The pattern of these elevations and depressions is com-  plex, but, despite individual variations, is similar in all normal  brains. For example, a /ongitudinal fissure separates the right and  left cerebral hemispheres; a transverse fissure separates the cere-  brum from the cerebellum; and sulci divide each hemisphere into  lobes (see figs. 11.6 and 11.7).    A fetus or newborn with anencephaly has a face and lower brain  structures but lacks most higher brain structures. A newborn  with this anomaly typically survives only a day or two.   Anencephaly is a type of neural tube defect (NTD). It occurs  at about the twenty-eighth day of prenatal development, when a  sheet of tissue that normally folds to form the neural tube, which  develops into the CNS, remains open at the top. In spina bifida,  an opening is farther down the neural tube, and in severe cases  may cause paralysis from that point downward. In some cases  surgery, before or shortly after birth, can partially correct spina  bifida. Taking folic acid supplements just before and during preg-  nancy can lower the risk of an NTD.   In a disorder called lissencephaly ("smooth brain”), a newborn  has a smooth cerebral cortex, completely lacking convolutions.  Absence of a protein early in prenatal development prevents cer-  tain neurons from migrating in the brain, which blocks formation  of convolutions. The child is profoundly disabled intellectually,  with frequent seizures and other neurological problems.    Most of the five lobes of the cerebral hemispheres (fig. 11.7)  are named after the skull bones that they underlie. The lobes  include the following:    1. The frontal lobe forms the anterior portion of each cerebral  hemisphere. It is bordered posteriorly by a central sulcus (fis-  sure of Rolando), which passes out from the longitudinal fis-  sure at a right angle, and inferiorly by a lateral sulcus (fissure  of Sylvius), which exits the undersurface of the brain along  its sides.   2. The parietal lobe is posterior to the frontal lobe and is sepa-  rated from it by the central sulcus.   3. The temporal lobe lies inferior to the frontal and parietal  lobes and is separated from them by the lateral sulcus.   4. The occipital lobe forms the posterior portion of each cerebral  hemisphere and is separated from the cerebellum by a shelf-  like extension of dura mater called the tentorium cerebelli.  The occipital lobe and the parietal and temporal lobes have no  distinct boundary.   5. The insula (island of Reil) is a lobe deep within the lateral  sulcus and is so named because it is covered by parts of  the frontal, parietal, and temporal lobes. A circular sulcus  separates the insula from the other lobes.    (Some sources include a sixth lobe, the limbic lobe, which is  deeper than the other lobes. This area is discussed as the “limbic  system” later in this chapter.)   A thin layer of gray matter (2 to 5 millimeters thick) called  the cerebral cortex (ser’é-bral kor’teks) constitutes the outermost  portion of the cerebrum. It covers the gyri, dipping into the sulci  and fissures. The cerebral cortex contains nearly 75% of all the  neuron cell bodies in the nervous system.   Just beneath the cerebral cortex is a mass of white mat-  ter that makes up the bulk of the cerebrum. This mass contains  bundles of myelinated axons that connect neuron cell bodies of  the cortex with other parts of the nervous system. Some of these  fibers pass from one cerebral hemisphere to the other by way of  the corpus callosum, and others carry sensory or motor impulses  from the cortex to areas of gray matter deeper in the brain or to  the spinal cord.    In a “stroke,” or cerebrovascular accident (CVA), a sudden  interruption in blood flow in a vessel supplying brain tissues  damages the cerebrum. The affected blood vessel may rup-  ture, bleeding into the brain, or be blocked by a clot. In either  case, brain tissues downstream from the vascular accident die  and some loss of function may occur. Temporary interruption  in cerebral blood flow, perhaps by a clot that quickly breaks  apart, produces a much less serious transient ischemic attack  (TIA), sometimes called a ministroke.    The cerebral cortex provides higher brain functions: interpreting  impulses from sense organs, initiating voluntary muscular move-  ments, storing information as memory, and retrieving this informa-    Skull Sulcus  Dura mater  Cerebrum  Thalamus  Diencephalon + Pineal gland  Hypothalamus  Midbrain ae  Brainstem 4 Pons callosum  Medulla Cerebellum  oblongata  ? . By 2 Spinal cord  AM i  (a)  Fornix  Cerebrum  Midbrain  Pons  Corpus  callosum  Thalamus Transverse fissure    (b)  FIGURE 11.6 (AP|R) Sagittal section of the brain and spinal cord, including the uncut medial surface of the right cerebral hemisphere.    (a) The major portions of the brain include the cerebrum, the diencephalon, the cerebellum, and the brainstem. (b) Photo of a midsagittal section  through a human brain.    FIGURE 11.7 Colors in this figure distinguish the lobes of the cerebral hemispheres. (a) Lateral view of the left hemisphere. (b) Hemispheres viewed    from above. (c) Lateral view of the left hemisphere with the insula exposed.    tion in reasoning. The cerebral cortex is also the part of the brain  responsible for intelligence and personality.   A variety of techniques are used to study the specific functions  of regions of the cerebral cortex. For example, From Science to  Technology 2.3, figure 2E (p. 78) shows how PET scans reveal the  frontal cortex turning sensations of sight, hearing, and touch into  concepts represented by words. Clues to cerebral functioning also  come from investigating deficits in people who have suffered brain  disease or injury.   In other studies, areas of cortices have been exposed surgi-  cally and stimulated mechanically or electrically. Researchers  observe the responses in certain muscles or the specific sensations  that result. Based on such investigations, researchers have divided  the cerebral cortex into sensory, association, and motor areas that  overlap somewhat. Each of these areas is a collection of neurons  that work together to provide a particular brain function.    Sensory areas in several lobes of the cerebrum receive and interpret  impulses from sensory receptors, producing feelings or sensations.  For example, the sensations of temperature, touch, pressure, and  pain in the skin arise in the postcentral gyri of the parietal lobes  posterior to the central sulcus (fig. 11.8). The posterior parts of the    occipital lobes provide vision, whereas the superior posterior por-  tions of the temporal lobes contain the centers for hearing. The sen-  sory areas for taste are near the bases of the lateral sulci and include  part of the insula. The sense of smell arises from centers deep in the  temporal lobes.   Sensory fibers from the PNS cross over in the spinal cord or the  brainstem. Thus, the centers in the right central hemisphere interpret  impulses originating from the left side of the body, and vice versa.  However, the sensory areas concerned with vision receive impulses  from both eyes, and those concerned with hearing receive impulses  from both ears.   Not all sensory areas are bilateral. The sensory speech area,  also called Wernicke’s area, is in the temporal lobe adjacent to the  parietal lobe, near the posterior end of the lateral sulcus, usually  in the left hemisphere (fig. 11.8). This area is important for under-  standing and formulating written and spoken language.    Association areas are neither primarily sensory nor motor.  They connect with each other and with other brain structures.  Association areas occupy the anterior portions of the frontal lobes  and are widespread in the lateral portions of the parietal, temporal,  and occipital lobes. Association areas analyze and interpret sen-  sory experiences and help provide memory, reasoning, verbaliz-  ing, judgment, and emotions (fig. 11.8).    Lateral view of the brain. (a) Some  sensory, association, and motor  areas of the left cerebral cortex.  (b) Photo of a human brain and  part of the spinal cord.    The association areas of the frontal lobes provide higher intel-  lectual processes, such as concentrating, planning, and complex  problem solving. The anterior and inferior portions of these lobes  (prefrontal areas) control emotional behavior and produce aware-  ness of the possible consequences of behaviors. These abilities are  also collectively called executive function.   The parietal lobes have association areas that help interpret  sensory information and aid in understanding speech and choosing  words to express thoughts and feelings. Awareness of the form of  objects, including one’s own body parts, stems from the posterior  regions of these lobes.    The association areas of the temporal lobes and the regions  at the posterior ends of the lateral sulci interpret complex sensory  experiences, such as those needed to understand speech and to read.  These regions also store memories of visual scenes, music, and  other complex sensory patterns.   The occipital lobes have association areas adjacent to the  visual centers. These are important in analyzing visual patterns  and combining visual images with other sensory experiences, such  as when one person recognizes another.   The functions of the insula are not as well known as those  of the other lobes because of the insula’s location deep within the    cerebrum. As mentioned earlier, it is the location of some sensory  areas processing taste information. Studies that use functional MRI  scanning suggest that the insula serves as a crossroads for translat-  ing sensory information into appropriate emotional responses, such  as feeling disgust at the sight of something unpleasant, or a feeling  of joy when hearing a symphony or when biting into a slice of pizza.  Some researchers hypothesize that the insula is, in some complex  way, responsible for some of the qualities that make us human.  Association areas often interact. The area where the occipital,  parietal, and temporal lobes meet processes sensory information    A person with dyslexia sees letters separately and must learn  to read differently than people whose nervous systems can  group letters into words. Three to 10% of people have dyslexia.  The condition probably has several causes, with inborn visual    and perceptual skills interacting with the way the child learns  to read. Dyslexia is not related to intelligence. Many brilliant  thinkers with dyslexia were “slow” in school because educators  did not know how to help them.    from all three of these association areas. It plays a role in integrating  visual, auditory, and other sensory information and then interpreting  a situation. For example, you hear a familiar voice, look up from  your notes, see a friend from class, and realize that it is time for  your study group.    The primary motor areas of the cerebral cortex lie in the precen-  tral gyri of the frontal lobes just in front of the central sulcus and  in the anterior wall of this sulcus (fig. 11.8). The nervous tissue in  these regions contains many large pyramidal cells, named for their  pyramid-shaped cell bodies.   Impulses from the pyramidal cells move downward through  the brainstem and into the spinal cord on descending tracts. Most  of the nerve fibers in these tracts cross over from one side of the  brain to the other within the brainstem.   Impulses conducted on these pathways in special patterns and  frequencies are responsible for movements in skeletal muscles.  More specifically, as figure 11.9 shows, cells in the upper por-  tions of the motor areas send impulses to muscles in the thighs and    FIGURE 11.9 Functional regions of the cerebral cortex. (a) Motor areas that control voluntary muscles (only left hemisphere shown). (b) Sensory areas    legs; those in the middle portions control muscles in the arms and  forearms; and those in lower portions activate muscles of the head,  face, and tongue. The relative (distorted) size of each area in the  figure reflects the extent of the cortex devoted to it.   In addition to the primary motor areas, certain other regions  of the frontal lobe control motor functions. For example, a region  called the motor speech area, also known as Broca’s area, 1s in  the frontal lobe, usually in the left hemisphere, just anterior to the  primary motor cortex and superior to the lateral sulcus. The motor  speech area is important in generating the complex pattern of mus-  cular actions of the mouth, tongue, and larynx, which make speech  possible (see fig. 11.8). Bundles of axons directly and indirectly con-  nect the motor speech area to the sensory speech area (Wernicke’s  area). Other regions of the cerebral cortex take part in the speech  process, but basically Broca’s area provides motor instructions for  written or spoken communication, whereas Wernicke’s area ensures  that the communication makes sense. For example, a person with an  injury to Broca’s area may be able to understand spoken words but  be unable to speak. A person with damage to Wernicke’s area could  initiate speech, but without control of its content.   In the superior part of the frontal lobe is a region called the fron-  tal eye field. The motor cortex in this area controls voluntary move-  ments of the eyes and eyelids. Nearby is the cortex responsible for  movements of the head that direct the eyes. Another region just ante-  rior to the primary motor area controls the muscular movements of  the hands and fingers that make such skills as writing possible (see  fig. 11.8). Table 11.3 summarizes the functions of the cerebral lobes.    An injury to a motor area of the cerebral cortex may impair the  ability to produce purposeful muscular movements. Such a con-  dition that affects use of the upper and lower limbs, head, or  eyes is called apraxia. When apraxia affects the speech muscles,  disrupting speaking ability, it is called aphasia.    Frontal Association areas carry on higher intellectual processes  lobes for concentrating, planning, complex problem solving,  and judging the consequences of behavior.   lobes touch, pressure, and pain involving the skin.  Association areas function in understanding speech  and in using words to express thoughts and feelings.   lobes nxt . :  Association areas interpret sensory experiences and  remember visual scenes, music, and other complex  sensory patterns.    7 How does the brain form during early development?  8 Describe the cerebrum.  9 List the general functions of the cerebrum.   Both cerebral hemispheres participate in basic functions, such  as receiving and analyzing sensory impulses, controlling skel-  etal muscles on opposite sides of the body, and storing memory.  However, one side usually acts as a dominant hemisphere for cer-  tain other functions.   In most people, the left hemisphere is dominant for the  language-related activities of speech, writing, and reading. It is  also dominant for complex intellectual functions requiring ver-  bal, analytical, and computational skills. In other people, the  right hemisphere is dominant, and in some, the hemispheres are  equally dominant.   The nondominant hemisphere specializes in nonverbal func-  tions, in addition to carrying on basic functions. Nonverbal func-  tions include motor tasks that require orientation of the body in  space, understanding and interpreting musical patterns, and visual  experiences. The nondominant hemisphere also provides emo-  tional and intuitive thought processes. For example, the region in  the nondominant hemisphere that corresponds to the motor speech  area does not control speech, but it influences the emotional  aspects of spoken language.   Nerve fibers of the corpus callosum, which connect the cere-  bral hemispheres, enable the dominant hemisphere to control the  motor cortex of the nondominant hemisphere. These fibers also  transfer sensory information reaching the nondominant hemi-  sphere to the general interpretative area of the dominant one,  where the information can be used in decision making.    Memory, one of the most astonishing capabilities of the brain, is  the consequence of learning. Whereas learning is the acquisition  of new knowledge, memory is the persistence of that learning,  with the ability to access it at a later time. Two stages of memory,  short term and long term, have been recognized for many years.  They differ in characteristics other than duration.   Short-term, or “working,” memories are thought to involve  neurons connected in a circuit and stimulated so rapidly that the  likelihood of neurons in the circuit reaching threshold is temporar-  ily increased. As long as the circuit is facilitated, the memory per-  sists, but if the stimulus is removed, the circuit becomes inactive.   Long-term memory can hold much more information than  short-term memory and lasts a lifetime. Some long-term memory  establishes new synaptic connections through increased branch-  ing of axons and dendrites. In another mechanism, long-term  potentiation, very rapid repeated stimulation of the same neurons  increases the number of postsynaptic neurotransmitter receptors  and causes physical changes at the synapse that make synaptic    transmission more effective. Both mechanisms—new synaptic  connections and repeated stimulation of the same neurons—fulfill  two requirements of long-term memory. First, sufficient synapses  form to encode an almost limitless number of memories. Each of  the 10 billion neurons in the cortex can make tens of thousands of  synaptic connections to other neurons, forming 60 trillion links.  Second, a certain pattern of synapses can persist for years.  Eventually memories are stored in various parts of the cere-  bral cortex in a process called memory consolidation. The hippo-  campus plays an important role in directing memory information  to the appropriate location in the cortex, although it does not actu-  ally store memories. Another area of the temporal lobe, the amyg-  dala, assigns value to a memory, such as whether it was pleasant.    Unusual behaviors and skills of people who have damaged the  hippocampus have taught researchers much about this intrigu-  ing part of the brain. In 1953, a surgeon removed parts of the  hippocampus and the amygdala of a young man to relieve  his severe epilepsy. His seizures became less frequent, but he  suffered a profound loss in the ability to consolidate short-  term memories into long-term ones. As a result, events in his  life faded quickly from his memory. He was unable to recall any  events that took place since surgery, living always as if it was  the 1950s. He would read the same magazine article repeatedly  with renewed interest each time.    The basal nuclei, also called the basal ganglia, are masses of gray  matter deep within the cerebral hemispheres. They include the cau-  date nucleus, the putamen, and the globus pallidus, and they develop  from the anterior portion of the forebrain (fig. 11.10). The basal  nuclei produce the inhibitory neurotransmitter dopamine. The neu-  rons of the basal nuclei interact with other brain areas, including  the motor cortex, thalamus, and cerebellum. These interactions,  through a combination of stimulation and inhibition, facilitate vol-  untary movement. Clinical Application 11.3 discusses Parkinson  disease, in which neurons in the basal nuclei degenerate.   14 What are the functions of the nondominant hemisphere?  15 Distinguish between short-term and long-term memory.  16 What is the function of the basal nuclei?    The diencephalon (di’en-sef’ah-lon) develops from the posterior  forebrain and is located between the cerebral hemispheres and  superior to the brainstem (see figs. 11.6 and 11.10). It surrounds  the third ventricle and is largely composed of gray matter. In the  diencephalon, a dense mass called the thalamus (thal’ah-mus)  bulges into the third ventricle from each side. Another region of    the diencephalon that includes many nuclei is the hypothalamus  (hi”po-thal’ah-mus). It lies inferior to the thalamic nuclei and  forms the lower walls and floor of the third ventricle (see reference  plates 9 and 13, pp. 46 and 49).   Other parts of the diencephalon include (1) the optic tracts,  which originate from the optic chiasma (formed by some of the  optic nerve fibers crossing over); (2) the infundibulum (pituitary  stalk), which is a conical process behind the optic chiasma to  which the pituitary gland is attached; (3) the posterior pituitary  gland, which hangs from the floor of the hypothalamus; (4) the  mammillary (mam’i-lar”e) bodies, which are two rounded struc-  tures behind the infundibulum; and (5) the pineal gland, which  forms as a cone-shaped projection from the roof of the diencepha-  lon (see chapter 13, p. 516).   The thalamus is a selective gateway for sensory impulses  ascending from other parts of the nervous system to the cerebral  cortex. It receives all sensory impulses (except those associated  with the sense of smell) and channels them to appropriate regions  of the cortex for interpretation. In addition, all regions of the  cerebral cortex can communicate with the thalamus by means of  descending fibers.   The thalamus relays sensory information by synchronizing  action potentials. Consider vision. An image on the retina stimu-  lates the lateral geniculate nucleus (LGN) region of the thalamus,  which then sends action potentials to a part of the visual cortex.  Those action potentials are synchronized—fired simultaneously—  by the LGN’s neurons only if the stimuli come from a single  object, such as a bar. If the stimulus is two black dots, the resulting  thalamic action potentials are not synchronized. The synchronic-  ity of action potentials, therefore, may be a way that the thalamus  selects which stimuli to relay to higher brain structures. Therefore,  the thalamus is not only a messenger but also an editor.   Pathways connect the hypothalamus to the cerebral cortex,  thalamus, and parts of the brainstem so that it can receive impulses  from them and send impulses to them. The hypothalamus main-  tains homeostasis by regulating a variety of visceral activities and  by linking the nervous and endocrine systems.   6. production of neurosecretory substances that stimulate the  pituitary gland to release hormones that help regulate growth,  control various glands, and influence reproductive physiology    Structures in the region of the diencephalon also are important  in controlling emotional responses. Parts of the cerebral cortex in  the medial parts of the frontal and temporal lobes connect with  the hypothalamus, thalamus, basal nuclei, and other deep nuclei.  These structures form a complex called the limbic system. It  controls emotional experience and expression and can modify  the way a person acts, producing such feelings as fear, anger,  pleasure, and sorrow. The limbic system reacts to potentially    Actor Michael J. Fox was in his late twenties when his wife noticed  the first sign of Parkinson disease (PD)—he leaned when walk-  ing. When one of his fingers began twitching, Fox consulted a  physician, and so began the journey toward his diagnosis. Of the  approximately 6 million people worldwide who have PD, only 10%  develop symptoms before the age of forty, like Michael J. Fox did.   Fox kept his diagnosis private, but by the late 1990s his co-  workers began to notice symptoms that emerged when medica-  tion wore off—rigidity, a shuffling and off-balance gait, and poor  small-motor control. Fox’s face became masklike, a characteristic  called hypomimia. It took effort to speak, a symptom called hypo-  phia. Even though his brain could string thoughts into sentences,  the muscles of his jaw, lips, and tongue could not utter them. He  also developed micrographia, or small handwriting. Fox founded  the Michael J. Fox Foundation for Parkinson’s Research, and he  continues to act on television.   In PD, neurons degenerate in the substantia nigra area of the  brainstem. Substantia nigra means “large black area,” named for  the dark pigment that the neurons release as a by-product of syn-  thesizing the neurotransmitter dopamine. When these neurons  degenerate, less dopamine reaches synapses with neurons in the  striatum of the basal nuclei. The decrease in dopamine causes the  motor symptoms of PD. Some patients develop other symptoms,  including depression, dementia, constipation, incontinence, sleep  problems, and orthostatic hypotension (dizziness upon standing).   Until recently PD was diagnosed based on neurological symp-  toms alone, because MRI and CT scans appear normal. However,  an imaging technology called SPECT (single photon emission com-  puted tomography) uses a chemical compound similar to cocaine  that binds specifically to dopamine transporter molecules in the  striatum, marking them. This compound used with SPECT is called  a DatTscan. It distinguishes tremors that are specifically due to PD,  which is useful both for diagnosis and in research to ensure that  people in clinical trials to evaluate PD treatments actually have PD.    FIGURE 11D Professional boxers are at higher risk of developing  Parkinson disease (PD) from repeated blows to the head. Muhammad Ali  has PD from many years of head injuries. Michael J. Fox, an actor, nota  boxer, first experienced symptoms of PD at age 29, which is unusual.    So far, no treatments can cure or slow the course of PD, but  replacing or enhancing use of dopamine can temporarily allevi-  ate symptoms. The standard treatment for many years has been  levodopa, a precursor to dopamine that crosses the blood-  brain barrier. In the brain, levodopa is converted to dopamine.  Levodopa provides temporary relief from twitching and rigidity.   Drug treatment for PD becomes less effective over time. By  a feedback mechanism the brain senses the external supply of  dopamine and decreases its own production, so that eventually  higher doses of levodopa are needed to achieve the effect. Taking  too much levodopa leads to another condition, tardive dyskine-  sia, that produces uncontrollable facial tics and spastic extensions  of the limbs. Tardive dyskinesia may result from effects of excess  dopamine in brain areas other than those affected in PD.   Surgery can alleviate Parkinson’s symptoms. Fox underwent  thalamotomy, in which an electrode caused a lesion in his thal-  amus that calmed violent shaking in his left arm. Another surgi-  cal procedure, pallidotomy, causes lesions in the globus pallidus  internus, a part of the basal nuclei, and the approach is also used  on an area posterior to the thalamus. Deep brain stimulation from  implants of electrodes may also control some symptoms.   Researchers are turning to cells in a patient's body as sources of  dopamine. For example, cells in the eye's retinal pigment epithelium  (chapter 12, pp. 478-479) can be cultured with biochemicals that  stimulate them to produce dopamine or levodopa. Perhaps cells can  be sampled from the patient without impairing vision and implanted  in the substantia nigra. Neural stem and progenitor cells may also be  useful. Implants of fetal dopamine-producing cells performed in the  late 1990s alleviated symptoms in some patients for several years.   PD has been attributed to use of certain drugs, exposure to  pesticides, and frequent violent blows to the head (fig. 11D), per-  haps combined with inherited susceptibility. For example, people  with a certain genetic makeup are two to six times more likely than  other individuals to develop PD after prolonged exposure to any  of a dozen types of pesticides. However, most cases of PD are not  directly inherited. One gene that causes PD when mutant encodes a  protein called alpha-synuclein. The abnormal protein folds improp-  erly, forming deposits in the brain called Lewy bodies (fig. 11E).    FIGURE 11E The chemical composition of Lewy bodies,  characteristic of the brains of some people with Parkinson disease,  may provide clues to the cause of the condition. Lewy bodies include  alpha-synuclein and other components.    FIGURE 11.10 (AP|R} Basal nuclei.  (a) A dorsal view of a frontal section of  the left cerebral hemisphere reveals  some of the basal nuclei, and (b) a  ventral view of a frontal section of    life-threatening upsets in a person’s physical or psychological  condition. By causing pleasant or unpleasant feelings about expe-  riences, the limbic system guides behavior that may increase the  chance of survival. In addition, parts of the limbic system interpret  sensory impulses from the receptors associated with the sense of  smell (olfactory receptors).    The brainstem connects the brain to the spinal cord. It consists  of the midbrain, pons, and medulla oblongata. These structures  include many tracts of nerve fibers and masses of gray matter  called nuclei (see figs. 11.6, 11.10, and 11.11).    The midbrain (mesencephalon) is a short section of the brainstem  between the diencephalon and the pons. It contains bundles of  myelinated nerve fibers that join lower parts of the brainstem and  spinal cord with higher parts of the brain. The midbrain includes  several masses of gray matter that serve as reflex centers. It also  contains the cerebral aqueduct that connects the third and fourth  ventricles (fig. 11.12).   Two prominent bundles of nerve fibers on the underside of the  midbrain comprise the cerebral peduncles. These fibers include  descending tracts and are the main motor pathways between the  cerebrum and lower parts of the nervous system (see fig. 11.11).    FIGURE 11.11 fAP|R) Brainstem.  (a) Ventral view of the brainstem. (b) Dorsal  view of the brainstem with the cerebellum  removed, exposing the fourth ventricle.    Beneath the cerebral peduncles are large bundles of sensory fibers  that carry impulses upward to the thalamus.   Two pairs of rounded knobs on the superior surface of the  midbrain mark the location of four nuclei, known collectively as  corpora quadrigemina. The upper masses (superior colliculi) con-  tain the centers for certain visual reflexes, such as those respon-  sible for moving the eyes to view something as the head turns. The  lower ones (inferior colliculi) contain the auditory reflex centers  that operate when it is necessary to move the head to hear sounds  more distinctly (see fig. 11.11).   Near the center of the midbrain is a mass of gray matter called  the red nucleus. This nucleus communicates with the cerebellum  and with centers of the spinal cord, and it plays a role in reflexes  that maintain posture. It appears red because it is richly supplied  with blood vessels.   The pons appears as a rounded bulge on the underside of the brain-  stem where it separates the midbrain from the medulla oblongata  (see fig. 11.11). The dorsal portion of the pons consists mostly of    longitudinal nerve fibers, which relay information between the  medulla oblongata and the cerebrum. Its ventral portion contains  large bundles of transverse nerve fibers, which conduct impulses  from the cerebrum to centers within the cerebellum.   Several nuclei of the pons relay sensory information from  peripheral nerves to higher brain centers. Other nuclei may func-  tion with centers of the medulla oblongata to control breathing.    The medulla oblongata (mé-dul’ah ob” long-ga’tah) is an enlarged  continuation of the spinal cord, extending from the level of the  foramen magnum to the pons (see fig. 11.11). Its dorsal surface  flattens to form the floor of the fourth ventricle, and its ventral sur-  face is marked by descending tracts, most of whose fibers cross  over at this level. On each side of the medulla oblongata is an oval  swelling called the olive, from which a large bundle of nerve fibers  arises and passes to the cerebellum.   The ascending and descending nerve fibers connecting the  brain and spinal cord must pass through the medulla oblongata  because of its location. As in the spinal cord, the white matter of the    medulla surrounds a central mass of gray matter. Here, however, the  gray matter breaks up into nuclei separated by nerve fibers. Some  of these nuclei relay ascending impulses to the other side of the  brainstem and then on to higher brain centers. The nucleus gracilis  and the nucleus cuneatus, for example, receive sensory impulses  from fibers of ascending tracts and pass them on to the thalamus or  the cerebellum.   Other nuclei in the medulla oblongata control vital visceral  activities. These reflex centers include the following:    1. Peripheral nerves conduct impulses originating in the cardiac  center to the heart, where they increase or decrease heart rate.  2. Certain cells of the vasomotor center initiate impulses  that affect smooth muscle in the walls of blood vessels  and stimulate them to contract, constricting the vessels  (vasoconstriction) and thereby increasing blood pressure.  A decrease in the activity of these cells can produce the  opposite effect—dilation of the blood vessels (vasodilation)  and a consequent drop in blood pressure.  3. The respiratory center maintains the basic rhythm of  breathing and adjusts the rate and depth of breathing to  meet changing needs.    Some nuclei in the medulla oblongata are centers for certain  nonvital reflexes, such as those associated with coughing, sneezing,  swallowing, and vomiting. However, because the medulla also  contains vital reflex centers, injuries to this part of the brainstem  are often fatal.   Scattered throughout the medulla oblongata, pons, and midbrain  is a complex network of nerve fibers associated with tiny islands  of gray matter. This network, the reticular formation (ré-tik’u-    extends from the superior portion of the spinal cord into the diencephalon.    lar for-ma’shun), or reticular activating system, extends from the  superior portion of the spinal cord into the diencephalon (fig.  11.12). Its neurons connect centers of the hypothalamus, basal  nuclei, cerebellum, and cerebrum with all of the major ascending  and descending tracts.   When sensory impulses reach the reticular formation, it  responds by activating the cerebral cortex into a state of wakeful-  ness. Without this arousal, the cortex remains unaware of stimula-  tion and cannot interpret sensory information or carry on thought  processes. Decreased activity in the reticular formation results in  sleep. If the reticular formation is injured and ceases to function,  the person remains unconscious, even with strong stimulation.  This is called a comatose state. The term ascending reticular acti-  vating system refers to this functional aspect of the reticular for-  mation. Without it the cerebral cortex cannot function consciously.   The reticular formation filters incoming sensory impulses.  Impulses judged to be important, such as those originating in pain  receptors, are passed on to the cerebral cortex, while others are dis-  regarded. This selective action of the reticular formation frees the  cortex from what would otherwise be a continual bombardment of  sensory stimulation and allows it to concentrate on more signifi-  cant information. Because the cerebral cortex can also activate the  reticular formation, intense cerebral activity keeps a person awake.  In addition, the reticular formation, through connections with the  basal nuclei and the motor cortex, influences motor activities to  ensure that skeletal muscles move together evenly. The reticular  formation also inhibits or enhances certain spinal reflexes.    A person in a persistent vegetative state may occasionally be  awake and responsive to stimuli, but is not aware; a person ina  coma does not appear awake and is not aware. In some cases fol-  lowing a severe injury, a person will become comatose and then  gradually enter a persistent vegetative state. Persistent vegeta-  tive state and coma are also seen in the end stage of neurode-  generative disorders such as Alzheimer disease; when there is an  untreatable mass in the brain, such as a blood clot or tumor; and  in anencephaly, when a newborn lacks higher brain structures.   The two types of normal sleep are non-rapid eye movement (non-  REM) and rapid eye movement (REM). Non-REM sleep occurs  when a person is very tired, and it reflects decreasing activity of the  reticular formation. It is restful, dreamless, and accompanied by  reduced blood pressure and respiratory rate. Non-REM sleep may  range from light to heavy and is described in three stages. The third  stage is also known as slow-wave sleep. It may last from seventy to  ninety minutes. Non-REM and REM sleep alternate.   REM sleep is also called “paradoxical sleep” because some  areas of the brain are active. As its name implies, the eyes can be  seen rapidly moving beneath the eyelids. Cats and dogs in REM  sleep sometimes twitch their limbs. In humans, REM sleep usually  lasts from five to fifteen minutes. This “dream sleep” is important.  If a person lacks REM sleep for just one night, sleep on the next    night makes up for it. During REM sleep, heart and respiratory Cerebellum  rates are irregular. Marijuana, alcohol, and certain other drugs,  such as benzodiazepines, interfere with REM sleep. Table 11.4  describes several disorders of sleep.    The cerebellum (ser’é-bel’um) is a large mass of tissue inferior  to the occipital lobes of the cerebrum and posterior to the pons  and medulla oblongata (fig. 11.13). It consists of two lateral hemi-  spheres partially separated by a layer of dura mater called the falx    17 What are the major functions of the thalamus? of the hypothalamus? hemispheres at the midline.  Like the cerebrum, the cerebellum is primarily composed of    white matter with a thin layer of gray matter, the cerebellar cor-  tex, on its surface. This cortex doubles over on itself in a series  of complex folds that have myelinated nerve fibers branching into  them. A cut into the cerebellum reveals a treelike pattern of white  matter, called the arbor vitae, surrounded by gray matter. A number    18 How may the limbic system influence a person’s behavior?  19 Which vital reflex centers are located in the brainstem?  20 What is the function of the reticular formation?    Fatal familial insomnia Inability to sleep; emotional instability; hallucinations; stupor; coma; death within Very rare  thirteen months of onset around age fifty; both slow-wave and REM sleep abolished    Narcolepsy Abnormal REM sleep causes extreme daytime sleepiness, begins between ages of  0.02-0.06%  fifteen and twenty-five    Obstructive sleep apnea Upper airway collapses repeatedly during sleep, blocking breathing; snoring and 4-5%  syndrome daytime sleepiness    Parasomnias Sleepwalking; sleeptalking; and night terrors <5% of children  REM-sleep behavior disorder Excessive motor activity during REM sleep, which disturbs continuous sleep Very rare    Restless legs syndrome Brief, repetitive leg jerks during sleep; leg pain forces person to get up several 5.5%  times a night    Sleep paralysis Inability to move for up to a few minutes after awakening or when falling asleep Very rare    FIGURE 11.13 The cerebellum, located inferior to the occipital lobes of the cerebrum, communicates with other parts of the nervous system by means  of the cerebellar peduncles.    of nuclei lie deep within each cerebellar hemisphere. The largest  and most important is the dentate nucleus.   The cerebellum communicates with other parts of the CNS  by means of three pairs of nerve tracts called cerebellar pedun-  cles (ser”é-bel’ar pe-dung’kls) (fig. 11.13). One pair, the inferior  peduncles, brings sensory information concerning the position of  body parts such as limbs and joints to the cerebellum via the spinal  cord and medulla oblongata. The middle peduncles send informa-  tion from the cerebral cortex about the desired position of these  body parts. After integrating and analyzing the information from  these two sources, the cerebellum sends correcting impulses from  the dentate nucleus via the superior peduncles to the thalamus and  eventually to the motor cortex (fig. 11.13). These corrections are  incorporated into motor impulses that travel downward through the  pons, medulla oblongata, and spinal cord to lower motor neurons in  the appropriate patterns to move the body in the desired way.   Overall, the cerebellum integrates sensory information con-  cerning the position of body parts and coordinates skeletal muscle  activity and maintains posture. It receives sensory impulses from  receptors in muscles, tendons, and joints (proprioceptors) and  from special sense organs, such as the eyes and ears. For exam-  ple, the cerebellum uses sensory information from the semicir-  cular canals of the inner ears concerning the motion and position  of the head to help maintain equilibrium (see chapter 12, p. 466).  Damage to the cerebellum can cause tremors, inaccurate move-  ments of voluntary muscles, loss of muscle tone, a reeling walk,  and loss of equilibrium.   Table 11.5 summarizes the characteristics and functions of  the major parts of the brain. Clinical Application 11.4 discusses  how brain waves reflect brain activity.    22 Where is the cerebellum located?  23 What are the major functions of the cerebellum?    The spinal cord is a slender column of nervous tissue that is continu-  ous with the brain and extends downward through the vertebral canal.  The spinal cord originates where nervous tissue leaves the cranial cav-  ity at the level of the foramen magnum (see reference plate 15, p. 50).  The cord tapers to a point and terminates near the intervertebral disc  that separates the first and second lumbar vertebrae (fig. 11.14a).    The spinal cord consists of thirty-one segments, each of which gives  rise to a pair of spinal nerves. These nerves branch to various body  parts and connect them with the CNS.   In the neck region, a thickening in the spinal cord, called the  cervical enlargement, supplies nerves to the upper limbs. A simi-  lar thickening in the lower back, the Jumbar enlargement, gives off  nerves to the lower limbs. Just inferior to the lumbar enlargement,  the spinal cord tapers to a structure called the conus medullaris. From  this tip, nervous tissue, including axons of both motor and sensory  neurons, extends downward within the vertebral canal to become  spinal nerves at the remaining lumbar and sacral levels. The result-  ing structure resembles a horse’s tail, and is called the cauda equina.  A thin cord of connective tissue originating from the pia mater and    Largest part of the brain; two hemispheres  connected by the corpus callosum    a. Midbrain Contains masses of gray matter and bundles of nerve  fibers that join the spinal cord to higher regions of  the brain   b. Pons A bulge on the underside of the brainstem that  contains masses of gray matter and nerve fibers    A large mass of tissue inferior to the cerebrum and  posterior to the brainstem; includes two lateral  hemispheres connected by the vermis    Controls higher brain functions, including interpreting sensory  impulses, initiating muscular movements, storing memory, reasoning,  and intelligence    Relay stations for motor impulses originating in the cerebral cortex  and passing into the brainstem and spinal cord; facilitate and help  coordinate voluntary movement    The thalamus is a relay station for sensory impulses ascending  from other parts of the nervous system to the cerebral cortex; the  hypothalamus helps maintain homeostasis by regulating visceral  activities and by linking the nervous and endocrine systems    Contains reflex centers that move the eyes and head; maintains  posture    Relays impulses between the medulla oblongata and cerebrum;  helps regulate rate and depth of breathing    Conducts ascending and descending impulses between the brain  and spinal cord; contains cardiac, vasomotor, and respiratory control  centers and various nonvital reflex control centers    Communicates with other parts of the CNS by tracts; integrates  sensory information concerning the position of body parts;  coordinates muscle activities and maintains posture    Brain waves are recordings of fluctuating electrical changes in the  brain. To obtain such a recording, electrodes are positioned on  the surface of a surgically exposed brain (an electrocorticogram,  ECoG) or on the outer surface of the head (an electroencepha-  logram, EEG). These electrodes detect electrical changes in the  extracellular fluid of the brain in response to changes in poten-  tial among large groups of neurons. The resulting signals from the  electrodes are amplified and recorded. Brain waves originate from  the cerebral cortex but also reflect activities in other parts of the  brain that influence the cortex, such as the reticular formation.  Because the intensity of electrical changes is proportional to the  degree of neuronal activity, brain waves vary markedly in ampli-  tude and frequency between sleep and wakefulness.   Brain waves are classified as alpha, beta, theta, and delta  waves (fig. 11F). Aloha waves are recorded most easily from the  posterior regions of the head and have a frequency of 8-13 cycles  per second. They occur when a person is awake but resting, with  the eyes closed. These waves disappear during sleep, and if the  wakeful person’s eyes open, higher-frequency beta waves replace  the alpha waves.   Beta waves have a frequency of more than 13 cycles per sec-  ond. Most are recorded in the anterior region of the head. They  occur when a person is actively engaged in mental activity or is  under tension.   Theta waves have a frequency of 4-7 cycles per second and  occur mainly in the parietal and temporal regions of the cere-  brum. They are normal in children but do not usually occur in  adults. However, some adults produce theta waves in early stages  of sleep or at times of emotional stress.   Delta waves have a frequency below 4 cycles per second and  happen during sleep. They originate from the cerebral cortex  when the reticular formation is not activating it.   Brain wave patterns can be useful for diagnosing disease  conditions, such as distinguishing types of seizure disorders  (epilepsy) and locating brain tumors. Brain waves are also used  to detect brain death, in which neuronal activity ceases. In some    dura mater descends to the upper surface of the coccyx. This cord,  called the filum terminale, anchors the spinal cord (fig. 11.14).   Two grooves, a deep anterior median fissure and a shallow pos-  terior median sulcus, extend the length of the spinal cord, dividing  it into right and left halves. A cross section of the cord (fig. 11.15)  reveals that it consists of white matter surrounding a core of gray  matter. The pattern the gray matter produces roughly resembles a  butterfly with its wings spread. These posterior and anterior “wings”  of gray matter are called the posterior horns and the anterior horns,  respectively. Between them on either side in some regions is a pro-  trusion of gray matter called the lateral horn. Motor neurons with  relatively large cell bodies in the anterior horns (anterior horn cells)  give rise to axons that pass out through spinal nerves to various skel-  etal muscles. However, the majority of neurons in the gray matter  are interneurons (see chapter 10, pp. 366 and 368).    countries including the United States, an EEG that lacks waves  (isoelectric EEG) verifies brain death. However, drugs that greatly  depress brain functions must be excluded as the cause of the flat  EEG pattern before confirming brain death.    FIGURE 11F Brain waves record fluctuating electrical changes in  the brain.    A horizontal bar of gray matter in the middle of the spinal  cord, the gray commissure, connects the wings of the gray matter  on the right and left sides. This bar surrounds the central canal,  which is continuous with the ventricles of the brain and contains  CSF. The central canal is prominent during embryonic develop-  ment, but it becomes almost microscopic in adulthood.   The gray matter divides the white matter of the spinal cord  into three regions on each side—the anterior, lateral, and poste-  rior funiculi. Each funiculus, or column, consists of longitudinal  bundles of myelinated nerve fibers that compose the major path-  ways called tracts.    The spinal cord has two main functions. It is a center for spinal  reflexes, and it is a conduit for impulses to and from the brain.    FIGURE 11.14 (AP|R) Spinal cord. (a) The spinal cord begins at the level of the foramen magnum. (b) Posterior view of the spinal cord with the   Communication in the nervous system combines a series of action  potentials along the axon of a neuron and synaptic transmission  between that neuron and a postsynaptic cell. Two or more neurons  involved in such communication constitute a nerve pathway. The  simplest of the nerve pathways begins with a sensory receptor and  ends with an effector, and includes as few as two neurons. Such a  nerve pathway is called a reflex (re’fleks).   All reflexes share the same basic components, which together  are known as a reflex arc, as figure 11.16a shows. A reflex arc  begins with a sensory receptor at the dendritic end of a sensory  neuron. Impulses on these sensory neurons enter the CNS and con-  stitute a sensory or afferent limb of the reflex. The CNS is a pro-  cessing center. Afferent neurons may synapse with interneurons,  which may in turn connect with other parts of the CNS. Afferent  neurons or interneurons ultimately connect with motor neurons,    whose fibers pass outward from the CNS to effectors. (It may help  to remember that efferent neurons control effector organs.)   Reflexes occur throughout the CNS. Those that involve the  spinal cord are called spinal reflexes and reflect the simplest level  of CNS function. Figure 11.16b shows the general components of  a spinal reflex.    Reflexes are automatic responses to changes (stimuli) inside or  outside the body. They help maintain homeostasis by controlling  many involuntary processes such as heart rate, breathing rate,  blood pressure, and digestion. Reflexes also carry out the auto-  matic actions involved in swallowing, sneezing, coughing, and  vomiting.   The patellar reflex (knee-jerk reflex) is an example of a simple  monosynaptic reflex, so-called because it uses only two neurons—a    FIGURE 11.15 (AP|R} Spinal cord. (a) A cross section of the spinal cord. (b) Identify the parts of the spinal cord in this micrograph (7.5x).    © Where would you expect to find the cell bodies of neurons in the above figure?    sensory neuron communicating directly to a motor neuron. Striking  the patellar ligament just below the patella initiates this reflex. The  quadriceps femoris muscle group, attached to the patella by a tendon,  is pulled slightly, stimulating stretch receptors in the muscle group.  These receptors, in turn, trigger impulses that pass along the periph-  eral process (see fig. 10.6c, p. 366) of the axon of a unipolar sensory  neuron, continuing along the central process of the axon into the lum-  bar region of the spinal cord. In the spinal cord, the sensory neuron  axon synapses with a motor neuron. An impulse is then triggered on  the motor neuron and is conducted along its axon to the neuromuscu-  lar junctions in that motor unit of the quadriceps femoris. The muscle  fibers involved respond by contracting, and the reflex is completed as  the leg extends (fig. 11.17).   The patellar reflex helps maintain an upright posture. For  example, if a person is standing still and the knee begins to bend    in response to gravity, the quadriceps femoris is stretched, the  reflex is triggered, and the leg straightens again. Adjustments  within the stretch receptors keep the reflex responsive at differ-  ent muscle lengths.   Another type of reflex, called a withdrawal reflex (fig. 11.18),  happens when a person touches something painful (and poten-  tially damaging), as in stepping on a tack. Activated skin receptors  send impulses to the spinal cord along the axons of sensory neu-  rons. There the sensory neurons synapse with interneurons, which  in turn synapse with motor neurons. The motor neurons activate  fibers in the flexor muscles of the leg and thigh, which contract in  response, pulling the foot away from the painful stimulus.   At the same time, some of the incoming sensory impulses  stimulate interneurons that inhibit the action of the antagonis-  tic extensor muscles (reciprocal innervation). This inhibition of    antagonists allows the flexor muscles to effectively withdraw the  affected part (fig. 11.19).   While flexor muscles on the affected side (ipsilateral side)  contract, the flexor muscles of the limb on the other side (contra-  lateral side) are inhibited. Furthermore, the extensor muscles on  the contralateral side contract, helping to support the body weight  shifted to that side. This phenomenon, called a crossed extensor  reflex, is due to interneuron pathways in the spinal cord that allow  sensory impulses arriving on one side of the cord to pass across to  the other side and produce an opposite effect (fig. 11.19). Reflexes  like these can be found at different levels of the spinal cord and in  the brain, depending on which body parts are involved.   Concurrent with the withdrawal reflex, other interneurons in  the spinal cord carry sensory impulses upward to the brain. The  person becomes aware of the experience and may feel pain.   A withdrawal reflex protects because it prevents or limits  tissue damage when a body part touches something potentially  harmful. Table 11.6 summarizes the components of a reflex arc.  Clinical Application 11.5 discusses some familiar reflexes.    The receptor end of a  dendrite or a specialized  receptor cell ina  sensory organ    Dendrite, cell body, and  axon of a neuron within  the brain or spinal cord    FIGURE 11.16 fAP|R) Reflex arc. (a) Schematic of a reflex arc. (b) A  reflex arc usually includes a receptor (1), a sensory neuron (2), integration  within the CNS involving at least one synapse (3), a motor neuron (4), and  an effector (5). In this example, a spinal reflex, the integration center is in    Conducts an impulse  from the receptor into  the brain or spinal cord    Serves as processing  center; conducts an  impulse from the sensory  neuron to its synapse  with a motor neuron    Conducts an impulse  from the brain or spinal  cord out to the synapse  with an effector    Responds to stimulation  by the motor neuron  and produces the reflex  or behavioral action    Normal reflexes require and reflect normal neuron functions.  Therefore, reflexes are commonly used to assess the condition of  the nervous system. An anesthesiologist, for instance, initiates a  reflex in a patient being anesthetized to determine how the anes-  thetic drug is affecting nerve functions. A physician assessing  a patient with injury to the nervous system observes reflexes to  judge the location and extent of damage.   Injury to any component of a reflex arc alters its function. For  example, stroking the sole of the foot normally initiates a plantar  reflex, which flexes the foot and toes. Damage to certain nerve  pathways (corticospinal tract) may trigger an abnormal response  called the Babinski reflex, which is a dorsiflexion that extends the  great toe upward and fans apart the smaller toes. If the injury is  minor, the response may consist of plantar flexion with failure of the  great toe to flex, or plantar flexion followed by dorsiflexion. The  Babinski reflex is normally present in infants up to the age of twelve  months and may reflect immaturity in their corticospinal tracts.   Other reflexes that may be tested during a neurological  examination include the following:    1. The biceps-jerk reflex is elicited by extending a person's  forearm at the elbow. The examiner places a finger on the    inside of the extended elbow over the tendon of the biceps  muscle and taps the finger. The biceps contracts in response,  flexing at the elbow.    . The triceps-jerk reflex is elicited by flexing a person's forearm    at the elbow and tapping the short tendon of the triceps  muscle close to its insertion near the tip of the elbow. The  muscle contracts in response, extending the elbow.    skin of the abdomen. For example, a dull pin drawn from  the sides of the abdomen upward toward the midline and  above the umbilicus contracts the abdominal muscles  underlying the skin, and the umbilicus moves toward the  stimulated region.    tendon just above its insertion on the calcaneus.  Contraction of the gastrocnemius and soleus muscles  causes plantar flexion.    . The cremasteric reflex is elicited in males by stroking the    upper inside of the thigh. In response, contracting muscles  elevate the testis on the same side.    FIGURE 11.17 The patellar reflex involves two neurons—a sensory neuron  and a motor neuron. Note the single synapse in the spinal cord.    Interneuron  _  Spinal cord  Axon of  Effector (flexor motor neuron Cell body of  muscles contract motor neuron  and withdraw part  being stimulated)  Dendrite of =  sensory  neuron Cell body of  ) sensory neuron  Pain  receptor - <  in skin _ f  Tack = .  —> Axon of sensory neuron  FIGURE 11.18 A withdrawal reflex involves a sensory neuron, an interneuron, and a motor neuron.  Stimulation = Interneuron  Inhibition    contracts. This helps to maintain balance. For simplicity, only the thigh muscles are shown.    FIGURE 11.19 When the flexor muscle on one side is stimulated to contract in a withdrawal reflex, the extensor muscle on the opposite side also    28 Describe the actions that are part of a withdrawal reflex.    The tracts of the spinal cord together with the spinal nerves pro-  vide a two-way communication system between the brain and  body parts outside the nervous system. The spinal tracts that con-  duct sensory information to the brain are called ascending tracts;  those that conduct impulses from the brain to motor neurons  reaching muscles and glands are descending tracts (fig. 11.20).   The ascending and descending tracts are comprised of axons.  Many of the names that identify nerve tracts reflect common ori-  gins and terminations. For example, a spinothalamic tract begins  at various levels of the spinal cord and conducts sensory impulses  associated with the sensations of pain and touch to the thalamus.  A corticospinal tract originates in the cerebral cortex and con-  ducts motor impulses on so-called upper motor neurons down-  ward through the spinal cord. These impulses control lower motor  neurons at various levels of the spinal cord whose cell bodies are  in the anterior horn and whose axons lead to skeletal muscles.   Ascending pathways typically involve three neurons between  a sensory receptor and the final destination of impulses within the  brain—the peripheral sensory neuron and two interneurons. Among  the major ascending tracts of the spinal cord are the following:    1. Fasciculus gracilis (fah-sik’u-lus gras’il-is) and fasciculus  cuneatus (ku’ne-at-us) are tracts in the posterior funiculi  of the spinal cord (fig. 11.20). Their fibers conduct sensory  impulses from the skin, muscles, tendons, and joints to the  brain, where they are interpreted as sensations of touch,  pressure, and body movement.    At the base of the brain in the medulla oblongata most  of the fasciculus gracilis and fasciculus cuneatus fibers cross  (decussate) from one side to the other—that is, those ascend-  ing on the left side of the spinal cord pass across to the right  side, and vice versa. As a result, the impulses originating  from sensory receptors on the left side of the body reach the  right side of the brain, and those originating on the right side  of the body reach the left side of the brain (fig. 11.21).   2. The lateral and anterior spinothalamic (spi”no-thah-lam’ik)  tracts are in the lateral and anterior funiculi, respectively (see  fig. 11.20). The lateral tracts conduct impulses from various  body regions to the brain and give rise to sensations of pain  and temperature. Impulses conducted on fibers of the anterior  tracts are interpreted as touch and pressure. Impulses in these  tracts cross over in the spinal cord (fig. 11.21).   3. The posterior and anterior spinocerebellar (spi’no-ser”é-  bel’ar) tracts lie near the surface in the lateral funiculi of  the spinal cord (see fig. 11.20). Fibers in the posterior tracts  remain uncrossed, whereas those in the anterior tracts cross  over in the medulla. Impulses conducted on their fibers  originate in the muscles of the lower limbs and trunk and  then travel to the cerebellum. These impulses coordinate  muscular movements.    The major descending tracts of the spinal cord include the following:    1. The lateral and anterior corticospinal (kor’ti-ko-spi’nal)  tracts occupy the lateral and anterior funiculi, respectively  (see fig. 11.20). Most of the fibers of the lateral tracts cross  over in the lower medulla oblongata. Some fibers of the  anterior tracts cross over at various levels of the spinal cord  (fig. 11.22). Axons in the corticospinal tracts conduct motor  impulses from the brain and synapse either directly or through  interneurons with lower motor neurons, whose axons continue  through spinal nerves to various skeletal muscles (fig. 11.22).  Thus, they carry instructions that control voluntary movements.    FIGURE 11.20 Major ascending and descending tracts in a cross section of the spinal cord. Ascending tracts are in pink, descending tracts in light  brown. (Tracts are shown only on one side.) The pattern varies with the level of the spinal cord. This pattern is representative of the midcervical region.    section)  = Thalamus  Midbrain  Lateral  spinothalamic  tract  Brainstem —J  (transverse  sections)  eee Fasciculus  cuneatus  tract  Medulla  | oblongata Sensory impulse  from temperature  or pain receptors  in skin  Spinal cord    FIGURE 11.21 Sensory impulses originating in skin touch receptors  ascend in the fasciculus cuneatus tract and cross over in the medulla   of the brain. Pain and temperature information ascends in the lateral  spinothalamic tract, which crosses over in the spinal cord.    The corticospinal tracts are also called pyramidal tracts  after the pyramid-shaped regions in the medulla oblongata  through which they pass. Other descending tracts are called  extrapyramidal tracts, and they include the reticulospinal and  rubrospinal tracts.   2. The lateral reticulospinal (ré-tik”u-lo-spi’nal) tracts are in  the lateral funiculi, whereas the anterior and medial reticulo-  spinal tracts are in the anterior funiculi (see fig. 11.20). Some  fibers in the lateral tracts cross over, whereas others remain   the cerebral cortex, cross over in the medulla, and descend in the spinal  cord, where they synapse with neurons whose fibers lead to spinal nerves  supplying skeletal muscles. Some fibers cross over in the spinal cord.    uncrossed. Those of the anterior and medial tracts remain  uncrossed. Motor impulses conducted on the reticulospinal  tracts originate in the brain and control muscular tone and  activity of sweat glands.   3. The fibers of the rubrospinal (roo”bro-spi’nal) tracts  cross over in the brain and pass through the lateral funiculi  (see fig. 11.20). They conduct impulses from the brain to  synapses with lower motor neurons, and help to coordinate  muscle actions.    Table 11.7 summarizes the nerve tracts of the spinal cord.  Clinical Application 11.6 describes injuries to the spinal cord.    A hemi-lesion of the spinal cord (severed on one side) affect-  ing the corticospinal and spinothalamic tracts can cause Brown-  Séquard syndrome. Ascending tracts cross over at different  levels, so the injured side of the body becomes paralyzed and  loses touch sensation. The other side of the body retains move-  ment but loses sensations of pain and temperature.    29 Describe the structure of the spinal cord.  30 What are ascending and descending tracts?  31 What is the consequence of fibers crossing over?    32 Name the major tracts of the spinal cord, and list the types of  impulses each conducts.    In amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease, or  motor neuron disease), motor neurons in the spinal cord, brain-  stem, and cerebral cortex degenerate. The disease may be due  to an inability of the motor neurons or associated astrocytes  to counter buildup of oxygen free radicals, or to overreactive  microglia that kill motor neurons.   The first symptoms of ALS may be vague and affect only  a small part of the body: difficulty speaking, a dragging foot,  clumsiness, fatigue, or problems with fine coordination such  as turning a key or pulling a zipper. Muscle twitches (fas-  ciculations) may prompt the person to seek medical atten-  tion. Diagnosis may take more than a year as a neurologist  observes spreading weakness and rules out other conditions,  such as multiple sclerosis or a spinal cord tumor. The aver-  age age at diagnosis is 55, but adolescents as well as the very  elderly have developed ALS.   ALS affects the upper and lower parts of the body, and  progresses faster if symptoms begin in the face or neck (bul-  bar onset) compared to the arms and legs (limb onset). Usually  the battle is lost two to five years after diagnosis, typically from  respiratory failure, but about 10% of patients live more than a  decade with the disease.   ALS has no cure, but a drug (Rilutek [riluzole]) may extend  time until respiratory difficulty. Assisted breathing devices  may be used, including a ventilator to sustain life. Although  about 50% of people with ALS experience some cognitive  decline, the mind remains sharp in many people. One patient  wrote a novel during his last months, and another remained a  brilliant songwriter.   About 10% of ALS cases are inherited, due to mutations in  any of several genes. Because prevalence has been increasing  over the past few years at a rate faster than the aging of the  population can explain, an environmental trigger may combine  with an inherited susceptibility to cause the disease.    1. Fasciculus Posterior Conduct sensory impulses  gracilis and funiculi associated with the senses  fasciculus of touch, pressure, and body  cuneatus movement from skin, muscles,   2. Spinothalamic Lateral Conduct sensory impulses  tracts (lateral and associated with the senses of  and anterior) anterior pain, temperature, touch, and    tracts (posterior —_ funiculli required for the coordination  and anterior) of muscle movements from  muscles of the lower limbs and  trunk to the cerebellum  Descending Tracts  1. Corticospinal Lateral Conduct motor impulses  tracts (lateral and associated with voluntary  and anterior) anterior movements from the brain to  funiculi skeletal muscles  2. Reticulospinal Lateral Conduct motor impulses  tracts (lateral, and associated with the  anterior, and anterior maintenance of muscle tone  medial) funiculi and the activity of sweat  glands from the brain  3. Rubrospinal Lateral Conduct motor impulses  tracts funiculi associated with muscular    The peripheral nervous system consists of the nerves that branch  from the CNS, connecting it to other body parts. The PNS includes  the cranial nerves that arise from the brain and the spinal nerves  that arise from the spinal cord.   The PNS can also be subdivided into somatic and autonomic  nervous systems. Generally, the somatic nervous system consists  of the cranial and spinal nerve fibers that connect the CNS to the  skin and skeletal muscles, so it plays a role in conscious activities.  The autonomic nervous system (aw”to nom’ik ner’vus sis’tem)  includes fibers that connect the CNS to viscera such as the heart,  stomach, intestines, and various glands. The autonomic nervous  system controls subconscious actions. Table 11.8 outlines the sub-  divisions of the nervous system.    Nerves are essentially bundles of axons, but they have specific  levels of organization. A small amount of loose connective tis-  sue called endoneurium surrounds individual axons. Axons are  organized in bundles called fascicles. Each fascicle is enclosed  in a sleeve of loose connective tissue called the perineurium. A  group of bundled fascicles, surrounded by an outermost layer of  dense connective tissue called the epineurium, constitutes a nerve    Thousands of people sustain spinal cord injuries each year. Treat-  ment for spinal cord injury begins as soon as help arrives at the  accident scene. Emergency health-care workers establish and  maintain the person's ability to breathe, then use a rigid neck col-  lar and carrying board to immobilize the person for transport. In  the emergency department, a steroid drug, methylprednisolone, is  given within the first 8 hours to minimize inflammation. Surgery may  be done to remove bone fragments. Continuing immobilization is  crucial because damage continues over days. During this time, the  vertebrae are compressed and may break, killing many neurons.  Dying neurons release calcium ions, which activate tissue-degrading  enzymes. Then white blood cells arrive and produce inflammation  that can destroy healthy as well as damaged neurons. Axons tear,  myelin coatings are stripped off, and vital connections between  neurons and muscle fibers are lost. The tissue cannot regenerate.  By the third day, a complete neurological exam and MRIs are done.   The severity of a spinal cord injury depends on the extent and  location of damage. Normal spinal reflexes require two-way com-  munication between the spinal cord and the brain. A complete  transection (damage through a cross section of the cord) injures  nerve pathways, depressing the cord’s reflex activities in sites  below the injury. At the same time, sensations and muscle tone  diminish in the parts that the affected fibers innervate. This con-  dition, called spinal shock, may last for days or weeks, although  normal reflex activity may eventually return. If axons are severed,  some of the cord’s functions may be permanently lost.   Less severe injuries to the spinal cord, such as from a blow to  the head, whiplash, or rupture of an intervertebral disc, can com-  press or distort the cord (fig. 11G). Pain, weakness, and muscu-  lar atrophy may develop in the regions the damaged nerve fibers  supply. A spinal cord injury increases risk of secondary problems.  These include difficulty breathing (if the injury is above the fifth  cervical vertebra), development of pneumonia, formation of blood  clots, low blood pressure, an irregular heartbeat, pressure ulcers,  spasticity, and impaired bowel, bladder, and sexual function.   The two most common causes of spinal cord injury are acci-  dents in the workplace and motor vehicle accidents. Third most  common are sports injuries. A spinal cord injury may result from  a sudden and unexpected movement. For example, one man suf-  fered a severe spinal cord injury after a powerful wave knocked  him down while he was standing in just a foot of water at a shore-  line. Regardless of the cause, if nerve fibers in ascending tracts    (figs. 11.23 and 11.24). Blood vessels in the epineurium and peri-  neurium give rise to a network of capillaries in the endoneurium  that provides oxygen and nutrients to the neurons.   The term “muscle fiber” refers to an entire muscle cell, whereas  the term “nerve fiber” refers to an axon. The terminology for the  connective tissue holding them together, however, is similar. In both  cases, for example, fibers are bundled into fascicles, epineurium  in nerves corresponds to epimysium in muscles, and so forth (see  figs. 11.23, 11.24, 9.2 and 9.3 on p. 294).    are cut, sensations arising from receptors below the level of  the injury are lost. Damage to descending tracts results in loss  of motor functions below the level of the injury. For example,  if the right lateral corticospinal tract is severed in the neck near  the first cervical vertebra, control of the voluntary muscles in the  left upper and lower limbs is lost, paralyzing them (hemiplegia).  Problems of this type in fibers of the descending tracts produce  upper motor neuron syndrome, characterized by spastic paralysis  in which muscle tone increases, with little atrophy of the muscles.   Injury to motor neurons in the anterior horns of the spinal  cord results in lower motor neuron syndrome. It produces flaccid  paralysis, a total loss of muscle tone and reflex activity, and the  muscles atrophy.   Basic research is exploring ways to limit damage after a spi-  nal cord injury and stimulate regeneration. Studies are identifying  molecules in the extracellular matrix (see Clinical Application 5.1,  p. 161) and in myelin that inhibit axon regeneration in the CNS  and might serve as drug targets, and finding growth factors and  other neurotrophins that might promote regeneration. Several  clinical trials are investigating the use of stem cells to treat spinal  cord injury. These include stem cells taken from a patient’s own  bone marrow or fat, from cord blood stem cells, or from neural  stem cells from a donor.    FIGURE 11G A dislocation of the atlas may cause a compression  injury to the spinal cord.    Recall that nerves are bundles of nerve fibers, or axons. Nerves that  have only fibers of sensory neurons, conducting impulses into the  brain or spinal cord, are called sensory nerves. Nerves that have  only fibers involved in motor control are motor nerves. Most nerves  include both sensory and motor fibers and are called mixed nerves.  Nerves originating from the brain that communicate with other  body parts are called cranial nerves, whereas nerves originating    1. Central nervous system (CNS)  a. Brain  b. Spinal cord  2. Peripheral nervous system (PNS)  a. Cranial nerves arising from the brain  (1) Somatic fibers connecting to the skin and skeletal muscles  (2) Autonomic fibers connecting to viscera  b. Spinal nerves arising from the spinal cord  (1) Somatic fibers connecting to the skin and skeletal muscles    from the spinal cord that communicate with other body parts are  called spinal nerves. The nerve fibers in the cranial and spinal  nerves can be subdivided further into four groups as follows:    1. General somatic efferent fibers conduct motor impulses  outward from the brain or spinal cord to skeletal muscles and  stimulate them to contract.   2. General visceral efferent fibers conduct motor impulses  outward from the brain or spinal cord to smooth muscle and  glands associated with internal organs.   3. General somatic afferent fibers conduct sensory impulses  inward to the brain or spinal cord from receptors in the skin  and skeletal muscles.   4. General visceral afferent fibers conduct sensory impulses to  the CNS from blood vessels and internal organs.    Q) In the axons found in a mixed  nerve, in which direction are the  impulses conducted?    The term general in each of these categories indicates that  the fibers are associated with general structures such as the skin,  skeletal muscles, glands, and viscera. Three other groups of fibers,  found only in cranial nerves, are associated with more specialized,  or special, structures:    1. Special somatic efferent fibers conduct motor impulses  outward from the brain to the muscles used in chewing,  swallowing, speaking, and forming facial expressions.   2. Special visceral afferent fibers conduct sensory impulses  inward to the brain from the olfactory and taste receptors.   3. Special somatic afferent fibers conduct sensory impulses  inward to the brain from the receptors of sight, hearing,  and equilibrium.    Twelve pairs of cranial nerves are located on the underside of the  brain. Most of the cranial nerves are mixed nerves, but some of  those associated with special senses, such as smell and vision, have  only sensory fibers. Other cranial nerves that innervate muscles    and glands are primarily composed of motor fibers. The first pair,  which is sensory, has fibers that begin in the nasal cavity and syn-  apse in the frontal lobe of the cerebrum. The second pair, also sen-  sory, originates in the eyes, and their fibers synapse in the thalamus.  The remaining cranial nerves attach to the the brainstem, and the  direction of their fibers depends on whether they are sensory, motor,  or mixed. All of the cranial nerves pass from their sites of attach-  ment through foramina of the skull and lead to areas of the head,  neck, and trunk. The cranial nerves that are described as primarily  motor do have limited sensory functions because they contain neu-  rons associated with certain receptors (proprioceptors) that respond  to the changes in length and force of contraction of skeletal muscles.  However, because these proprioceptive fibers contribute directly  to motor control, cranial nerves whose only sensory component is  from such proprioceptors are usually considered motor nerves. This  pertains to cranial nerves II, IV, VI, XI, and XII.   Neuron cell bodies from which the sensory fibers in the cranial  nerves arise are outside the brain, and most are in groups called  ganglia (sing., ganglion). However, most motor neuron cell bodies  are in the gray matter of the brain.   Numbers and names designate cranial nerves. The numbers  indicate the order in which the nerves arise from the brain, from  anterior to posterior. The names describe primary functions or the  general distribution of cranial nerve fibers (fig. 11.25).   The first pair of cranial nerves, the olfactory (ol-fak’to-re)  nerves (I), are associated with the sense of smell and include only  sensory neurons. These bipolar neurons, located in the lining of the  upper nasal cavity, serve as olfactory receptor cells. Axons from  these receptor cells pass upward through the cribriform plates of  the ethmoid bone, conducting impulses to the olfactory neurons in  the olfactory bulbs, which are extensions of the cerebral cortex just  beneath the frontal lobes. Sensory impulses move from the olfac-  tory bulbs along olfactory tracts to cerebral centers where they pro-  duce the sensation of smell.    The second pair of cranial nerves, the optic (op’tik) nerves (II),  are sensory and lead from the eyes to the brain. They are associated  with vision. The cell bodies of these neurons form ganglion cell lay-  ers in the eyes, and their axons pass through the optic foramina of  the orbits and continue into the visual nerve pathways of the brain  (see chapter 12, p. 481).   The third pair of cranial nerves, the oculomotor (ok’u-lo-  mo’tor) nerves (III), arise from the midbrain and pass into the  orbits of the eyes. One component of each nerve connects to a num-  ber of voluntary muscles, including those that raise the eyelids and  four of the six muscles that move the eye.   A second portion of each oculomotor nerve is part of the auto-  nomic nervous system, supplying involuntary muscles inside the  eyes. These muscles help adjust the amount of light that enters the  eyes and help focus the lenses. This nerve is considered motor,  with some proprioceptive fibers.   The fourth pair of cranial nerves, the trochlear (trok’le-ar)  nerves (IV), are the smallest. They arise from the midbrain and  conduct motor impulses to a fifth pair of external eye muscles, the  superior oblique muscles, which are not supplied by the oculomo-  tor nerves. The trochlear nerve is considered motor, with some  proprioceptive fibers.   The fifth pair of cranial nerves, the trigeminal (tri-jem’i-nal)  nerves (V), are the largest and arise from the pons. They are mixed  nerves, with more extensive sensory portions. Each sensory com-  ponent includes three large branches, called the ophthalmic, maxil-  lary, and mandibular divisions (fig. 11.26).   The ophthalmic division of each the trigeminal nerve consists  of sensory fibers that conduct impulses to the brain from the sur-  face of the eye; the tear gland; and the skin of the anterior scalp,  forehead, and upper eyelid. The fibers of the maxillary division  conduct sensory impulses from the upper teeth, upper gum, and upper  lip, as well as from the mucous lining of the palate and facial skin.  The mandibular division includes both motor and sensory fibers. The    FIGURE 11.24 Scanning electron micrograph of a peripheral nerve in cross section (20x). Note the bundles or fascicles of nerve fibers.  Fibers include axons of motor neurons as well as peripheral processes of sensory neurons.    FIGURE 11.25 fAP|R) The cranial nerves, except for the first two pairs, arise from the brainstem. (a) They are identified either by numbers indicating  their order, their function, or the general distribution of their fibers. (b) An enlargement showing the detail of the olfactory nerve fibers passing through the    sensory branches conduct impulses from the scalp behind the ears,  the skin of the jaw, the lower teeth, the lower gum, and the lower  lip. The motor branches supply the muscles of mastication and  certain muscles in the floor of the mouth.    A disorder of the trigeminal nerve called trigeminal neuralgia (tic  douloureux) causes severe recurring pain in the face and fore-  head on one side. If drugs cannot help, surgery may be used to  sever the sensory part of the nerve. However, with surgery the  patient loses sensations in other body regions that the sensory    branch supplies. After surgery, care must be taken when eat-  ing or drinking hot foods or liquids, and the mouth must be  inspected daily for food particles or damage to the cheeks from  biting. The cause of trigeminal neuralgia is unknown.    The sixth pair of cranial nerves, the abducens (ab-du’senz)  nerves (VI), are small and originate from the pons near the  medulla oblongata. They enter the orbits of the eyes and supply  motor impulses to the remaining pair of external eye muscles, the  lateral rectus muscles. This nerve is considered motor, with some  proprioceptive fibers.   The seventh pair of cranial nerves, the facial (fa’shal) nerves  (VII), are mixed nerves that arise from the lower part of the pons  and emerge on the sides of the face. Their sensory branches are  associated with taste receptors on the anterior two-thirds of the  tongue, and some of their motor fibers conduct impulses to mus-  cles of facial expression (fig. 11.27). Still other motor fibers of  these nerves function in the autonomic nervous system by stimu-  lating secretions from tear glands and certain salivary glands (sub-  mandibular and sublingual glands).    FIGURE 11.26 fAP|R) Each trigeminal nerve has three large  branches that supply various regions of the head and face: the ophthalmic  division (sensory), the maxillary division (sensory), and the mandibular  division (sensory and motor to muscles of mastication).    A common cause of facial paralysis, called Bell’s palsy, is usually  limited to one side. It occurs from damage to the facial nerve  from unknown causes, although it is thought to be linked to viral  infections. This condition usually resolves within a few months,  but may be permanent.    The eighth pair of cranial nerves, the vestibulocochlear (ves-  tib”u-lo-kok’le-ar) nerves (VIII, acoustic, or auditory, nerves),  are sensory nerves that arise from the medulla oblongata. Each  of these nerves has two distinct parts—a vestibular branch and a  cochlear branch.   The neuron cell bodies of the vestibular branch fibers are  located in ganglia near the vestibule and semicircular canals of the  inner ear. These structures contain receptors that sense changes  in the position of the head and, in response, initiate and send  impulses to the cerebellum, where they are used in reflexes that  maintain equilibrium.   The neuron cell bodies of the cochlear branch fibers are  located in a ganglion of the cochlea, a part of the inner ear that  houses the hearing receptors. Impulses from this branch pass  through the medulla oblongata and midbrain on their way to the  temporal lobe, where they are interpreted.   The ninth pair of cranial nerves, the glossopharyngeal (glos”o-  fah-rin’je-al) nerves (IX), are associated with the tongue and phar-  ynx. These nerves arise from the medulla oblongata. They are mixed  nerves, with predominant sensory fibers that conduct impulses from    taste receptors on the tongue and with muscles of facial expression.    the lining of the pharynx, tonsils, and posterior third of the tongue  to the brain. Fibers in the motor component of the glossopharyngeal  nerves innervate certain salivary glands and a constrictor muscle in  the wall of the pharynx that functions in swallowing.   The tenth pair of cranial nerves, the vagus (va’gus) nerves  (X), originate in the medulla oblongata and extend downward  through the neck into the chest and abdomen. These nerves are  mixed, including both somatic and autonomic branches, with the  autonomic fibers predominant.   Among the somatic components of the vagus nerves are motor  fibers that conduct impulses to muscles of the larynx and pharynx.  These fibers are associated with speech and swallowing reflexes  that use muscles in the soft palate and pharynx. Vagal sensory  fibers conduct impulses from the linings of the pharynx, larynx,  and esophagus and from the viscera of the thorax and abdomen to  the brain. Autonomic motor fibers of the vagus nerves supply the  heart and many smooth muscles and glands in the viscera of the  thorax and abdomen (fig. 11.28).    FIGURE 11.28 (AP|R) The vagus nerves (only the left vagus is    shown) extend from the medulla oblongata downward into the chest  and abdomen to supply many organs.    The eleventh pair of cranial nerves, the accessory (ak-ses’o-re)  nerves (XI, spinal accessory), originate in the medulla oblongata  and the spinal cord. Therefore, these nerves have both cranial and  spinal branches. Each cranial branch of an accessory nerve joins a  vagus nerve and conducts impulses to muscles of the soft palate, phar-  ynx, and larynx. The spinal branch descends into the neck and sup-  plies motor fibers to the trapezius and sternocleidomastoid muscles.  This nerve is considered motor, with some proprioceptive fibers.   The twelfth pair of cranial nerves, the hypoglossal (hi’po-  glos’al) nerves (XID), arise from the medulla oblongata and pass into  the tongue. They primarily consist of fibers that conduct impulses  to muscles that move the tongue in speaking, chewing, and swal-  lowing. This nerve is considered motor, with some proprioceptive  fibers. Table 11.9 summarizes the functions of the cranial nerves.   34 Distinguish between somatic and autonomic nerve fibers.  35 Describe the structure of a peripheral nerve.    37 Name the cranial nerves, and list the major functions of each.    Thirty-one pairs of spinal nerves originate from the spinal cord.  All but the first pair are mixed nerves, and they provide two-way  communication between the spinal cord and parts of the upper and  lower limbs, neck, and trunk.    Motor fibers conduct impulses to muscles that raise the eyelids, move the eyes, adjust the amount  of light entering the eyes, and focus the lenses.    Some sensory fibers conduct impulses associated with proprioceptors.  Motor fibers conduct impulses to muscles that move the eyes.    Sensory fibers conduct impulses from the surface of the eyes, tear glands, scalp, forehead, and  Sensory fibers conduct impulses from the upper teeth, upper gum, upper lip, lining of the palate, and    Sensory fibers conduct impulses from the scalp, skin of the jaw, lower teeth, lower gum, and lower lip.  Motor fibers conduct impulses to muscles of mastication and to muscles in the floor of the mouth.  Motor fibers conduct impulses to muscles that move the eyes.   Sensory fibers conduct impulses associated with taste receptors of the anterior tongue.    Motor fibers conduct impulses to muscles of facial expression, tear glands, and salivary glands.   Sensory fibers conduct impulses from the pharynx, tonsils, posterior tongue, and carotid arteries.  Motor fibers conduct impulses to salivary glands and to muscles of the pharynx used in swallowing.  Sensory fibers conduct impulses from the pharynx, larynx, esophagus, and viscera of the thorax    Somatic motor fibers conduct impulses to muscles associated with speech and swallowing;  autonomic motor fibers conduct impulses to the viscera of the thorax and abdomen.    Motor fibers conduct impulses to muscles of the soft palate, pharynx, and larynx.  Motor fibers conduct impulses to muscles of the neck and back; some proprioceptor input.    Motor fibers conduct impulses to muscles that move the tongue; some proprioceptor input.    IV Trochlear Primarily motor  Vv Trigeminal Mixed  Ophthalmic division  upper eyelids.  Maxillary division  skin of the face.  Mandibular division  Vi Abducens Primarily motor  Vil Facial Mixed  Vill = Vestibulocochlear Sensory  Vestibular branch  Cochlear branch  IX Glossopharyngeal Mixed  Xx Vagus Mixed  and abdomen.  Xl Accessory Primarily motor  Cranial branch  Spinal branch  XIl Hypoglossal Primarily motor  424 — UNIT3 | INTEGRATION AND COORDINATION    Spinal nerves are not named individually but are grouped  by the level from which they arise. Each nerve is numbered in  sequence (fig. 11.29). On each vertebra the vertebral notches,  which are the major parts of the intervertebral foramina, are associ-  ated with the inferior portion of their respective vertebrae. For this  reason, each spinal nerve, as it passes through the intervertebral  foramen, is associated with the vertebra above it. The cervical spi-  nal nerves are an exception because spinal nerve Cl passes supe-    FIGURE 11.29 The thirty-one pairs  of spinal nerves are grouped according  to the level from which they arise and  are numbered in sequence. Spinal  nerves are shown on the right side of  the figure. Portions of the peripheral  nerves that result from branching are  shown on the left.    rior to the vertebra C1. Therefore, although there are seven cervical  vertebrae, there are eight pairs of cervical nerves (numbered C1 to  C8). There are twelve pairs of thoracic nerves (numbered T1 to T12),  five pairs of lumbar nerves (numbered L1 to LS), five pairs of sacral  nerves (numbered S1 to S5), and one pair of coccygeal nerves (Co).  Each spinal nerve, except for the first pair, emerges from the  cord by two short branches, or roots, which lie within the vertebral  column. The roots arising from the superior part of the spinal cord    pass outward almost horizontally, whereas those from the inferior  portions of the spinal cord descend at sharp angles. This anatomi-  cal feature is a consequence of growth. In early life, the spinal cord  extends the entire length of the vertebral column, but with age, the  column grows more rapidly than the cord. Thus, the adult spinal  cord ends at the level between the first and second lumbar verte-  brae, so the roots associated with the lumbar, sacral, and coccy-  geal nerves descend to their exits beyond the end of the cord, still  within the vertebral canal. These descending roots form a structure  called the cauda equina (horse’s tail) (fig. 11.29).   The ventral root (anterior, or motor, root) of each spinal  nerve consists of axons from the motor neurons whose cell bod-  ies lie within the gray matter of the cord. The dorsal root (poste-  rior, or sensory, root) can be identified by an enlargement called  the dorsal root ganglion. This ganglion contains the cell bodies of  the sensory neurons whose axons (peripheral processes) conduct  impulses inward from peripheral body parts. The axons (central   and (b) on the posterior surface.  Spinal nerve C1 does not supply  any skin area.    processes) of these neurons continue through the dorsal root and  into the spinal cord, where they form synapses with other neurons  or ascend to the brain (see fig. 11.21). A ventral root and a dorsal  root unite to form a spinal nerve, which extends outward from the  vertebral canal through an intervertebral foramen (the dorsal root  is usually absent from the first pair of spinal nerves).   Each spinal nerve below Cl contains sensory fibers that  reach the skin, and the region innervated is called a derma-  tome. (Similarly, the collection of muscles innervated by motor  nerve fibers of a particular spinal nerve is called a myotome.)  Dermatomes are highly organized, but they vary considerably in  size and shape, as figure 11.30 indicates. A map of the derma-  tomes is useful in localizing the sites of injuries to dorsal roots or  to the spinal cord.   Just beyond its foramen, each spinal nerve branches. One of  these parts, the small meningeal branch, reenters the vertebral  canal through the intervertebral foramen and supplies (innervates)    the meninges and blood vessels of the cord, as well as the interver-  tebral ligaments and the vertebrae. A dorsal branch (dorsal ramus)  of each spinal nerve turns posteriorly and innervates the muscles  and skin of the back, as figure 11.31 shows. The main portion of the  nerve, the ventral branch (ventral ramus), continues forward to sup-  ply muscles and skin on the front and sides of the trunk and limbs.  The spinal nerves in the thoracic and lumbar regions have a fourth  branch, or visceral branch, which is part of the autonomic nervous  system. Motor fibers associated with this branch form synapses in  ganglia (paravertebral ganglia) adjacent to the vertebral column.   Ventral branches of the spinal nerves form complex networks  called plexuses instead of continuing directly to the peripheral body  parts, except in the thoracic regions T2 through T12. In a plexus,  the fibers of various spinal nerves are sorted and recombined in  a way that enables fibers associated with a particular peripheral  body part to reach it in the same peripheral nerve, even though the  fibers originate from different spinal nerves (fig. 11.32).    g \  | The specific spinal segment or segments that supply a body  part is called “segmental innervation.” For example, the biceps  brachii is innervated by the musculocutaneous nerve with axons  originating from C5, Cé, and C7. Similarly, the gastrocnemius  is innervated by the tibial nerve with axons originating from $1  and S2.    The ventral branches of the first four cervical nerves form the cer-  vical plexuses, which lie deep in the neck on either side. Fibers  from these plexuses supply the muscles and skin of the neck. In  addition, fibers from the third, fourth, and fifth cervical nerves  pass into the right and left phrenic (fren’ik) nerves, which con-  duct motor impulses to the muscle fibers of the diaphragm.    The ventral branches of the lower four cervical nerves and the first  thoracic nerve give rise to brachial plexuses. These networks of  nerve fibers are deep in the shoulders between the neck and the  axillae (armpits). The major branches emerging from the brachial  plexuses include the following (fig. 11.33):    1. Musculocutaneous nerves supply muscles of the arms on the  anterior sides and the skin of the forearms.   2. Ulnar nerves supply muscles of the forearms and hands and  the skin of the hands.   3. Median nerves supply muscles of the forearms and muscles  and skin of the hands.   4. Radial nerves supply muscles of the arms on the posterior  sides and the skin of the forearms and hands.   5. Axillary nerves supply muscles and skin of the anterior,  lateral, and posterior regions of the arm.    FIGURE 11.31 fAP|R) Spinal nerve. (a) Each spinal nerve has a dorsal and ventral branch. (b) The thoracic and lumbar spinal nerves also have    FIGURE 11.32 The ventral branches of the spinal nerves in the thoracic region give rise to intercostal nerves.  Those in other regions combine to form complex networks called plexuses.    The lateral and medial pectoral nerves supply the pectoralis  major and pectoralis minor muscles.   The dorsal scapular nerve supplies the rhomboid major and  levator scapulae muscles.    . The thoracodorsal nerve supplies the latissimus dorsi muscle.  . The suprascapular nerve supplies the supraspinatus and    The ventral branches of the lumbar and first four sacral nerves  form the lumbosacral (lum”bo-sa’kral) plexuses. These networks  of nerve fibers extend from the lumbar and sacral regions of the  back into the pelvic cavity, giving rise to a number of motor and  sensory fibers associated with the lower abdominal wall, external  genitalia, buttocks, thighs, legs, and feet. The major branches of  these plexuses include the following (fig. 11.34):    1. The obturator nerves supply the adductor muscles of the  thighs.    WW ventral rami: C5, C6, C7, C8, T1  WB Trunks: superior, middle, inferior  ea Anterior divisions  ia Posterior divisions    FIGURE 11.33 (AP|R) Nerves of the brachial plexus. (a) Close up.    2. The femoral nerves divide into many branches, supplying  motor impulses to muscles of the anterior thighs and receiv-  ing sensory impulses from the skin of the thighs and legs.   3. The sciatic nerves are the largest and longest nerves in the  body, formed by the common fibular nerve and the tibial  nerve wrapped in a connective tissue sheath. They pass  downward into the buttocks and descend into the thighs,  where they re-emerge as the tibial and common fibular  nerves. The many branches of these nerves supply muscles  and skin in the thighs, legs, and feet.    Other nerves associated with the lumbosacral plexus that  innervate various skeletal muscles include the following:    2. The inferior and superior gluteal nerves supply the gluteal  muscles and the tensor fasciae latae muscle.    Except for T1, the ventral branches of the thoracic spinal  nerves do not enter a plexus. Instead, they extend into spaces  between the ribs as intercostal (in”ter-kos’tal) nerves (T2-T11)  or under the ribs as subcostal nerves (T12). These nerves supply  motor impulses to the intercostal muscles and the upper abdomi-  nal wall muscles. They also receive sensory impulses from the  skin of the thorax and abdomen. Clinical Application 11.7 discusses  injuries to the spinal nerves.    Birth injuries, dislocations, vertebral fractures, stabs, gunshot  wounds, and pressure from tumors can all injure spinal nerves. Sud-  denly bending the neck, called whiplash, can compress the nerves  of the cervical plexuses, causing persistent headache and pain  in the neck and skin, which the cervical nerves supply. If a broken  or dislocated vertebra severs or damages the axons reaching the  phrenic nerves from the cervical plexuses, partial or complete paral-  ysis of the diaphragm may result.   Intermittent or constant pain in the neck, shoulder, or upper  limb may result from prolonged flexion of the arm, such as in  painting or typing. This is due to too much pressure on the bra-  chial plexus. Called thoracic outlet syndrome, this condition may  also result from a congenital skeletal malformation that com-  presses the plexus during upper limb and shoulder movements.    Superior  gluteal n.  Inferior  gluteal n. j  Common 3,  ne fibular . a  Sciatic n. — (peroneal) n.  Tibial n.  Pudendal n.  (a) (b)    Degenerative changes may compress an intervertebral disc  in the lumbar region, producing sciatica, which causes pain in  the lower back and gluteal region that can radiate to the thigh,  calf, and foot. Sciatica is most common in middle-aged people,  particularly distance runners. It usually compresses spinal nerves  between L2 and S1, which contain fibers of the sciatic nerve. Rest,  drugs, or surgery are used to treat sciatica.   In carpal tunnel syndrome, repeated hand movements, such  as typing or weeding, inflame the tendons that pass through the  carpal tunnel, which is a space between bones in the wrist. The  swollen tendons compress the median nerve in the wrist, send-  ing pain up the upper limb. Surgery or avoiding repetitive hand  movements can relieve symptoms.    FIGURE 11.34 (AP|R) Nerves of the lumbosacral plexus. (a) Close up. (b) Anterior view. (c) Posterior view.    38 How are spinal nerves grouped?  39 Describe how a spinal nerve emerges from the spinal cord.    The autonomic nervous system is the part of the PNS that func-  tions independently (autonomously) and continuously, without  conscious effort. This system controls visceral activities by regu-  lating the actions of smooth muscles, cardiac muscles, and various  glands. It oversees heart rate, blood pressure, breathing rate, body  temperature, and other visceral activities that aid in maintain-  ing homeostasis. Portions of the autonomic nervous system also  respond during times of emotional stress and prepare the body to  meet the demands of strenuous physical activity.    Reflexes in which sensory signals originate from receptors in the  viscera and in the skin regulate autonomic activities. Afferent  nerve fibers conduct these signals to neural centers in the brain  or spinal cord. In response, motor impulses leave these centers on  efferent nerve fibers in cranial and spinal nerves. Typically, these  efferent fibers lead outside the CNS to ganglia. The impulses they  conduct are integrated in the ganglia and are relayed to organs  (muscles or glands) that respond by contracting, secreting, or  being inhibited. The integrative function of the ganglia provides  the autonomic nervous system with some degree of indepen-  dence from the brain and spinal cord, and the visceral efferent  nerve fibers associated with these ganglia comprise the autonomic  nervous system.   The autonomic nervous system includes two divisions, the  sympathetic (sim”’pah-thet’ik) and parasympathetic (par”ah-  sim” pah-thet’ik) divisions. Many organs receive input from both  divisions. Impulses from one division may activate an organ, and  impulses from the other division inhibit it. Thus, the divisions may  function antagonistically, regulating the actions of some organs by  alternately activating or inhibiting them. One example of this, dis-  cussed in chapter 15 (p. 587), concerns the baroreflex control of  heart rate. In that reflex, parasympathetic activity decreases heart  rate and sympathetic activity increases it. Moment to moment  changes between the two keep heart rate at a level appropriate to  maintaining homeostasis.   Neither division is entirely excitatory or inhibitory. Each acti-  vates some organs and inhibits others. The sympathetic division  speeds the heart but slows the digestive system. The parasympa-  thetic division slows the heart but activates digestion.   The sympathetic division is always operating, usually without  our noticing, but is most active during energy-expending, stressful,  or emergency situations (so-called “fight or flight”). Conversely,  the parasympathetic division is most active under ordinary, restful  conditions (often described as “rest and digest’’). It also counters  the effects of the sympathetic division and restores the body to a  resting state following a stressful experience. For example, during    an emergency the sympathetic division increases heart and breath-  ing rates. Following the emergency, the parasympathetic division  decreases these activities.    The motor pathways of the autonomic nervous system have a dis-  tinct pattern. In the motor pathways of the somatic nervous sys-  tem, a single neuron typically links the CNS and a skeletal muscle.  In the autonomic system, motor pathways include two neurons, as  figure 11.35 shows. The cell body of one neuron is in the brain  or spinal cord. Its axon, the preganglionic (pre” gang-gle-on’ik)  fiber, leaves the CNS and synapses with one or more neurons  whose cell bodies are within an autonomic ganglion. The axon of  such a second neuron is called a postganglionic (post” gang-gle-  on’ik) fiber, and it extends to a visceral effector.   In the sympathetic division (thoracolumbar division), the pregan-  glionic fibers originate from neurons in the lateral horn of the spi-  nal cord. These neurons are found in all of the thoracic segments  and in the upper two lumbar segments of the cord (T1-L2). Their  axons exit through the ventral roots of spinal nerves along with  various somatic motor fibers.   Preganglionic fibers extend a short distance, then leave the spi-  nal nerves through branches called white rami (sing., ramus) and  enter sympathetic ganglia. Two groups of such ganglia, called sym-  pathetic chain ganglia (paravertebral ganglia), form chains along  the sides of the vertebral column. These ganglia, with the fibers that  connect them, compose the sympathetic trunks (fig. 11.36).   The paravertebral ganglia lie just beneath the parietal pleura in  the thorax and beneath the parietal peritoneum in the abdomen (see  chapter |, p. 20). Although these ganglia are some distance from the  viscera they help control, other sympathetic ganglia are nearer to the  viscera. The collateral ganglia, for example, are in the abdomen,  closely associated with certain large blood vessels (fig. 11.37).   Some of the preganglionic fibers that enter paravertebral gan-  glia synapse with neurons in these ganglia. Other fibers extend  through the ganglia and pass up or down the sympathetic trunk  and synapse with neurons in ganglia at higher or lower levels in  the chain. Still other fibers pass through to collateral ganglia  before they synapse. Typically, a preganglionic axon will synapse  with several other neurons in a sympathetic ganglion. This is an  example of divergence (see chapter 10, pp. 383 and 385).   The axons of the second neurons in sympathetic pathways,  the postganglionic fibers, extend from the sympathetic ganglia to  visceral effectors. Most axons leaving paravertebral ganglia pass  through branches called gray rami and return to a spinal nerve  before extending to an effector (fig. 11.37). These branches appear  gray because the postganglionic axons generally are unmyelin-  ated, whereas nearly all of the preganglionic axons in the white  rami are myelinated.   An important exception to the usual arrangement of sympathetic  fibers is in a set of preganglionic fibers that pass through the sym-  pathetic ganglia and extend to the medulla of each adrenal gland.  These fibers terminate in the glands on special hormone-secreting  cells that release norepinephrine (20%) and epinephrine (80%)    FIGURE 11.35 Motor pathways. (a) Autonomic pathways include two neurons between the CNS and an effector. (b) Most somatic pathways have a  single neuron between the CNS and an effector. In both cases the motor fibers pass through the ventral root of the spinal cord.    FIGURE 11.36 A chain of paravertebral ganglia extends along each  side of the vertebral column.    when they are stimulated. Chapter 13 (pp. 508-510) discusses the  functions of the adrenal medulla and its hormones. Figure 11.38  shows the sympathetic division.    The preganglionic fibers of the parasympathetic division (cra-  niosacral division) arise from neurons in the midbrain, pons, and  medulla oblongata of the brainstem and from part of the sacral  region (S2-4) of the spinal cord (fig. 11.39). From there, the  preganglionic fibers lead outward on cranial or sacral nerves to  ganglia near or in various organs (terminal ganglia). The short  postganglionic fibers continue from the ganglia to specific muscles  or glands in these organs (fig. 11.40). Most parasympathetic pre-  ganglionic axons are myelinated, and the parasympathetic post-  ganglionic fibers are unmyelinated.   The parasympathetic preganglionic fibers associated with parts  of the head are included in the oculomotor, facial, and glossopha-  ryngeal nerves. Those fibers that innervate organs of the thorax and  upper abdomen are parts of the vagus nerves. (The vagus nerves  carry about 75% of all parasympathetic fibers.) Preganglionic fibers  arising from the sacral region of the spinal cord lie in the branches  of the second through the fourth sacral spinal nerves, and they con-  duct impulses to the viscera in the pelvic cavity (see fig. 11.39).    FIGURE 11.37 Sympathetic fibers leave the spinal cord in the ventral roots of spinal nerves, enter paravertebral ganglia, and synapse with other    41 What is the general function of the autonomic nervous system?    43 Describe a sympathetic nerve pathway and a parasympathetic  nerve pathway.    The different postganglionic neurotransmitters (mediators) are  responsible for the different effects that the sympathetic and para-  sympathetic divisions have on organs. The preganglionic neurons of  the sympathetic and parasympathetic divisions all secrete acetylcho-  line, and for this reason they are called cholinergic (ko”lin-er’jik).  The parasympathetic postganglionic fibers are also cholinergic  (one exception, parasympathetic neurons that secrete nitric oxide,  is described in chapter 22, p. 835). Most sympathetic postgangli-  onic neurons, however, secrete norepinephrine (noradrenalin) and  are called adrenergic (ad”ren-er’jik) (fig. 11.40). Exceptions to  this include the sympathetic postganglionic neurons that stimulate  sweat glands and a few sympathetic neurons to blood vessels in skin  (which cause vasodilation); these neurons secrete acetylcholine and  therefore are cholinergic (adrenergic sympathetic fibers to blood  vessels cause vasoconstriction).    Most organs receive innervation from both sympathetic and  parasympathetic divisions, usually with opposing actions. For exam-  ple, the sympathetic nervous system increases heart rate and dilates  pupils, whereas parasympathetic stimulation decreases heart rate and  constricts pupils. However, this is not always the case. For example,  the diameters of most blood vessels lack parasympathetic innervation  and are thus regulated by the sympathetic division. Smooth muscle in  the walls of these vessels is continuously stimulated by sympathetic  impulses; thereby being maintained in a state of partial contraction  called sympathetic tone. Decreasing sympathetic stimulation allows  the muscular walls of such blood vessels to relax, increasing their  diameters (vasodilation). Conversely, increasing sympathetic stimula-  tion vasoconstricts vessels. Table 11.10 summarizes the effects of  autonomic stimulation on various visceral effectors.    The actions of autonomic neurotransmitters result from their bind-  ing to protein receptors in the membranes of effector cells, such as  in the case of stimulation at neuromuscular junctions (see chapter 9,  p. 297) and synapses (see chapter 10, p. 378). Receptor binding alters  the membrane. For example, the membrane’s permeability to certain  ions may increase, and in smooth muscle cells, an action potential  followed by muscular contraction may result. Similarly, a gland cell  may respond to a change in its membrane by secreting a product.    FIGURE 11.38 {APF The preganglionic fibers of the sympathetic division of the autonomic nervous system arise from the thoracic and lumbar  regions of the spinal cord. A preganglionic fiber directly innervates the adrenal medulla.    FIGURE 11.39 (AP|R) The preganglionic fibers of the parasympathetic division of the autonomic nervous system arise from the brain and sacral  region of the spinal cord.    Effector Location  Integumentary system  Apocrine glands  Eccrine glands  Special senses  Iris of eye  Tear gland  Endocrine system  Adrenal cortex  Adrenal medulla  Digestive system  Muscle of gallbladder wall  Muscle of intestinal wall  Muscle of internal anal sphincter  Pancreatic glands  Salivary glands  Respiratory system  Muscle in walls of bronchioles  Cardiovascular system  Blood vessels supplying skeletal muscles  Blood vessels supplying skin    Acetylcholine can combine with two types of cholinergic  receptors, called muscarinic receptors and nicotinic receptors.  These receptor names come from muscarine, a toxin from a fun-  gus that can activate muscarinic receptors, and nicotine, a toxin  in tobacco that can activate nicotinic receptors. The muscarinic  receptors are in the membranes of effector cells at the ends of all  postganglionic parasympathetic nerve fibers and at the ends of the  cholinergic sympathetic fibers. Responses from these receptors are  excitatory and relatively slow. The nicotinic receptors are in the  synapses between the preganglionic and postganglionic neurons    of the parasympathetic and sympathetic pathways. They produce  rapid, excitatory responses (see Table 11.10). (Receptors at neuro-  muscular junctions of skeletal muscles are also nicotinic.)  Epinephrine and norepinephrine are the two chemical  mediators of the sympathetic nervous system. The adrenal gland  releases both as hormones, but only norepinephrine is released  as a neurotransmitter by the sympathetic nervous system. These  biochemicals can then bind adrenergic receptors of effector cells.  The two major types of adrenergic receptors are alpha and  beta (both types have subgroups). Exciting them elicits different    From the  thoracic  and upper  lumbar  regions of  the spinal  cord    FIGURE 11.40 Most sympathetic fibers are adrenergic and secrete norepinephrine at the ends of the postganglionic fiber; parasympathetic fibers  are cholinergic and secrete acetylcholine at the ends of the postganglionic fibers. Two arrangements of parasympathetic postganglionic fibers are seen  in both cranial and sacral portions. Similarly, sympathetic paravertebral and collateral ganglia are seen in both the thoracic and lumbar portions of the    responses in the effector organs. For example, stimulation of the  alpha receptors in vascular smooth muscle causes vasoconstriction,  whereas stimulation of the beta receptors in bronchial smooth  muscle causes relaxation leading to bronchodilation. Furthermore,  although norepinephrine has a somewhat stronger effect on alpha  receptors, both of these mediators can stimulate both types of  receptors. Consequently, the way each of these adrenergic sub-  stances influences effector cells depends on the relative numbers  of alpha and beta receptors in the cell membranes.    The enzyme acetylcholinesterase rapidly decomposes the acetyl-  choline that cholinergic fibers release. (Recall that this decomposi-  tion also occurs at the neuromuscular junctions of skeletal muscle,  chapter 9, p. 299.) Thus, acetylcholine usually affects the postsyn-  aptic membrane for only a fraction of a second.   Much of the norepinephrine released from adrenergic fibers is  removed from the synapse by active transport back into the nerve  endings. The enzyme monoamine oxidase, in mitochondria, then  inactivates norepinephrine. This may take a few seconds, during  which some molecules may diffuse into nearby tissues or the blood-  stream, where other enzymes decompose them. However, some  norepinephrine molecules may escape decomposition and remain  active for awhile. For these reasons, norepinephrine is likely to pro-  duce a more prolonged effect than acetylcholine. In fact, the adrenal  medulla releases norepinephrine and epinephrine into the blood in  response to sympathetic stimulation that may trigger sympathetic  responses in organs throughout the body lasting up to 20 minutes.    Many drugs influence autonomic functions. Some, like ephed-  rine, enhance sympathetic effects by stimulating release of nor-  epinephrine from postganglionic sympathetic nerve endings.  Others, like reserpine, inhibit sympathetic activity by prevent-  ing norepinephrine synthesis. Another group of drugs, which  includes pilocarpine, produces parasympathetic effects, and  some, like atropine, block the action of acetylcholine on vis-  ceral effectors.    Control of the autonomic nervous system rests mainly in the hypo-  thalamus, although impulse integration in the autonomic nervous  system’s ganglia provides some independence. In contrast to con-  trol of skeletal muscle in the somatic nervous system, which is  voluntary, control of the autonomic nervous system is involuntary.  Through the autonomic nervous system, the hypothalamus helps  regulate body functions such as temperature, hunger, thirst, and  water and electrolyte balance.   In addition to the hypothalamic activity, important autonomic  reflex centers involve the medulla oblongata and the spinal cord.  For example, reflex centers in the medulla oblongata for cardiac,  vasomotor, and respiratory activities receive sensory impulses  from viscera on sensory fibers in the vagus nerve, and use auto-  nomic nerve pathways to stimulate motor responses in smooth  muscle, cardiac muscle, and glands.   Still higher levels in the brain can have important impacts  on autonomic function. Connections from the cerebral cortex,    including the limbic system, can influence autonomic centers and  increase both sympathetic and parasympathetic activities. A famil-  iar example involving the parasympathetic division is salivating at  the anticipation of eating, an action that originates in the cortex.  An example involving the sympathetic division is the increase in heart  rate and blood pressure when a person becomes agitated or upset,  which is again a result of input from the cerebral cortex. Subsequent  chapters discuss autonomic regulation of particular organs.    45 Explain how the fibers of one autonomic division can control the  actions of a particular organ.    47 Describe two types of cholinergic receptors and two types of  adrenergic receptors.    The redundancies and overlap of function in our nervous systems  ensure that we can perceive and interact with the environment for  many decades. In a sense, aging of this organ system begins before  birth, as apoptosis, a form of programmed cell death, carves out  the structures that will remain in the brain. This normal dying off  of neurons continues throughout life. When brain apoptosis fails,  disease results. For example, the brains of individuals who die of  schizophrenia as young adults contain the same numbers of neurons  as do newborns. These extra neurons may produce the extra dopa-  mine that can lead to hallucinations, the hallmark of this illness.   By age thirty, the die-off of neurons accelerates somewhat,  although pockets of neural stem cells lining the ventricles retain  the capacity to give rise to cells that differentiate as neurons and  neuroglia. Over an average lifetime, the brain shrinks by about  10%, with more loss in gray matter than white. Neuron loss is  uneven. Many cells die in the temporal lobe, for example, but  very few die in the brainstem. By age ninety the frontal cortex    11.1 Overview of Divisions of the Nervous  System (page 390)  The central nervous system (CNS) consists of the brain and  spinal cord.  1. The brain oversees sensation and perception, movement,  and thinking.  2. The brainstem connects the brain and spinal cord, allowing  communication between the two.    3. The spinal cord provides communication between the CNS  and the PNS.    has lost about half its neurons, but this deficit doesn’t necessarily  hamper function.   The nervous system changes over time in several ways. The  number of dendritic branches in the cerebral cortex falls. Signs  of slowing neurotransmission include decreasing levels of neu-  rotransmitters, the enzymes necessary to synthesize them, and  the numbers of postsynaptic receptors. The rate of action poten-  tial propagation may decrease by 5% to 10%. Nervous system  disorders that may begin to cause symptoms in older adulthood  include stroke, depression, Alzheimer disease, Parkinson dis-  ease, and multi-infarct dementia.   Noticeable signs of a normally aging nervous system include  fading memory and slowed responses and reflexes. Decline in  function of the sympathetic nervous system may cause transient  drops in blood pressure, which, in turn, may cause fainting. By the  seventh decade, waning ability of nerves in the ankles to respond  to vibrations from walking may affect balance, raising the risk of  falling. Poor eyesight, anemia, inner ear malfunction, and effects  of drugs also contribute to poor balance in the later years. Because  of these factors, nearly a third of individuals over age sixty-five  have at least one serious fall a year.   Changes in sleep patterns accompany aging, reflecting the  functioning of the reticular activating system. Older individuals  generally sleep fewer hours per night than they once did, experi-  encing transient difficulty in getting to sleep and staying asleep,  with more frequent movements when they are sleeping. Many  have bouts with insomnia, sometimes not sleeping more than an  hour or two a night. Changing electroencephalogram patterns indi-  cate that stage IV slow-wave sleep as well as REM sleep diminish.  All of these changes may result in daytime sleepiness.    48 How does aging of the nervous system begin even before birth?  49 What are some diseases that affect the aging nervous system?    50 What are some of the physical and functional signs of an aging  nervous system? Hl    Bone and protective membranes called meninges surround the  brain and spinal cord.  1. The meninges consist of a dura mater, arachnoid mater,  and pia mater.  2. Cerebrospinal fluid (CSF) occupies the space between the  arachnoid and pia maters.    Ventricles, filled with cerebrospinal fluid, are connected  cavities in the cerebral hemispheres and brainstem.    1. Choroid plexuses in the walls of the ventricles secrete CSF.    2. Ependymal cells of the choroid plexus regulate the  composition of CSF.    3. CSF circulates through the ventricles and is reabsorbed  into the blood of the dural sinuses.    4. CSF helps maintain a stable ion concentration in the CNS  and provides a pathway to the blood for waste.    The brain is the largest and most complex part of the nervous  system. It contains nerve centers associated with sensations.  The brain issues motor commands and carries on higher  mental functions.   The brain develops from a neural tube with three  cavities—the forebrain, midbrain, and hindbrain.   The cavities persist as ventricles, and the walls give rise  to structural and functional regions.    The cerebrum consists of two cerebral hemispheres  connected by the corpus callosum.   Its surface is marked by ridges and grooves; sulci divide  each hemisphere into lobes.   The cerebral cortex is a thin layer of gray matter near  the surface.   White matter consists of myelinated nerve fibers that  connect neurons and communicate with other body parts.    The cerebrum provides higher brain functions, such as  thought, reasoning, interpretation of sensory impulses,  control of voluntary muscles, and memory storage.   are in the parietal lobes near the central sulcus; other  specialized sensory areas are in the temporal lobes and  occipital lobes.   The primary motor regions lie in the frontal lobes  near the central sulcus. Other areas of the frontal lobes  control special motor functions.    term memory is thought to be encoded in patterns of  synaptic connections.    Basal nuclei are masses of gray matter deep within the  cerebral hemispheres.   The neurons of the basal nuclei interact with other brain  areas to facilitate voluntary movement.   The thalamus selects incoming sensory impulses and  relays them to the cerebral cortex.    The brainstem extends from the base of the brain to  the spinal cord.   The midbrain contains reflex centers associated with  eye and head movements.   The pons conducts impulses between the cerebrum  and other parts of the nervous system.   The medulla oblongata conducts all ascending and  descending impulses and contains several vital  reflex centers including those involved with the  cardiovascular and respiratory systems.   The reticular formation filters incoming sensory  impulses, arousing the cerebral cortex into wakefulness  in response to meaningful impulses.   Normal sleep results from decreasing activity of the  reticular formation, and paradoxical sleep occurs  when some parts of the brain, but not others, receive  activating impulses.   A thin cortex of gray matter surrounds the white matter  of the cerebellum.    The spinal cord is a nerve column that extends from the brain  into the vertebral canal. It terminates at the level between the  first and second lumbar vertebrae.    The spinal cord is composed of thirty-one segments,  each of which gives rise to a pair of spinal nerves.   It is characterized by a cervical enlargement, a lumbar  enlargement, and two deep longitudinal grooves that  divide it into right and left halves.   White matter surrounds a central core of gray matter.  The white matter is composed of bundles of myelinated  nerve fibers.   (3) The knee-jerk reflex employs only two neurons.  Other reflexes involve more neurons.   (1) Ascending tracts conduct sensory impulses to the  brain; descending tracts conduct motor impulses  to muscles and glands.   (2) Many of the fibers in the ascending and  descending tracts cross over in the spinal cord  or brain.    The peripheral nervous system consists of cranial and spinal  nerves that branch out from the brain and spinal cord to all  body parts. It is subdivided into the somatic nervous system  and the autonomic nervous system.    A nerve consists of a bundle of nerve fibers surrounded  by connective tissues.   The connective tissues form an outer epineurium, a  perineurium enclosing bundles of nerve fibers, and an  endoneurium surrounding each fiber.    Nerves are cordlike bundles of nerve fibers. Nerves are  classified as sensory nerves, motor nerves, or mixed  nerves, depending on fiber type.   Nerve fibers in the CNS are subdivided into groups  with general and special functions.    Twelve pairs of cranial nerves connect the brain to  parts in the head, neck, and trunk.   Most cranial nerves are mixed, but some are pure  sensory and others are primarily motor.   The names of cranial nerves indicate their primary  functions or the general distributions of their fibers.  Some cranial nerve fibers are somatic and others are  autonomic.   Each nerve emerges by a dorsal root and a ventral root.   (1) A dorsal root contains sensory fibers and has a  dorsal root ganglion.    The autonomic nervous system functions without conscious  effort. It regulates visceral activities that maintain homeostasis.    Autonomic functions are reflexes controlled from centers  in the hypothalamus, brainstem, and spinal cord.  Autonomic nerve fibers are associated with ganglia  where impulses are integrated before distribution to  effectors.   The integrative function of the ganglia provides a  degree of independence from the CNS.   The autonomic nervous system consists of the visceral  efferent fibers associated with these ganglia.   The autonomic nervous system is subdivided into two  divisions—sympathetic and parasympathetic.   The sympathetic division prepares the body for  stressful and emergency conditions.   a. Sympathetic fibers leave the spinal cord and synapse in  ganglia.   b. Preganglionic fibers pass through white rami to reach  paravertebral ganglia.   e. Most postganglionic fibers pass through gray rami to  reach spinal nerves before passing to effectors.   f. A special set of sympathetic preganglionic fibers passes  through ganglia and extends to the adrenal medulla.   fibers that begin in the brainstem and sacral region of the   spinal cord and synapse in ganglia near various organs or  in the organs themselves.   b. Most sympathetic postganglionic fibers secrete  norepinephrine and are adrenergic; postganglionic  parasympathetic fibers secrete acetylcholine and  are cholinergic.   c. The different effects of the autonomic divisions are due  to the different neurotransmitters the postganglionic  fibers release.   b. There are two types of cholinergic receptors and two  types of adrenergic receptors.   c. How cells respond to neurotransmitters depends upon  the number and type of receptors in their membranes.   d. Acetylcholine acts very briefly; norepinephrine and  epinephrine may have more prolonged effects.   a. The central nervous system largely controls the  autonomic nervous system.   b. The medulla oblongata uses autonomic fibers to  regulate cardiac, vasomotor, and respiratory activities.   d. The limbic system and cerebral cortex control  emotional responses through the autonomic nervous  system.    Aging of the nervous system is a gradual elimination of cells  and, eventually, slowed functioning.   In adulthood, numbers of dendrites in the cerebral cortex  fall, as more generally neurotransmission slows.   Nervous system changes in older persons increase the risk  of falling.    Explain the general functions of the brain and spinal cord,  and their interrelationship. (p. 390)    Name the layers of the meninges, and explain their functions.  (pp. 390-391)    Describe the relationship among the cerebrospinal fluid, the  ventricles, the choroid plexuses, and arachnoid granulations.  (pp. 391-395)   Describe the structure of the cerebrum. (pp. 395 and 397)  Define cerebral cortex. (p. 397)   Describe the location and function of the sensory areas of  the cortex. (p. 399)   Explain the function of the association areas of the lobes of  the cerebrum. (pp. 399-401)   Describe the location and function of the motor areas of the  cortex. (pp. 401-402)   The conducts sensory information from other  parts of the nervous system to the cerebral cortex. (p. 403)   List the parts of the limbic system, and explain its functions.  (pp. 403 and 405)   Name the functions of the midbrain, pons, and medulla  oblongata. (pp. 405-407)   Describe the location and function of the reticular formation.  (p. 407)    Describe the structure of the spinal cord. (pp. 409-410)  List the two main functions of the spinal cord. (p. 410)  Distinguish between a reflex arc and a reflex. (p. 411)    Which of the choices is the correct sequence of events in a   Describe the connective tissue and nervous tissue making up  a peripheral nerve. (pp. 418-419)   Which of the following conduct sensory impulses to the CNS  from receptors in muscle or skin? (pp. 420)   Draw the underside of a brain and label the cranial nerves.  (pp. 421-424)   Match the cranial nerve with its function(s). Functions may be  used more than once. (pp. 421-424)    nerve  (9) glossopharyngeal F. conducts impulses to muscles  hana of neck  (10) vagus nerve G. conducts impulses associated  with hearing    Explain how the spinal nerves are grouped and numbered.  (p. 425)   Describe the parts of a spinal nerve and their functions.  (pp. 426-427)   Define plexus, and locate the major plexuses of the spinal  nerves. (pp. 427-428)   39 Contrast the sympathetic and parasympathetic divisions of  the autonomic nervous system. (p. 431)   40 Distinguish between a preganglionic fiber and a  postganglionic fiber. (p. 431)    1. In planning treatment for a patient who has had a cerebrovascular  accident (CVA), why would it be important to know whether the  CVA was caused by a ruptured or obstructed blood vessel?    2. Ifa physician plans to obtain a sample of spinal fluid from a  patient, what anatomical site can be safely used, and how  should the patient be positioned to facilitate this procedure?    3. What functional losses would you expect to observe in a patient  who has suffered injury to the right occipital lobe of the cerebral  cortex? To the right temporal lobe?   46 Explain how autonomic neurotransmitters influence the  actions of effector cells. (pp. 433 and 436-437)   47 Distinguish between alpha adrenergic and beta adrenergic  receptors. (pp. 436-437)    11.8 Life-Span Changes  48 Explain the effects of apoptosis on the developing brain.  (p. 438)  49 List three ways that the nervous system changes as we age.  (p. 438)  50 Describe sleep problems that may accompany aging.  (p. 438)    4. Brown-Seguard syndrome is due to an injury on one side of  the spinal cord. It is characterized by paralysis below the injury  and on the same side as the injury, and by loss of sensations  of temperature and pain on the opposite side. How would you  explain these symptoms?    5. The biceps-jerk reflex employs motor neurons that exit from the  spinal cord in the fifth spinal nerve (C5), that is, fifth from the top  of the cord. The triceps-jerk reflex involves motor neurons in the  seventh spinal nerve (C7). How might these reflexes be used to  help locate the site of damage in a patient with a neck injury?    6. What symptoms might the sympathetic division of the autonomic  nervous system produce in a patient experiencing stress?    |ANATOMY & PHYSIOLOGY  Connect Interactive Questions Reinforce your knowledge  using assigned interactive questions covering the parts of the  nervous system.    Connect Integrated Activity Could you help a neurologist  determine the location of a lesion in the central or peripheral  nervous system?    Anatomy & Physiology Revealed Go more in depth into the  human body by exploring cadaver dissections of the brain and spinal  cord, as well as viewing animations on physiological processes.    my» LEARNING OUTCOMES  After you have studied this chapter, you should be able to:    2 Name the five types of receptors and state the function of  each. (p. 444)    The spiral organ, in the inner ear, has rows of hair cells. Each row bears up 12.3 General Senses  to 100 hairs, which translate sound into neural messages that travel to the 5  brain. In this falsely colored micrograph, the cells appear red and the hairs    Describe the differences among receptors associated  with the senses of touch, pressure, temperature, and  pain. (pp. 446-447)    6 Describe how the sensation of pain is produced. (p. 449)  ears 7 Explain the importance of stretch receptors in muscles  THE WHOLE PICTU RE and tendons. (pp. 449-451)  12.4 Special Senses    8 Explain the relationship between the senses of smell  and taste. (p. 452)    The senses provide information about what is happening in  the world outside and inside the body, whether it is the feel    of clothing against your skin as you are getting dressed, an 9 Describe how the sensations of smell and taste are   unusual smell, or the awareness that your heart is pounding in produced and interpreted. (pp. 452-456)   your chest when you are excited. 10 Name the parts of the ear and explain the function of  Despite the fact that all action potentials are the same, we each part. (pp. 456-461)   are able to distinguish among a wide variety of stimuli. What 11 Distinguish between static and dynamic equilibrium.   we hear, smell, taste, and see, and how those senses combine, (pp. 464 and 466)   reflect both the parts of the brain that process the incoming 12 Describe the roles of the accessory organs to the eye.    13 Name the parts of the eye and explain the function of  each part. (pp. 470-475)    14 Explain how the eye refracts light. (pp. 475 and 478)    15 Distinguish between rods and cones, and discuss their  respective visual pigments. (pp. 478-481)    information, and the rich collection of receptors tuned in to the  world. At the same time, the nervous system also “tunes out”  unimportant information. If your brain seems overloaded now,  imagine how it would be if you were aware of all of the sounds,  smells, and other sensory stimuli present in your environment all    of the time! 16 Explain how the brain perceives depth and distance. (p. 481)    17. Describe the visual nerve pathways. (p. 481)  12.5 Life-Span Changes    Our senses not only make our lives meaningful, connecting us to  the sights, sounds, smells, tastes, and textures of the outside world,  but also help our bodies maintain homeostasis by providing infor-  mation about what is happening on the inside. Sensory receptors  are the portals that link our nervous systems to all of these events.  The general senses are those with receptors widely distributed  throughout the body, including the skin, various organs, and joints.  The special senses have more specialized receptors and are con-  fined to structures in the head, such as the eyes and ears.   All senses work in basically the same way. Sensory receptors  are specialized cells (receptor cells) or multicellular structures that  collect information from the environment. In some senses, such as  smell and taste, the receptor cells have specific molecules on the  cell membrane (membrane receptors). Stimulated receptor cells in  turn stimulate neurons to conduct impulses along sensory fibers to  the brain. There the cerebral cortex interprets the information.   Chapter 11 (p. 419) uses the terms axon and nerve fiber syn-  onymously. Also recall from chapter 10 (p. 366) that unipolar  neurons, which include most sensory neurons, are unusual in that  the portion of the neuron associated with the dendrites, called a  peripheral process, functions like an axon (see fig. 10.6, p. 366).  Because of this, and for simplicity, we call the neuron processes  that bring sensory information into the CNS “sensory fibers” or  “afferent fibers,” no matter the type of neuron.    The body’s ability to interpret different sensory events depends partly  on receptors that respond to specific stimuli. Sensory receptors are  diverse but share certain features. Each type of receptor is particularly  sensitive to a distinct type of environmental change and is much less  sensitive to other forms of stimulation. The raw form in which these  receptors send information to the brain is called sensation. The way  the brain interprets this information is called perception.    Five types of sensory receptors are recognized, based on their sen-  sitivities to specific stimuli:    1. Chemoreceptors (ke”mo-re-sep’torz) respond to changes in  the concentration of chemicals. Receptors associated with the  senses of smell and taste are of this type. Chemoreceptors in  internal organs detect changes in the blood concentrations of  oxygen, hydrogen ions, glucose, and other chemicals.   2. Pain receptors, also called nociceptors (no”se-sep’torz),  respond to tissue damage. Triggering stimuli include exposure  to excess mechanical, electrical, thermal, or chemical energy.   4. Mechanoreceptors (mek’ah-no re-sep’torz) are of several  types and sense mechanical forces by detecting changes that  deform the receptors. They include a number of receptors in  the skin that respond to physical contact, and several receptors  in the ear that provide information about balance and vibra-  tions from sound. Proprioceptors (pro”pre-o-sep’torz) sense  changes in the tensions of muscles and tendons; barorecep-  tors (bar”o-re-sep’torz), also called pressoreceptors, in certain  blood vessels detect changes in blood pressure; and stretch  receptors in the lungs sense degree of inflation.    Sensory receptors can be ends of neurons or other types of cells  that are near neuron extensions. In either case, stimulation locally  changes the cells’ membrane potentials (receptor potentials), gen-  erating a graded electric current that reflects the intensity of stimu-  lation (see chapter 10, p. 377).   If a receptor is a neuron and the change in membrane potential  reaches threshold, an action potential is generated and is propa-  gated along the afferent fiber. However, if the receptor is another  type of cell, its receptor potential must be transferred to a neuron  to trigger an action potential. Peripheral nerves conduct the resulting  impulses to the central nervous system (CNS), where they are ana-  lyzed and interpreted in the brain.    A sensation occurs when sensory neurons reach threshold and the  resulting action potentials cause the brain to become aware of that  sensory event. A perception occurs when the brain interprets those  sensory impulses. Thus, pain is a sensation, but realizing that you  have just stepped on a tack is a perception. Table 12.1 outlines  the pathways from sensing to perceiving an apple using the special  senses: smell, taste, sight, and hearing.   At the same time that a sensation forms, the cerebral cortex  interprets it as coming from the receptors being stimulated. This  process, which is closely related to perception, is called projection,  because the brain projects the sensation back to its apparent source.  Projection allows a person to pinpoint the region of stimulation. In  this way, we perceive that the eyes see an apple, the nose smells it,  and the ears hear the teeth crunch into it.   Because all of the impulses conducted on sensory fibers into  the CNS are alike, the resulting sensation depends on which region  of the cerebral cortex receives the impulse. For example, impulses  reaching one region are always interpreted as sounds, and those  reaching another are always sensed as touch. (Some receptors,  such as those that measure oxygen levels in the blood, do not trig-  ger sensations.)    LE ~ ™,  Imagine two cell phones in front of you, one on the left and  one on the right. The ring tones are identical and equally loud.  In fact, there is no way to tell them apart other than by their  location. Yet from experience you know that the one on the  left always handles calls from your best friend, and the one on  the right is always someone else. Similarly, impulses that trans-  mit sensations are just as alike as the two cell phone ring tones,  but they are interpreted differently because they go to different  parts of the brain.    ® RECONNECT  ~ To Chapter 11, Functions of the Cerebrum, pages 399-401.    Sensory receptors are specialized to respond to certain types  of stimuli, but they may respond to other stimuli that are strong  enough. In either case the sensations are the same. Pain receptors,  for example, can be stimulated by heat, cold, or pressure, but the  sensation is always the same because, in each case, the same part  of the brain interprets the resulting impulses as pain. Similarly, a  stimulus other than light, such as a sharp blow to the head, may  trigger impulses in visual receptors. When this happens, the person  may “see stars,” even though no light is entering the eye, because  any impulses reaching the visual cortex are interpreted as light.  Receptors respond only to specific stimuli, and the brain typically  creates the correct sensation for that particular stimulus.    The brain must prioritize the sensory input it receives, or incoming  unimportant information would be overwhelming. For example,  until this sentence prompts you to think about it, you are probably    unaware of the pressure of your clothing against your skin, or the  background noise in the room. This ability to ignore unimportant  stimuli is called sensory adaptation (sen’so-re ad” ap-ta’shun). It  may reflect a decreased response to a particular stimulus from the  receptors (peripheral adaptation) or along the CNS pathways lead-  ing to the sensory regions of the cerebral cortex (central adapta-  tion). Once adaptation to a particular stimulus occurs, a sensation  will occur only if the strength of the stimulus changes.    Distinguish between general and special senses.  List the five general types of sensory receptors.  What do all types of receptors have in common?    The young man awoke in a military hospital just as a medical  professional approached. She pointed to her pin, which said  “audiology” above her name, and started to speak, but he  couldn't hear a word she was saying. When the man pointed  to his ears, she pulled out a pad and pen and wrote “blast  injury—lIED” and showed it to him. The man realized he'd  been exposed to an improvised explosive device, and the  pressure of the bomb had damaged his ears.   The audiologist gave her new patient printed  information on blast injuries that explained how she would  assess the severity of his hearing loss: visual inspection  for eardrum injury, and computed tomographic scans to  examine bones of the middle ears and the cochlea in the  inner ears. Hearing would return if the damage was confined  to the outer or middle ears, but a cochlear implant might be  necessary if the inner ear was damaged.   Audiology grew out of the need for specialists to  treat hearing loss among soldiers returning from World  War Il. Today audiologists examine, diagnose, and treat  individuals who have problems with hearing or balance.  They fit hearing aids, remove wax, and provide protective  devices for people who are exposed to loud sounds, such  as construction workers and musicians. Patients range  from young children with hearing loss from repeated ear  infections, to the very elderly.   An audiologist uses a device called an audiometer to  test how loud a sound must be for a patient to hear it, and  whether the person can distinguish sounds. For patients  with dizziness, an audiologist can determine whether the  vestibular system in the ear is implicated.   Audiologists may work in private practice or in  hospitals, clinics, schools, the military, long-term care  facilities or forensics laboratories. A doctoral degree in  audiology (Au.D.), typically earned after college, takes  three years plus a year of externship.    TABLE 12.1 Information Flow from the Environment Through the Nervous System    General senses are those whose sensory receptors are widespread,  associated with the skin, muscles, joints, and viscera. These senses  can be divided into three groups:    1. Exteroreceptive senses are associated with changes at the  body surface. They include the senses of touch, pressure,  temperature, and pain.   2. Interoceptive (visceroceptive) senses are associated with  changes in viscera (blood pressure stretching blood vessels, an  ingested meal stimulating pH receptors in the small intestine,  and so on).   3. Proprioceptive senses are associated with changes in muscles  and tendons and in body position.    The senses of touch and pressure derive from three types of  receptors (fig. 12.1). As a group, these receptors sense mechani-  cal forces that deform or displace tissues. The touch and pressure  receptors include the following:    1. Free nerve endings, the simplest receptors, are common  in epithelial tissues, where they lie between epithelial cells.  They are responsible for the sensation of itching (fig. 12.1a).   2. Tactile (Meissner’s) corpuscles are small, oval masses of flat-  tened connective tissue cells in connective tissue sheaths. Two  or more sensory fibers branch into each corpuscle and end  within it as tiny knobs.   Tactile corpuscles are abundant in hairless areas of skin,  such as the lips, fingertips, palms, soles, nipples, and external  genital organs. They provide fine touch, such as distinguishing  two points on the skin where an object touches, to judge its  texture (fig. 12.1b).   3. Lamellated (Pacinian) corpuscles are relatively large, ellip-  soidal structures composed of connective tissue fibers and  cells. They are common in the deeper dermal tissues of the  hands, feet, penis, clitoris, urethra, and breasts and also in    the connective tissue capsules of synovial joints (fig. 12.1c).  Heavier pressure and stretch stimulate lamellated corpuscles.  They also detect vibrations in tissues.    Temperature receptors (thermoreceptors) include two groups  of free nerve endings in the skin. Those that respond to warmer  temperatures are warm receptors, and those that respond to colder  temperatures are cold receptors.   The warm receptors are most sensitive to temperatures above  25°C (77°F) and become unresponsive at temperatures above  45°C (113°F). Temperatures near and above 45°C also trigger pain  receptors, producing a burning sensation.   Cold receptors are most sensitive to temperatures between  10°C (50°F) and 20°C (68°F). Temperature dropping below 10°C  also stimulates pain receptors, producing a freezing sensation.   At intermediate temperatures, the brain interprets sensory  input from different combinations of warm and cold receptors as  an intermediate temperature sensation. Both types of receptors  rapidly adapt, so within about a minute of continuous stimula-  tion, the sensation of warm or cold begins to fade. This is why we  quickly become comfortable after jumping into a cold swimming  pool or submerging into a steaming hot tub.    Pain receptors (nociceptors) consist of free nerve endings. These  receptors are widely distributed throughout the skin and internal  tissues, except in the nervous tissue of the brain, which lacks pain  receptors. Pain receptors protect in that they are stimulated when  tissues are damaged and may prevent further damage. Most pain  sensations are perceived as unpleasant, signaling the individual to  remove the source of the stimulation.   More than one type of change stimulates most pain recep-  tors. However, some pain receptors are most sensitive to mechani-  cal damage, while others are particularly sensitive to temperature  extremes. Some pain receptors are most responsive to chemicals,    FIGURE 12.1 Touch and pressure receptors include (a) free ends of sensory nerve fibers, (b) a tactile corpuscle (with 225x micrograph), and    such as hydrogen ions, potassium ions, or specific breakdown prod-  ucts of proteins, histamine, and acetylcholine. A deficiency of blood  flow (ischemia) and the resulting deficiency of oxygen (hypoxia)  in a tissue also trigger pain sensation. For example, the sharp  pain of a muscle cramp results from interruption of blood flow as  the sustained contraction squeezes capillaries, as well as from the  stimulation of mechanoreceptors. Additionally, when blood flow  is interrupted, pain-stimulating chemicals accumulate. Increasing  blood flow through the sore tissue may relieve the resulting pain,  and this is why heat is sometimes applied to reduce muscle sore-  ness. The heat dilates blood vessels and thus promotes blood flow,  which helps reduce the concentration of the pain-stimulating sub-  stances. In some conditions, accumulating chemicals lower the  thresholds of pain receptors, making inflamed tissues more sensitive  to heat or pressure.   Pain receptors adapt very little, if at all. Once a pain receptor is  activated, even by a single stimulus, it may continue to send impulses  into the CNS for some time. Clinical Application 3.1 (p. 89) describes  the genetic basis of how people vary in their sensitivity to pain.   As a rule, pain receptors are the only receptors in viscera whose  stimulation produces sensations. Pain receptors in these organs  respond differently to stimulation than those associated with    surface tissues. For example, localized damage to intestinal tis-  sue during surgical procedures may not elicit any pain sensations,  even in a conscious person. However, when visceral tissues are  subjected to more widespread stimulation, such as when intes-  tinal tissues are stretched or when the smooth muscle in the  intestinal walls undergoes spasms, a strong pain sensation may  follow. Once again, the resulting pain comes from stimulation of  mechanoreceptors and from decreased blood flow accompanied  by lower tissue oxygen levels and accumulation of pain-causing  chemicals stimulating chemoreceptors.   Visceral pain may feel as if it is coming from some part of the  body other than the part being stimulated, in a phenomenon called  referred pain. For example, pain originating in the heart may be  referred to the left shoulder or the medial surface of the left upper  limb. Pain from the lower esophagus, stomach, or small intestine  may seem to be coming from the upper central (epigastric) region  of the abdomen. Pain from the urogenital tract may be referred to  the lower central (hypogastric) region of the abdomen or to the  sides between the ribs and the hip (fig. 12.2).   Referred pain may derive from common nerve pathways that  sensory impulses coming both from skin areas and from internal  organs use. Pain impulses from the heart seem to be conducted over  the same nerve pathways as those from the skin of the left shoul-  der and the inside of the left upper limb, as shown in figure 12.3.    FIGURE 12.3 Pain originating in the heart may feel as if it is  coming from the skin because sensory impulses from the heart  and the skin follow common nerve pathways to the brain.    During a heart attack, the cerebral cortex may incorrectly interpret  the source of the impulses as the shoulder and the medial surface of  the left upper limb, rather than the heart.   Pain originating in the parietal layers of the thoracic and  abdominal membranes—parietal pleura, parietal pericardium, or  parietal peritoneum—is usually not referred. Instead, such pain is  felt directly over the area being stimulated.    Neuropathic pain is an overreaction to a stimulus that would  ordinarily cause pain, or a pain response to a normally innocu-  ous stimulus. Reflex sympathetic dystrophy is a form of neuro-  pathic pain that causes an intense burning sensation in a hand or  foot, even if the extremity is paralyzed or has been amputated.  During the Civil War, it was called “causalgia.” Union Army  Surgeon S. Weir Mitchell described causalgia as “the most ter-  rible of all tortures.”    The axons (fibers) that conduct impulses away from pain receptors  are of two main types: fast pain fibers and slow pain fibers.   The fast pain fibers (also known as A-delta fibers) are  myelinated. They conduct impulses rapidly, at velocities up to  30 meters per second. These impulses are associated with the  immediate sensation of sharp pain, which typically seems to origi-  nate in a local area of skin. This type of pain seldom continues  after the pain-producing stimulus stops.   The slow pain fibers (C fibers) are unmyelinated. They con-  duct impulses more slowly than fast pain fibers, at velocities up to  2 meters per second. These impulses cause a delayed, dull, ach-  ing pain sensation that may be widespread and difficult to pin-  point. Such pain may continue after the original stimulus ceases.  Although immediate pain is usually sensed as coming from the  surface, delayed pain is felt in deeper tissues as well as in the skin.  Visceral pain impulses are typically carried on C fibers.   Usually, an event that stimulates pain receptors triggers  impulses on both fast and slow pain fibers. The result is a dual  sensation—a sharp, pricking pain, then a dull, aching pain that is  more intense and may worsen over time. Chronic pain that resists  relief and control can be debilitating.   Pain impulses that originate from tissues of the head reach the  brain on sensory fibers of the fifth, seventh, ninth, and tenth cranial  nerves (see chapter 11, pp. 421-423). All other pain impulses are  conducted on sensory fibers of spinal nerves, and they pass into  the spinal cord by way of the dorsal roots of these spinal nerves.   Upon reaching the spinal cord, these sensory fibers enter the  gray matter of the posterior horn. There they synapse with neurons  whose axons cross over to the opposite side of the spinal cord at  that level and then ascend in the anterior and lateral spinothalamic  tracts (anterolateral system). These pathways also involve one or  more interneurons before reaching the long fibers that cross over  and ascend to the brain.   In the brain, most of the pain fibers synapse in the reticular  formation (see chapter 11, p. 407), and from there impulses are  conducted on fibers of still other neurons to the thalamus, hypo-    thalamus, and cerebral cortex. Fibers of the spinothalamic tracts  bring pain and temperature information directly to the thalamus.   Sensation of pain begins when pain impulses reach the level of  the thalamus—that is, even before they reach the cerebral cortex.  However, the cerebral cortex must judge the intensity of pain and  locate its source, and it is also responsible for emotional and motor  responses to pain.   Still other parts of the brain, including areas of gray matter in  the midbrain, pons, and medulla oblongata, regulate the flow of  pain impulses from the spinal cord (see chapter 11, pp. 405-407).  Impulses from special neurons in these areas descend in the lateral  funiculus to various levels within the spinal cord. The impulses  stimulate the ends of certain nerve fibers to release biochemicals  that can block pain signals by inhibiting presynaptic nerve fibers  in the posterior horn of the spinal cord.   Among the inhibiting substances released in the posterior  horn are neuropeptides called enkephalins and the amine sero-  tonin (see chapter 10, pp. 380-382). Enkephalins can suppress  both acute and chronic pain impulses. Therefore, they can relieve  strong pain sensations, much as morphine and other opiate drugs  do. In fact, enkephalins were discovered because they bind to the  same receptors on neuron membranes as does morphine. Serotonin  stimulates other neurons to release enkephalins.    Cannabinoids are chemicals in the plant Cannibus sativa, the  source of marijuana, that may relieve pain. Neurons in areas of  the brain, brainstem, and peripheral nervous system have recep-  tors for cannabinoids that bind a type of neurotransmitter made  in the body called anandamide. A synthetic version of the com-  pound in marijuana responsible for most of marijuana’s effects  (delta-9-tetrahydrocannabinol), as well as the plant itself, are  used to alleviate nausea and vomiting in people receiving cancer  chemotherapy and to boost appetite in people who have AIDS.    The endorphins are another group of neuropeptides with pain-  suppressing, morphinelike actions. They are found in the pituitary  gland and in regions of the nervous system, such as the hypothala-  mus, that relay pain information. Enkephalins and endorphins are  released in response to extreme pain, providing natural pain control.  Clinical Application 12.1 discusses treatments for severe pain.    Describe three types of touch and pressure receptors.  Describe thermoreceptors.  What types of stimuli excite pain receptors?    Proprioception  Proprioceptors are mechanoreceptors that send information to the  CNS about body position and the length and tension of skeletal    About 25% of all people have moderate to severe pain, anda  quarter of them may be undertreated. Pain remedies include  nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin  (fig. 12A), ibuprofen, and COX-2 inhibitors; opiates (fig. 12B);  and drugs such as acetaminophen, which is the top-selling pain-  killer. Acetaminophen does not have the side effects of gas-  trointestinal irritation of the NSAIDs nor is it addicting like the  opiates, but in large doses it can damage the liver.   Several painkillers are being reformulated as particles that are  up to 20 times smaller than older preparations of the drugs. The  new versions of old standards, such as indomethacin, dissolve faster  and relieve pain faster, so that patients can take lower doses for  shorter periods, making the drugs safer.   In 2004 a new painkiller became  available. Ziconotide is a synthetic ver-  sion of a peptide that the marine cone  snail Conus magus releases to paralyze  its fish prey (fig. 12C). When research-  ers noticed that the natural peptide  binds to a type of calcium channel pro-  tein on spinal cord neurons that receive  pain impulses, the effort began to turn  the snail's weapon into a pain reliever.  Ziconotide is delivered by catheter into  the cerebrospinal fluid and is prescribed  to relieve intractable chronic pain.   The types of patients in greatest  need of pain relief are people with can-  cer or chronic pain syndromes. Cancer  patients take NSAIDs, weak narcotics  such as hydrocodone, strong narcotics  such as morphine, and opiates deliv-  ered directly to the spinal cord via an  implanted reservoir. Narcotics are much  more likely to be addicting when they  are abused to induce euphoria than  when they are taken to relieve severe  pain. Patients may use devices to con-    muscles. Recall that lamellated corpuscles function as pressure  receptors in joints. The other main proprioceptors are stretch recep-  tors: muscle spindles and Golgi tendon organs.   Muscle spindles are located throughout skeletal muscles.  Each spindle consists of several small, modified skeletal muscle  fibers (intrafusal fibers) enclosed in a connective tissue sheath.  Each intrafusal fiber has near its center a specialized nonstriated  region with the end of a sensory nerve fiber wrapped around it  (fig. 12.4a).   The striated portions of the intrafusal fiber contract to keep the  spindle taut at different muscle lengths. Thus, if the whole muscle  is stretched, the muscle spindle is also stretched, triggering sen-  sory impulses on its nerve fiber. These sensory fibers synapse in    FIGURE 12A Painkillers come from nature.  Aspirin derives from bark of the willow tree.    trol the delivery of pain medications. Anti-anxiety medications  can ease the perception of pain.   Some types of chronic pain are lower back pain, migraine, and  myofascial syndrome (inflammation of muscles and their fascia).  Treatment approaches include NSAIDs, stretching exercises,  injection of local anesthetic drugs into cramping muscles, and  antidepressants to raise serotonin levels in the CNS. Chronic pain  may also be treated with electrodes implanted near the spinal  cord; transcutaneous electrical nerve stimulation (TENS), which  also places electrodes on pain-conducting nerves; and an inva-  sive nerve block, which interrupts a pain signal by freezing or by  introducing an anesthetic drug.    FIGURE 12C A newer analgesic for extreme  chronic pain is based on a peptide from the  marine cone snail Conus magus.    the spinal cord with lower motor neurons leading back to the same  muscle. In this way, stretch of the muscle spindle triggers impulses  that contract the skeletal muscle of which it is a part. This action,  called a stretch reflex, opposes the lengthening of the muscle and  helps maintain the desired position of a limb despite gravitational  or other forces tending to move it (see chapter 11, pp. 411-412).    A leg cramp in the middle of the night may be so painful that it |  makes you leap out of bed. The contraction of a cramp may result  from local changes in electrolyte levels in a part of a muscle that  inappropriately trigger impulses from the muscle spindle.    FIGURE 12.4 Stretch receptors maintain posture. (a) Increased muscle length stimulates muscle spindles, which stimulate muscle contraction.    (b) Golgi tendon organs occupy tendons, where they inhibit muscle contraction.    Golgi tendon organs are in tendons close to their attach-  ments to muscles. Each Golgi tendon organ connects to a set of  skeletal muscle fibers and is innervated by a sensory neuron (fig.  12.4b). Golgi tendon organs have high thresholds, and increased  tension stimulates them. Sensory impulses from them produce a  reflex that inhibits contraction of the muscle whose tendon they  occupy. Therefore, the Golgi tendon organs stimulate a reflex  with an effect that is the opposite of a stretch reflex. The Golgi  tendon reflex also helps maintain posture, and it protects muscle  attachments from being pulled away from their insertions by  excessive tension. Table 12.2 summarizes some of the receptors  of the general senses and their functions.    Receptors in internal organs include lamellated corpuscles and free  nerve endings. The information these receptors convey includes the  sense of fullness after eating a meal, the discomfort of intestinal gas,  and the pain that signals a heart attack.    11. Describe a muscle spindle.  12 Explain how muscle spindles help maintain posture.  13 Where are Golgi tendon organs located?    Special senses are those whose sensory receptors are part of  large, complex sensory organs in the head. These senses and their  respective organs include the following:    The ability to detect the strong scent of a fish market, the antisep-  tic odor of a hospital, the aroma of a ripe melon—and thousands of  other smells—is possible thanks to a yellowish patch of tissue the  size of a quarter high up in the nasal cavity. This fabric of sensation  is a layer of as many as 6 million specialized cells.   Olfactory receptor cells, and their membrane receptor molecules,  sense odors. The receptor cells are similar to those for taste in that they  are chemoreceptors sensitive to chemicals dissolved in liquids. The  two chemical senses function closely together and aid in food selec-  tion, because we smell food at the same time we taste it. It is often dif-  ficult to tell what part of a food sensation is due to smell and what part  is due to taste. For this reason, an onion tastes different when sampled  with the nostrils closed, because much of the usual onion sensation  is due to odor. Similarly, if copious mucous secretions from an upper  respiratory infection cover the olfactory receptors, food may seem  tasteless. About 75% to 80% of flavor derives from the sense of smell.    The olfactory organs, which contain the olfactory receptor cells,  also include epithelial supporting cells. These organs appear as    yellowish brown masses within pinkish mucous membrane. They  cover the upper parts of the nasal cavity, the superior nasal con-  chae, and a portion of the nasal septum (fig. 12.5).   The olfactory receptor cells are bipolar neurons surrounded by  columnar epithelial cells. These neurons have knobs at the distal  ends of their dendrites covered with hairlike cilia. The cilia project  into the nasal cavity and are the sensitive portions of the receptor  cells (fig. 12.6). Each of a person’s 12 million olfactory receptor cells  has ten to twenty cilia.    Dogs can sense subtle odors that people emit when becoming  ill with certain conditions. Service dogs are used to sense immi-  nent seizures, drops in blood glucose, and accelerated heart  rate. Dogs can detect a chemical in urine that prostate cancer    Chemicals that stimulate olfactory receptor cells, called odor-  ant molecules, enter the nasal cavity and dissolve at least partially  in the watery fluids that surround the cilia before they can bond to  receptor proteins on the cilia and be detected. Foods, flowers, and  many other objects and substances release odorant molecules.   An odorant molecule may bind to several of the almost 400  types of olfactory membrane receptors that are part of the olfac-  tory receptor cells, depolarizing these cells and thereby generat-  ing action potentials if the depolarization reaches threshold. Note  the distinction between sensory receptors and membrane recep-  tors. Sensory receptors may be as small as individual cells or as  large as complex organs such as the eye or ear. Sensory receptors  respond to sensory stimuli. In contrast, membrane receptors are  molecules such as proteins and glycoproteins on the cell mem-  branes. They enable cells, such as olfactory receptor cells, to  respond to specific molecules.    (a) Columnar epithelial cells support olfactory receptor  cells, which have cilia at their distal ends. (b) The olfactory  area is associated with the superior nasal concha.    One in 1,000 people has a condition called synesthesia ("joined  sensation”), in which the brain interprets a stimulus to one sense  as coming from another. Most common is grapheme-color type  synesthesia, in which letters, numbers, or time evoke specific col-  ors. In lexical-gustatory synesthesia, a name evokes perception of  a strong taste or odor. One woman thought of the name Suzanne  as a strawberry and Anthony as a pork chop. These associations  are involuntary and specific, and persist over a lifetime.   Most synesthesia is present for as long as a person can remem-  ber, but it may develop following brain damage. One woman began  to feel touch sensations in response to certain sounds after suffering  a stroke. Brain imaging traced the formation of unusual connections  between her midbrain and the tactile part of her cerebral cortex.  Positron-emission tomography scanning, which highlights blood  flow in the cerebral cortex, shows dual areas lit up in synesthetes,  corresponding to their shared sensations, and involvement of an  area where the temporal, parietal, and occipital lobes meet.   Mutations in at least four genes cause synesthesia. The condi-  tion is eight times more prevalent among highly creative individu-    FIGURE 12.6 (AP| FJ Light micrograph  of the olfactory epithelium (250x).    Once olfactory receptor cells are stimulated, impulses are con-  ducted along their axons through tiny openings in the cribriform  plates of the ethmoid bone. These fibers (which collectively  form the first cranial nerves) synapse with neurons located in    als than in the general population. Musicians John Mayer, Duke  Ellington, Tori Amos, and Syd Barrett are synesthetes, as were  architect Frank Lloyd Wright and novelist Vladimir Nabokov.   The physical basis of this curious condition is not well under-  stood. It has been attributed to an immature nervous system  that cannot sort out sensory stimuli, or to altered brain circuitry  that routes stimuli to the wrong part of the cerebral cortex.  Synesthesia may be common in infants, vanishing as synapses are  cut back as part of normal development. Perhaps in synesthesia,  too many synapses persist, and the person has the burden, or  gift, of synesthesia.   Experimental devices that help people with deficient senses  use the concept of synesthesia. For example, the “Brainport  vision system” enables a person who cannot see to perceive a  moving object with touch sensations on the tongue. The device  has three parts. Special sunglasses housing a digital video cam-  era link to a base unit worn on a belt, which sends the signals  from incoming light patterns to an electrode array the size of a  postage stamp, which is implanted on the surface of the tongue  tip. Recipients report sensing “pictures painted on the tongue”  that feel like bubbles of differing intensities. With practice, the  visual cortex learns to interpret the “tactile image” sent to the  tongue, and the person becomes able to tell when an object is in  the visual field—which can be lifesaving.    the enlargements of the olfactory bulbs, which are structures  that lie on either side of the crista galli of the ethmoid bone (see  fig. 7.24, p. 220, and fig. 12.5).   In the olfactory bulbs, the sensory impulses are analyzed, and  as a result, additional impulses travel along the olfactory tracts    to portions of the limbic system (see chapter 11, pp. 403 and  405), a brain center for memory and emotions. This is why we  may become nostalgic over a scent from the past. A whiff of the  perfume that grandma used to wear may bring back a flood of  memories. The input to the limbic system also explains why odors  can alter mood so easily. For example, the scent of new-mown  hay or rain on a summer’s morning generally makes us feel good.  The main interpreting areas for the olfactory impulses (olfactory  cortex) are deep within the temporal lobes and at the bases of the  frontal lobes, anterior to the hypothalamus.    Biologists are not certain how stimulated receptors encode specific  smells, but a leading hypothesis is that each olfactory receptor cell  has many copies of only one type of olfactory receptor membrane  protein, but that a receptor protein can bind several related types of  odorant molecules. In addition, any one odorant molecule can bind  several types of olfactory receptors. The brain interprets this binding  information as an olfactory code. In a simplified example, banana  might stimulate receptors 2, 4, and 7; garlic, receptors 1, 5, and 9.  The olfactory organs are high in the nasal cavity above the usual  pathway of inhaled air, so in order to smell a faint odor, a person  may have to sniff and force air up to the receptor areas. Olfaction  undergoes sensory adaptation rather rapidly, so the intensity of an  odor drops about 50% within a second following the stimulation.  Within a minute, the receptors may become almost insensitive to a    given odor. This is why the odor of a fish market becomes tolerable  quickly. However, olfactory receptors that have adapted to one  scent remain sensitive to others.   The olfactory receptor neurons are the only nerve cells in  direct contact with the outside environment, and as such are prone  to damage. Fortunately, basal cells along the basement membrane  of the olfactory epithelium regularly divide and yield cells that  differentiate to replace lost olfactory receptor neurons. These neu-  rons are unusual in that they are regularly replaced when damaged.    16 Trace the pathway of an olfactory impulse from a receptor to  the cerebrum.    Taste buds are the special organs of taste. They resemble orange  sections and associate on the surface of the tongue with tiny eleva-  tions called papillae (figs. 12.7 and 12.8). Taste buds are also scat-  tered in the roof of the mouth, the linings of the cheeks, and the  walls of the pharynx.    Each taste bud includes a group of modified epithelial cells, the  taste cells (gustatory cells), that function as sensory receptors.    surface of the tongue are associated with nipplelike elevations  called papillae. (b) A taste bud contains taste cells and has an  opening, the taste pore, at its free surface. (b)    FIGURE 12.8 fAP|R) A light micrograph of some taste buds  (arrows) (225x).    Each of our 10,000 taste buds houses 50 to 150 taste cells. The  taste bud also includes epithelial supporting cells. The entire struc-  ture of a taste bud is somewhat spherical, with an opening, the  taste pore, on its free surface. Tiny projections (microvilli), called  taste hairs, protrude from the outer ends of the taste cells and jut  through the taste pore. These taste hairs are the sensitive parts of  the receptor cells.   Interwoven among and wrapped around the taste cells is a net-  work of sensory fibers whose ends closely contact the receptor cell  membranes. A stimulated receptor cell triggers an impulse, which  is conducted along a nearby fiber into the brain.   A chemical to be tasted must dissolve in saliva, which is the  watery fluid surrounding the taste buds. The salivary glands sup-  ply this fluid. To demonstrate the importance of saliva, blot your  tongue and try to taste some dry food; then repeat the test after  moistening your tongue with saliva.   The sense of taste derives from combinations of chemicals  binding specific receptor cells. This takes place on taste hair sur-  faces. The binding of the chemical alters membrane polarization,  generating impulses on nearby sensory nerve fibers. The degree of  change is directly proportional to the concentration of the stimu-  lating substance.   The five primary taste sensations are sweet, sour, salty, bitter, and  umami (00-mom’ee). Each of the many flavors we experience  results from one of the primary sensations or from a combina-  tion of them. The way we experience flavors may also reflect the  concentration of chemicals as well as the sensations of smell, texture  (touch), and temperature. Furthermore, chemicals in some foods—  such as capsaicin in chili peppers—may stimulate pain receptors  that cause a burning sensation.    Experiments indicate that each taste receptor cell is most sen-  sitive to one taste stimulus. Salts and acids act through specific ion  channels. The sensations of bitter, sweet, and umami involve spe-  cific membrane receptors.   Taste cells for each of the five taste sensations are in all areas  of the tongue, but are distributed such that each sensation seems to  arise most strongly from a particular region. Sensitivity to a sweet  stimulus peaks at the tip of the tongue, whereas responsiveness to  sour is greatest at the margins of the tongue, and to bitter at the back.  Receptors particularly responsive to salt are widely distributed.   Sweet receptors are usually stimulated by carbohydrates, but  a few inorganic substances, including some salts of lead and beryl-  lium, also elicit sweet sensations. Acids stimulate sour receptors.  The intensity of a sour sensation is roughly proportional to the  concentration of the hydrogen ions in the substance being tasted.  Ionized inorganic salts mainly stimulate salt receptors. The qual-  ity of the sensation that each salt produces depends upon the type  of positively charged ion that it releases into solution, such as Na*  from table salt. A variety of chemicals stimulates bitter receptors,  including many organic compounds. Inorganic salts of magnesium  and calcium produce bitter sensations, too. Extreme sensitivity  to bitter tastes is inherited, which is why diet colas taste sweet to  some people but are bitter to others. Twenty-five types of bitter  receptors have been identified. Quite a few of them detect flavors  unique to fermented foods.   One group of bitter compounds of medical interest are the  alkaloids, which include a number of poisons such as strychnine,  nicotine, and morphine. Spitting out bitter substances may be a pro-  tective mechanism to avoid ingesting poisonous alkaloids in foods.   The taste sensation called umami has long been recognized  in Japan (the word means “delicious” in Japanese) but has only  recently come to the attention of Western taste researchers. Umami  arises from the binding of certain amino acids, including glutamic  acid and aspartic acid, to specific receptors. The flavor enhancer  monosodium glutamate (MSG), used in many prepared foods, is  formed from glutamic acid and also stimulates umami receptors.   Taste receptors, like olfactory receptors, rapidly undergo  sensory adaptation. The resulting loss of taste can be avoided by  moving bits of food over the surface of the tongue to stimulate dif-  ferent receptors at different moments.    We experience a series of flavors as we savor some foods because  of a sequence of chemical reactions that take place in foods as  we chew them. Imagine biting into a juicy ripe peach. The fruit’s    tissues tear, first releasing aromatic hydrocarbons. Thirty seconds  later, products of fatty acid breakdown appear and, finally, several  alcohols are released. This gradual flood of stimulating molecules  is one reason why we enjoy eating so much.    Although taste cells are close to the surface of the tongue and  are therefore exposed to environmental wear and tear, taste cells  are modified epithelial cells that divide continually and differenti-  ate into new taste cells. A taste cell functions for only about three  days before it is replaced.    Imagine a spicy slice of pizza or freshly brewed coffee, and your  mouth waters in anticipation. But for millions of people, the senses  of smell and taste are dulled, distorted, or gone. Many more of us get  some idea of their plight when a cold temporarily stifles these senses.   Compared to the loss of hearing or sight, being unable to taste  or smell may seem more an oddity than an illness. People with such  ailments would probably disagree. In some situations, a poor or  absent sense of smell can be dangerous, such as in a house on fire.   The direct connection between the outside environment and  the brain makes the sense of smell vulnerable to damage. Smell  and taste disorders can be triggered by colds and flu, allergies,  nasal polyps, swollen mucous membranes inside the nose, a head  injury, chemical exposure, a nutritional or metabolic problem, ora  disease. In many cases, a cause cannot be identified.    Sensory impulses from taste receptor cells in the anterior two-  thirds of the tongue travel on fibers of the facial nerve (VII);  impulses from receptors in the posterior one-third of the tongue  and the back of the mouth pass along the glossopharyngeal nerve  (IX); and impulses from receptors at the base of the tongue and the  pharynx travel on the vagus nerve (X). These cranial nerves con-  duct the impulses into the medulla oblongata. From there, impulses  ascend to the thalamus and are directed to the gustatory cortex of  the cerebrum, located in the insula. Clinical Application 12.3 and  table 12.3 discuss disorders of smell and taste.    17 Why is saliva necessary to taste?  18 Name the five primary taste sensations.    19 What characteristic of taste receptors helps maintain a sense of  taste with age?    20 Trace a sensory impulse from a taste receptor to the cerebral  cortex.    Sense of Hearing  The organ of hearing, the ear, has outer (external), middle, and    inner (internal) sections. In addition to making hearing possible,  the ear provides the sense of equilibrium.   The outer ear consists of all of the structures that face the outside.  These include an outer, funnel-like structure called the auricle  (pinna), an S-shaped tube, the external acoustic (ah-kGés’tik)  meatus (external auditory canal) that leads inward for about 2.5 cen-    Drugs can alter taste and smell in many ways, affecting cell  turnover, the neural conduction system, the status of receptors,  and changes in nutritional status. Drugs containing sulfur atoms,  for example, squelch taste. They include the anti-inflammatory  drug penicillamine, the antihypertensive drug captopril (Capoten),  and transdermal (patch) nitroglycerin to treat chest pain. The anti-  biotic tetracycline and the antiprotozoan metronidazole (Flagyl)  impart a metallic taste. Cancer chemotherapy and radiation treat-  ment often alter taste and smell.   Exposure to toxic chemicals can affect taste and smell, too.  For example, excess exposure to organic solvents in paint thinner  can cause cacosmia, the association of an odor of decay with nor-  mally inoffensive stimuli.    Smell Taste  Loss of sensation Anosmia Ageusia  Diminished sensation Hyposmia Hypogeusia  Heightened sensation Hyperosmia Hypergeusia  Distorted sensation Dysosmia Dysgeusia    timeters, and the tympanic membrane (eardrum) (fig. 12.9). The  meatus terminates with the tympanic membrane. {AP| FJ   The external acoustic meatus passes into the temporal bone.  Near this opening, hairs guard the tube. The opening and tube are  lined with skin that has many modified sweat glands called ceru-  minous glands, which secrete wax (cerumen). The hairs and wax  help keep large foreign objects, such as insects, out of the ear.    Ear wax may be “wet” or “dry.” The wet type has a higher lipid  content and is brown. It is found among people of European or  African ancestry. The dry form is grey and is found among Asians  and American Indians. A single DNA base difference determines  whether ear wax is wet or dry.    The transfer of vibrations through matter produces sound.  These vibrations travel in waves, much like ripples on the surface  of a pond. The higher the wave, the louder the sound. The more  waves per second, the higher the frequency, or pitch, of the sound.  Just as vibrating strings on a guitar or reeds on an oboe provide the  sounds of these musical instruments, vibrating vocal folds (vocal  cords) in the larynx provide the sounds of the human voice. The    FIGURE 12.9 fAP|R) Major parts of the ear. (a) The outer ear  includes the auricle, the external acoustic meatus, and the tympanic  membrane. The middle ear includes the auditory ossicles and the oval  window. The inner ear includes the semicircular canals and the cochlea.  (b) Size comparison of the auditory ossicles to a penny.    auricle of the ear helps collect sound waves traveling through air  and directs them into the external acoustic meatus.   After entering the meatus, the sound waves pass to the end  of the tube and alter the pressure on the tympanic membrane. The  tympanic membrane is a semitransparent membrane covered by a  thin layer of skin on its outer surface and by mucous membrane on  the inside. It has an oval margin and is cone-shaped, with the apex  of the cone directed inward. The tympanic membrane vibrates  back and forth in response to sound waves, reproducing the vibra-  tions of the sound-wave source.    The middle ear, or the tympanic cavity, is an air-filled space  in the temporal bone that separates the outer and inner ears. It is  bounded by the tympanic membrane laterally and the inner ear   The three auditory ossicles, called the malleus, the incus, and  the stapes, are attached to the wall of the tympanic cavity by tiny  ligaments and are covered by mucous membrane. These bones  bridge the tympanic membrane and the inner ear, transferring  vibrations between these parts. Specifically, the malleus is attached  to the tympanic membrane, helping to maintain its conical shape.  When the tympanic membrane vibrates, the malleus vibrates in  unison with it. The malleus vibrates the incus, and the incus passes  the movement on to the stapes. Ligaments hold the stapes to an  opening in the wall of the tympanic cavity called the oval window  (fig. 12.9). Vibration of the stapes, which acts like a piston at the  oval window, transfers the vibrations to a fluid within the inner ear.  These vibrations of the fluid stimulate the hearing receptors.    In addition to transferring vibrations, the auditory ossicles form  a lever system that helps increase (amplify) the force of the vibra-  tions as they pass from the tympanic membrane to the oval window.  Also, because the ossicles transfer vibrations from the large surface  of the tympanic membrane to a much smaller area at the oval win-  dow, the vibrational force strengthens as it travels from the outer to  the inner ear. As a result, the pressure (per square millimeter) that the  stapes applies at the oval window is about twenty-two times greater  than that which sound waves exert on the tympanic membrane.   The middle ear also has two small skeletal muscles attached to  the auditory ossicles that are controlled by a reflex. One of them,  the tensor tympani, is inserted on the medial surface of the mal-  leus and is anchored to the cartilaginous wall of the auditory tube.  When it contracts, it pulls the malleus inward. The other muscle,  the stapedius, is attached to the posterior side of the stapes and  the inner wall of the tympanic cavity. It pulls the stapes outward  when it contracts (fig. 12.10). These muscles are the effectors in  the tympanic reflex, which is elicited in about one-tenth of a sec-  ond after a loud, external sound. The reflex contracts the muscles,  and the malleus and stapes move. As a result, the bridge of ossicles    in the middle ear becomes more rigid, reducing its effectiveness in  transferring vibrations to the inner ear.   The tympanic reflex reduces pressure from loud sounds  that might otherwise damage the hearing receptors. Ordinary  vocal sounds also elicit the tympanic reflex, such as when a per-  son speaks or sings. This action muffles the lower frequencies of  such sounds, improving the hearing of higher frequencies, which  are common in human vocal sounds. In addition, the tensor tym-  pani muscle maintains tension on the tympanic membrane. This is  important because a loose tympanic membrane would not be able  to effectively transmit vibrations to the auditory ossicles.    The muscles of the middle ear take 100 to 200 milliseconds to  contract. For this reason, the tympanic reflex cannot protect the  hearing receptors from the effects of very sudden loud sounds,    such as from an explosion or a gunshot. On the other hand, this  protective mechanism can reduce the effects of intense sounds  that arise slowly, such as the roar of thunder.    FIGURE 12.10 Two small muscles attached to the (a) malleus and (b) stapes, the tensor tympani and the stapedius, are effectors in the tympanic reflex.    An auditory (aw’di-to”’re) tube (eustachian tube) connects each  middle ear to the throat. This tube allows air to pass between the  tympanic cavity and the outside of the body by way of the throat  (nasopharynx) and mouth. It helps maintain equal air pressure on  both sides of the tympanic membrane. This is necessary for normal  hearing (fig. 12.10).   The function of the auditory tube becomes noticeable during  rapid change in altitude. As a person descends from a high alti-  tude, the air pressure on the outside of the tympanic membrane  steadily increases. This may push the tympanic membrane inward,  out of its normal position, impairing hearing.   When the air pressure difference on the sides of the tympanic  membrane is great enough, some air may force its way up through  the auditory tube into the middle ear. This equalizes the pressure  on both sides of the tympanic membrane, which moves back into  its regular position, causing a popping sound as normal hearing  returns. A reverse movement of air ordinarily occurs when a per-  son ascends from a low altitude.   The auditory tube is usually closed by valvelike flaps in the  throat, which may inhibit air movements into the middle ear.  Swallowing, yawning, or chewing aid in opening the flaps and can  hasten equalization of air pressure.    Signs of a middle ear infection (otitis media) in a toddler  include irritability, fever, and tugging on the painful ear. Using  an instrument called an otoscope reveals a red and bulging  tympanic membrane.   Ear infections occur because the mucous membranes that  line the auditory tubes are continuous with the linings of the  middle ears, enabling bacteria infecting the throat or nasal  passages to reach the ear. The bacteria that most commonly  cause middle ear infection are Streptococcus pneumoniae,  Haemophilus influenzae, and Moraxella catarrhalis. This route  to infection is greater in young children because their auditory  tubes are shorter than those in adults.   Acute otitis media is treated with antibiotics, but these  might not be prescribed at first for a child older than two years  who is not in severe pain, because such infections tend to clear  up on their own in a few days. A child with recurrent otitis media  might have brief surgery to fit the affected ear with a tympanos-  tomy tube, to lower the risk of hearing loss. The tube drains the  ear through a small hole in the tympanic membrane. fAP|R)    The inner ear is a complex system of intercommunicating cham-  bers and tubes called a labyrinth (lab’i-rinth). Each ear has two  such regions—the bony labyrinth and the membranous labyrinth.   The bony (osseous) labyrinth is a cavity within the temporal  bone; the membranous labyrinth is a tube that lies within the bony  labyrinth and has a similar shape (fig. 12.11a). Between the bony  and membranous labyrinths is a fluid called perilymph, secreted  by cells in the wall of the bony labyrinth. In the membranous laby-  rinth is a slightly different fluid called endolymph.    The parts of the labyrinths include a cochlea (kok’le-ah) that  functions in hearing and three semicircular canals that provide  a sense of equilibrium. A bony chamber called the vestibule,  between the cochlea and the semicircular canals, houses membra-  nous structures that serve both hearing and equilibrium.   The cochlea is a tube shaped a bit like a snail shell, coiled  around a bony core, the modiolus. A thin, bony shelf (spiral  lamina) extends out from the core and coils around it within the  tube (fig. 12.11b). A portion of the membranous labyrinth in  the cochlea, called the cochlear duct (scala media), runs inside  the tube opposite the spiral lamina, and together these structures  divide the tube into upper and lower compartments.   The upper compartment, called the scala vestibuli, leads from  the oval window to the apex of the spiral. The lower compart-  ment, the scala tympani, extends from the apex of the spiral to a  membrane-covered opening in the wall of the inner ear facing the  tympanic cavity, called the round window. These compartments  form the bony labyrinth of the cochlea, and they are filled with  perilymph. The cochlear duct between them is filled with endo-  lymph. At the apex of the cochlea, beyond the tip of the cochlear  duct, a small opening, the helicotrema, connects the perilymph in  the upper and lower compartments and allows the fluid pressures  in them to equalize (fig. 12.12).   The cochlear duct ends as a closed sac at the apex of the cochlea.  The duct is separated from the scala vestibuli by a vestibular mem-  brane (Reissner’s membrane) and from the scala tympani by a basi-  lar membrane (fig. 12.12). Clinical Application 12.4 describes an  effective treatment for hearing loss called a cochlear implant.   The basilar membrane extends from the bony shelf of the  cochlea and forms the floor of the cochlear duct. It has many thou-  sands of elastic fibers and becomes thinner from the base of the  cochlea to its apex. Vibrations entering the perilymph at the oval  window travel along the scala vestibuli and pass through the vestib-  ular membrane to enter the endolymph of the cochlear duct, where  they move the basilar membrane. After passing through the basilar  membrane, the vibrations enter the perilymph of the scala tympani,  and movement of the membrane covering the round window dissi-  pates their force into the air in the tympanic cavity (fig. 12.12).   The spiral organ (organ of Corti), which contains about  16,000 hearing receptor cells, is on the superior surface of the basi-  lar membrane and stretches from the apex to the base of the cochlea.  The receptor cells, called hair cells, are in four parallel rows, with  many hairlike processes known as stereovilli (also called stereocilia)  that extend into the endolymph of the cochlear duct. Above these  hair cells is a tectorial membrane, attached to the bony shelf of the  cochlea. It passes like a roof over the receptor cells, contacting the  tips of their hairs (figs. 12.13 and 12.14).   Different frequencies of vibration move different regions along  the length of the basilar membrane. A particular sound frequency  bends the hairs of a specific group of receptor cells, activating  them. Other frequencies activate receptor cells elsewhere along the  cochlea (fig. 12.15, and see fig. 12.12). If sound activates receptors  at different places along the basilar membrane simultaneously, we  hear multiple tones at the same time.   The greater the deflection of the basilar membrane pushing  the hair cells upward against the tectorial membrane, the louder  the sound. However, recall from chapter 10 (p. 377) that action    inner ear (a) perilymph separates the  bony labyrinth from the membranous  labyrinth, which contains endolymph.  Note that areas of bony labyrinth have  been removed to reveal underlying  structures. (b) The spiral lamina coils  around a bony core, the modiolus.    potentials are all-or-none. More intense stimulation of the hair  cells causes more action potentials per second to reach the brain,  and we perceive a louder sound.   Hearing receptor cells are epithelial cells, but they respond to  stimuli somewhat like neurons (see chapter 10, pp. 371-372). For  example, when a receptor cell is at rest, its membrane is polar-  ized. When its hairs bend, selective ion channels open and its  cell membrane depolarizes. The membrane then becomes more  permeable, specifically to calcium ions. The receptor cell has no  axon or dendrites, but it does have neurotransmitter-containing  vesicles in the cytoplasm near its base. As calcium ions diffuse  into the cell, some of these vesicles fuse with the cell membrane  and release neurotransmitter to the outside. The neurotransmitter  stimulates the dendritic ends of nearby sensory neurons, and in  response their axons conduct impulses along the cochlear branch  of the vestibulocochlear nerve (cranial nerve VII) to the brain.   The ear of a young person with normal hearing can detect  sound waves with frequencies varying from about 20 to 20,000  or more vibrations per second. The range of greatest sensitivity is  between 2,000 and 3,000 vibrations per second (fig. 12.15).   The cochlear branches of the vestibulocochlear nerves enter the  auditory nerve pathways that extend into the medulla oblongata  and proceed through the midbrain to the thalamus. From there    FIGURE 12.12 (AP|R) Vibrations of the stapes at the oval window cause reciprocal  vibrations at the round window. Different frequencies (pitches) of vibrations cause movement  of the basilar membrane at different points along the cochlear duct (three example points  shown in this figure), stimulating different groups of hair cells.    they pass into the auditory cortices of the temporal lobes of the  cerebrum, where they are interpreted. On the way, some of these  fibers cross over, so that impulses arising from each ear are inter-  preted on both sides of the brain. Consequently, damage to a tem-  poral lobe on one side of the brain is not necessarily accompanied  by complete hearing loss in the ear on that side (fig. 12.16).   Table 12.4 summarizes the pathway of vibrations through the  parts of the middle and inner ears. Clinical Application 12.5 exam-  ines types of hearing loss.    Units called decibels (dB) measure sound intensity as a loga-  rithmic scale. The decibel scale begins at 0 dB, which is the  intensity of the sound least perceptible by a normal human  ear. A sound of 10 dB is 10 times as intense as the least per-  ceptible sound; a sound of 20 dB is 100 times as intense;  and a sound of 30 dB is 1,000 times as intense. A whisper  has an intensity of about 40 dB, normal conversation mea-    sures 60-70 dB, and heavy traffic produces about 80 dB.  Listening to a music device through earbuds exposes the ears  to 110 dB. A sound of 120 dB, such as a rock concert, produces  discomfort; and a sound of 140 dB, such as a jet plane at take-  off, causes pain. Frequent or prolonged exposure to sounds with  intensities above 90 dB can cause permanent hearing loss.    FIGURE 12.13 Cochlea. (a) Cross section of the cochlea. (b) Spiral organ and the tectorial membrane.    The little boy probably lost his hearing when he suffered a high  fever at eight weeks of age. When he was nine months old and  still didn’t babble like his age-mates, his parents suspected he  might be deaf. With hearing aids he did well at a preschool for the  deaf. Then his parents read about the cochlear implant, a device  that does not magically restore hearing, but enables a person to  hear certain sounds. Unlike a hearing aid that amplifies sound, a  cochlear implant directly stimulates the auditory nerve.   The boy received his cochlear implant when he was three  years old. Before three is the best time because the brain is rap-  idly processing speech and hearing as the person masters lan-  guage. Some children who receive the devices are only one year  old. However, even people who lose their hearing as adults can  benefit from cochlear implants, because they link the sounds they  hear through the device to memories of what sounds were like,  perhaps using clues from other senses.   The cochlear implant consists of a part inserted under the skin  above the ear that leads to two dozen electrodes placed near the  auditory nerve in the cochlea, the snail-shaped part of the inner  ear. A headset includes a microphone lodged at the back of the  ear to pick up incoming sounds and a fanny pack containing a  speech processor that digitizes the sounds into coded signals. A  transmitter on the headset sends the coded signals, as FM radio  waves, to the implant, which changes them to electrical signals  and delivers them to the cochlea. Here, the auditory nerve is stim-  ulated, and it conducts neural messages to the brain’s cerebral  cortex, which interprets the input as sound.    FIGURE 12.14 (AP|R) Spiral organ. (a) A micrograph of the  spiral organ and the tectorial membrane (400x). (6) A scanning electron  micrograph of hair cells in the spiral organ, looking down on the “hairs”  (bright yellow) (6,700x).    The boy’s audiologist (see the Career Corner, p. 445) turned  on the speech processor a month after the surgery. At first, the  youngster heard low sounds and sometimes responded with a low  hum. He grabbed at the processor, realizing it was the source of  the sound. Gradually, the child learned from context what certain  sounds meant. About 325,000 people worldwide have received  cochlear implants since the devices became available in 1984.    FIGURE 12D A cochlear implant enables this child to detect  enough sounds to effectively communicate.   might look if it could  be straightened out.  Receptors in regions of  the cochlear duct sense  different frequencies of  vibration, expressed in  cycles per second (cps).    oblongata, proceeds through the midbrain to the thalamus, and passes  into the auditory cortex of the cerebrum.    2. Waves of changing pressures cause the tympanic membrane  to reproduce the vibrations coming from the sound-wave  source.    3. Auditory ossicles amplify and conduct vibrations to the end  of the stapes.    4. Movement of the stapes at the oval window conducts  vibrations to the perilymph in the scala vestibuli.    5. Vibrations pass through the vestibular membrane and enter  the endolymph of the cochlear duct.    6. Different frequencies of vibration in endolymph move  specific regions of the basilar membrane, stimulating specific  sets of receptor cells.    7. A receptor cell depolarizes; its membrane becomes more  permeable to calcium ions.    8. In the presence of calcium ions, vesicles at the base of the  receptor cell release neurotransmitter.    10. Sensory impulses are conducted along fibers of the cochlear  branch of the vestibulocochlear nerve.    11. The auditory cortex of the temporal lobe interprets the  sensory impulses.    About 8% of people have some degree of hearing loss. Several  factors can impair hearing, including interference with conduction  of vibrations to the inner ear (conductive deafness) or damage to  the cochlea or the auditory nerve and its pathways (sensorineural  deafness). Disease, injury, and heredity all can impair hearing.  There are more than 100 forms of inherited deafness, and many  are part of syndromes. About 95% of cases of hearing loss are  conductive. One cause is accumulated dry wax or a foreign object  in the ear, which plugs the acoustic meatus. Changes in the tym-  panic membrane or auditory ossicles can also block hearing. The  tympanic membrane may harden as a result of disease, becoming  less responsive to sound waves, or an injury may tear or perforate  it. Sudden pressure changes, very loud sounds, infection, or stick-  ing an object into the ear may rupture the tympanic membrane.   A common disorder of the auditory ossicles is otosclerosis, in  which new bone deposited abnormally around the base of the sta-  pes interferes with the movement of the ossicles that is necessary  to conduct vibrations to the inner ear. Surgery often can restore  some hearing by chipping away the bone that holds the stapes in  position or replacing the stapes with a wire or plastic substitute.   Two tests used to diagnose conductive deafness are the  Weber test and the Rinne test. In the Weber test, the handle of  a vibrating tuning fork is pressed against the forehead. A person  with normal hearing perceives the sound coming from directly in  front, whereas a person with sound conduction blockage in one  middle ear hears the sound coming from the impaired side.   In the Rinne test, a vibrating tuning fork is held against the  bone behind the ear. After the sound is no longer heard by con-  duction through the bones of the skull, the fork is moved to just  in front of the external acoustic meatus. In middle ear conductive  deafness, the vibrating fork can no longer be heard, but a normal  ear will continue to hear its tone.   Very loud sounds can cause sensorineural deafness. If expo-  sure is brief, hearing loss may be temporary, but when exposure    22 Explain how sound waves are transmitted through the parts of  the ear.    23 Describe the tympanic reflex.  24 Distinguish between the osseous and membranous labyrinths.    The feeling of equilibrium (balance) derives from two senses—  static equilibrium (stat’ik e’kwi-lib’re-um) and dynamic equilib-  rium (di-nam’ik e’kwi-lib’re-um). Different sensory organs provide  these two components of equilibrium. The organs associated with    is repeated and prolonged, such as occurs in foundries, near jack-  hammers, or on a firing range, impairment may be permanent.  Frequent and prolonged listening to very loud music through  earbuds can cause desensitization—becoming able to tolerate  louder and louder sounds—and damage inner ear hair cells.   Sensorineural hearing loss begins as the hair cells develop  blisterlike bulges that eventually pop. The tissue beneath the hair  cells swells and softens until the hair cells, and sometimes the  neurons, leaving the cochlea become blanketed with scar tissue  and degenerate. Other causes of sensorineural deafness include  tumors in the CNS, brain damage as a result of vascular accidents,  and the use of certain drugs. Exposure to blasts, such as in com-  bat, can damage all parts of the ear.   Hearing loss and other ear problems can begin gradually.  Signs include:   ® inability to understand speech when there is background noise  ¢ ringing or a sensation of fullness in the ears   e difficulty distinguishing high-pitched sounds from each other  e the need to turn up the volume on a television or phone    New parents should notice whether their infant responds to  sounds in a way that indicates normal hearing. Hearing exams are  part of a well-baby visit to a doctor. If the baby’s responses indi-  cate a possible problem, the next step is to see an audiologist,  who identifies and measures hearing loss.   Often a hearing aid can help people with conductive hear-  ing loss. A hearing aid has a tiny microphone that picks up sound  waves and converts them to electrical signals, which are then  amplified. An ear mold holds the device in place, either behind  the outer ear, in the outer ear, or in the ear canal.    static equilibrium sense the position of the head, maintaining stabil-  ity and posture when the head and body are still. When the head and  body suddenly move or rotate, the organs of dynamic equilibrium  detect the motion and aid in maintaining balance.    Static Equilibrium  The organs of static equilibrium are in the vestibule, a bony cham-  ber between the semicircular canals and the cochlea. The mem-  branous labyrinth inside the vestibule consists of two expanded  chambers—a utricle (u’tri-kl) and a saccule (sak’tl). The larger  utricle communicates with (is continuous with) the saccule and the  membranous portions of the semicircular canals; the saccule, in  turn, communicates with the cochlear duct (fig. 12.17).   The utricle and saccule each has a small patch of hair cells and  supporting cells called a macula (mak’u-lah) on its wall. When the    FIGURE 12.17 (AP|R) The saccule and utricle, expanded portions of the membranous labyrinth, are in the bony chamber of the vestibule.    (Compare with figure 12.11. The oval window is not shown in this figure.)    head is upright, the hairs of the macula in the utricle project ver-  tically, while those in the saccule project horizontally. In both the  utricle and saccule, the hairs contact a sheet of gelatinous material  (otolithic membrane) that has crystals of calcium carbonate (oto-  liths) embedded on its surface. These particles add weight to the  gelatinous sheet, making it more responsive to changes in posi-  tion. The hair cells, which are the sensory receptors, have dendrites  of sensory neurons wrapped around their bases. These neurons are  associated with the vestibular portion of the vestibulocochlear nerve.   Gravity stimulates hair cells to respond. This usually happens  when the head bends forward, backward, or to one side. Such move-  ments tilt the gelatinous mass of one or more maculae, and as the  material sags in response to gravity, the hairs projecting into it bend.  This action stimulates the hair cells, and they signal their associ-  ated neurons (figs. 12.18 and 12.19). The resulting impulses are  conducted into the CNS by means of the vestibular branch of the  vestibulocochlear nerve, informing the brain of the head’s position.  The brain responds by sending motor impulses to skeletal muscles,  which may contract or relax appropriately to maintain balance.   The maculae also participate in the sense of dynamic equilib-  rium. For example, if the head or body is thrust forward or back-  ward abruptly, the gelatinous mass of the maculae lags slightly  behind, and the hair cells are stimulated. In this way, the maculae  aid the brain in detecting movements such as falling and in main-  taining posture while walking.   Each semicircular canal follows half of a roughly circular path about  6 millimeters in diameter. The three bony semicircular canals lie at  right angles to each other and occupy three different planes in space.    Two of them, the anterior canal and the posterior canal, are ori-  ented vertically, whereas the third, the /ateral canal, is horizontal.   Suspended in the perilymph of each bony canal is a mem-  branous semicircular duct that ends in a swelling called an  ampulla (am-pul’ah). The ampullae communicate with the utricle  of the vestibule (see fig. 12.17).   An ampulla contains a ridge that crosses the tube and houses  a sensory organ. Each of these organs, called a crista ampullaris,  has a number of sensory hair cells and supporting cells. As in the  maculae, the hairs of the hair cells extend upward into a dome-  shaped gelatinous mass called the cupula. Also, the hair cells are  connected at their bases to dendrites of neurons that make up part  of the vestibular branch of the vestibulocochlear nerve (fig. 12.20).   When the head or torso moves, the semicircular canals move  as well, but initially the fluid inside the membranous ducts tends  to remain stationary because of inertia. (Imagine turning rapidly  while holding a full glass of water.) This bends the cupula in one  or more of the semicircular canals in a direction opposite that of  the head and torso movement, and the hairs embedded in it also  bend. The moving of the hairs stimulates the hair cells to signal  their associated neurons, and as a result, impulses are conducted  to the brain (fig. 12.21). Movements in different directions affect  different combinations of semicircular canals. The brain inter-  prets impulses originating from these different combinations as  different movements.   Parts of the cerebellum are particularly important in inter-  preting impulses from the semicircular canals. Analysis of such  information allows the brain to predict the consequences of rapid  body movements, and by modifying signals to appropriate skeletal  muscles, the cerebellum can maintain balance.    FIGURE 12.18 The maculae respond to changes in head position. (a) Macula  of the utricle with the head in an upright position. (b) Macula of the utricle with    Other sensory structures aid in maintaining equilibrium.  Various proprioceptors, particularly those associated with the  joints of the neck, inform the brain about the position of body  parts. The eyes detect changes in posture that result from body  movements. Such visual information is so important that even if  the organs of equilibrium are damaged, keeping the eyes open and  moving slowly may be sufficient to maintain normal balance.    Motion sickness is a disturbance of the inner ear’s sensation of bal-  ance. Nine out of ten people have experienced this nausea and  vomiting, usually when riding in a car or on a boat. Astronauts suf-  fer a form of motion sickness called space adaptation syndrome.  Motion sickness is thought to result when visual information    contradicts the inner ear’s sensation that a person is motionless.  Consider a woman riding in a car. Her inner ears tell her that she  is not moving, but the passing scenery tells her eyes that she is  moving. The problem is compounded if she tries to read. The  brain reacts to these seemingly contradictory sensations by caus-  ing a feeling of queasiness, which may lead to vomiting.    FIGURE 12.19 Scanning electron micrograph of hairs of hair cells,  such as those in the utricle and saccule (8,000x).    FIGURE 12.20 Acrista ampullaris is in the ampulla of each  semicircular canal.    28 How does sensory information from other receptors help  maintain equilibrium?    A number of accessory organs assist the visual receptors in the  eyes. These include the eyelids and lacrimal apparatus that help  protect the eyes and a set of extrinsic muscles that move them.    Each eye, lacrimal gland, and associated extrinsic muscles are  housed in the orbital cavity of the skull. The orbit, lined with the  periosteum of various bones, also contains fat, blood vessels,  nerves, and connective tissues.   Each eyelid (palpebra) is composed of four layers—skin,  muscle, connective tissue, and conjunctiva. The skin of the eyelid,  the thinnest of the body, covers the lid’s outer surface and fuses  with its inner lining near the margin of the lid (fig. 12.22).   The muscles that move the eyelids include the orbicularis  oculi and the levator palpebrae superioris. Fibers of the orbicu-  laris oculi encircle the opening between the lids and spread out    FIGURE 12.21 Equilibrium. (a) When the head is stationary, the  cupula of the crista ampullaris remains upright. (b) When the head is  moving rapidly, (c) the cupula bends opposite the motion of the head,  stimulating sensory receptors.    FIGURE 12.22 Sagittal section of the closed eyelids and the anterior portion of the eye.    onto the cheek and forehead. This muscle acts as a sphincter that  closes the lids when it contracts. Fibers of the levator palpebrae  superioris muscle arise from the roof of the orbit and are inserted  in the connective tissue of the upper lid. When these fibers con-  tract, the upper lids are raised, and the eye opens.   The connective tissue layer of the eyelid, which helps give it  form, contains many modified sebaceous glands (tarsal glands).  Ducts carry the oily secretions of these glands to openings along  the borders of the lids. This secretion helps keep the lids from  sticking together.   The conjunctiva is a mucous membrane that lines the inner  surfaces of the eyelids and folds back to cover the anterior surface  of the eyeball, except for its central portion (cornea). Although the  tissue that lines the eyelids is relatively thick, the conjunctiva that  covers the eyeball is very thin. It is also freely movable and trans-  parent, so that blood vessels are clearly visible beneath it.    Most children who arrive at school with “pinkeye” are sent  home. Pinkeye is a form of conjunctivitis, or inflammation of the    conjunctiva. When caused by bacteria, it is highly contagious. It  is not usually contagious when caused by a virus.    The lacrimal apparatus consists of the lacrimal gland,  which secretes tears, and a series of ducts, which carry the tears  into the nasal cavity (fig. 12.23). The gland is in the orbit, supe-  rior and lateral to the eye. It secretes tears continuously, which  pass through tiny tubules and flow downward and medially  across the eye.   Two small ducts (superior and inferior canaliculi) collect tears,  and their openings (puncta) can be seen on the medial borders of  the eyelids. From these ducts, the fluid moves into the lacrimal sac,  which lies in a deep groove of the lacrimal bone, and then into the  nasolacrimal duct, which empties into the nasal cavity.   Glandular cells of the conjunctiva also secrete a tearlike liquid  that, together with the secretion of the lacrimal gland, moistens and  lubricates the surface of the eye and the lining of the lids. Tears con-  tain an enzyme, lysozyme, that has antibacterial properties, reducing  the risk of eye infections.   Tear glands secrete excessively when a person is upset or when  the conjunctiva is irritated. Tears spill over the edges of the eyelids,  and the nose fills with fluid. When a person cries, parasympathetic  nerve fibers conduct motor impulses to the lacrimal glands.   The extrinsic muscles of the eye arise from the bones of the orbit  and are inserted by broad tendons on the eye’s tough outer surface.  Six such muscles move the eye in different directions (fig. 12.24).    Although any given eye movement may use more than one muscle,  each one is associated with a primary action, as follows:    5. Superior oblique—rotates the eye downward and away from  the midline.   6. Inferior oblique—rotates the eye upward and away from the  midline.    The motor units of the extrinsic eye muscles have the fewest  muscle fibers (five to ten) of any muscles in the body, enabling  them to move the eyes with great precision. Also, the eyes move  together so that they align when looking at something. Such  alignment is the result of complex motor adjustments that con-  tract certain eye muscles while relaxing their antagonists. For  example, when the eyes move to the right, the lateral rectus of  the right eye and the medial rectus of the left eye must contract.  At the same time, the medial rectus of the right eye and the lat-  eral rectus of the left eye must relax. A person whose eyes are not  coordinated well enough to align has strabismus. Table 12.5 sum-  marizes the muscles associated with the eyelids and eye.    One eye deviating from the line of vision produces double vision  (diplopia). If it persists, the brain may eventually suppress the  image from the deviated eye, and the turning eye may experi-    ence partial vision loss (suppression amblyopia). Treating the eye  deviation early in life with exercises, eyeglasses, and surgery can  prevent such monocular vision loss. Vision screening programs for  children can detect this problem.    FIGURE 12.23 The lacrimal apparatus consists of a tear secreting  gland and a series of ducts.    "Skeletal Muscles _ Innervation Function  Muscles of the eyelids  Orbicularis oculi Facial nerve (VII) Closes eye  Levator palpebrae Oculomotor nerve (Ill) Opens eye    Superior oblique Trochlear nerve (IV) Rotates eye  downward  and away from  midline  Inferior oblique Oculomotor nerve (Il) Rotates eye  upward and away  from midline  Function    29 Explain how the eyelid is moved.  30 Describe the conjunctiva.  31. What is the function of the lacrimal apparatus?    The eye is a hollow, spherical structure about 2.5 centimeters in  diameter. Its wall has three distinct layers—an outer fibrous tunic,  a middle vascular tunic, and an inner nervous tunic. The spaces in  the eye are filled with fluids that support its wall and internal struc-  tures that help maintain its shape. Figure 12.25 shows the major  parts of the eye.    Light is often described as moving in straight lines called rays of  light. The anterior sixth of the outer tunic bulges forward as the  transparent cornea (kor’ne-ah), the window of the eye. The cornea  helps focus entering light rays. It is largely composed of connective    FIGURE 12.24 (AP|R} Extrinsic muscles of the right eye (lateral view).    FIGURE 12.25 (AP|R} Transverse section of the right eye (superior view).    tissue with a thin surface layer of epithelium. The cornea is trans-  parent because it contains no blood vessels and the collagen fibers  form unusually regular patterns.   The cornea is well supplied with sensory nerve fibers that  enter its margin and radiate toward its center. These fibers are  associated with many pain receptors that have very low thresholds.  Cold receptors are also abundant in the cornea, but heat and touch  receptors are not.    The most common cause of blindness worldwide is loss of trans-  parency of the cornea. Each year, 40,000 corneal transplants are  performed in the United States. Corneal transplants do not evoke  an immune response, but they are effective only if the trans-    planted tissue includes stem cells that are normally found in a cell  layer, called the limbus, which separates the cornea from the con-  junctiva. The cornea itself does not contain stem cells—their nuclei  are so large that they would block light rays, impairing vision.    The cornea is continuous with the sclera (skle’rah), the white  portion of the eye. The sclera makes up the posterior five-sixths of  the outer tunic and is opaque due to many large, seemingly disor-  ganized collagen and elastic fibers. The sclera protects the eye and  is an attachment for the extrinsic muscles.   In the back of the eye, the optic (op’tik) nerve and blood ves-  sels pierce the sclera. The dura mater that encloses these structures  is continuous with the sclera.    The middle, or vascular, tunic of the eyeball (uveal layer) includes  the choroid coat, the ciliary body, and the iris. The choroid coat,  in the posterior five-sixths of the globe of the eye, loosely joins  the sclera. Blood vessels pervade the choroid coat and nourish  surrounding tissues. The choroid coat also contains abundant  pigment-producing melanocytes that give it a brownish-black    appearance. The melanin of these cells absorbs excess light and  helps keep the inside of the eye dark.   The ciliary body, which is the thickest part of the middle tunic,  extends anteriorly and inward from the choroid coat and forms  a ring within the front of the eye. In the ciliary body are radiating  folds called ciliary processes and groups of smooth muscle cells that  constitute the ciliary muscles. Figure 12.26 shows these structures.   Many strong but delicate fibers, called suspensory ligaments  (zonular fibers), extend inward from the ciliary processes and hold  the transparent lens in position. The distal ends of these fibers are  attached along the margin of a thin capsule that surrounds the lens.  The body of the lens, which lacks blood vessels, lies directly behind  the iris and pupil and is composed of specialized epithelial cells.   The cells of the lens originate from a single layer of epithe-  lium beneath the anterior portion of the lens capsule. The cells  divide, and the new cells on the surface of the lens capsule differ-  entiate into specialized columnar epithelial cells called lens fibers,  which constitute the substance of the lens. Lens fiber production  continues slowly throughout life, thickening the lens from front  to back. Simultaneously, the deeper lens fibers are compressed  toward the center of the structure (fig. 12.27). More than 90% of  the proteins in a lens cell are lens crystallins, which aggregate into  the fibers. These proteins, along with the absence of organelles  that scatter light (mitochondria, endoplasmic reticula, and nuclei),  provide the transparency of the lens.   The lens capsule is a clear, membranelike structure largely  composed of intercellular material (fig. 12.28). It is quite elastic,  a quality that keeps it under constant tension. As a result, the lens  can assume a globular shape. However, the suspensory ligaments  attached to the margin of the capsule are also under tension, and  they pull outward, flattening the capsule and the lens.   If the tension on the suspensory ligaments relaxes, the elastic  capsule rebounds, and the lens surface becomes more convex. This  change, called accommodation (ah-kom”o-da’shun), occurs in the  lens when the eye focuses to view a close object.   The ciliary muscles relax the suspensory ligaments during  accommodation. One of these muscles forms a circular sphincter-    FIGURE 12.27 Ascanning electron micrograph of the long,  flattened lens fibers (2,650x). Note the fingerlike junctions where one  fiber joins another.    like structure around the ciliary processes. The other muscle extends  back from fixed points in the sclera to the choroid coat. When the  circular muscle contracts, the diameter of the ring formed by the  ciliary processes decreases; when the other muscle contracts, the  choroid coat is pulled forward, and the ciliary body shortens. Both  of these actions relax the suspensory ligaments, thickening the lens.  In this thickened state, the lens is focused for viewing objects closer  than before (fig. 12.29a).   To focus on a distant object, the ciliary muscles relax, increasing  tension on the suspensory ligaments. The lens thins again (fig. 12.29b).    33 Describe the outer and middle tunics of the eye.  34 What factors contribute to the transparency of the cornea?  35 How does the shape of the lens change during accommodation?    The iris is a thin diaphragm mostly composed of connective  tissue and smooth muscle. Seen from the outside, it is the colored  portion of the eye. The iris extends forward from the periphery  of the ciliary body and lies between the cornea and the lens. It  divides the space separating these parts, called the anterior cavity,  into an anterior chamber (between the cornea and the iris) and  a posterior chamber (between the iris and the vitreous humor,  occupied by the lens).   The epithelium on the inner surface of the ciliary body con-  tinuously secretes a watery fluid called aqueous humor into the  posterior chamber. The fluid circulates from this chamber through    the pupil, which is a circular opening in the center of the iris, and  into the anterior chamber (fig. 12.30). Aqueous humor fills the  space between the cornea and the lens, providing nutrients and  maintaining the shape of the front of the eye. It leaves the ante-  rior chamber through veins and a special drainage canal, called the  scleral venous sinus (canal of Schlemm), in the wall of the anterior  chamber at the junction of the cornea and the sclera (fig. 12.30).   The smooth muscle cells of the iris form two groups, a circular  set and a radial set. These control the size of the pupil, through  which light passes. The circular set (pupillary constrictor) acts  as a sphincter, and when it contracts, the pupil gets smaller and  the intensity of the light entering decreases. When the radial set  (pupillary dilator) contracts, the diameter of the pupil increases  and the intensity of the light entering increases.   The sizes of the pupils change constantly in response to  pupillary reflexes triggered by such factors as light intensity,  gaze, accommodation, and variations in emotional state. For  example, bright light elicits a reflex, and impulses are conducted  along parasympathetic nerve fibers to the pupillary constrictors  of the irises. The pupils constrict in response. Conversely, in dim  light, impulses are conducted on sympathetic nerve fibers to the  pupillary dilators of the irises, and the pupils dilate (fig. 12.31).    ® RECONNECT  > To Chapter 11, Autonomic Nervous System, pages 431-436.    The amount and distribution of melanin in the irises and the den-    sity of the tissue in the body of the iris determine eye color. If mela-  nin is present only in the epithelial cells on the iris’s posterior surface,    FIGURE 12.29 In accommodation, (a) the lens thickens as the ciliary  muscles contract. (b) The lens thins as the ciliary muscles relax.    the iris reflects more colors of light, and appears blue or green. When  the same distribution of melanin is denser in the body of the iris,  eye color is gray. When melanin is within the body of the iris as  well as in the posterior epithelial covering, the iris appears brown.    The inner tunic of the eye consists of the retina (ret’i-nah), which  contains the visual receptor cells (photoreceptors). This nearly  transparent sheet of tissue is continuous with the optic nerve in the  back of the eye and extends forward as the inner lining of the eye-  ball. It ends just behind the margin of the ciliary body.   The retina is thin and delicate, but its structure is complex. It  has distinct layers, including retinal pigment epithelium, neurons,  nerve fibers, and limiting membranes (figs. 12.32 and 12.33).   There are five major groups of retinal neurons. The nerve fibers  of three of these groups—the photoreceptors, bipolar neurons, and  ganglion cells—provide a direct pathway for impulses triggered in  the photoreceptors to the optic nerve and brain. The nerve fibers  of the other two groups of retinal cells, called horizontal cells and  amacrine cells, pass laterally between retinal cells (see fig. 12.32).  The horizontal and amacrine cells modify the pattern of impulses  conducted on the fibers of the direct pathway.   In the central region of the retina is a yellowish spot called the  macula lutea that occupies about 1 square millimeter. A depression  in its center, called the fovea centralis, is in the region of the retina  that produces the sharpest vision.   Just medial to the fovea centralis is an area called the optic  disc (fig. 12.34). Here the nerve fibers from the retina leave the  eye and become parts of the optic nerve. A central artery and vein  also pass through at the optic disc. These vessels are continuous  with capillary networks of the retina, and together with vessels in  the underlying choroid coat, they supply blood to the cells of the  inner tunic. The optic disc lacks receptor cells, so it is commonly  referred to as the blind spot of the eye.    FIGURE 12.30 Aqueous humor (arrows), secreted into the posterior chamber, circulates into the anterior chamber and leaves it through the scleral    FIGURE 12.31 Dim light stimulates the radial muscle of the iris to  contract, and the pupil dilates. Bright light stimulates the circular muscle  of the iris to contract, and the pupil constricts.    The space enclosed by the lens, ciliary body, and retina is the  largest compartment of the eye and is called the posterior cavity. It  is filled with a transparent, jellylike fluid called vitreous humor,  which with some collagen fibers comprise the vitreous body. The  vitreous body supports the internal structures of the eye and helps  maintain its shape.   In summary, light entering the eye must pass through the  cornea, aqueous humor, lens, vitreous humor, and several layers  of the retina before it reaches the photoreceptors (see fig. 12.32).  Table 12.6 summarizes the layers of the eye.    37 Explain the origin of aqueous humor and trace its path through  the eye.   When a person sees an object, either the object is giving off light,  or it is reflecting light from another source. Rays of light enter the  eye, and an image of what is seen focuses upon the retina. The  light rays must bend to be focused, a phenomenon called refrac-  tion (re-frak’shun).   Refraction occurs when light rays pass at an angle from a  medium of one density into a medium of a different density. For  example, as figure 12.35 shows, when light passes from a less-  dense medium such as air into a denser medium such as glass, or  from air into the cornea of the eye, the light bends toward a line  perpendicular to the surface between these substances. The light  bends again when it reenters the air. When the surface between  such refracting media is curved, a lens is formed. A lens with a  convex surface causes light waves to converge, and a lens with a  concave surface causes light waves to diverge (fig. 12.36). Note  how the first example is similar to the shape of both the cor-  nea and the lens of the eye. Clinical Application 12.6 discusses  familiar visual problems resulting from abnormal refraction.   In the previous example, light rays were bent going from air  to glass and from glass to air. Inside the eye, however, the lens  and various fluids are more alike in density than air is compared to  glass. About 75 percent of the refraction occurs when light passes  from the air through the convex surface of the cornea. The light  is refracted again by the convex surface of the lens and to a lesser  extent at the surfaces of the fluids in the eye chambers. The lens  is the only one of these structures that can change its amount of  refraction to achieve a focused image (accommodation).   If the shape of the eye is normal, light rays are focused sharply  upon the retina, much as a motion-picture image is focused on a  screen for viewing. Unlike the motion-picture image, however, the  one formed on the retina is upside down and reversed from left to  right (fig. 12.37). When the visual cortex of the cerebrum inter-  prets such an image, it corrects the reversals and objects are seen  in their real positions.    For many people, after the age of forty-five, it seems as if the print  in magazines and on medicine bottles suddenly becomes too  small to read. The problem is not in the print, but in a lessening of  the elastic quality of the lens capsule. In the condition presbyopia,  or farsightedness of age, eyes remain focused for distant vision.  Eyeglasses or contact lenses can usually make up for the eyes’ loss  of refracting power.   Other visual problems result from eyeballs that are too long  or too short for sharp focusing. If an eyeball is too long, light  waves focus in front of the retina, blurring the image. In other  words, the refracting power of the eye, even when the lens is flat-  tened, is too great. Although a person with this problem may be  able to focus on close objects by accommodation, distance vision  is invariably poor. For this reason, the person is said to be near-  sighted. Eyeglasses or contact lenses with concave surfaces that    FIGURE 12E Point of focus. (a) Myopia (nearsightedness)—lIf an  eye is too long, the focus point of images lies in front of the retina.  (b) In a normal eye, the focus point is on the retina. (c) Hyperopia  (farsightedness)—If an eye is too short, the focus point lies behind  the retina.    focus images farther from the front of the eye treat nearsighted-  ness (myopia).   If an eye is too short, light waves are not focused sharply on  the retina because their point of focus lies behind it. A person  with this condition may be able to bring the image of distant  objects into focus by accommodation, but this requires contrac-  tion of the ciliary muscles at times when these muscles are at  rest in a normal eye. Still more accommodation is necessary to  view closer objects, and the person may suffer from ciliary muscle  fatigue, pain, and headache when doing close work.   Most people with short eyeballs are unable to accommo-  date enough to focus on very close objects. They are farsighted.  Eyeglasses or contact lenses with convex surfaces can remedy  this condition (hyperopia) by focusing images closer to the front  of the eye (figs. 12E and 12F).   Another refraction problem, astigmatism, reflects a defect in  the curvature of the cornea or the lens. The normal cornea has a  spherical curvature, like the inside of a ball; most astigmatic cor-  neas have an elliptical curvature, like the bowl of a spoon. As a  result, some portions of an image are in focus on the retina, but  other portions are blurred, and vision is distorted.   Without corrective lenses, astigmatic eyes tend to accommo-  date back and forth reflexly to sharpen focus. The consequence of  this continual action is often ciliary muscle fatigue and headache.    FIGURE 12F Corrective lenses. (a) A concave lens corrects  nearsightedness. (b) A convex lens corrects farsightedness.    FIGURE 12.33 fAP|R) Note the layers of cells and nerve fibers in this light micrograph of the retina (75x).    (a)  FIGURE 12.34 (AP|R) The retina. (a) Major features of the retina.    (b) Nerve fibers leave the retina in the area of the optic disc (arrow) to  form the optic nerve in this magnified view (53x). (b)    Light rays coming from objects more than 20 feet away travel  in nearly parallel lines, and the cornea and the lens in its more flat-  tened or “‘at-rest” condition focus the light rays on the retina. Light  arriving from objects less than 20 feet away, however, reaches the  eye along more divergent lines—the closer the object, the more  divergent the lines.   Divergent light rays focus behind the retina unless something  increases the refracting power of the eye. Accommodation accom-  plishes this increase, thickening the lens. As the lens thickens,  light rays converge more strongly so that light coming from close  objects focuses on the retina.    FIGURE 12.35 When light passes at an oblique angle from air into  glass, the light waves bend toward a line perpendicular to the surface of  the glass.    42 Why is it necessary to accommodate for viewing close objects?    The photoreceptors of the eye are modified neurons of two dis-  tinct types. One group of receptor cells, called rods, have long,  thin projections at their terminal ends. The cells of the other group,  called cones, have short, blunt projections. The retina has about  100 million rods and 3 million cones.   Rods and cones occupy a deep layer of the retina, closely  associated with a layer of retinal pigment epithelium (see figs.  12.32 and 12.33). The projections from the receptors extend into  the pigmented layer and contain light-sensitive visual pigments.    Albinism is an inherited condition in which an enzyme required  to produce pigment is missing, causing very pale, highly sun-  sensitive skin. More severe forms of albinism also affect the  eyes, making vision blurry and intolerant to light. A person may    squint even in very faint light. This separate extra sensitivity  arises because light reflects inside the lenses, overstimulating  visual receptors. The eyes of many people with albinism also  dart about uncontrollably, in a condition called nystagmus.    FIGURE 12.36 Light waves passing through a lens. (a) A lens with a convex surface causes light waves to converge. (b) A lens with a concave surface    FIGURE 12.37 The image of an object forms upside down on the retina.    The retinal pigment epithelium absorbs light that the recep-  tor cells do not absorb, and with the pigment of the choroid coat,  keeps light from reflecting off the surfaces inside the eye. The reti-  nal pigment epithelium also stores vitamin A, which the receptor  cells use to synthesize visual pigments.   The visual receptors are stimulated only when light reaches  them. A light image focused on an area of the retina stimulates  some receptors, which conduct impulses to the brain. However,  the impulse leaving each activated receptor provides only a  small portion of the information required for the brain to inter-  pret a complete scene.   Rods and cones function differently. Rods are hundreds of  times more sensitive to light than are cones, and as a result, rods  provide vision in dim light. In addition, rods produce colorless  (black and white) vision, whereas cones can detect colors.   Cones provide sharp images, whereas rods produce more  general outlines of objects. This is because nerve fibers associated  with many rods may converge, so their impulses may be conducted  to the brain on a single nerve fiber (see chapter 10, pp. 382-383).  Thus, if light stimulates a rod, the brain cannot tell which one of  many receptors has been stimulated. Such convergence is much  less common among cones, so when a cone is stimulated, the brain  is able to pinpoint the stimulation more accurately (fig. 12.38).   The area of sharpest vision, the fovea centralis in the macula  lutea, lacks rods but has densely packed cones with few or no con-  verging fibers. Also, the overlying layers of the retina, as well as the  retinal blood vessels, are displaced to the sides in the fovea, which  more fully exposes the receptors to incoming light. Consequently, to    view something in detail, a person moves the eyes so that the impor-  tant part of an image falls upon the fovea centralis.   The concentration of cones decreases in areas farther away from  the macula lutea, whereas the concentration of rods increases in these  areas. Also, the degree of convergence among the rods and cones  increases toward the periphery of the retina. As a result, the visual  sensations from images focused on the sides of the retina are blurred  compared with those focused on the central portion of the retina.    A forceful blow to the bony orbit can displace structures in and  around the eye. The suspensory ligaments may tear, and the  lens may become dislocated into the posterior cavity, or the  retina may pull away from the underlying vascular choroid coat.  Once the retina is detached, photoreceptor cells may die from  lack of oxygen and nutrients. Unless such a detached retina is  repaired surgically, visual loss or blindness may result.    Rods and cones contain light-sensitive pigments that decompose  when they absorb light energy. The light-sensitive pigment in rods  is rhodopsin (ro-dop’sin), or visual purple, and it is embedded in  membranous discs stacked in these receptor cells (fig. 12.39). A  single rod cell may have 2,000 interconnected discs, derived from  the cell membrane. In the presence of light, rhodopsin molecules  break down into molecules of a colorless protein called opsin and    FIGURE 12.38 fAP|R) Rods and cones. (a) A single sensory nerve fiber conducts impulses from several rods to the brain. (b) Separate  sensory nerve fibers conduct impulses from cones to the brain. (c) Scanning electron micrograph of rods and cones (1,350x).    FIGURE 12.39 Rhodopsin is embedded in discs of membrane  stacked in the rod cells.    a yellowish organic molecule called retinal (retinene) synthesized  from vitamin A.   In darkness, a nucleotide called cyclic guanosine mono-  phosphate (cGMP) keeps sodium and calcium channels open in  portions of the receptor cell membranes. The resultant release  of neurotransmitter by the rods inhibits the generation of action  potentials along the optic nerve. When rhodopsin molecules  absorb light, they change shape and release opsin, in trillionths  of a second. The released opsin then becomes an active enzyme,  which activates a second enzyme (transducin), which, in turn, acti-  vates another enzyme (phosphodiesterase). The third enzyme of    this series breaks down cGMP, and as the concentration of cGMP  decreases, sodium and calcium channels close, and the receptor  cell membrane hyperpolarizes (see chapter 10, p. 375). The degree  of hyperpolarization is directly proportional to the intensity of the  light stimulating the receptor cells.   The hyperpolarization reaches the synaptic end of the cell,  inhibiting release of neurotransmitter. Decreased release of neu-  rotransmitter by photoreceptor cells triggers action potentials in  nearby retinal neurons. Consequently, impulses are conducted  away from the retina, through the optic nerve, and into the brain,  where they are interpreted as vision. This process is essentially the  same in both rods and cones.   In bright light, nearly all of the rhodopsin in the rods decom-  poses, sharply reducing the sensitivity of these receptors (the rhodop-  sin loses its purplish color as a result, and is said to have “bleached”’).  The cones continue to function, however, and in bright light, we  therefore see in color. In dim light, rhodopsin can be regenerated  from opsin and retinal faster than it is broken down. This regeneration  requires cellular energy, which ATP provides (see chapter 4, p. 126).  Under these conditions, the rods continue to function and the cones  remain unstimulated. Hence, we see only shades of gray in dim light.   The light sensitivity of an eye whose rods have converted the  available opsin and retinal to rhodopsin increases about 100,000  times, and the eye is said to be dark adapted. A person needs  dark-adapted eyes to see in dim light. For example, when going  from daylight into a darkened theater, it may be difficult to see  well enough to locate a seat, but soon the eyes adapt to the dim  light, and vision improves. Later, leaving the theater and enter-  ing the sunlight may cause discomfort or even pain. This occurs  at the moment that most of the rhodopsin decomposes in response  to the bright light. Consequently, the light sensitivity of the eyes  decreases greatly, and they become light adapted.    Too little vitamin A in the diet reduces the amount of retinal,  impairing rhodopsin production and sensitivity of the rods. The  result is poor vision in dim light, called nightblindness.    The light-sensitive pigments of cones, called iodopsins, are  similar to rhodopsin in that they are composed of retinal combined  with a protein; the protein, however, differs from the protein in the  rods. The three sets of cones in the retina all contain an abundance  of one of three different visual pigments.   Daylight, as well as so-called white light from indoor lighting,  is actually a mixture of light of different colors. A familiar illustra-  tion of this phenomenon is a rainbow, which appears seemingly  out of nowhere when light passing through water vapor in the  air after a storm separates into its component colors. The colors  are described either by a physical property, called a wavelength,  or simply by the name, such as blue, red, or green. The shortest  wavelengths of visible light are perceived as violet, whereas the  longest wavelengths of visible light are seen as red. One type of  cone pigment (erythrolabe) is most sensitive to red light, another  (chlorolabe) to green light, and a third (cyanolabe) to blue light.  The sensitivities of these pigments overlap somewhat. For exam-  ple, both red and green light pigments are sensitive to orange light.  Red pigment absorbs orange light most effectively.    The color perceived depends upon which cones the light in a  given image stimulates. If all three types of cones are stimulated  with equal intensity, the light is perceived as white, and if none are  stimulated, it is seen as black.   Examination of the retinas of different people reveals that indi-  viduals have unique patterns of these three cone types, all apparently  able to provide color vision. Some parts of the retina are even nor-  mally devoid of one particular type, yet the brain integrates informa-  tion from all over to “fill in the gaps,” creating a continuous overall  image. People who lack a cone type due to a mutation are colorblind.    Stereoscopic vision (stereopsis) simultaneously perceives distance,  depth, height, and width of objects. Such vision is possible because  the pupils are 6—7 centimeters apart. Consequently, close objects  (less than 20 feet away) produce slightly different retinal images.  That is, the right eye sees a little more of one side of an object, while  the left eye sees a little more of the other side. The visual cortex  superimposes and interprets the two images. The result is the per-  ception of a single object in three dimensions (fig. 12.40).   Stereoscopic vision requires vision with two eyes (binocular  vision). Therefore, a person with only one functional eye is less  able to accurately judge distance and depth. To compensate, a per-  son with one eye can use the relative sizes and positions of famil-  iar objects as visual clues.    The axons of the ganglion cells in the retina leave the eyes, forming  the optic nerves (see chapter 11, p. 421). Just anterior to the pituitary  gland, these nerves give rise to the X-shaped optic chiasma, and in  the chiasma, some of the fibers cross over. Specifically, the fibers  from the nasal (medial) half of each retina cross over, whereas those  from the temporal (lateral) halves do not. In this way, fibers from the  nasal half of the left eye and the temporal half of the right eye form    FIGURE 12.40 Stereoscopic vision results from formation of two  slightly different retinal images.    the right optic tract; fibers from the nasal half of the right eye and  the temporal half of the left eye form the left optic tract.   The nerve fibers continue in the optic tracts, and before they  reach the thalamus, a few of them enter nuclei that function in vari-  ous visual reflexes. Most of the fibers, however, enter the thalamus  and synapse in a part of its posterior portion (lateral geniculate  body). From this region, the visual sensory fibers enter pathways  called optic radiations that lead to the visual cortex of the occipital  lobe (fig. 12.41).    Each visual cortex receives impulses from each eye, so a person  may develop partial blindness in both eyes if either visual cortex  is injured. For example, if the right visual cortex (or the right optic  tract) is injured, sight may be lost in the temporal side of the right    eye and the nasal side of the left eye. Similarly, damage to the cen-  tral portion of the optic chiasma, where fibers from the nasal sides  of the eyes cross over, blinds the nasal sides of both eyes.    Sensory fibers not leading to the thalamus conduct visual  impulses downward into the brainstem. These impulses are impor-  tant for controlling head and eye movements associated with  visually tracking an object; for controlling the simultaneous move-  ments of both eyes; and for controlling certain visual reflexes,  such as those that move the muscles of the iris.    43 Distinguish between the rods and the cones of the retina.  44 Explain the roles of visual pigments.  45 What factors make stereoscopic vision possible?    46 Trace the pathway of visual impulses from the retina to the  visual cortex of the occipital lobe.    We often first become aware of aging-associated changes through  diminished senses. By age forty, a book may need to be held far-  ther away from the eyes. By the fifties, the senses of smell and  taste may begin to diminish, which usually reflects anosmia, a loss  of olfactory receptors.   By age sixty, a quarter of the population experiences noticeable  hearing loss, and from ages sixty-five to seventy-four, the percent-  age reaches a third. Half of all people over age eighty-five can-  not hear adequately. Age-related hearing loss may be the result of  decades of cumulative damage to the sensitive hair cells of the spiral  organ in the inner ear. It becomes more difficult to hear high pitches,  as well as particular sounds, such as f, g, s, t, sh, th, z, and ch.  Hearing loss may also be due to a degeneration or failure of nerve  pathways to the brain. This condition, called presbycusis, may affect  the ability to understand speech. It gradually worsens. Tinnitus, a  ringing or roaring in the ears, is also more common among older  adults. Hearing aids can often restore some hearing. A person to  whom the ordinary sounds of life are hopelessly garbled may show  symptoms of paranoia, depression, or social withdrawal.   Vision may decline with age for several reasons. “Dry eyes”  are common. Too few tears, or poor quality tears, lead to itching  and burning eyes, and diminished vision. In some cases, too many  tears result from oversensitivity to environmental effects, such as  wind, intense light, or a change in temperature.   With age, tiny dense clumps of gel or crystal-like deposits  form in the vitreous humor. When these clumps cast shadows on the  retina, the person sees small moving specks in the field of vision.  These specks, or floaters, are most apparent when looking at a plain  background, such as the sky or a blank wall. Also with age, the vit-  reous humor may shrink and pull away from the retina. This may  mechanically stimulate receptor cells of the retina, and the person  may see flashes of light.   The inability to read small print up close as one gets older,  called presbyopia, results from a loss of elasticity in the lens, pre-    Sensory receptors are sensitive to internal and external  environmental changes and initiate impulses to the brain and  spinal cord.    1. Receptor types  a. Each type of receptor is sensitive to a distinct type of  stimulus.  b. The major types of receptors include:  (1) Chemoreceptors, sensitive to changes in chemical  concentration.  (2) Pain receptors (nociceptors), sensitive to tissue  damage.  (3) Thermoreceptors, sensitive to temperature  changes.    venting it from changing shape easily. After age seventy, the pupil  cannot dilate as well as it once did, halving the amount of light that  can enter the eye. Brighter lights can counter this effect.   Glaucoma develops in the eyes as a person ages when the rate  of aqueous humor formation exceeds the rate of its removal. Fluid  accumulates in the anterior chamber of the eye, raising the fluid  pressure. As this pressure is transmitted to all parts of the eye, in  time, the blood vessels that supply the receptor cells of the retina  may squeeze shut, cutting off the nutrient and oxygen supply. The  result may eventually be permanent blindness.   Drugs, or traditional or laser surgery to promote the outflow  of aqueous humor, can treat glaucoma if it is diagnosed early.  However, because glaucoma in its early stages typically produces no  symptoms, discovery of the condition usually depends on measur-  ing the intraocular pressure using an instrument called a tonometer.   A common eye disorder particularly in older people is cata-  ract. The lens or its capsule slowly becomes cloudy, opaque, and  discolored, adding a yellowish tinge to a person’s view of the  world. Clear images cannot focus on the retina, and in time, the  person may become blind. Removing the lens with a laser and  replacing it with an artificial implant can treat cataract. Afterward,  patients report that their surroundings are no longer yellow.   Several conditions affect the retinas of an older person. In a  form of age-related macular degeneration, and also in people with  diabetes who develop diabetic retinopathy, tiny blood vessels  extend into the macula, making images in the center of the visual  field appear wavy. Retinal detachment becomes more common.  Despite these various problems, many older individuals continue to  enjoy sharp, functional senses well into the upper decades of life.    47 Why do smell and taste diminish with age?  48 What are some causes of age-related hearing loss?    (4) Mechanoreceptors, sensitive to mechanical  forces.  (5) Photoreceptors, sensitive to light.  2. Sensory impulses  a. When receptors are stimulated, membrane potentials  change.  b. Receptor potentials are transferred to nerve fibers,  triggering action potentials.  3. Sensation and perception  a. Sensation is an awareness resulting from sensory  stimulation.  b. Perception is when a particular part of the sensory  cortex interprets the sensory stimulation.  c. Projection occurs when the cerebral cortex interprets a  sensation to come from the receptors being stimulated.  4. Sensory adaptation is the adjustment of sensory  receptors to continuous stimulation. Impulses are  triggered at slower rates.    skin, muscles, joints, and viscera. They can be grouped as the head.  exteroceptive, interoceptive, and proprioceptive senses. i; Sewenteneii  1. Touch and pressure senses a. Olfactory receptors  a. Free nerve endings, common in epithelial tissues, are (1) Olfactory receptors are chemoreceptors that  responsible for the sensation of itching. chemicals dissolved in nasal secretions stimulate.  b. Tactile corpuscles are the receptors for the sensations (2) Olfactory receptors function with taste receptors  of light touch. and aid in food selection.  c. Lamellated corpuscles are the receptors for the b. Olfactory organs  sensations of heavy pressure and vibrations. (1) The olfactory organs consist of receptor cells and  2. Temperature senses supporting cells in the nasal cavity.  a. Thermoreceptors include two sets of free nerve endings (2) Olfactory receptor cells are neurons with cilia  that are heat and cold receptors. containing membrane receptor proteins.  b. Combinations of input from both receptor types are c. Olfactory pathways.  interpreted as intermediate temperatures. (1) Smell information travels from the olfactory  3. Sense of pain receptor cells through the olfactory bulbs and  a. Pain receptors olfactory tracts.  (1) Pain receptors are free nerve endings that tissue (2) This information goes to interpreting centers in  damage stimulates. the limbic system.  (2) Pain receptors provide protection; do not adapt d. Olfactory stimulation    rapidly; and can be stimulated by changes in  temperature, mechanical force, and chemical    (1) Olfactory impulses may result when an  odorant molecule stimulates a distinct set of    concentration. receptor cells.  b. The only receptors in viscera that provide sensations are (2) Olfaction undergoes rapid sensory adaptation.  pain receptors. (3) Olfactory receptors are often damaged by    (1) These receptors are most sensitive to certain  chemicals and lack of blood flow.    (2) The sensations they produce may feel as if they come    environmental factors and are replaced from a  pool of stem cells.    from some other part of the body (referred pain). a. Taste receptors  c. Pain pathways (1) Taste buds consist of receptor cells and  (1) The two main types of pain fibers are acute pain supporting cells.  fibers and chronic pain fibers. (2) Taste cells have taste hairs that sense particular  (2) Acute pain fibers are fast conducting; chronic pain chemicals dissolved in water.  fibers are slower conducting. (3) Taste hairs are the chemosensitive structures that  (3) Pain impulses are processed in the dorsal trigger impulses to the brain.  horn of the spinal cord, and they ascend in the b. Taste sensations  spinothalamic tracts. (1) The five primary taste sensations are sweet, sour,  (4) Within the brain, pain information passes through salty, bitter, and umami.  the thalamus or the reticular formation before being (2) Various taste sensations result from the stimulation  relayed to the cerebral cortex. of one or more sets of taste cells.  d. Regulation of pain impulses (3) Each of the five primary types of taste cells  (1) Awareness of pain occurs when impulses reach the is particularly sensitive to a certain group  thalamus. of chemicals.  (2) The cerebral cortex judges the intensity of pain and c. Taste pathways   (4) Impulses descending from the brain cause neurons  to release pain-relieving substances, such as  enkephalins and serotonin.    (1) Sensory information from taste receptors travels  on fibers of the facial, glossopharyngeal, and  vagus nerves.   (2) This information is carried to the medulla  oblongata and ascends to the thalamus and then  to the gustatory cortex in the parietal lobes.    produced in the brain. a. The outer ear includes the auricle, the external  4. Proprioception acoustic meatus, and the tympanic membrane. It  a. Stretch receptors provide information about the collects sound waves created by vibrating objects and  condition of muscles and tendons. transfers the vibrations to the middle ear.  b. Muscle spindles are stimulated when a muscle is b. Middle ear    tension increases, and they initiate a reflex that relaxes  the muscle.    (1) Auditory ossicles of the middle ear transfer  sound waves from the tympanic membrane to the  oval window of the inner ear. They also increase  the force of these waves.   (2) Skeletal muscles attached to the auditory ossicles  provide the tympanic reflex, which protects the  inner ear from the effects of loud sounds.    Auditory tubes connect the middle ears to the throat  and help maintain equal air pressure on both sides of  the tympanic membranes.   (1) The inner ear consists of a complex system  of connected tubes and chambers—the bony  labyrinth and the membranous labyrinth. It  includes the cochlea, which houses the spiral  organ.   (2) The spiral organ includes the hearing receptors  that are stimulated by vibrations in the fluids of the  inner ear.   (3) Different frequencies of vibrations stimulate  different sets of receptor cells; the human ear can  detect sound frequencies from about 20 to 20,000  vibrations per second.   (1) The axons from hearing receptors are found in the  cochlear branch of the vestibulocochlear nerves.   (2) Auditory information travels into the medulla  oblongata, midbrain, and thalamus and is  interpreted in the temporal lobes of the cerebrum.    Static equilibrium maintains the stability of the head  and body when they are motionless. The organs of  static equilibrium are in the vestibule.   Dynamic equilibrium balances the head and body  when they are suddenly moved or rotated. The organs  of this sense are in the ampullae of the semicircular  canals.   Other structures that help maintain equilibrium include  the proprioceptors associated with certain joints and  the eyes.    Visual accessory organs include the eyelids and  lacrimal apparatus that protect the eye and the  extrinsic muscles that move the eye.    (1) The wall of the eye has an outer, a middle, and an  inner tunic that function as follows:   (a) The outer layer (sclera) is protective, and its  transparent anterior portion (cornea) refracts  light entering the eye.   (b) The middle layer (choroid coat) is vascular  and has pigments that help keep the inside of  the eye dark.   (2) The lens is a transparent, elastic structure. The  ciliary muscles control its shape.   (3) The iris is a muscular diaphragm that controls the  amount of light entering the eye; the pupil is an  opening in the iris.   (4) Spaces in the eye are filled with fluids (aqueous  and vitreous humors) that help maintain its shape.   (1) Light rays are primarily refracted by the cornea and  lens to focus an image on the retina.   (2) Rods are responsible for colorless vision in dim  light, and cones provide color vision.   (1) A light-sensitive pigment in rods (rhodopsin)  decomposes in the presence of light and triggers  a complex series of reactions that initiate action  potentials on the optic nerve.   (2) Three types of cones provide color vision. Each  type has a different light-sensitive pigment, and  each type is sensitive to a different wavelength of  light; the color perceived depends on which cones  are stimulated.   (2) Stereoscopic vision occurs because of the  formation of two slightly different retinal images  that the brain superimposes and interprets as one  image in three dimensions.   (3) A one-eyed person uses relative sizes and positions  of familiar objects to judge distance and depth.   (3) Most of the fibers enter the thalamus and synapse  with others that continue to the visual cortex of the  occipital lobe.   (4) Other impulses pass into the brainstem and  function in various visual reflexes.    Diminished senses are often one of the first noticeable signs  of aging.   1. Age-related hearing loss may reflect damage to hair cells  of the spiral organ, degeneration of nerve pathways to the  brain, or tinnitus.   2. Age-related visual problems include dry eyes, floaters and  light flashes, presbyopia, glaucoma, cataracts, macular  degeneration, and retinal detachment.    Explain the difference between a general sense and a special  sense. (p. 444)    Match each sensory receptor to the type of stimulus to which  it is likely to respond: (p. 444)  (1) chemoreceptor   You fill up the tub to take a hot bath, but the water is too  hot. You test it a second and third time within a few seconds,  and it feels okay. Which of the following is the most likely  explanation? (p. 446)   c. Your nervous system is suddenly not functioning properly.  d. Someone added ice cubes to your bath.    Explain how general senses can be grouped. (p. 446)  Describe the functions of free nerve endings, tactile  corpuscles, and lamellated corpuscles. (p. 446)   Compare pain receptors with the other types of somatic  receptors. (p. 446)   List the conditions likely to stimulate visceral pain receptors.  (p. 447)   Define referred pain, and provide an example. (pp. 447  and 449)   Contrast the pathways involved in the production of acute  and chronic pain. (p. 449)   Explain how neuropeptides relieve pain. (p. 449)  Distinguish between muscle spindles and Golgi tendon  organs. (pp. 450-451)    Explain how the senses of smell and taste function together  to create the perception of the flavors of foods. (p. 452)  Which two of the following are part of the olfactory organs?  (p. 452)   Trace each step in the pathway from an olfactory receptor to  the interpreting center of the cerebrum. (pp. 453-454)  Salivary glands are important in taste because   Name the five primary taste sensations and indicate a  specific stimulus for each. (p. 455)    Explain why taste sensation is less likely to diminish with age  than olfactory sensation. (p. 455)   Trace each step in the pathway from a taste receptor to the  interpreting center of the cerebrum. (p. 456)    (pp. 456-459)  (1) outer ear A. cochlea  (2) middle ear B. tympanic membrane   The function of the auditory tube is to . (p. 459)   a. equalize air pressure on both sides of the tympanic  membrane   Trace each step in the pathway from the spiral organ to the   Name the three layers of the eye wall and describe the   The following are compartments in the eye. In which one is   Explain how light is focused on the retina. (pp. 475 and 478)   Explain why looking at a close object causes fatigue in terms   Explain why rod vision may be more important in dim light    47 Describe the relationship between light wavelength and  color vision. (pp. 480-481)   49 Explain why a person with normal binocular vision is able to  judge distance and depth of close objects more accurately  than a person who has lost one eye. (p. 481)   50 Trace each step in the pathway from the retina to the visual  cortex. (p. 481)    1. Positron emission tomography (PET) scans of the brains of  people who have been blind since birth reveal high neural  activity in the visual centers of the cerebral cortex when these  people read Braille. When sighted individuals run their fingers    over the raised letters of Braille, their visual centers do not show    2. Why are some serious injuries, like a bullet entering the  abdomen, relatively painless, but others, such as a burn,  considerably more painful?    3. Loss of the sense of smell often precedes the major symptoms  of Alzheimer disease and Parkinson disease. What additional    information is needed to use this association to prevent or treat    12.5 Life-Span Changes  51 Explain the basis of fading senses of smell and taste with  aging. (p. 482)  52. List three causes of hearing loss associated with aging.  (p. 482)  53 Explain five problems that can interfere with vision as a  person ages. (p. 482)    4. A patient with heart disease experiences pain at the base of the  neck and in the left shoulder and upper limb during exercise. How  would you explain the likely origin of this pain to the patient?    5. People who are deaf due to cochlear damage do not suffer  motion sickness. Why not?    6. Labyrinthitis is an inflammation of the inner ear. What symptoms  would you expect in a patient with this disorder?    Connect Interactive Questions Reinforce your knowledge using  assigned interactive questions covering the general senses (touch,  pressure, temperature, and pain) and special senses (smell, taste,  hearing, balance, and vision).    Connect Integrated Activity Can you predict the effects on vision  of injuries at various locations along the visual pathways?    Anatomy & Physiology Revealed Go more in depth into the  human body and explore the structures associated with your senses  of hearing and vision.    In this electron micrograph of a hormone-secreting cell from the adrenal  cortex, the upper portion of the cell has been removed to reveal the  nucleus (brown) and the edge of the cell membrane (grey) (14,400x).    The hormones that the endocrine system produces have many  and diverse effects on the body. A new mother hears her baby  cry and her breasts release milk. A busy executive attends meet-  ings all day without a break to eat but still maintains enough  blood glucose to function. The early morning smell of smoke and  the clang of fire alarms in a dormitory elevate heart rates, dilate  airways, and send students streaming from the building.   The endocrine system, like the nervous system, is all about  communication as cells secrete chemicals that act on other cells.  Whereas the nervous system releases neurotransmitter mole-  cules at synapses, the endocrine system releases its characteristic  substances, hormones, into the bloodstream.   Some hormones act briefly, while others have quite long-  lasting effects. Hormone actions may be subtle, their levels  requiring constant adjustment to maintain homeostasis. Other  hormones have dramatic effects, from overseeing the gradual  growth and development of an infant into a toddler, an adolescent,  and then an adult, to the immediate excitement of participating  in an athletic competition.    After you have studied this chapter, you should be able to:    2 Explain what makes a cell a target cell for a hormone.  (p. 488)    4 Describe how hormones can be classified according to  their chemical composition. (pp. 489-490)    5 Explain how steroid and nonsteroid hormones affect their  target cells. (pp. 490-496)    6 Discuss how negative feedback mechanisms regulate  hormone secretion. (p. 496)    7 Explain how the nervous system controls hormone  secretion. (p. 496)    8 Name and describe the locations of the major endocrine  glands, and list the hormones that they secrete.  (pp. 498-515)    9 Describe the actions of the various hormones and their  contributions to homeostasis. (pp. 500-515)    10 Explain how the secretion of each hormone is regulated.  (pp. 500-515)  13.10 Stress and Its Effects    12 Describe the general stress response. (pp. 517-518)  13.11 Life-Span Changes    13 Describe some of the changes associated with aging of  the endocrine system. (pp. 519-521)    Endocrine means “internal secretion.” The endocrine system is so  named because the cells, tissues, and organs that compose it, col-  lectively called endocrine glands, secrete substances into the inter-  nal environment. The secreted substances, called hormones, diffuse  from the interstitial fluid into the bloodstream and eventually act  on cells, called target cells, some distance away (fig. 13.1a). In  contrast to endocrine secretions, exocrine secretions are released  externally. Secretions from exocrine glands enter tubes or ducts  that lead to body surfaces. Two examples of exocrine secretions  are stomach acid reaching the lumen of the digestive tract and  sweat released at the skin’s surface (fig. 13.1b).   Other glands secrete substances into the internal environment  that are not hormones by the traditional definition, but they func-  tion similarly as messenger molecules and are sometimes termed  “local hormones.” These include paracrine secretions, which  enter the interstitial fluid but affect only nearby cells, and auto-  crine secretions, which affect only the cell secreting the substance.   Cells of the endocrine system and the nervous system both  communicate using chemical signals that bind to receptor molecules.  Table 13.1 summarizes some similarities and differences between  the two systems. In contrast to the nervous system, which releases  neurotransmitter molecules into synapses, the endocrine system  releases hormones into the bloodstream, which carries these mes-  senger molecules everywhere. However, the endocrine system is  also precise, because only target cells can respond to a particular  type of hormone (fig. 13.2). A hormone’s target cells have spe-  cific receptors that are not on other cells. These receptors are pro-  teins or glycoproteins with binding sites for a specific hormone.  The non-endocrine chemical messengers, paracrine and autocrine  substances, also bind to specific receptors. This chapter includes  examples of them.   Endocrine glands and their hormones help regulate metabolic  processes. They control the rates of certain chemical reactions; aid in  transporting substances through membranes; and help regulate water  balance, electrolyte balance, and blood pressure. Endocrine hormones  also play vital roles in reproduction, development, and growth.   -tropic, influencing: adrenocorticotropic  hormone—a hormone secreted by the  anterior pituitary gland that stimulates  the adrenal cortex.    FIGURE 13.1 Types of glands. (a) Endocrine glands release hormones  into the internal environment (body fluids). (b) Exocrine glands secrete to  the outside environment through ducts that lead to body surfaces.    FIGURE 13.2 Chemical communication. (a) Neurons release  neurotransmitters into synapses, affecting postsynaptic cells. (b) Glands  release hormones into the bloodstream. Blood carries hormone molecules  throughout the body, but only target cells respond.    @ Which is more specific in terms of which cells are affected,  a neurotransmitter or a hormone?    Small groups of specialized cells produce some hormones.  However, the larger endocrine glands—the pituitary gland, thyroid  gland, parathyroid glands, adrenal glands, and pancreas—are the  subject of this chapter (fig. 13.3). Subsequent chapters discuss sev-  eral other hormone-secreting glands and tissues.    Hormones are released into the extracellular spaces surrounding  endocrine cells. From there, they diffuse into the bloodstream and  are carried to all parts of the body.    May be brief or may  last for days even if  secretion ceases    Hormones are organic compounds. They are of two major types:  steroids, or steroidlike substances; and nonsteroids, which include  amines, peptides, proteins, and glycoproteins. Hormones can stim-  ulate changes in target cells even in extremely low concentrations.   Steroids (ste’roidz) are lipids that include complex rings of carbon  and hydrogen atoms (fig. 13.4a). Steroids differ by the types and  numbers of atoms attached to these rings and the ways they are  joined (see fig. 2.16, p. 72). All steroid hormones are derived from  cholesterol (see chapter 2, p. 72). They include sex hormones such  as testosterone and the estrogens, and secretions of the adrenal cor-  tex (the outer portion of the adrenal gland), including aldosterone  and cortisol. Vitamin D is a modified steroid and when converted  to the active form in the kidneys and liver becomes a hormone (see  “Parathyroid Hormone” on pp. 507-508, and chapter 18, p. 706).    Nonsteroid Hormones  Hormones called amines, including norepinephrine and epineph-  rine, are derived from the amino acid tyrosine. These hormones    are also synthesized in the adrenal medulla (the inner portion of  the adrenal gland) (fig. 13.4b).    The young woman had been controlling her type 2 diabetes  mellitus for several years with a strict low-carbohydrate  diet, exercise whenever she could manage it, and oral  medications. But her blood glucose levels over the past  three months had been too elevated, and so her physician  advised that she begin injecting insulin once a day. The  woman was very upset about having to inject herself, and  wondered how she would travel for business and maintain  her daily treatment. Fortunately her physician prescribed  regular sessions with a diabetes educator, who helped the  patient adjust to her change in treatment plan.   A diabetes educator is a health-care professional with  a degree in nursing, dietetics, pharmacy, or another related  field. The educator is knowledgeable about the many aspects  of maintaining stable blood glucose levels and treating  diabetes, and is also expert in counseling and communicating  complex medical information.   Living with diabetes requires more self-care, on a daily  basis, than living with many other diseases. The diabetes  educator helps the patient understand how to maintain  healthful diet and exercise habits, how to time her monitoring  of her blood glucose level and take various medications,  and how to recognize and reduce risks of diabetes-related  complications. A diabetes educator can tailor a care plan to  the individual, for although diabetes is a common condition,  no two patients have exactly the same experience.   Diabetes educators work in doctor’s offices, clinics, and  hospitals. They may provide one-on-one care, or lead groups  in discussing how to live with diabetes.    surface of  thyroid gland) Thymus  Adrenal gland  Kidney Pancreas  Ovary  (in female)  Testis  (in male)    Protein hormones, like all proteins, are composed of long  chains of amino acids that are linked and folded into specific  molecular structures (see chapter 2, pp. 72-75, and fig. 13.4c).  They include the hormone secreted by the parathyroid gland and  some of those secreted by the anterior pituitary gland. Certain  other hormones secreted from the anterior pituitary gland are glyco-  proteins, which consist of carbohydrates joined to proteins.   The peptide hormones are short chains of amino acids (fig.  13.4d). This group includes hormones associated with the poste-  rior pituitary gland and some produced in the hypothalamus.   Another group of compounds, called prostaglandins  (pros”tah-glan’dinz), are paracrine substances. They regulate  neighboring cells. Prostaglandins are lipids (20-carbon fatty  acids that include 5-carbon rings) and are synthesized from a type  of fatty acid (arachidonic acid) in cell membranes (fig. 13.4e).  Prostaglandins are produced in a wide variety of cells, including  those of the liver, kidneys, heart, lungs, thymus, pancreas, brain,  and reproductive organs.   Table 13.2 lists the names and abbreviations of some of the  hormones discussed in this chapter. Table 13.3 and figure 13.4  summarize the chemical composition of hormones.    1. What is a hormone?  2 How do endocrine glands and exocrine glands differ?    Hormones exert their effects by altering metabolic processes. A  hormone might change the activity of an enzyme necessary for syn-  thesizing a particular substance or alter the rate at which particu-  lar chemicals are transported through cell membranes. A hormone  delivers its message to a cell by uniting with the binding site of its  receptor. The more receptors the hormone binds on its target cells,  the greater the response.   The number of receptors on target cells may change.  Upregulation is an increase in the number of receptors on a target  cell, which often occurs as a response to a prolonged decrease in  the level of a hormone. Downregulation is the opposite, a decrease  in the number of receptors in response to a prolonged increase in  hormone levels. Therefore, the number of receptors changes in ways  that maintain an appropriate response to hormone level.   Steroid hormones are poorly soluble in water. They are carried in the  bloodstream bound to plasma proteins in a way that they are released  in sufficient quantity to affect their target cells. Unlike amine, pep-  tide, and protein hormones, steroid hormones are soluble in the lip-  ids that make up the bulk of cell membranes. For this reason, these  hormones can diffuse into cells relatively easily and are able to enter  any cell in the body, although only target cells will respond.    Thyroid hormones are also poorly soluble in water and are  transported in the blood bound to plasma proteins. They have  often been described as entering cells the same way that steroids  enter, but recent evidence suggests that specific membrane trans-  port mechanisms may move them.   Once inside a target cell, steroid and thyroid hormones com-  bine (usually in the nucleus) with specific protein receptors. The  resulting hormone-receptor complex binds to particular DNA  sequences, either activating or repressing specific genes. Activated  genes are transcribed into messenger RNA (mRNA) molecules.  The mRNAs enter the cytoplasm, where they direct the synthesis  of specific proteins, which may be enzymes, transport proteins,  or even hormone receptors. The activities of these hormones pro-  duce the cellular changes associated with the particular hormone  (fig. 13.5, table 13.4, and Clinical Application 13.1). An example  of a steroid hormone is aldosterone (al’do-ster-dn”, al-dos’ter-6n),  which is secreted from the adrenal glands and stimulates the kid-  neys to retain sodium. In response to aldosterone, cells that form  tubules in the kidney begin to synthesize more Na*/K* pumps,  which are the proteins that actively transport these ions across the  cell membrane, in this case returning sodium to the bloodstream.    “ To Chapter 4, Nucleic Acids and Protein Synthesis,  pages 138-142.    In some cases, steroid hormones may repress a particular gene,  so it is not transcribed. The cellular response results from decreased  levels of the encoded protein.   Growth hormone-releasing hormone  Prolactin release-inhibiting hormone  Prolactin-releasing factor*  Thyrotropin-releasing hormone  Anterior pituitary gland Adrenocorticotropic hormone  Follicle-stimulating hormone  Growth hormone   Thyroid gland Calcitonin  Thyroxine  Triiodothyronine  Parathyroid gland Parathyroid hormone  Adrenal medulla Epinephrine  Norepinephrine  Adrenal cortex Aldosterone  Cortisol  Pancreas Glucagon    A nonsteroid hormone, such as an amine, peptide, or protein, com-  bines with specific receptor molecules on the target cell membrane.  Each receptor molecule is a protein that has a binding site and an  activity site. The hormone combines with the binding site, which  causes the receptor’s activity site to interact with other membrane  proteins. The hormone that triggers this first step in what becomes  a cascade of biochemical activity is considered a first messenger.  The biochemicals in the cell that induce the changes leading to the  hormone effect are called second messengers.   Many hormones use cyclic adenosine monophosphate (cyclic  AMP, or cAMP) as a second messenger. In this mechanism, a hor-  mone binds to its receptor, and the resulting hormone-receptor  complex activates a protein called a G protein, which then activates    Abbreviation  CRH  GnRH  SS  GHRH  PIH  BRE  TRH  ACTH  FSH  GH  LH  PRL  TSH  ADH    FIGURE 13.4 Structural  formulas of (a) a steroid hormone  (cortisol) and (b) an amine hormone  (norepinephrine). Amino acid    7 ' sequences of (c) a protein hormone  HO C—C—NH (PTH) and (d) a peptide hormone    an enzyme called adenylate cyclase (ah-den’i-lat si’klas), which is  an integral membrane protein with its active site facing the inside  of the cell. Activated adenylate cyclase removes two phosphates  from ATP and reconnects the exposed oxygen, forming cyclic  AMP (fig. 13.6). Cyclic AMP activates another set of enzymes  called protein kinases (ki’nas-ez) that transfer phosphate groups  from ATP molecules to protein substrate molecules, a process  called phosphorylation. Phosphorylation activates some proteins,  and renders others inactive.   Next, the phosphorylated proteins alter various cellular pro-  cesses, bringing about the effect of that particular hormone (fig.  13.7). The response of a cell to a hormone is determined by the type  of membrane receptors present and by the types of protein substrate  molecules in the cell. Table 13.5 summarizes these events.    . Steroid hormone diffuses through target cell membrane  and enters cytoplasm or nucleus.    . Hormone combines with a receptor molecule in the  cytoplasm or nucleus.    . Steroid hormone-receptor complex binds to DNA and  promotes transcription of messenger RNA.    @ A steroid hormone  reaches a target cell  and crosses the cell  membrane    @ The hormone combines  with a protein receptor,  usually in the nucleus    @ The hormone-receptor  complex activates  synthesis of specific  messenger RNA  (mRNA) molecules    @ The mRNA molecules  leave the nucleus and  enter the cytoplasm    3) Translation of mRNA  molecules leads to  synthesis of the  encoded proteins  associated with the  hormone’s action    FIGURE 13.5 §AP|RJ Steroid hormones. Thyroid hormones, which are non-steroids, act in much the same way, but may enter the cell    FIGURE 13.6 Adenylate cyclase catalyzes conversion of (a) ATP molecules into cyclic AMP    (b). The atoms forming the new bond are shown in red.    Cellular responses to second messenger activation include  altering membrane permeabilities, activating enzymes, promot-  ing synthesis of certain proteins, stimulating or inhibiting specific  metabolic pathways, promoting cellular movements, and initiating  secretion of hormones and other substances. A specific example  is the action of epinephrine to raise blood sugar during periods  of physical stress. Epinephrine acts through the second messen-    ger cAMP to increase the activity of the enzyme that breaks down  liver glycogen, increasing the number of glucose molecules that  can diffuse out of liver cells and enter the bloodstream.   Another enzyme, phosphodiesterase, quickly and continuously  inactivates cAMP, so its action is short-lived. For this reason, a con-  tinuing response in a target cell requires a continuing signal from  hormone molecules binding receptors in the target cell membrane.    Abuse of performance-enhancing drugs among athletes, both  amateur and professional, is a common problem and not new  (table 13A). Athletes have used drugs for a competitive edge  since the earliest Olympics, when cocaine, heroin, morphine, and  strychnine were the drugs of choice. Amphetamines joined the list  after World War II, when soldiers took these stimulants to mask  the fatigue that accompanies great exertion. The drugs boosted  energy in sports, too. Today, the general focus of performance  enhancement is misuse of certain hormones. Three examples are  described here.    Athletes who abuse steroids seek the hormone’s ability to increase  muscular strength. Abusers are caught when the steroids or their  metabolites are detected in urine or when natural testosterone  levels plummet in a negative feedback response to the outside  supply of the hormone.   Abusing steroids carries serious risks to health. Steroids  hasten adulthood, stunting height and causing early hair loss. In  males, excess steroid hormones lead to breast development, and  in females to a deepened voice, hairiness, and a male physique.  The kidneys, liver, and heart may be damaged, and atherosclero-  sis may develop because steroids raise LDL and lower HDL—the  opposite of a healthy cholesterol profile. Steroids can also cause  psychiatric symptoms, including delusions, depression, and vio-  lent behavior.   For some athletes, illicit steroid use cannot be detected  because of a natural mutation that deletes part of a gene. The result  is a block in the conversion of testosterone from fat soluble to water  soluble, and the hormone is not excreted into the urine as it nor-  mally is. This mutation is responsible for variations seen in different  populations in the amount of testosterone excreted in the urine.  In one telling experiment, researchers in Sweden injected fifty-five  male volunteers with a high dose of testosterone, and seventeen of  the men showed no traces of the steroid in their urine!   The urine ratio of testosterone to an inactive form of the hor-  mone called epitestosterone can reveal the taking of exogenous  (outside) testosterone. The body normally produces testoster-  one and epitestosterone in about equal amounts. The presence  of much more testosterone than epitestosterone therefore indi-  cates “doping.”    Some athletes take human growth hormone (HGH) prepara-  tions instead of, or to supplement, the effects of steroids. HGH  enlarges muscles; steroids strengthen them. HGH has been avail-  able as a prescription drug since 1985, and it is used as such to  treat children with certain forms of inherited dwarfism. However,  HGH is available from other nations without prescription and can  be obtained illegally to enhance athletic performance. Unlike ste-  roids, HGH has a half-life of only seventeen to forty-five minutes,  which means that it becomes so scant that it is undetectable in  body fluids within an hour. At first only elite athletes abused HGH    to enhance performance. One recent study of young weight lifters  in the United States, however, found that 12% of them took HGH  or insulin-like growth factor-1 (which HGH stimulates synthesis of  in the body).   Increasing the number of red blood cells can increase oxygen  delivery to muscles and thereby enhance endurance. Athletes  introduced “blood doping” in 1972. The athletes would have  blood removed a month or more prior to performance, then rein-  fuse the blood shortly before a competition, boosting the number  of red blood cells. Easier than blood doping is to take erythro-  poietin (EPO), a hormone secreted from the kidneys that signals  the bone marrow to produce more red blood cells. EPO is used  to treat certain forms of anemia. Using it to improve athletic per-  formance is ill advised. In 1987, EPO abuse led to heart attacks  and death in twenty-six cyclists. Some runners and swimmers also  abuse EPO.   Testing for drugs or for mutations that enable athletes  to mask abuse is expensive. Testing for biomarkers that are  the breakdown products of abused drugs may be a less costly  approach to detecting the practice of cheating by manipulating  the endocrine system.   Hormones and related substances  EPO  Growth factors  Gonadotropins (LH, hCG in males)  Insulin  Corticotropins   Hormone antagonists and modulators  Aromatase inhibitors  Selective estrogen receptor modulators  Other antiestrogens    . Endocrine gland secretes nonsteroid hormone.  . Blood carries hormone molecules throughout the body.    . Hormone combines with receptor site on membrane of its  target cell, activating G protein.    . Adenylate cyclase converts ATP into cyclic AMP.  . Cyclic AMP activates protein kinases.    . Protein kinases activate protein substrates in the cell that  change metabolic processes.    Hormones whose actions require cyclic AMP include releas-  ing hormones from the hypothalamus; thyroid-stimulating hormone  (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating  hormone (FSH), and luteinizing hormone (LH) from the anterior  pituitary gland; antidiuretic hormone (ADH) from the posterior  pituitary gland; parathyroid hormone (PTH) from the parathyroid  glands; norepinephrine and epinephrine from the adrenal glands;  calcitonin from the thyroid gland; and glucagon from the pancreas.    @ Adenylate cyclase  catalyzes conversion of  ATP into cyclic adenosine  monophosphate (cAMP)    © cAMP activates existing  proteins, causing a series  of reactions leading to  the cellular changes  associated with the  hormone’s action    An abnormality in cCAMP-mediated signaling can lead to symp-  toms from many endocrine glands. In McCune-Albright syn-  drome, for example, a defect in the G protein that activates  adenylate cyclase results in conversion of ATP to cAMP even  without hormonal stimulation. As a result, cells in the pitu-    itary, thyroid, gonads, and adrenal glands secrete hormones in  excess. One symptom is precocious puberty. Infant girls men-  struate, and boys as young as six years produce mature sperm.  Abnormal or deficient G proteins also cause colorblindness and  retinitis pigmentosa.    Certain nonsteroid hormones use second messengers other  than cAMP. For example, a second messenger called diacylglyc-  erol (DAG), like cAMP, activates a protein kinase, leading to a cel-  lular response.   In another mechanism, a hormone binding its receptor increases  calcium ion concentration in the cell. Such a hormone may stim-  ulate transport of calcium ions inward through the cell membrane  or induce release of calcium ions from cellular storage sites via a  second messenger called inositol triphosphate (IP3). The calcium  ions combine with the protein calmodulin (see chapter 9, p. 307),  altering its molecular structure in a way that activates the molecule.  Activated calmodulin can then interact with enzymes, altering their  activities and thus eliciting diverse responses.    Still another hormonal mechanism uses cyclic guanosine  monophosphate (cyclic GMP, or cGMP). Like cAMP, cGMP is a  nucleotide derivative and functions in much the same manner as a  second messenger.   The cellular response to a hormone operating through a second  messenger is greatly amplified. This is possible because many sec-  ond messenger molecules can be activated in response to just a few  hormone-receptor complexes, and the enzymes that are activated  as a result can repeatedly catalyze reactions. Because existing pro-  teins are activated, the response is fast. Cells are highly sensitive  to changes in the concentrations of nonsteroid hormones because  of such rapid amplification. Cellular response to a steroid hormone  (and thyroid hormones) is directly proportional to the number of  hormone-receptor complexes that form. Some amplification occurs  because more than one mRNA may be transcribed from an acti-  vated gene and each mRNA may be translated into multiple copies  of a protein. The response is much slower than the response to hor-  mones acting through second messengers because protein synthesis  takes some time, although the response lasts longer.    4 How does a steroid hormone act on its target cells?  5 How does a nonsteroid hormone act on its target cells?    Prostaglandins are paracrine substances, acting locally, that are in  small amounts, but potent. They are not stored in cells but are syn-  thesized just before they are released. They are rapidly inactivated.   Some prostaglandins regulate cellular responses to hor-  mones. For example, different prostaglandins can either activate  or inactivate adenylate cyclase in cell membranes, thereby con-  trolling production of cAMP and altering the cell’s response to  a hormone.   Prostaglandins produce a variety of effects. Some prostaglan-  dins relax smooth muscle in the airways of the lungs and in the  blood vessels, dilating these passageways. Yet other prostaglan-  dins can contract smooth muscle in the walls of the uterus, causing  menstrual cramps and labor contractions. They stimulate secre-  tion of hormones from the adrenal cortex and inhibit secretion of  hydrochloric acid from the wall of the stomach. Prostaglandins  also influence movements of sodium ions and water in the kid-  neys, help regulate blood pressure, and have powerful effects on  both male and female reproductive physiology. When tissues are  injured, prostaglandins promote inflammation.    Understanding prostaglandin function has medical applica-  tions. Drugs such as aspirin and certain steroids that relieve the  joint pain of rheumatoid arthritis inhibit production of prosta-  glandins in the synovial fluid of affected joints. Daily low doses  of aspirin may reduce the risk of heart attack by altering prosta-  glandin activity.    The body must be able to turn processes on and off. For example,  removal of acetylcholine from the neuromuscular junction stops  skeletal muscle contraction. A value called the half-life is used to  indicate the rate of a hormone’s removal. Half-life is the time it takes  for half of the hormone molecules to be removed from the plasma.  For example, a hormone with a half-life of ten minutes would start  out at 100% of its blood concentration, and if secretion were to stop,  it would drop to 50% in ten minutes, 25% in another ten minutes,  12.5% in another ten minutes, and so on. Hormones with short  half-lives (a few minutes) control body functions that turn on and  off quickly, whereas the effects of hormones with longer half-lives,  such as thyroid hormone and steroids, may last for days.   Hormones are continually excreted in the urine and broken  down by enzymes, primarily in the liver. Therefore, increasing  or decreasing blood levels of a hormone requires increased or  decreased secretion. Hormone secretion is precisely regulated.    Control of hormone secretion is essential to maintaining the internal  environment. In a few cases, primarily in the reproductive systems,  positive feedback affects this control.   Generally, hormone secretion is controlled in three ways, all  of which employ negative feedback (see chapter 1, p. 16). In each  case, an endocrine gland or the system controlling it senses the  concentration of the hormone the gland secretes, a process the hor-  mone controls, or an action the hormone has on the internal envi-  ronment (fig. 13.8).    1. The hypothalamus, which constantly receives information  about the internal environment, controls the anterior pitu-  itary gland’s release of hormones. Many anterior pituitary  hormones affect the activity of other glands. Hormones that  act on other glands are called tropic hormones (fig. 13.8a)  (fig. 13.9).   The adrenal medulla, for example, secretes its hormones  (epinephrine and norepinephrine) in response to impulses  from preganglionic sympathetic neurons. The secretory cells  replace the postganglionic sympathetic neurons, which would  normally secrete norepinephrine alone as a neurotransmitter  (see fig. 13.8b).   3. Another group of glands responds directly to changes in the  composition of the internal environment. For example, when  the blood glucose level rises, the pancreas secretes insulin,  and when the blood glucose level falls, it secretes glucagon  (see “Hormones of the Pancreatic Islets” on pp. 514-515  and fig. 13.8c).    FIGURE 13.8 Examples of endocrine system control: (a) one way the hypothalamus controls the anterior pituitary, (b) the nervous system controls some  glands directly, and (c) some glands respond directly to changes in the internal environment. @ indicates negative feedback inhibition.    (cut) Medial surface  of hypothalamus  Optic nerve  Pituitary stalk O  ; culomotor  (infundibulum) nerve  Anterior lobe Trochlear  ad nerve  Posterior lobe  Sphenoidal eq  sinus ae  Sella turcica    FIGURE 13.9 §AP|R The pituitary gland is attached to the hypothalamus and lies in the sella turcica of the sphenoid bone.    In each of these cases, as hormone levels rise in the blood and the  hormone exerts its effects, negative feedback inhibits the system  and hormone secretion decreases. Then, as hormone levels in  the blood decrease and the hormone’s effects wane, inhibition of  the system ceases, and secretion of that hormone increases again  (fig. 13.10). As a result of negative feedback, hormone levels in the  bloodstream remain relatively stable, fluctuating slightly around  an average value (fig. 13.11).    FIGURE 13.11 Asa result of negative feedback, hormone  concentrations remain relatively stable, although they may fluctuate  slightly above and below average concentrations.    The pituitary (pi-tu’i-tar”e) gland (hypophysis), at the base of  the brain, is about one centimeter in diameter. It is attached to the  hypothalamus by the pituitary stalk, or infundibulum, and lies in  the sella turcica of the sphenoid bone, as figure 13.9 shows.   The pituitary gland consists of two distinct portions: an anterior  lobe (adenohypophysis) and a posterior lobe (neurohypophy-  sis). The anterior lobe secretes a number of hormones, including  growth hormone (GH), thyroid-stimulating hormone (TSH), adre-  nocorticotropic hormone (ACTH), follicle-stimulating hormone  (FSH), luteinizing hormone (LH), and prolactin (PRL). The cells  that make up the posterior lobe (pituicytes) do not synthesize hor-  mones. However, specialized neurons, whose axon endings enter  the posterior lobe of the pituitary, secrete into the bloodstream two  important hormones: antidiuretic hormone (ADH) and oxytocin  (OT). The cell bodies of these neurons are in the hypothalamus.    In the fetus, a narrow region develops between the anterior and  posterior lobes of the pituitary gland. Called the intermediate  lobe (pars intermedia), it produces melanocyte-stimulating hor-  mone (MSH), which regulates the synthesis of melanin—the pig-  ment in skin and in parts of the eyes and brain. In most adults  this intermediate lobe is no longer a distinct structure, but its  secretory cells persist in the two remaining lobes.    The brain controls most of the pituitary gland’s activities  (fig. 13.12). In fact, the posterior pituitary is actually part of the ner-  vous system. The axons of certain neurons whose cell bodies are in  the hypothalamus extend down into the posterior pituitary gland.  Impulses on these axons trigger the release of chemicals from their  axon terminals, which then enter the bloodstream as posterior pitu-  itary hormones. The anterior pituitary consists of glandular cells  rather than neurons, but it, too, is under the brain’s control. Axon  terminals of another population of hypothalamic neurons release  chemicals called releasing hormones (or in some cases release-  inhibiting hormones). These releasing hormones are carried in the    FIGURE 13.12 (AP|R) Pituitary gland. (a) Hypothalamic releasing hormones stimulate cells of the anterior lobe to secrete hormones.  (b) Impulses originating in the hypothalamus stimulate nerve endings in the posterior lobe of the pituitary gland to release hormones.    blood via a capillary bed associated with the hypothalamus. The  vessels merge to form the hypophyseal (hi”po-fiz’e-al) portal  veins that pass downward along the pituitary stalk and give rise to  a second capillary bed in the anterior lobe. In this way, substances  released into the blood from the hypothalamus are carried directly  to the anterior lobe. The hypothalamus, therefore, functions as an  endocrine gland, yet it also controls other endocrine glands. This  dual activity is also true of the anterior pituitary.    The arrangement of two capillaries in series is unusual and is  called a portal system. It exists in three places in the body: the  hepatic portal vein connects intestinal capillaries to special  liver capillaries called sinusoids, the efferent arteriole of kidney    nephrons connects two sets of capillaries, and the hypophyseal  portal vein gives rise to a capillary net in the anterior lobe of the  pituitary gland.    Each of the hypothalamic releasing hormones acts on a spe-  cific population of cells upon reaching the anterior lobe of the pitu-  itary gland. Some of the resulting actions are inhibitory (prolactin  release-inhibiting hormone and somatostatin), but most stimu-  late the anterior pituitary to release hormones that stimulate the  secretions of peripheral endocrine glands. In many of these cases,  important negative feedback relationships regulate hormone levels  in the bloodstream. Figure 13.13 shows this general relationship.    FIGURE 13.13 Hypothalamic control of the peripheral endocrine  glands may use as many as three types of hormones, with multiple  negative feedback controls. (@ = stimulation; @ = inhibition)    13 List the hormones that the anterior and posterior lobes of the  pituitary gland secrete.    14 Explain how the hypothalamus controls the actions of the  pituitary gland.    The anterior lobe of the pituitary gland is enclosed in a capsule of  connective tissue and largely consists of epithelial tissue organized  in blocks around many thin-walled blood vessels. The epithelial  tissue has five types of secretory cells. They are somatotropes  that secrete GH, mammatropes that secrete PRL, thyrotropes that  secrete TSH, corticotropes that secrete ACTH, and gonadotropes  that secrete FSH and LH (figs. 13.14 and 13.15). In males, LH  (luteinizing hormone) is also referred to as ICSH (interstitial cell-  stimulating hormone) because it affects the interstitial cells of the  testes (see chapter 22, p. 838).   Growth hormone, also called somatotropin (or somatotro-  phic hormone, STH), is a protein that stimulates cells to enlarge  and more rapidly divide. It enhances the movement of amino acids  through cell membranes and increases the rate of protein synthe-  sis. GH also decreases the rate at which cells use carbohydrates  and increases the rate at which they use fats.   Growth hormone secretion varies during the day, peaking dur-  ing sleep. Two biochemicals from the hypothalamus control its  secretion. They are released alternately, exerting opposite effects.  Growth hormone-releasing hormone (GHRH) stimulates secretion  of GH, and somatostatin (SS) inhibits secretion.   Nutritional state can affect control of GH. More GH is  released during periods of protein deficiency and abnormally low  blood glucose concentration. Conversely, when blood protein  and glucose concentrations increase, growth hormone secretion    FIGURE 13.14 (AP|R) Light micrograph of the anterior pituitary  gland (240x).    decreases. Apparently the hypothalamus can sense changes in the  concentrations of certain blood nutrients and it releases GHRH in  response to some of them.   Growth hormone can stimulate elongation of bone tissue  directly, but its effect on cartilage requires a mediator protein,  insulin-like growth factor-1 (IGF-1). Growth hormone releases  IGF-1 from the liver and other tissues. Clinical Application 13.2  discusses some clinical uses of growth hormone.   Prolactin is a protein, and as its name suggests, it promotes  milk production. No normal physiological role for this hormone  in human males has been firmly established. Abnormally elevated  levels of the hormone can disrupt sexual function in both sexes.   Prolactin secretion is mostly under inhibitory control by dopa-  mine from the hypothalamus, which is also called prolactin release-  inhibiting hormone (PRIH). The hypothalamus likely releases  more than one prolactin-releasing factor (PRF).   Thyroid-stimulating hormone, also called thyrotropin, is a  glycoprotein. It controls secretion of certain hormones from the  thyroid gland. TSH can also stimulate growth of the gland, and  abnormally high TSH levels may lead to an enlarged thyroid  gland, or goiter.   The hypothalamus partially regulates TSH secretion by pro-  ducing thyrotropin-releasing hormone (TRH). Circulating thy-  roid hormones help regulate TSH secretion by inhibiting release  of TRH and TSH. Therefore, as the blood concentration of thy-  roid hormones increases, secretion of TRH and TSH declines  (fig. 13.16).   External factors influence release of TRH and TSH. Exposure  to extreme cold, for example, increases hormonal secretion.  Emotional stress can either increase or decrease TRH and TSH  secretion, depending upon circumstances.    After the thyroid gland is removed to treat cancer, an endocri-  nologist monitors a patient’s TSH level to determine the appro-  priate daily dose of synthetic thyroid hormone. Enough thyroid  hormone must be taken to suppress secretion of TSH. TSH is a  useful marker for thyroid hormone levels because of negative  feedback, even though TSH itself would be ineffectual because    15 How does growth hormone affect the cellular metabolism of  carbohydrates, fats, and proteins?    16 What are the functions of prolactin?  17 How is TSH secretion regulated?    Adrenocorticotropic (ah-dre”no-kor’te-ko-trop’ik) hormone  also called “corticotropin,” is a peptide that controls the manufac-  ture and secretion of certain hormones from the outer layer (cor-  tex) of the adrenal gland. The secretion of ACTH is stimulated by  corticotropin-releasing hormone (CRH), which the hypothalamus    Insufficient secretion of human growth hormone (HGH) during  childhood produces hypopituitary dwarfism. Body proportions  and mental development are normal, but because secretion of  other anterior pituitary hormones is also below normal, addi-  tional hormone deficiency symptoms may appear. For example,  a child with growth hormone deficiency might not develop adult  sexual features without hormone therapy.   HGH used as a drug can treat hypopituitary dwarfism if  administration begins before the bones completely ossify. In  children it is also used to treat conditions that include very  short stature but in which HGH is not deficient, such as chronic  renal failure, Turner syndrome, intrauterine growth retardation,  and Prader-Willi syndrome. In adults HGH is used to treat short  bowel syndrome, muscle wasting in people who have AIDS,  and rare pituitary tumors. The Food and Drug Administration has  not approved HGH to slow aging or to build muscle in healthy  individuals.   The reputation of HGH as an anti-aging agent stems from a  1990 study in which a dozen men over age sixty who received the  hormone showed slight improvements in muscle mass and bone    mineral density. HGH given to older individuals can increase mus-  cle mass and decrease fat but, it does not improve strength and  likely just replaces some fat with water. Excess HGH can cause  joint pain and swelling and increased risk of diabetes mellitus.  HGH used for approved indications is injected. Oral preparations  are digested in the stomach before they can exert an effect.   Oversecretion of growth hormone in childhood may result in  gigantism, in which height may eventually exceed 8 feet. Gigantism  is usually caused by a tumor of the pituitary gland, which secretes  excess pituitary hormones, including HGH. As a result, a person  with gigantism may have other metabolic disturbances. An inher-  ited form of gigantism is seen in families in Ireland.   Growth hormone oversecretion in an adult after the epiphy-  ses of the long bones have ossified causes a condition called acro-  megaly. The person does not grow taller, but soft tissues continue  to enlarge and bones thicken, producing a large tongue, nose,  hands, and feet, and a protruding jaw. The heart and thyroid  enlarge. Early symptoms include headache, joint pain, fatigue,  and depression. A pituitary tumor or abuse of growth hormone  (as a drug) can cause acromegaly.    FIGURE 13.15 Hormones released from the hypothalamus, the corresponding hormones released from the anterior lobe of the pituitary gland,  and their target organs.    FIGURE 13.16 Thyrotropin-releasing hormone (TRH) from the  hypothalamus stimulates the anterior pituitary gland to release thyroid-  stimulating hormone (TSH), which stimulates the thyroid gland to release  hormones. These thyroid hormones reduce the secretion of TSH and TRH  by negative feedback. (® = stimulation; @ = inhibition)    releases in response to decreased concentrations of adrenal cortical  hormones. Stress can increase secretion of ACTH by stimulating  release of CRH.   Both follicle-stimulating hormone and luteinizing (lu’te’in-  jiz”ing) hormone are glycoproteins and are called gonadotropins,  which means they act on the gonads or reproductive organs. FSH  controls growth and development of follicles that house egg cells in  the ovaries. It also stimulates the follicular cells to secrete a group  of female sex hormones, collectively called estrogen (or estrogens).   In males, FSH stimulates the production of sperm cells in the  testes. LH promotes secretion of sex hormones in both males and  females and is essential for release of egg cells from the ovaries.  Other functions of the gonadotropins and their interactions are dis-  cussed in chapter 22 (pp. 838, 849-850).   Gonadotropin secretion is under the control of gonadotropin-  releasing hormone (GnRH). Gonadotropins are absent in the body  fluids of infants and children. Secretion of GnRH, and the result-  ing increase in blood levels of gonadotropins, mark the the onset  of puberty.    18 What is the function of ACTH?  19 What is a gonadotropin?    20 Describe the functions of FSH and LH in a female and in a male.    The posterior lobe of the pituitary largely consists of neuroglia  (pituicytes) and the axons of hypothalamic neurons. This is dif-  ferent from the anterior lobe, which is primarily glandular epi-  thelium. The neuroglia support the axons. The secretions of these  neurons function not as neurotransmitters but as hormones (see  fig. 13.12).   Specialized neurons in the hypothalamus produce the two  hormones associated with the posterior pituitary—antidiuretic  (an’ti-di”u-ret’ik) hormone (also known as vasopressin) and oxy-  tocin (ok”si-to’sin). These hormones are transported down axons  through the pituitary stalk to the posterior pituitary and are stored  in vesicles (secretory granules) near the ends of the axons. The  hormones are released into the blood in response to action poten-  tials conducted on the axons of the neurosecretory cells. Therefore,  posterior pituitary hormones are synthesized in the hypothalamus,  and their secretion is controlled by the hypothalamus, but they are  named for where they enter the bloodstream.   Antidiuretic hormone and oxytocin are short polypeptides  with similar sequences (fig. 13.17). A diuretic is a chemical that  increases urine production. An antidiuretic, then, is a chemical  that decreases urine formation. ADH produces its antidiuretic  effect by reducing the volume of water that the kidneys excrete. In  this way, ADH plays an important role in regulating the concentra-  tion of body fluids (see chapter 20, p. 787).   son must replace the lost body fluid to maintain normal water   balance. Drinking too much beer can actually lead to dehydra-  | tion because the body loses more water than it takes in.    FIGURE 13.17 (AP|R) The structure of oxytocin differs from that of  ADH by only two amino acids, yet they function differently.    A sufficient concentration of ADH contracts certain smooth  muscle, including the smooth muscle in the walls of blood vessels.  As a result, vascular resistance and blood pressure may increase.  (This is why ADH is also called vasopressin.) Although ADH is  seldom at high enough levels to cause high blood pressure, its  secretion increases following severe blood loss. In this situation,  ADH’s vasoconstrictor effect may help to minimize the drop in  blood pressure that results from profuse bleeding and help return  blood pressure toward normal.   ADH’s two effects—vasoconstriction and water retention—are  possible because the hormone binds two different receptors on tar-  get cells. The binding of ADH to V1 receptors increases the con-  centration of the second messenger inositol triphosphate, which  increases the intracellular calcium ion concentration in the smooth  muscle of blood vessel walls, leading to vasoconstriction. The second  receptor, V2, is on parts of the kidneys’ microscopic tubules called  collecting ducts. ADH binding there activates the cAMP second  messenger system, which ultimately causes collecting duct cells to  reabsorb water that would otherwise be excreted in the urine.   The hypothalamus regulates ADH secretion. Certain neurons in  this part of the brain, called osmoreceptors, sense changes in the con-  centration of body fluids. For example, if a person is dehydrating due  to a lack of water intake, the solutes in blood become more concen-  trated. The osmoreceptors, sensing the resulting increase in osmotic  pressure, signal the posterior pituitary to release ADH, which causes  the kidneys to retain water. On the other hand, if a person drinks a  large volume of water, body fluids become more dilute, which inhib-  its the release of ADH. In response, the kidneys excrete a more dilute  urine until the concentration of body fluids returns to normal.   Blood volume also affects ADH secretion. Increased blood vol-  ume stretches the walls of certain blood vessels, stimulating volume  receptors that signal the hypothalamus to inhibit release of ADH.  However, if hemorrhage decreases blood volume, these receptors  are stretched less and therefore send fewer inhibiting impulses. As  a result, ADH secretion increases and the kidneys conserve water,  countering further volume loss.    Diabetes insipidus impairs ADH regulation of water balance. A  baby with the condition first displayed symptoms at five months  of age—he drank huge volumes of water. By thirteen months,  he had become severely dehydrated, despite nearly continuous  drinking. The boy was drinking sufficient fluids, but his kidneys  could not retain the water because ADH V2 receptors on the kid-  ney collecting ducts were defective. The hormone could bind,  but the receptor failed to trigger cAMP formation. The boy’s  ADH was still able to constrict blood vessels because the V1  receptors were unaffected. A high-calorie diet and providing lots  of water preserved the boy's mental abilities, but he remained  small for his age. Tumors and injury affecting the hypothalamus  and posterior pituitary can also cause diabetes insipidus.    Oxytocin has an antidiuretic action, but less so than ADH. In  addition, oxytocin can contract smooth muscle in the uterine wall,  playing a role in the later stages of childbirth. The uterus becomes    more sensitive to oxytocin’s effects during pregnancy. Stretching  of uterine and vaginal tissues late in pregnancy, as the fetus grows,  initiates sensory impulses to the hypothalamus, which then signals  the posterior pituitary to release oxytocin, which, in turn, stimu-  lates the uterine contractions of labor.   In the breasts, oxytocin contracts certain cells near the milk-  producing glands and their ducts. In lactating breasts, this action  forces liquid from the milk glands into the milk ducts and ejects  the milk.   The mechanical stimulation of suckling initiates sensory  impulses that travel to the mother’s hypothalamus, which signals  the posterior pituitary to release oxytocin, which, in turn, stimulates  milk release. Milk is normally not ejected from the milk glands and  ducts until the baby suckles. The fact that milk is ejected from both  breasts in response to suckling is a reminder that all target cells  respond to a hormone.    Oxytocin may be given intravenously to stimulate uterine con-  tractions, inducing labor, if the uterus is not sufficiently con-  tracting to expel a fully developed fetus. Oxytocin may also be  administered to the mother following childbirth to ensure that  the uterine smooth muscle contracts enough to squeeze broken  blood vessels closed, minimizing bleeding.    Oxytocin has no established function in males, although it  is present in the male posterior pituitary and it may stimulate the  movement of sperm and certain fluids in the male reproductive tract  during sexual activity. Oxytocin is called the “cuddle hormone”  because studies on pregnant women show that higher levels of the  hormone during pregnancy correlate to more intense maternal bond-  ing behavior with the infant, such as more eye contact, touching,  and singing. Table 13.6 reviews the hormones of the pituitary gland.    21 What is the function of ADH?  22 How is the secretion of ADH controlled?    The thyroid gland (thi’roid gland), as figure 13.18 shows, is a  vascular structure that consists of two large lateral lobes connected  by a broad isthmus (is’mus). The thyroid lies just below the larynx  (voicebox) on either side and anterior to the trachea (windpipe).  The gland is specialized to remove iodine from the blood.    A capsule of connective tissue covers the thyroid gland, which is  made up of many secretory parts called follicles. Cavities in the  follicles are lined with a single layer of cuboidal epithelial cells,  called follicular cells. A clear viscous substance called colloid fills    Stimulates increase in size and rate of division  of body cells; enhances movement of amino  acids through membranes; promotes growth  of long bones    Sustains milk production after birth; amplifies  the effect of LH in males    Development of egg-containing follicles in  ovaries; stimulates follicular cells to secrete  estrogen; in males, stimulates production of  sperm cells    Promotes secretion of male and female sex  hormones; releases egg cell in females    Causes kidneys to reduce water excretion; in  high concentration, raises blood pressure    Secretion inhibited by somatostatin (SS) and  stimulated by growth hormone-releasing hormone  (GHRH) from the hypothalamus    Secretion inhibited by prolactin release-inhibiting  hormone (PIH) and may be stimulated by yet to  be identified prolactin-releasing factor (PRF) from  the hypothalamus    Hypothalamus in response to changes in body fluid  concentration and blood volume    Hypothalamus in response to stretching uterine and  vaginal walls and stimulation of breasts    FIGURE 13.18 (AP|R) Thyroid gland. (a) The thyroid gland consists of two lobes connected anteriorly by an isthmus. (b) Follicular cells secrete  thyroxine and triiodothyronine. Extrafollicular cells secrete calcitonin.    the cavities. It consists primarily of a glycoprotein called thyro-  globulin. The follicular cells produce and secrete hormones that  are either stored in the colloid or released into nearby capillaries  (fig. 13.19). Other hormone-secreting cells, called extrafollicular  cells (C cells), lie outside the follicles.    The thyroid gland produces three important hormones. The fol-  licular cells synthesize two of these, which have marked effects on  the metabolic rates of body cells. The extrafollicular cells produce  the third type of hormone, which influences blood concentrations  of calcium and phosphate ions.   The two thyroid hormones that affect cellular metabolic rates  are thyroxine (thi-rok’sin) and triiodothyronine (tri’i-o”do-  thi’ro-nén). Thyroxine, or tetraiodothyronine, is also called T 7  because it includes four atoms of iodine. Triiodothyronine is also  called T, because it includes three atoms of iodine (fig. 13.20).  These hormones help regulate the metabolism of carbohydrates,  lipids, and proteins. Specifically, thyroxine and triiodothyro-  nine increase the rate at which cells release energy from carbo-  hydrates, enhance the rate of protein synthesis, and stimulate  breakdown and mobilization of lipids. These hormones are the  major factors determining how many calories the body must  consume at rest to maintain life, which is measured as the basal  metabolic rate (BMR). The two hormones are essential for nor-  mal growth and development and for maturation of the nervous  system. TSH from the anterior pituitary gland controls the levels  of thyroid hormones.   Follicular cells require iodine salts (iodides) to produce thy-  roxine and triiodothyronine. Such salts are normally obtained  from foods, and after they have been absorbed from the intestine,  the blood carries some of them in the form of iodide (I) to the thy-  roid gland. An efficient active transport protein called the iodide  pump moves the iodides into the follicular cells, where they are    (240x). The open spaces that follicular cells surround are filled with colloid.    converted to iodine and concentrated. The iodine, with the amino  acid tyrosine, is used to synthesize these thyroid hormones.   Follicular cells synthesize thyroglobulin, whose protein por-  tion includes molecules of tyrosine, many of which have already  had iodine attached by an enzymatic reaction. As the protein  part of thyroglobulin folds into its tertiary structure, bonds form  between some of the tyrosine molecules, forming and storing  potential thyroid hormones. The follicular cells take up mol-  ecules of thyroglobulin by endocytosis, break down the protein,  and release the individual thyroid hormones into the bloodstream.  When the thyroid hormone levels in the bloodstream drop below  a certain level, accessing thyroglobulin accelerates, returning thy-  roid hormone levels to normal.   Thyroxine (T,) accounts for at least 95% of circulating thy-  roid hormones, but once in the blood, most of the dt and T , com-  bine with blood proteins (alpha globulins). It is the small fraction  of hormone molecules that are not protein-bound (so called “free”  hormone) that act on target cells. Thus T,, which has a 50-fold  higher free concentration in the plasma, is physiologically more  important. Additionally, T, is nearly five times more potent than  T,, and about a third of T, is converted to T, in peripheral tissues.   The thyroid gland produces calcitonin, which is usually not  referred to as a “thyroid hormone” because it is synthesized by the  C cells, distinct from the gland’s follicles. Calcitonin plays a role  in the control of blood calcium and phosphate ion concentrations.  It helps lower concentrations of calcium and phosphate ions by  decreasing the rate at which they leave the bones and enter extra-  cellular fluids by inhibiting the bone-destroying activity of osteo-  clasts. At the same time, calcitonin increases the rate at which  calcium and phosphate ions are deposited in bone matrix by stim-  ulating activity of osteoblasts (see chapter 7, p. 202). Calcitonin  also increases the excretion of calcium ions and phosphate ions by  the kidneys.   A high blood calcium ion concentration stimulates calcito-  nin secretion. This may occur following absorption of calcium  ions from a recent meal. Certain hormones also prompt calcitonin  secretion, such as gastrin, released from active digestive organs.    OH OH  | |  O O  | |  4 CH,  NH,CHCOOH NH,CHCOOH    FIGURE 13.20 The hormones thyroxine and triiodothyronine have  very similar molecular structures.    Calcitonin helps prevent prolonged elevation of the blood calcium  ion concentration after eating.   Research suggests that calcitonin may be most important dur-  ing early growth and physiological stress. In the young, calcitonin  stimulates the increase in bone deposition associated with growth.  In females, it helps protect bones from resorption during preg-  nancy and lactation, when calcium is required for growth of the  fetus and synthesis of breast milk.   Table 13.7 summarizes the actions and sources of con-  trol of the thyroid hormones. From Science to Technology 2.1  (chapter 2, p. 61), table 13.8, and figures 13.21, 13.22, and 13.23  discuss disorders of the thyroid gland.    25 Which hormones of the thyroid gland affect carbohydrate  metabolism, the mobilization of lipids, and protein synthesis?   26 What substance is essential for the production of thyroxine and  triiodothyronine?    27 How does calcitonin influence the concentrations of blood  calcium and phosphate ions?    The parathyroid glands (par”’ah-thi’roid glandz) are on the pos-  terior surface of the thyroid gland, as figure 13.24 shows. Most  individuals have four of them—a superior and an inferior gland  associated with each of the thyroid’s bilateral lobes. The para-  thyroid glands secrete a hormone that regulates the concentrations  of calcium and phosphate ions in the blood.   Increases rate of  energy release from  carbohydrates;  increases rate of  protein synthesis;  accelerates growth;  stimulates activity in  the nervous system    Triiodothyronine = Same as above, but  ce) five times more potent  than thyroxine    Lowers blood calcium  and phosphate ion  concentrations by  inhibiting release of    calcium and phosphate  ions from bones and  by increasing the rate  at which calcium and  phosphate ions are  deposited in bones;  increases excretion of  calcium by the kidneys    Each parathyroid gland is a small, yellowish brown structure cov-  ered by a thin capsule of connective tissue. The body of the gland  consists of many tightly packed secretory cells closely associated  with capillary networks (fig. 13.25).    FIGURE 13.22 Graves disease (a form  of hyperthyroidism) may cause the eyes to  protrude (exopthalmia).    FIGURE 13.21 Infantile hypothyroidism  is due to an underactive thyroid gland during  infancy and childhood.    causes simple (endemic) goiter and results in  high levels of TSH.    High metabolic rate, sensitivity to heat, restlessness, hyperactivity, weight loss, protruding eyes, goiter    Autoantibodies (against self) bind TSH receptors on thyroid cell membranes, mimicking action of TSH, overstimulating    Autoantibodies (against self) destroy thyroid cells, resulting in hypothyroidism  Stunted growth, abnormal bone formation, intellectual disability, sluggishness  Low metabolic rate, sensitivity to cold, sluggishness, poor appetite, swollen tissues, mental dullness    Deficiency of thyroid hormones due to iodine deficiency; because no thyroid hormones inhibit pituitary release of TSH,    FIGURE 13.24 The parathyroid glands are embedded in the  posterior surface of the thyroid gland.    The parathyroid glands secrete a protein, parathyroid hormone  (PTH), or parathormone (see fig. 13.4c). This hormone increases  blood calcium ion concentration and decreases blood phosphate ion  concentration through actions in the bones, kidneys, and intestines.    The extracellular matrix of bone tissue contains a consider-  able amount of calcium phosphate and calcium carbonate. PTH  stimulates bone resorption by osteoclasts and inhibits the activity of  osteoblasts (see chapter 7, pp. 202, 205, and 207). As bone resorp-  tion increases, calcium and phosphate ions are released into the  blood. At the same time, PTH causes the kidneys to conserve blood  calcium ions and to excrete more phosphate ions in the urine. PTH  also indirectly stimulates absorption of calcium ions from food in  the intestine by influencing metabolism of vitamin D.   Vitamin D (cholecalciferol) synthesis begins when intestinal  enzymes convert dietary cholesterol into the inactive form, pro-  vitamin D (dehydrocholesterol). This provitamin is largely stored  in the skin, and exposure to the ultraviolet wavelengths of sunlight  changes it to vitamin D. Some vitamin D also comes from foods.   The liver changes vitamin D to hydroxycholecalciferol, which  is carried in the bloodstream or stored in tissues. When PTH is pres-  ent, hydroxycholecalciferol can be changed in the kidneys into the  active form of vitamin D (dihydroxycholecalciferol), which controls  absorption of calcium ions from the intestine (fig. 13.26).   A negative feedback mechanism operating between the para-  thyroid glands and the blood calcium ion concentration regulates    FIGURE 13.26 Mechanism by which PTH promotes calcium  absorption in the intestine.    secretion of PTH (fig. 13.27). As the concentration of blood calcium  ions rises, less PTH is secreted; as the concentration of blood cal-  cium ions drops, more PTH is released.   The opposite effects of calcitonin and PTH maintain calcium  ion homeostasis (see fig. 7.14, p. 211). This is important in a num-  ber of physiological processes. For example, if the blood calcium  ion concentration drops below the normal range (hypocalcemia),  the nervous system becomes abnormally excitable, and impulses  may be triggered spontaneously. As a result, muscles, including    Fatigue, muscular weakness, painful joints, altered mental functions,  depression, weight loss, bone weakening. Increased PTH secretion    Muscle cramps and seizures. Decreased PTH secretion reduces  osteoclast activity, diminishing blood calcium ion concentration.    the respiratory muscles, may undergo tetanic contractions, and the  person may suffocate. In contrast, an abnormally high concentra-  tion of blood calcium ions (hypercalcemia) depresses the nervous  system. Consequently, muscle contractions are weak and reflexes  are sluggish. Table 13.9 lists disorders of the parathyroid glands.    29 How does parathyroid hormone help regulate the  concentrations of blood calcium and phosphate ions?    30 How does the negative feedback system of the parathyroid  glands differ from that of the thyroid gland?    The adrenal glands (suprarenal glands) are closely associated  with the kidneys. A gland sits atop each kidney like a cap and is  embedded in the mass of adipose tissue that encloses the kidney.    The adrenal glands are shaped like pyramids. Each adrenal gland is  vascular and consists of two parts. The central portion is the adre-  nal medulla, and the outer part is the adrenal cortex (fig. 13.28).  These regions are not sharply divided, but they are distinct in that  they secrete different hormones.   The adrenal medulla (ah-dre’nal me-dul’ah) consists of irregu-  larly shaped cells grouped around blood vessels. These cells are inti-  mately connected with the sympathetic division of the autonomic  nervous system. The adrenal medullary cells (chromaffin cells) are  modified postganglionic neurons, and preganglionic autonomic  nerve fibers lead to them directly from the central nervous system  (see chapter 11, pp. 431-432).   The adrenal cortex (ah-dre’nal kor’teks) makes up the bulk  of the adrenal gland. It is composed of closely packed masses of  epithelial layers that form outer, middle, and inner zones—the  zona glomerulosa, the zona fasciculata, and the zona reticularis,  respectively (fig.13.28 and fig. 13.29).    The chromaffin cells of the adrenal medulla produce, store, and  secrete two closely related hormones, epinephrine (ep”i-nef’rin),  also called adrenalin, and norepinephrine (nor’ep-i-nef’rin), also  called noradrenalin. Both of these substances are a type of amine    FIGURE 13.27 fAP|R) Parathyroid hormone (PTH) stimulates bone to release calcium (Ca*?) and the kidneys to conserve calcium. It indirectly stimulates  the intestine to absorb calcium. The resulting increase in blood calcium concentration inhibits secretion of PTH by negative feedback. (@ = stimulation;  @ = inhibition)    FIGURE 13.28 (AP|R) Adrenal glands. (a) An adrenal gland consists of an outer cortex and an inner medulla. (b) The cortex consists of three layers,  or zones, of cells.    hormone called a catecholamine, and they have similar molecular  structures and physiological functions (fig. 13.30). Epinephrine is  synthesized from norepinephrine.   The synthesis of catecholamines begins with the amino  acid tyrosine. In the first step of the pathway, an enzyme (tyro-  sine hydroxylase) in the secretory cells catalyzes a reaction that  converts tyrosine into a substance called dopa. A second enzyme  (dopa decarboxylase) catalyzes a reaction that modifies dopa into  dopamine, and a third enzyme (dopamine betahydroxylase) cata-  lyzes a reaction that alters dopamine to form norepinephrine. Still  another enzyme (phenylethanolamine N-methyltransferase) then  catalyzes conversion of norepinephrine to epinephrine. About 15%  of the norepinephrine is stored unchanged. The hormones occupy  tiny vesicles (chromaffin granules), much like neurotransmitters  are stored in vesicles in neurons.    FIGURE 13.30 Epinephrine and norepinephrine have similar  molecular structures and similar functions.    The effects of the adrenal medullary hormones generally  resemble those that result when sympathetic neurons stimulate  their effectors: increased heart rate and force of cardiac muscle  contraction, elevated blood pressure, increased breathing rate,  and decreased digestive activity (see table 11.10, p. 436). The hor-  monal effects last up to ten times longer than the neurotransmitter  effects because the hormones are slowly removed from the tissues.   The ratio of the two hormones in the adrenal medullary secre-  tion varies with different physiological conditions, but usually it  is about 80% epinephrine and 20% norepinephrine. Although  these hormones’ effects are generally similar, certain effector cells  respond differently, due to the relative numbers of alpha and beta  receptors in their membranes. Both hormones can stimulate both  classes of receptors, but norepinephrine has a greater effect on  alpha receptors.   Impulses arriving on sympathetic nerve fibers stimulate the  adrenal medulla to release its hormones at the same time as sym-  pathetic impulses stimulate other effectors. As a rule, all of these  impulses originate in the hypothalamus in response to stress. Thus,  the adrenal medullary secretions function together with the sym-  pathetic division of the autonomic nervous system in preparing  the body for energy-expending action, also called “fight or flight”  responses. Table 13.10 compares some of the differences in the  effects of epinephrine and norepinephrine.    31 Describe the location and structure of the adrenal glands.  32 Name the hormones the adrenal medulla secretes.    33 What general effects do hormones secreted by the adrenal  medulla produce?    34 What usually stimulates release of hormones from the adrenal  medulla?    The cells of the adrenal cortex produce more than thirty different  steroids, including several hormones (corticosteroids). Unlike the  adrenal medullary hormones, without which a person can survive,  some of those released by the cortex are vital. In the absence of these  adrenal cortical secretions, without extensive electrolyte therapy a  person usually dies within a week. The most important adrenal cor-  tical hormones are aldosterone, cortisol, and certain sex hormones.   Cells in the outer zone (zona glomerulosa) of the adrenal cortex  synthesize aldosterone. This hormone is called a mineralocorti-  coid because it helps regulate the concentration of mineral electro-  lytes, such as sodium and potassium ions. Specifically, aldosterone  causes the kidney to conserve sodium ions and to excrete potas-  sium ions. The cells that secrete aldosterone respond directly to  changes in the composition of blood plasma. However, whereas  an increase in plasma potassium strongly stimulates these cells, a  decrease in plasma sodium only slightly stimulates them. Control    Vasoconstriction in skin and viscera shifts blood flow to  other areas, such as exercising skeletal muscle    Some increase due to increased cardiac output and  vasoconstriction (offset in some areas, such as exercising  skeletal muscle, by local vasodilation due to other factors)    of aldosterone secretion is indirectly linked to plasma sodium level  by the renin-angiotensin system.   Groups of specialized kidney cells (juxtaglomerular cells)  are able to respond to changes in blood pressure and the plasma  sodium ion concentration. If the level of either of these factors  decreases, the cells release an enzyme called renin (re’nin). Renin  reacts with a blood protein called angiotensinogen (an”je-o-ten-  sin’o-jen) to catalyze the partial breakdown of angiotensinogen  into a peptide called angiotensin I. Another enzyme (angiotensin-  converting enzyme, or ACE), found primarily in lung blood vessels,    @ Decreasing blood pressure  and/or sodium ion concentration  stimulate secretion of the    catalyzes a reaction that converts angiotensin I into another form,  angiotensin II, which is carried in the bloodstream (fig. 13.31).  When angiotensin II reaches the adrenal cortex, it stimulates the  release of aldosterone. ACTH is necessary for the adrenal gland to  respond to this and other stimuli.   Aldosterone, in conserving sodium ions, indirectly retains  water by osmosis. This action helps maintain both the blood sodium  ion concentration and blood volume (fig. 13.31). Angiotensin II is  also a powerful vasoconstrictor and thereby helps maintain systemic  blood pressure.    @ Blood pressure and/or sodium  ion concentration return toward  normal, inhibiting further  secretion of renin    @ Aldosterone acts on the  kidney to conserve sodium  ions and (by osmosis) water    FIGURE 13.31 Aldosterone increases blood volume and pressure by promoting conservation of sodium ions and water (steps 1-4).    ACE inhibitors are a class of drugs used to treat some forms  of high blood pressure (hypertension). They work by binding to  the active site on angiotensin-converting enzyme, blocking for-  mation of angiotensin Il and preventing inactivation of brady-  kinin, a vasodilator. Both effects dilate blood vessels, lowering  blood pressure.    Cortisol (hydrocortisone) is a glucocorticoid, which means it  affects glucose metabolism. It is produced primarily in the middle  zone (zona fasciculata) of the adrenal cortex and has a molecu-  lar structure similar to aldosterone (fig. 13.32). In addition to  affecting glucose, cortisol influences protein and fat metabolism.  Among the more important actions of cortisol are the following:    1. It inhibits the synthesis of protein in various tissues, increasing  the blood concentration of amino acids.   2. It stimulates liver cells to synthesize glucose from noncarbo-  hydrates (gluconeogenesis), such as circulating amino acids  and glycerol, thus increasing the blood glucose concentration.   3. It promotes the release of fatty acids from adipose tissue,  increasing the use of fatty acids and decreasing the use  of glucose as energy sources, thus preserving glucose  availability for the brain.    Cortisol’s actions help keep the blood glucose concentration  within the normal range between meals. These actions are impor-  tant because just a few hours without food can exhaust liver gly-  cogen, which is another major source of glucose.   A negative feedback mechanism much like that control-  ling the thyroid hormones T, and T, regulates cortisol release.  It involves the hypothalamus, anterior pituitary gland, and adre-  nal cortex. The hypothalamus secretes CRH (corticotropin-  releasing hormone) into the hypophyseal portal veins, which  carry the CRH to the anterior pituitary gland, stimulating it to  secrete ACTH. In turn, ACTH stimulates the adrenal cortex  to release cortisol. Cortisol inhibits release of both CRH and  ACTH. As concentration of these substances falls, cortisol pro-  duction drops.   The set point of the feedback loop controlling cortisol secre-  tion changes, adapting hormone output to changing conditions.  For example, under stress—injury, disease, extreme temperature,  or emotional upset—information reaches the brain concerning the  situation. In response, brain centers signal the hypothalamus to  release more CRH, leading to a higher concentration of cortisol  until the stress subsides (fig. 13.33).    Cells in the inner zone (zona reticularis) of the adrenal cortex  mostly produce sex hormones. These hormones are male (adrenal  androgens), but some of them are converted into female hormones  (estrogens) by the skin, liver, and adipose tissues. The amounts of  these adrenal hormones are very small compared to the supply of  sex hormones from the gonads, but they may contribute to early  development of the reproductive organs. Adrenal androgens may    FIGURE 13.32 Cortisol and aldosterone are steroids with similar  molecular structures.    also play a role in the female sex drive. Table 13.11 summarizes  the actions of the cortical hormones. Clinical Application 13.3  discusses some of the effects of a malfunctioning adrenal gland  on health.    Cortisol and related compounds are used as drugs to reduce  inflammation. They relieve pain by:  e decreasing permeability of capillaries, preventing leakage  of fluids that swell surrounding tissues  e stabilizing lysosomal membranes, preventing release of  their enzymes, which destroy tissue  e inhibiting prostaglandin synthesis    Because the concentrations of cortisol compounds used to stifle  inflammation have significant side effects, these drugs can be  used for only a limited time. They are used to treat autoimmune  disorders, allergies, asthma, and recipients of organ transplants  or tissue grafts.    35 Name the important hormones of the adrenal cortex.  36 What is the function of aldosterone?  37 What does cortisol do?    President John F. Kennedy’s bronze complexion may have resulted  not from sunbathing, but from a disorder of the adrenal glands.  When he ran for president in 1960, Kennedy knew he had Addison  disease, but his staff kept his secret, for fear it would affect his career.  Kennedy had almost no adrenal tissue, but he functioned by receiv-  ing mineralocorticoids and glucocorticoids, the standard treatment.   In Addison disease, the adrenal cortex does not secrete hor-  mones sufficiently. This may be due to immune system attack  (autoimmunity) or an infection such as tuberculosis. Signs and  symptoms include decreased blood sodium, increased blood  potassium, low blood glucose level (hypoglycemia), dehydration,  low blood pressure, frequent infections, fatigue, nausea and vom-  iting, loss of appetite, and increased skin pigmentation. Some  sufferers experience salt cravings—one woman reported eating  many bowls of salty chicken noodle soup, with pickles and briny  pickle juice added! Without treatment, death comes within days  from severe disturbances in electrolyte balance.   Cushing syndrome is hypersecretion of cortisol from any  cause, such as an adrenal tumor or oversecretion of ACTH by  the anterior pituitary. The condition may also result from taking    corticosteroid drugs for many years, such as to treat asthma or  rheumatoid arthritis. Tissue protein level plummets, due to mus-  cle wasting and loss of bone tissue. Blood glucose level remains  elevated, and excess sodium is retained. As a result, tissue fluid  increases, blood pressure rises, and the skin appears puffy. The  skin may appear thin due to inhibition of collagen synthesis by  the excess cortisol. Adipose tissue deposited in the face and  back produce a characteristic “moon face” and “buffalo hump.”  Increase in adrenal sex hormone secretion may masculinize a  female, causing growth of facial hair and a deepening voice.  Other symptoms include extreme fatigue, sleep disturbances,  skin rashes, headache, and leg muscle cramps.   Treatment of Cushing syndrome attempts to reduce ACTH  secretion. This may entail removing a tumor in the pituitary gland  or partially or completely removing the adrenal glands.   Both Addison disease and Cushing syndrome are rare, and  for this reason, they are often misdiagnosed, or, in early stages,  the patient's report of symptoms is not taken seriously. Addison  disease affects thirty-nine to sixty people of every million, and  Cushing syndrome affects five to twenty-five people per million.    FIGURE 13.33 Negative feedback regulates cortisol secretion, similar to the regulation of thyroid hormone secretion (see fig. 13.16).  (® = stimulation; @ = inhibition)    Helps regulate the concentration of extracellular electrolytes  by conserving sodium ions and excreting potassium ions    Decreases protein synthesis, increases fatty acid release, and  stimulates glucose synthesis from noncarbohydrates    The pancreas (pan’kre-as) consists of two major types of secretory  tissues. This organization reflects the dual function of the pancreas  as an exocrine gland that secretes digestive juice through a duct,  and an endocrine gland that releases hormones into body fluids.    The pancreas is an elongated, somewhat flattened organ located pos-  terior to the stomach and partly between the parietal peritoneum and  the posterior abdominal wall (retroperitoneal) (fig. 13.34). A duct  that attaches the pancreas to the first section of the small intestine  (duodenum) transports its digestive juice into the intestine. Chapter 17  (pp. 668-669) discusses the digestive functions of the pancreas.    FIGURE 13.34 (AP|R) The hormone-secreting cells of the pancreas  are grouped in clusters, or islets, closely associated with blood vessels.  Other pancreatic cells secrete digestive enzymes into ducts.    The endocrine portion of the pancreas consists of cells  grouped around blood vessels. These groups, called pancreatic  islets (islets of Langerhans), include three distinct types of hormone-  secreting cells—alpha cells, which secrete glucagon; beta cells,  which secrete insulin; and delta cells, which secrete somatostatin  (fig.13.34 and fig. 13.35).    Glucagon is a protein that stimulates the liver to break down glyco-  gen into glucose (glycogenolysis) and to convert noncarbohydrates,  such as amino acids, into glucose (gluconeogenesis). Glucagon also  stimulates breakdown of fats into fatty acids and glycerol.   In a negative feedback system, a low concentration of blood  glucose stimulates release of glucagon from the alpha cells. When  the blood glucose concentration returns toward normal, glucagon  secretion decreases (fig. 13.36). This mechanism prevents hypo-  glycemia when the blood glucose concentration is relatively low,  such as between meals, or when glucose is being used rapidly,  such as during exercise.   The hormone insulin is also a protein, and its main effect is  exactly opposite that of glucagon. Insulin stimulates the liver to  form glycogen from glucose and inhibits conversion of noncarbo-  hydrates into glucose. Insulin also has the special effect of pro-  moting the facilitated diffusion (see chapter 3, pp. 100-101) of  glucose through the membranes of cells bearing insulin receptors.    FIGURE 13.36 fAP|R) Insulin and glucagon function together to  stabilize blood glucose concentration. Negative feedback responding  to blood glucose concentration controls the levels of both hormones.    © Four hours after a meal, would you expect blood levels  of insulin to be high or low? What about blood levels  of glucagon?    These cells include those of adipose tissue, liver, cardiac muscle,  and skeletal muscle (glucose uptake by active muscle is not depen-  dent on insulin). Insulin action decreases the concentration of  blood glucose, promotes transport of glucose and amino acids into  cells, and increases glycogen and protein synthesis. It also stimu-  lates adipose cells to synthesize and store fat.    An enzyme called glucokinase enables pancreatic cells to “sense”  the blood glucose level, which is important in regulating synthe-  sis of glucagon and insulin. In one form of a rare type of diabetes  mellitus, maturity-onset diabetes of the young (MODY), a muta-  tion in a gene encoding glucokinase impairs the ability of beta  cells to assess when to produce insulin. Other mutations that  cause MODY alter insulin’s structure, secretion, or cell surface  receptors or the ability of liver cells to form glycogen in response  to insulin. MODY is treated with drugs or dietary modification.    A negative feedback system sensitive to the concentration of  blood glucose regulates insulin secretion. When glucose concen-  tration is relatively high, such as after a meal, the beta cells release  insulin. By promoting formation of glycogen in the liver and  entrance of glucose into adipose and muscle cells, insulin helps  prevent excessive rise in blood glucose concentration (hyperglyce-  mia). Then, when the glucose concentration falls, between meals  or during the night, insulin secretion decreases.   If the blood glucose concentration falls, insulin secretion  decreases. As blood insulin levels drop, less glucose enters adi-  pose and muscle cells, and the glucose remaining in the blood is  available for cells, such as nerve cells, that do not require insulin  to take up glucose. Neurons readily tap the energy in a continuous  supply of glucose to produce ATP.    Hypoglycemia, or low blood glucose level due to excess insu-  lin in the bloodstream, causes episodes of shakiness, weakness,  and anxiety. Following a diet of frequent, small meals low in car-  bohydrates and high in protein can often control symptoms by  preventing the surges of insulin that lower the blood glucose  level. Hypoglycemia is most often seen when a person with dia-  betes mellitus injects too much insulin, but it can also reflect a  tumor of the insulin-producing cells of the pancreas, or it may  occur transiently following strenuous exercise.    Neurons, including those of the brain, obtain glucose by a  facilitated diffusion mechanism not dependent on insulin, but  rather only on the glucose concentration gradient. A consequence  of this independence is that neurons are particularly sensitive to  changes in blood glucose concentration. Conditions that cause  such changes are likely to affect brain functions.   Insulin and glucagon secretion respond in opposite direc-  tions to changes in blood glucose level. When one increases, the  other decreases (fig. 13.36). These hormones function together to  maintain a relatively constant blood glucose concentration, despite  great variations in the amounts of ingested carbohydrates.   Somatostatin (similar to the hypothalamic hormone), which  the delta cells release, may help regulate glucose metabolism by  inhibiting secretion of glucagon and insulin, but its inhibitory  effect in the pancreas is not strong. Table 13.12 summarizes the  hormones of the pancreatic islets, and Clinical Application 13.4    Diabetes mellitus is a metabolic disease that arises from a lack of  insulin or an inability of cells to recognize insulin. The persistent  elevated blood glucose level can damage the eyes, heart, kidneys,  and peripheral nerves. For a person with diabetes, controlling  blood glucose requires daily monitoring and action. According to  data from the National Health and Nutrition Examination Survey,  in the United States about 21 million people have diabetes, and  the prevalence is on the rise. From 1988 to 1994, 6.2% of the pop-  ulation had diabetes, from 1999 to 2004 the percentage was 8.8%,  and from 2005 to 2010 it was 9.9%. Many people have the condi-  tion and do not yet know that they do.   Both insulin deficiency and impaired insulin response disturb  carbohydrate, protein, and fat metabolism. Because insulin helps  glucose cross some cell membranes, diabetes impairs movement  of glucose into adipose and resting skeletal muscle cells. At the  same time, the formation of glycogen, which is a long chain of  glucose molecules, declines. As a result, blood glucose concen-  tration rises (hyperglycemia). When it reaches a certain level, the  kidneys begin to excrete the excess. Glucose in the urine (glycos-  uria) raises the urine’s osmotic pressure, and too much water is  excreted. Excess urine output causes dehydration and extreme  thirst (polydipsia).   Diabetes mellitus also hampers protein and fat synthesis.  Glucose-starved cells increasingly use proteins for energy, and as  a result, tissues waste away as weight drops, hunger increases,  exhaustion becomes overwhelming, children stop growing, and  wounds do not heal. Changes in fat metabolism cause fatty acids  and ketone bodies to accumulate in the blood, which lowers pH  (acidosis). Dehydration and acidosis may harm brain cells, causing  disorientation, coma, and eventually death.   The two most common forms of diabetes mellitus are type 1  (insulin-dependent or juvenile diabetes) and type 2 (non-insulin-  dependent or maturity-onset diabetes).    Type 1 diabetes mellitus usually appears before age twenty. It is an  autoimmune disease: the immune system destroys the beta cells  of the pancreas (see chapter 16, p. 639).    Stimulates the liver to break down glycogen and convert noncarbohydrates into glucose; stimulates    Promotes formation of glycogen from glucose, inhibits conversion of noncarbohydrates into glucose,  and enhances movement of glucose through adipose and muscle cell membranes, decreasing blood    People with type 1 diabetes must carefully monitor their  blood glucose levels. They do this in two ways. Every three  months, a laboratory test checks the levels of hemoglobin mol-  ecules in the blood that bind glucose. This measurement is called  "A1C" and should be between 6% and 7%. A1C represents blood  glucose level over the preceding three months, which is the life  span of the red blood cells that transport hemoglobin.   The second type of test for a person with type 1 diabetes is  self-monitoring of blood glucose. A person uses a test kit to draw  a drop of blood, applies it to a test strip, then uses a meter to  read the concentration of glucose in the blood (in milligrams per  deciliter). Normal plasma levels of glucose range from 90 to 130  mg/dL before meals and less than 180 mg/dL one to two hours  after meals. Most people with type 1 diabetes check their glu-  cose this way two to four times a day. Smartphone apps record  blood glucose levels with foods eaten and exercise done during  the testing period.    About 90-95% of people with diabetes have type 2, in which the  beta cells produce insulin but body cells lose the ability to recog-  nize it. The condition usually has milder symptoms than type 1  diabetes but can become much more severe over time if blood  glucose is not rigorously controlled. Most affected individuals  are overweight when symptoms begin. Type 2 diabetes is being  increasingly diagnosed in children and adolescents.   The National Diabetes Education Program estimates that  about 79 million people in the United States have prediabetes,  which is blood glucose levels above the normal range but not yet  indicative of type 2 diabetes, corresponding to an A1C from 5.7  to 6.4. A diabetes educator (see Career Corner on p. 489) can be  very helpful in guiding an individual new to the world of diabetes  in choosing foods wisely.   People with any type of diabetes must monitor and regu-  late their blood glucose levels to forestall complications, which  include coronary artery disease, peripheral nerve damage, and  retinal damage. Evidence suggests that complications may begin  even before blood glucose levels indicate disease.    glucose concentration; promotes transport of amino acids into cells; enhances synthesis of proteins    and From Science to Technology 13.1 discuss diabetes mellitus,  which is a disruption of the control of glucose metabolism that  affects millions of people.    43 Why are nerve cells particularly sensitive to changes in blood  glucose concentration?    Other organs that produce hormones are part of the endocrine  system, too. They include the pineal gland; the thymus; repro-  ductive organs; and certain cells of the digestive tract, the heart,  and the kidneys.   The pineal gland (pin’e-al gland) is a small, oval structure  deep between the cerebral hemispheres, where it attaches to the  upper portion of the thalamus near the roof of the third ventricle.  It largely consists of specialized pineal cells and supportive neuro-  glia (see fig. 11.11b, p. 406).   The pineal gland secretes a hormone, melatonin, that is  synthesized from serotonin. Varying patterns of light and dark  outside the body control the gland’s activities. In the presence  of light, action potentials from the retina travel to the hypothala-  mus, then to the reticular formation, and then downward into the  spinal cord. From here, the impulses travel along sympathetic  nerve fibers back into the brain, and finally they reach the pineal  gland, where they decrease melatonin secretion. In the absence  of light, impulses from the retina decrease and secretion of mela-  tonin increases.   Melatonin secretion is part of the regulation of circadian  rhythms, which are patterns of repeated activity associated with  cycles of night and day, such as sleep/wake rhythms. Melatonin  binds to two types of receptors on brain neurons, one that is abun-  dant and one that is scarce. The major receptors are on cells of the  suprachiasmatic nucleus, a region of the hypothalamus that regu-  lates the circadian clock. Binding to the second, less abundant type  of receptor induces sleepiness.   The thymus (thi’mus), which lies in the mediastinum posterior  to the sternum and between the lungs, is large in young children    The fact that melatonin secretion responds to day length  explains why traveling across several time zones produces the  temporary insomnia of jet lag. Some clinical trials have found  that taking melatonin 30 minutes before bedtime in the new  location, for several days, hastens return to a normal sleep  schedule, decreases daytime fatigue, and increases alertness.  Studies have found that melatonin helps about half of people  who take it for jet lag.    but shrinks with age. This gland secretes a group of hormones,  called thymosins, that affect production and differentiation of  certain white blood cells (T lymphocytes). The thymus plays an  important role in immunity and is discussed in chapter 16 (p. 623).   The reproductive organs that secrete important hormones  include the testes, which produce testosterone; the ovaries, which  produce estrogens and progesterone; and the placenta, which pro-  duces estrogens, progesterone, and a gonadotropin. Chapters 22  and 23 discuss these glands and their secretions (pp. 838, 849,  and 876).   The digestive glands that secrete hormones are generally  associated with the linings of the stomach and small intestine.  The small intestine alone produces dozens of hormones, many of  which have not been well studied. Chapter 17 (pp. 665, 669,  and 674) describes these structures and their secretions.   Other organs that produce hormones include the heart, which  secretes two natriuretic peptides (chapter 15, p. 586), and the kid-  neys, which secrete erythropoietin that stimulates red blood cell  production (chapter 14, p. 533). Clinical Application 13.1 (p. 494)  discusses abuse of EPO to improve athletic performance.    44 Where is the pineal gland located?  45 What is the function of the pineal gland?  46 Where is the thymus gland located?    Factors that change the body’s internal or external environment  are potentially life threatening. Sensory receptors detecting such  changes trigger impulses that reach the hypothalamus, initiating  physiological responses that resist a loss of homeostasis. These  responses include increased activity in the sympathetic division  of the autonomic nervous system and increased secretion of adre-  nal hormones. A factor capable of stimulating such a response  is called a stressor, and the condition it produces in the body is  called stress.   Stressors may be physical or psychological, or a combination.  Physical stress threatens tissues. Extreme heat or cold, decreased  oxygen concentration, infections, injuries, prolonged heavy exer-  cise, and loud sounds inflict physical stress. Unpleasant or painful  sensations often accompany physical stress.   Psychological stress results from thoughts about real or imag-  ined dangers, personal losses, unpleasant social interactions (or  lack of social interactions), or any threatening factors. Feelings of  anger, fear, grief, anxiety, depression, and guilt cause psychological  stress. Psychological stress may also stem from pleasant stimuli,  such as friendly social contact, feelings of joy or happiness, or  sexual arousal. The factors that produce psychological stress vary  greatly from person to person. A situation that is stressful to one  person may not affect another, and what is stressful at one time  may not be at another time.    The sweet-smelling urine that is the hallmark of type 1 diabe-  tes mellitus was noted as far back as an Egyptian papyrus from  1500 s.c. In A.D. 96 in Greece, Aretaeus of Cappadocia described  the condition as a “melting down of limbs and flesh into urine.”  One of the first people to receive insulin as a drug was a three-  year-old boy whose body could not produce the hormone  (fig. 13A). In December 1922, before treatment, he weighed only  fifteen pounds. The boy rapidly improved after beginning insulin  treatment, doubling his weight in just two months.   In 1921, Canadian physiologists Sir Frederick Grant Banting  and Charles Herbert Best discovered the link between lack of  insulin and diabetes. They induced diabetes symptoms in dogs  by removing their pancreases, then cured them by administer-  ing insulin from other dogs’ healthy pancreases. A year later,  people with diabetes began to receive insulin extracted  from pigs or cattle. The medication allowed them to control  their disease.   In 1982, pure human insulin became available by geneti-  cally altering bacteria to produce the human protein (recombi-  nant DNA technology). Human insulin helps people with type  1 diabetes who are allergic to the product from pigs or cows.  Today, people receive insulin in several daily injections, from an  implanted insulin pump, and/or in aerosol form; a transdermal  insulin delivery system (skin patch) is in development.   Providing new pancreatic islets is a longer-lasting treatment  for type 1 diabetes. An initial technical challenge was separating  islets from cadaver pancreases, and then collecting enough beta  cells, which account for only 2% of pancreas cells. Many patients’  immune systems rejected transplants. By the 1990s, automated  islet isolation and new anti-rejection drugs helped. In 1996 in  Germany, and then in 1999 in Edmonton, Canada, islet transplan-  tation to treat type 1 diabetes began.    The hypothalamus controls the response to stress, termed the gen-  eral adaptation (or general stress) syndrome. This response pro-  ceeds through two stages: the immediate “alarm” stage and the  long-term “resistance” stage, and works to maintain homeostasis.   Recall that the hypothalamus receives information from nearly  all body parts, including visceral receptors, the cerebral cortex, the  reticular formation, and the limbic system. In the immediate stage,  the hypothalamus activates the “fight or flight” response. Specifically,  sympathetic impulses from the hypothalamus raise the blood glucose  concentration, the level of blood glycerol and fatty acids, heart rate,  blood pressure and breathing rate, and dilate the air passages. The  response also shunts blood from the skin and digestive organs into  the skeletal muscles and increases secretion of epinephrine from the  adrenal medulla. The epinephrine, in turn, intensifies these sympa-  thetic responses and prolongs their effects (fig. 13.37).    FIGURE 13A Before and after insulin treatment. The boy in  his mother’s arms is three years old but weighs only 15 pounds  because he has untreated type 1 diabetes mellitus. The inset    In the resistance stage, the hypothalamus secretes corticotropin-  releasing hormone (CRH). This stimulates the anterior pituitary  gland to secrete ACTH, which increases the adrenal cortex’s secre-  tion of cortisol. Cortisol supplies cells with amino acids and extra  energy sources and allows glucose to be spared for brain tissue  (fig. 13.37). Stress can also stimulate release of glucagon from the  pancreas, growth hormone (GH) from the anterior pituitary gland,  antidiuretic hormone (ADH) from the posterior pituitary gland,  and renin from the kidneys.   Glucagon and growth hormone help mobilize energy sources,  such as glucose, glycerol, and fatty acids, and stimulate cells to  take up amino acids, facilitating repair of injured tissues. ADH  stimulates the kidneys to retain water. This action decreases urine  output and helps to maintain blood volume, which is important  if a person is bleeding or sweating heavily. Renin, by increas-  ing angiotensin II levels, helps stimulate the kidneys to retain    FIGURE 13B A person with either common form of diabetes  mellitus must monitor his or her blood glucose level and be very  diligent about proper diet and exercise.    Since 2000, several hundred people have received islet  transplants in a procedure called the Edmonton protocol, which  introduces islets into a vein in the liver. By a year after transplant,  from 50% to 68% of patients do not need to receive additional  insulin, but by five years after the procedure, fewer than 10% of  total patients are free of daily insulin supplementation. The pro-  cedure is risky—12% of patients hemorrhage, and 4% develop  blood clots in the liver vein. These risks, plus the apparent short-  term improvement, have prompted physicians to carefully evalu-  ate which patients are most likely to benefit from the few years  of insulin independence that the procedure may offer. Researchers    sodium (through aldosterone), and through the vasoconstrictor  action of angiotensin II contributes to maintaining blood pressure.  Table 13.13 summarizes the body’s reactions to stress.    47 What is stress?  48 Distinguish between physical stress and psychological stress.    With age, the glands of the endocrine system generally decrease  in size and increase in the proportion of each gland that is fibrous  in nature. At the cellular level, lipofuscin pigment accumulates    are also investigating implants of stem cells and progenitor cells  from a patient’s body.   Treatment for type 2 diabetes includes following a low-  carbohydrate, high-protein diet; regular aerobic and weight-  bearing exercise; and maintaining a healthy body weight (fig. 13B).  Several oral drugs can help control blood glucose levels, which  can delay the onset of complications. A new drug that increases  insulin production is injected once a week. Some people with  type 2 diabetes may need to inject insulin. Another treatment for  type 2 diabetes is gastric bypass surgery, which removes parts  of the stomach and small intestine to help people lose weight.  Isolated reports since the 1950s noted cases of morbidly obese  people with diabetes having gastric bypass surgery, and then,  within days and with lasting effect, not needing to inject insulin.  By the 1980s, doctors noticed that some patients who had normal  regulation of blood glucose before the surgery, a few months after  began to experience confusion, altered behavior, seizures, and  unconsciousness—signs of low blood glucose.   Today the effect of gastric bypass surgery on blood glucose  levels is well recognized, and in some surgical centers more than  90% of patients with diabetes have levels of blood glucose within  the normal range without medication just days or a few weeks  after surgery. One proposed mechanism is that food reaching  the small intestine has larger pieces than normal because of the  smaller stomach capacity, and when the small intestine requires  more energy to digest, it comes from blood glucose. Another  hypothesis is that the shortened digestive tract alters the micro-  biome (gut bacteria) in a way that lowers blood glucose levels.  Surgeons are now performing the surgery on people with severe  diabetes who are only moderately overweight, and someday gas-  tric bypass, or a way to mimic its effects or mechanism, may be a  frontline treatment for type 2 diabetes.    as glands age. Hormone levels change with advancing years.  Treatments for endocrine disorders associated with aging supple-  ment deficient hormones, remove part of an overactive gland, or  use drugs to block the action of an overabundant hormone.   Aging affects different hormones in characteristic ways. For  growth hormone, the surge in secretion that typically occurs at  night lessens with age. Lower levels of GH are associated with  declining strength in the skeleton and muscles with advancing age.  Levels of antidiuretic hormone increase with age due to slowed  elimination by the liver and kidneys, rather than increased synthe-  sis, stimulating the kidneys to reabsorb more water.   The thyroid gland shrinks with age, as individual follicles  shrink and more abundant fibrous connective tissue separates  them. Thyroid nodules, which may be benign or cancerous,  become more common with age, and are often first detected upon  autopsy. Although blood levels of T, and T, may diminish with    stimulates the adrenal cortex to * Breathing rate increases. * Release of fatty acids increases.  release cortisol, which promotes * Air passages dilate. * Glucose formed from noncarbohydrates—  longer-term responses that resist e Pupils dilate. amino acids (from proteins) and glycerol    . In response to stress, impulses are conducted to the hypothalamus.    . Sympathetic impulses originating from the hypothalamus increase blood glucose concentration, blood glycerol concentration,  blood fatty acid concentration, heart rate, blood pressure, and breathing rate. They dilate air passages, shunt blood into skeletal  muscles, and increase secretion of epinephrine from the adrenal medulla.    . Epinephrine intensifies and prolongs sympathetic actions.  . The hypothalamus secretes CRH, which stimulates secretion of ACTH by the anterior pituitary gland.  . ACTH stimulates release of cortisol by the adrenal cortex.    . Cortisol increases the concentration of blood amino acids, releases fatty acids, and stimulates formation of glucose from  noncarbohydrate sources.    . Secretion of glucagon from the pancreas and growth hormone from the anterior pituitary increase.  8. Glucagon and growth hormone aid mobilization of energy sources and stimulate uptake of amino acids by cells.  9. Secretion of ADH from the posterior pituitary increases.   . ADH promotes the retention of water by the kidneys, which increases blood volume.    . Renin increases blood levels of angiotensin II, which acts as a vasoconstrictor and also stimulates the adrenal cortex to secrete  aldosterone.    age, in general, the thyroid gland’s control over the metabolism of which it rises and contributes to osteoporosis risk. Fat accumulates   various cell types is maintained throughout life. Calcitonin levels between the cells of the parathyroid glands.   decline with age, which raises the risk of osteoporosis. The adrenal glands illustrate the common theme of aging-  Parathyroid function differs between the sexes with age. related physical changes, yet continued function. Fibrous con-   Secretion peaks in males at about age fifty, whereas in women, the nective tissue, lipofuscin pigment, and increased numbers of   level of parathyroid hormone decreases until about age forty, after abnormal cells characterize the aging adrenal glands. However,    thanks to the fine-tuning of negative feedback systems, blood  levels of glucocorticoids and mineralocorticoids usually remain  within the normal range, although the ability to maintain homeo-  stasis of osmotic pressure, blood pressure, acid-base balance, and  sodium and potassium ion distributions may falter with age.   The most obvious changes in the aging endocrine system  involve blood glucose regulation. The pancreas may be able to main-  tain secretion of insulin and glucagon, but lifestyle changes, such  as increase in fat intake and less exercise, may increase the blood  insulin level. The development of insulin resistance—the decreased  ability of muscle, liver, and fat cells to take in glucose even in the  presence of insulin—reflects impaired ability of these target cells to  respond to the hormone, rather than compromised pancreatic func-  tion. Blood glucose buildup may signal the pancreas to secrete more  insulin, setting the stage for type 2 diabetes mellitus.    The nervous system and the endocrine system work together  to control body functions.    1. Endocrine glands secrete their products (hormones) into  body fluids (the internal environment); exocrine glands  secrete their products into ducts that lead to the outside of  the body.    Endocrine glands secrete hormones into the bloodstream,  which carries them to all parts of the body.  1. Chemistry of hormones  a. Steroid hormones are lipids that include complex rings  of carbon and hydrogen atoms.  b. Nonsteroid hormones are amines, peptides, and  proteins.  2. Actions of hormones  a. Steroid hormones and thyroid hormones  (1) Steroid hormones and thyroid hormones enter  target cells and combine with receptors to form  complexes.  (2) These complexes activate specific genes in the  nucleus, which direct synthesis of specific proteins.  (3) The degree of cellular response is proportional  to the number of hormone-receptor complexes  formed.  b. Nonsteroid hormones  (1) Nonsteroid hormones combine with receptors in  the target cell membrane.  (2) A hormone-receptor complex stimulates membrane  proteins, such as adenylate cyclase, to induce the  formation of second messenger molecules.    The daily fall and rise of melatonin may level out with age,  which can affect the sleep/wake cycle. People usually require less  sleep as they age. Changes to the tempo of the body clock may, in  turn, affect secretion of other hormones.   The thymus begins to noticeably shrink before age twenty, with  accompanying declining levels of thymosins. By age sixty, thymo-  sin secretion is nil. The result is a slowing of the maturation of B and  T cells, which increases susceptibility to infections as a person ages.    50 What general types of changes occur in the glands of the  endocrine system with aging?    51 How do the structures and functions of particular endocrine  glands change over a lifetime? Hi    (3) A second messenger, such as cAMP, activates  protein kinases.  (4) Protein kinases activate certain protein substrate  molecules, which, in turn, change cellular processes.  (5) The cellular response to a nonsteroid hormone  is amplified because the enzymes induced by a  small number of hormone-receptor complexes can  catalyze formation of a large number of second  messenger molecules.  3. Prostaglandins  a. Prostaglandins are paracrine substances that have  powerful hormonelike effects, even in small amounts.  b. Prostaglandins modulate hormones that regulate  formation of cyclic AMP.    13.3 Control of Hormonal Secretions  (page 496)  The concentration of each hormone in the body fluids is  precisely regulated.  1. Some endocrine glands secrete hormones in response to  releasing hormones that the hypothalamus secretes.  2. Some endocrine glands secrete in response to nervous  stimulation.  3. Some endocrine glands secrete in response to changes in  the plasma concentration of a substance.  4. Inanegative feedback system, a gland is sensitive to the  physiological effect that its hormone brings about.  5. When the physiological effect reaches a certain level, it  inhibits the gland.  6. As the gland secretes less hormone, the physiological  effect is lessened.    The pituitary gland, attached to the base of the brain, has an  anterior lobe and a posterior lobe. Releasing hormones from  the hypothalamus control most pituitary secretions.    Glands secrete hormones that have a  variety of effects on cells, tissues, organs,  and organ systems.    bones to control  calcium balance.  Muscular System  Hormones help  increase blood  4 flow to exercising  \ muscles.  '  Nervous System  Neurons control the  secretions of the  anterior and  posterior pituitary    Hormones are carried  in the bloodstream;  some have direct  actions on the heart  and blood vessels.    Decreased oxygen  causes hormonal  stimulation of red  blood cell production;  red blood cells  transport oxygen  and carbon dioxide.    Hormones act on  the kidneys to  help control water  and electrolyte  balance.    Sex hormones play  a major role in  development of  secondary sex  characteristics, egg,  and sperm.   (2) Growth hormone-releasing hormone and  somatostatin from the hypothalamus control  GH secretion.   (2) A normal function of prolactin in males has not  been established.   (3) Prolactin release-inhibiting hormone from the  hypothalamus restrains secretion of prolactin,  whereas prolactin-releasing factors are thought to  promote its secretion.   (2) The hypothalamus, by secreting thyrotropin-  releasing hormone, regulates TSH secretion.   (1) ACTH controls the secretion of certain hormones  from the adrenal cortex.   (2) The hypothalamus, by secreting corticotropin-  releasing hormone, regulates ACTH secretion.   f. Follicle-stimulating hormone (FSH) and luteinizing  hormone (LH) are gonadotropins that affect the  reproductive organs.   a. The posterior lobe of the pituitary gland largely  consists of neuroglia and nerve fibers that originate  in the hypothalamus.   b. The two hormones of the posterior pituitary are  produced in the hypothalamus.   (2) Inhigh concentration, ADH constricts blood  vessel walls, raising blood pressure.   (1) OT has an antidiuretic effect and can contract  smooth muscle in the uterine wall.   (2) OT also contracts certain cells associated with  production and ejection of milk from the milk  glands of the breasts.    The thyroid gland is located in the neck and consists of two  lateral lobes.  1. Structure of the gland  a. The thyroid gland consists of many hollow secretory  parts called follicles.  b. The follicles are fluid filled and store the thyroxine  and triiodothyronine the follicular cells secrete.  c. Extrafollicular cells secrete calcitonin.  2. Thyroid hormones  a. Thyroxine and triiodothyronine  (1) These hormones increase the rate of metabolism,  enhance protein synthesis, and stimulate lipid  breakdown.    (2) These hormones are needed for normal growth  and development and for maturation of the  nervous system.   (2) This hormone prevents prolonged elevation of  calcium after a meal.    The parathyroid glands are on the posterior surface of  the thyroid gland.  1. Structure of the glands   a. Each gland is small and yellow-brown, within a thin  connective tissue capsule.   b. Each gland consists of secretory cells well supplied  with capillaries.   a. PTH increases blood calcium ion concentration and  decreases blood phosphate ion concentration.   b. PTH stimulates resorption of bone tissue, causes the  kidneys to conserve calcium ions and excrete phosphate  ions, and indirectly stimulates absorption of calcium  ions from the intestine.   c. A negative feedback mechanism operating between the  parathyroid glands and the blood regulates these glands.    The adrenal glands are located atop the kidneys.  1. Structure of the glands  a. Each adrenal gland consists of a medulla and a cortex.  b. The adrenal medulla and adrenal cortex are distinct  in that they secrete different hormones.  2. Hormones of the adrenal medulla  a. The adrenal medulla secretes epinephrine and  norepinephrine.  b. These hormones are synthesized from tyrosine and are  chemically similar.  c. These hormones produce effects similar to those of the  sympathetic nervous system.  d. Sympathetic impulses originating from the hypothalamus  stimulate secretion of these hormones.  3. Hormones of the adrenal cortex  a. The cortex produces several types of steroids that  include hormones.  b. Aldosterone  (1) It causes the kidneys to conserve sodium ions and  water and to excrete potassium ions.  (2) Itis secreted in response to increased potassium ion  concentration or the presence of angiotensin II.  (3) By conserving sodium ions and water, it helps  maintain blood volume and pressure.  c. Cortisol  (1) It inhibits protein synthesis, releases fatty  acids, and stimulates glucose formation from  noncarbohydrates.  (2) A negative feedback mechanism involving  secretion of CRH from the hypothalamus and  ACTH from the anterior pituitary gland controls  its level.    d. Sex hormones  (1) These hormones are of the male type although  some can be converted into female hormones.  (2) They supplement the sex hormones produced by  the gonads.    The pancreas secretes digestive juices as well as hormones.  1. Structure of the gland   a. The pancreas is posterior to the stomach and is attached  to the small intestine.   b. The endocrine portion, called the pancreatic islets  (islets of Langerhans), secretes glucagon, insulin, and  somatostatin.   a. Glucagon stimulates the liver to produce glucose,  increasing concentration of blood glucose. It also  breaks down fat.   b. Insulin activates facilitated diffusion of glucose through  cell membranes, stimulates its storage, promotes  protein synthesis, and stimulates fat storage.   c. Facilitated diffusion of glucose into nerve cells does not  depend on insulin.    1. Pineal gland  a. The pineal gland is attached to the thalamus near the  roof of the third ventricle.  b. Postganglionic sympathetic nerve fibers innervate it.  c. It secretes melatonin, which regulates some circadian  rhythms.  2. Thymus  a. The thymus lies posterior to the sternum and  between the lungs.  b. It shrinks with age.  c. Itsecretes thymosins, which affect the production of  certain lymphocytes that, in turn, provide immunity.  3. Reproductive organs  a. The testes secrete testosterone.    b. The ovaries secrete estrogens and progesterone.  c. The placenta secretes estrogens, progesterone, and a  gonadotropin.  4. The digestive glands include certain glands of the stomach  and small intestine that secrete hormones.  5. Other hormone-producing organs include the heart and  kidneys.    Stress occurs when the body responds to stressors that threaten  the maintenance of homeostasis. Stress responses include  increased activity of the sympathetic nervous system and  increased secretion of adrenal hormones.   a. Physical stress results from environmental factors that  are harmful or potentially harmful to tissues.   b. Psychological stress results from thoughts about real or  imagined dangers. Factors that produce psychological  stress vary with the individual and the situation.   b. The hypothalamus controls a general adaptation  (or general stress) syndrome.    Life-Span Changes (page 519)  With age, endocrine glands shrink and accumulate fibrous  connective tissue, fat, and lipofuscin, but hormonal activities  usually remain within the normal range.  1. GH levels even out, as muscular strength declines.  2. ADH levels increase due to slowed breakdown.  3. The thyroid shrinks but control of metabolism continues.  4. Decreasing levels of calcitonin and increasing levels of  parathyroid hormone increase osteoporosis risk.  5. The adrenal glands show aging-related changes, but  negative feedback maintains functions.  6. Muscle, liver, and fat cells may develop insulin resistance.  7. Changes in melatonin secretion affect the body clock.  8. Thymosin production declines, hampering resistance  to disease.   Explain the specificity of a hormone for its target cell. (p. 488)  List six general functions of hormones. (p. 488)    Explain how hormones can be grouped on the basis of their  chemical composition. (pp. 489-490)   List the steps of the action of most nonsteroid hormones.  (pp. 491-496)   Explain how prostaglandins are similar to hormones and how  they are different. (p. 496)    Diagram the three mechanisms that control hormone  secretion, including negative feedback in each mechanism.  (p. 496)   from the list on the right may be used more than once):   and posterior lobes of the pituitary gland. (pp. 500 and 502)   b. The posterior pituitary is removed because it has a tumor.   c. An individual is rescued after three days in the desert  without food or water.    Describe the location and structure of the parathyroid  glands. (p. 506)    Adrenal Glands  Distinguish between the adrenal medulla and the adrenal  cortex. (p. 508)   Match the adrenal hormones with their source and actions:  (pp. 508-512)  (1) cortisol    cortex; sodium retention  cortex; male sex hormones  medulla; fight-or-flight response  cortex; gluconeogenesis    Diagram control of aldosterone secretion. (pp. 510-511)  Diagram control of cortisol secretion. (p. 512)    Describe the location and structure of the pancreas. (p. 514)  List the hormones the pancreatic islets secrete and their  general functions. (pp. 514-515)    Describe the location and general function of the pineal  gland. (p. 517)   Describe the location and general function of the thymus.  (p. 517)   List several factors that cause physical and/or psychological  stress. (p. 517)    Levels of which hormones decrease with age? Which  increase? (pp. 519-521)    1. When a nuclear reactor explodes, a great plume of radioactive  isotopes erupts into the air and may spread for thousands of  miles. Most of the isotopes emitted immediately following  the blast are of the element iodine. Which of the glands of the  endocrine system would be most seriously—and immediately—  affected by exposure to the isotopes, and how do you think this  will become evident in the nearby population?    2. Why might oversecretion of insulin reduce glucose uptake by  nerve cells?    3. A young mother feels shaky, distracted, and generally ill. She  lives with her mother, who is dying. A friend tells the young  woman, “It’s just stress, it’s all in your head.” Is it?    4. Growth hormone is administered to people who have pituitary  dwarfism. Parents wanting their normal children to be taller have  requested the treatment for them. Do you think that this is a  wise request? Why or why not?    5. An adult has had her anterior pituitary removed. Which hormone  supplements will she require?    6. The adrenal cortex of a patient who has lost a large volume of  blood will increase secretion of aldosterone. What effect will this  increased secretion have on the patient’s blood concentrations  of sodium and potassium ions?    7. What problems might result from the prolonged administration  of cortisol to a person with severe inflammatory disease?    Connect Interactive Questions Reinforce your knowledge  using assigned interactive questions covering the location and  structure of endocrine glands, actions of hormones, and the  body's response to stress.    Anatomy & Physiology Revealed Go more in depth into the  human body by exploring cadaver dissections, viewing histological  slides, and watching animations related to endocrine glands and  hormonal secretions.    A micrograph of blood—a complex mixture of cells, cell fragments, and  many types of dissolved biochemicals that provides nutrients, oxygen, and  other vital substances to our cells (1,800x).    Blood signifies life, and for good reason—it has many vital func-  tions. This complex mixture of cells, cell fragments, and dissolved  biochemicals carries nutrients, oxygen, wastes, and hormones;  helps maintain the stability of the intestinal fluid; and distributes  heat. The blood, heart, and blood vessels form the cardiovascular  system and link the body’s internal and external environments.    After you have studied this chapter, you should be able to:    Distinguish among the formed elements of blood and the  liquid portion of blood. (pp. 528-529)    Explain the significance of red blood cell counts and how  they are used to diagnose disease. (p. 531)    Discuss the life cycle of a red blood cell. (pp. 531, 533,  and 535)    Distinguish among the five types of white blood cells,  and give the function(s) of each type. (pp. 536-537)   Describe the functions of each of the major components  of plasma. (pp. 541-542)    Define hemostasis, and explain the mechanisms that help  to achieve it. (pp. 542-543)    Explain blood typing and how it is used to avoid adverse  reactions following blood transfusions. (pp. 548-551)    Describe how blood reactions may occur between fetal  and maternal tissues. (p. 551)   -crit, to separate: hematocrit—percentage  by volume of red blood cells in a blood  sample, determined by separating the  red blood cells from the plasma.   erythr-, red: erythrocyte—red blood cell.  hema-, blood: hematocrit—percentage of  red blood cells in a given volume of blood.    -poie, make, produce: erythropoietin—  hormone that stimulates the production  of red blood cells.   thromb-, clot: thrombocyte—blood platelet  involved in the formation of a blood clot.    Blood is a type of connective tissue whose cells are suspended in  a liquid extracellular matrix. Blood is vital in carrying substances  between body cells and the external environment, thereby promot-  ing homeostasis.   Blood volume varies with body size, changes in fluid and  electrolyte concentrations, and the amount of adipose tissue.    Blood volume is typically about 8% of body weight. An average-  size adult has about 5 liters of blood.   Whole blood is slightly heavier and three to four times more  viscous than water. Its cells include red blood cells and white  blood cells. Blood also contains cellular fragments called platelets  (fig. 14.1). The cells and platelets are termed “formed elements” of  the blood, in contrast to the liquid portion.   a solid portion (the formed  elements) that includes red  blood cells, white blood  cells, and platelets. (Note:  When blood components are  separated, the white blood  cells and platelets form a thin  layer, called the “buffy coat,”  between the plasma and the  red blood cells.) Blood cells  and platelets can be seen  under a light microscope  when a blood sample is  smeared onto a glass slide.    FIGURE 14.2 Ifa blood-filled capillary tube is centrifuged, the red cells  pack in the lower portion and the percentage of red cells (hematocrit) can be  determined. Values shown are within the normal range for healthy humans.    If a blood sample stands in a tube for a while and is prevented  from clotting, the cells separate from the liquid portion and settle to  the bottom. Centrifuging the sample quickly packs the cells into the  lower part of the centrifuge tube, as figure 14.2 shows. The percent-  ages of cells and liquid in the blood sample can then be calculated.   Most blood samples are about 45% red blood cells by volume.  This percentage is called the hematocrit (HCT), or packed cell  volume (PCV). The white blood cells and platelets account for  less than 1%. The remaining blood sample, about 55%, is the clear,  straw-colored plasma (plaz’mah). Plasma is a complex solution  that includes water, amino acids, proteins, carbohydrates, lipids,  vitamins, hormones, electrolytes, and cellular wastes (fig. 14.3).  Appendix C, Laboratory Tests of Clinical Importance, lists values  for the hematocrit and other blood tests commonly performed on  healthy individuals. Clinical Application 14.1 discusses the use of  universal precautions for handling blood and other body fluids.    Hematopoiesis (he”mat-o-poi-e’sis) is the formation of blood  cells. Blood cells originate in red bone marrow from hemato-  poietic stem cells, also known as hemocytoblasts (he”mo-si’to-  blastz) (fig. 14.4). A stem cell can divide to give rise to specialized  (more differentiated) cells as well as more stem cells. As hema-  topoietic stem cells divide, the new cells, myeloid and lymphoid  stem cells, respond to different secreted growth factors, called  hematopoietic growth factors, that turn on some genes and turn  off others. This exposure to growth factors ultimately sculpts  the distinctive formed elements of blood, including the cellular  components of the immune system.    ® RECONNECT  “ To Chapter 3, Stem and Progenitor Cells, pages 112-113.    Red blood cells, also called erythrocytes (é-rith’ro-sitz), are tiny,  approximately 7.5 um in diameter. They are biconcave discs, thin  near their centers and thicker around their rims (fig. 14.5). This  distinctive shape is an adaptation for the red blood cell’s function  of transporting gases—it increases the surface area through which  gases can diffuse. The shape also places the cell membrane closer  to oxygen-carrying hemoglobin (he”mo-glo’bin) molecules in the  cell. A red blood cell’s shape and flexibility enable it to readily  squeeze through the narrow capillaries.   Each red blood cell is about one-third hemoglobin by volume.  This protein imparts the color of blood. The rest of the cell mainly  consists of membrane, water, electrolytes, and enzymes. When  hemoglobin combines with oxygen, the resulting oxyhemoglobin is  bright red; when the oxygen is released, the resulting deoxyhemo-  globin is darker. Blood rich in deoxyhemoglobin may appear bluish  when it is viewed through blood vessel walls.    When a large truck jackknifed on an icy highway, the  resulting ten-car pile-up sent many injured people to the  emergency department of the closest hospital. Alerts  requesting blood donations went out on social and  traditional media right away, and soon people began to  arrive to donate blood.   At the hospital, one blood bank technologist helped to  collect blood from the donors, while another working in a  laboratory processed and typed the blood so that physicians  could match blood to patients, on the lookout for rare blood  types. The technologist in the laboratory also tested the  blood for viral contamination and presence of antibodies,  and when too many donors showed up, prepared the extra  blood for storage, separating its components.   In addition to expertise in blood banking, blood bank  technologists must have coursework that covers molecular  testing, immunology, genetics, regenerative medicine,  cell therapies, transfusion practices, and transplantation,  and be aware of complications that may arise from giving  one person’s blood to another. Computer skills, manual  dexterity, and normal color vision are important for the job.   Blood bank technologists work in blood donor centers,  transfusion services, research institutions, reference  laboratories, transplant centers, and suppliers of blood  bank equipment. They must have a degree and certification  in medical technology and complete a 12- or 24-month  training program, or a four-year degree in a science with  work experience at a blood bank plus the postgraduate  program. The American Society for Clinical Pathology  (ASCP) certifies blood bank technologists.   The career has room for growth. Blood bank  technologists may become regulatory experts involved  with clinical trials, administrators of laboratories, technical/  procedural advisors, quality assessors and managers, or  educators to train other health-care professionals in blood  transfusion medicine.    Blood can contain more than cells, nutrients, proteins, and  water—a single drop from an infected individual can harbor bil-  lions of viruses. In the wake of the AIDS epidemic, in 1988 the  U.S. Centers for Disease Control and Prevention (CDC) devised  “universal precautions,” which are specific measures that health-  care workers should take to prevent transmission of bloodborne  infectious agents in the workplace (fig. 14A). The CDC singled  out HIV and the hepatitis B virus. The guidelines grew out of ear-  lier suggestions for handling patients suspected to have been  exposed to viruses. The term universal refers to the assumption  that any patient may have been exposed to a pathogen that can  be transmitted in a body fluid such as blood.   Attention to safety in the health-care setting can prevent  transmission of infectious diseases. The World Health Organization  estimates that 4% to 7% of new infections worldwide are transmit-  ted via unsafe injections. Specific recommendations include:    e use of personal protective equipment, such as gloves, goggles,  and masks   ¢ work-practice controls, such as handwashing before and after  performing procedures    Universal precautions were designed for, and work well  in, preventing transmission of viral illnesses in settings already  relatively safe, such as clinics. This isn’t necessarily the case for  outbreaks, natural disasters, and combat zones. For example, in  2005 several pediatric nurses who aided neighbors infected with  the Marburg virus in the isolated town of Uige in Angola, in south-  western Africa, died from this hemorrhagic fever along with hun-  dreds of other people.   Headache, fever, vomiting, and diarrhea begin three to nine  days after exposure to the Marburg virus. Then the person bleeds  from all body openings, internally and under the skin. Plummeting  blood pressure kills most infected individuals within a week, and any-  one contacting their blood is in danger of infection. Infected indi-    Prolonged oxygen deficiency (hypoxia) causes cyanosis, in which  the skin and mucous membranes appear bluish due to an abnor-  mally high blood concentration of deoxyhemoglobin. Exposure  to low temperature may also result in cyanosis by constricting  superficial blood vessels. This slows blood flow, allowing removal  of more oxygen than usual from blood flowing through the ves-  sels, thereby increasing the amount of deoxyhemoglobin.    Red blood cells have nuclei during their early stages of devel-  opment but extrude the nuclei as they mature, providing more space  for hemoglobin. Because mature red blood cells lack nuclei, they  cannot synthesize proteins or divide. Mature red blood cells pro-    FIGURE 14A_ Health-care workers wear personal protective  equipment to shield themselves from body fluids containing disease-  causing viruses.    P  © Which protective gear is worn by this health-care worker?    viduals must be isolated and not touched, but the scourge spreads  because many family members become infected while tending to  their loved ones.   In the 2005 outbreak, contaminated medical equipment con-  tributed to the rapid and deadly spread of the infection. Untrained  clinic workers reused needles, and some people reused needles  and intravenous equipment in their homes. However, even universal  precautions might not have contained this outbreak, because the  body fluids were so copious and infectious.    duce ATP through glycolysis only and use none of the oxygen they  carry because they also lack mitochondria. As long as cytoplasmic  enzymes function, these cells can carry on vital energy-releasing  processes. With time, however, red blood cells become less active,  more rigid, and more likely to be damaged or worn. Eventually the  spleen and liver remove older red blood cells from the circulation.    4 How do blood cells form?  5 Describe a red blood cell.    6 How does the biconcave shape of a red blood cell make  possible its function?    Formed elements Plasma  Platelets Red blood cells = White blood cells Electrolytes Water Proteins Wastes Nutrients Gases  (4.8%) (95.1%) (0.1%) (92%) (7%)  Vitamins  ° | Hormones  Neutrophils | Eosinophils Basophils Monocytes Lymphocytes Albumins Globulins Fibrinogen QO, COs  (54-62%) (1-3%) (<1%) (3-9%) (25-33%)    FIGURE 14.3 Blood composition. Blood is a complex mixture of formed elements in a liquid extracellular matrix, plasma.  Note that water and proteins account for 99% of the plasma.    i ee : i : The number of red blood cells in a microliter (uL or mcL or  aeeamio acid in the protein part of hemoglobin; cauaiga 1 mm?) of blood is called the red blood cell count (RBCC or  the molecule to peach within itself at many more pein The RCC). The typical range for adult males is 4,700,000-6,100,000  gguemnal hemoglobin makes the red blood cells sticig7igi cells per microliter, and that for adult females is 4,200,000-—  ‘ é : 5,400,000 cells per microliter. For children, the average range  bloodstream (see owe 1a EE) The fragile cells lode in nar- is 4,500,000-5,100,000 cells per microliter. These values may  row blood vessels, cutting off local blood supplies. Once a vary slightly with the hospital, physician, and type of equipment  used to make blood cell counts, and even in a healthy individ-  ual from time to time. The number of red blood cells generally  increases for several days following strenuous exercise or an  increase in altitude.   Red blood cell counts are routinely consulted to help diag-  nose and evaluate the courses of certain diseases. Changes in red  blood cell count may affect health by altering the blood’s oxygen-  carrying capacity.    | In sickle cell disease, a single DNA base mutation changes    likely to deform into sickle shapes as they move through the    blockage occurs, the falling oxygen level hastens sickling and  the shape change spreads, blocking circulation further. The  result is great pain in the blocked body parts, particularly in  the hands, feet, and bones. As red blood cells die too quickly,  their depletion causes the profound fatigue of anemia while  the spleen becomes overworked in breaking down the cells,  increasing the risk of infection.   Children with sickle cell disease are typically diagnosed at  birth. The spleen is usually damaged early on, so they receive  antibiotics daily for years to prevent infection. Hospitalization   A drug, hydroxyurea, is used to activate production of a yolk sac, liver, and spleen. After birth, these cells are produced  form of hemoglobin that more effectively binds oxygen, nor- almost exclusively by tissue lining the spaces in bones, which are  mally produced only in the fetus. Fetal hemoglobin slows filled with red bone marrow.   marrow transplant or an umbilical cord stem cell transplant > To Chapter 7, Blood Cell Formation, pages 210-211.  from a donor can completely cure sickle cell disease, but has a  | 5% risk of fatality.    In the red bone marrow, hematopoietic stem cells divide and  give rise to erythroblasts (€-rith’ro-blastz). The erythroblasts also  divide and give rise to many new cells. The nuclei of these newly  formed cells soon shrink and are pinched off from the cell along    stem cells in bone marrow. (b) Light micrograph of a hematopoietic stem cell (arrow) in red bone marrow (500x).    FIGURE 14.5 fAP|R) Red blood cells. (a) The biconcave shape of a  red blood cell makes possible its function of transporting oxygen. (b) Falsely  colored scanning electron micrograph of human red blood cells (5,000x).    with a thin covering of cytoplasm and cell membrane, in a pro-  cess called nuclear extrusion. Macrophages (see chapter 5, p. 160)  engulf and degrade the extruded materials. For a day or two, some  of these young red cells may contain a netlike structure (retic-  ulum) that appears when the cells are stained. These cells are  called reticulocytes (ré-tik’u-lo-sitz). This is the stage in which  cells exit the bone marrow to enter the blood. When the remaining  organelles degenerate the cells are fully mature. The resulting cells  are erythrocytes.   The average life span of a red blood cell is 120 days. During  that time, it travels through the body about 75,000 times. Many  red blood cells are removed from the circulation each day, yet the  number in the circulating blood remains relatively stable. These  numbers suggest a homeostatic control of the rate of red blood  cell production.    A negative feedback mechanism using the hormone erythro-  poietin (e-rith”ro-poi’é-tin) (EPO) controls the rate of red blood  cell formation. In response to prolonged oxygen deficiency, EPO  is released from the kidneys and to a lesser extent from the liver.  (In a fetus, the liver is the main site of EPO production.) At high  altitudes, for example, although the percentage of oxygen in the  air remains the same, the atmospheric pressure decreases, reduc-  ing availability of oxygen. The amount of oxygen delivered to  the tissues initially decreases. As figure 14.6 shows, this drop in  oxygen triggers release of EPO, which travels via the blood to  the red bone marrow and increases erythrocyte production.   After a few days in the high-altitude environment, many  newly formed red blood cells appear in the circulating blood.  The increased rate of production continues until the number of  erythrocytes is sufficient to supply tissues with oxygen. When the  availability of oxygen returns to normal, EPO release decreases  and the rate of red blood cell production returns to normal.    “ To Chapter 13, Abusing Hormones to Improve Athletic  Performance, page 494.    Other conditions can lower oxygen levels and stimulate EPO  release. These include loss of blood, which decreases the oxygen-  carrying capacity of the cardiovascular system, and chronic lung  diseases, which decrease the respiratory surface area available for  gas exchange. An excessive increase in red blood cells is poly-  cythemia. This increases blood viscosity, slowing blood flow and  impairing circulation.    FIGURE 14.6 Low blood oxygen causes the kidneys and, to a lesser  degree, the liver to release erythropoietin. Erythropoietin stimulates target  cells in the red bone marrow to increase the production of red blood cells,  which carry oxygen to tissues.    8 What is the typical red blood cell count for an adult male?  For an adult female?    9 Where are red blood cells produced?  10 How does a red blood cell change as it matures?    Availability of B-complex vitamins B ,, and folic acid significantly  influences red blood cell production. These vitamins, required for  DNA synthesis, are necessary for the growth and division of all  cells. Because hematopoietic stem cells frequently divide, they are  especially vulnerable to a deficiency of either of these vitamins.  Lack of vitamin B,, is usually due to a disorder in the stomach  lining rather than to a dietary deficiency, because parietal cells in  the stomach secrete a substance called intrinsic factor required to  absorb vitamin B.,.    In the absence of intrinsic factor, vitamin B,, absorption  decreases, causing the red bone marrow to form abnormally  large, irregularly shaped, thin-membraned fragile red blood  cells, resulting in a condition called pernicious anemia. B,, defi-    ciency can also cause permanent brain damage if not treated  promptly with vitamin B,, injections. Taking excess folic acid can  mask a vitamin B,, deficiency by correcting the anemia, but will  not prevent the neurological damage.    Iron is required for hemoglobin synthesis. Although much of  the iron released during the decomposition of hemoglobin is avail-  able for reuse, some iron is lost each day and must be replaced.  Only a small fraction of ingested iron is absorbed. Iron absorp-    tion is slow, but the rate varies with the total amount of iron in  the body. When iron stores are low, absorption rate increases, and  when the tissues are becoming saturated with iron, the rate greatly  decreases. Table 14.1 summarizes the dietary factors that affect  red blood cell production.    Vitamin C increases absorption of iron in the digestive tract. Drinking  orange juice with a meal is a good way to boost iron absorption.    Drinking tea with a meal reduces absorption of iron because tan-  nic acid in tea binds dietary iron and prevents its absorption.    A deficiency of red blood cells or a reduction in the amount of  hemoglobin they contain results in a condition called anemia. This  reduces the oxygen-carrying capacity of the blood, and the affected  person may appear pale and lack energy. Figure 14.7 shows red  blood cells of someone who has iron-deficiency anemia (fig. 14.7a)  and of someone with sickle cell disease (fig. 14.7b). A pregnant    lron Absorbed from small  intestine; conserved  during red blood cell  destruction and made  available for reuse    FIGURE 14.7 Abnormal red blood cells. (a) Light micrograph of erythrocytes with central pallor or paleness (arrow) as seen in iron-deficiency anemia (1,000).  The purple color is due to the stain used in the preparation. (b) Light micrograph of sickled erythrocytes (arrow) from a person with sickle cell disease (1,000x).    woman may become anemic if she doesn’t eat enough iron-rich  foods, because her blood volume increases due to fluid retention.  This increased blood volume decreases the hematocrit. Table 14.2  describes some types of anemia.    13 Why is iron required for the formation of red blood cells?    Red blood cells are elastic and flexible, and they readily bend as  they pass through small blood vessels. With age, however, these  cells become more fragile, and may be damaged by passing through  capillaries, particularly those in active muscles that must withstand  strong forces.   Damaged or worn red blood cells rupture as they pass through  the spleen or liver. In these organs, macrophages phagocytize and  destroy damaged red blood cells and their contents. Hemoglobin  molecules liberated from the red blood cells break down into their  four component polypeptide “globin” chains, each surrounding a  heme group (fig. 14.8a,b).   The heme further decomposes into iron and a greenish pig-  ment called biliverdin. The iron, combined with a protein called  transferrin, may be carried by the blood to the hematopoietic tis-  sue in the red bone marrow and reused in synthesizing new hemo-  globin. About 80% of the iron is stored in the liver cells in the form  of an iron-protein complex called ferritin. In time, the biliverdin is  converted to an orange pigment called bilirubin. Biliverdin and  bilirubin are secreted in the bile as bile pigments (fig. 14.8c,d and  fig. 14.9).   The polypeptide globin chains break down into amino acids.  The individual amino acids are metabolized by the macrophages  or released into the blood. Table 14.3 summarizes the process of  red blood cell destruction. Figure 14.9 summarizes the life cycle  of a red blood cell.    FIGURE 14.8 Structural formulas. (a) When a hemoglobin  molecule decomposes, (b) the heme groups break down into  (c) iron (Fe) and biliverdin. (d) Most of the biliverdin is then  converted to bilirubin.    1. Squeezing through the capillaries of active tissues damages  red blood cells.    2. Macrophages in the spleen and liver phagocytize damaged  red blood cells.    3. Hemoglobin from the red blood cells is decomposed into  heme and globin.    5. lron is made available for reuse in the synthesis of new  hemoglobin or is stored in the liver as ferritin.    6. Some biliverdin is converted into bilirubin.  7. Biliverdin and bilirubin are secreted in bile as bile pigments.    8. The globin is broken down into amino acids metabolized by  macrophages or released into the plasma.    14 What happens to damaged red blood cells?  15 What are the products of hemoglobin breakdown?    White blood cells, or leukocytes (lu’ko-sitz), protect against dis-  ease. Leukocytes develop from hematopoietic stem cells in the    @ Red blood cells  are produced in  the red bone  marrow.    @ Red blood cells  circulate in the  bloodstream for  about 120 days.    @ Iron is recycled via  the bloodstream;  biliverdin and  bilirubin are  secreted in the bile.    red bone marrow in response to hormones, much as red cells form  from precursors upon stimulation from EPO. These hormones  fall into two groups—interleukins (in”ter-lu-kinz) and colony-  stimulating factors (CSFs). Interleukins are numbered, whereas  most colony-stimulating factors are named for the cell popula-  tion they stimulate. Blood transports white blood cells to sites of  infection. White blood cells may then leave the bloodstream, as  described later in this chapter (p. 538).   Normally, five types of white cells are in circulating blood.  They differ in size, the nature of their cytoplasm, the shape of the  nucleus, and their staining characteristics, and they are named  for these distinctions. Leukocytes with markedly granular cyto-  plasm are called granulocytes (gran’u-lo-sitz”), whereas those  with less obvious cytoplasmic granules are called agranulocytes  (a-gran’u-lo-sitz).   A typical granulocyte is about twice the size of a red blood  cell. Members of this group include neutrophils, eosinophils, and  basophils. Granulocytes develop in red bone marrow, as do red  blood cells. However, they have a short life span, averaging about  twelve hours.   Neutrophils (nu’tro-filz) have fine cytoplasmic granules that  appear light purple with a combination of acid and base stains. The  nucleus of a more mature neutrophil is lobed and consists of two  to five sections (or segments, so these cells are sometimes called  segs) connected by thin strands of chromatin (fig. 14.10). They are  also called polymorphonuclear leukocytes (PMNs) due to the vari-  ation of nucleus shape from cell to cell. Younger neutrophils may  be called bands because their nuclei are curved bands. Neutrophils  are the first white blood cells to arrive at an infection site. These    FIGURE 14.10 (AP|RY A neutrophil has a lobed nucleus with two to  five segments (2,000x).    cells phagocytize bacteria, fungi, and some viruses. Neutrophils  account for 54% to 62% of the leukocytes in a typical blood sam-  ple from an adult.   Eosinophils (e”o-sin’o-filz) contain coarse, uniformly sized  cytoplasmic granules that stain deep red in acid stain (fig. 14.11).  The nucleus usually has two lobes (bilobed). Eosinophils mod-  erate allergic reactions and defend against parasitic worm infes-  tation. These cells make up 1% to 3% of the total number of  circulating leukocytes.   Basophils (ba’so-filz) are similar to eosinophils in size and in  the shape of their nuclei. However, they have fewer, more irregu-  larly shaped cytoplasmic granules than eosinophils, and these  granules appear deep blue in basic stain (fig. 14.12). A basophil’s  granules can obscure a view of the nucleus. Basophils migrate to  damaged tissues where they release histamine, which promotes  inflammation (discussed in the next section, p. 538), and heparin,  which inhibits blood clotting, actions that increase blood flow  to injured tissues. Basophils usually account for less than 1% of  the leukocytes.   The leukocytes of the agranulocyte group include monocytes  and lymphocytes. Monocytes generally arise from red bone mar-  row. Lymphocytes form in the organs of the lymphatic system as  well as in the red bone marrow.   Monocytes (mon’o-sitz), the largest of the white blood cells,  are two to three times greater in diameter than red blood cells. Their  nuclei are spherical, kidney-shaped, oval, or lobed (fig. 14.13).  Monocytes leave the bloodstream and become macrophages that  phagocytize bacteria, dead cells, and other debris in the tissues.  They usually make up 3% to 9% of the leukocytes in a blood sample  and live for several weeks or even months.   Lymphocytes (lim’fo-sitz), the smallest of the white blood  cells, are only slightly larger than erythrocytes. A typical lym-  phocyte has a large, spherical nucleus surrounded by a thin layer  of cytoplasm (fig. 14.14). The major types of lymphocytes are  T cells and B cells, which are both important in immunity. T cells  directly attack microorganisms, tumor cells, and transplanted cells  (see chapter 16, pp. 629-630). B cells produce antibodies (see  chapter 16, p. 630), which are proteins that attack foreign mol-  ecules. Lymphocytes account for 25% to 33% of the circulating  leukocytes. They may live for years.    FIGURE 14.12 (AP|R} A basophil has cytoplasmic granules that  stain deep blue (2,000x).    FIGURE 14.13 [AP|F A monocyte is the largest of the blood cells  (2,000x).    he i) PRACTICE  16 Which hormones are necessary for the differentiation of white  blood cells from hematopoietic stem cells in red bone marrow?  17 Distinguish between granulocytes and agranulocytes.    18 List five types of white blood cells, and explain how they differ  from one another.    19 Describe the function of each type of white blood cell.    Leukocytes can squeeze between the cells that form the walls of  the smallest blood vessels. This movement, called diapedesis  (di”ah-pé-de’sis), allows the white blood cells to leave the circula-  tion (fig. 14.15). A series of proteins called cellular adhesion mol-  ecules help guide leukocytes to the site of injury. Once outside the  blood, leukocytes move through interstitial spaces using a form of  self-propulsion called ameboid motion.    ® RECONNECT  ial To Chapter 3, Cellular Adhesion Molecules, pages 88-89.    The most mobile and active phagocytic leukocytes are neu-  trophils and monocytes. Neutrophils cannot ingest particles much  larger than bacterial cells, but monocytes can engulf larger struc-  tures. Monocytes contain many lysosomes, which are filled with  digestive enzymes that break down organic molecules in captured  bacteria. Neutrophils and monocytes can become so engorged  with digestive products and bacterial toxins that they die.    FIGURE 14.15 Ina type of movement called diapedesis, leukocytes  squeeze between the endothelial cells of a capillary wall and enter the  tissue space outside the blood vessel.    4  (Q) What is a monocyte called once it has left the bloodstream    When microorganisms invade human tissues, basophils  respond by releasing biochemicals that dilate local blood vessels.  For example, histamine dilates smaller blood vessels and makes the  smallest vessels more permeable. As more blood flows through the  smallest vessels, the tissues redden and copious fluids leak into the  interstitial spaces. This response, called an inflammatory reaction  (inflammation), produces swelling that delays the spread of invad-  ing microorganisms into other regions (see chapter 16, p. 626). At  the same time, damaged cells release chemicals that attract leuko-  cytes. This phenomenon is called positive chemotaxis (poz’i-tiv  ke”mo-tak’sis) and, when combined with diapedesis, it quickly  brings many white blood cells into inflamed areas (fig. 14.16).   As bacteria, leukocytes, and damaged cells accumulate in  inflamed tissue, a thick fluid called pus forms and remains while the  invading microorganisms are active. If the pus is not moved to the  outside of the body or into a body cavity, it may remain trapped in  the tissues for some time. Eventually, surrounding cells absorb it.    White blood cells protect against infection in various  ways. Neutrophils and monocytes remove any foreign particles  from the body as part of the innate (nonspecific) defense against  disease. As part of the adaptive (specific) defense, lymphocytes  participate in the formation of specific antibody proteins in the  immune response.   »>  R r] PRACTICE  20 How do white blood cells reach microorganisms outside  blood vessels?  21. Which white blood cells are the most active phagocytes?  22 How do white blood cells fight infection?    The procedure used to count white blood cells is similar to that  used for counting red blood cells. However, before a white blood  cell count (WBCC or WCC) is made, the red blood cells in the  blood sample are destroyed so they will not be mistaken for white  blood cells. Normally, a microliter of blood includes 3,500 to  10,500 white blood cells.   The total number and percentages of different white blood  cell types are of clinical interest. A rise in the number of circu-  lating white blood cells may indicate infection. A total number of  white blood cells exceeding 10,500 per microliter of blood con-  stitutes leukocytosis (lu”ko-si-to’sis), indicating acute infection,  such as appendicitis. Leukocytosis may also follow vigorous exer-  cise, emotional disturbances, or great loss of body fluids.   A total white blood cell count below 3,500 per microliter of  blood is called leukopenia (lu”ko-pe’ne-ah). Such a deficiency may  accompany typhoid fever, influenza, measles, mumps, chickenpox,  AIDS, or poliomyelitis. Leukopenia may also result from anemia or  from lead, arsenic, or mercury poisoning.   A differential white blood cell count lists percentages of the  various types of leukocytes in a blood sample. This test is useful  because the relative proportions of white blood cells may change in  particular diseases. The number of neutrophils, for instance, usually    @ Injured cells release  histamine, causing  blood vessels to dilate  and become leaky    FIGURE 14.16 When bacteria invade the tissues, leukocytes migrate into the region and destroy the microbes by phagocytosis.    increases during bacterial infections, and eosinophils may become  more abundant during certain parasitic infections and allergic reac-  tions. In HIV infection and AIDS, the number of helper T cells, a  type of lymphocyte, drops sharply.   Table 14.4 lists some disorders that alter the numbers of par-  ticular types of white blood cells. Clinical Application 14.2 exam-  ines leukemia, which is cancer of the white blood cells.    »  R y PRACTICE  23 What is the normal human white blood cell count?  24 Distinguish between leukocytosis and leukopenia.  25 What is a differential white blood cell count?    Platelets (plat’letz), or thrombocytes (throm’bo-sitz), are not  complete cells (see fig.14.11). They arise from very large cells  in the red bone marrow called megakaryocytes (meg”ah-kar’o-  sitz). The megakaryocytes develop long cellular extensions that  break off in small sections in the bone marrow. These small  pieces fragment, when they reach the circulation, to form the  platelets. Megakaryocytes, and therefore platelets, develop from  hematopoietic stem cells (see fig. 14.4) in response to the hor-  mone thrombopoietin (throm”bo-poi’é-tin).   Each platelet is surrounded by membrane, but lacks a nucleus  and is less than half the size of a red blood cell. It is capable of ame-  boid movement and may live for about ten days. In normal blood, the  platelet count varies from 150,000 to 350,000 platelets per microliter.    Thrombocytopenia (throm”bo-si”to-pe’ne-ah) occurs when the  platelet count drops below 150,000 platelets per microliter of  blood. Symptoms include bleeding easily; capillary hemor-  rhages throughout the body; and small, bruiselike spots on the  skin called petechiae. Thrombocytopenia is a common side    effect of cancer chemotherapy and radiation treatments and  can be a complication of pregnancy, leukemia, bone marrow  transplantation, infectious disease, cardiac surgery, or anemia.  Conventional treatment is transfusion of platelets. Treatment  with thrombopoietin (TPO) stimulates formation and maturation  of megakaryocytes and thereby boosts platelet levels.    When the twenty-three-year-old had a routine physical examination,  she expected reassurance that her healthy lifestyle had indeed been  keeping her healthy. What she got, a few days later, was a shock.  Instead of having 3,500 to 10,500 white blood cells per microliter of  blood, she had more than ten times that number—and many of the  cells were cancerous. She had chronic myeloid leukemia (CML). Her  red bone marrow was flooding her circulation with too many granu-  locytes, most of them poorly differentiated (fig. 14B).   Another type of leukemia is lymphoid, in which the cancer  cells are lymphocytes, produced in lymph nodes. Both myeloid  and lymphoid leukemia can cause fatigue, headaches, nosebleeds  and other bleeding, frequent respiratory infections, fever, bone  pain, bruising, and other signs of slow blood clotting.   The symptoms arise from the disrupted proportions of the  blood’s formed elements and their malfunction. Immature white  blood cells increase the risk of infection. Leukemic cells crowd out  red blood cells and their precursors in the red marrow, causing  anemia and the resulting fatigue. Platelet deficiency (thrombocy-  topenia) slows clotting time, causing bruises and bleeding.   Leukemia is also classified as acute or chronic. An acute con-  dition appears suddenly, symptoms progress rapidly, and without  treatment, death occurs in a few months. Chronic forms begin    more slowly and may remain undetected for months or even years  or, in rare cases, decades. Without treatment, life expectancy after  symptoms develop is about three years.   Traditional cancer treatments destroy any cell that is actively  dividing. A newer drug, Gleevec, specifically targets cancer cells  by nestling into ATP-binding sites on a version of an enzyme called  tyrosine kinase that is found only on cancer cells. If cancer cells  become resistant to Gleevec, even newer drugs are available that  target the cancer cells in different ways. People with leukemia  have other options. Bone marrow and stem cell transplants may  cure the condition.   Another way that leukemia treatment is improving is refin-  ing diagnosis, based on identifying the proteins that leukemia  cells produce. This information is used to predict which drugs  are most likely to be effective, and which will cause intolerable  side effects, in particular individuals. For example, some people  with acute lymphoblastic leukemia (ALL), diagnosed on the basis  of the appearance of the cancer cells in a blood smear, do not  respond to standard chemotherapy. Their cells produce different  proteins than the cancer cells of patients who do respond. The  nonresponders actually have a different form of leukemia, called  mixed-lineage leukemia. For them, different drugs may work.    FIGURE 14B Leukemia and blood cells. (a) Normal blood cells (700x). (b) Blood cells from a person with granulocytic leukemia, a type of    Platelets help repair damaged blood vessels by sticking to  broken surfaces. They release serotonin, which contracts smooth  muscle in the vessel walls, reducing blood flow. Table 14.5 sum-  marizes the characteristics of blood cells and platelets.    26 What is the normal human blood platelet count?  27 What is the function of blood platelets?    The absolute numbers for red blood cell, white blood cell, and  platelet counts can vary depending on how they are measured    and the instruments used to measure them. For this reason, dif-  ferent sources may present different, but very similar, ranges of  normal values.    Component Description  Red blood cell Biconcave disc without a nucleus, about one-third  (erythrocyte) hemoglobin    Neutrophil Nucleus with two to five lobes; cytoplasmic granules  stain light purple in combined acid and base stains    Monocyte Two to three times larger than a red blood cell;  nucleus shape varies from spherical to lobed  Lymphocyte Only slightly larger than a red blood cell; its nucleus  nearly fills cell  Platelet Cellular fragment  (thrombocyte)    Plasma is the clear, straw-colored, liquid part of the blood in which  the cells and platelets are suspended. It is approximately 92% water  and contains a complex mixture of organic and inorganic biochemi-  cals, including amino acids, nucleic acids, carbohydrates, and a  great variety of lipids. Functions of plasma include carrying nutri-  ents, gases, hormones, and vitamins; helping to regulate fluid and  electrolyte balance; and maintaining a favorable pH.    By weight, plasma proteins are the most abundant dissolved sub-  stances (solutes) in plasma. These proteins remain in the blood  and interstitial fluids and ordinarily are not used as energy sources.  The three main types of plasma proteins are albumins, globulins,  and fibrinogen. The groups differ in composition and function.   Albumins (al-bu’minz) are the smallest of the plasma proteins,  yet account for 60% of these proteins by weight. They are synthe-  sized in the liver, and because they are so plentiful, albumins are an  important determinant of the osmotic pressure of the plasma.   Recall from chapter 3 (p. 101) that the presence of an imper-  meant solute on one side of a selectively permeable membrane  creates an osmotic pressure and that water always moves toward  a greater osmotic pressure. Plasma proteins are too large to pass  through the capillary walls, so they are impermeant, and they cre-  ate an osmotic pressure that holds water in the capillaries despite  blood pressure forcing water out of capillaries by filtration (see  chapter 3, pp. 102-103). The term colloid osmotic pressure is used  to describe this osmotic effect due to the plasma proteins.    4,700,000-6, 100,000  per microliter, male  4,200,000 to 5,400,000  per microliter, female    If the concentration of plasma proteins falls, tissues swell, a  condition called edema. Low plasma protein may result from  starvation or a protein-deficient diet or from an impaired liver  that cannot synthesize plasma proteins. As the concentration  of plasma proteins drops, so does the colloid osmotic pressure,  allowing water to leave the blood vessels and to accumulate in  the interstitial spaces.    Albumins and other plasma proteins help regulate water  movement between the blood and the tissues by maintaining the  colloid osmotic pressure of plasma. In doing so, they help control  blood volume, which, in turn, directly affects blood pressure (see  chapter 15, p. 586). For this reason, it is important that the concen-  tration of plasma proteins remains relatively stable. Albumins also  bind and transport certain molecules, such as bilirubin, free fatty  acids, many hormones, and certain drugs.   Globulins (glob’u-linz), which make up about 36% of the plasma  proteins, can be subdivided into alpha, beta, and gamma globulins.  The liver synthesizes alpha and beta globulins, which have a variety  of functions, including transport of lipids and fat-soluble vitamins.  Lymphatic tissues produce the gamma globulins, which are the  antibodies in the immune response (see chapter 16, p. 632).   Fibrinogen (fi-brin’o-jen), which constitutes about 4% of  the plasma proteins, plays a primary role in blood coagulation.  Synthesized in the liver, it is the largest of the plasma proteins. The  function of fibrinogen is discussed later in this chapter under the sec-  tion “Blood Coagulation” on page 543. Table 14.6 summarizes the  characteristics of the plasma proteins.    29 How do albumins help maintain water balance between the  blood and the tissues?    30 Which of the globulins functions in immunity?  31. What is the role of fibrinogen?    The most important blood gases are oxygen and carbon dioxide.  Plasma also contains a considerable amount of dissolved nitro-  gen, which ordinarily has no physiological function. Chapter 19  (pp. 758-760) discusses blood gases and their transport.    As a rule, blood gases are evaluated using a fresh sample of whole  blood obtained from an artery. This blood is cooled to decrease  the rates of metabolic reactions, and an anticoagulant is added to  prevent clotting. Laboratory tests determine the levels of oxygen  and carbon dioxide, measure blood pH, and calculate the plasma  bicarbonate concentration. Such information is used to diagnose  and treat disorders of circulation, respiration, and electrolyte bal-  ance. Appendix C lists average values for these laboratory tests.    The plasma nutrients include amino acids, simple sugars,  nucleotides, and lipids absorbed from the digestive tract. For exam-  ple, plasma carries glucose from the small intestine to the liver,  where it may be stored as glycogen or converted to fat. If the blood  glucose concentration drops below the normal range, glycogen  may be broken down into glucose, as chapter 13 describes (p. 514).   Like glucose, recently absorbed amino acids are carried to the  liver. Here they may be used to manufacture proteins or deaminated  and used as an energy source (see chapter 18, p. 698).   Plasma lipids include the familiar fats (triglycerides), phos-  pholipids, and cholesterol, but researchers are identifying hundreds  and possibly thousands of additional lipids. Free fatty acids in the    plasma are associated with albumins, and more complex lipids join  with other proteins to form lipoproteins. Abnormal levels of certain  plasma lipids serve as biomarkers of specific metabolic, cardiovas-  cular, or neurological diseases.    Molecules that contain nitrogen atoms but are not proteins com-  prise a group called nonprotein nitrogenous substances (NPNs).  In plasma, this group includes amino acids, urea, uric acid, creatine  (kre’ah-tin), and creatinine (kre-at’i-nin). Amino acids come from  protein digestion and amino acid absorption. Urea and uric acid are  products of protein and nucleic acid catabolism, respectively, and  creatinine results from the metabolism of creatine. Creatine is pres-  ent as creatine phosphate in muscle and brain tissues as well as in  the blood, where it stores energy in phosphate bonds, much like those  of ATP molecules. Chapter 9 (p. 300) discussed creatine phosphate.   Normally, the concentration of nonprotein nitrogenous  substances in plasma remains relatively stable because protein  intake and use are balanced with excretion of nitrogenous wastes.  Because about half of the NPN substances is urea, which the kid-  neys ordinarily excrete, a rise in the blood urea nitrogen (BUN)  may suggest a kidney disorder. Excess protein catabolism or infec-  tion may also elevate BUN.    Plasma contains a variety of electrolytes that are absorbed from the  intestine or released as by-products of cellular metabolism. They  include sodium, potassium, calcium, magnesium, chloride, bicarbon-  ate, phosphate, and sulfate ions. Of these, sodium and chloride ions  are the most abundant. Bicarbonate ions are important in maintain-  ing the osmotic pressure and the pH of plasma, and like other plasma  constituents, they are regulated so that their blood concentrations  remain relatively stable. These electrolytes are discussed in chapter 21  (pp. 809-812) in connection with water and electrolyte balance.    35 Why does kidney disease increase the blood concentration of  these substances?    Hemostasis (he”mo-sta’sis) is the stoppage of bleeding, which is  vitally important when blood vessels are damaged. Following an  injury to the blood vessels, several actions may help to limit or pre-  vent blood loss, including blood vessel spasm, platelet plug forma-  tion, and blood coagulation. These mechanisms are most effective in  minimizing blood losses from small vessels. Injury to a larger vessel  may result in a severe hemorrhage that requires special treatment.    Cutting or breaking a small blood vessel stimulates vascular  spasm, the rapid contraction of smooth muscle in the blood ves-  sel walls. Blood loss lessens almost immediately, and the ends of  the severed vessel may close completely. This effect results from  direct stimulation of the vessel wall as well as from reflexes elic-  ited by pain receptors in the injured tissues.   Although the reflex response may last only a few minutes, the  effect of the direct stimulation usually continues for about thirty  minutes. By then, a blockage called a platelet plug has formed,  and blood is coagulating. Also, platelets release serotonin, which  contracts smooth muscle in the blood vessel walls. This vasocon-  striction further helps to reduce blood loss.    Platelets adhere to exposed ends of injured blood vessels. They  stick to any rough surface, particularly to the collagen in connec-  tive tissue underlying the endothelial lining of blood vessels.   When platelets contact collagen, their shapes change as many  spiny processes begin to extend from their membranes. At the  same time, platelets adhere to each other, forming a platelet plug  in the vascular break. A plug may control blood loss from a small  break, but a larger break may require a blood clot to halt bleeding.  Figure 14.17 shows the steps in platelet plug formation.    Coagulation (ko-ag”u-la’shun), the most effective hemostatic  mechanism, forms a blood clot in a series of reactions, each one acti-  vating the next in a cascade. Coagulation may occur in two ways:  extrinsically or intrinsically. Release of biochemicals from broken  blood vessels or damaged tissues triggers the extrinsic clotting  mechanism (tissue factor pathway). Blood contact with foreign  surfaces in the absence of tissue damage stimulates the intrinsic  clotting mechanism (contact activation pathway). The following  sections describe these responses.   Blood coagulation is complex and uses many biochemicals  called clotting factors. They are designated by Roman numerals  indicating the order of their discovery. Vitamin K is necessary for  some clotting factors to function. Whether the blood coagulates  depends on the balance between factors that promote coagulation  (procoagulants) and others that inhibit it (anticoagulants). Normally,  the anticoagulants prevail, and the blood does not clot. However, as  a result of injury (trauma), biochemicals that favor coagulation may  increase in concentration, and the blood may coagulate.   The major event in blood clot formation is conversion of the  soluble plasma protein fibrinogen (factor I) into insoluble threads of  the protein fibrin (fig. 14.18). Activation of certain plasma proteins  by still other protein factors triggers conversion of fibrinogen to fibrin.  Table 14.7 summarizes the three primary hemostatic mechanisms:  blood vessel spasm, platelet plug formation, and blood coagulation.    @ Platelets adhere  to each other,  to the end of the  broken vessel,  and to exposed  collagen    FIGURE 14.18 A scanning electron micrograph of red blood cells  caught in a meshwork of fibrin threads (2,800x).   The extrinsic clotting mechanism is triggered when blood contacts  damaged blood vessel walls or tissues outside blood vessels. Such  damaged tissues release tissue thromboplastin (factor HI), that is  associated with disrupted cell membranes. Tissue thromboplastin  activates factor VII, which combines with and activates factor X.  Further, factor X combines with and activates factor V. These reac-  tions, which also require calcium ions (factor IV), lead the plate-  lets to produce and release prothrombin activator.    Smooth muscle in vessel  walls contracts reflexly;  vasoconstriction helps  maintain prolonged  vascular spasm    Prothrombin (factor II) is an alpha globulin that the liver  continually produces and is thus a normal constituent of plasma.  In the presence of calcium ions, prothrombin activator converts  prothrombin into thrombin (factor Ila). Thrombin, in turn, cata-  lyzes a reaction that fragments fibrinogen (factor I). The fibrino-  gen fragments join, forming long threads of fibrin. Fibrinogen is a  soluble plasma protein, but fibrin is insoluble. Thrombin also acti-  vates factor XIII, which strengthens and stabilizes fibrin threads  (fig. 14.19).   Once fibrin threads form, they stick to exposed surfaces of  damaged blood vessels, creating a meshwork that entraps blood  cells and platelets. The resulting mass is a blood clot, which may  block a vascular break and prevent further blood loss.   The amount of prothrombin activator in the blood is directly  proportional to the degree of tissue damage. Once a blood clot  begins to form, it promotes additional clotting, because thrombin  also acts directly on prothrombin activator, causing prothrombin  to form still more thrombin. This type of self-initiating action is an  example of a positive feedback mechanism, in which the original  action stimulates more of the same type of action. Such a mecha-  nism produces unstable conditions and can operate for only a short  time in a living system, because life requires the maintenance of a  stable internal environment (see chapter 1, p. 15).   Normally, blood flow throughout the body prevents formation  of a massive clot in the cardiovascular system by rapidly carrying  excess thrombin away and keeping its concentration too low to pro-  mote further clotting. In addition, a substance called antithrombin,  in the blood and on the surfaces of endothelial cells that line blood    In disseminated intravascular coagulation (DIC), clotting is  abnormally activated in several regions of the cardiovascular  system. This condition is usually associated with bacterial infec-  tion or bacterial toxins in the blood or with a disorder causing  widespread tissue damage. Many small clots form and obstruct  blood flow into various tissues and organs, particularly the  kidneys. As plasma clotting factors and platelets are depleted,  severe bleeding occurs.    vessels, limits thrombin formation. Consequently, blood coagula-  tion usually occurs only in blood that is standing still or moving  slowly, and clotting ceases where a clot contacts circulating blood.    Unlike the extrinsic clotting mechanism, the intrinsic clotting mech-  anism can begin without tissue damage. Activation of a substance  called the Hageman factor (factor XII) initiates intrinsic clotting.  This happens when blood is exposed to a foreign surface such as col-  lagen in connective tissue instead of the smooth endothelial lining  of intact blood vessels or when blood is stored in a glass container.  Activated factor XII activates factor XI, which activates factor IX.  Factor IX then joins with factor VIII and platelet phospholipids to  activate factor X. These reactions, which also require calcium ions,  lead to the production of prothrombin activator. The subsequent  steps of blood clot formation are the same as those described for the  extrinsic mechanism (fig. 14.19). Table 14.8 compares extrinsic and  intrinsic clotting mechanisms. Table 14.9 lists the clotting factors,  their sources, and clotting mechanisms.    Laboratory tests commonly used to evaluate blood coagulation  mechanisms include prothrombin time (PT) and partial thrombo-  plastin time (PTT). These tests measure the time it takes for fibrin  threads to form in a sample of blood plasma. The prothrombin  time test checks the extrinsic clotting mechanism, whereas the  partial thromboplastin test evaluates intrinsic clotting.    A newly formed blood clot soon begins to retract as the tiny exten-  sions from the platelet membranes adhere to strands of fibrin  within the clot and contract. The blood clot shrinks, pulling the  edges of the broken vessel closer together and squeezing a fluid  called serum from the clot. Serum is essentially plasma minus all    Series of reactions  involving several  clotting factors and  calcium ions (Ca*?) lead  to the production of:    Prothrombin activator  and calcium ions cause  the conversion of:  Thrombin causes Fibrinogen to fibrin Fibrinogen to fibrin  fragmentation, then    of its fibrinogen and most other clotting factors. Platelets associ-  ated with a blood clot also release platelet-derived growth factor  (PDGF), which stimulates smooth muscle cells and fibroblasts to  repair damaged blood vessel walls.   Fibroblasts (see chapter 5, p. 160) invade blood clots that  form in ruptured vessels, producing fibrous connective tissue  throughout the clots, which helps strengthen and seal vascular  breaks. Many clots, including those that form in tissues as a result  of blood leakage (hematomas), disappear in time. In clot dissolu-  tion, fibrin threads absorb a plasma protein called plasminogen  (profibrinolysin). Then a substance called plasminogen activator  released from the lysosomes of damaged tissue cells converts plas-    minogen to plasmin. Plasmin is a protein-splitting enzyme that can  digest fibrin threads and other proteins associated with blood clots.  Plasmin formation may dissolve a whole clot. However, clots that  fill large blood vessels are seldom removed naturally.   A blood clot abnormally forming in a vessel is a thrombus  (throm’bus). A clot that dislodges, or a fragment of a clot that  breaks loose and is carried away by the blood flow, is called an  embolus (em’bo-lus). Generally, emboli continue to move until  they reach narrow places in vessels where they may lodge and  block blood flow, causing an embolism. Other than a blood clot,  an embolus could be an air bubble, a fat globule, or plaque—any  obstructive object in the bloodstream.    (calcium ions) Plasma electrolyte Extrinsic and intrinsic  (proaccelerin) Synthesized in liver, released by platelets Extrinsic and intrinsic  (serum prothrombin conversion accelerator) Synthesized in liver, requires vitamin K Extrinsic  (antihemophilic factor) Released by platelets and endothelial cells Intrinsic  (plasma thromboplastin component) Synthesized in liver, requires vitamin K Intrinsic  (Stuart-Prower factor) Synthesized in liver, requires vitamin K Extrinsic and intrinsic  (plasma thromboplastin antecedent) Synthesized in liver Intrinsic  (Hageman factor) Synthesized in liver Intrinsic    (fibrin-stabilizing factor) Synthesized in liver, released by platelets Extrinsic and intrinsic    There is no clotting factor VI. The chemical once thought to be factor VI is apparently a combination of activated factors V and X.    A blood clot forming in a vessel that supplies a vital organ, (pulmonary embolism), affects the portion of the organ that the  such as the heart (coronary thrombosis) or the brain (cerebral blocked blood vessel supplies.  thrombosis), blocks blood flow and kills tissues the vessel serves Abnormal clot formations are often associated with condi-  (infarction) and may be fatal. A blood clot that travels and then tions that change the endothelial linings of vessels. For example,  blocks a vessel that supplies a vital organ, such as the lungs in atherosclerosis (ath”er-o”skle-ro’sis), accumulations of fatty   Tissue plasminogen activator (tPA) may restore cerebral circu- Coagulation may also occur in blood flowing too slowly. The  lation blocked by a clot if given within 3 to 4 1/2 hours of a concentration of clot-promoting substances may increase to a  stroke. A drug derived from bacteria, called streptokinase, may critical level instead of being carried away by more rapidly mov-  also be successful. Another plasminogen activator used as a ing blood, and a clot may form. This imbalance is the usual cause  drug is urokinase, an enzyme produced by certain kidney cells. of thrombosis in veins. Clinical Application 14.3 discusses deep  vein thrombosis.    FIGURE 14.20 Artery cross sections. (a) Light micrograph of a normal artery (50x). (b) The inner wall of an artery changed as a result of atherosclerosis (100x).    After a transcontinental flight, a man complained of cramps  behind his knees. He mentioned the unfamiliar sensations to his  traveling companion, who urged him to call his doctor. The nurse  who took the call told the man to seek immediate medical atten-  tion, but because he was already starting to feel better, he didn’t  take her advice. Instead, he continued his trip, reaching his desti-  nation after a short bus ride. Three days later, the man suddenly  collapsed and died from a pulmonary embolism, a complication of  the condition called deep vein thrombosis (DVT). He had several  risk factors for DVT: prolonged periods of immobility on flights;  dehydration; and an inherited clotting disorder that he had not  known about called factor V Leiden. Other risk factors for DVT are  prolonged immobility due to surgery; oral contraceptive use; hor-  mone replacement therapy (estrogen); surgery (of the abdomen,  pelvis, or limbs); and cancer (of the ovaries, pancreas, colon, liver,  or stomach, or lymphoma).   In DVT, stagnant blood pools, leading to clot formation, typi-  cally in the femoral or popliteal veins or in the deep veins of the  pelvis. Symptoms occur in half of all affected individuals. These  include deep muscle pain, redness, swelling, and possibly discol-  oration and dilation of surface veins (phlebitis). Part of the clot  may break off hours or days after it forms and follow the path    FIGURE 14C Exercising the toes and ankles ona  long flight can lower the risk of deep vein thrombosis.    40 Distinguish between extrinsic and intrinsic clotting mechanisms.  41 Which clotting factor is converted to fibrin?    42 What prevents the formation of massive clots throughout the  cardiovascular system?    In a healthy cardiovascular system, the endothelium of the blood  vessels partly prevents spontaneous blood clot formation. This  smooth lining lowers the risk of platelets and clotting factors  accumulating. Endothelial cells also produce a prostaglandin  (see chapter 13, p. 496) called prostacyclin (PGI,), which inhib-  its the adherence of platelets to the inner surface of healthy blood  vessel walls.   Several mechanisms confine clotting to the area where it is  needed. When a clot is forming, fibrin threads latch onto or adsorb  thrombin, thus helping prevent the spread of the clotting reac-    of circulation, lodging in the pulmonary arteries. This is a pulmo-  nary embolism, and it is life threatening. Symptoms include chest  pain, anxiety, racing pulse, sweating, cough with bloody sputum,  and loss of consciousness. In the United States, approximately  2 million people a year develop DVT, and 200,000 die from pul-  monary embolism.   Guidelines from the American College of Chest Physicians  recommend preventive measures against DVT for patients at  higher risk. These actions include taking anticoagulants if immo-  bilization is expected and wearing compression stockings that  help keep blood flowing in the legs. Doing exercises while immo-  bilized during travel is a good idea for everyone, and some air-  lines advise passengers on how to exercise on cramped flights,  such as by curling the toes up and down and moving the ankles  (fig. 14C).    tion. A plasma alpha globulin, antithrombin, inactivates additional  thrombin by binding to it and blocking its action on fibrinogen.  In addition, basophils and mast cells in the connective tissue  surrounding capillaries secrete the anticoagulant heparin. This  substance interferes with formation of prothrombin activator, pre-  vents the action of thrombin on fibrinogen, and promotes removal  of thrombin by antithrombin and fibrin adsorption. Heparin and  another compound, Coumadin (warfarin), are used as drugs to pre-  vent abnormal clotting.   Heparin-secreting cells are particularly abundant in the liver  and lungs, where capillaries trap small blood clots that commonly  form in the slow-moving blood of veins. These cells continually  secrete heparin, preventing additional clotting in the cardiovascu-  lar system. Table 14.10 summarizes clot-inhibiting factors.    45 How does the lining of a blood vessel help prevent blood  clot formation?    Prostacyclin Inhibits adherence of platelets to blood vessel wall Heparin from mast    Early blood transfusion experiments, which date from the late 1600s,  used lamb blood. By the 1800s, human blood was being used with  unpredictable results—some recipients were cured, but some were  killed when their kidneys failed under the strain of handling clumping  red blood cells when blood types were incompatible. So poor was the  success rate that, by the late 1800s, many nations banned transfusions.  Around this time, Austrian physician Karl Landsteiner began  investigating why transfusions sometimes worked and sometimes  did not. In 1900, he determined that blood was of differing types  and that only certain combinations of them were compatible. In  1910, identification of the ABO blood antigen gene explained the  observed blood type incompatibilities. Today, thirty-three differ-  ent genes are known to contribute to the surface features of red  blood cells, which determine compatibility between blood types.    An antigen (an’ti-jen) is any molecule that triggers an immune  response. When the immune system encounters an antigen not found  on the body’s own cells, it will attack that antigen by producing pro-  tein antibodies (an’ti-bod”ez) against that antigen. Antibodies are  carried in the plasma. In a transfusion reaction, antigens (agglu-  tinogens) on the surface of the donated red blood cells react with  antibodies (agglutinins) in the plasma of the recipient, resulting in  agglutination (clumping) of the donated red blood cells.   Only a few of the 33 known antigens on red blood cell mem-  branes can produce serious transfusion reactions. These include  the antigens of the ABO group and those of the Rh group. Avoiding  the mixture of certain types of antigens and antibodies prevents  adverse transfusion reactions. From Science to Technology 14.1  discusses genetic testing to prevent transfusion mismatches.    A mismatched blood transfusion quickly produces telltale signs  of agglutination—anxiety; breathing difficulty; facial flushing;  headache; and severe pain in the neck, chest, and lumbar area.  Red blood cells burst, releasing free hemoglobin. Liver cells  and macrophages phagocytize the hemoglobin, breaking it    down into heme and globin. Some of the heme is recycled. The  rest of the heme is converted to bilirubin, which may sufficiently  accumulate to cause the yellow skin of jaundice. Free hemo-  globin carried in the plasma and reaching the kidneys may  ultimately cause them to fail.    The ABO blood group is based on the presence (or absence) of two  major antigens on red blood cell membranes—antigen A and anti-  gen B. A and B antigens are carbohydrates attached to glycolipids  projecting from the red blood cell surface. The carbohydrate por-  tions of red blood cell antigens are best known for being the basis  of blood types, but the fact that they are not found exclusively on  red blood cells indicates that they have other functions in addition to  marking the surfaces of red blood cells as coming from “self” or not.  In epithelial cells, for example, these same A and B antigens provide  points of cellular adhesion and cell membrane stability and function  as receptors or parts of transport systems across the membrane for  various molecules. A person’s erythrocytes have one of four antigen  combinations: only A, only B, both A and B, or neither A nor B.   An individual with only antigen A has type A blood; a person  with only antigen B has type B blood; one with both antigen A and  antigen B has type AB blood; and one with neither antigen A nor  antigen B has type O blood. The resulting ABO blood type is inher-  ited because a gene specifies an enzyme that catalyzes the final  step in the synthesis of the A or B antigen. Table 14.11 indicates  some of the frequencies of ABO blood types in the diverse popula-  tion of the United States.   Antibodies that affect the ABO blood groups are synthesized  about two to eight months following birth as a result of exposure  to foods or microorganisms containing the antigen(s) absent on the  individual’s red blood cells. The stimulus for their synthesis has not  clearly been established. However, whenever antigen A is absent  on the red blood cells, an antibody called anti-A is produced, and  whenever antigen B is absent, an antibody called anti-B is produced.    Typing and matching blood is essential to minimize the chance  that the immune response of a blood transfusion recipient will  reject the blood. Familiar blood types are A, B, AB, and O. Rh  blood types become important in pregnancy, when woman and  offspring may be incompatible (see figure 14.23). However, human  blood can be classified into at least thirty-three major types based  on protein and carbohydrate molecules (antigens) on the surfaces  of red blood cells. Each type includes many subtypes, generating  hundreds of ways that the topographies of our red blood cells dif-  fer from individual to individual.   For more than a century, an approach called serology has  been used to type blood into major groups by identifying red  blood cell antigens. Different reagents are required to detect dif-  ferent antigens, and so typing by serology beyond a few blood  groups is costly and time consuming. It can miss variants of anti-  gens that are small or hidden among the embedded proteins and  emanating carbohydrate chains of the cell surface. A more infor-  mative way to type blood is to identify the instructions for the cell-  surface antigens—the genes that encode these proteins.   A consortium of European blood banks and universi-  ties, called Bloodgen, has pioneered this more discriminating  approach, called genotyping. A tiny device called a BLOODchip  detects, with one test, 128 distinct DNA “signatures” that rep-  resent all known gene variant combinations that underlie blood    Therefore, persons with type A blood have anti-B antibodies in  their plasma; those with type B blood have anti-A antibodies; those  with type AB blood have neither of these antibodies; and those with  type O blood have both anti-A and anti-B antibodies (fig. 14.21  and table 14.12). The anti-A and anti-B antibodies are too large to  cross the placenta. If a pregnant woman and her fetus are of different  ABO blood types, agglutination in the fetus will not occur.   The major concern in blood transfusion procedures is that the  cells in donated blood do not clump due to antibodies in the recipi-  ent’s plasma. For example, a person with type A blood makes anti-  B antibodies and therefore must not receive blood of type B or AB,  either of which would clump (fig. 14.22). Likewise, a person with  type B blood must not be given type A or AB blood, and a person  with type O blood must not be given type A, B, or AB blood.   . A A anti-B  B B anti-A  AB A and B Neither anti-A nor anti-B  Oo Neither A nor B Both anti-A and anti-B    types traditionally defined by serology (fig. 14D). BLOODchip  is able to accurately type 99.8% of samples; serology can accu-  rately type 97%. Another device, called BeadChip, tests for a  different group of antigens. Other variations on the DNA chip  theme are in development.   Accurate blood matching for many blood groups may be life-  saving for a person who has a chronic disorder that requires mul-  tiple transfusions, such as leukemia  or sickle cell disease. After years of ~S  receiving blood transfusions, these  individuals produce so many anti-  bodies (immune system proteins)  against so many types of donor  blood that serology is insufficient to  identify blood types that they can  tolerate. DNA blood typing may  eventually become routine.    Type AB blood lacks both anti-A and anti-B antibodies, so an  AB person can receive a transfusion of blood of any other type.  For this reason, type AB people are sometimes called universal  recipients. However, type A blood, type B blood, and type O blood  still contain antibodies (either anti-A and/or anti-B) that could  agglutinate type AB cells. Consequently, even for AB individuals,  it is always best to use donor blood of the same type as the recipi-  ent blood. If the matching type is not available and type A, B, or O  is used, it should be transfused slowly and in limited amounts so  that the recipient’s larger blood volume dilutes the donor blood.  This precaution usually avoids serious reactions between the  donor’s antibodies and the recipient’s antigens.   Type O blood does not have antigen A or B. Therefore, theo-  retically this type could be transfused into people with blood of  any other type. Individuals with type O blood are also called uni-  versal donors. Type O blood, however, does contain both anti-A  and anti-B antibodies, and if it is given to a person with blood  type A, B, or AB, it too should be transfused slowly and in lim-  ited amounts to minimize the chance of an adverse reaction. When  type O blood is given to blood types A, B, or AB, it is gener-  ally transfused as “packed cells,” meaning the plasma has been  removed. This minimizes adverse reactions due to the anti-A and  anti-B antibodies in the plasma of type O blood. Table 14.13 sum-  marizes preferred blood types for normal transfusions and permis-  sible blood types for emergency transfusions.    FIGURE 14.22 Agglutination. (a) If red blood cells with antigen A are added to blood containing anti-A antibody, (b) the antigens react with  the antibodies, causing clumping (agglutination). (c) Nonagglutinated blood. (d) Agglutinated blood. (Cells and antibodies in a and b not drawn to scale.)    A person with a rare genetic condition called the Bombay  phenotype lacks an enzyme that inserts a particular molecule  onto red blood cell surfaces. Without that molecule, the A  and B antigens cannot bind. The result is blood that tests as  O (because it lacks A and B antigens) but can genetically be of  any ABO type—A, B, AB, or O. Although the Bombay pheno-  type does not affect health, it can sometimes explain a child's  ABO type that cannot otherwise be predicted genetically from  those of the parents. Taking a cue from the genetic condition,  researchers are using enzymes to cleave the A and B antigens  from red blood cells, creating more type O blood for transfu-  sions in emergency situations.    49 What is the main concern when blood is transfused from one  individual to another?    The Rh blood group was named after the rhesus monkey in which  it was first studied. In humans, this group includes several Rh anti-  gens (factors). The most prevalent of these is antigen D, a trans-  membrane protein. If antigen D or other Rh antigens are present  in red blood cell membranes, the blood is said to be Rh-positive.  Conversely, if red blood cells lack Rh antigens, the blood is  called Rh-negative. About 15% of Caucasians and 5% of African  Americans in the U.S. population are Rh-negative. The remaining  ethnic groups are all Rh-positive. The presence (or absence) of Rh  antigens is an inherited trait.    Anti-Rh antibodies (anti-Rh) form only in Rh-negative indi-  viduals in response to the presence of red blood cells with Rh anti-  gens. This happens, for example, if an Rh-negative person receives  a transfusion of Rh-positive blood. The Rh antigens stimulate the  recipient’s antibody-producing cells to make anti-Rh antibodies.  Generally, no serious consequences result from the first transfu-  sion, but if the Rh-negative person—now sensitized to Rh-positive  blood—receives another transfusion of Rh-positive blood some  months later, the donated red blood cells are likely to agglutinate.   A similar situation of Rh incompatibility arises when an  Rh-negative woman is pregnant with an Rh-positive fetus.  Her first pregnancy with an Rh-positive fetus would probably be  uneventful. However, if at the time of this infant’s birth the pla-  cental membranes that separated the maternal blood from the fetal  blood tear, and some of the infant’s Rh-positive blood cells enter  the maternal circulation, these cells may stimulate the maternal  tissues to produce anti-Rh antibodies (fig. 14.23). This situation  may also arise if the pregnancy ends before the birth or fetal cells  enter the maternal circulation during an invasive prenatal test  such as amniocentesis. If a woman who has already developed  anti-Rh antibodies becomes pregnant with a second Rh-positive  fetus, these anti-Rh antibodies, called hemolysins, can cross the  placental membrane and destroy the fetal red cells. The fetus then  develops a condition called erythroblastosis fetalis (€rith”ro-blas-  to’sis fe’tal-iz), also known as hemolytic disease of the newborn  (fig. 14.23).    Erythroblastosis fetalis is extremely rare today because obste-  tricians carefully track Rh status. An Rh-negative woman who  might carry an Rh-positive fetus receives an injection of a drug  called RhoGAM at week 28 of her pregnancy and after delivery  of an Rh-positive baby. RhoGam is a preparation of anti-Rh anti-  bodies, which bind to and shield any Rh-positive fetal cells that    might enter the woman’s bloodstream and sensitize her immune  system. RhoGAM must be given within 72 hours of possible  contact with Rh-positive cells—including giving birth, terminating  a pregnancy, miscarrying, or undergoing amniocentesis (a pre-  natal test in which a needle is inserted into the uterus).    52 What is the Rh blood group?  53 What are two ways that Rh incompatibility can arise?    Table 14.14 describes a few of the many and diverse inherited  disorders that affect the blood.   Rh incompatibility. If a  man who is Rh-positive  and a woman who is  Rh-negative conceive a  child who is Rh-positive,  the woman's body may  manufacture antibodies  that attack future  Rh-positive offspring.    Chronic granulomatous disease Granulocytes cannot produce superoxide, which kills pathogenic bacteria  Erythrocytosis Reticulocytes have extra EPO receptors, enhancing stamina    Factor V Leiden Increases risk of abnormal clotting; elevates risk of deep vein thrombosis    Hereditary hemochromatosis Excess absorption of dietary iron into bloodstream deposits iron in various organs    Porphyria variegata Enzyme deficiency excretes porphyrin ring of hemoglobin into urine; metabolic blockage causes sequence of  varied symptoms    Sickle cell disease Abnormal hemoglobin crystallizes under low-oxygen conditions, sickling red blood cells, which block circulation  causing anemia, pain, and other symptoms    Von Willebrand disease Lack of clotting factor (von Willebrand factor), which stabilizes factor VIII, causes bleeding; less severe than hemophilia    14.1 Characteristics of Blood (page 528) 2. Characteristics of red blood cells  a. Red blood cells are biconcave discs with shapes that    provide increased surface area and place their cell  membranes close to oxygen-carrying hemoglobin.  . Red blood cells contain hemoglobin, which combines  loosely with oxygen.  c. The mature form lacks nuclei and mitochondria, but  contains enzymes needed for glycolysis.    Blood is a type of connective tissue in which cells are  suspended in a liquid extracellular matrix. Blood volume  varies with body size, fluid and electrolyte balance, and adipose is  tissue content. Blood can be separated into formed elements  (mostly red blood cells) and a liquid, plasma, portion.    3. Red blood cell counts  14.2 Blood Cells pages?) a. The red blood cell count equals the number of cells per  1. The origin of blood cells microliter of blood.  a. Blood cells develop from hematopoietic stem cells, b. The average count may range from approximately  or hemocytoblasts, in red bone marrow. 4,000,000 to 6,000,000 cells per microliter.  b. Blood cells descended from stem cells respond to c. Red blood cell count determines the oxygen-carrying  hematopoietic growth factors to specialize. capacity of the blood and is used in diagnosing and    4. Red blood cell production and its control . Plasma proteins  a. During fetal development, red blood cells form in the a. Plasma proteins remain in the blood and interstitial  yolk sac, liver, and spleen; after birth, red blood cells fluids and are not normally used as energy sources.  are produced by the red bone marrow. b. Three major types exist.  b. Ina person in good health, the number of red blood (1) Albumins help maintain the colloid osmotic pressure.  cells remains relatively stable. (2) Globulins transport lipids and fat-soluble vitamins  c. A negative feedback mechanism involving and include antibodies that provide immunity.  erythropoietin from the kidneys and liver controls rate (3) Fibrinogen functions in blood clotting.  of red blood cell production. . Gases and nutrients  (1) Erythropoietin is released in response to low a. Gases in plasma include oxygen, carbon dioxide, and  oxygen levels. nitrogen.  (2) High altitude, loss of blood, or chronic lung disease b. Plasma nutrients include simple sugars, amino acids,  can lower oxygen concentration in the blood. and lipids.  5. Dietary factors affecting red blood cell production (1) Glucose is stored in the liver as glycogen  a. The availability of vitamin B.,, iron, and folic acid and is released whenever the blood glucose  affects red blood cell production. concentration falls.  b. The rate of iron absorption, needed for hemoglobin (2) Amino acids are used to synthesize proteins and  synthesis, varies with the amount of iron in the body. are deaminated for use as energy sources.  6. Destruction of red blood cells (3) Lipoproteins transport lipids.  a. Red blood cells are fragile and are damaged while . Nonprotein nitrogenous substances  moving through capillaries. a. Nonprotein nitrogenous substances are composed  b. Macrophages in the spleen and liver phagocytize of molecules that contain nitrogen atoms but are not  damaged red blood cells. proteins.  c. Hemoglobin molecules are decomposed, and nearly all b. They include amino acids, urea, uric acid, creatine, and  of the iron from the heme portion is recycled. creatinine.  d. Biliverdin and bilirubin are pigments, released from (1) Urea and uric acid are products of catabolism.  the heme portion, excreted in bile. (2) Creatinine results from the metabolism of creatine.  e. The globin portion is broken down into amino acids c. Levels of these substances usually remain stable; an  metabolized by macrophages or released into the blood. increase may indicate a kidney disorder.  7. Types of white blood cells . Plasma electrolytes  a. Granulocytes include neutrophils, eosinophils, and a. Plasma electrolytes are absorbed from the intestines  basophils. and are released as by-products of cellular metabolism.  b. Agranulocytes include monocytes and lymphocytes. b. They include ions of sodium, potassium, calcium,  8. Functions of white blood cells magnesium, chloride, bicarbonate, phosphate, and sulfate.    c. They are important in maintaining the osmotic pressure  and pH of plasma.    d. Chemicals released by damaged cells attract and Hemostasis is the stoppage of bleeding. Hemostatic mechanisms    stimulate leukocytes. are most effective in controlling blood loss from small vessels.    9. White blood cell counts 1. Vascular spasm (blood vessel spasm)    a. Normal total white blood cell counts vary from 3,500  to 10,500 cells per microliter of blood.   b. The number of white blood cells may change in  abnormal conditions such as infections, emotional  disturbances, or excessive loss of body fluids.   c. Because relative proportions of white blood cells may  change in particular diseases, the differential white  blood cell count, which indicates the percentages of  various types of leukocytes, is a useful test.   b. The normal count varies from 150,000 to 350,000  platelets per microliter.    Plasma is the liquid part of the blood that is composed of water  and a mixture of organic and inorganic substances. It carries  nutrients and gases, helps regulate fluid and electrolyte balance,  and helps maintain stable pH.    a. Smooth muscle in the walls of smaller blood vessels  reflexly contracts following injury.   b. Platelets release serotonin that stimulates  vasoconstriction and helps maintain blood vessel spasm.    a. Platelets adhere to rough surfaces and exposed collagen.  b. Platelets adhere together at the sites of injuries and  form platelet plugs in broken vessels.    a. Blood coagulation or clotting, the most effective  means of hemostasis, is a series of reactions wherein  each reaction stimulates the next (cascade), which may  be initiated by extrinsic or intrinsic mechanisms.   b. The major event of coagulation is the conversion of  soluble fibrinogen into insoluble fibrin.   c. The extrinsic clotting mechanism (tissue factor pathway)  is triggered when blood contacts damaged tissue.   d. The intrinsic clotting mechanism (contact activation  pathway) is triggered when blood contacts a foreign  surface.   e. Clot formation reflects balance between clotting factors  that promote or inhibit clotting.    f. A formed clot retracts and pulls the edges of a broken  blood vessel closer together.   g. A thrombus is an abnormal blood clot in a blood  vessel; an embolus is a clot or fragment of a clot that  moves in a blood vessel.   a. The smooth inner lining of blood vessels discourages  the accumulation of platelets.   b. As aclot forms, fibrin adsorbs thrombin and prevents  the reaction from spreading.    Blood can be typed on the basis of the surface structures of  its cells.    1. Antigens and antibodies  a. An antigen is any molecule that triggers an immune  response.  b. Antibodies are protein molecules produced in an  immune response to an encounter with an antigen that  is not found on the body’s own cells.    Indicate where blood cells differentiate, and explain the  process. (p. 529)  Describe a red blood cell. (p. 529)  Contrast oxyhemoglobin and deoxyhemoglobin. (p. 529)  Explain the significance of red blood cell counts. (p. 531)  Describe the life cycle of a red blood cell from production  through destruction. (pp. 531, 533, and 535)  Define erythropoietin, and explain its function. (p. 533)  Explain how vitamin B,, and folic acid deficiencies affect red  blood cell production. (p. 534)  List two sources of iron that can be used for the synthesis of  hemoglobin. (p. 534)  Distinguish between biliverdin and bilirubin. (p. 535)  Distinguish between granulocytes and agranulocytes. (1.536)  Name five types of leukocytes, and list the major functions of  each type. (pp. 536-537)  Explain the significance of white blood cell counts as aids to  diagnosing disease. (pp. 538-539)  are fragments of megakaryocytes that   a. Blood can be grouped according to the presence or  absence of antigens A and B.   b. Wherever antigen A is absent, anti-A antibody is  present; wherever antigen B is absent, anti-B antibody  is present.   c. Preventing the mixing of red blood cells that have an  antigen with plasma that contains the corresponding  antibody avoids a transfusion reaction.   d. Adverse reactions are due to agglutination (clumping)  of the red blood cells.   a. Rh antigens are present on the red blood cell  membranes of Rh-positive blood; they are absent in  Rh-negative blood.   b. An Rh-negative person exposed to Rh-positive blood  produces anti-Rh antibodies in response.   c. Mixing Rh-positive red cells with plasma that contains  anti-Rh antibodies agglutinates the positive cells.   d. If an Rh-negative female is pregnant with an  Rh-positive fetus, some of the positive cells may enter  the maternal blood at the time of birth and stimulate the  maternal tissues to produce anti-Rh antibodies.   e. Anti-Rh antibodies in maternal blood can cross the  placental membrane and react with the red blood cells  of an Rh-positive fetus.   Name three types of plasma proteins, and indicate the  function of each type. (p. 541)   Define nonprotein nitrogenous substances, and name those  commonly present in plasma. (p. 542)    is the term for stoppage of bleeding. (p. 542)  Explain how vascular spasm is stimulated following an injury.  (pp. 542-543)  Platelets adhering to form a plug may control blood loss  from a break, but a larger break may require  a to halt bleeding. (p. 543)  Name a vitamin required for blood clotting. (p. 543)  Distinguish between fibrinogen and fibrin. (p. 543)  Indicate the trigger and outline the steps for extrinsic  clotting and for intrinsic clotting. (pp. 543-544)  Describe the major steps leading to the formation of a blood  clot. (p. 544)  Describe a positive feedback mechanism that operates  during blood clotting. (p. 544)  Define serum. (p. 544)  Explain how a blood clot may be removed naturally from a  blood vessel. (p. 545)    34 Distinguish between a thrombus and an embolus. (p. 545)  35 Describe how blood coagulation may be prevented. (p. 547)    14.5 Blood Groups and Transfusions  36 Distinguish between an antigen and an antibody. (p. 548)  37 Explain the basis of ABO blood types. (p. 548)  38 Explain why a person with blood type AB is sometimes called  a universal recipient. (p. 549)    39 Explain why a person with blood type O is sometimes called  a universal donor. (p. 549)   41 Describe how a person may become sensitized to Rh-positive  blood. (p. 551)   42 Describe erythroblastosis fetalis, and explain how this  condition may develop. (p. 551)    1. Ifa patient with inoperable cancer is treated using a drug that  reduces the rate of cell division, how might the patient's white  blood cell count change? How might the patient’s environment  be modified to compensate for the effects of these changes?    2. Erythropoietin is available as a drug, as are drugs that mimic  the effects of erythropoietin. Why would athletes abuse these  drugs? Why is it difficult to detect erythropoietin that has been  taken as a drug?    3. Some athletes have been accused of performing “blood doping’  to improve their athletic performance. Why would removing  blood a month or so prior to performance, then reinfusing the  blood shortly before a competition, boost performance?    4. Hypochromic (iron-deficiency) anemia is common among  aging persons admitted to hospitals for other conditions. What  environmental and sociological factors might promote this form  of anemia?    5. How would you explain to a patient with leukemia, who has  a greatly elevated white blood cell count, the importance of  avoiding bacterial infections?    6. Inthe United States between 1977 and 1985, more than 10,000  men contracted the human immunodeficiency virus (HIV) from  contaminated factor VIII that they received to treat hemophilia.  What are two abnormalities in the blood of these men?    7. Why do patients with liver diseases commonly develop blood  clotting disorders?    8. Commercially available antiserum samples containing antibodies  for antigens A, B, and D are used to determine the type of  a particular patient's blood. The antiserum is mixed with the  sample of blood, and if agglutination (clumping) occurs, that  means that the antigen with the same name as the antiserum  is present on those RBCs. Indicate the blood type (both ABO  and Rh) of this individual: What blood type(s) could safely  receive blood from this individual? What blood type(s) could  this individual safely receive? (Note: The control indicates the  absence of aggultination, or clumping.)    Connect Interactive Questions Reinforce your knowledge  using assigned interactive questions covering the components of  blood and their functions, as well as the processes of blood cell  formation and hemostasis.   human body by exploring the histology of the formed elements  in blood, as well as viewing animations that illustrate blood cell    After you have studied this chapter, you should be able to:    Explain the roles of the heart and blood vessels in  circulating the blood. (p. 557)    Describe the location of the heart within the body. (p. 557)    Distinguish between the coverings of the heart and the  layers that compose the wall of the heart. (pp. 557-560)    Identify and locate the major parts of the heart and  discuss the function of each part. (pp. 560-563)    Trace the pathway of the blood through the heart and  the vessels of coronary circulation. (pp. 561-566)    Describe the cardiac cycle and explain how heart sounds  are produced. (pp. 566-568)    Identify the parts of a normal ECG pattern and discuss  the significance of this pattern. (pp. 570-572)    Compare the structures and functions of the major types  of blood vessels. (pp. 577-582)    Describe how substances are exchanged between blood  in the capillaries and the tissue fluid surrounding body  cells. (p. 581)    Describe the mechanisms that aid in returning venous  blood to the heart. (p. 588)  Paths of Circulation    Compare the pulmonary and systemic circuits of the  cardiovascular system. (pp. 590-591)    Identify and locate the major arteries and veins.  (pp. 591-606)  Life-Span Changes    Falsely colored scanning electron micrograph of a cross section through an  artery containing red blood cells (400x). The typical thick wall (pink/brown)  is adapted to withstand the high pressure of blood that the beating heart  pumps throughout the body.    At rest, the heart pumps about 7,000 liters of blood through the  body each day, contracting about 2.5 billion times in an aver-  age lifetime. This muscular pump forces blood through arter-  ies, which connect to smaller-diameter vessels called arterioles.  Arterioles branch into the tiniest tubes, the capillaries, which are  sites of nutrient, electrolyte, gas, and waste exchange. Capil-  laries converge into venules, which in turn converge into veins  that return blood to the heart, completing the closed system of  blood circulation. These structures—the pump and its vessels—  form the cardiovascular system.    The term “cardiovascular” refers to both the heart and the blood  vessels. The pumping action of the heart moves blood through  the body’s blood vessels. The blood vessels form two circuits.  The pulmonary (pul’mo-ner’e) circuit sends oxygen-poor  blood to the lungs to pick up oxygen and unload carbon dioxide.  The systemic (sistem’ ik) circuit sends oxygen-rich blood and  nutrients to all body cells and removes wastes. Without circula-  tion, tissues would lack a supply of oxygen and nutrients, and  wastes would accumulate. Such deprived cells soon begin irre-  versible change, which quickly leads to their death. The heart is  really two pumps in one. The right side of the heart pumps blood  to the pulmonary circuit and the blood returns to the left side of  the heart. At the same time, the left side of the heart pumps blood  through the systemic circuit, and that blood returns to the right  side of the heart (fig.15.1).    The heart is a hollow, cone-shaped, muscular pump. It is in the  mediastinum of the thorax and rests on the diaphragm.    Heart size varies with body size. An average adult’s heart is gener-  ally about 14 centimeters long and 9 centimeters wide (fig. 15.2).   The heart is bordered laterally by the lungs, posteriorly by  the vertebral column, and anteriorly by the sternum (fig. 15.3  and reference plates 10, 16, 21, and 22, pp. 47, 50, and 53). The  base of the heart, which attaches to several large blood vessels,  lies beneath the second rib. The heart’s inferior end extends down-  ward and to the left, terminating as a bluntly pointed apex at the  level of the fifth intercostal space. Because of the heart’s location,  it is possible to detect the apical heartbeat by feeling or listening  to the chest wall between the fifth and sixth ribs, about 7.5 centi-  meters to the left of the midline.    The pericardium (per’i-kar’de-um), or pericardial sac, is a covering  that encloses the heart and the proximal ends of the large blood ves-  sels to which it attaches. The pericardium consists of an outer fibrous  bag, the fibrous pericardium, that surrounds a more delicate, double-  layered serous membrane. The innermost layer of this serous mem-    The fifty-six-year-old man has survived three heart attacks,  and his heart has continued to weaken. He is in heart failure  and is put on a transplant list. When a heart becomes  available, the surgical team assembles quickly. One key  member is the perfusionist.   When the patient’s heart is temporarily stopped so  that the surgeon can remove it and replace it with the  donor heart, the perfusionist sets up and operates the  heart-lung machine that keeps the circulation going, in  some cases for many hours. The perfusionist makes sure  that the rate of blood flow, the patient’s temperature, and  blood composition are within normal range. If the surgeon  orders that the patient receive drugs or blood products, the  perfusionist delivers them through the heart-lung machine.   Training for a career as a perfusionist entails earning  a certificate beyond a four-year degree in a field such as  biology, nursing, or medical technology. The job requires  familiarity with several types of devices and the reasons why  they are used. The perfusionist must learn to use several types  of heart-lung machines as well as extracorporeal membrane  oxygenation (ECMO) machines to assist breathing, perform at  least 125 perfusion procedures, and pass a certification exam  from the American Board of Cardiovascular Perfusion.   The job requires stamina, concentration, attention to  detail, and excellent communication skills. The perfusionist  may also order supplies and equipment and advise support  staff. These medical professionals work at hospitals and  surgical centers. They may go into teaching or work at  companies that manufacture equipment used in procedures  involving the heart and/or lungs.    FIGURE 15.1 (APIFY The  right ventricle forces blood to the  lungs, whereas the left ventricle  forces blood to all other body parts.  (Structures are not drawn to scale.)    Right atrium  Tricuspid valve (cut)  Pulmonary valve  Right ventricle  Inferior vena cava   human heart. This photo  is not life-size, so a  proportionately reduced  ruler has been included  as a size reference to help  the student grasp the  true size of the organ.    brane, the visceral pericardium (epicardium), covers the heart. At the  base of the heart, the visceral pericardium turns back upon itself to  become the parietal pericardium, which covers the inner surface of  the fibrous pericardium (fig. 15.4).   The fibrous pericardium is a tough, protective sac composed of  dense connective tissue. It is attached to the central portion of the  diaphragm, the posterior of the sternum, the vertebral column, and  the large blood vessels emerging from the heart. Between the pari-  etal and visceral serous layers of the pericardium is a space, the peri-  cardial cavity, that contains a small volume of serous fluid that the  pericardial membranes secrete (see fig. 1.10b, p. 19 and reference  plates 16 and 17, pp. 50-51 and fig. 15.4). This fluid reduces friction  between the pericardial membranes as the heart moves within them.    viral or bacterial infection. This painful condition interferes with  heart movements.    is (a) within the mediastinum and  (b) enclosed by a layered pericardium.    1 Where is the heart located?  2 Where would you listen to hear the apical heartbeat?    4 What is the function of the fluid in the pericardial cavity?    The wall of the heart is composed of three distinct layers: an outer epi-  cardium, a middle myocardium, and an inner endocardium (fig. 15.5).   The epicardium (ep”i-kar’de-um), which corresponds to the  visceral pericardium, protects the heart by reducing friction. It is  a serous membrane that consists of connective tissue covered by  epithelium, and it includes capillaries and nerve fibers. The deeper  portion of the epicardium may contain fat, particularly along the  paths of coronary arteries and cardiac veins that provide blood  flow through the myocardium.   The middle layer of the heart wall, or myocardium (mi”o-  kar’de-um), is thick and consists largely of the cardiac muscle tis-  sue that pumps blood out of the heart chambers. The muscle fibers  lie in planes that are separated by connective tissues richly sup-  plied with blood capillaries, lymph capillaries, and nerve fibers.   The inner layer of the heart wall, or endocardium (en’do-  kar’de-um), consists of epithelium and underlying connective  tissue that contains many elastic and collagen fibers. The endo-  cardium also contains blood vessels and covers some special-  ized cardiac cells called Purkinje fibers, described in the section  “Cardiac Conduction System” (p. 569).   The endocardium lines all of the heart chambers and covers  the structures, such as the heart valves, that project into them. This    FIGURE 15.5 The heart wall has three layers: an endocardium, a  myocardium, and an epicardium.    inner lining is also continuous with the inner linings (endothe-  lium) of the blood vessels attached to the heart and throughout the  cardiovascular system. Table 15.1 summarizes the characteristics  of the three layers of the heart wall.    Internally the heart is divided into four hollow chambers, two  on the left and two on the right. The upper chambers, called  atria (a’tre-ah) (sing., atrium), have thin walls and receive blood  returning to the heart. Small, earlike projections called auricles  (aw’ri-klz) extend anteriorly from the atria, slightly increasing  atrial volume (see fig. 15.4). The lower chambers, the ventricles  (ven’tri-klz), force the blood out of the heart into arteries.   A structure called the interatrial septum separates the right  from the left atrium. An interventricular septum separates the two  ventricles. The atrium on each side communicates with its corre-  sponding ventricle through an opening called the atrioventricu-  lar orifice (a”tre-o-ven-trik’u-lar ori-fis), which is guarded by an  atrioventricular valve (AV valve).   Grooves on the surface of the heart mark the divisions between  its chambers, and they also contain major blood vessels that sup-  ply the heart tissues. The deepest of these grooves is the atrioven-  tricular (coronary) sulcus (a”tre-o-ven-trik’u-lar sul’kus), which  encircles the heart between the atria and ventricles. Two interven-  tricular (anterior and posterior) sulci mark the septum that sepa-  rates the right and left ventricles (see fig. 15.4).    The right atrium receives blood from two large veins: the  superior vena cava and the inferior vena cava. These veins return  blood, which is low in oxygen, from tissues. A smaller vein, the  coronary sinus, also drains venous blood into the right atrium  from the myocardium of the heart.   A large tricuspid valve (right atrioventricular valve) guards  the atrioventricular orifice between the right atrium and the right    Endocardium Membrane of epithelium and  underlying connective tissue,  including blood vessels and    ventricle. It is composed of three leaflets, or cusps, as its name  implies. This valve permits the blood to move from the right  atrium into the right ventricle and prevents it from moving in the  opposite direction. The cusps fold passively out of the way against  the ventricular wall when the blood pressure is greater on the atrial  side, and they close passively when the pressure is greater on the  ventricular side (figs. 15.6, 15.7, and 15.8).   Strong, fibrous strings, called chordae tendineae (kor’de  ten’di-ne), attach to the cusps of the tricuspid valve on the ven-  tricular side. These strings originate from small mounds of cardiac  muscle tissue, the papillary muscles (pap’i-ler’e mus’elz), that  project inward from the walls of the ventricle (see fig. 15.7). The  papillary muscles contract when the right ventricle contracts. As  the tricuspid valve closes, these muscles pull on the chordae ten-  dineae and prevent the cusps from swinging back (prolapsing) into  the right atrium.   The right ventricle has a thinner muscular wall than the left  ventricle (see fig. 15.6). This right chamber pumps the blood a fairly  short distance to the lungs against a relatively low resistance to  blood flow. In contrast, the left ventricle must force the blood to all  the other parts of the body against a much greater resistance to flow.   When the muscular wall of the right ventricle contracts, the  blood inside its chamber is put under increasing pressure, and the  tricuspid valve closes passively. As a result, the only exit for the  blood is through the pulmonary trunk, which divides to form the  left and right pulmonary arteries that lead to the lungs. At the base  of this trunk is a pulmonary valve (pulmonary semilunar valve),  which consists of three cusps (fig. 15.8). This valve opens as the  right ventricle contracts. However, when the ventricular muscles  relax, the blood begins to back up in the pulmonary trunk. This  closes the pulmonary valve, preventing backflow into the right  ventricle. Unlike the tricuspid valve, the pulmonary valve does not  have chordae tendineae or papillary muscles attached to its cusps.   The left atrium receives the blood from the lungs through  four pulmonary veins—two from the right lung and two from the  left lung. The blood passes from the left atrium into the left ven-  tricle through the atrioventricular orifice, which a valve guards.  This valve consists of two leaflets and is named the mitral valve  (shaped like a mitre, a type of headpiece) or bicuspid valve or left  atrioventricular valve. It prevents the blood from flowing back into  the left atrium from the left ventricle when the ventricle contracts.  As with the tricuspid valve, the papillary muscles and the chor-  dae tendineae prevent the cusps of the mitral valve from swinging  back (prolapsing) into the left atrium.   When the left ventricle contracts, the mitral valve closes pas-  sively, and the only exit is through a large artery called the aorta. Its  branches distribute blood to all parts of the body.   At the base of the aorta is an aortic valve (aortic semilunar  valve) which consists of three cusps (fig. 15.8). It opens and allows  blood to leave the left ventricle as it contracts. When the ventricular  muscles relax, this valve closes and prevents blood from backing up  into the left ventricle.   The mitral and tricuspid valves are also called atrioventricu-  lar valves because they are between atria and ventricles. The pul-  monary and aortic valves are also called semilunar because of the  half-moon shapes of their cusps. Table 15.2 summarizes the loca-  tions and functions of the heart valves.    valve atrioventricular the right ventricle into the right  orifice atrium during ventricular contraction  Pulmonary Entrance to Prevents blood from moving from  valve pulmonary the pulmonary trunk into the right  trunk ventricle during ventricular relaxation  Mitral Left Prevents blood from moving from  valve atrioventricular the left ventricle into the left atrium  orifice during ventricular contraction  Aortic Entrance to Prevents blood from moving from  valve aorta the aorta into the left ventricle    Mitral valve prolapse (MVP) affects up to 6% of the U.S. popula-  tion. In this condition, one (or both) of the cusps of the mitral  valve stretches and bulges into the left atrium during ventricu-  lar contraction. The valve usually continues to function ade-  quately, but sometimes blood regurgitates (flows back) into the  left atrium. Symptoms of MVP include chest pain, palpitations,  fatigue, and anxiety.   People with MVP are particularly susceptible to infective  endocarditis. This inflammation of the endocardium due to an  infection appears as a plantlike growth on the valve. Some peo-  ple with MVP may be advised by their physicians to take antibi-  otics before undergoing dental work, to prevent Streptococcus  bacteria in the mouth from migrating through the bloodstream  to the heart and spreading this infection.    7 Which blood vessels carry blood into the right atrium?  Where does blood go after it leaves the right ventricle?  Which blood vessels carry blood into the left atrium?    10 What prevents blood from flowing back into the ventricles when  they relax?    Rings of dense connective tissue surround the pulmonary trunk and  aorta at their proximal ends. These rings are continuous with others  that encircle the atrioventricular orifices. They provide firm attach-  ments for the heart valves and for muscle fibers and prevent the out-  lets of the atria and ventricles from dilating during contraction. The  fibrous rings, together with other masses of dense connective tissue  in the part of the septum between the ventricles (interventricular  septum), constitute the skeleton of the heart (fig. 15.8).    Blood low in oxygen (oxygen-poor blood) and high in carbon  dioxide enters the right atrium through the venae cavae and the    FIGURE 15.6 (AP|R) Frontal sections of the heart. (a) Drawings show the connection between the right ventricle and the pulmonary trunk and  (b) the connection between the left ventricle and the aorta, as well as the four hollow chambers. (c) A section through a cadaver heart.    coronary sinus. As the right atrial wall contracts, the blood passes  through the right atrioventricular orifice and enters the chamber of  the right ventricle (see fig. 15.1).   When the right ventricular wall contracts, the tricuspid valve  closes the right atrioventricular orifice, and the blood passes  through the open pulmonary valve into the pulmonary trunk and  its branches (pulmonary arteries). From these vessels, blood  enters the capillaries associated with the alveoli (microscopic air  sacs) of the lungs. Gas exchange occurs between the blood in the  capillaries and the air in the alveoli. The oxygen-rich blood, now  relatively low in carbon dioxide, returns to the heart through the  pulmonary veins that lead to the left atrium.   The left atrial wall contracts, and the blood moves through  the left atrioventricular orifice and into the chamber of the left  ventricle. When the left ventricular wall contracts, the mitral  valve closes the left atrioventricular orifice, and the blood passes  through the open aortic valve into the aorta and its branches.  Figure 15.9 summarizes the path the blood takes as it passes  through the heart to the alveolar capillaries and systemic capillaries,  then back to the heart.    The first two branches of the aorta, called the right and left cor-  onary arteries, supply blood to the tissues of the heart. Their  openings lie just superior to the aortic valve (fig. 15.10).    FIGURE 15.8 Heart valves. (a) Photograph of a transverse section  through the heart, showing the four valves (superior view). (b) The skeleton  of the heart consists of fibrous rings to which the heart valves are attached  (superior view). Note that (b) is in anatomically correct orientation.    The right coronary artery passes along the atrioventricular  sulcus between the right atrium and the right ventricle. It gives off  two major branches—a posterior interventricular artery, which  travels along the posterior interventricular sulcus and supplies the  posterior walls of both ventricles, and a marginal artery, which  passes along the lower border of the heart. Branches of the mar-  ginal artery supply the walls of the right atrium and the right ven-  tricle (figs. 15.11 and 15.12).    Magnetic resonance imaging (MRI) can image coronary arteries.  Blood flow appears as a bright signal, and areas of diminished or  absent blood flow, or blood turbulence, appear as blank areas.  This approach is less invasive than coronary angiography, in which  a catheter is inserted into a blood vessel in the arm, groin, or neck  and threaded through various blood vessels until it enters the  coronary arteries. Dye is then forced through the catheter, and an  X-ray machine takes images (angiograms) showing the condition  of the blood vessels as the dye flows through them.    One branch of the left coronary artery, the circumflex artery,  following the atrioventricular sulcus between the left atrium and  the left ventricle encircles the heart and travels posteriorly. Its  branches supply blood to the walls of the left atrium and the left  ventricle. Another branch of the left coronary artery, the anterior    FIGURE 15.10 The openings of the coronary arteries lie just superior  to the aortic valve.    interventricular artery (or left anterior descending artery), lies in  the anterior interventricular sulcus. Its branches supply the walls  of both ventricles (figs. 15.11 and 15.12).   The heart must beat continually to supply blood to the tissues.  To do this, myocardial cells require a constant supply of oxygen-  rich blood. The myocardium contains many capillaries fed by  branches of the coronary arteries. The smaller branches of these  arteries usually have connections (anastomoses) between vessels  that provide alternate pathways for blood, called collateral circula-  tion. These detours in circulation may supply oxygen and nutrients  to the myocardium when a coronary artery is blocked.   A thrombus or embolus that partially blocks or narrows a cor-  onary artery branch causes a decrease in blood flow called  ischemia. This deprives myocardial cells of oxygen, producing  a painful condition called angina pectoris. The pain usually hap-  pens during physical activity, when oxygen demand exceeds  supply. Pain lessens with rest. Emotional disturbance may also  trigger angina pectoris.   Angina pectoris feels like heavy pressure, tightening, or  squeezing in the chest, usually behind the sternum or in the ante-  rior upper thorax. The pain may radiate to the neck, jaw, throat,  left shoulder, left upper limb, back, or upper abdomen. Profuse  perspiration (diaphoresis), difficulty breathing (dyspnea), nausea,  or vomiting may occur.   A blood clot may completely obstruct a coronary artery (cor-  onary thrombosis), killing tissue in that part of the heart. This is a  myocardial infarction (MI) or heart attack.    veins Left auricle  Left coronary artery  Right auricle Great cardiac vein    FIGURE 15.11 (AP|R) Blood vessels associated with the surface of the heart. (a) Anterior view. (b) Posterior view.    FIGURE 15.12 An angiogram (radiograph) of the coronary arteries is  a diagnostic procedure used to examine specific blood vessels.    In most body parts, blood flow in arteries peaks during ven-  tricular contraction. However, blood flow in the vessels of the  myocardium is poorest during ventricular contraction. This is  because the muscle fibers of the myocardium compress nearby  vessels as they contract, interfering with blood flow. Also, the  openings into the coronary arteries are partially blocked as the  flaps of the aortic valve open. Conversely, during ventricular relax-  ation, the myocardial vessels are no longer compressed, and the    aortic valve does not block the orifices of the coronary arteries.  This increases blood flow into the myocardium.   Branches of the cardiac veins drain blood that has passed  through the capillaries of the myocardium. Their paths roughly  parallel those of the coronary arteries. As figure 15.11b shows,  these veins join the coronary sinus, which is an enlarged vein on  the posterior surface of the heart in the atrioventricular sulcus. The  coronary sinus empties into the right atrium. Figure 15.13 sum-  marizes the path of blood that supplies the tissues of the heart.    11. Which structures make up the skeleton of the heart?  12 Review the path of blood through the heart.    13 How does blood composition differ in the right and left  ventricle?    15 How does blood return from the cardiac tissues to the right atrium?    Contraction of the heart chambers is called systole (sis’to-le),  whereas relaxation of the heart chambers is called diastole  (di-as’to-le). The heart chambers function in coordinated fashion.  Their actions are regulated so that atria contract, called atrial sys-  tole, while ventricles relax, called ventricular diastole; then ventri-  cles contract (ventricular systole) while atria relax (atrial diastole)  (fig. 15.14). Then the atria and ventricles both relax for a brief  interval. This series of events constitutes a complete heartbeat, or  cardiac cycle (kar’de-ak si’kl). From Science to Technology 15.1  describes treatments for a failing heart.    Medical science offers several ways to aid or even replace a failing  heart. In a heart transplant, the recipient's failing heart is removed,  except for the posterior walls of the right and left atria and their  connections to the venae cavae and pulmonary veins. The donor  heart is similarly prepared and is attached to the atrial cuffs remain-  ing in the recipient's thorax. Finally, the recipient's aorta and pulmo-  nary arteries are connected to those of the donor heart (fig. 15A).   Donor hearts are scarce. A mechanical half-heart, called a  left ventricular assist device (LVAD), can in some cases maintain  cardiac function and counter deterioration long enough for a  heart to become available. An LVAD allows a patient to resume  some activities and to exercise, which can increase the chance  of success of an eventual heart transplant. Some patients too ill  to receive transplants are surviving with permanently implanted  LVADs. Developed as a way to keep a patient alive for a short  time until a donor heart became available, the LVAD is now con-  sidered a long-term therapy.   An implantable replacement heart is available for people who  are not candidates for heart transplantation and have less than a  month to live. The two-pound, titanium and plastic cardiac stand-  in consists of an internal motor-driven hydraulic pump, a battery  and electronics package, and an external battery pack. The elec-  tronics component manages the rate and force of the pump’s  actions, tailoring them to the patient's condition. Newer implant-  able replacement hearts are smaller and can provide up to five  years of life.   Stem cell technology may allow researchers to patch failing  hearts with new cardiac muscle. Human cardiac muscle tissue can  be cultured from reprogrammed somatic cells (see From Science  to Technology 3.1, p. 114) or from stem cells. In laboratory dishes,  the tissue contracts, as cardiac muscle would in the body. These  cells are combined with a synthetic, compatible biomaterial elastic  enough to stretch as the cells divide and that will degrade in a con-    During a cardiac cycle, the pressure in the heart chambers  rises and falls. These pressure changes open and close the valves,  much like a door opened and closed by the wind. Pressure in the  ventricles is low early in ventricular diastole, and the pressure  difference between atria and ventricles opens the AV valves. The  ventricles fill. About 70% of the returning blood enters the ven-  tricles prior to contraction, and ventricular pressure gradually  increases. During atrial systole, the remaining 30% of return-  ing blood is pushed into the ventricles, and ventricular pressure  increases. Then, as the ventricles contract, ventricular pressure  rises sharply. As soon as the ventricular pressure exceeds atrial  pressure, the AV valves close. At the same time, the papillary mus-  cles contract. By pulling on the chordae tendineae, they prevent  the cusps of the AV valves from bulging too far into the atria.   During ventricular systole, the AV valves remain closed. The  atria are now relaxed, and pressure in the atria is low, even lower    trolled way. The idea is that “stem cell heart patches” would consist  of scaffolding made of such a biomaterial that would support the  cells as they nestle into a damaged heart. As the cells contract, the  synthetic portion degrades, leaving the pulsating patch. If the cells  originate from the patient, the patch would not be rejected.    FIGURE 15A A heart transplant can save a life. A heart that  might have died with its donor may provide a new lease on life for  a recipient, thanks to our understanding of the cardiovascular and  immune systems—and a well-trained medical team.    than venous pressure. As a result, blood flows into the atria from  the large, attached veins. That is, as the ventricles are contracting,  the atria are filling, already preparing for the next cardiac cycle  (fig. 15.14).   As ventricular systole progresses, ventricular pressure contin-  ues to increase until it exceeds the pressure in the pulmonary trunk  (right side) and aorta (left side). At this point, the pressure differences  across the semilunar valves open the pulmonary and aortic valves,  and blood is ejected from each valve’s ventricle into these arteries.   As blood flows out of the ventricles, ventricular pressure  begins to drop, and it falls even farther as the ventricles relax.  When ventricular pressure is lower than the blood pressure in the  aorta and pulmonary trunk, the semilunar valves close. The ven-  tricles continue to relax, and as soon as ventricular pressure is less  than atrial pressure, the AV valves open, and the ventricles begin  to fill once more. Atria and ventricles relax for a brief interval.    A heartbeat heard through a stethoscope sounds like “lubb-dupp.”  These sounds are due to vibrations in the heart tissues produced as  the blood flow is suddenly slowed with the contraction and relax-  ation of the heart chambers and with the closing of the valves.   The first part of a heart sound (Jubb) occurs during ventricular  systole, when the AV valves are closing. The second part (dupp)  occurs during ventricular diastole, when the pulmonary and aortic  valves are closing.   Heart sounds are of particular interest because they can indi-  cate the condition of the heart valves. For example, inflammation  of the endocardium (endocarditis) may erode the edges of the val-  vular cusps. As a result, the cusps may not close completely, and  some blood may leak back through the valve, producing an abnor-  mal sound called a murmur. The seriousness of a murmur depends  on the degree of valvular damage. Many heart murmurs are  harmless. Open-heart surgery may be needed to repair or replace  severely damaged valves.   Using a stethoscope, it is possible to hear sounds associated  with the aortic and pulmonary valves by listening from the second  intercostal space on either side of the sternum. The aortic sound  comes from the right, and the pulmonic sound from the left. The  sound associated with the mitral valve can be heard from the fifth  intercostal space at the nipple line on the left. The sound of the  tricuspid valve can be heard at the fifth intercostal space just to the  left of the sternum (fig. 15.15).    Recall that cardiac muscle cells function like those of skeletal  muscles, but the cells connect in branching networks (chapter 9,  pp. 308-309). The intercalated discs, which include gap junctions,  join cardiac muscle cells, allowing action potentials to spread  throughout a network of cells that contracts as a unit (chapter 5,  p. 170).   A mass of merging cells that act as a unit is called a functional  syncytium (funk’shun-al sin-sish’e-um). Two such structures  are in the heart—in the atrial walls and in the ventricular walls.  Portions of the heart’s fibrous skeleton separate these masses of    cardiac muscle, except for a small area in the right atrial floor.  In this region, specialized conduction fibers connect the atrial  syncytium and the ventricular syncytium.    16 Describe the pressure changes in the atria and ventricles during  a cardiac cycle.    17 What causes heart sounds?  18 What is a functional syncytium?  19 Where are the functional syncytia of the heart?    The heart is autorhythmic, able to initiate contraction itself with-  out external nervous stimulation. Throughout the heart are clumps  and strands of specialized cardiac muscle tissue whose cells con-  tain only a few myofibrils. Instead of contracting, these areas ini-  tiate and distribute impulses (cardiac impulses) throughout the  myocardium. They comprise the cardiac conduction system,  which coordinates the events of the cardiac cycle.   A key portion of the conduction system is the SA node (sino-  atrial node or sinuatrial node), which is a small, elongated mass  of specialized cardiac muscle tissue just beneath the epicardium. It  is in the right atrium near the opening of the superior vena cava, and  its cells are continuous with those of the atrial syncytium.   The cells of the SA node reach threshold spontaneously.  Recall from chapter 10 (p. 375) that an action potential in a neu-  ron is triggered by a depolarizing input from presynaptic neurons.  In contrast, an SA node reaches threshold and triggers an action  potential on its own. A number of changing conditions appear to  play a role in stimulating the SA node to reach threshold. These  include a progressive increase in permeability to calcium ions and  sodium ions and decreasing permeability to potassium ions.   SA node activity is rhythmic. The SA node initiates one  impulse after another, more than 80 times a minute in an adult  (resting heart rate is usually closer to 70 beats per minute due  to inhibition by the parasympathetic nervous system). The SA  node is also called the pacemaker because it initiates the heart’s    FIGURE 15.14 fAP|R) A cardiac cycle. The atria (a) empty during atrial systole and (b) fill with blood during atrial diastole.    FIGURE 15.15 Thoracic regions where the sounds of each heart valve are most easily heard. Note that where the sound is heard may    rhythmic contractions. From the SA node, bundles of atrial  muscle, called internodal atrial muscle, preferentially conduct  impulses to more distant regions of the atria. Then, because gap  junctions connect cardiac muscle cells, the resulting impulse  spreads into the surrounding atrial myocardium and stimulates  the muscle cells to contract.   The right and left atria contract almost simultaneously. The  cardiac impulse does not pass directly into the ventricular syncy-  tium, which is separated from the atrial syncytium by the fibrous  skeleton of the heart. Instead the cardiac impulse passes along spe-  cialized muscle cells, called junctional fibers, of the cardiac con-  duction system that lead to a mass of specialized cardiac muscle  tissue called the AV node (atrioventricular node). This node is  in the inferior part of the interatrial septum and just beneath the  endocardium. It provides the only normal conduction pathway  between the atrial and ventricular syncytia, because the fibrous  skeleton does not conduct the impulse.   The junctional fibers that conduct the cardiac impulse into  the AV node have small diameters. Small fibers conduct impulses  slowly, and thus they delay conduction of the impulse. Therefore,  the impulse is delayed further as it moves through the AV node.  This allows time for the atria to contract completely so they  empty all their blood into the ventricles prior to ventricular sys-  tole. Once the cardiac impulse reaches the distal side of the AV  node, it passes into a group of large conduction fibers that make  up the AV bundle (atrioventricular bundle or bundle of His), and  the impulse moves rapidly through them. The AV bundle enters the    upper part of the interventricular septum and divides into right and  left bundle branches that lie just beneath the endocardium. About  halfway down the septum, the branches give rise to enlarged  Purkinje fibers (pur-kin’je fi’berz). These larger fibers conduct  the impulse to distant regions of the ventricular myocardium much  faster than cell-to-cell conduction could. As a result, the massive  ventricular myocardium contracts as a functioning unit.    The base of the aorta, which includes the aortic valve, protrudes  somewhat into the interatrial septum close to the AV bundle.  Consequently, inflammatory conditions, such as bacterial endo-  carditis affecting the aortic valve (aortic valvulitis), may also  affect the AV bundle.   If a portion of the bundle is damaged, it may no longer con-  duct impulses normally. As a result, cardiac impulses may reach    the two ventricles at different times so that they fail to contract  together. This condition is called a bundle branch block.    The Purkinje fibers spread from the interventricular septum  into the papillary muscles, which project inward from the ventric-  ular walls, and then continue downward to the apex of the heart.  There they curve around the tips of the ventricles and pass upward  over the lateral walls of these chambers. Along the way, the  Purkinje fibers give off many small branches, which become con-    tinuous with cardiac muscle cells. Figure 15.16 shows the parts of  the conduction system and figure 15.17 summarizes them.   The muscle cells in the ventricular walls form irregular whorls.  When impulses on the Purkinje fibers stimulate these mus-  cle cells, the ventricular walls contract with a twisting motion  (fig. 15.18). This action squeezes blood out of the ventricular  chambers and forces it into the aorta and pulmonary trunk.   Another property of the conduction system is that the Purkinje  fibers conduct the impulse to the apex of the heart first. As a result,  contraction begins at the apex and pushes the blood superiorly  toward the aortic and pulmonary semilunar valves, rather than  originating the impulse superiorly and pushing blood toward the  apex, as it would if the impulse traveled from cell to cell.    he PRACTICE  20 What is the function of the cardiac conduction system?  21 What types of tissues make up the cardiac conduction system?  22 How is a cardiac impulse initiated?    23 Howis a cardiac impulse conducted from the right atrium to the  other heart chambers?    An electrocardiogram (e-lek”tro-kar’de-o-gram”) (ECG, EKG)  is a recording of the electrical changes in the myocardium during  a cardiac cycle. (This pattern occurs as action potentials stim-  ulate cardiac muscle cells to contract, but it is not the same as  individual action potentials.) Because body fluids can conduct  electrical currents, such changes can be detected on the surface  of the body.    To record an ECG, electrodes are placed on the skin and con-  nected by wires to an instrument that responds to small electrical  changes. These changes are recorded on a moving strip of paper.  Up-and-down movements, or deflections from the baseline, cor-  respond to electrical changes in the myocardium. The paper moves  at a known rate, so the distance between deflections indicates time  elapsing between phases of the cardiac cycle.   A normal ECG pattern includes several deflections, or waves,  during each cardiac cycle, as figure 15.19a illustrates. Between  cycles, the muscle cells remain polarized, with no detectable elec-  trical changes. When the SA node triggers a cardiac impulse, the  atrial cells depolarize, producing an electrical change. A deflec-  tion occurs, and at the end of the electrical change the recording  returns to the baseline. This first deflection produces a P wave,    FIGURE 15.18 The muscle cells within the ventricular walls  interconnect to form whorled networks. The networks of groups (a)  and (b) surround both ventricles in these anterior views of the heart.    FIGURE 15.19 ECG pattern. (a) A normal ECG. In this set of drawings (b-h), the yellow areas of the hearts indicate where depolarization is occurring,  and the green areas indicate where tissues are repolarizing; the portion of the ECG pattern produced at each step is shown by the continuation of the line  on the graph paper.    corresponding to a depolarization of the atrial cells that will lead  to contraction of the atria (fig. 15.19b-d).   When the cardiac impulse reaches the ventricular cells, they  rapidly depolarize. The ventricular walls are thicker than those  of the atria, so the electrical change is greater, and the deflection  is greater. When the electrical change ends, the pen returns to the  baseline. This leaves a mark called the QRS complex, which usu-  ally consists of a Q wave, an R wave, and an S wave. The com-  plex appears due to depolarization of the ventricles just prior to the  contraction of the ventricular walls (fig. 15.19e,f).   The electrical changes that accompany ventricular repolariza-  tion slowly produce a T wave as deflection occurs again, ending  the ECG pattern (fig. 15.199,h). The record of the atrial repolariza-  tion seems to be missing from the pattern because the atria repo-  larize at the same time that the ventricles depolarize. The greater  deflection from the baseline of the QRS complex obscures the  recording of the atrial repolarization. The graph in figure 15.20  summarizes some of the changes that occur during a cardiac cycle  with corresponding ECG patterns and heart sounds.   Physicians use ECG patterns to assess the heart’s ability to  conduct impulses. For example, the period between the beginning  of a P wave and the beginning of a QRS complex called the PQ  interval (or if a Q wave is not visible, the PR interval) indicates the  time for the cardiac impulse to travel from the SA node through  the AV node. Ischemia or other problems affecting the fibers of the  AV conduction pathways can prolong this PQ interval. Similarly,  injury to the AV bundle can extend the QRS complex, because it  may take longer for an impulse to spread throughout the ventricu-  lar walls (fig. 15.21).    25. Which cardiac events do the P wave, QRS complex, and T wave  represent?    The volume of blood pumped through the body changes to accom-  modate cellular requirements. For example, during strenuous exer-  cise, skeletal muscles require more blood, and heart rate increases  in response. Because the SA node normally controls heart rate,  changes in this rate often involve factors that affect the pace-  maker, such as the motor impulses carried on the parasympathetic  and sympathetic nerve fibers (see figs. 11.38 p. 434, 11.39 p. 435,  fig. 15.22, and figs.15.35, 15.36).   The parasympathetic fibers that innervate the heart arise from  neurons in the medulla oblongata and make up parts of the vagus  nerves. Most of these fibers branch to the SA and AV nodes. When  the series of action potentials reach nerve fiber endings, they  secrete acetylcholine, which decreases SA and AV nodal activity.  As aresult, heart rate decreases.   The vagus nerves continually conduct impulses to the SA and  AV nodes, “braking” heart action. Consequently, parasympathetic  activity can change heart rate in either direction. An increase in  the impulses slows the heart rate, and a decrease in the impulses  releases the parasympathetic “brake” and increases heart rate.    Sympathetic fibers reach the heart by means of the accelera-  tor nerves, whose branches join the SA and AV nodes as well as  other areas of the atrial and ventricular myocardium. The end-  ings of these fibers secrete norepinephrine in response to series of  action potentials. Norepinephrine increases the rate and force of  myocardial contractions.   Reflexes called baroreceptor reflexes arising from the  cardiac control center of the medulla oblongata maintain  balance between inhibitory effects of the parasympathetic fibers  and excitatory effects of the sympathetic fibers. In this region  of the brain, masses of neurons function as cardioinhibitor and  cardioaccelerator reflex centers. These centers receive sensory  impulses from throughout the cardiovascular system and relay  motor impulses to the heart in response. For example, receptors  sensitive to stretch are located in certain regions of the aorta (aor-  tic arch) and in the carotid arteries (carotid sinuses). These recep-  tors, called baroreceptors (pressoreceptors), can detect changes  in blood pressure (fig. 15.22). Rising pressure stretches the recep-  tors, and they signal the cardioinhibitor center in the medulla.  In response, the medulla sends parasympathetic motor impulses  to the heart via the vagus nerve, decreasing the heart rate. This  action helps lower blood pressure toward normal.   Another regulatory reflex uses stretch receptors in the venae  cavae near the entrances to the right atrium. If venous blood pres-  sure abnormally increases in these vessels, the receptors signal the  cardioaccelerator center, and sympathetic impulses reach the heart.  As a result, heart rate and force of contraction increase, and the  venous pressure is reduced.   Impulses from the cerebrum or hypothalamus also influence  the cardiac control center. These impulses may decrease heart rate,  such as occurs when a person faints following an emotional upset,  or they may increase heart rate during a period of anxiety.   Two other factors that influence heart rate are temperature  change and certain ions. Rising body temperature increases heart  action, which is why heart rate usually increases during fever.  Abnormally low body temperature decreases heart action.   The most important ions that influence heart action are potas-  sium (K*) and calcium (Ca*’). Potassium affects the electrical  potential of the cell membrane, altering its ability to reach the  threshold for conducting an impulse (see chapter 10, p. 375). Some  calcium ions cross the cell membrane of cardiac muscle cells and  bind to the sarcoplasmic reticulum, causing the release of many  calcium ions into the sarcoplasm. These calcium ions bind to tro-  ponin, resulting in cardiac muscle cell contraction much like skel-  etal muscle cell contraction. Although homeostatic mechanisms  normally maintain the concentrations of these ions within narrow  ranges, these mechanisms sometimes fail, and the consequences  can be serious or even fatal. Clinical Application 15.1 examines  abnormal heart rhythms.    >.  I ) PRACTICE  26 Which nerves supply parasympathetic fibers to the heart? Which  nerves supply sympathetic fibers?    27 How do parasympathetic and sympathetic impulses help control  heart rate?    FIGURE 15.20 A graph of some of the changes that occur in  the heart during a cardiac cycle with corresponding ECG pattern  and heart sounds.    caused by an obstructed coronary artery,  tric shock, or traumatic injury to the heart or chest wall.    A premature beat occurs before it is expected in a normal  series of cardiac cycles. Cardiac impulses originating from unusual  (ectopic) regions of the heart probably cause a premature beat.  That is, the impulse originates from a site other than the SA node.  Cardiac impulses may arise from ischemic tissues or from muscle  cells irritated by disease or drugs.   Any interference or block in cardiac impulse conduction may  cause arrhythmia, the type varying with the location and extent of  the block. Such arrhythmias may arise from ectopic pacemakers  (pacemakers outside the SA node).   The SA node usually initiates 70-80 heartbeats per minute,  called a sinus rhythm. If the SA node is damaged, impulses origi-  nating in the AV node may take over and travel upward into the  atrial myocardium and downward into the ventricular walls, stimu-  lating them to contract. Under the influence of the AV node act-  ing as a secondary pacemaker, the heart may continue to pump    blood, but at a rate of 40-60 beats per minute, called a nodal  rhythm. Similarly, the Purkinje fibers can initiate cardiac impulses,  contracting the heart 15-40 times per minute.   An artificial pacemaker can treat a disorder of the cardiac  conduction system. This device includes an electrical pulse gen-  erator and a lead wire that communicates with a portion of the  myocardium. The pulse generator contains a permanent battery  that provides energy and a microprocessor that can sense the car-  diac rhythm and signal the heart to alter its contraction rate.   An artificial pacemaker is surgically implanted beneath the  patient’s skin in the shoulder. A programmer adjusts its func-  tions from the outside. The first pacemakers, made in 1958, were  crude. Today, thanks to telecommunications advances, a physician  can check a patient's pacemaker over the phone. A device called  a pacemaker-cardioverter-defibrillator attempts to correct ventric-  ular fibrillation should it occur.    FIGURE 15E Atrial flutter is an abnormally rapid rate of atrial depolarization.    The blood vessels are organs of the cardiovascular system. They  form a closed circuit of tubes that carries blood from the heart  to the body cells and back again. These vessels include arteries,  arterioles, capillaries, venules, and veins. The arteries and arte-  rioles conduct blood away from the ventricles of the heart and  lead to the capillaries, where substances are exchanged between  blood and the body cells. Venules and veins return blood from  the capillaries to the atria. From Science to Technology 15.2  describes angiogenesis, the formation of new blood vessels in  the body.    Researchers create replacement blood vessels from cells and  their products plus synthetic materials. One such blood vessel  consists of smooth muscle cells seeded onto tubes of a biode-  gradable polymer. The cells secrete collagen and extracellular  matrix, which replace the polymer, and then detergent is applied  to remove the cells. The tubes can be stored for long periods  of time. Another approach uses rubber tubing and a nutrient  solution that prompts the cells to produce extra elastin, which  makes the replacement vessels more flexible. Because construc-  tion of tissues and organs in the laboratory (part of regenerative  medicine) requires a blood supply, tissue engineers are creating  cell-lined tubules using 3D printing to function as part of a semi-  synthetic, ex vivo (“outside the body”) cardiovascular system.    Angiogenesis is the formation of new blood vessels. Under the influ-  ence of vascular endothelial growth factor (VEGF), endothelial cells  divide and assemble into the tubules that form capillaries as well  as the innermost linings of larger blood vessels. In normal devel-  opment, angiogenesis is crucial to build a blood supply to serve a  growing body. New blood vessels deliver nutrients, hormones, and  growth factors to tissues and remove wastes. Angiogenesis is also  essential for healing. After a heart attack, for example, new vessels  form in the remaining healthy cardiac muscle.   As is the case for most biological processes, angiogenesis  must be highly controlled. Drugs that increase or decrease the  activity of VEGF are used to target several common diseases  caused by excess, deficient, or inappropriate angiogenesis. Two  specific applications are healing hearts and removing extra capil-  laries in tumors and in eyes.   A clot blocks a coronary artery. Within seconds, the localized lack  of oxygen stimulates muscle cells to activate hypoxia-inducible  factor (HIF-1). This protein turns on several genes whose prod-  ucts restore homeostasis by stimulating glycolysis (anaerobic  respiration) and by signaling the kidneys to produce erythro-  poietin, which boosts the red blood cell supply and turns on  production of VEGF. Capillaries extend and restore some blood  flow to the blocked cardiac muscle. Fibroblast growth factor  also assists in angiogenesis.   When natural angiogenesis isn’t sufficient, part of the heart  dies. Coronary bypass surgery and angioplasty are treatments that  restore blood flow by circumventing a blockage or opening up an  artery, respectively. However, for patients who cannot undergo    Arteries (ar’-te-réz) are strong, elastic vessels adapted for trans-  porting blood away from the heart under relatively high pressure.  These vessels subdivide into progressively thinner tubes and even-  tually give rise to the finer, branched arterioles (ar-te’re-olz).   The wall of an artery consists of three distinct layers, or  tunics, shown in figure 15.23a. The innermost tunic, tunica interna  (intima), is composed of a layer of simple squamous epithelium,  called endothelium, that rests on a connective tissue membrane  rich in elastic and collagen fibers.   The endothelial lining of an artery provides a smooth surface  that allows blood cells and platelets to flow through without being  damaged. Additionally, endothelium helps prevent blood clotting  by secreting biochemicals that inhibit platelet aggregation (see  chapter 14, p. 547). Endothelium also may help regulate local  blood flow by secreting substances that dilate or constrict blood  vessels. For example, endothelium releases the gas nitric oxide,  which relaxes the smooth muscle of the vessel.   The middle layer, tunica media, makes up the bulk of the arte-  rial wall. It includes smooth muscle cells, which encircle the tube,    these procedures or whose blockages are in vessels too narrow or  difficult to reach, targeting angiogenesis may help to save starved  heart parts. One approach is to package VEGF in time-release  capsules implanted near small vessels while large blood vessels  are being surgically bypassed. Another strategy is gene therapy,  which delivers the genes that encode VEGF to oxygen-starved  areas of the heart.    Preventing Angiogenesis  Once a tumor reaches the size of a pinhead, it secretes VEGF,  which stimulates nearby capillaries to branch and extend toward  it. At the same time, endothelial cells that are part of the tumor  assemble into sheets, roll into tubules, and snake out of the tumor  as new capillaries. Other cancer cells wrap around the capillaries,  spreading out on this scaffolding into nearby tissues. Some can-  cer cells enter blood vessels and travel to other parts of the body.  For a time, maybe even years, these secondary tumors stay small,  adhering to the outsides of the blood vessels that delivered them.  From the observation by many surgeons that when a primary  tumor is removed, secondary tumors grow, Harvard researcher  Judah Folkman hypothesized that the primary tumor secretes anti-  angiogenesis factors that keep the secondary tumors small. Once  factors that promote or block angiogenesis were discovered in  the 1980s, researchers began to study the antiangiogenesis fac-  tors that keep secondary tumors small, to develop them as can-  cer treatments. The first antiangiogenesis drug to treat cancer  became available in 2004, for colorectal cancer that has spread  to other organs. Today antiangiogenesis drugs are also used to  treat age-related macular degeneration, in which extra capillaries  extend into the retina and block central vision.    and a thick layer of elastic connective tissue. The connective tissue  gives the vessel a tough elasticity that enables it to withstand the  force of blood pressure and, at the same time, to stretch and accom-  modate the sudden increase in blood volume that accompanies ven-  tricular contraction.   The outer layer, tunica externa (adventitia), is relatively thin  and chiefly consists of connective tissue with irregular elastic and  collagen fibers. This layer attaches the artery to the surrounding  tissues. It also contains tiny vessels (vasa vasorum) that give rise  to capillaries and provide blood to the more external cells of the  artery wall.   The sympathetic branches of the autonomic nervous system  innervate smooth muscle in artery and arteriole walls. Vasomotor  fibers stimulate the smooth muscle cells to contract, reducing the  diameter of the vessel. This is called vasoconstriction (vas”o-kon-  strik’-shun). If vasomotor impulses are inhibited, the muscle cells  relax, and the diameter of the vessel increases. This is called vaso-  dilation (vas”o-di-la’shun). Changes in the diameters of arteries  and arterioles greatly influence blood flow and blood pressure.   The walls of the larger arterioles have three layers similar to  those of arteries (fig. 15.23c), but the middle and outer layers thin as    FIGURE 15.23 Blood vessels. (a) The wall of an artery. (b) The wall of a vein. (c) Note the structural differences in these cross sections of an  arteriole (bottom) and a venule (top) (200x).    the arterioles approach the capillaries. The wall of a very small arte-  riole consists only of an endothelial lining and some smooth muscle  cells, surrounded by a small amount of connective tissue (fig. 15.24).  Arterioles, which are microscopic continuations of arteries, give off  branches called metarterioles that, in turn, join capillaries.   The arteriole and metarteriole walls are adapted for vasocon-  striction and vasodilation in that their smooth muscle cells respond  to impulses from the autonomic nervous system by contracting or  relaxing. In this way, these vessels help control the flow of blood  into the capillaries.  hag A GLIMPSE AHEAD | To Chapter 22  Local vasodilation, increasing blood flow to the arteries  associated with the genitalia, stiffens erectile tissue in both sexes.    FIGURE 15.24 The smallest arterioles have only a few smooth muscle  fibers in their walls. Capillaries lack these fibers.    In some places metarterioles connect directly to venules, and  blood entering them can bypass the capillaries. These connections  between arteriole and venous pathways, shown in figure 15.25, are  called arteriovenous shunts.   R r] -PRACTICE  29 Describe the wall of an artery.  30 What is the function of the smooth muscle in the arterial wall?  31 How is the structure of an arteriole different from that of an artery?    Capillaries (kap’i-ler’éz), the smallest-diameter blood ves-  sels, connect the smallest arterioles and the smallest venules.  Capillaries are extensions of the inner linings of arterioles in that  their walls are endothelium—a single layer of squamous epithe-  lial cells (fig. 15.26a). These thin walls form the semipermeable  layer through which substances in the blood are exchanged for  substances in the tissue fluid surrounding body cells.    Capillary Permeability  The openings or intercellular passageways in the capillary walls  are thin slits where endothelial cells overlap (fig. 15.26b,c). The  sizes of these openings, and consequently the permeability of the  capillary wall, vary from tissue to tissue. For example, the open-  ings are relatively smaller in the capillaries of smooth, skeletal,  and cardiac muscle than they are in capillaries associated with  endocrine glands, the kidneys, and the lining of the small intestine.  Capillaries with the largest openings include those of the liver,  spleen, and red bone marrow. These capillaries are discontinuous,  and the spaces between the individual cells of their walls appear as    FIGURE 15.25 Some metarterioles provide arteriovenous shunts by connecting arterioles directly to venules.    small cavities (sinusoids) in the organ. Discontinuous capillaries  allow large proteins and even intact cells to pass through as they enter  or leave the circulation. From Science to Technology 5.1 (p. 150)  discusses the blood-brain barrier, which is formed by the protective    FIGURE 15.26 Capillary structure. (a) In capillaries, substances are  exchanged by diffusion between the blood and tissue fluid through openings  (slits) separating endothelial cells. (b) Transmission electron micrograph of a  capillary cross section (11,500x). (c) Micrograph (b) cropped and enlarged to  show the narrow slitlike opening at the junction of the cells (62,500x).    tight capillaries in the brain. The blood-brain barrier is not present in  the pituitary and pineal glands and parts of the hypothalamus.   The higher a tissue’s rate of metabolism, the denser its capillary  networks. Muscle and nerve tissues, which use abundant oxygen  and nutrients, are richly supplied with capillaries. Tissues with  slower metabolic rates have fewer capillaries, such as cartilage, or  lack them entirely, such as in the cornea.    y \  If the capillaries of an adult were unwound and lined up end to  end, they would be between 25,000 and 60,000 miles long.    The spatial patterns of capillaries also differ in various body  parts. For example, some capillaries pass directly from arte-  rioles to venules, but others lead to highly branched networks  (fig. 15.27). Because capillaries are physically organized in diverse  ways, blood can follow different pathways through a tissue, attuned  to cellular requirements.   Blood flow can vary among tissues as well. During exercise,  for example, blood is directed into the capillary networks of the  skeletal muscles, where the cells require more oxygen and nutri-  ents. At the same time, the blood bypasses some of the capillary  networks in the tissues of the digestive tract, where demand for  blood is less critical. Conversely, when a person is relaxing after a  meal, blood can be shunted from the inactive skeletal muscles into  the capillary networks of the digestive organs.    Blood flow through a capillary is mainly regulated by the smooth  muscle that encircles the capillary where it branches off of an  arteriole or a metarteriole. As figures 15.24 and 15.25 show, this    band of smooth muscle forms a precapillary sphincter, which may  close a capillary by contracting or open it by relaxing. A precapil-  lary sphincter responds to the demands of the cells the capillary  supplies. When these cells have low concentrations of oxygen  and nutrients, the precapillary sphincter relaxes, and blood flow  increases; when cellular requirements have been met, the precapil-  lary sphincter may contract again.    32 Describe a capillary wall.  33 What is the function of a capillary?   The vital function of exchanging gases, nutrients, and metabolic by-  products between the blood and the tissue fluid surrounding the cells  takes place in the capillaries. The biochemicals exchanged move  through the capillary walls by diffusion, filtration, and osmosis.    “~ To Chapter 3, Movements Into and Out of the Cell,  pages 98-102.    Diffusion is the most important means of transfer between  the blood and tissue fluid. Because blood entering systemic capil-  laries carries high concentrations of oxygen and nutrients, these  substances diffuse through the capillary walls and enter the tissue  fluid. Conversely, the concentrations of carbon dioxide and other  wastes are generally greater in the tissues, and such wastes tend to  diffuse into the capillary blood.   The paths these substances follow depend primarily on their  solubilities in lipids. Substances that are soluble in lipid, such  as oxygen, carbon dioxide, and fatty acids, can diffuse through  most areas of the cell membranes that make up the capillary wall  because the membranes are largely lipid. Lipid-insoluble sub-  stances, such as water, sodium ions, and chloride ions, diffuse  through channels in the cell membranes and through the slitlike  openings between the endothelial cells that form the capillary wall  (fig. 15.28). Plasma proteins generally remain in the blood because  they are not soluble in the lipid of the endothelial cell membranes,  and they are too large to diffuse through the membrane channels or  openings between endothelial cells of most capillaries.   In filtration, hydrostatic pressure forces molecules through a  membrane. In the capillaries, the blood pressure generated when  ventricle walls contract provides the force for filtration.   Blood pressure also moves blood through the arteries and  arterioles. This pressure decreases as the distance from the heart  increases because of friction (peripheral resistance) between  the blood and the vessel walls. For this reason, blood pressure is  greater in the arteries than in the arterioles and greater in the arte-  rioles than in the capillaries. It is similarly greater at the arteriolar  end of a capillary than at the venular end. The flow is always from  high pressure to low pressure.   The walls of arteries and arterioles are too thick to allow  blood components to pass through. However, the hydrostatic pres-    sure of the blood pushes water and other small molecules through  capillary walls by filtration primarily at the arteriolar ends of cap-  illaries, whereas diffusion takes place along their entire lengths.   The presence of an impermeant solute on one side of a cell  membrane creates an osmotic pressure. Plasma proteins trapped in  the capillaries create an osmotic pressure that draws water into the  capillaries. The term colloid osmotic pressure describes this osmotic  effect due to the plasma proteins, which include the albumins.   The effect of the plasma colloid osmotic pressure, which  favors reabsorption, opposes the action of capillary blood pres-  sure, which favors filtration. Because at the arteriolar end of capil-  laries the blood pressure is higher (35 mm Hg outward) than the  colloid osmotic pressure (24 mm Hg inward), filtration predomi-  nates here. At the venular end, the colloid osmotic pressure is  essentially unchanged (24 mm Hg inward), but the blood pressure  has decreased due to resistance through the capillary (16 mm Hg  outward). Thus, at the venular end, fluid reabsorption predomi-  nates (fig. 15.28). (The interstitial fluid also has hydrostatic pres-  sure and osmotic pressure, but the values are low and cancel each  other; as such, they are omitted from this discussion.)   Normally, more fluid leaves the capillaries than returns to them  because the net inward pressure at the venular ends of the capillar-  ies is less than the net outward pressure at the arteriolar ends of the  capillaries. Closed-ended vessels called lymphatic capillaries collect  the excess fluid and return it through lymphatic vessels to the venous  circulation. Chapter 16 (pp. 617-618) discusses this mechanism.   Unusual events may increase blood flow to capillaries, caus-  ing excess fluid to enter the spaces between tissue cells (intersti-  tial spaces). This may occur in response to certain chemicals, such  as histamine, that vasodilate the metarterioles and increase capil-  lary permeability. Enough fluid may leak out of the capillaries to  overwhelm lymphatic drainage. Affected tissues become swollen  (edematous) and painful.    35 Which forces affect the exchange of substances between blood  and tissue fluid?    36 Why is the fluid movement out of a capillary greater at its  arteriolar end than at its venular end?    37 More fluid leaves the capillary than returns to it, so how is the  remainder returned to the vascular system?    If the right ventricle of the heart is unable to pump blood out as  rapidly as it enters, other parts of the body may develop edema  because the blood backs up into the veins, venules, and capil-  laries, increasing blood pressure in these vessels. As a result of  this increased back pressure, osmotic pressure of the blood in  the venular ends of the capillaries is less effective at balancing  filtration, and the tissues swell. This is true particularly in the  lower extremities if the person is upright, or in the back if the  person is supine. In the terminal stages of heart failure, edema  is widespread, and fluid accumulates in the peritoneal cavity of  the abdomen. This painful condition is called ascites.    Outward force of hydrostatic pressure = 35 mm Hg  Inward force of osmotic pressure = 24 mm Hg  Net outward pressure =11mmHg    Outward force of hydrostatic pressure = 16 mmHg  Inward force of osmotic pressure = 24 mmHg  Net inward pressure = 8 mmHg    FIGURE 15.28 fAP|R) Water and other substances leave capillaries because of a net outward pressure at the capillaries’ arteriolar ends. Water enters at  the capillaries’ venular ends because of a net inward pressure. Substances move in and out along the length of the capillaries according to their respective    (Q) Which substances do not leave the blood at the arteriolar end of the capillary and whose presence at the venular end of the    Venules (ven’iilz) are the microscopic vessels that continue from  the capillaries and merge to form veins (vanz). The veins, which  transport blood back to the atria, follow pathways that roughly  parallel those of the arteries.   The walls of veins are similar to those of arteries in that they  are composed of three distinct layers. However, the tunica media  of the venous wall is less developed compared to that of the arterial  wall. Consequently, veins have thinner walls that have less smooth  muscle and less elastic connective tissue than those of comparable  arteries, but their lumens have a greater diameter (see fig. 15.23).   Many veins, particularly those in the upper and lower limbs,  have flaplike valves (called semilunar valves), which project  inward from their linings. Valves, shown in figure 15.29, are usu-  ally composed of two leaflets that close if blood begins to back up    FIGURE 15.29 Venous valves. (a) allow blood to move toward the  heart, but (b) prevent blood from moving backward away from the heart.    in a vein. These valves aid in returning blood to the heart because  they are open as long as the blood flow is toward the heart but pre-  vent flow in the opposite direction.   Veins also function as blood reservoirs, which are useful in  times of blood loss. For example, in hemorrhage accompanied by  a drop in arterial blood pressure, sympathetic impulses reflexly  stimulate the muscular walls of the veins to constrict, which helps  maintain blood pressure by returning more blood to be pumped  by the heart. This mechanism helps ensure a nearly normal blood  pressure even when as much as 25% of blood volume is lost.  Figure 15.30 illustrates the relative volumes of blood in the veins  and other blood vessels.   Table 15.3 summarizes the characteristics of blood vessels.  Clinical Application 15.2 examines disorders of blood vessels.    38 How does the structure of a vein differ from that of an artery?  39 What are the functions of veins and venules?    40 How does venous circulation help to maintain blood pressure  when hemorrhaging causes blood loss?    Blood pressure is the force the blood exerts against the inner walls  of the blood vessels and that circulates the blood. Although this  force is present throughout the vascular system, the term blood  pressure most commonly refers to pressure in arteries supplied  by branches of the aorta (systemic arteries). Pressure differences  throughout the vascular system keep the blood moving from  higher pressure to lower pressure.    Systemic Lungs Heart Systemic Capillaries  veins 10-12% 8-11% arteries 4-5%  60-70% 10-12%    Vessel Type of Wall Function  Artery Thick, strong wall with three Carries blood under  layers—an endothelial lining, a relatively high  middle layer of smooth muscle pressure from the  and elastic connective tissue, heart to arterioles  and an outer layer of connective  tissue  Arteriole — Thinner wall than an artery Connects an artery  but with three layers; smaller to a capillary, helps  arterioles have an endothelial control the blood  lining, some smooth muscle flow into a capillary  tissue, and a small amount of by vasoconstricting  connective tissue or vasodilating  Capillary Single layer of squamous Allows nutrients,  epithelium gases, and wastes  to be exchanged  between the blood  and tissue fluid;  connects an arteriole  to a venule  Venule Thinner wall than an arteriole, Connects a capillary  less smooth muscle and elastic to a vein  connective tissue  Vein Thinner wall than an artery but Carries blood under  with similar layers; the middle relatively low pressure  layer is more poorly developed; —_ from a venule to the  some have flaplike valves heart; valves prevent  a backflow of blood;  serves as a blood  reservoir    Arterial blood pressure rises and falls in a pattern corresponding to  the phases of the cardiac cycle. That is, when the ventricles contract  (ventricular systole), their walls squeeze the blood inside their cham-  bers and force it into the pulmonary trunk and aorta. As a result, the  pressures in these arteries sharply increase. The maximum pressure    achieved during ventricular contraction is called the systolic pres-  sure. When the ventricles relax (ventricular diastole), the arterial pres-  sure drops, and the lowest pressure that remains in the arteries before  the next ventricular contraction is termed the diastolic pressure.   Systemic arterial blood pressure usually is measured using an  instrument called a sphygmomanometer (sfig”mo-mah-nomré-ter)  (fig. 15.31). This device consists of an inflatable cuff connected by  tubing to a compressible bulb and a pressure gauge. The bulb is used  to pump air into the cuff, and a rise in pressure is indicated on the  pressure gauge. The pressure in the cuff is expressed in millimeters  of mercury (mm Hg) based on older equipment that used a glass  tube containing a column of mercury in place of a pressure gauge.   To measure arterial blood pressure, the cuff of the sphygmo-  manometer is wrapped around the arm so that it surrounds the  brachial artery. Air is pumped into the cuff until the cuff pressure  exceeds the pressure in that artery, squeezing the vessel closed  and stopping its blood flow. At this moment, if the diaphragm of  a stethoscope is placed over the brachial artery at the distal bor-  der of the cuff, no sounds can be heard from the vessel because  the blood flow is interrupted. As air is slowly released from the  cuff, the air pressure inside it decreases. When the cuff pressure  is just slightly lower than the systolic blood pressure in the bra-  chial artery, the artery opens enough for a small volume of blood to  spurt through, producing a sharp sound (Korotkoff’s sound) heard  through the stethoscope. Turbulence in the narrowed artery causes  the sound. The pressure indicated on the pressure gauge when this  first tapping sound is heard represents a good estimate of the arte-  rial systolic pressure (SP).   As the cuff pressure continues to drop, increasingly louder  sounds are heard. Then, when the cuff pressure is just slightly  lower than that within the fully opened artery, the sounds become  abruptly muffled and disappear. The pressure indicated on the  pressure gauge when this happens represents a good estimate of  the arterial diastolic pressure (DP).   The results of a blood pressure measurement are reported as  a fraction, such as 127/74 (with normal being less than 120/less    FIGURE 15.31 A sphygmomanometer is used to measure arterial  blood pressure. The use of the column of mercury is the most accurate  measurement, but due to environmental concerns, it has been replaced  by alternative gauges and digital readouts.    In the arterial disease atherosclerosis (ath”er-o-sklé-ro’sis), depos-  its of fatty materials, particularly cholesterol, form within and on  the inner lining of the arterial walls. Such deposits, called plaque,  protrude into the lumens of the vessels and interfere with blood  flow (fig. 15F). Furthermore, plaque often forms a surface texture  that can initiate formation of a blood clot, increasing the risk of  developing thrombi or emboli that cause decreased blood flow  (ischemia), causing tissue death (necrosis) downstream from the  obstruction. In addition, the walls of diseased arteries may degen-  erate, losing their elasticity and becoming hardened or sclerotic. In  this stage of the disease, a sclerotic vessel may rupture under the  force of blood pressure.   Risk factors for developing atherosclerosis include a fatty  diet, elevated blood pressure, tobacco smoking, obesity, and lack  of physical exercise (see chapter 18, pp. 702-703). Genetic fac-  tors may increase the risk of developing atherosclerosis.   If blood pressure dilates a weakened area of an artery wall, a  bulge called an aneurysm may form and enlarge. If the lining of  the vessel tears and allows blood to enter the middle layer of the  arterial wall, it is called a dissecting aneurysm. An aneurysm may  cause symptoms by pressing on nearby organs, or it may rupture  and cause great blood loss, which is life-threatening.   Aneurysms may also result from trauma, high blood pressure,  certain infections, inherited disorders such as Marfan syndrome,  or congenital defects in blood vessels. Common sites of aneu-  rysms include the thoracic and abdominal aorta and an arterial  circle at the base of the brain (circle of Willis).   Phlebitis, or inflammation of a vein, is relatively common. It  may occur in association with an injury or infection or after sur-  gery, or it may develop for no apparent reason. If inflammation is  restricted to a superficial vein, such as the greater or lesser saphe-  nous veins, blood flow may be rechanneled through other vessels.  But if it occurs in a deep vein, such as the tibial, peroneal, popli-  teal, or femoral veins, the consequences can be serious, particu-  larly if the blood in the affected vessel clots and blocks normal  circulation (see Clinical Application 14.3, p. 547). This condition,  called thrombophlebitis, introduces a risk that a blood clot in a  vein will detach, move with the venous blood, pass through the  heart, and lodge in the pulmonary arterial system in a lung (pul-  monary embolism).   Varicose veins are abnormal and irregular dilations in super-  ficial veins, particularly in the legs. This condition is usually asso-  ciated with prolonged, increased back pressure in the affected  vessels due to gravity, such as when a person stands. Crossing the  legs or sitting in a chair so that its edge presses against the area  behind the knee can obstruct venous blood flow and aggravate  varicose veins.   Increased venous back pressure stretches and widens the  veins. The valves in these vessels lose their ability to block the  backflow of blood, and blood accumulates in the veins upstream  from the valves. The resulting increased venous pressure is  accompanied by rising pressure in the venules and capillaries that  supply the veins. Consequently, tissues in affected regions typi-  cally become edematous and painful.    Genetics, pregnancy, obesity, and standing for long periods  raise the risk of developing varicose veins. Elevating the legs  above the level of the heart or putting on support hosiery before  arising in the morning can relieve discomfort. Intravenous injec-  tion of a substance that destroys veins (a sclerosing agent) or sur-  gical removal of the affected veins may be necessary.    FIGURE 15F Development of atherosclerosis. (a) Normal arteriole  (100x). (b, c) Accumulation of plaque on the inner wall of the arteriole  (b and c 100x).    than 80). The upper number indicates the systolic pressure in  mm Hg, and the lower number indicates the diastolic pressure  in mm Hg. Figure 15.32 shows how these pressures decrease as  distance from the left ventricle increases.   The surge of blood entering the arterial system during ven-  tricular systole distends the elastic arterial walls, but the pressure  begins to drop almost immediately as the contraction ends, and  the arterial walls recoil. This alternate expanding and recoiling of the  arterial wall can be felt as a pulse in an artery that runs close to the  body surface. Figure 15.33 shows several sites where a pulse can be  detected. The radial artery, for example, courses near the surface at  the wrist and is commonly used to sense a person’s radial pulse.   The radial pulse rate is equal to the rate at which the left ven-  tricle contracts, and for this reason, it can be used to determine heart  rate. A pulse can also reflect blood pressure, because an elevated  pressure produces a pulse that feels strong and full, whereas a low  pressure produces a pulse that is weak and easily compressed.   The difference between the systolic and diastolic pressures  (SP— DP), called the pulse pressure (PP), is normally about 40 mm Hg  and is what one feels when taking a pulse. The average pressure in  the arterial system is also of interest because it represents the aver-  age force throughout the cardiac cycle driving blood to the tissues.  To approximate this force, called the mean arterial pressure, add the  diastolic pressure to one-third of the pulse pressure (DP + 1/3PP).    FIGURE 15.32 Blood pressure decreases as the distance from the left  ventricle increases. Systolic pressure occurs during maximal ventricular  contraction. Diastolic pressure occurs when the ventricles relax.    Arterial pressure depends on a variety of factors. These include  cardiac output, blood volume, peripheral resistance, and blood vis-  cosity (fig. 15.34).    Each ventricular contraction determines the volume of blood that  enters the arterial system, which is called the stroke volume. In  an average-weight male at rest, the stroke volume equals about  70 milliliters. The volume discharged from the ventricle per  minute is called the cardiac output. It is calculated by multiply-  ing the stroke volume by the heart rate, expressed in beats per  minute. [Cardiac output (CO) = stroke volume (SV) x heart rate  (HR).] For example, if the stroke volume is 70 milliliters per beat  and the heart rate is 72 beats per minute, the cardiac output is  5,040 milliliters per minute.    FIGURE 15.34 Some of the factors that influence arterial blood pressure.    Blood pressure varies with the cardiac output. If either the  stroke volume or the heart rate increases, so does the cardiac out-  put, and, blood pressure would increase. Conversely, if the stroke  volume or the heart rate decreases, the cardiac output decreases,  and blood pressure would also decrease.    Blood volume equals the sum of the formed elements and plasma  volumes in the vascular system. Although the blood volume varies  somewhat with age, body size, and sex, it is usually about 5 liters  for adults or 8% of body weight in kilograms (1 kilogram of water  equals | liter).   Normally blood pressure is directly proportional to the volume  of the blood in the cardiovascular system. Thus, any changes in the  blood volume can initially alter the blood pressure. For example, if  a hemorrhage reduces blood volume, blood pressure at first drops. If  a transfusion restores normal blood volume, normal pressure may be  reestablished. Blood volume can also fall if the fluid balance is upset,  as happens in dehydration. Fluid replacement can reestablish normal  blood volume and pressure.    The heart secretes the hormones atrial natriuretic peptide  (ANP) when blood volume increases and ventricular natriuretic  peptide (BNP) when blood pressure increases. Both hormones  inhibit the renin-angiotensin system. The result is increased  excretion of sodium ions and water from the kidneys and low-  ered blood volume and blood pressure. Researchers are inves-  tigating drugs that increase these peptides to treat the excess  volume associated with congestive heart failure.    Peripheral Resistance  Friction between the blood and the walls of the blood ves-  sels produces a force called peripheral resistance (pé-rif’er-al  re-zis tans), which impedes blood flow. Blood pressure must over-  come peripheral resistance if the blood is to continue flowing.  Factors that alter the peripheral resistance change blood pressure.  For example, when smooth muscle in arteriolar walls contracts,  this increases the peripheral resistance by constricting these ves-  sels (decreasing the lumen diameter). Blood backs up into the  arteries supplying the arterioles, and the arterial pressure rises.  Dilation of the arterioles (increasing the lumen diameter) has the  opposite effect—peripheral resistance decreases, and the arterial  blood pressure drops in response.   Arterial walls are elastic, so when the ventricles discharge  a surge of blood, arteries swell. Almost immediately, the elastic  tissues recoil, and the vessel walls press against the blood inside.  This action helps force the blood onward against the peripheral  resistance in arterioles and capillaries. Recoiling of the arteries  maintains blood pressure during diastole. If there were no elas-  ticity in the arterial walls, blood pressure would fall dramatically  between ventricular contractions. Elastic recoil also converts the  intermittent flow of blood, a result of the cardiac cycle, into a more  continuous movement through the blood vessels.   Viscosity (vis-kos’i-te) is the difficulty with which the molecules  of a fluid flow past one another. The greater the viscosity, the  greater the resistance to flow.   Blood cells and plasma proteins increase blood viscosity. The  greater the blood’s resistance to flowing, the greater the force needed  to move it through the vascular system, so blood pressure rises as  blood viscosity increases and drops as blood viscosity decreases.   The viscosity of blood normally remains stable. However, any  condition that alters the concentrations of blood cells or plasma  proteins may alter blood viscosity. For example, anemia may  decrease viscosity and consequently lower blood pressure. Excess  red blood cells increase viscosity and blood pressure.    44 How is cardiac output calculated?  45 How are cardiac output and blood pressure related?  46 How does blood volume affect blood pressure?    47 What is the relationship between peripheral resistance and  blood pressure? between blood viscosity and blood pressure?    Blood pressure (BP) is determined by cardiac output (CO)  and peripheral resistance (PR) according to this relationship:  BP = CO x PR. Maintenance of normal blood pressure there-  fore requires regulation of these two factors (fig. 15.35).   Cardiac output depends on the stroke volume and heart rate.  Stroke volume, the amount of blood pumped in a single beat, is  reflected by the difference between end-diastolic volume (EDV),  the volume of blood in each ventricle at the end of ventricular dias-  tole, and end-systolic volume (ESV), the volume of blood in each  ventricle at the end of ventricular systole. Mechanical, neural, and  chemical factors affect stroke volume and heart rate.   Cardiac output is limited by the amount of blood return-  ing to the ventricles, called the venous return. Usually, however,  stroke volume can be increased by sympathetic stimulation, which  increases the force of ventricular contraction. Because only about  60% of the end-diastolic volume is pumped out in a normal con-  traction, increasing the force of ventricular contraction may  increase that fraction and help maintain stroke volume if venous  return should decrease.    “<~ To Chapter 9, Recording of a Muscle Contraction,  page 304 and fig. 9.15 on page 305.    Another mechanism increases stroke volume independently  of sympathetic stimulation. As blood enters the ventricles, myo-  cardial cells in the ventricular walls are mechanically stretched.  This constitutes the preload. The greater the EDV, the greater the  preload. Within limits, the longer these fibers, the greater the force  with which they contract. This relationship between cell length  (due to stretching of the cardiac muscle cell just before contraction)  and force of contraction is called the Frank-Starling law of the  heart, or Starling’s law of the heart. The law becomes important,    for example, during exercise, when venous blood returns more  rapidly to the heart. The more blood that enters the heart from the  veins, the greater the ventricular distension, the stronger the contrac-  tion, the greater the stroke volume, and the greater the cardiac output.   Conversely, the less blood that returns from the veins, the less  the ventricle distends, the weaker the ventricular contraction, and    FIGURE 15.35 Controlling cardiac output and peripheral resistance  regulates blood pressure. Normal values for blood pressure increase with age.    the lesser the stroke volume and cardiac output. This mechanism  helps to ensure that the volume of blood discharged from the heart  is equal to the volume entering its chambers.   Some blood remains in the ventricles after contraction and  stroke volume ejection. This ESV is influenced by preload, contrac-  tility of the ventricle, and afterload. Contractility, the strength of a  contraction at a given preload (EDV), is influenced by autonomic  innervation and hormones (epinephrine, norepinephrine, thyroid  hormones). Sympathetic stimulation contracts the ventricles more  forcefully, increasing the volume ejected and decreasing the ESV.  Decreased sympathetic stimulation produces the opposite effect.  The force that the ventricles must produce to open the semilunar  valves to eject blood is the afterload. Increased arterial pressure  (hypertension), especially the diastolic pressure, increases after-  load and the heart must work harder to eject blood.   Cardiac output and peripheral resistance are controlled in  part by baroreceptor reflexes. Recall from chapter 12 (p. 444) that  baroreceptors in the walls of the aortic arch and carotid sinuses  sense changes in blood pressure. If arterial pressure increases,  impulses travel from the receptors to the cardiac center of the  medulla oblongata. This center relays parasympathetic impulses to  the SA node in the heart, and heart rate decreases in response. As a  result of this cardioinhibitor reflex, cardiac output falls and blood  pressure decreases toward the normal level. Figure 15.36 summa-  rizes this mechanism.   Conversely, decreasing arterial blood pressure initiates the  cardioaccelerator reflex, which sends sympathetic impulses to the  SA node. As a result of these cardiostimulatory effects, the heart  beats faster, increasing cardiac output and arterial pressure.   Recall that epinephrine increases heart rate (chapter 13,  p. 510) and consequently alters cardiac output and blood pressure.    FIGURE 15.36 If blood pressure rises, baroreceptors initiate the  cardioinhibitor reflex, which lowers the blood pressure.    Other factors that increase heart rate and blood pressure include  emotional responses, such as fear and anger; physical exercise;  and a rise in body temperature.   Changes in arteriole diameters regulate peripheral resistance.  Because blood vessels with smaller diameters offer a greater resis-  tance to blood flow, factors that vasoconstrict arterioles increase  peripheral resistance, raising blood pressure; factors that vasodilate  arterioles decrease peripheral resistance, lowering blood pressure  (see fig. 15.35).   The vasomotor center of the medulla oblongata continually  sends sympathetic impulses to the smooth muscle in the arteriole  walls, keeping them in a state of tonic contraction, which helps  maintain the peripheral resistance associated with normal blood  pressure. The vasomotor center responds to changes in blood pres-  sure, so it can increase peripheral resistance by increasing its out-  flow of sympathetic impulses, or it can decrease such resistance by  decreasing its sympathetic outflow. In the latter case, the vessels  vasodilate as sympathetic stimulation decreases.   Whenever arterial blood pressure suddenly increases, baro-  receptors in the aortic arch and carotid sinuses signal the vaso-  motor center, and the sympathetic outflow to the arteriole walls  falls (fig. 15.37). The resulting vasodilation decreases peripheral  resistance, and blood pressure decreases toward the normal level.  Similarly, if blood pressure drops, as it would following a hem-  orrhage, the vasomotor center increases sympathetic outflow. The  resulting release of epinephrine and norepinephrine vasoconstricts  most systemic vessels, increasing peripheral resistance. This helps  return blood pressure toward normal.   The vasomotor center’s control of vasoconstriction and vasodi-  lation is especially important in the arterioles of the abdominal vis-  cera (splanchnic region). These vessels, if fully dilated, could accept  nearly all the blood of the body and plunge the arterial pressure  toward zero. Control of the diameters of these arterioles is essential  in regulating normal peripheral resistance.    Certain chemicals, including carbon dioxide, oxygen, and  hydrogen ions, influence peripheral resistance by affecting precap-  illary sphincters and smooth muscle in arteriole and metarteriole  walls. For example, increasing blood carbon dioxide, decreasing  blood oxygen, and lowering blood pH relaxes smooth muscle in  the systemic circulation. This increases local blood flow to tissues  with high metabolic rates, such as exercising skeletal muscles.   Other chemicals also influence peripheral resistance and  thus blood pressure. Nitric oxide, produced by endothelial cells,  and bradykinin, formed in the blood, are both vasodilators.  Angiotensin II plays a role in vasoconstriction; and endothelin,  released by cells of the endothelium, is a powerful vasoconstrictor.  Clinical Application 15.3 discusses high blood pressure.    48 What factors affect cardiac output?  49 Explain the Frank-Starling law of the heart.    50 What is the function of the baroreceptors in the aortic arch and  carotid sinuses?    Blood pressure decreases as blood moves through the arterial system  and into the capillary networks, so little pressure remains at the ven-  ular ends of capillaries (see fig. 15.32). Instead, blood flow through  the venous system is only partly the direct result of heart action and  depends on other factors, such as skeletal muscle contraction, respi-  ratory movements, and vasoconstriction of veins. For example, con-  tracting skeletal muscles press on veins, moving blood from one valve  section to another. This contraction of skeletal muscles helps push  the blood through the venous system toward the heart (fig. 15.38).   Respiratory movements also move venous blood. During  inspiration, the pressure in the thoracic cavity is reduced as the  diaphragm contracts and the rib cage moves upward and outward.  At the same time, the pressure in the abdominal cavity is increased  as the diaphragm presses downward on the abdominal viscera.  Consequently, blood is squeezed out of the abdominal veins and  forced into thoracic veins. During exercise, these respiratory  movements, along with skeletal muscle contractions, increase the  return of venous blood to the heart.   Venoconstriction also returns venous blood to the heart. When  venous pressure is low, sympathetic reflexes stimulate smooth  muscle in the walls of veins to contract. The veins also provide  a blood reservoir that can adapt its capacity to changes in blood  volume (see fig. 15.30). If some blood is lost and blood pressure  falls, venoconstriction can force blood out of this reservoir, return-  ing venous blood to the heart. By maintaining venous return to the  heart, venoconstriction helps to maintain blood pressure.    All veins, except those returning to the heart from the lungs, drain into  the right atrium. Therefore, the pressure in the right atrium is called  central venous pressure. It affects the pressure in the peripheral veins.  For example, if the heart is failing and beating weakly, the central  venous pressure increases and blood backs up in the peripheral veins,    Hypertension, or high blood pressure, is persistently elevated  arterial pressure. It is a prevalent disease of the cardiovascular sys-  tem in industrialized nations.   High blood pressure with unknown cause is called essential  (also primary or idiopathic) hypertension. Elevated blood pres-  sure that is a consequence of another problem, such as kidney  disease, is called secondary hypertension.   Kidney disease often produces changes that interfere with  blood flow to kidney cells. In response, certain kidney cells may  release an enzyme called renin that leads to the production of  angiotensin II, a powerful vasoconstrictor that increases peripheral  resistance in the arterial system, raising arterial pressure (fig. 15G).  Angiotensin II also stimulates the adrenal cortex to release aldo-  sterone, which stimulates the kidneys to retain sodium ions and  water. The resulting increase in blood volume contributes to  increased blood pressure. Normally, this mechanism ensures that a  decrease in blood flow to the kidneys is followed by an increase in  arterial pressure, which, in turn, restores blood flow to the kidneys.   In some individuals, high sodium intake leads to increased  blood pressure. Obesity also is a risk factor for hypertension  because it increases peripheral resistance. Psychological stress,  which activates sympathetic nerve impulses that cause generalized  vasoconstriction, may also lead to hypertension. Yet another cause  of hypertension may be an inability of endothelium to respond to  a relaxing factor, leading to vasoconstriction.   Hypertension is called a “silent killer” because it may not  have direct symptoms, yet can raise the risk for serious cardio-  vascular complications. For example, as the left ventricle works  harder to pump blood at a higher pressure, the myocardium thick-  ens, enlarging the heart. If coronary blood flow cannot support  this overgrowth, parts of the heart muscle die and fibrous tissue  replaces them. Eventually, the enlarged and weakened heart fails  to maintain adequate output for survival.   Hypertension also contributes to the development of athero-  sclerosis. As arteries accumulate plaque, a coronary thrombosis or    FIGURE 15G Renin stimulates production of angiotensin II, which  elevates blood pressure.    a coronary embolism may occur. Similar changes in the arteries of  the brain increase the chances of a cerebral vascular accident (CVA),  or stroke, due to a cerebral thrombosis, embolism, or hemorrhage.  When an embolus or hemorrhage causes a stroke, paralysis and  other functional losses suddenly appear. A thrombus-caused stroke  is slower because the clot takes time to develop. It may begin with  clumsiness, progress to partial visual loss, then affect speech. One  arm may become paralyzed, then a day later, perhaps an entire side  of the body is affected. Table 15A lists risk factors for a stroke.   A transient ischemic attack (TIA, or “ministroke”) is a tempo-  rary block in a small artery. Symptoms include difficulty in speak-  ing or understanding speech; numbness or weakness in the face,  upper limb, lower limb, or one side; dizziness; falling; an unsteady  gait; blurred vision; or blindness. These symptoms typically  resolve within twenty-four hours with no lasting effects, but may  be a warning of an impending, more serious stroke.   Exercising regularly, maintaining a healthy weight, reducing  stress, and limiting dietary sodium can help prevent hypertension.  If necessary, medications may include diuretics and/or inhibitors of  sympathetic nerve action. Diuretics increase urinary excretion of  sodium and water, reducing the volume of body fluids. Sympathetic  inhibitors block the synthesis of neurotransmitters, such as norepi-  nephrine, or block receptors on effector cells. Table 15B describes  how drugs that treat hypertension work.    Lower heart rate, reduce  contractility by blocking beta  adrenergic receptors on the heart    Calcium channel blockers Dilate blood vessels by keeping  calcium ions out of smooth muscle    FIGURE 15.38 The  massaging action of skeletal  muscles helps move blood  through the venous system  toward the heart.    raising their pressure, too. This can lead to peripheral edema because  the resulting higher capillary hydrostatic pressure favors movement  of fluid into the tissues. However, if the heart is beating normally,  the central venous pressure and the pressure in the venous network  remain low.   An increase in blood volume or widespread venoconstriction  also increases blood flow into the right atrium, elevating the central  venous pressure. Clinical Application 15.4 discusses the effects of  exercise on the heart and blood vessels.    Blood or tissue fluid accumulating in the pericardial cavity (peri-  cardial effusion) increases pressure, causing a potentially deadly  condition called acute cardiac tamponade. Increasing pressure  around the heart may compress it, interfering with the flow of  blood into its chambers and preventing pumping action. An  early symptom of acute cardiac tamponade is increased central  venous pressure, with visible engorgement of the veins in the  neck. Other symptoms include anxiety, rapid or difficulty breath-  ing, light-headedness, palpitations, pallor, and chest pain. Acute  cardiac tamponade has several causes, including bacterial or  viral infection, injury, acute myocardial infarction, advanced lung  cancer, and dissecting aortic aneurysm.    53 How do skeletal muscles affect venous blood flow?  54 How do respiratory movements affect venous blood flow?    The blood vessels form two circuits (fig. 15.39). The pulmonary  circuit sends oxygen-poor blood to the lungs to pick up oxygen  and unload carbon dioxide. The systemic circuit sends oxygen-  rich blood and nutrients to all body cells and removes wastes.   The pathways described in the following sections are those of  an adult. Chapter 23 (pp. 883-887) describes the somewhat differ-  ent fetal pathways.    Blood enters the pulmonary circuit as it leaves the right ventri-  cle through the pulmonary trunk. The pulmonary trunk extends  upward and posteriorly from the heart. About 5 centimeters above  its origin, the pulmonary trunk divides into the right and left  pulmonary arteries, which penetrate the right and left lungs,  respectively. In the lungs, they diverge into lobar branches (three  on the right side and two on the left) that accompany the main  divisions of the bronchi (airways) into the lobes of the lungs. After  repeated divisions, the lobar branches give rise to arterioles that  continue into the capillary networks associated with the walls of  the alveoli (air sacs).   The blood in the arteries and arterioles of the pulmonary circuit  is low in oxygen and high in carbon dioxide. Gases are exchanged  between the blood and the air as the blood moves through the alveo-  lar capillaries, discussed in chapter 19 (pp. 755—756).   The right ventricle contracts with less force than the left ven-  tricle. Therefore, the arterial pressure in the pulmonary circuit is  less than that in the systemic circuit. As a result, the alveolar capil-  lary pressure is low.   The force that moves fluid out of an alveolar capillary is  23 mm Hg; the force pulling fluid into it is 22 mm Hg. Thus, such  a capillary has a net filtration pressure of 1 mm Hg. This pressure  propels a slight, continuous flow of fluid into the narrow intersti-  tial space between the alveolar capillary and the alveolus.   The epithelial cells of the alveoli are so tightly joined that  sodium, chloride, and potassium ions, as well as glucose and  urea, enter the interstitial space but usually do not enter the alve-  oli. This helps maintain a relatively high osmotic pressure in the  interstitial fluid compared to fluid on the inner alveolar surface.  Consequently, osmosis rapidly moves any water that gets into  the alveoli back into the interstitial space. Although the alveolar  surface must be moist to allow diffusion of oxygen and carbon  dioxide, this mechanism keeps excess water out of the alveoli, pre-  venting them from filling with fluid (fig. 15.40).   Fluid in the interstitial space may be drawn back into the  alveolar capillaries by the somewhat higher osmotic pressure of  the blood. Alternatively, lymphatic capillaries (see chapter 16,  pp. 617-618) may return fluid to the circulation (fig. 15.40).   As a result of gas exchange between the blood and the alveo-  lar air, blood entering the venules of the pulmonary circuit is rich  in oxygen and low in carbon dioxide. These venules merge to form  small veins, and these veins in turn converge to form larger veins.  Four pulmonary veins, two from each lung, return blood to the left  atrium. This completes the vascular loop of the pulmonary circuit.    We know that exercise is good for the heart. Yet each year, a few  individuals die of sudden cardiac arrest while shoveling snow, run-  ning, or engaging in some other strenuous activity. The expla-  nation for this apparent paradox is that exercise is good for the  heart—but only if the exercise is a regular part of life.   The cardiovascular system adapts to aerobic exercise. The aer-  obically conditioned athlete experiences increases in heart pump-  ing efficiency, blood volume, blood hemoglobin concentration,  and the number of mitochondria in muscle fibers. These adapta-  tions improve oxygen delivery to, and use by, muscle tissue.   An athlete’s heart typically changes in response to these  increased demands and may enlarge 40% or more. Myocardial  mass increases, the ventricular cavities expand, and the ventricle  walls thicken. At rest, stroke volume increases, and heart rate  and blood pressure decrease. To a physician unfamiliar with a  conditioned cardiovascular system, a trained athlete may appear  to be abnormal.   The cardiovascular system responds beautifully to a slow,  steady buildup in exercise frequency and intensity. It does not  react well to sudden demands, such as when a person who never  exercises suddenly shovels snow or runs 3 miles. Sedentary peo-  ple have two- to sixfold increased risk of cardiac arrest while exer-    Pulmonary edema, in which lungs fill with fluid, can accompany  a failing left ventricle or a damaged mitral valve. A weak left  ventricle may be unable to move the normal volume of blood  into the systemic circuit. Blood backing up into the pulmo-  nary circuit increases pressure in the alveolar capillaries, flood-  ing the interstitial spaces with fluid. Increasing pressure in the  interstitial fluid may rupture the alveolar membranes, and fluid  may enter the alveoli more rapidly than it can be removed. This  reduces the alveolar surface available for gas exchange, and  the person may suffocate.    Oxygen-rich blood moves from the left atrium into the left ventricle.  Contraction of the left ventricle forces this blood into the systemic  circuit, which includes the aorta and its branches that lead to all  of the body tissues, as well as the companion system of veins that  returns blood to the right atrium.    56 Distinguish between the pulmonary and systemic circuits of the  cardiovascular system.    57 Trace the path of blood through the pulmonary circuit from the  right ventricle.    58 Explain why the alveoli normally do not fill with fluid.    cising than when not; people in shape have little or no excess risk  while exercising.   For exercise to benefit the cardiovascular system, the heart  rate must be elevated to 70% to 85% of its “theoretical maxi-  mum” for 30 to 60 minutes at least three to four times a week,  according to the American Heart Association. To calculate your  theoretical maximum, subtract your age from 220. If you are eigh-  teen years old, your theoretical maximum is 202 beats per min-  ute. A rate of 141-172 beats per minute is 70% to 85% of this  value. Examples of activities that raise heart rate are tennis, skat-  ing, skiing, handball, vigorous dancing, hockey, basketball, bik-  ing, and fast walking.   It is wise to consult a physician before starting an exercise  program. People over the age of thirty are advised to have a  stress test, which is an electrocardiogram taken while exercising.  (The standard electrocardiogram is taken at rest.) An arrhythmia  that appears only during exercise may indicate heart disease that  has not yet produced symptoms. The American Heart Association  suggests that after a physical exam, a sedentary person wishing  to start an exercise program begin with 30 minutes of activity  (perhaps broken into two 15-minute sessions at first) at least five  times per week.    The aorta is the largest diameter artery in the body. It extends  upward from the left ventricle, arches over the heart to the left, and  descends just anterior and to the left of the vertebral column.    The part of the aorta attached to the heart is called the aortic root.  From there, the first part of the aorta is called the ascending aorta.  At the root are the three cusps of the aortic valve, and opposite  each cusp is a swelling in the aortic wall called an aortic sinus.  The right and left coronary arteries arise from two of these aortic  sinuses. The elastic recoil of the aortic wall following contraction  of the left ventricle helps drive blood flow into these arteries.   Three major arteries originate from the arch of the aorta  (aortic arch). They are the brachiocephalic artery, the left com-  mon carotid artery, and the left subclavian artery. The aortic arch  has baroreceptors that detect changes in blood pressure. Several  small structures called aortic bodies lie in the epithelial lining of  the aortic arch. The aortic bodies house chemoreceptors that sense  blood pH and blood levels of oxygen and carbon dioxide.   The brachiocephalic (brak”e-o-sé-fal’ik) artery supplies  blood to the tissues of the upper limb and head, as its name sug-  gests. It is the first branch from the aortic arch and rises through  the mediastinum to a point near the junction of the sternum and  the right clavicle. There it divides, giving rise to the right common  carotid (kah-rot’id) artery, which transports blood to the right    Right atrium  Tricuspid valve (cut)  Pulmonary valve  Right ventricle  Inferior vena cava    FIGURE 15.39 (AP|R) The cardiovascular system transports blood between the body cells and organs such as the lungs, intestines, and kidneys that  communicate with the external environment. Vessels in the pulmonary circuit carry blood from the heart to the lungs and back to the heart, replenishing oxygen  (O,) and releasing the metabolic waste carbon dioxide (CO,). Vessels of the systemic circuit supply all of the other cells. (Structures are not drawn to scale.)    side of the neck and head, and the right subclavian (sub-kla’ve-an)  artery, which leads into the right arm. Branches of the subclavian  artery also supply blood to parts of the shoulder, neck, and head.  The left common carotid artery and the left subclavian  artery are respectively the second and third branches of the aor-  tic arch. They supply blood to regions on the left side of the body  corresponding to those supplied by their counterparts on the  right (fig. 15.41 and reference plates 21, 22, and 23, pp. 53-54).  The upper part of the descending aorta is left of the midline,  but it gradually extends medially and lies directly anterior to the  vertebral column at the level of the twelfth thoracic vertebra. The  part of the descending aorta above the diaphragm is the thoracic  aorta (tho-ras’ik a-or’tah). It gives off many small branches to  the thoracic wall and the thoracic viscera. These branches, the  bronchial, pericardial, and esophageal arteries, supply blood to    the structures for which they were named. Other branches become  mediastinal arteries, supplying various tissues in the medias-  tinum, and posterior intercostal arteries, which pass into the  thoracic wall.   Below the diaphragm, the descending aorta becomes the  abdominal aorta, and it branches to the abdominal wall and sev-  eral abdominal organs. These branches include the following:    1. The celiac (se’le-ak) artery gives rise to the left gastric,  splenic, and hepatic arteries, which supply upper portions  of the digestive tract, the spleen, and the liver, respectively.  (Note: The hepatic artery supplies the liver with about one-  third of its blood flow, and this blood is oxygen-rich. The  remaining two-thirds of the liver’s blood flow arrives by  means of the hepatic portal vein and is oxygen-poor.)    @ Solutes fail to enter  alveoli but contribute to  the osmotic pressure of    @ Any excess water in  alveolus is drawn out by  the higher osmotic pressure  of the interstitial fluid    FIGURE 15.40 Cells of the alveolar wall are tightly joined. The relatively high osmotic pressure of the interstitial fluid draws water out of the alveoli.    FIGURE 15.41 (AP|R) The major blood vessels associated with the heart. (a. stands for artery, v. stands for vein, vv. stands for veins.)    2. The phrenic (fren’ik) arteries are paired arteries that supply  blood to the diaphragm.   3. The superior mesenteric (mes”en-ter’ik) artery is a large,  unpaired vessel that branches to many parts of the intestinal  tract, including the jejunum, ileum, cecum, ascending colon,  and transverse colon.   5. The renal (re’nal) arteries pass laterally from the aorta  into the kidneys. Each artery then divides into several lobar  branches in the kidney tissues.   In a female, paired ovarian arteries arise from the aorta and  pass into the pelvis to supply the ovaries. In a male, spermatic  arteries originate in similar locations. They course downward  and pass through the body wall by way of the inguinal canal  to supply the testes.   7. Branches of the inferior mesenteric artery lead to the  descending colon, the sigmoid colon, and the rectum.   8. Three or four pairs of lumbar arteries arise from the poste-  rior surface of the aorta in the region of the lumbar vertebrae.  These arteries supply muscles of the skin and the posterior  abdominal wall.   9. The middle sacral artery, a small vessel, descends medially  from the aorta along the anterior surfaces of the lower lumbar  vertebrae. It transports blood to the sacrum and coccyx.    The abdominal aorta terminates near the brim of the pelvis,  where it divides into right and left common iliac arteries. These  vessels supply blood to lower regions of the abdominal wall, the  pelvic organs, and the lower extremities (fig. 15.42). Table 15.4  summarizes the major branches of the aorta.    Branches of the subclavian and common carotid arteries sup-  ply blood to structures in the brain, head, and neck (figs. 15.43  and 15.44). The main divisions of the subclavian artery to these  regions are the vertebral, thyrocervical, and costocervical arteries.  The common carotid artery communicates with these regions by  means of the internal and external carotid arteries.   The vertebral arteries arise from the subclavian arteries in  the base of the neck near the tips of the lungs. They pass upward  through the foramina of the transverse processes of the cervical  vertebrae and enter the skull by way of the foramen magnum.  Along their paths, these vessels supply blood to vertebrae and to  their associated ligaments and muscles.   In the cranial cavity, the vertebral arteries unite to form a single  basilar artery. This vessel passes along the ventral brainstem and  gives rise to branches leading to the pons, midbrain, and cerebellum.  The basilar artery terminates by dividing into two posterior cerebral  arteries that supply parts of the occipital and temporal lobes of the  cerebrum. The posterior cerebral arteries also help form the cere-  bral arterial circle (circle of Willis) at the base of the brain, which  connects the vertebral artery and internal carotid artery systems  (fig. 15.45). The union of these systems provides alternate pathways  for blood to circumvent blockages and reach brain tissues. It also  equalizes blood pressure in the brain’s blood supply. The circle is  complete in only 20% to 30% of the population.   The thyrocervical (thi’ro-ser’vi-kal) arteries are short ves-  sels that give off branches at the thyrocervical axis to the thyroid  gland, parathyroid glands, larynx, trachea, esophagus, and phar-  ynx, as well as to various muscles in the neck, shoulder, and back.  The costocervical (kos”to-ser’ vi-kal) arteries, the third vessels to  branch from the subclavians, carry blood to muscles in the neck,  back, and thoracic wall.    Intestinal  branches from  superior  mesenteric a.  Branches  from inferior  mesenteric a.    FIGURE 15.43 (APIFY The  major arteries of the head and neck.  The clavicle has been removed.    An angiogram of the arteries  associated with the head. (a. stands  for artery.)    The left and right common carotid arteries ascend deeply in  the neck on either side. At the level of the upper laryngeal border,  they divide to form the internal and external carotid arteries.   The external carotid artery courses upward on the side of  the head, giving off branches to structures in the neck, face, jaw,  scalp, and base of the skull. The main vessels that originate from  this artery include the following:    1. superior thyroid artery to the hyoid bone, larynx, and thyroid  gland   2. lingual artery to the tongue, muscles of the tongue, and sali-  vary glands beneath the tongue   3. facial artery to the pharynx, palate, chin, lips, and nose   4. occipital artery to the scalp on the back of the skull, the menin-  ges, the mastoid process, and various muscles in the neck   5. posterior auricular artery to the ear and the scalp over the ear    The external carotid artery terminates by dividing into the max-  illary and superficial temporal arteries. The maxillary artery sup-  plies blood to the teeth, gums, jaws, cheek, nasal cavity, eyelids,  and meninges. The superficial temporal artery extends to the parotid  salivary gland and to various surface regions of the face and scalp.   The internal carotid artery begins lateral to the external  carotid artery, then follows a deep course upward along the pharynx  to the base of the skull. Entering the cranial cavity, it provides the  major blood supply to the brain. The major branches of the internal  carotid artery include the following:    1. ophthalmic artery to the eyeball and to various muscles and  accessory organs within the orbit   2. posterior communicating artery that forms part of the cerebral  arterial circle   3. anterior choroid artery to the choroid plexus within the lateral  ventricle of the brain and to nerve structures in the brain    The internal carotid artery terminates by dividing into the ante-  rior and middle cerebral arteries. The middle cerebral artery passes   ME Nep ial et FIGURE 15.45 (AP|R) View of inferior surface of the  brain. The cerebral arterial circle (circle of Willis) is formed    through the lateral tissue and supplies the lateral surface of the cere-  brum, including the primary motor and sensory areas of the face and  upper limbs, the optic radiations, and the speech area (see chapter 11,  pp. 401-402). The anterior cerebral artery extends anteriorly between  the cerebral hemispheres and supplies the medial surface of the brain.   Near the base of each internal carotid artery is an enlargement  called a carotid sinus. Like the aortic arch, these structures con-  tain baroreceptors that control blood pressure. A number of small  epithelial masses, called carotid bodies, are also in the wall of  the carotid sinus. The carotid bodies have chemoreceptors that act  with those of the aortic bodies in monitoring blood chemistry, to  regulate circulation and respiration.    The subclavian artery, after giving off branches to the neck, con-  tinues into the arm (fig. 15.46). It passes between the clavicle and  the first rib and becomes the axillary artery.   The axillary artery supplies branches to structures in the  axilla and the chest wall, including the skin of the shoulder; part  of the mammary gland; the upper end of the humerus; the shoulder  joint; and muscles in the back, shoulder, and chest. As this vessel  leaves the axilla, it becomes the brachial artery.   The brachial artery courses along the humerus to the  elbow. It gives rise to a deep brachial artery that curves posteri-  orly around the humerus and supplies the triceps brachii muscle.  Shorter branches pass into the muscles on the anterior side of the  arm, whereas others descend on each side to the elbow and con-  nect with arteries in the forearm. The resulting arterial network  allows blood to reach the forearm even if a portion of the distal  brachial artery becomes obstructed.   In the elbow, the brachial artery divides into an ulnar artery and  a radial artery. The ulnar artery leads downward on the ulnar side of  the forearm to the wrist. Some of its branches join the anastomosis  around the elbow joint, whereas others supply blood to flexor and  extensor muscles in the forearm.    The radial artery, which is a continuation of the brachial  artery, extends along the radial side of the forearm to the wrist.  As it nears the wrist, it comes close to the surface and provides a  convenient vessel for taking the pulse (radial pulse). Branches of  the radial artery join the anastomosis of the elbow and supply the  lateral muscles of the forearm.   At the wrist, the branches of the ulnar and radial arteries join  to form a network of vessels. Arteries arising from this network  supply blood to structures in the hand.    Blood reaches the thoracic wall through several vessels. These  include branches from the subclavian artery and the thoracic aorta  (fig. 15.47).   The subclavian artery contributes to this supply through a  branch called the internal thoracic artery. This vessel originates in  the base of the neck and passes downward on the pleura and behind  the cartilages of the upper six ribs. It gives off two anterior inter-  costal arteries to each of the upper six intercostal spaces; these two  arteries supply the intercostal muscles, other intercostal tissues, and  the mammary glands.    The posterior intercostal arteries arise from the thoracic aorta  and enter the intercostal spaces between the third through the elev-  enth ribs. These arteries branch to supply the intercostal muscles,  the vertebrae, the spinal cord, and deep muscles of the back.   Branches of the internal thoracic and external iliac arteries  provide blood to the anterior abdominal wall. Paired vessels origi-  nating from the abdominal aorta, including the phrenic and lum-  bar arteries, supply blood to structures in the lateral and posterior  abdominal wall.    The abdominal aorta divides to form the common iliac (il’e-ak)  arteries at the level of the pelvic brim. These vessels provide blood  to the pelvic organs, gluteal region, and lower limbs.   Each common iliac artery descends a short distance and  divides into an internal (hypogastric) branch and an external  branch. The internal iliac artery gives off many branches to  various pelvic muscles and visceral structures, as well as to the  gluteal muscles and the external genitalia. Parts of figure 15.48  show important branches of this vessel, including the following:    1. iliolumbar artery to the ilium and muscles of the back   2. superior and inferior gluteal arteries to the gluteal muscles,  pelvic muscles, and skin of the buttocks   3. internal pudendal artery to muscles in the distal portion of the  alimentary canal, the external genitalia, and the hip joint   4. superior and inferior vesical arteries to the urinary bladder; in    The external iliac artery provides the main blood supply to  the lower limbs (fig. 15.49). It passes downward along the brim  of the pelvis and gives off two large branches—an inferior epi-  gastric artery and a deep circumflex iliac artery. These vessels  supply the muscles and skin in the lower abdominal wall. Midway  between the pubic symphysis and the anterior superior iliac spine,  the external iliac artery becomes the femoral artery.   The femoral (fem’or-al) artery, which passes fairly close to  the anterior surface of the upper thigh, gives off many branches  to muscles and superficial tissues of the thigh. These branches also  supply the skin of the groin and the lower abdominal wall. Important  subdivisions of the femoral artery include the following:    1. superficial circumflex iliac artery to the lymph nodes and skin  of the groin   2. superficial epigastric artery to the skin of the lower abdominal  wall   3. superficial and deep external pudendal arteries to the skin of  the lower abdomen and external genitalia   4. deep femoral artery (the largest branch of the femoral artery)  to the hip joint and muscles of the thigh   5. deep genicular artery to distal ends of thigh muscles and to  an anastomosis around the knee joint    As the femoral artery reaches the proximal border of the  space behind the knee (popliteal fossa), it becomes the popliteal    Femoral a. Inferior gluteal a.  Umbilical ligament  Umbilical a. Internal pudendal a.    FIGURE 15.48 (AP|R) Arteries that supply the pelvic region. (a. stands for artery.)    7 Internal  External iliac a. iliac a  Superficial circumflex  iliac a.  Superficial  pudendal a.  Deep femoral a. Femoral a.  Lateral femoral  circumflex a.  Descending  genicular a.    (pop li-te’al) artery. Branches of this artery supply blood to the  knee joint and to certain muscles in the thigh and calf. Also, many  of its branches join the anastomosis of the knee and help provide  alternate pathways for blood in the case of arterial obstructions. At  the lower border of the popliteal fossa, the popliteal artery divides  into the anterior and posterior tibial arteries.   The anterior tibial (tib’e-al) artery passes downward  between the tibia and the fibula, giving off branches to the skin and  muscles in the anterior and lateral regions of the leg. It also com-  municates with the anastomosis of the knee and with a network of  arteries around the ankle. This vessel continues into the foot as the  dorsalis pedis artery, which supplies blood to the instep and toes.    The posterior tibial artery, which is the larger of the two  popliteal branches, descends beneath the calf muscles, giving off  branches to the skin, muscles, and other tissues of the leg along the  way. Some of these vessels join the anastomoses of the knee and  ankle. As it passes between the medial malleolus and the heel, the  posterior tibial artery divides into the medial and lateral plantar  arteries. Branches from these arteries supply blood to tissues of  the heel, instep, and toes.   The largest branch of the posterior tibial artery is the fibular  artery, which extends downward along the fibula and contributes  to the anastomosis of the ankle. Figure 15.50 shows the major  vessels of the arterial system.    Common carotid a. Vertebral a.  Brachiocephalic trunk Subclavian a.  Axillary a.   Celiac trunk  Suprarenal a.  Renal a. Superior mesenteric a.  Radial a.    59 Name the parts of the aorta.  60 Name the vessels that arise from the aortic arch.  61 Name the branches of the thoracic and abdominal aorta.    62 Which vessels supply blood to the head? To the upper limb? To  the abdominal wall? To the lower limb?    Venous circulation returns blood to the heart after gases, nutrients,  and wastes are exchanged between the blood and body cells.    The vessels of the venous system originate with the merging of  capillaries into venules. Venules then merge into small veins, and  small veins meet to form larger ones. Unlike the arterial pathways,  those of the venous system are difficult to follow because the  smaller vessels commonly connect in irregular networks. Many  unnamed tributaries may join to form a large vein. The pathways  of larger veins are easier to follow. These veins typically parallel  the courses of named arteries, and many bear the same names as  their arterial counterparts. For example, the renal vein parallels  the renal artery, and the common iliac vein accompanies the com-  mon iliac artery.   The veins that carry the blood from the lungs and myocar-  dium back to the heart have been described. The veins from all  the other parts of the body converge into two major vessels, the  superior and inferior venae cavae, which lead to the right atrium.    The external jugular (jug’u-lar) veins drain blood from the face,  scalp, and superficial regions of the neck. These vessels descend  on either side of the neck, passing over the sternocleidomastoid  muscles and beneath the platysma. They empty into the right and  left subclavian veins in the base of the neck (fig. 15.51).   The internal jugular veins, which are somewhat larger than  the external jugular veins, arise from many veins and venous  sinuses of the brain and from deep veins in parts of the face and  neck. They descend through the neck beside the common carotid  arteries and also join the subclavian veins. These unions of the  internal jugular and subclavian veins form large brachioce-  phalic veins on each side. These vessels then merge in the medi-  astinum and give rise to the superior vena cava, which enters the  right atrium.    A lung cancer, enlarged lymph node, or an aortic aneurysm  can compress the superior vena cava, interfering with return of  blood from the upper body to the heart. This produces pain;    shortness of breath; distension of veins draining into the supe-  rior vena cava; and swelling of tissues in the face, head, and  upper limbs.    A set of deep veins and a set of superficial ones drain the upper  limb. The deep veins generally parallel the arteries in each region  and have similar names. Deep venous drainage of the upper limbs  begins in the digital veins that drain into pairs of radial veins and  ulnar veins, which merge to form a pair of brachial veins. The  superficial veins connect in complex networks just beneath the  skin. They also communicate with the deep vessels of the upper  limb, providing many alternate pathways through which the blood  can leave the tissues (fig. 15.52).   The major vessels of the superficial network are the basilic and  cephalic veins. They arise from anastomoses in the palm and wrist  on the ulnar and radial sides, respectively.   The basilic (bah-sil’ik) vein passes along the back of the fore-  arm on the ulnar side for a distance and then curves forward to  the anterior surface below the elbow. It continues ascending on the  medial side until it reaches the middle of the arm. There it deeply  penetrates the tissues and joins the brachial vein. As the basilic  and brachial veins merge, they form the axillary vein.   The cephalic (sé-fal’ik) vein courses upward on the lateral side  of the upper limb from the hand to the shoulder. In the shoulder,    FIGURE 15.51 (AP|R) The major veins of the brain, head, and    FIGURE 15.52 (AP|R} The major veins of the upper limb and    y.  © Blood from the brachial and basilic veins drains into which  vein(s)?    it pierces the tissues and joins the axillary vein, which beyond the  axilla becomes the subclavian vein.   In the bend of the elbow, a median cubital vein ascends from  the cephalic vein on the lateral side of the forearm to the basilic  vein on the medial side. This large vein is usually visible beneath  the skin. It is often used as a site for venipuncture, when it is nec-  essary to remove a sample of blood for examination or to add flu-  ids to the blood.    Tributaries of the brachiocephalic and azygos veins drain the  abdominal and thoracic walls. For example, the brachiocephalic  vein receives blood from the internal thoracic vein, which generally  drains the tissues the internal thoracic artery supplies. Some inter-  costal veins also empty into the brachiocephalic vein (fig. 15.53).  The azygos (az’i-gos) vein originates in the dorsal abdominal  wall and ascends through the mediastinum on the right side of the  vertebral column to join the superior vena cava. It drains most of  the muscular tissue in the abdominal and thoracic walls.  Tributaries of the azygos vein include the posterior intercos-  tal veins on the right side, which drain the intercostal spaces, and    the superior and inferior hemiazygos veins, which receive blood  from the posterior intercostal veins on the left. The right and left  ascending lumbar veins, with tributaries that include vessels from  the lumbar and sacral regions, also connect to the azygos system.    Veins transport blood directly to the atria of the heart, except for por-  tal veins, such as those that drain the abdominal viscera (fig. 15.54).  They originate in the capillary networks of the stomach, intestines,  pancreas, and spleen and transport blood from these organs through  a hepatic portal (por’tal) vein to the liver (fig. 15.55). There the  blood enters capillary-like hepatic sinusoids (hé-pat’ik si’nt-soidz).  This unique venous pathway is called the hepatic portal system,  which allows blood to flow from the gastrointestinal organs to the  liver before returning to the heart.   The tributaries of the hepatic portal vein include the following  vessels:   2. superior mesenteric vein from the small intestine, ascending  colon, and transverse colon   3. splenic vein from a convergence of several veins draining the  spleen, the pancreas, and a portion of the stomach; as well  as its largest tributary, the inferior mesenteric vein, from the  descending colon, sigmoid colon, and rectum    About 80% of the blood flowing to the liver in the hepatic  portal system comes from the capillaries in the stomach and  intestines and is oxygen-poor, but nutrient-rich (see chapter 17,  pp. 670-671). The liver handles these nutrients in a variety of ways.  It regulates blood glucose concentration by polymerizing excess  glucose into glycogen for storage or by breaking down glycogen  into glucose when blood glucose concentration drops below normal.   The liver helps regulate blood concentrations of recently  absorbed amino acids and lipids by modifying them into forms  cells can use, by oxidizing them, or by changing them into storage  forms. The liver also stores certain vitamins and detoxifies harm-  ful substances.   Blood in the hepatic portal vein nearly always contains bacte-  ria that have entered through intestinal capillaries. Large Kupffer  cells lining the hepatic sinusoids phagocytize these microorganisms,  removing them from the portal blood before it leaves the liver.   After passing through the hepatic sinusoids of the liver, the  blood in the hepatic portal system travels through a series of merg-  ing vessels into hepatic veins. These veins empty into the inferior  vena cava, returning the blood to the general circulation.   Other veins empty into the inferior vena cava as it ascends  through the abdomen. They include the /umbar, gonadal, renal,  suprarenal, and phrenic veins. These vessels drain regions that  arteries with corresponding names supply.    Veins that drain the blood from the lower limb can be divided into  deep and superficial groups, as in the upper limb (fig. 15.56). The  deep veins of the leg, such as the paired anterior and posterior tib-  ial veins, have names that correspond to the arteries they accom-  pany. At the level of the knee, these vessels form a single trunk, the    FIGURE 15.55 In this schematic drawing of the cardiovascular system, note how the hepatic portal vein drains one set of capillaries and leads to    popliteal vein. This vein continues upward through the thigh as  the femoral vein, which, in turn, becomes the external iliac vein.   The superficial veins of the foot, leg, and thigh connect to form  a complex network beneath the skin. These vessels drain into two  major trunks: the small and great saphenous veins.   The small saphenous (sah-fe’nus) vein begins in the lateral  portion of the foot and passes upward behind the lateral malleolus.  It ascends along the back of the calf, enters the popliteal fossa, and  joins the popliteal vein.   The great saphenous vein, the longest vein in the body, origi-  nates on the medial side of the foot. It ascends in front of the medial    malleolus and extends upward along the medial side of the leg and  thigh. In the thigh just below the inguinal ligament, it deeply pen-  etrates and joins the femoral vein. Near its termination, the great  saphenous vein receives tributaries from a number of vessels that  drain the upper thigh, groin, and lower abdominal wall.   In addition to communicating freely with each other, the  saphenous veins communicate extensively with the deep veins of  the leg and thigh. Blood can thus return to the heart from the lower  extremities by several routes.   In the pelvic region, vessels leading to the internal iliac veins  transport blood away from organs of the reproductive, urinary,    FIGURE 15.56 (AP|R} The major veins of the lower limb and pelvis. (v. stands for vein, w. stands for veins.)    and digestive systems. These veins are formed by tributaries  corresponding to the branches of the internal iliac artery, such  as the gluteal, pudendal, vesical, rectal, uterine, and vaginal  veins. Typically, these veins have many connections and form  complex networks (plexuses) in the regions of the rectum, uri-  nary bladder, and prostate gland (in the male) or uterus and  vagina (in the female).   The internal iliac veins originate deep within the pelvis and  ascend to the pelvic brim. There they unite with the right and left  external iliac veins to form the common iliac veins. These vessels,    in turn, merge to produce the inferior vena cava at the level of the  fifth lumbar vertebra. Figure 15.57 shows the major vessels of the  venous system.    63 Name the veins that return blood to the right atrium.    64 Which major veins drain blood from the head? From the  upper limbs? From the abdominal viscera? From the  lower limbs?    Axillary v. Superior vena cava  Cephalic v. REYGOS'Y:  Brachial vv.  7 Inferior vena cava  Basilic v.  Hepatic v.  Median cubital v.  Renal v.  Radial wv. :  ‘iigarae Ascending lumbar v.    The years take a toll on the cardiovascular system. Signs of car-  diovascular disease may appear long before symptoms arise.  Autopsies of soldiers killed in the Korean and Vietnam Wars, for  example, revealed significant plaque buildup in the arterial walls  of otherwise healthy young men. Incidence of disease of the heart  and blood vessels increases exponentially with age. About 60% of  men over age sixty have at least one narrowed coronary artery; the  same is true for women over age eighty.   Assessing cardiac output over a lifetime vividly illustrates  how cardiovascular disease prevalence can interfere with study-  ing the changes associated with normal aging. Recall that car-  diac output is the ability of the heart to meet the body’s oxygen  requirements and is calculated as the heart rate in beats per minute  multiplied by the stroke volume in milliliters per beat. For many  years, studies indicated that cardiac output declines with age, but  when researchers began to screen participants for hidden heart  disease with treadmill stress tests, then evaluated only individuals  with completely healthy cardiovascular systems, they discovered  that cardiac output at rest is maintained as a person ages. It does  decline during exercise for some people, however.   The heart may normally shrink slightly with age, but disease  may enlarge it. The proportion of the heart that is cardiac muscle  declines with age, even in a healthy person, because cardiac mus-  cle cells do not divide. Lipofuscin pigments become especially  prominent in these cells. Fibrous connective tissue and adipose  tissue fill in the spaces left by the waning population of cardiac  muscle cells, thickening the endocardium. Adipose cells may also  accumulate in the ventricle walls and the septum between them.  The left ventricular wall may be up to 25% thicker at age eighty  than it was at age thirty. The heart valves thicken and become  more rigid after age sixty, although these changes may begin as  early as the third decade. The valves may calcify.   The heart slows slightly with age, the cardiac cycle lengthen-  ing by 2% to 5% per year. The cardiac conduction system may  remain functional despite changes to the heart. The sinoatrial and  atrioventricular nodes and the atrioventricular bundle become  more elastic. These changes may alter the ECG pattern.   Systolic blood pressure increases with age; a blood pressure  reading of 140/90 is not abnormal in an older person. In about  40% of the elderly, the systolic pressure exceeds 160. The increase  may be due to the decreasing diameters and elasticity of arter-  ies. Regular exercise can slow these changes. Resting heart rate  declines from 145 or more beats per minute in a fetus to 140 beats    per minute in a newborn, then levels out in an adult to about 70  (range of 60-99) beats per minute.   In the vascular system, age-related changes are most appar-  ent in the arteries. The tunica interna thickens and, over time, the  lumens of the larger arteries narrow. Rigidity increases as colla-  gen, calcium, and fat are deposited as elastin production declines.  Arterial elasticity at age seventy is only about half of what it was  at age twenty. The arterioles have diminished ability to contract  in response to cold temperatures and to dilate in response to heat,  contributing to the loss of temperature control common among the  elderly. The extent of change in arteries may reflect stress—that is,  not all arteries “age” at the same rate.   Veins may accumulate collagen and calcify but, in general,  do not change as much with age as do arteries. Thickened patches  may appear in the inner layer, and fibers in the valves, but venous  diameters are large enough that these changes have little impact  on function. The venous supply to many areas is so redundant that  alternate veins can in many cases compensate for damaged ones.   The once-sleek endothelium changes as the cells become  less uniform in size and shape. The endothelial inner linings of  blood vessels are important to health because these cells release  nitric oxide, which signals the vessels to dilate to increase blood  flow, which counters atherosclerosis and thrombosis. In addition  to the changes in arteries and veins, the number of capillaries  declines with age.   Exercise can help maintain a “young” vascular system. One  study compared the vascular endothelial linings of athletic and  sedentary individuals of various ages and found that the status of  the vessels of the exercising elderly were very similar to those of  either athletic or sedentary people in their twenties. Many studies  have correlated regular exercise to lowered heart disease risk in  older people.   Overall, aging-related changes affect many components of the  cardiovascular system. But in the absence of disease, the system  is so fine-tuned and redundant that effective oxygen delivery can  continue well into the later decades of life.   Clinical Application 15.5 looks at molecular explanations of  certain cardiovascular disorders. Clinical Application 15.6 dis-  cusses coronary artery disease.    65 Explain why the heart may enlarge with age.  66 Describe what happens to resting heart rate with age. Hl    Several environmental and inherited factors contribute to car-  diovascular disease, including poor diet, sedentary lifestyle, and  genetic predisposition. Disorders of the heart and blood vessels  caused by single genes are rare, but understanding how they arise  can provide insights useful in developing treatments for more  prevalent forms of disease. For example, widely used cholesterol-  lowering drugs called statins were developed based on under-  standing an inherited condition, familial hypercholesterolemia,  which produces faulty LDL (low-density lipoprotein) receptors and  that affects one in a million children.    Just after midnight, the college basketball player lay in her bed  watching TV. At about 2 a.m., her roommate heard sounds of dis-  turbed breathing and could not rouse the young player. The nine-  teen-year-old athlete died within an hour of reaching the hospital.  Her aorta had burst. She had Marfan syndrome, an inherited con-  dition that also caused the characteristics that led her to excel in  her sport—her great height and long fingers.   In Marfan syndrome, an abnormal form of a connective tissue  protein called fibrillin weakens the aorta wall, dilating the aortic  root (fig. 15H). Identifying the mutation can make it possible to  locate and surgically repair a weakened aorta, or to take a drug  that can slow the effect of the disease on the aorta. This can pre-  vent a tragic first symptom—sudden death.    Each year, one or two seemingly healthy young people die sud-  denly during a sports event, usually basketball. The cause of  death is often familial hypertrophic cardiomyopathy, an inher-  ited overgrowth of the myocardium. The defect in this disorder  is different from that behind Marfan syndrome. It is an abnor-  mality in one of the myosin chains that comprise cardiac mus-  cle. Again, detecting the responsible gene can alert affected  individuals to their increased risk of sudden death. They can  adjust the type of exercise they do to avoid stressing the car-  diovascular system.    FIGURE 15H The symptoms of Marfan  syndrome, including a progressive dilation  of the aortic root, arise from an abnormal  form of the connective tissue protein  fibrillin that in turn increases signaling by a  protein called transforming growth factor B  (TGF-beta). A drug originally developedto —Ayricle  treat hypertension, losartan, lowers levels of right  of TGF-beta and slows the life-threatening atrium  ballooning out of the ascending aorta.  Surgery can replace the aortic root with  a synthetic graft. Losartan is helpful even  after surgery.    Inherited heart disease can strike early in life. Jim D. died at four  days of age, two days after suffering cardiac arrest. Two years later,  his parents had another son. Like Jim, Kerry seemed normal at birth,  but when he was thirty-six hours old, his heart rate plummeted, he  had a seizure, and he stopped breathing. He was resuscitated. A  blood test revealed excess long-chain fatty acids, indicating inabil-  ity to use fatty acids. Hunger triggered the symptoms because  the boys could not use fatty acids for energy, as healthy people  do. Kerry survived for three years by following a diet low in fatty  acids and eating frequently. Once he became comatose because he  missed a meal. Eventually, he died of respiratory failure.   Jim and Kerry had inherited a deficiency of a mitochondrial  enzyme that processes long-chain fatty acids. Because long-chain  fatty acids are a primary energy source for cardiac muscle, their  hearts failed.    Low-density lipoprotein (LDL) receptors on liver cells admit cho-  lesterol into the cells, keeping the lipid from building up in the  bloodstream and occluding arteries. When LDL receptors bind  cholesterol, they activate a negative feedback mechanism that  temporarily halts the cell's production of cholesterol. In the severe  form of familial hypercholesterolemia, a person inherits two defec-  tive copies of the gene encoding the LDL receptors. Yellowish  lumps of cholesterol are deposited behind the knees and elbows,  and heart failure usually causes death in childhood. People who  inherit one defective gene have a milder form of the illness. They  develop coronary artery disease in young adulthood, but can delay  symptoms by following a heart-healthy diet and regularly exercis-  ing. These people have half the normal number of LDL receptors.   In Niemann-Pick type C disease, a defective protein disturbs  the fate of cholesterol inside cells. Normally, the protein escorts  cholesterol out of a cell’s lysosomes, which triggers the negative  feedback mechanism that shuts off cholesterol synthesis. When  the protein is absent or malfunctions, the cell keeps producing  cholesterol and LDL receptors. Coronary artery disease develops,  and is typically fatal in childhood.    Dave R., a fifty-two-year-old overweight accountant, had been  having occasional chest pains for several months. The mild pain  occurred during his usual weekend tennis match, and he attrib-  uted it to indigestion. The discomfort almost always diminished  after the game, but recently, the pain seemed more severe and  prolonged. When Dave asked his physician about the problem,  she explained that he was probably experiencing angina pectoris,  a symptom of coronary artery disease (CAD), and suggested an  exercise stress test. Dave walked on a treadmill, increasing speed  and incline while he exercised. An ECG was recorded and his  blood pressure monitored. Near the end of the test, when Dave's  heart reached the desired rate, a small amount of radioactive thal-  lium-201 was injected into a vein. A scintillation counter scanned  Dave's heart to determine if branches of his coronary arteries car-  ried the blood marked with the thallium uniformly throughout the  myocardium.   The test revealed that Dave was developing CAD. He also  had hypertension and high serum cholesterol. The physician  advised Dave to lose weight; avoid stress; stop smoking; reduce  his intake of foods high in saturated fats, cholesterol, refined car-  bohydrates, and sodium; and exercise regularly. Dave also started  taking medications to lower his blood pressure and relieve the  pain of angina.   Six months later, like 1.2 million other people in the United  States each year, despite following medical advice, Dave suffered  a heart attack (myocardial infarction). Blood flow to part of his  myocardium was obstructed, producing oxygen deficiency. The  attack began as severe, crushing chest pain, shortness of breath,  and sweating. Paramedics stabilized Dave’s condition and trans-  ported him to a hospital. There, a cardiologist concluded from an  ECG that Dave's heart attack was caused by a blood clot blocking  a coronary artery (occlusive coronary thrombosis). The cardiologist  intravenously administered a thrombolytic (“clot-busting”) drug.   A repeat ECG a few hours later showed that the blood ves-  sel remained partially obstructed, so the cardiologist ordered a  coronary angiogram (see fig. 15.12). In this X-ray procedure, con-  ducted in a cardiac catheterization laboratory, a thin plastic cathe-  ter was passed through a guiding sheath inserted into the femoral    1. The heart pumps blood to the pulmonary circuit and the  systemic circuit.   2. The pulmonary circuit reaches the lungs, where the blood  picks up oxygen and unloads carbon dioxide.   3. The systemic circuit delivers oxygen to all body cells and  picks up carbon dioxide to be excreted.    artery of Dave's right inguinal area. From there, the catheter was  pushed into the aorta until it reached the region of the openings  to the coronary arteries. Then, dye was injected to track coronary  blood flow in sequential X rays.   X-ray fluoroscopy monitored the progress of the catheter.  Each time the catheter was in proper position, a radiopaque dye  (contrast medium) was released from its distal end into the blood.  X-ray images that revealed the path of the dye as it entered a  coronary artery and its branches were digitally recorded and later  analyzed frame by frame, revealing a single severe narrowing  near the origin of Dave's left anterior descending artery. The car-  diologist decided to perform percutaneous transluminal coronary  angioplasty (PTCA) to enlarge the opening (lumen) of that vessel.   The PTCA passed another plastic catheter through the guid-  ing sheath used for the angiogram. This second tube had a tiny  deflated balloon at its tip that was placed in the region of the arte-  rial narrowing and inflated briefly under high pressure. The inflated  balloon compressed the atherosclerotic plaque (atheroma)  obstructing the arterial wall and stretched the blood vessel wall,  widening its lumen (recanalization). Blood flow to the myocardial  tissue downstream from the obstruction immediately improved.   About 50% of the time, a vessel opened with PTCA becomes  occluded again, because the underlying disease persists. To pre-  vent this restenosis, the doctor inserted a coronary stent, which is  an expandable tube or coil that holds the vessel wall open. The  cardiologist had two other options that have a slightly higher  risk of causing damage. She might have vaporized the plaque  obstructing the vessel with an excimer laser pulse delivered along  optical fibers threaded through the catheter. Or, she could have  performed atherectomy, in which a cutting device attached to  the balloon inserted into the catheter spins, removing plaque by  withdrawing it on the catheter tip.   Should the coronary stent fail, or an obstruction block another  heart vessel, Dave might benefit from coronary bypass surgery. A  portion of his internal mammary artery inside his chest wall would  be removed and sutured between the aorta and the blocked coro-  nary artery at a point beyond the obstruction, restoring circulation  through the myocardium.    1. Size and location of the heart  a. The heart is about 14 centimeters long and  9 centimeters wide.  b. It is located in the mediastinum and rests on the  diaphragm.  2. Coverings of the heart  a. A layered pericardium encloses the heart.  b. The pericardial cavity is a space between the visceral  and parietal layers of the pericardium.    The heart pumps blood through as many as  60,000 miles of blood vessels, delivering nutrients  to, and removing wastes from, all body cells.    The digestive system  breaks down nutrients  into forms readily  absorbed by the  bloodstream.    The respiratory  system oxygenates  the blood and  removes carbon  dioxide. Respiratory  movements help the  blood circulate.    The kidneys clear the  blood of wastes. The  kidneys help control  blood pressure and  blood volume.    Wall of the heart  a. The wall of the heart has three layers.  b. These layers include an epicardium, a myocardium,  and an endocardium.  Heart chambers and valves  a. The heart is divided into four chambers—two atria  and two ventricles—that communicate through  atrioventricular orifices on each side.  b. Right chambers and valves  (1) The right atrium receives blood from the venae  cavae and coronary sinus.   (4) A pulmonary valve guards the base of the  pulmonary trunk.   c. Left chambers and valves  (1) The left atrium receives blood from the pulmonary   veins.  (2) The mitral valve guards the left atrioventricular  orifice.  (3) The left ventricle pumps blood into the aorta.  (4) An aortic valve guards the base of the aorta.   a. The skeleton of the heart consists of fibrous rings that  enclose the bases of the pulmonary trunk, aorta, and  atrioventricular orifices.   b. The fibrous rings provide attachments for valves and  muscle cells and prevent the orifices from excessively  dilating during ventricular contractions.   a. Blood low in oxygen (oxygen-poor blood) and high in  carbon dioxide enters the right side of the heart from  the venae cavae and coronary sinus and then is pumped  into the pulmonary circulation.   b. After the blood is oxygenated in the lungs and some  of its carbon dioxide is removed, the oxygen-rich  blood returns to the left side of the heart through the  pulmonary veins.   c. From the left ventricle, the blood moves into the aorta.   b. It is returned to the right atrium through the cardiac  veins and coronary sinus.   a. The atria contract (atrial systole) while the ventricles  relax (ventricular diastole); the ventricles contract  (ventricular systole) while the atria relax (atrial diastole).   b. Heart sounds are due to the vibrations that the valve  movements produce.   c. The first part of the sound occurs as AV valves close,  and the second part is associated with the closing of  pulmonary and aortic valves.   b. If any part of the syncytium is stimulated, the whole  structure contracts as a unit.   c. Except for a small region in the floor of the right atrium,  the fibrous skeleton separates the atrial syncytium from  the ventricular syncytium.   a. This system, composed of specialized cardiac muscle  tissue, initiates and conducts depolarization waves  through the myocardium.   b. Impulses from the SA node pass slowly to the AV node;  impulses are conducted rapidly along the AV bundle  and Purkinje fibers.   c. Muscle cells in the ventricular walls form whorls that  squeeze blood out of the contracting ventricles.   a. An electrocardiogram (ECG, EKG) records electrical  changes in the myocardium during a cardiac cycle.   (1) The P wave represents atrial depolarization.  (2) The QRS complex represents ventricular  depolarization.  (3) The T wave represents ventricular repolarization.  13. Regulation of the cardiac cycle   a. Physical exercise, body temperature, and concentration  of various ions affect heart rate.   b. Branches of parasympathetic and sympathetic nerve  fibers innervate the SA and AV nodes.   (1) Parasympathetic impulses decrease heart action;  sympathetic impulses increase heart action.   (2) The cardiac center in the medulla oblongata  regulates autonomic impulses to the heart.    The blood vessels form a closed circuit of tubes that transports  blood between the heart and body cells. The tubes include  arteries, arterioles, capillaries, venules, and veins.  1. Arteries and arterioles  a. The arteries are adapted to transport blood under  relatively high pressure away from the heart.  b. The arterioles are branches of arteries.  c. The walls of arteries and arterioles consist of layers of  endothelium, smooth muscle, and connective tissue.  d. Autonomic fibers innervate smooth muscle in vessel  walls, causing vasoconstriction or vasodilation.  2. Capillaries  Capillaries connect arterioles and venules. The capillary  wall is a single layer of squamous epithelial cells that  forms a semipermeable membrane.  a. Capillary permeability  (1) Openings in the capillary walls are thin slits  between endothelial cells.  (2) The sizes of the openings vary from tissue to tissue.  (3) Endothelial cells of brain capillaries are tightly  fused, forming a blood-brain barrier.  b. Capillary arrangement  Capillary density varies directly with tissue  metabolic rates.  c. Regulation of capillary blood flow  (1) Precapillary sphincters regulate capillary blood flow.  (2) Precapillary sphincters open when cells are low in  oxygen and nutrients and close when cellular needs  are met.  d. Exchanges in the capillaries  (1) Gases, nutrients, and metabolic by-products are  exchanged between the capillary blood and the  tissue fluid.  (2) Diffusion provides the most important means of  transport.  (3) Diffusion pathways depend on lipid solubilities.   (5) Filtration, due to the hydrostatic pressure of blood,  causes a net outward movement of fluid at the  arteriolar end of a capillary.   (6) Colloid osmotic pressure causes a net inward  movement of fluid at the venular end of a capillary.   c. Venous walls are similar to arterial walls but are thinner  and contain less muscle and elastic tissue.   d. Many veins contain flaplike valves that open, allowing  blood to flow to the heart, but close to prevent flow in  the opposite direction.    Blood pressure is the force blood exerts against the inner walls  of blood vessels.  1. Arterial blood pressure  a. The arterial blood pressure is produced primarily by heart  action; it rises and falls with phases of the cardiac cycle.  b. Systolic pressure occurs when the ventricles contract;  diastolic pressure occurs when the ventricles relax.  2. Factors that influence arterial blood pressure  a. Cardiac output, blood volume, peripheral resistance,  and blood viscosity influence arterial blood pressure.  b. Arterial pressure increases as cardiac output, blood  volume, peripheral resistance, or blood viscosity  increases.  3. Control of blood pressure  a. Blood pressure is controlled in part by the mechanisms  that regulate cardiac output and peripheral resistance.  b. Cardiac output depends on the volume of blood  discharged from the ventricle with each beat (stroke  volume) and on the heart rate.   (1) The more blood that enters the heart, the stronger  the ventricular contraction, the greater the stroke  volume, and the greater the cardiac output.   (2) The baroreceptor reflexes involving the cardiac  center of the medulla oblongata regulate heart rate.   c. Changes in the diameter of arterioles, controlled by the  vasomotor center of the medulla oblongata, regulate  peripheral resistance.   a. Venous blood flow is not a direct result of heart action;  it depends on skeletal muscle contraction, breathing  movements, and venoconstriction.   a. Central venous pressure is the pressure in the right  atrium.   b. Factors that influence it alter the flow of blood into the  right atrium.    1. Pulmonary circuit  a. The pulmonary circuit consists of vessels that transport  oxygen-poor blood from the right ventricle to the    alveolar capillaries in the lungs, and vessels that  transport oxygen-rich blood back to the left atrium.   b. Alveolar capillaries exert less pressure than those of the  systemic circuit.   c. Tightly joined epithelial cells of alveolar walls prevent  most substances from entering the alveoli.   d. Osmotic pressure rapidly draws water out of alveoli  into the interstitial fluid, so alveoli do not fill with fluid.   a. The systemic circuit is composed of vessels that lead  from the left ventricle to all body parts (including  vessels supplying the heart itself) and back to the heart.   b. It includes the aorta and its branches as well as the  system of veins that return blood to the right atrium.   a. The branches of the ascending aorta include the right  and left coronary arteries.   b. The branches of the aortic arch include the  brachiocephalic, left common carotid, and left  subclavian arteries.   c. The branches of the descending aorta include the  thoracic and abdominal groups.   d. The abdominal aorta terminates by dividing into right  and left common iliac arteries.   2. Arteries to the brain, head, and neck include branches of  the subclavian and common carotid arteries.  3. Arteries to the shoulder and upper limb   a. The subclavian artery passes into the arm, and in  various regions, it is called the axillary and brachial  arteries.   b. Branches of the brachial artery include the ulnar and  radial arteries.   a. Branches of the subclavian artery and thoracic aorta  supply the thoracic wall.   b. Branches of the abdominal aorta and other arteries  supply the abdominal wall.   a. The common iliac artery supplies the pelvic organs,  gluteal region, and lower limb.   b. The femoral artery of the lower limb becomes the  popliteal artery that branches into the anterior and  posterior tibial arteries.    1. Characteristics of venous pathways  a. The veins return blood to the heart.  b. Larger veins usually parallel the paths of major arteries.  2. Veins from the brain, head, and neck  a. The jugular veins drain these regions.  b. Jugular veins unite with subclavian veins to form the  brachiocephalic veins.  3. Veins from the upper limb and shoulder  a. Sets of superficial and deep veins drain the upper limb.  b. Digital veins drain into pairs of radial veins and ulnar  veins, which merge to form a pair of brachial veins.  c. The major superficial veins are the basilic and cephalic  veins.  d. Basilic and brachial veins merge to form the axillary vein.  e. The median cubital vein in the bend of the elbow is  often used as a site for venipuncture.    4. Tributaries of the brachiocephalic and azygos veins drain  the abdominal and thoracic walls.  5. Veins from the abdominal viscera  a. The blood from the abdominal viscera generally  enters the hepatic portal system and is transported  to the liver.  b. The blood in the hepatic portal system is rich in nutrients.  c. The liver helps regulate the blood concentrations of  glucose, amino acids, and lipids.  d. Phagocytic cells in the liver remove bacteria from the  portal blood.  e. From the liver, hepatic veins transport blood to the  inferior vena cava.  6. Veins from the lower limb and pelvis  a. Sets of deep and superficial veins drain these regions.    circuit delivers oxygen to the body's cells. (p. 557)  The Heart   flows into the , through the mitral valve to the  , and through the to the aorta.   List the vessels through which blood flows from the aorta to   Distinguish between the roles of the SA node and AV node.    Distinguish between an artery and an arteriole. (p. 577)  Explain control of vasoconstriction and vasodilation. (p. 577)  Describe the structure and function of a capillary. (p. 579)    b. The deep veins include the tibial veins, and the  superficial veins include the saphenous veins.   2. Fibrous connective tissue and adipose tissue enlarge the  heart by filling in when the number and size of cardiac  muscle cells fall.   4. Blood pressure increases with age, while resting heart rate  decreases with age.   5. Moderate exercise correlates to lowered risk of heart  disease in older people.    Describe the function of the blood-brain barrier. (p. 580)  Explain control of blood flow through a capillary.   Relate how diffusion functions in the exchange of substances  between blood plasma and tissue fluid. (p. 581)   Explain why water and dissolved substances leave the  arteriolar end of a capillary and enter the venular end.  (p. 581)   Describe the effect of histamine on a capillary. (p. 581)  Distinguish between a venule and a vein. (p. 582)  Explain how veins function as blood reservoirs. (p. 582)    Distinguish between the pulmonary and systemic circuits of  the cardiovascular system. (pp. 590-591)   Explain why the alveoli normally do not fill with fluid. (p. 590)   Discuss the relationship between the major venous pathways  and the major arterial pathways to the head, upper limbs,  abdominal viscera, and lower limbs. (pp. 594-606)    List and discuss changes in the aging cardiovascular system.  (p. 608)    2. Why is ventricular fibrillation more likely to be life-threatening  than atrial fibrillation?    3. How might the results of a cardiovascular exam differ for an  athlete in top condition and a sedentary, overweight individual?    4. Cigarette smoke contains thousands of chemicals, including  nicotine and carbon monoxide. Nicotine constricts blood  vessels. Carbon monoxide prevents oxygen binding to  hemoglobin. How do these two components of smoke affect the  cardiovascular system?    5. Ifa cardiologist inserts a catheter into a patient's right femoral  artery, which arteries will the tube have to pass through to reach  the entrance of the left coronary artery?    6. Given the way capillary blood flow is regulated, do you think it is  wiser to rest or to exercise following a heavy meal? Cite a reason  for your answer.    7. Cirrhosis of the liver, a disease commonly associated with  alcoholism, obstructs blood flow through the hepatic blood  vessels. As a result the blood backs up, and the capillary  pressure greatly increases in the organs drained by the hepatic  portal system. What effects might this increasing capillary  pressure produce, and which organs would it affect?    8. If a patient develops a blood clot in the femoral vein of the left  lower limb and a portion of the clot breaks loose, where is the  blood flow likely to carry the embolus? What symptoms are likely?    Connect Interactive Questions Reinforce your knowledge using  assigned interactive questions covering structures of the heart,  locations of the blood vessels, parts of an ECG, factors that affect  blood pressure, and more.    Connect Integrated Activity Can you predict the effect(s) of  different factors on a patient's blood pressure?    Anatomy & Physiology Revealed Go more in depth into the  human body by exploring cadaver dissections of the heart and  blood vessels, or by viewing animations demonstrating blood    After you have studied this chapter, you should be able to:    16.1 Lymphatic Pathways  1 Describe the functions of the lymphatic vessels. (p. 617)    2 Identify and describe the parts of the major lymphatic  pathways. (pp. 617-618)    3 Describe how tissue fluid and lymph form, and explain  the function of lymph. (p. 620)    4 Explain how lymphatic circulation is maintained, and  describe the consequence of lymphatic obstruction. (p. 621)    5 Describe a lymph node and its major functions.  (pp. 621-623)    6 Identify the locations of the major chains of lymph nodes.  (p. 622)    7 Discuss the locations and functions of the thymus and  spleen. (p. 623)    8 Distinguish between innate (nonspecific) and adaptive  (specific) defenses. (pp. 625-626)    9 List seven innate body defense mechanisms, and  describe the action of each mechanism. (pp. 626-627)    10 Explain how two major types of lymphocytes are  formed and activated and how they function in immune  mechanisms. (pp. 628-630)    12 Discuss the actions of the five types of antibodies.  (pp. 634-635)    15 Explain how hypersensitivity reactions, tissue rejection  reactions, and autoimmunity arise from immune  mechanisms. (pp. 636-640)    16.5 Life-Span Changes  16 Describe life-span changes in immunity. (p. 640)    A falsely colored leukocyte (blue) engulfs rod-shaped Bacillus cereus  bacteria (orange), and will use enzymes to break them down (20,000x).    The lymphatic system is a vast collection of cells and biochemicals  that travel in lymphatic vessels, and the organs and glands that  produce them. The lymphatic system includes a network of ves-  sels that assist in circulating body fluids, so it is closely associ-  ated with the cardiovascular system. The system performs three  important functions: return of interstitial fluid to the blood-  stream, lipid absorption, and defense against disease. The term  immune system is linked with the lymphatic system because  many of the cells that are part of the lymphatic system provide  not only a defense against disease, but also immunity against  future infection.    auto-, self: autoimmune disease—the immune  system attacking the body's own tissues.    The lymphatic (lim-fat’ik) pathways begin as lymphatic capillaries  that merge to form lymphatic vessels. These, in turn, lead to larger  vessels, trunks, and ducts that unite with the veins in the thorax.   Lymphatic vessels transport excess fluid away from the  interstitial spaces in most tissues and return it to the bloodstream  (fig. 16.1). Without the lymphatic system, this fluid would accumu-  late in tissue spaces. Special lymphatic capillaries (lacteals) in the  lining of the small intestine absorb digested fats, then transport the  fats to the venous circulation.   Lymphatic capillaries are microscopic, closed-ended tubes. They  extend into the interstitial spaces, forming complex networks that  parallel the blood capillaries (fig. 16.2). The walls of lymphatic  capillaries, like those of blood capillaries, are formed from a sin-  gle layer of squamous epithelial cells called endothelium. These  thin walls allow tissue fluid (interstitial fluid) from the interstitial  space to enter the lymphatic capillaries. Once inside lymphatic cap-  illaries, the fluid is called lymph (limf). The lymphatic capillaries  merge into lymph vessels.    The walls of lymphatic vessels are similar to those of veins, but  thinner. Each lymphatic vessel is composed of three layers: an  endothelial lining, a middle layer of smooth muscle and elastic  fibers, and an outer layer of connective tissue. The lymphatic ves-  sels are also like some peripheral veins in that they have semilunar  valves, which help prevent backflow of lymph (fig. 16.3).   The larger lymphatic vessels lead to specialized organs called  lymph nodes (limf noddz). These vessels merge into larger lym-  phatic trunks after leaving the lymph nodes.    The lymphatic trunks, which drain lymph from the lymphatic  vessels, are named for the regions they serve. For example, the  lumbar trunk drains lymph from the lower limbs, lower abdomi-  nal wall, and pelvic organs; the intestinal trunk drains the abdomi-  nal viscera; the intercostal and bronchomediastinal trunks drain  lymph from portions of the thorax; the subclavian trunk drains  the upper limb; and the jugular trunk drains portions of the neck    and head. These lymphatic trunks then join one of two collecting  ducts—the thoracic duct or the right lymphatic duct. Figure 16.4  shows the location of the major lymphatic trunks and collecting  ducts, and figure 16.5 shows a lymphangiogram, which is a radio-  graph of lymphatic vessels and lymph nodes.   The thoracic duct is the wider and longer of the two col-  lecting ducts. It originates as an enlarged sac, the cisterna chlyi  (sis-ter’nah ki’li) in the abdomen, and passes upward through the  diaphragm beside the aorta (fig. 16.6a). The thoracic duct ascends  anterior to the vertebral column through the mediastinum, and  empties into the left subclavian vein near the junction of the left  jugular vein. This duct drains lymph from the intestinal, lumbar,  and intercostal trunks, as well as from the left subclavian, left jug-  ular, and left bronchomediastinal trunks.    When a hurricane approaching New England veered inland  unexpectedly, the historic Stockade district of Schenectady,  New York, suddenly was under water as the Mohawk River  overflowed its banks. Residents were evacuated, and when  they returned weeks later to assess the damage, public  health nurses went door to door, warning people about the  dangers of exposure to respiratory irritants such as mold and  assisting them with getting help.   A public health nurse is a registered nurse with  specialized training in community-based care. Training  includes courses in public policy, health administration, and  public health, and being bilingual (such as being fluent in  English and Spanish) is very helpful. Volunteer work at the  community level is a good way to prepare for this career.   Public health nurses work in a variety of facilities. They  may vaccinate children in schools, talk to senior citizens about  coping with chronic illness or physical limitations, educate  parents of preschoolers about avoiding or treating scalp lice,  or conduct a blood pressure screening at a shopping mall.  These health-care professionals are particularly valuable in  underserved communities, where they educate the public and  help them to access health-care services.   In contrast to a nurse in a hospital setting, a public health  nurse must be able to work well with groups. Employment  requires passing a national licensing exam.    The right lymphatic duct originates in the right thorax at the  union of the right jugular, right subclavian, and right bronchome-  diastinal trunks. It empties into the right subclavian vein near the  junction of the right jugular vein.   Lymph from the lower body regions, the left upper limb, and  the left side of the head and neck enters the thoracic duct; lymph  from the right side of the head and neck, the right upper limb, and  the right thorax enters the right lymphatic duct (fig. 16.6). After  lymph leaves the two collecting ducts, it enters the venous system    and becomes part of the plasma just before blood returns to the  right atrium. Figure 16.7 summarizes the lymphatic pathway.    3) Through which lymphatic structures would lymph pass in  traveling from a lower limb back to the bloodstream?   duct  Intercostal :  trunk Intestinal  trunk  Lumbar  Lymphatic trunk  vessel  FIGURE 16.2 Lymphatic capillaries are microscopic, closed-ended  tubes that originate in the interstitial spaces of most tissues.  Lymphatic  vessels    FIGURE 16.4 Lymphatic vessels merge into larger lymphatic trunks,  which, in turn, drain into collecting ducts.    FIGURE 16.3 Light micrograph of the flaplike valve (arrows) within a FIGURE 16.5 fAP|R) A lymphangiogram (radiograph) of the lymphatic  lymphatic vessel (60x). vessels and lymph nodes of the lumbar and upper pelvic regions.    FIGURE 16.6 (AP|R} Lymphatic pathways. (a) The right lymphatic  duct drains lymph from the upper right side of the body, whereas the  thoracic duct drains lymph from the rest of the body. (b) Lymph drainage  of the right breast illustrates a localized function of the lymphatic system.  Surgery to treat breast cancer can disrupt this drainage, causing painful  swelling (edema) in the arm.    FIGURE 16.7 The lymphatic pathway. This pathway is true for both  right and left sides.    Lymph is essentially tissue fluid that has entered a lymphatic  capillary. Therefore, lymph formation depends upon tissue fluid  formation.    Capillary blood pressure filters water and small molecules from the  plasma. The resulting fluid has much the same composition as the  plasma (including nutrients, gases, and hormones), with the impor-  tant exception of the plasma proteins, most of which are too large to  pass through the blood capillary walls. The osmotic effect of these  plasma proteins (called the plasma colloid osmotic pressure) helps  to draw fluid back into the blood capillaries by osmosis.    Filtration from the plasma normally exceeds reabsorption, leading  to the net formation of tissue fluid. This increases the tissue fluid  hydrostatic pressure, the force which moves tissue fluid into lym-  phatic capillaries, forming lymph. In this way, lymph formation pre-  vents the accumulation of excess tissue fluid, or edema (&’de-mah).    5 How do plasma proteins in blood capillaries affect lymph  formation?    Lymph within lymphatic vessels, like venous blood, is under rel-  atively low hydrostatic pressure. It may not flow readily through  the lymphatic vessels without help from contracting skeletal  muscles in the limbs, contraction of smooth muscle in the walls of  the larger lymphatic trunks, and pressure changes from the action  of skeletal muscles used in breathing. Lymph flow peaks during  physical exercise, due to the actions of skeletal muscles and pres-  sure changes associated with breathing.   Contracting skeletal muscles compress lymphatic vessels.  This squeezing action moves the lymph inside lymphatic vessels.  Valves in these vessels prevent backflow, so lymph can only move  toward a collecting duct. Additionally, the smooth muscle in the  walls of the larger lymphatic trunks contracts rhythmically and  compresses the lymph inside, forcing the fluid onward.   Breathing aids lymph circulation by creating a relatively low  pressure in the thorax during inhalation. At the same time, the con-  tracting diaphragm increases the pressure in the abdominal cavity.  Consequently, lymph is squeezed out of the abdominal vessels and  forced into the thoracic vessels. Once again, the valves of the lym-  phatic vessels prevent lymph backflow.   The continuous movement of fluid from interstitial spaces  into blood capillaries and lymphatic capillaries stabilizes the vol-  ume of fluid in these spaces. Conditions that interfere with lymph  movement cause tissue fluid to accumulate in interstitial spaces,  producing edema. This can happen when the extent of a breast  tumor requires that the surgeon remove nearby axillary lymph  nodes, which can obstruct drainage from the upper limb, causing  edema (see fig. 16.6d).   Lymphatic capillaries in the small intestine play a major role in  the absorption of dietary fats (chapter 17, pp. 678-679). Lymph  also returns to the bloodstream most of the small proteins that the  blood capillaries filtered. At the same time, lymph transports for-  eign particles, such as bacteria and viruses, to lymph nodes.   Lymphatic capillaries are adapted to receive proteins and for-  eign particles in a way that blood capillaries are not. The epithelial  cells that form the walls of lymphatic capillaries overlap but are not  attached to each other. This configuration, shown in figure 16.8,  creates flaplike valves in the lymphatic capillary wall. The valves  are pushed inward when the hydrostatic pressure is greater on the  outside of the lymphatic capillary but close when the hydrostatic  pressure is greater on the inside.   The epithelial cells of the lymphatic capillary wall are also  attached to surrounding connective tissue cells by thin protein  filaments. As a result, the lumen of a lymphatic capillary remains  open even when the outside hydrostatic pressure is greater than the  hydrostatic pressure inside the lymph capillary.    6 What factors promote lymph flow?  7 What is the consequence of lymphatic obstruction?    FIGURE 16.8 Tissue fluid enters lymphatic capillaries through flaplike  valves between epithelial cells.    Lymphatic tissue contains lymphocytes, macrophages, and other  cells. The unencapsulated diffuse lymphatic tissue associated with  the digestive, respiratory, urinary, and reproductive tracts is called  the mucosa-associated lymphoid tissue (MALT). Included in the  MALT are compact masses of lymphatic tissue, called lymphatic  nodules, which comprise the tonsils and appendix. These are  described in Chapter 17 (pp. 653-654 and 683-684, respectively).  MALT aggregates of lymphatic nodules, called Peyer’s patches,  are scattered throughout the mucosal lining of the distal portion of  the small intestine.   The lymphatic organs, including the lymph nodes, thymus,  and spleen, are encapsulated lymphatic tissue. A capsule of con-  nective tissue with many fibers encloses each organ.    Lymph nodes vary in size and shape but are usually less than  2.5 centimeters long and are somewhat bean-shaped (fig. 16.9).  Figure 16.10 illustrates a section of a typical lymph node.   Blood vessels and nerves join a lymph node through the  indented region of the node, called the hilum. The lymphatic ves-  sels leading to a node (afferent vessels) enter separately at various  points on its convex surface, but the lymphatic vessels leaving the  node (efferent vessels) exit from the hilum.   The capsule surrounding the lymph node extends into the  node and partially subdivides it into compartments. Masses of  lymphocytes (B cells) and macrophages in the cortex are con-  tained within these lymphatic nodules, also called lymphatic fol-  licles, the functional units of the lymph node. Within the lymph  nodules are germinal centers where B lymphocytes proliferate.    FIGURE 16.9 Lymph enters and leaves a lymph node through  lymphatic vessels.    Spaces in a lymph node, called lymphatic sinuses, provide a  complex network of chambers and channels through which lymph  circulates. Lymph enters a lymph node through afferent lymphatic  vessels, moves slowly through the lymph sinuses, and leaves  through efferent lymphatic vessels (fig. 16.10a).    Superficial lymphatic vessels inflamed in response to bacterial  infection (lymphangitis) appear as red streaks beneath the skin.    Inflammation of the lymph nodes, called lymphadenitis, often  follows. Affected nodes enlarge and may be painful.    Locations of Lymph Nodes  Lymph nodes are found in groups or chains along the paths of the  larger lymphatic vessels throughout the body, but they are not in  the central nervous system. The major locations of lymph nodes,  shown in figure 16.11, are as follows:    1. The lymph nodes in the cervical region follow the lower bor-  der of the mandible, anterior to and posterior to the ears, and  lie deep in the neck along the paths of the larger blood vessels.  These nodes are associated with the lymphatic vessels that drain  the skin of the scalp and face, as well as the tissues of the nasal  cavity and pharynx.   2. Lymph nodes in the axillary region receive lymph from ves-  sels that drain the upper limbs, the wall of the thorax, the mam-  mary glands (breasts), and the upper wall of the abdomen.   3. The lymph nodes in the supratrochlear region are located  superficially on the medial side of the elbow. They often  enlarge in children in response to infections acquired through  cuts and scrapes on the hands.   4. Lymph nodes in the inguinal region receive lymph from  the lower limbs, the external genitalia, and the lower  abdominal wall.    FIGURE 16.10 (AP|R) Lymph node. (a) A section through a lymph  node. (b) Light micrograph of a lymph node (20x).    5. In the pelvic cavity lymph nodes primarily follow the iliac  blood vessels. They receive lymph from the lymphatic vessels  of the pelvic viscera.   6. The lymph nodes in the abdominal cavity form chains along  the main branches of the mesenteric arteries and the abdominal  aorta and receive lymph from the abdominal viscera.   7. The lymph nodes in the thoracic cavity are in the  mediastinum and along the trachea and bronchi. They receive  lymph from the thoracic viscera and from the internal wall of  the thorax.   Lymph nodes have two primary functions: filtering potentially  harmful particles from lymph before returning it to the blood-  stream and monitoring body fluids (immune surveillance) through  the actions of lymphocytes and macrophages. The lymph nodes  and the red bone marrow are centers for lymphocyte production.  Lymphocytes attack viruses, bacteria, and parasitic cells that are  brought to the lymph nodes by lymphatic vessels. Macrophages in  the lymph nodes engulf and destroy foreign substances, damaged  cells, and cellular debris.    ss  R r] -PRACTICE  9 What is the MALT?  10 Distinguish between a lymph node and a lymph nodule.  11 In which body regions are lymph nodes most abundant?    The thymus (thi’mus) is a soft, bilobed gland enclosed in a connec-  tive tissue capsule. It is in the mediastinum, anterior to the aortic arch  and posterior to the upper part of the body of the sternum, and extends  from the root of the neck to the pericardium (fig. 16.12a). The thymus  varies in size and is usually proportionately larger during infancy and  early childhood. After puberty, the thymus shrinks, and in an adult, it  may be small (fig. 16.13). In elderly persons, adipose and other con-  nective tissues replace lymphatic tissue in the thymus.   Connective tissues extend inward from the surface of the thy-  mus, subdividing it into lobules (see fig. 16.12). The lobules  house many lymphocytes that developed from progenitor cells in  the bone marrow. Most of these cells (thymocytes) are inactive;  however, some mature into T lymphocytes, also called T cells,  which leave the thymus and provide immunity. Epithelial cells  in the thymus secrete protein hormones called thymosins, which  stimulate maturation of T lymphocytes.    The spleen (splén) is the largest lymphatic organ. It is in the upper  left portion of the abdominal cavity, just inferior to the diaphragm,  posterior and lateral to the stomach (see fig. 16.12a and reference  plates 4, 5, and 6, pp. 41-43).   The spleen resembles a large lymph node. It is enclosed in con-  nective tissue that extends inward from the surface and partially  subdivides the organ into lobules. The organ also has a hilum on  one surface through which blood vessels and nerves enter. However,  unlike the lymphatic sinuses of a lymph node, the spaces (venous  sinuses) in the spleen are filled with blood instead of lymph.   The tissues in the lobules of the spleen are of two types. White  pulp is distributed throughout the spleen in tiny islands. This tissue  is composed of splenic nodules, which are similar to the lymphatic  nodules in lymph nodes and are packed with lymphocytes. The red  pulp, which fills the remaining spaces of the lobules, includes the  venous sinuses and the space around the venous sinuses. This pulp  contains abundant red blood cells, which impart its color, plus  many lymphocytes and macrophages (fig. 16.14).    Thoracic Cervical  lymph lymph  node node  Axillary  lymph  node  Supratrochlear  lymph  node  Abdominal  lymph  node  Pelvic  Inguinal lymph  lymph node  node  FIGURE 16.11 Locations of major lymph nodes.  fa \    During fetal development, pulp cells of the spleen produce blood  cells, much as red bone marrow cells do after birth. As the time  of birth approaches, the spleen stops producing red blood cells.  However, in certain diseases, such as erythroblastosis fetalis (see  chapter 14, page 551), in which many red blood cells are destroyed,  the splenic pulp cells may resume their hematopoietic activity.    The venous sinuses in the red pulp are quite permeable. Red  blood cells can squeeze through pores in the sinus walls and enter  the surrounding spaces. The older, more fragile red blood cells  may rupture during this passage. Macrophages in the splenic  sinuses remove the resulting cellular debris.   Macrophages engulf and destroy foreign particles, such as  bacteria, that may be carried in the blood as it flows through the  splenic sinuses. Lymphocytes of the spleen, like those of the thy-  mus and lymph nodes, also help defend the body against infec-  tions. Thus, the spleen filters blood much as the lymph nodes filter  lymph. Table 16.1 summarizes the characteristics of the major  organs of the lymphatic system.    FIGURE 16.12 fAP|R) Thymus  and spleen. (a) The thymus is bilobed,  located between the lungs and  superior to the heart. The spleen is  located inferior to the diaphragm and  posterior and lateral to the stomach.  (b) A section through the thymus (15x).  Note how the thymus is subdivided  into lobules. (b)    Lymph nodes In groups or chains along the paths of larger Filter foreign particles and debris from lymph; produce and house  lymphatic vessels lymphocytes that destroy foreign particles in lymph; house macrophages  that engulf and destroy foreign particles and cellular debris carried in lymph    Thymus In the mediastinum posterior to the upper portion Houses lymphocytes; differentiates thymocytes into T lymphocytes  of the body of the sternum    Spleen In the upper left portion of the abdominal cavity, Houses macrophages that remove foreign particles, damaged red blood  inferior to the diaphragm and posterior and lateral cells, and cellular debris from the blood; contains lymphocytes  to the stomach    thymus in the fetus is large, but in the adult is small. Figure is not to scale.    >  R r] PRACTICE  13> Why are the thymus and spleen considered organs of the  lymphatic system?  14 What are the major functions of the thymus and the spleen?    The organs of the lymphatic system also help defend the body  against infection by disease-causing agents, or pathogens (path’o-  jenz). The presence and multiplication of a pathogen in the body  may cause an infection. Pathogens include simple microorganisms  such as bacteria, complex microorganisms such as protozoa, and  spores of multicellular organisms such as fungi. Viruses are patho-  gens, but they are not considered organisms, because their structure  is much simpler than that of a living cell and they must infect a liv-  ing cell to reproduce. An infection may be present even if an indi-  vidual feels well.   The human body can prevent entry of pathogens or destroy  them if they enter. Some mechanisms are quite general and protect    FIGURE 16.14 (§AP|FR} Spleen. (a) The spleen resembles a large  lymph node. (b) Light micrograph of the spleen (40x).    against many types of pathogens, providing innate (nonspecific)  defense. These general responses function the same way regardless  of the type of pathogen or the number of exposures. Such mech-  anisms include species resistance, mechanical barriers, chemi-  cal barriers (enzyme action, interferon, and complement), natural  killer cells, inflammation, phagocytosis, and fever. Other protec-  tive mechanisms are very precise, targeting specific pathogens with  an adaptive (specific) defense, also called immunity. These more  directed responses are carried out by specialized lymphocytes that  recognize foreign molecules (nonself antigens) in the body and act    against them. Together, innate and adaptive defense mechanisms  protect the body against infection. The innate defenses respond  quite rapidly, whereas adaptive defenses develop more slowly.   Species resistance refers to the fact that a species may be resistant  to diseases that affect other species because its cells do not have  receptors for the pathogen or its tissues do not provide the temper-  ature or chemical environment that a particular pathogen requires.  For example, humans are infected by the infectious agents that  cause measles, mumps, gonorrhea, and syphilis, but other animal  species are not. Similarly, humans are resistant to canine distem-  per that affects dogs.    The skin and mucous membranes lining the passageways of the  respiratory, digestive, urinary, and reproductive systems create  mechanical barriers that prevent the entrance of some infectious  agents and provide a first line of defense. As long as these barri-  ers remain intact, many pathogens are unable to penetrate them.  Another protection is that the epidermis sloughs off, removing  superficial bacteria with it. In addition, the mucus coated ciliated  epithelium, described in chapter 19 (p. 737), that lines the respira-  tory passages entraps particles and sweeps them out of the airways  and into the pharynx, where they are swallowed. Hair traps infec-  tious agents associated with the skin and mucous membranes, and  sweat and mucus rinse away microorganisms. Tears, saliva, and  urine also wash away microorganisms before they become firmly  attached. The rest of the nonspecific defenses discussed in this  section are part of the second line of defense.    Enzymes in body fluids provide a chemical barrier to pathogens.  Gastric juice, for example, contains the protein-splitting enzyme  pepsin and has a low pH due to hydrochloric acid in the stomach.  The combined effect of pepsin and hydrochloric acid kills many  pathogens that enter the stomach. Similarly, tears contain the  enzyme lysozyme, which destroys certain bacteria on the eyes. The  accumulation of salt from perspiration also kills certain bacteria on  the skin.   Interferons (in”ter-fér’onz) are proteins that lymphocytes  and fibroblasts produce in response to viruses or tumor cells. Once  released from a virus-infected cell, interferon binds to receptors on  uninfected cells, stimulating them to synthesize proteins that block  replication of a variety of viruses. Thus, interferon’s effect is non-  specific. Interferons also stimulate phagocytosis and enhance the  activity of other cells that help to resist infections and the growth  of tumors.   Other antimicrobial biochemicals are defensins and collec-  tins. Defensins are peptides produced by neutrophils and other  types of granular white blood cells in the intestinal epithelium,  the urogenital tract, the kidneys, and the skin. Recognition of  a nonself cell surface or viral particle triggers the expression  of genes that encode defensins. Some defensins make holes in  bacterial cell walls and membranes, crippling the microbes.    Collectins are proteins that provide broad protection against  bacteria, yeasts, and some viruses. These proteins home in on  slight differences in the structures and arrangements of sugars  that protrude from the surfaces of pathogens. Collectins detect  not only the sugar molecules, but the pattern in which they are  clustered, binding much like velcro clings to fabric, thus making  the pathogen more easily phagocytized.   Complement (kom’plé-ment) is a group of proteins (comple-  ment system), in plasma and other body fluids, that interact in an  expanding series of reactions or cascade. Complement activation  can rapidly occur by the classical pathway when a complement  protein binds to an antibody attached to its specific antigen (dis-  cussed later in this chapter, pp. 634-635), or more slowly by the  alternative pathway triggered by exposure to foreign antigens, in  the absence of antibodies. Activation of complement stimulates  inflammation, attracts phagocytes, and enhances phagocytosis.    Natural killer (NK) cells are a small population of lymphocytes  that are distinctly different from the lymphocytes that provide  adaptive defense mechanisms. NK cells defend the body against  various viruses and cancer cells by secreting cytolytic (“cell-  cutting’) substances called perforins that lyse the cell membrane,  destroying the infected cell. NK cells also secrete chemicals that  enhance inflammation.    Inflammation is a reaction that produces localized redness,  swelling, heat, and pain. The redness is a result of blood vessel  dilation that increases blood flow and volume in affected tissues  (hyperemia). This effect, coupled with an increase in permeabil-  ity of nearby capillaries and subsequent leakage of protein-rich  fluid into tissue spaces, swells tissues (edema). The heat comes  as blood enters from deeper body parts, which are warmer than  the surface. Pain results from stimulation of nearby pain receptors.  Most inflammation is a tissue response to pathogen invasion, but  physical factors (heat, ultraviolet light) or chemical factors (acids,  bases) can also cause it.   White blood cells accumulate at the sites of inflammation,  where some of them help control pathogens by phagocytosis.  Neutrophils are the first to arrive at the site, followed by mono-  cytes. Monocytes pass through capillary walls (diapedesis),  becoming macrophages that remove pathogens from surrounding  tissues. In bacterial infections, the resulting mass of white blood  cells, bacterial cells, and damaged tissue may form a thick fluid  called pus.   Fluids called exudates also collect in inflamed tissues. These  fluids contain fibrinogen and other clotting factors that may  stimulate formation of a network of fibrin threads in the affected  region. Later, fibroblasts arrive and secrete fibers around the  area, enclosing it in a sac of connective tissue. This walling off  of the infected area helps inhibit the spread of pathogens and  toxins to adjacent tissues.   Once an infection is controlled, phagocytic cells remove  dead cells and other debris from the site of inflammation. Cell  division replaces lost cells. Table 16.2 summarizes the process  of inflammation.    Blood vessels dilate. Capillary  permeability increases and fluid  leaks into tissue spaces.    Pus may form as white blood  cells, bacterial cells, and  cellular debris accumulate.    Phagocytosis  Phagocytosis (fag”o-si-to’sis) removes foreign particles from the  lymph as it moves from the interstitial spaces to the bloodstream.  Phagocytes in the blood vessels and in the tissues of the spleen,  liver, or bone marrow usually remove particles that reach the blood.  Recall from chapter 14 (p. 538) that the most active phagocytic cells  of the blood are neutrophils and monocytes. Chemicals released from  injured tissues attract these cells (chemotaxis). Neutrophils engulf and  digest smaller particles; monocytes phagocytize larger ones.  Monocytes that leave the blood differentiate to become mac-  rophages, which may be free or fixed in various tissues, including  the lymph nodes, spleen, liver, and lungs, or attached to the inner  walls of blood and lymphatic vessels. A macrophage can engulf  up to 100 bacteria, compared to the twenty or so bacteria that a  neutrophil can engulf. Monocytes and macrophages constitute the  mononuclear phagocytic system (reticuloendothelial system).    Fever  A fever is a nonspecific defense that offers powerful protection. A  fever begins as a viral or bacterial infection that stimulates lympho-  cytes to proliferate, producing cells that secrete a substance called  interleukin-1 (IL-1), more colorfully known as endogenous pyrogen  (“fire maker from within’’). IL-1 raises the thermoregulatory set point  in the brain’s hypothalamus to maintain a higher body temperature.  Fever indirectly counters microbial growth because higher body  temperature causes the liver and spleen to sequester iron, which  reduces the level of iron in the blood. Because bacteria and fungi  require iron for normal metabolism, their growth and reproduction in  a fever-ridden body slow and may cease. Also, phagocytic cells attack  more vigorously when the temperature rises. For these reasons, low-  grade fever of short duration may be a desired natural response,  not a symptom to be treated aggressively with medications.  Chemical barriers, natural killer cells, inflammation, phago-  cytosis, and fever all provide a second line of defense against  pathogens. Table 16.3 summarizes the types of innate (nonspe-  cific) defenses.    A species is resistant to certain diseases to which  other species are susceptible.    Unbroken skin and mucous membranes prevent the  entrance of some infectious agents. Fluids wash  away microorganisms before they can firmly attach  to tissues.    Enzymes in various body fluids kill pathogens. pH  extremes and high salt concentration also harm  pathogens. Interferons induce production of   other proteins that block reproduction of viruses,  stimulate phagocytosis, and enhance the activity of  cells such that they resist infection and the growth  of tumors. Defensins damage bacterial cell walls  and membranes. Collectins bind to microbes.  Complement stimulates inflammation, attracts  phagocytes, and enhances phagocytosis.    Natural killer Distinct type of lymphocyte that secretes perforins  cells that lyse virus-infected cells and cancer cells.    Fever Elevated body temperature indirectly inhibits  microbial growth and increases phagocytic activity.    ® RECONNECT  ~ To Chapter 6, Clinical Application 6.4, page 191.    The third line of defense, immunity (i-mu’ni-te), is resistance to  specific pathogens or to their toxins or metabolic by-products.  An immune response is based upon the ability to distinguish mole-  cules that are part of the body (“self”’) from those that are not (“non-  self,” or foreign). Such nonself molecules that can elicit an immune  response are called antigens (an’ti-jenz). Lymphocytes and  macrophages that recognize specific nonself antigens carry out  adaptive immune responses, which include the cellular immune  response and humoral immune response. Figure 16.15 shows a  schematic representation of body defenses against pathogens.    Eggs and sperm have the potential of being recognized  as nonself and eliciting an immune response. Fortunately, their  development is hidden from the immune system. Eggs develop within  follicles in the ovary, where they are protected by layers of cells. Soerm  cells developing in the testes are protected by the blood-testis barrier.    ¢ Chemical barriers  (enzymes, pH, salt, interferons,  defensins, collectins, complement)  ¢ Natural killer cells  ¢ Inflammation  e Phagocytosis  ¢ Fever   Before birth, cells inventory the proteins and other large molecules  in the body, learning to identify these as self. The lymphatic sys-  tem responds to nonself antigens, but not normally to self antigens.  Receptors on lymphocyte surfaces enable these cells to recognize  nonself antigens.   Antigens may be proteins, polysaccharides, glycopro-  teins, or glycolipids. The antigens most effective in eliciting an  immune response are large and complex, with few repeating parts.  Sometimes, a smaller molecule that cannot by itself stimulate an  immune response combines with a larger one, which makes it  able to do so (become antigenic). Such a small molecule is called  a hapten (hap’ten). Stimulated lymphocytes react either to the  hapten or to the larger molecule of the combination. Hapten mol-  ecules are in drugs, such as penicillin; in household and industrial  chemicals; in dust particles; and in animal dander.    Lymphocyte Origins  Lymphocyte production begins during fetal development (before  birth) and continues throughout life, with red bone marrow releasing  unspecialized precursors of lymphocytes into the circulation. About  half of these cells reach the thymus, where they remain for a time.  Here, these thymocytes specialize into T lymphocytes, or T cells.  (T refers to thymus-derived lymphocytes.) Some of these T cells con-  stitute 70% to 80% of the circulating lymphocytes in blood. Other  T cells reside in lymphatic organs and are particularly abundant in the  lymph nodes, the thoracic duct, and the white pulp of the spleen.  Other lymphocytes remain in the red bone marrow until they  differentiate fully into B lymphocytes, or B cells. (Historically,  the “B” stands for bursa of Fabricius, an organ in the chicken  where these cells were discovered.) The blood distributes B  cells, which constitute 20% to 30% of circulating lymphocytes  (fig. 16.16). B cells settle in lymphatic organs along with T cells  and are abundant in the lymph nodes, spleen, bone marrow, and  intestinal lining (fig. 16.17).    Each person has millions of varieties of T and B cells. The  members of each variety originate from a single early cell, so they  are all alike, forming a clone (kl6on) of cells (genetically identical  cells originating from division of a single cell). The members of  each variety have a particular type of antigen receptor on their cell  membranes that can respond only to a specific antigen. Table 16.4    Provide cellular  immune response in  which T cells interact  directly with the  antigens or antigen-  bearing agents, to  destroy them    Provide humoral  immune response in  which B cells interact  indirectly, producing  antibodies that  destroy the antigens  or antigen-bearing  agents    @ Stem cells  in red bone  marrow give  rise to  lymphocyte  precursors    @ Some lymphocyte  precursors are  processed in the  thymus to become  T cells    @ Both T cells and B cells  are transported through  the blood to lymphatic  organs, such as the  lymph nodes and  spleen    FIGURE 16.17 During fetal development, red bone marrow releases unspecialized lymphocyte precursors, which after processing specialize as T cells  (T lymphocytes) or B cells (B lymphocytes). Lymphocyte production continues throughout life, with most T cells arising before puberty.    A lymphocyte must be activated before it can respond to an anti-  gen. T cell activation requires that processed fragments of the anti-  gen be attached to the surface of another type of cell, called an  antigen-presenting cell (accessory cell). Dendritic cells located  in the epidermis, mucous membrane, and lymphatic organs may  engulf the antigen by receptor-mediated endocytosis, process  the antigen, and display antigen fragments on their cell surfaces.  Macrophages and B cells can also be antigen-presenting cells.   T cell activation may occur when a macrophage phagocy-  tizes a bacterium, and digests it within a phagolysosome formed  by the fusion of the vesicle containing the bacterium (phago-  some) and a lysosome. Some of the resulting bacterial antigens  are displayed on the macrophage’s cell membrane near certain  protein molecules that are part of a group of proteins called the  major histocompatibility complex (MHC) or human leukocyte    antigens (HLA) because they were first identified on white blood  cells. MHC antigens help T cells recognize that a newly displayed  antigen is foreign, not self. Class I MHC antigens are in cell mem-  branes of all body cells except red blood cells. Class If MHC anti-  gens are on the surfaces of antigen-presenting cells, thymus cells,  and activated T cells.   Activated T cells interact directly with the antigen-presenting  cell. Such cell-to-cell contact is called the cellular immune  response, or cell-mediated immunity.   T cells (and some macrophages) also synthesize and secrete  polypeptides called cytokines that enhance certain cellular  responses to antigens. For example, interleukin-1 and interleukin-2  stimulate synthesis of several other cytokines from other T cells. In  addition, interleukin-1 helps activate T cells, whereas interleukin-2  causes T cells to proliferate. Other cytokines called colony-  stimulating factors (CSFs) stimulate production of leukocytes in the  red bone marrow, cause B cells to grow and mature, and activate  macrophages. Certain cytokine combinations shut off the immune  response. Table 16.5 summarizes several cytokine types.   In addition to cytokines, T cells may secrete other substances.  These include toxins that kill their antigen-bearing target cells,  growth-inhibiting factors that prevent target cell growth, and inter-  ferons that inhibit the proliferation of viruses and tumor cells.    Several types of T cells have specific functions. A particularly  important specialized type of T cell, called a helper T cell, is acti-  vated when its antigen receptor combines with a displayed foreign  antigen (fig. 16.18). The activated helper T cell stimulates a type  of B cell (plasma cell) to produce antibodies specific for the dis-  played antigen.   A subtype of helper T cell called a CD4 cell is the prime target  of HIV, the virus that causes AIDS. (CD4 stands for the “cluster-  of-differentiation” antigen the T cell bears that enables it to recog-  nize a macrophage displaying a foreign antigen.) Considering the  central role of CD4 helper T cells in establishing immunity—they  stimulate B cells and secrete cytokines—it is no wonder that when  HIV harms them, immunity declines.   Another type of T cell is a cytotoxic T cell, which recognizes  and combines with nonself antigens that cancerous cells or virally  infected cells display on their surfaces near certain MHC proteins.  Cytokines from helper T cells activate the cytotoxic T cell (fig.  16.18a). Next the cytotoxic T cell proliferates, enlarging its clone  of cells. Cytotoxic T cells then bind to the surfaces of antigen-  bearing cells, where they release perforin protein that cuts pore-  like openings, destroying these cells. In this way, cytotoxic T cells  continually monitor the body’s cells, recognizing and eliminating  tumor cells and cells infected with viruses.   Certain cytotoxic T cells, called CD8 T cells, give rise to  memory T cells that provide for future immune protection. When  a CD8 T cell contacts an antigen-presenting cell, it contorts into  a dumbbell shape. The side of the dumbbell that contacts the  antigen-presenting cell accumulates different receptors and other  proteins from the side facing farthest from the provoking antigen.  When the CD8 T cell divides, the daughter cell that was the part of  the original cell closest to the antigen becomes an active cytotoxic  T cell. The daughter cell farther from the antigen becomes a mem-  ory T cell. As its name implies, a memory T cell does not respond  to an initial exposure to an antigen, but upon subsequent exposure  immediately divides and differentiates into a cytotoxic T cell. This  memory cell response usually destroys the pathogen before the  body responds to it with the signs and symptoms of disease.    20 How doT cells become activated?  21 What are some functions of cytokines?  22 Name three types of T cells.    B Cells and the Humoral Immune Response  When a B cell encounters an antigen whose molecular shape fits  the shape of the B cell’s antigen receptors, it becomes activated  (fig. 16.18a). In response to the receptor-antigen combination, the  B cell divides repeatedly. Such B cell activation typically requires  T cell “help.”   When an activated helper T cell encounters a B cell already  combined with an identical foreign antigen, the helper T cell releases  certain cytokines that stimulate the B cell to proliferate, enlarging its  clone of cells (fig. 16.19). The cytokines also attract macrophages  and leukocytes into inflamed tissues and help keep them there.    Interferons Block viral replication, stimulate macrophages  to engulf viruses, stimulate B cells to produce  antibodies, attack cancer cells    Tumor necrosis Stops tumor growth, releases growth factors,  factor causes fever that accompanies bacterial  infection, stimulates lymphocyte differentiation    Some members of the activated B cell’s clone differentiate  further into plasma cells, which produce and secrete large globu-  lar proteins called antibodies (an’ti-bod”éz), also termed immuno-  globulins (im”u-no-glob’u-linz). Antibodies are similar in structure  to the antigen-receptor molecules on the original B cell’s surface  (fig. 16.19). An antibody can combine with the antigen on the patho-  gen and react against it. A plasma cell is an antibody factory, as evi-  denced by its characteristically huge Golgi apparatus. At the peak of  an infection, a plasma cell may produce and secrete 2,000 antibody  molecules per second! Body fluids carry antibodies, which then  react in various ways to destroy specific antigens or antigen-bearing  particles. This antibody-mediated immune response is called the  humoral immune response (“humoral” refers to fluid). Table 16.6  summarizes the steps leading to antibody production as a result of  B and T cell activities. T cells can suppress antibody formation by  releasing cytokines that inhibit B cell function.   A single type of B cell carries information to produce a single  type of antibody. However, different B cells respond to different  antigens on a pathogen’s surface. Therefore, an immune response  may include several types of antibodies manufactured against  a single microbe or virus. This involvement of more than one  antibody type is called a polyclonal response. From Science to  Technology 16.1 discusses how researchers use clones of single B  cells to produce single, or monoclonal, antibodies.    | The human body can manufacture more than 1,000,000,000 dif-  ferent antibodies, each reacting against a specific antigen. The  enormity and diversity of the antibody response defends against  many pathogens.   There are a limited number of antibody genes. During the  early development of B cells, sections of their antibody genes  move to other chromosomal locations, creating new genetic  instructions for antibodies. The great diversity of antibody types is  increased further because different antibody protein subunits com-  bine. Antibody diversity is like using the limited number of words  in a language to compose an almost unlimited variety of stories.    Other members of the activated B cell’s clone differentiate  further into memory cells (fig. 16.19). Like memory T cells, these  memory B cells respond rapidly to subsequent exposure to a spe-  cific antigen.    FIGURE 16.18 fAP|R) T cell and B cell activation. (a) Antigen-    presenting cells activate T cells @-© and B cells @®-©®), triggering an  immune response. (b) In the photograph, the small round cells are helper  T cells, and the large cells bearing projections are macrophages (1,040x).    FIGURE 16.19 An activated B cell proliferates after stimulation by cytokines released by helper T cells. The B cell's clone enlarges.  Some cells of the clone give rise to antibody-secreting plasma cells and others to dormant memory cells.    Antibodies are soluble, globular proteins that constitute the  gamma globulin fraction of plasma proteins (see chapter 14,  p. 541). Each antibody molecule consists of four chains of amino  acids linked by pairs of sulfur atoms that attract by disulfide  bonds. The four chains form a Y-shaped structure (fig. 16.20).  Two of these amino acid chains are identical light chains  (L-chains), and two are identical heavy chains (H-chains). The  heavy chains have about twice as many amino acids as the light  chains. The five major types of antibody molecules are distin-  guished by a particular type of heavy chain. Most of the types  of antibody molecules consist of a single Y-shaped structure, but  some have as many as five (see fig. 14.21, p. 550).   The sequences of amino acids of the heavy and light chains  confer the unique, three-dimensional structure (conformation)  of each type of antibody, as is the case for other proteins. This    special conformation, in turn, imparts the physiological prop-  erties of the molecule. One end of each of the heavy and light  chains consists of variable sequences of amino acids (variable  regions). These regions are specialized to fit the shape of a spe-  cific antigen molecule.   Antibodies can bind to certain antigens because of the confor-  mation of the variable regions. The antibody contorts, forming a  pocket around the antigen. These specialized ends of the antibody  molecule are called antigen-binding sites, and the parts that bind  the antigen are called idiotypes (id’e-o-tipz’).   The remaining parts of the heavy and light chains are termed  constant regions because their amino acid sequences are similar.  Constant regions impart other properties of the antibody molecule,  such as its ability to bond to cellular structures or to combine with  certain chemicals (fig. 16.20).    Immunotherapy uses immune system components to fight dis-  ease—both the humoral immune response (antibodies) and the  cellular immune response (cytokines).    Tapping the specificity of a single B cell and using its single type,  or monoclonal, antibody to target a specific antigen (such as on a  cancer or bacterial cell) awaited finding a way to entice the nor-  mally short-lived mature B cells into persisting in culture. In 1975,  British researchers Cesar Milstein and Georges Kohler devised  monoclonal antibody (MAb) technology to capture the antibody-  making capacity of a single B cell.   Milstein and K6hler injected a mouse with antigen-laden red  blood cells from a sheep. They then isolated a single B cell from  the mouse’s spleen and fused it with a cancerous white blood cell  from a mouse. The result was a fused cell, or hybridoma, with a  valuable pair of talents: Like the B cell, it produced large amounts  of a single antibody type; like the cancer cell, it divided continu-  ously (fig. 16A). Human versions of MAbs are now used.   MAbs are important in basic research, veterinary and human  health care, and agriculture. Cell biologists use MAbs to localize and  isolate proteins. Diagnostic MAb “kits” detect tiny amounts of a sin-  gle molecule. Most kits consist of a paper strip containing a MAb,  to which the user adds a body fluid. For example, a woman who  suspects she is pregnant places drops of her urine onto the paper.  A color change ensues if the MAb binds to the hormone human cho-  rionic gonadotropin (see chapter 23, p. 872), indicating pregnancy.   MAbs can highlight a new cancer or detect recurrence. The  MAb is attached to a radioactive chemical, which emits a signal  when the MAb binds an antigen unique to the cancer cell surface.   MAbs can ferry conventional cancer treatments or radioac-  tive chemicals to tumors and spare healthy tissue. MAbs can also  combat cancer directly by blocking receptors for growth factors  on cancer cells, so the cells do not receive signals to divide.    Cytokines  Immunotherapy experiments were difficult to do before the 1970s  because cytokines and antibodies could be obtained only in small    Types of Immunoglobulins  Three of the five major types of immunoglobulins include  most of the circulating antibodies. These types are immuno-  globulin G, which accounts for about 80% of the antibodies;  immunoglobulin A, which makes up about 13%; and immuno-  globulin M, responsible for about 6%. The remainder of the anti-  bodies are immunoglobulin D or immunoglobulin E.  Immunoglobulin G (IgG) is in plasma and tissue fluids and  is effective against bacteria, viruses, and toxins. IgG also acti-  vates complement proteins (see p. 626; also see the next section  “Antibody Actions’’). Anti-Rh antibodies are examples of IgG and,  as described in chapter 14 (p. 551), can cross the placenta.  Immunoglobulin A (IgA) is in exocrine gland secretions. It is  in breast milk, tears, nasal fluid, gastric juice, intestinal juice, bile,  and urine.   Interferon was the first cytokine tested on a large scale. It is  used to treat a few conditions, including a type of leukemia, multiple  sclerosis, hepatitis, and genital warts. Interleukin-2 is used to treat  metastatic melanoma and metastatic kidney cancer, and colony-  stimulating factors boost the white blood cell supply in people  receiving drugs to treat cancer or AIDS, or transplant recipients.   Increasingly, cancer treatment consists of combinations of  immune system cells or biochemicals, plus standard therapies.  Immunotherapy can enable a patient to withstand higher doses  of a conventional drug or may be used to directly destroy cancer  cells remaining after standard treatment.    FIGURE 16A Monoclonal antibodies are produced by a type of  artificial cell combination called a hybridoma. It consists of a cancer  cell (the flat blue cell) fused with a B cell (the round green cell). The  cancer cell contributes rapid and continuous division; the B cell  secretes a single antibody type (7,000x).    A newborn does not yet have its own antibodies but has IgG  that passed through the placenta from the mother that pro-  tect the infant against some illnesses to which the mother is  immune. The maternally obtained antibodies begin to dis-  appear just about when the infant begins to make its own  antibodies. The newborn also receives IgA from colostrum,  a yellowish fluid that the mother’s breasts secrete for the  first few days after giving birth, and then from breast milk.  Antibodies in colostrum and breast milk protect against cer-  tain digestive and respiratory infections.    . Either alone or more often in conjunction with helper T cells, the  B cell is activated. The B cell proliferates, enlarging its clone.    . Some of the newly formed B cells differentiate further to  become plasma cells.    . Plasma cells synthesize and secrete antibodies whose  molecular structure is similar to the activated B cell’s antigen  receptors.    2. An accessory cell, such as a macrophage, phagocytizes the  antigen-bearing agent, and the macrophage’s lysosomes  digest the agent.    3. Antigens from the digested antigen-bearing agents are  displayed on the membrane of the accessory cell.    4. Helper T cell becomes activated when it encounters a  displayed antigen that fits its antigen receptors.    5. Activated helper T cell releases cytokines when it encounters  a B cell that has previously combined with an identical  antigen-bearing agent.    7. Some of the newly formed B cells give rise to cells that  differentiate into antibody-secreting plasma cells.    Immunoglobulin M (IgM) is a type of antibody produced in  plasma in response to contact with certain antigens in foods or bacte-  ria. Examples of IgM are the anti-A and anti-B antibodies, described  in chapter 14 (pp. 548-549). IgM also activates complement.   Immunoglobulin D (IgD) is on the surfaces of most B cells,  especially those of infants. IgD acts as an antigen receptor and is  important in activating B cells (see fig. 16.18).   Immunoglobulin E (IgE) appears in exocrine secretions with  IgA. It is associated with allergic responses (see “Hypersensitivity  Reactions” on pages 636-638). Table 16.7 summarizes the major  immunoglobulins and their functions.    25 How does the antibody response protect against many different  infections?    27 Describe the structure of an immunoglobulin molecule, and  name the five major types of immunoglobulins.    In general, antibodies react to antigens in three ways. Antibodies  directly attack antigens, activate complement, or stimulate localized  changes (inflammation) that help prevent spread of the pathogen.    FIGURE 16.20 An antibody (immunoglobulin) molecule consists  basically of two identical light chains of amino acids and two identical  heavy chains of amino acids.    Plasma and tissue Defends against bacteria, viruses,  fluid and toxins; activates complement    Plasma Reacts with antigens on some red  blood cell membranes following  mismatched blood transfusions;  activates complement    In a direct attack, antibodies combine with antigens and cause  them to clump (agglutination) or to form insoluble substances (pre-  cipitation). Such actions make it easier for phagocytic cells to engulf  the antigen-bearing pathogens and eliminate them. In other instances,  antibodies bind to and cover the toxic parts of antigen molecules.  This neutralizes the effects (neutralization) of the antigen molecules.  However, under normal conditions, complement activation is more  important in protecting against infection than is direct antibody attack.   When certain IgG or IgM antibodies combine with antigens, they  expose reactive sites on the antibody constant regions. This triggers  a series of reactions leading to activation of complement proteins.  Activated complement proteins coat the antigen-antibody complexes  (opsonization), making the complexes more susceptible to phagocyto-  sis; attract macrophages and neutrophils into the region (chemotaxis);  agglutinate antigen-bearing cells; rupture cell membranes (lysis) of    foreign cells; and neutralize viruses by altering their molecular struc-  ture, making them harmless. Other proteins promote inflammation,  which helps prevent the spread of infectious agents.   Immunoglobulin E promotes inflammation that may be so  intense that it damages tissues. This antibody is usually attached  to the membranes of widely distributed mast cells (see chapter 5,  p. 160). When antigens combine with the antibodies, the result-  ing antigen-antibody complexes stimulate mast cells to release  biochemicals, such as histamine, that cause the changes associated  with inflammation, such as vasodilation and edema. Table 16.8  summarizes the actions of antibodies.    The immune response occurs in two parts. A primary immune  response occurs when B cells and T cells become activated after first  encountering the antigens for which they are specialized to react.  During this response, plasma cells release antibodies (IgM, followed  by IgG). The antibodies are carried by the blood throughout the  body, where they help destroy antigen-bearing agents. Production  and release of antibodies continues for several weeks, maintaining  higher numbers of antibodies in the plasma. The antibody titer is the  number of circulating antibodies in the bloodstream.   After a primary immune response, some of the B cells produced  during proliferation of the clone will serve as memory cells (see  fig. 16.19). If the same type of antigen is encountered in the future,  the clones of these memory cells enlarge, and they can respond rap-  idly with IgG. These memory B cells along with memory T cells  produce a secondary immune response (anamnestic response). In  lymph nodes, follicular dendritic cells may help memory by harbor-  ing and slowly releasing viral antigens after an initial infection. This    General Type of  Action Effect Description  Direct Attack  Agglutination Antigens clump  Precipitation Antigens become insoluble  Neutralization Antigens lose toxic properties  Activation of  Complement Opsonization Alters antigen cell membranes  (Antibodies so cells are more susceptible  combined with to phagocytosis  antigens)  | Chemotaxis Attracts macrophages and  neutrophils into the region  Agglutination Clumps antigen-bearing cells  Lysis Allows rapid movement of  water and ions into the foreign  cell causing osmotic rupture of  the foreign cell  Neutralization Alters the molecular structure of  viruses, making them harmless  Localized  Changes    exposure constantly stimulates memory B cells, which present the  antigens to memory T cells, maintaining immunity.   A primary immune response leads to detectable concentra-  tions of antibodies in the plasma within five to ten days after expo-  sure to antigens. If the same type of antigen is encountered again  later, a secondary immune response may produce additional anti-  bodies within a day or two (fig. 16.21). Although newly formed    FIGURE 16.21 A primary immune response occurs after the first exposure to an antigen. A secondary immune response occurs after subsequent  exposure(s) to the same antigen. The break in the time line represents a lapse between initial and subsequent exposure(s) to the antigen.    @ Which immune response produces antibodies to a specific antigen more rapidly, primary or secondary?    antibodies may persist in the body for only a few months or years,  memory cells live much longer. A secondary immune response  may be very long-lasting.    Before vaccines against “childhood diseases” began to be devel-  oped in the 1960s, suffering through measles, mumps, rubella, and  chickenpox was common. However, most children had each illness  only once, thanks to naturally acquired active immunity. This form  of immunity develops after a primary immune response and is a  response to exposure to a live pathogen.   Today, most children in developed countries do not contract  measles, mumps, rubella, or chickenpox because they develop  another type of active immunity, produced in response to receiv-  ing a vaccine (vak’sén). A vaccine is a preparation that includes an  antigen that can stimulate a primary immune response against a par-  ticular pathogen but does not produce symptoms of the associated  infectious disease.   A vaccine might include bacteria or viruses that have been  killed or attenuated (weakened) so that they cannot cause a serious  infection, or a toxoid, which is a toxin from an infectious organism  that has been chemically altered to destroy its dangerous effects. A  “subunit” vaccine consists of a single glycoprotein or similar large  molecule from the pathogen’s surface, which provides enough of  a foreign antigen to alert the immune system. A vaccine causes a  person to develop artificially acquired active immunity.   Individuals receive vaccines, but the ultimate effect is at the  population level. If a critical number of people are vaccinated,  becoming immune, the infectious agent can no longer easily pass  from person to person. This population protection that results from  widespread vaccination is called herd immunity.   Viruses whose genetic material rapidly mutates present a great  challenge to vaccine development because their surfaces, which  serve as antigens, change. It is a little like fighting an enemy who is  constantly changing disguises. For this reason, pharmaceutical com-  panies must develop a new vaccine against influenza each year. HIV  is particularly changeable, which has severely hampered efforts to  produce a vaccine.    Vaccines stimulate active immunity against a variety of diseases,  including typhoid fever, cholera, whooping cough (pertussis),  diphtheria, tetanus, polio, influenza, hepatitis A and B, and bac-  terial pneumonia. A vaccine has eliminated naturally acquired  smallpox from the world.   For some infections, developing a vaccine is challenging.  This is the case for norovirus infection, also known as “winter  vomiting disease.” The virus and receptors for it on small intes-  tine lining cells are diverse, so the virus always finds a place to  infect. Norovirus passes readily in feces and vomit, especially  in crowded areas such as on cruise ships and in schools. Some  people do not develop symptoms, yet can pass the virus, and  immunity does not last until the next winter.    In some situations a person who has been exposed to infection  needs protection against a pathogen but lacks time to develop active  immunity from a vaccine. This happens with hepatitis A, which is a    viral infection of the liver. In such a case, it may be possible to inject  the person with antiserum, which has ready-made antibodies from  gamma globulin separated from the blood plasma of people who  have already developed immunity against the disease.   An injection of antiserum (antibody-rich serum) or antitoxin  (antibodies against a toxin) provides artificially acquired passive  immunity. It is called passive because the recipient’s cells do not  produce the antibodies. Such immunity is short-term, seldom lasting  more than a few weeks. Furthermore, because the recipient’s lym-  phocytes might not have time to react to the pathogens for which  protection was needed, susceptibility to infection may persist.   During pregnancy, certain antibodies (IgG) pass from the  maternal blood into the fetal bloodstream. Receptor-mediated endo-  cytosis (see chapter 3, p. 104) using receptor sites on cells of the  fetal yolk sac accomplishes the transfer. These receptor sites bind to  a region common to the structure of IgG molecules. After entering  the fetal cells, the antibodies are secreted into the fetal blood. The  fetus acquires limited immunity against the pathogens for which the  pregnant woman has developed active immunities. Thus, the fetus  has naturally acquired passive immunity, which may persist for six  months to a year after birth. The newborn may naturally acquire  passive immunity through breast milk as well. Table 16.9 summa-  rizes the types of immunity.    A hypersensitivity reaction is an exaggerated immune response to  a non-harmful antigen. In all hypersensitivities, the individual is  pre-sensitized to a particular antigen. Some hypersensitivities can  affect almost anyone, but others happen only to people with an  inherited tendency toward an exaggerated immune response.   A type I hypersensitivity (immediate-reaction hypersensitivity)  is commonly called an allergy and the antigens that trigger aller-  gic responses are called allergens (al’er-jenz). In a type I hyper-  sensitivity a person becomes sensitized by producing IgE antibodies  in response to a certain allergen. In the initial exposure to the  allergen, IgE attaches to the cell membranes of widely distrib-  uted mast cells and basophils. When a subsequent exposure to the  same allergen occurs, these cells rapidly release allergy mediators  such as histamine, prostaglandin D2, and leukotrienes (fig. 16.22).  This subsequent reaction occurs within seconds, therefore the  term “immediate-reaction”.   The effect of an allergy depends on how widespread the  response is. Allergy mediators dilate arterioles and increase  vascular permeability, causing edema and also contraction of  bronchial and intestinal smooth muscle and increased mucus  production. The overall result is an inflammatory reaction  responsible for the symptoms of the allergy, such as hives, hay  fever, asthma, eczema, or gastric disturbances. Anaphylaxis is a  severe form of immediate-reaction hypersensitivity and may be  life threatening. Large amounts of histamine and other allergy  mediators spread throughout the body. The person may at first   (a) B cells contact the allergen, and subsequent contact with  the allergen leads to mast cells releasing allergy mediators,  which cause the symptoms of the allergy attack. (b) A mast  cell releases histamine granules (1,750x).    Exposure to a vaccine containing weakened  or dead pathogens or their components    Antibodies passed to fetus from pregnant  woman with active immunity or to newborn    feel an inexplicable apprehension, and then suddenly, the entire  body itches and breaks out in red hives. Vomiting and diarrhea  may follow, and systemic vasodilation may lead to anaphylac-  tic shock. The face, tongue, and larynx may swell from edema,  and breathing become difficult. Anaphylactic shock most often  results from an allergy to penicillin or from insect stings, but  thanks to prompt medical attention and avoidance of allergens  by people who know they have allergies, fewer than 100 people  a year die of it.    Immediate-reaction allergies may result from the dry, cracked  skin of eczema early in life. When tiny cuts in dry skin allow  allergens to penetrate, dendritic cells signal inflammation and  eczema results. At the same time, the dendritic cells activate  immune memory. Years later, inhaling the same allergens that  once crossed the broken skin triggers hay fever and asthma.    Peanut allergy is also linked to early breaks in the skin. One  in ten people inherit a mutation in a gene that encodes a skin  protein called filaggrin, causing the early cracked skin and set-  ting the stage for later allergy. Researchers are investigating  whether treatment of dry skin in childhood can prevent develop-  ment of allergies.    Hypersensitivities that involve IgG (sometimes IgM) anti-  bodies and take one to three hours to develop include type II  (antibody-dependent cytotoxic reactions) and type II (immune  complex reactions). In a type II reaction, an antigen binds to a  specific cell, stimulating phagocytosis and complement-mediated  lysis of the antigen. A transfusion reaction to mismatched blood is  a type II hypersensitivity reaction.   In a type III reaction, soluble antibody-antigen complexes form  and deposit in certain tissues. There they can trigger tissue dam-  age through phagocytosis or complement binding. Rheumatoid  arthritis is an example of a Type III hypersensitivity reaction, and  because the antibody-antigen complexes that deposit in the joints  trigger an immune response, it is also an example of autoimmunity.  Autoimmunity is discussed further on the next page.    A type IV (delayed-reaction hypersensitivity) may affect  anyone. It results from repeated exposure of the skin to cer-  tain chemicals—commonly, household or industrial chemicals  or some cosmetics. Eventually the foreign substance activates  T cells, many of which collect in the skin. The T cells and the  macrophages they attract release chemical factors, which, in turn,  cause eruptions and inflammation of the skin (dermatitis). This  reaction is called delayed because it usually takes about forty-  eight hours to begin. Table 16.10 summarizes the responses of, and  provides examples for, the four types of hypersensitivity reactions.    The tuberculin skin test is used to detect individuals who are sus-  pected of having tuberculosis (TB), who have had it (or a closely  related infection), or have been exposed to it. The test (Mantoux  test) introduces a tuberculin preparation called purified protein  derivative (PPD) into the superficial layers of the skin. If the per-  son's T cells have been sensitized to the antigens of the myco-  bacteria that cause tuberculosis, a Type IV reaction ensues within  forty-eight to seventy-two hours, and a localized region of the  skin and subcutaneous tissue hardens (indurates). The absence  of this reaction (negative result) signifies that the person’s T cells  have not previously encountered these mycobacterial antigens.    Transplantation and Tissue Rejection  When a car breaks down, replacing the damaged or malfunction-  ing part often fixes the trouble. The same is sometimes true for  the human body. Transplanted tissues and organs include bone,  corneas, kidneys, lungs, pancreases, bone marrow, pieces of skin,  livers, and hearts. A transplant is risky. The recipient’s cells may  recognize the donor’s tissues as foreign and attempt to destroy  the transplanted tissue in a tissue rejection reaction. If the trans-  planted tissue is immunologically active, as is bone marrow, it may  produce molecules that harm the recipient’s tissue, in a response  called graft-versus-host disease (GVHD).   Tissue rejection resembles the cellular immune response  against a foreign antigen. The greater the antigenic difference  between the cell surface molecules (MHC antigens, discussed    Type | (immediate-reaction)  Type II (antibody-dependent cytotoxic reaction)  Type III (immune complex reaction)    earlier in this chapter on page 629) of the recipient tissues and the  donor tissues, the more rapid and severe the rejection reaction.  Matching the cell surface molecules of donor and recipient tissues  as closely as possible can minimize the rejection reaction. This  means locating a donor whose tissues are antigenically similar to  those of the person needing a transplant.   * autograft, tissue from elsewhere in a person’s body  (Technically, this is not a transplant because it is within an  individual.)   ¢ allograft, tissue from another person who is not an identical twin   * xenograft, tissue from a different species, such as pigs and  baboons    Table 16.11 presents examples of transplants.  Immunosuppressive drugs are used to reduce the recipient  immune system’s rejection of transplanted tissue. These drugs  suppress T cell or antibody production, thereby dampening the  cellular and humoral immune responses, which may also make  the recipient more susceptible to infection. Severe side effects,  including kidney damage and cancer, may result from use of  immunosuppressive drugs. When they first came into use, in the  1980s, immunosuppressive drugs were typically given for the  remainder of the recipient’s life. That approach is now less com-  mon, as cases accumulate of patients who received well-matched  transplants and are surviving without continued immunosuppres-  sive therapy. These patients received, along with standard trans-  plants such as kidneys, bone marrow stem cells from the donors.  Apparently the influx of donor cells establishes a “stable coexis-  tence” with the recipient’s cells—they accept each other. When  this balance is disturbed, tissue rejection or graft-versus-host    Overproduction of IgE antibodies  Phagocytosis and complement-mediated lysis of antigen  Phagocytosis and lysis cannot clear antigen-antibody complexes    disease can result. Researchers hypothesize that bombarding the  recipient’s body with immunosuppressive drugs immediately  after the transplant can disturb this process. The emerging new  view is to give the drugs before the transplant, and in some cases  minimize their use after.    The immune system can fail to distinguish self from nonself,  producing antibodies, called autoantibodies, and cytotoxic  T cells that attack and damage the body’s tissues and organs.  This attack against self is called autoimmunity. The signs and  symptoms of autoimmune disorders reflect the affected cell  types. In autoimmune hemolytic anemia, autoantibodies destroy  red blood cells. Autoimmune ulcerative colitis harms colon cells  and severe abdominal pain results. Table 16.12 lists some auto-  immune disorders.   Why might the immune system attack body tissues? Perhaps  a virus, while replicating in a human cell, takes proteins from the  host cell’s surface and incorporates them onto its own surface.  When the immune system “learns” the surface of the virus in order  to destroy it, it also learns to attack the human cells that normally  bear those particular proteins. Another explanation of autoimmu-  nity is that somehow T cells never learn to distinguish self from  nonself, like a soldier unable to recognize his country’s uniform.   A third possible route of autoimmunity is when a nonself anti-  gen coincidentally resembles a self antigen. For example, dam-  age to heart valve cells in acute rheumatic fever is due to attack  by antibodies present from a recent throat infection with group A  streptococcus bacteria. The surfaces of the cells that make up the  heart valve resemble those of the bacteria.   Some disorders thought to be autoimmune may have a  stranger cause—fetal cells persisting in a woman’s circulation for  decades. In response to an as yet unknown trigger, the fetal cells, per-  haps “hiding” in a tissue such as skin, emerge, stimulating antibody  production. The resulting antibodies and symptoms appear to be  an autoimmune disorder. The presence of more than one geneti-  cally distinct cell population in an individual is called micro-  chimerism (“small mosaic’). Microchimerism that reflects the  retention of cells from a fetus may explain the higher prevalence  of autoimmune disorders among women. It is seen in a disorder  called scleroderma, which means “hard skin.”   Scleroderma, which is four times more common in women,  typically begins between ages forty-five and fifty-five. It is  described as “the body turning to stone.” Symptoms include  fatigue, swollen joints, stiff fingers, and a masklike face. The  hardening may affect blood vessels, the lungs, and the esophagus.    Clues that scleroderma is a delayed response to persisting fetal  cells include the following observations:   e Symptoms resemble those of graft-versus-host disease  (GVHD), in which transplanted tissue produces chemicals  that destroy the recipient’s tissues.   ¢ Mothers who have scleroderma and their sons have cell  surfaces more similar than those of unaffected mothers and  their sons. Perhaps the similarity of cell surfaces enables  the fetal cells to escape destruction by the woman’s immune  system. Female fetal cells probably have the same effect,  but they are not observable because the method used to  detect fetal cells identifies a DNA sequence unique to the  Y chromosome (which is only in males.)    Perhaps other disorders considered autoimmune reflect an immune  system response to lingering fetal cells.    33 How are allergic reactions and immune reactions similar yet different?  34 How does a tissue rejection reaction involve an immune response?    35 How is autoimmunity an abnormal functioning of the immune  response?    The immune system begins to decline early in life. The thymus  reaches its maximal size in adolescence and then slowly shrinks.  By age seventy, the thymus is one-tenth the size it was at the age of  ten, and the immune system is only 25% as powerful.    The declining strength of the immune response is why elderly  people have a higher risk of developing cancer and succumb more  easily to infections that they easily fought off at an earlier age, such  as influenza, tuberculosis, and pneumonia. HIV infection progresses  to AIDS faster in people older than forty. AIDS is more difficult to  diagnose in older people, sometimes because physicians do not ini-  tially suspect the condition, instead attributing the fatigue, confu-  sion, loss of appetite, and swollen glands to other causes. However,  11% of new cases of AIDS occur in those over age fifty.   Interestingly, numbers of T cells diminish only slightly with  increasing age, and numbers of B cells not at all. However, activ-  ity levels change for both types of lymphocytes. Because T cell  function controls production of B cells, effects on B cells are sec-  ondary. The antibody response to antigens slows, and as a result,  vaccines may require an extra dose. The proportions of the dif-  ferent antibody classes shift, with IgA and IgG increasing, and  IgM and IgE decreasing. A person may produce more autoanti-  bodies than at a younger age, increasing the risk of developing an  autoimmune disorder.   Elderly people may not be candidates for certain medical  treatments that suppress immunity, such as cancer chemotherapy  and steroids to treat inflammatory disorders, because of the declin-  ing function of the immune system. Overall, the immune system  enables us to survive in a world that is home to many microorgan-  isms. Clinical Application 16.1 looks at the devastation of immu-  nity that is AIDS.    36 At about what age is the thymus at its largest?    37 Explain how the strength of the immune response declines in  elderly people. Hf    In the early 1980s, physicians from large cities began report-  ing cases of rare infections in otherwise healthy young men who  also had severe cases of more common infections, such as herpes  simplex virus and cytomegalovirus. Some of the men contracted  infections known only in nonhuman animals, and conditions known  only in individuals with suppressed immune systems, particularly  pneumonia caused by the fungus Pneumocystis jiroveci and a can-  cer, Kaposi sarcoma (fig. 16B). The infections were opportunistic,  which means that they seemed to take advantage of a weakened  immune system.   These young men were among the first to have been infected  with the human immunodeficiency virus (HIV). Table 16A lists how  HIV is, and isn’t, spread. The infection typically remains silent  for several years and then may progress to acquired immune  deficiency syndrome, or AIDS, which starts with recurrent fever,  weakness, and weight loss. Then, usually after a healthy period,  opportunistic infections begin.    How HIV Ravages the Immune System  First HIV crosses a mucosal barrier, such as in the anus or vagina    was a rare cancer seen only in elderly Jewish and Italian men and in  people with suppressed immune systems. In these groups, it produces    these cells and later in helper T cells, the virus adheres with a sur-  face protein, called gp120, to two receptors on the host cell sur-    face, called CD4 and CCR5. Once the virus enters the cell, a viral purplish patches on the lower limbs, but in AIDS patients, Kaposi  enzyme (reverse transcriptase) catalyzes construction of a DNA sarcoma patches appear all over the body and sometimes internally,  strand complementary to the viral RNA sequence (the virus has too. These lower limbs display characteristic lesions.   Sexual contact, particularly anal intercourse, but also vaginal intercourse and oral sex  Contaminated needles (intravenous drug use, injection of anabolic steroids, accidental needle stick in medical setting)  During birth from infected mother    RNA as its genetic material). Synthesis of a second DNA strand  complementary to the first results in a viral DNA double helix,  which is transported into the cell’s nucleus and inserted into a  chromosome. The cell then uses the viral DNA sequences to mass-  produce pieces of HIV, which are then assembled into new viral  particles that burst from the cell.   Once infected helper T cells start to rapidly die, bacterial  infections begin because B cells aren't activated to produce anti-  bodies. Much later in infection, HIV variants arise that bind to  receptors called CXCR4 on cytotoxic T cells, killing them, too.  Loss of these cells renders the body vulnerable to other infec-  tions and to cancers. More than 200 drugs are used to treat AIDS-  associated infections and cancers.   HIV replicates quickly and its surface features are altered  by mutation in ways that evade recognition and attack by the  immune system. The virus is especially prone to mutation,  because it cannot repair DNA replication errors. The immune sys-  tem cannot keep up; antibodies against one viral variant are use-  less against another.    Within days of initial infection, viral variants arise that resist  drugs used to treat HIV infection and AIDS. Combining drugs  that act at different steps in infection minimizes the number of  viruses (viral load) and delays symptom onset and progression.  This approach is called “combined antiretroviral therapy” (cART),  formerly called “highly active antiretroviral therapy,” or HAART.  These drugs block HIV from binding to cells, fusing with the cell  membrane, entering the cell, replicating viral genetic material,  or processing viral proteins to functional sizes. Many people with  HIV infection who use antiretroviral drugs can keep their viral  levels low enough to stay healthy. The World Health Organiza-  tion now recommends that cART start within hours of birth for  newborns infected with HIV, after case reports demonstrated the    ability of the drugs to lower viral RNA to undetectable levels. An  ongoing clinical trial is evaluating the long-term efficacy of treat-  ing newborns with cART.   A different approach to treating HIV infection mimics the few  lucky people who inherit a double dose of a mutation that pre-  vents their cells from making the CCR5 receptor that HIV requires  to enter cells. A drug blocks the CCR5 receptor, and bone mar-  row stem cell transplants replace a patient’s cells with cells lacking  CCRS. A variation on this strategy alters a patient's own cells, per-  manently. The idea arose in 2008 when a forty-year-old man with  HIV infection and leukemia, known first as “the Berlin patient” but  then identifying himself as Timothy, received a stem cell trans-  plant from a donor who had the CCR5 mutation. Timothy was  apparently cured of both the leukemia and the HIV infection as  his T cells became incapable of manufacturing the receptor that  the virus requires to enter. An ongoing clinical trial in the United  States is giving patients their own blood stem cells after the cells  have been removed and their CCR5 genes replaced with nonfunc-  tional ones. So far, this gene therapy has delayed the course of  AIDS in a dozen patients.    Developing a vaccine for HIV/AIDS has been challenging, both  because of the great variability of HIV and the difficulty of testing  a vaccine. A live vaccine is too dangerous; a killed vaccine does  not generate a sufficient immune response; and insertion of viral  genetic material into human chromosomes happens too fast for  antibodies or memory cells to form. Some clinical trials did not  go on for long enough to see an effect. Many people dropped  out of clinical trials or failed to comply with complex drug regi-  mens. HIV infection may be prevented in other ways, including  education about reducing risk factors, and giving infected preg-  nant women antiretroviral drugs to prevent transmission of the  virus to offspring.    The lymphatic system is an important link  between tissue fluid and the plasma; it  also plays a major role in the body's  response to infection.    Cells of the immune  system patrol the  respiratory system  to defend against  infection.    inhibit the female  immune system in  its attack of sperm  as foreign invaders.    16.1 Lymphatic Pathways (page 617) 1. Lymph nodes  i: omenae ‘lari Lymph nodes are typically bean-shaped, enclosed  er te see ° . ; ; in connective tissue that extends into the nodes and  a. Lymphatic capillaries are TMCTOSCOPICs closed-ended subdivides them into nodules which contain masses of  tubes that extend ia interstitial Spa lymphocytes and macrophages and spaces through which  b. They receive tissue fluid through their thin walls. lymph flows  eo: Temes Heals ; a. Locations of lymph nodes  as Lymphatic vessels are formed by the merging of (1) Lymph nodes aggregate in groups or chains along  lymphatic capillaries. ; . the paths of larger lymphatic vessels.  b. They have walls similar to veins, only thinner, and (2) They are in the cervical, axillary, supratrochlear,  possess valves that prevent backflow of lymph. and inguinal regions and in the pelvic,  c. The larger lymphatic vessels lead to lymph nodes and abdominal. and thoracic cavities  . . 9 7  then merge into lymphatic trunks. b. Functions of lymph nodes  3. Lymphatic unk and awe ducts : (1) Lymph nodes filter potentially harmful foreign  a. Lymphatic trunks drain lymph from large body regions. particles from the lymph before it is returned to the  b. Trunks lead to two collecting ducts—the thoracic bloodstream.  duct and the right lymphatic duct. : (2) Lymph nodes are centers for the production of  c. Collecting ducts empty into the subclavian veins. lymphocytes that act against foreign particles.  (3) They contain macrophages that remove foreign  16.2 Tissue Fluid and Lymph (page 620) particles from lymph.  1. Tissue fluid formation oo ene ; ft bj thi  a. Tissue fluid originates from plasma and includes water - eae re SUE Eilieelon can wi tnesine  and dissolved substances that have passed through the oo Seats  hlaed capillary wall b. It slowly shrinks after puberty.  . ; : : c. Itis composed of lymphatic tissue subdivided into  b. Tissue fluid generally lacks large proteins, but some lobul  smaller proteins are filtered out of blood capillaries into d i i. gant Kanes  . fd . Lobules contain lymphocytes.  interstitial spaces. Sane d  c. As the protein concentration of tissue fluid increases, . Pale sa eave is ipius nee adie a  colloid osmotic pressure increases. : as Nei ea ee  : maturation of T lymphocytes.  2. Lymph formation 3. Spl  : een  a. Increasing hydrostatic pressure in interstitial spaces p ‘hesoleen ea ih ich ais fth  forces some tissue fluid into lymphatic capillaries. 7 a - Ps i ae ai ales  ne abdominal cavity.  This fluid b lymph.  de ee NEA: ; b. It resembles a large lymph node encapsulated and  b. Lymph formation prevents accumulation of excess siibdividsdanes lobulesbycomiective uasue  ti fluid (ed , .  3 aes nena) c. Spaces in splenic lobules are filled with blood.  ae . . : d. The spleen, which filters foreign particles and  a. Lymph is under relatively low hydrostatic pressure and damaged red blood cells from the blood, contains  may not flow readily without external aid. sairin adehGniees awl Neanhioesine ,  b. Contraction of skeletal muscles, contraction of smooth y pe Sievenna nee  muscle in the walls of the large lymphatic trunks, : :  and low pressure in the thorax created by breathing 16.4 Body Defenses Against Infection (page 625)  MOVeIENS OLE lymph. The presence and reproduction of pathogens may cause an  c. Any condition that interferes with the flow of lymph infection. Pathogens include bacteria, protozoa, fungi, and  results in edema. viruses. The body has innate (nonspecific) and adaptive  4. Lymph function (specific) defenses against infection.  a. Lymphatic capillaries in the small intestine absorb and 1. Innate (nonspecific) defenses  transport lipids. . a. Species resistance  b. Lymph eventually returns small protein molecules and Each species is resistant to certain diseases that may  fluid to the bloodstream.    affect other species but is susceptible to diseases other  species may resist.   b. Mechanical barriers  (1) Mechanical barriers include the skin and mucous    tissue (MALT) which is associated with the digestive,  respiratory, urinary, and reproductive tracts. The lymph nodes,  thymus, and spleen are lymphatic organs.    (3) Hair traps infectious agents. Fluids such as tears,  sweat, saliva, mucus, and urine wash away micro-  organisms before they can firmly attach.   Interferons stimulate uninfected cells to  synthesize antiviral proteins that block  proliferation of viruses, stimulate phagocytosis,  and enhance activity of cells that help resist  infections and stifle tumor growth.   Collectins broadly protect against a wide variety  of microbes by binding to them, facilitating  phagocytosis.   Activation of complement proteins in plasma  stimulates inflammation, attracts phagocytes, and  enhances phagocytosis.    d. Natural killer (NK) cells  Natural killer cells secrete perforins, which destroy  cancer cells and cells infected with viruses.   Chemicals released by damaged tissues attract  white blood cells to the site.   Clotting may occur in body fluids that accumulate  in affected tissues.   Connective tissue may form a sac around the  injured tissue and thus aid in preventing the spread  of pathogens.    The most active phagocytes in blood are  neutrophils and monocytes. Monocytes give rise   to macrophages, which may be free or fixed in  various tissues.   Phagocytic cells associated with the linings of  blood vessels, in the liver, spleen, and lymph nodes  constitute the mononuclear phagocytic system.  Phagocytes remove foreign particles from tissues  and body fluids.    Viral or bacterial infection stimulates certain  lymphocytes to secrete IL-1, which temporarily  raises body temperature.   Elevated body temperature and the resulting  decrease in blood iron level and increased  phagocytic activity hamper infection.   After inventory, lymphocytes develop receptors  that allow them to differentiate between nonself  (foreign) and self antigens.   Haptens are small molecules that can combine  with larger ones, becoming antigenic.    Lymphocytes originate in red bone marrow and are  released into the blood.   Others, the B cells, mature in the red bone marrow.  Both T cells and B cells reside in lymphatic tissues  and organs.   Varieties of T cells and B cells number in the  millions.   Originating from a single cell, the members of each  variety form a clone.    T cells are activated when an antigen-presenting  cell displays a foreign antigen.   it phagocytizes an antigen-bearing agent, digests  the agent, and displays the resulting antigens on  its cell membrane in association with certain  MHC proteins.   T cells respond to antigens by cell-to-cell contact  (cellular immune response).   T cells secrete cytokines, such as interleukins, that  enhance cellular responses to antigens.   T cells may also secrete substances that are toxic to  their target cells.   A helper T cell becomes activated when it  encounters displayed antigens for which it is  specialized to react.   Once activated, a helper T cell stimulates a type of  B cell (plasma cell) to produce antibodies for the  specific antigen.   Cytotoxic T cells recognize foreign antigens on  tumor cells and cells whose surfaces indicate that  they are infected by viruses. Stimulated cytotoxic  T cells secrete perforin to destroy these cells.  Memory T cells allow for immediate response    Sometimes a B cell is activated when it encounters  an antigen that fits its antigen receptors, or more  often a B cell is activated when stimulated by a  helper T cell.   An activated B cell proliferates (especially when  stimulated by a T cell), enlarging its clone.   Antibodies react against the antigen-bearing  agent that stimulated their production (humoral  immune response).    (9) Each immunoglobulin molecule consists of four  linked chains of amino acids.   (10) Variable regions at the ends of these chains are  specialized antigen-binding sites that react with  different antigens.   (11) The five major types of immunoglobulins are IgG,  IgA, IgM, IgD, and IgE.   (12) IgG, IgA, and IgM make up most of the circulating  antibodies.   (13) Antibodies directly attach to antigens, activate  complement, or stimulate local tissue changes  that are unfavorable to antigen-bearing agents.   (15) Activated complement proteins alter infected  cells so they become more susceptible to  phagocytosis, attract phagocytes, and lyse foreign  cell membranes.   (1) Bcells and T cells first encountering an antigen  for which they are specialized to react constitutes  a primary immune response.   (b) Some T cells and B cells remain dormant as  memory cells.   (2) Asecondary immune response occurs as memory  cells rapidly respond to subsequent exposure to  an antigen.   (1) A person who encounters a pathogen and has a  primary immune response develops naturally  acquired active immunity.   (2) A person who receives a vaccine containing a  dead or weakened pathogen, or part of it, develops  artificially acquired active immunity. Herd  immunity protects populations.   (3) A person who receives an injection of antiserum  or antitoxin has artificially acquired passive  immunity.   (4) When antibodies pass through a placental  membrane from a pregnant woman to her fetus,  the fetus naturally acquires passive immunity.   (1) Hypersensitivity reactions are excessive misdirected  immune responses that may damage tissues.    (2) Type I hypersensitivity (immediate-reaction  hypersensitivity) is an inborn ability to  overproduce IgE in response to an allergen.   (a) Allergic reactions result from mast cells  bursting and releasing allergy mediators such  as histamine.   (b) The released chemicals cause allergy symptoms  such as hives, hay fever, asthma, eczema, or  gastric disturbances.   (c) In anaphylactic shock, allergy mediators  flood the body, causing severe symptoms,  including decreased blood pressure and  difficulty breathing.   (3) Type I hypersentivity (antibody-dependent  cytotoxic hypersensitivity) reactions occur when  blood transfusions are mismatched.   (4) Type II hypersensitivity (immune complex  hypersensitivity) reactions involve autoimmunity,  an immune reaction against self antigens.   (5) Type IV hypersensitivity (delayed-reaction  hypersensitivity), which can occur in anyone and  inflame the skin, results from repeated exposure to  household or industrial chemicals or some cosmetics.    (1) A transplant recipient’s immune system may react  against the donated tissue in a tissue rejection  reaction.   (2) Transplants may take place between genetically  identical twins, from one body part to another,  between unrelated individuals of the same species,  or between individuals of different species.   (3) Matching cell surface molecules (MHC antigens) of  donor and recipient tissues, transplanting stem cells  from the donor, and the use of immunosuppressive  drugs can help the body accept the foreign tissue.   (2) Autoimmune disorders may result from a previous  viral infection, faulty T cell development, or  reaction to a nonself antigen that resembles a self  antigen.   (3) Retained fetal cells can cause a condition that  resembles an autoimmune disorder.    The immune system begins to decline early in life, in part  due to the shrinking thymus.    Numbers of T cells and B cells do not significantly change,  but activity levels do.   Describe two functions of the lymphatic vessels. (p. 617)  Trace the general pathway of lymph from the interstitial  spaces to the bloodstream. (pp. 617-618)   Tissue fluid forms as a result of filtration from blood  capillaries exceeding , whereas lymph  forms due to increasing  in the tissue fluid. (p. 620)    (p. 621)  Explain how a lymphatic obstruction leads to edema. (p. 621)  Describe the primary functions of lymph. (p. 621)   Draw a lymph node, and label its parts. (pp. 621-622)  On a drawing of the body locate the major body regions  containing lymph nodes. (p. 622)   Indicate the locations of the thymus and spleen. (p. 623)  Compare and contrast the functions of the thymus and  spleen. (p. 623)   of pathogens and destroy them if they enter, provide  (nonspecific) defense. Precise mechanisms   Review the origin of T cells and B cells. (p. 628)   List three types of T cells, and describe the function of each  in the immune response. (p. 630)   Explain the humoral immune response, including the  activation of B cells. (p. 630)   Draw and label the parts of an antibody molecule. (p. 632)  Distinguish between the variable region and the constant  region of an antibody molecule. (p. 632)   Match the types of antibodies with their function and/or  where each is found. (pp. 633-634)    (1) associated with allergic reactions A. IgA  (2) important in B cell activation, on surfaces B. IgM  of most B cells C. IgG  (3) activates complement, anti-A and D. IgD  anti-B in blood E. IgE   in plasma and tissue fluids  (5) found in exocrine secretions, including breast milk  Describe three ways in which an antibody’s direct attack on  an antigen helps remove that antigen. (p. 634)  List the various effects of complement activation.  (pp. 634-635)  Contrast a primary and a secondary immune response.  (p. 635)  Contrast active and passive immunity. (p. 636)  Define vaccine. (p. 636)  Explain how a vaccine produces its effect. (p. 636)  Describe how a fetus may obtain antibodies from maternal  blood. (p. 636)  Explain the relationship between a hypersensitivity reaction  and an immune response. (p. 636)  Distinguish between an antigen and an allergen. (p. 636)  Describe how an immediate-reaction hypersensitivity  response may occur. (p. 636)  List the major events leading to a delayed-reaction  hypersentivity response. (p. 637)  Explain the relationship between tissue rejection and an  immune response. (pp. 637-638)  Describe two methods used to reduce the severity of a tissue  rejection reaction. (p. 639)  Explain the goal of using immunosuppressive drugs before a  transplant. (p. 639)  Explain the relationship between autoimmunity and an  immune response. (p. 639)    Life-Span Changes  Explain the causes for a decline in the strength of the  immune response in the elderly. (p. 640)    1. Why is injecting a substance into the skin like injecting it into the  lymphatic system?    2. How can removal of enlarged lymph nodes for microscopic  examination aid in diagnosing certain diseases?    3. What functions of the lymphatic system would be affected ina  person born without a thymus?    4. The immune response is specific, diverse, and has memory. Give  examples of each of these characteristics.    . Some parents keep their preschoolers away from other children  to prevent them from catching illnesses. How might these well-  meaning parents be harming their children?    . Why is a transplant consisting of fetal tissue less likely to provoke    from her brother, who was an HLA match, along with stem cells  from his blood. The surgery was so successful that she was able  to return to competitive swimming within a year and made the  Olympic team. However, she was disqualified due to blood test  results that found a male Y chromosome in her blood. Explain  one way that this could have happened.    Connect Interactive Questions Reinforce your knowledge  using assigned interactive questions covering lymphatic system  structures, lymph flow, and innate and adaptive immunity.    Connect Integrated Activity Can you differentiate between  an allergic reaction, an autoimmune response, and an immune  deficiency?    Anatomy & Physiology Revealed Go more in depth into  the human body by exploring the lymphatic organs. Also view  animations on the immune response.    Falsely colored transmission electron micrograph (TEM) of microvilli on  intestinal cells (20,000x).    The main part of the digestive system is a long tube that extends  through the body. Just as a tunnel through a mountain is filled  with air, not the material of the mountain, the inside of the diges-  tive tube is really part of the outside world, not part of the inter-  nal environment. Whereas the pH, electrolyte concentrations,  and water volume of the internal environment are tightly regu-  lated, they change from the beginning of the tube to its end, and  vary with the chemical nature of what we eat.   Material that enters the tube is first broken down into its  chemical building blocks, such as simple sugars, amino acids,  nucleotides, fatty acids, and glycerol, and then absorbed across  the wall of the tube, often by specific transport processes. Your  body then recombines those building blocks into the molecules  it needs. If you are trying to build muscles, your cells need to  synthesize muscle protein, but that doesn’t mean you need to  eat actin and myosin. As long as all of the necessary amino acids  are present in your diet in sufficient amounts, the digestive sys-  tem will bring them into the internal environment, and your mus-  cles will be able to use them to build the proteins that they need.    After you have studied this chapter, you should be able to:    Which processes are carried out by the digestive system.  (p. 650)    Describe the structure of the wall of the alimentary canal.  (p. 650)    Explain how the contents of the alimentary canal are  mixed and moved. (pp. 650-651)   Discuss the general effects of innervation of the  alimentary canal by the sympathetic and parasympathetic  divisions of the autonomic nervous system. (pp. 651-652)    Describe the functions of the structures associated with  the mouth. (pp. 653-656)   Describe how different types of teeth are adapted for  different functions, and list the parts of a tooth. (p. 656)    Locate each of these organs and glands of the digestive  system; then describe the general structure and function  of each. (pp. 658-685)    Identify the function of each enzyme secreted by these  digestive organs and glands. (pp. 658-680)    Explain control of movement of material through the  alimentary canal. (pp. 653, 660-667, 682-686)    Describe the mechanisms of swallowing, vomiting, and  defecating. (pp. 660-661, 667, 686)    Explain how the products of digestion are absorbed.  (pp. 666, 681-686)  Life-Span Changes   chym-, juice: chyme—semifluid paste of  food particles and gastric juice formed  in the stomach.    pyl-, gatekeeper, door: pyloric sphincter—  muscle that serves as a valve between  the stomach and small intestine.    branous fold that anchors the tongue to  the floor of the mouth.    Digestion (di-jest’yun) is the mechanical and chemical breakdown  of foods into forms that cell membranes can absorb. Mechanical  digestion breaks large pieces into smaller ones without altering their  chemical composition. Chemical digestion breaks food into simpler  chemicals. The organs of the digestive system carry out these pro-  cesses, as well as ingestion, propulsion, absorption, and defecation.   The digestive system consists of the alimentary canal (al’i-  men’tar-e kah-nal’), extending from the mouth to the anus, and  several accessory organs, which release secretions into the canal.  The alimentary canal includes the mouth, pharynx, esophagus,  stomach, small intestine, large intestine, and anal canal. The acces-  sory organs include the salivary glands, liver, gallbladder, and pan-  creas. Figure 17.1 and reference plates 4, 5, and 6 (pp. 41-43)  show the major organs of the digestive system.   The digestive system originates from the inner layer (endo-  derm) of the embryo, which folds to form the tube of the alimen-  tary canal. The accessory organs develop as buds from the tube.    The alimentary canal is a muscular tube about 8 meters long that  passes through the body’s thoracic and abdominopelvic cavities  (fig. 17.2). The structure of its wall, how it moves food, and its  innervation are similar throughout its length.    The wall of the alimentary canal consists of four distinct layers  that vary somewhat from region to region. Although the four-  layered structure persists throughout the alimentary canal, certain    regions are specialized for particular functions. Beginning with  the innermost tissues, these layers, shown in figure 17.3, include  the following:    1. The mucosa (mu-ko’sah), or mucous membrane has a surface  of epithelium, underlying connective tissue (lamina propria),  and a small amount of smooth muscle (muscularis mucosae). In  some regions, the mucosa is folded, with tiny projections that  extend into the passageway, or lumen, of the digestive tube.  These folds increase the absorptive surface area. The mucosa  also has glands into which the lining cells secrete mucus and  digestive enzymes. The mucosa protects the tissues beneath it,  secretes into the lumen, and absorbs substances from the diet.   2. The submucosa (sub”mu-ko’sah) contains considerable loose  connective tissue as well as glands, blood vessels, lymphatic  vessels, and nerves. Its vessels nourish the surrounding tissues  and carry away absorbed materials.   3. The muscularis externa, or muscularis, which provides  movements of the tube, consists of two layers of smooth  muscle tissue. The cells of the inner layer encircles the tube.  When the circular layer contracts, the diameter of the tube  decreases. The cells of the outer muscular layer run length-  wise. When the longitudinal layer contracts, the tube shortens.  Coordinated contractions of both muscle layers cause move-  ments associated with digestion and absorption of food.   4. The serosa (ser-o’sah), or serous layer, is the outer covering  of the tube. It is composed of the visceral peritoneum, which  is formed of epithelium on the outside and connective tissue  beneath. The cells of the serosa protect underlying tissues  and secrete serous fluid, which moistens and lubricates the  tube’s outer surface. Serous fluid enables the organs in the  abdominal cavity to slide freely against one another.    Table 17.1 summarizes the characteristics of the layers of the ali-  mentary canal wall.    The motor functions of the alimentary canal are of two basic types—  mixing movements and propelling movements. Mixing occurs when    smooth muscle in small segments of the tube contracts rhythmically.  For example, when the stomach is full, waves of muscular contrac-  tions move along its wall from one end to the other (fig. 17.4a).  These waves pass every twenty seconds or so and mix foods with  the digestive juices secreted by the mucosa. In the small intestine,  segmentation is a type of movement that aids mixing by alternately  contracting and relaxing the smooth muscle in segments of the  organ (fig. 17.4b). Because segmentation follows a back-and-forth  pattern, materials are not moved along the tract in one direction.   Propelling movements include a wavelike motion called  peristalsis (per’i-stal’sis), in which a ring of contraction occurs in  the wall of the tube and moves progressively along its length (fig.  17.4c). At the same time, the muscular wall just ahead of the ring  relaxes—a phenomenon called receptive relaxation. As the peristal-  tic wave of contraction moves along the tube, it pushes the contents  of the tube ahead of it. Peristalsis begins when food expands the tube.  It causes the sounds that can be heard through a stethoscope applied  to the abdominal wall.    A "GI camera” the size of a large vitamin pill can image the ali-  mentary canal, revealing blockages and sites of bleeding and  helping to diagnose celiac disease, Crohn's disease, and cancer.  The patient swallows the capsule, which contains a camera, a  light source, radio transmitter, and batteries. Peristalsis moves it  along, and about six hours after swallowing, it transmits images    from the small intestine to a device worn on the physician's belt.  The information goes to a computer, which downloads still or  video images. The disposable device leaves the body in the  feces. Millions of people have had the procedure, which has an  advantage over endoscopy of not requiring sedation.    Branches of the sympathetic and parasympathetic divisions of the  autonomic nervous system extensively innervate the alimentary  canal. Some of these postganglionic fibers, which are associated  with the tube’s muscular layer, maintain muscle tone and regulate  the strength, rate, and velocity of muscular contractions. Many of the  postganglionic fibers are organized into a network or nerve plexus  within the wall of the canal (see fig. 17.3). The submucosal plexus is  important in controlling secretions by the gastrointestinal tract. The  myenteric plexus of the muscular layer is more extensive and controls  gastrointestinal motility. The plexuses also include sensory neurons.  Parasympathetic impulses generally increase the activities of  the digestive system such as motility and enzyme secretion. Some    of these impulses originate in the brain and are conducted through  branches of the vagus nerves to the esophagus, stomach, pancreas,  gallbladder, small intestine, and proximal half of the large intestine.  Other parasympathetic impulses arise in the sacral region of the spi-  nal cord and supply the distal half of the large intestine.   The effects of sympathetic impulses on digestive actions  usually oppose those of the parasympathetic division, meaning    The young woman had undergone gastric bypass surgery  five weeks earlier, and instead of being able to eat more  foods, as she had anticipated, she was now unable to keep  anything down. She recognized the danger signs and went  to the emergency department at the hospital where the  bypass had been performed, and was admitted for an  endoscopy to find the blockage.   An endoscope is a flexible fiberoptic instrument that  is passed through an opening in the body or inserted  through an incision. It provides a direct view of internal  anatomy. Endoscopy of the gastrointestinal tract can detect  inflammation, ulcerations, and other superficial lesions and  abnormalities. The endoscopy procedure can also obtain  tissue samples for biopsies.   The endoscopy technician works as part of a team,  providing support for physicians and nurses throughout  procedures. The technician prepares materials, obtains  specimens, maintains a sterile field and instruments during  procedures, and may administer medications, monitor  vital signs, and change dressings. Setting up and cleaning  equipment is also part of the job.   Training to become an endoscopy technician begins  with a high school diploma. This is followed by an associate  of science degree in Surgical Technology, which includes  courses in anatomy and physiology and medical terminology.  Additional clinical training may take place on the job or in  an internship program at a health-care facility. Because the  job requires informing and reassuring patients, excellent  communication skills are a must. In addition, solid critical  thinking skills enable the technician to function as part of a  team. The job also requires physical strength and stamina.   Most endoscopy technicians work in hospitals or clinics.  Jobs may also be available in long-term care facilities and  nursing homes. Hours may be long and unusual, and the pace  of performing procedures rapid.   Secretes acid and  enzymes; mixes food  with secretions to  begin enzymatic  digestion of proteins    Pancreas  Produces and secretes  pancreatic juice, containing  digestive enzymes and  bicarbonate ions,   pathetic impulses inhibit mixing and propelling movements,  but stimulate contraction of the sphincter muscles in the wall of  the alimentary canal, blocking movement of materials through    3 Describe the wall of the alimentary canal.  4 Name the types of movements in the alimentary canal.    5 How do parasympathetic nerve impulses affect digestive  the tube. actions? What effect do sympathetic nerve impulses have?    FIGURE 17.2 The alimentary canal is a muscular tube about 8 meters long.    What is the distance from the tongue to the duodenum, in  English units?    The mouth, the first portion of the alimentary canal, receives food  and begins digestion by mechanically breaking solid particles into  smaller pieces and mixing them with saliva. This action is called  mastication (mas”ti-ka’shun). The mouth also functions as an organ  of speech and sensory reception. It is surrounded by the lips, cheeks,  tongue, and palate and includes a chamber between the palate and  tongue called the oral cavity, as well as a narrow space between the  teeth, cheeks, and lips called the oral vestibule (fig. 17.5 and refer-  ence plate 9, p. 46).    The cheeks form the lateral walls of the mouth. They consist of  outer layers of skin, pads of subcutaneous fat, muscles associated  with expression and chewing, and inner linings of moist, stratified  squamous epithelium.    Cells lining the cheek are sampled to provide DNA for genetic  testing. A person rubs the inside of the cheek with a cotton  swab or swishes with mouthwash and expectorates into a small  tube. The sample is sent to a lab, the DNA extracted, and infor-  mative DNA sequences identified. DNA tests performed on  cheek cells are used in diagnostic medicine, ancestry testing,  and forensics.    The lips are highly mobile structures that surround the  mouth opening. They contain skeletal muscles and sensory  receptors useful in judging the temperature and texture of foods.  Their normal reddish color is due to the many blood vessels near  their surfaces. The external borders of the lips mark the boundar-  ies between the skin of the face and the mucous membrane that  lines the alimentary canal.    The tongue (tung) is a thick, muscular organ that occupies the  floor of the mouth and nearly fills the oral cavity when the mouth  is closed. Mucous membrane covers the tongue, and a membra-  nous fold called the lingual frenulum (ling’gwahl fren’u-lum)  connects the midline of the tongue to the floor of the mouth.   The body of the tongue is largely composed of skeletal muscle  fibers that run in several directions. Muscular action mixes food  particles with saliva during chewing and moves food toward the  pharynx during swallowing. The tongue also helps move food  underneath the teeth for chewing. The surface of the tongue has  rough projections, called papillae (pah-pil’a) (fig. 17.6). Some of  these provide friction, which helps move food. Other papillae con-  tain taste buds, which are used in detecting sweet, salty, bitter, sour,  and umami (see chapter 12, pp. 454-455). Although most of the  taste buds are located on papillae, some are scattered elsewhere in  the mouth, particularly in children.   The posterior region, or root, of the tongue is anchored to the  hyoid bone. It is covered with rounded masses of lymphatic tissue  called lingual tonsils (ton’silz) (fig. 17.7).    FIGURE 17.3 The wall of the small intestine, as in other portions  of the alimentary canal, consists of four layers: the inner mucosa, the  submucosa, the muscularis, and the outer serosa.    The palate (pal’at) forms the roof of the oral cavity and consists  of a hard anterior part and a soft posterior part. The hard palate is  formed by the palatine processes of the maxillae in front and the  horizontal portions of the palatine bones in back. The soft palate  forms a muscular arch, which extends posteriorly and downward  as a cone-shaped projection called the uvula (u’vu-lah).   During swallowing, muscles draw the soft palate and the uvula  upward. This action closes the opening between the nasal cavity and  the pharynx, preventing food from entering the nasal cavity.   In the back of the mouth, on either side of the tongue and  closely associated with the palate, are masses of lymphatic tis-  sue called palatine (pal’ah-tin) tonsils (fig. 17.7). These struc-  tures lie beneath the epithelial lining of the mouth and, like other  lymphatic tissues, help protect the body against infections (see  chapter 16, p. 621).    Other masses of lymphatic tissue, called pharyngeal (fah-  rin’je-al) tonsils, or adenoids, are on the posterior wall of the phar-  ynx, above the border of the soft palate (fig. 17.7). If the adenoids  enlarge and block the passage between the nasal cavity and phar-  ynx, surgical removal may be necessary.    The palatine tonsils are common sites of infection and become  inflamed in tonsillitis. Infected tonsils may swell so greatly that  they block the passageways of the pharynx and interfere with  breathing and swallowing. Because the mucous membranes of the  pharynx, auditory tubes, and middle ears are continuous, an infec-    tion can spread from the throat into the middle ears (otitis media).   When tonsillitis recurs and does not respond to antibiotic  treatment, the tonsils may be surgically removed. Such tonsillec-  tomies are done less often today than they were a generation  ago because the tonsils’ role in immunity is now recognized.    (c)  FIGURE 17.4 Movements through the alimentary canal. (a) Mixing  movements occur when small segments of the muscular wall of the    stomach rhythmically contract. (b) Segmentation mixes the contents of  the small intestine. (c) Peristaltic waves move the contents along the canal.    6 What are the functions of the mouth?  7 How does the tongue function as part of the digestive system?    The teeth are the hardest structures in the body. They are not con-  sidered part of the skeletal system because they have at least two  types of proteins that are not found in bone, and their structure is  different from that of bone.    FIGURE 17.5 The mouth is adapted for ingesting food and beginning  digestion, both mechanically and chemically.    Teeth develop within sockets in the alveolar processes of  the mandible and maxillae. They are unique in that two sets form  during development (fig. 17.8). The first set, the primary teeth  (deciduous teeth), usually erupt through the gums (gingiva) at  regular intervals between the ages of six months and two to four  years. The ten primary teeth are anchored in each jaw from the  midline toward the sides in the following sequence: central incisor,  lateral incisor, canine (cuspid), first molar, and second molar.   The primary teeth are usually shed in the same order as they  erupted. After their roots are resorbed, the secondary (permanent)  teeth push the primary teeth out of their sockets. This secondary  set consists of thirty-two teeth—sixteen in each jaw—and they are    Hard palate Soft palate  Vestibule Nasopharynx  Oral cavity  |  Tongue a  Tooth Palatine tonsil  Lip Oropharynx  Lingual tonsil  Epiglottis  Byala Bone Laryngopharynx  Larynx  Esophagus  Trachea  FIGURE 17.7 (AP|R} Sagittal section of the mouth, nasal cavity, and pharynx.  arranged from the midline as follows: central incisor, lateral inci- Primary Secondary  sor, canine (cuspid), first premolar (bicuspid), second premolar teeth teeth  (bicuspid), first molar, second molar, and third molar (fig. 17.9). : — = pa    Table 17.2 summarizes the types and numbers of primary and sec-  ondary teeth.   The secondary teeth usually begin to erupt at six years of age,  but the set may not be completed until the third molars emerge  between seventeen and twenty-five years of age. Sometimes these  third molars, also called wisdom teeth, become wedged in abnor-  mal positions in the jaws and fail to erupt. Such impacted wisdom  teeth may be removed to alleviate pain.   The teeth break food into smaller pieces, which begins  mechanical digestion. Chewing increases the surface area of the  food particles, enabling digestive enzymes to interact more effec-  tively with nutrient molecules.   Different teeth are adapted to handle food in different ways.  The sharp edges of the chisel-shaped incisors bite off large pieces  of food. The cone-shaped canines grasp and tear food. The flattened  surfaces of the premolars and molars grind food particles.   Each tooth consists of two main parts—the crown, which  projects beyond the gum, and the root, which is anchored to the  alveolar process of the jaw. These structures meet at the neck of FIGURE 17.8 This partially dissected child’s skull reveals primary and  the tooth. Glossy, white enamel covers the crown. Enamel mainly developing secondary teeth in the maxilla and mandible.    the upper and lower jaws. (b) Anterior view of the secondary teeth.    consists of calcium salts and is the hardest substance in the body.  If abrasive action or injury damages enamel, it is not replaced.  Enamel may wear away with age.   The bulk of a tooth beneath the enamel is composed of a  living cellular tissue called dentin, which is similar to bone but  harder. Dentin, in turn, surrounds a central cavity (pulp cavity) that  is filled with pulp. Pulp is a mass of tissue including blood vessels,  nerves, and connective tissue. Blood vessels and nerves reach the  central cavity through tubular root canals, which extend into the  root. Tooth loss is most often associated with diseases of the gums  (gingivitis) and the dental pulp (endodontitis).   A thin layer of bonelike material called cementum, surrounded  by a periodontal ligament (periodontal membrane), encloses the  root. This ligament, composed of collagen, passes between the    Primary Teeth Secondary Teeth  (Deciduous) (Permanent)  Type Number Type Number  Incisor Incisor  Central 4 | Central 4  Lateral 4 Lateral 4  Canine (cuspid) 4 Canine (cuspid) 4  Premolar (bicuspid)  First 4  Second 4  Molar Molar  First 4 First 4  Second 4 Second 4  Third 4  Total 20 | Total 32  Enamel  Crown  Dentin  Pulp  (in pulp  cavity)  = Gingiva  Alveolar  process  Root —  Periodontal  ligament  Root canal  Cementum    cementum and the bone of the alveolar process, firmly attaching  the tooth to the jaw. The ligament also contains blood vessels and  nerves near the surface of the cementum-covered root (fig. 17.10).  Clinical Application 17.1 describes the effect of bacteria on teeth.  Table 17.3 summarizes the mouth parts and their functions.    Sticky foods, such as caramel, lodge between the teeth and in the  crevices of molars, feeding bacteria such as Actinomyces, Strepto-  coccus mutans, and Lactobacillus. These microbes metabolize car-  bohydrates in the food, producing acid by-products that destroy  tooth enamel and dentin (fig. 17A). The bacteria also produce  sticky substances that hold them in place.   If a person eats candy, for example, but does not brush the  teeth soon afterward, the acid-forming bacteria may cause tooth  decay, creating cavities within the enamel called dental caries.  Unless a dentist cleans and fills the cavity that forms where enamel  is destroyed, the damage will spread to the underlying dentin.   3. Talk with your dentist about receiving a fluoride treatment.  Fluoride is added to the water supply in many communities.  Fluoride is incorporated into the enamel’s chemical structure,  strengthening it.    Extracted primary and wisdom teeth may one day provide stem  cells that can be used to regenerate tooth roots and supporting  periodontal ligaments or even replace teeth. The stem cells are  in the pulp of the developing tooth.    9 How do primary teeth differ from secondary teeth?  10 How are types of teeth adapted to provide specialized functions?  11 Describe the structure of a tooth.    12 Explain how a tooth is attached to the bone of the jaw.    The salivary (sal’i-ver-e) glands secrete saliva. This fluid moist-  ens food particles, helps bind them, and begins the chemical diges-  tion of carbohydrates. Saliva is also a solvent, dissolving foods so  that they can be tasted. Saliva helps cleanse the mouth and teeth.  Bicarbonate ions (HCO,,) in saliva help buffer acid in the mouth,  keeping the pH near neutral, between 6.5 and 7.5. This is a favor-  able range for the action of the salivary enzyme and protects the  teeth from exposure to acids in foods.   Many minor salivary glands are scattered throughout the  mucosa of the tongue, palate, and cheeks. They continuously  secrete fluid, moistening the lining of the mouth. The three pairs    causing bacteria. The sealant is a coating that keeps acids  from eating away at tooth enamel.    For information on how to care for teeth over a lifetime, see the  American Dental Association's website.    FIGURE 17A Actinomyces bacteria (falsely colored) clinging to  teeth release acids that decay tooth enamel (1,250x).    of major salivary glands are the parotid glands, the submandibular  glands, and the sublingual glands.    The different salivary glands have varying proportions of two  types of secretory cells, serous cells and mucous cells. Serous cells  produce a watery fluid that contains a digestive enzyme, salivary  amylase (am’i-las). This enzyme splits starch and glycogen mol-  ecules into disaccharides, starting the chemical digestion of carbo-  hydrates. Mucous cells secrete a thick liquid called mucus, which  binds food particles and acts as a lubricant during swallowing.    Branches of both sympathetic and parasympathetic nerves  innervate the salivary glands, as they do other digestive struc-  tures. Impulses arriving on sympathetic fibers stimulate the gland  cells to secrete a small volume of viscous saliva. Parasympathetic  impulses, on the other hand, elicit the secretion of a large vol-  ume of watery saliva. Such parasympathetic impulses are acti-  vated reflexly when a person sees, smells, tastes, or even thinks  about pleasant foods. Conversely, if food looks, smells, or tastes  unpleasant, parasympathetic activity is inhibited. Less saliva is  produced, and swallowing may become difficult.    The parotid (pah-rot’id) glands are the largest of the major  salivary glands. Each gland lies anterior to and somewhat infe-  rior to each ear, between the skin of the cheek and the masseter  muscle. A parotid duct (Stensen’s duct) passes from the gland  inward through the buccinator muscle, entering the mouth just  opposite the upper second molar on either side of the jaw. The  parotid glands secrete a clear, watery fluid rich in salivary amy-  lase because their secretory cells are primarily serous cells  (figs. 17.11 and 17.12a).   The submandibular (sub”’man-dib’u-lar) glands are in  the floor of the mouth on the inside surface of the mandible.  The secretory cells of these glands are about equally serous and  mucous. Consequently, the submandibular glands secrete a more  viscous fluid than the parotid glands (see figs. 17.11 and 17.12b).  The ducts of the submandibular glands (Wharton’s ducts) open  inferior to the tongue, near the lingual frenulum.    The sublingual (sub-ling’gwal) glands are the smallest of the  major salivary glands. They are in the floor of the mouth inferior  to the tongue. Because the secretory cells of the sublingual glands  are primarily the mucous type, their secretions, which enter the  mouth through many separate ducts (Rivinus’s ducts), are thick  and stringy (see figs. 17.11 and 17.12c). Table 17.4 summarizes  the characteristics of the major salivary glands.    Anterior to  and somewhat  inferior to the  ears between  the skin of the  cheeks and  the masseter  muscles    In the floor  of the mouth  on the inside  surface of the  mandible    Some serous  fluid with  some mucus;  more viscous  than parotid  secretion    FIGURE 17.12 Light micrographs of (a) the parotid salivary gland (100x), (b) the submandibular salivary gland (180x), and (c) the sublingual salivary    13 What is the function of saliva?  14 What stimulates the salivary glands to secrete saliva?    The pharynx is a cavity posterior to the mouth. It extends from the  nasal cavity to the esophagus, which in turn leads to the stomach.  The pharynx and the esophagus do not assist in food digestion.  However, both are important passageways, and their muscular walls  function in swallowing.    The pharynx (far’ingks) connects the nasal and oral cavities with  the larynx and esophagus (see fig. 17.7). It can be divided into the  following parts:    1. The nasopharynx (na”zo-far’ingks) is superior to the soft  palate. It communicates with the nasal cavity and provides  a passageway for air during breathing. The auditory tubes,  which connect the pharynx with the middle ears, open  through the walls of the nasopharynx (see chapter 12, p. 459).   2. The oropharynx (0”ro-far’ingks) is posterior to the oral cavity.  It is posterior to the soft palate and inferior to the nasopharynx,  projecting downward to the upper border of the epiglottis. This  portion is a passageway for food moving downward from the  mouth and for air moving to and from the nasal cavity.   3. The laryngopharynx (lah-ring” go-far’inks) is just inferior  to the oropharynx. It extends from the upper border of  the epiglottis downward to the lower border of the cricoid  cartilage of the larynx and is a passageway to the esophagus.    The muscles in the walls of the pharynx form inner circular  and outer longitudinal groups (fig. 17.13). The circular mus-  cles, called constrictor muscles, pull the walls inward during  swallowing. The superior constrictor muscles, attached to bony  processes of the skull and mandible, curve around the upper  part of the pharynx. The middle constrictor muscles arise from  projections on the hyoid bone and fan around the middle of the  pharynx. The inferior constrictor muscles originate from carti-  lage of the larynx and pass around the lower portion of the pha-  ryngeal cavity. Some of the lower inferior constrictor muscle  fibers contract most of the time, which prevents air from enter-  ing the esophagus during breathing.   The pharyngeal muscles are skeletal muscles, but they are  under voluntary control only in the sense that swallowing (deglu-  tition) can be voluntarily initiated. Complex reflexes control the  precise actions of these muscles during swallowing.    Swallowing can be divided into three stages. In the first stage,  which is voluntary, food is chewed and mixed with saliva. Then,  the tongue rolls this mixture into a mass, or bolus, and forces it  into the oropharynx.   The second stage of swallowing begins as food reaches the  oropharynx and stimulates sensory receptors around the pharyn-  geal opening. This triggers the swallowing reflex, illustrated in fig-  ure 17.14, which includes the following actions:    1. The soft palate (including the uvula) raises, preventing food  from entering the nasal cavity.   2. The hyoid bone and the larynx are elevated. A flaplike struc-  ture attached to the larynx, called the epiglottis (ep’i-glot’is),  closes off the top of the trachea so that food is less likely to    3. The tongue is pressed against the soft palate and uvula, sealing  off the oral cavity from the nasal cavity.   4. The longitudinal muscles in the pharyngeal wall contract, pull-  ing the pharynx upward toward the food.   5. The lower portion of the inferior constrictor muscles relaxes,  opening the esophagus.   6. The superior constrictor muscles contract, stimulating a  peristaltic wave to begin in other pharyngeal muscles. This  wave forces the food into the esophagus.    The swallowing reflex momentarily inhibits breathing. Then, dur-  ing the third stage of swallowing, peristalsis transports the food in  the esophagus to the stomach.    Esophagus  The esophagus (&-sof’ah-gus) is a straight, collapsible tube about  25 centimeters long. It provides a passageway for food, and its  muscular wall propels food from the pharynx to the stomach. The  esophagus begins at the base of the laryngopharynx and descends  through the thorax posterior to the trachea, passing through the  mediastinum. It penetrates the diaphragm through an opening, the  esophageal hiatus (€-sof’ah-je’al hi-a’tus), and is continuous with  the stomach on the abdominal side of the diaphragm (fig. 17.15  and reference plates 17 and 23, pp. 51 and 54).   Mucous glands are scattered throughout the submucosa of the  esophagus (fig. 17.16). Their secretions moisten and lubricate the  inner lining of the tube.    Just superior to the point where the esophagus joins the stom-  ach, some of the cells of the circular smooth muscle layer have  increased sympathetic muscle tone and form the lower esopha-  geal sphincter (loh’er é-sof”ah-je’al sfingk’ter), or cardiac sphinc-  ter (fig. 17.17). These cells usually remain contracted and close the  entrance to the stomach. In this way, they help prevent regurgitation  of the stomach contents into the esophagus. When peristaltic waves  in the esophagus reach the stomach, the smooth muscle cells of the  sphincter temporarily relax and allow the swallowed food to enter.    The stomach (stum’ak) is a J-shaped, pouchlike organ, about  25-30 centimeters long, which hangs inferior to the diaphragm in  the upper-left portion of the abdominal cavity (see figs. 17.1 and  17.15; reference plates 4 and 5, pp. 41-42). The stomach has a  capacity of about one liter or more. Its inner lining has thick gas-  tric folds (rugae) of the mucosal and submucosal layers that unfold  when the wall is distended. The stomach receives food from the  esophagus, mixes it with gastric juice, initiates the digestion of    (c) Superior constrictor muscles contract and  initiate a peristaltic wave that forces food  into the esophagus.    (b) The soft palate, hyoid bone, and larynx are raised,  the tongue is pressed against the palate, the epiglottis  closes, and the inferior constrictor muscles relax so  that the esophagus opens.    (d) A peristaltic wave moves food through the  esophagus to the stomach.    FIGURE 17.14 Steps in the swallowing reflex. (The mucosa in (a), (b), and (c) has been removed to reveal the underlying muscles.)    Longitudinal é .  layer of smooth have three layers of smooth muscle. (b) Major regions of the stomach and  (a) muscle cells its associated structures.    proteins, carries on limited absorption, and moves food into the  small intestine.   In addition to the two layers of smooth muscle—an inner  circular layer and an outer longitudinal layer—which are also  in other regions of the alimentary canal, some parts of the stom-  ach have an additional inner oblique layer, which strengthens the  stomach wall and help the mixing and churning. This third inner-  most muscular layer is most highly developed near the opening of  the esophagus and in the body of the stomach (fig. 17.17).    The stomach, shown in figure 17.17 and figure 17.18, can be  divided into the cardia, fundus, body, and pylorus. The cardia is  a small area near the esophageal opening. The fundus, which bal-  loons superior to the cardia, is a temporary storage area and some-  times fills with swallowed air. This produces a gastric air bubble,  which may be used as a landmark on a radiograph of the abdo-  men. The dilated body, which is the main part of the stomach, lies  between the fundus and pylorus. The pyloric antrum is a funnel-  shaped portion that narrows and becomes the pyloric canal as it  approaches the small intestine.    At the end of the pyloric canal, a thickening of the circular  layer of smooth muscle forms the powerful pyloric sphincter.  This sphincter acts as a valve that controls gastric emptying into  the small intestine.    Hypertrophic pyloric stenosis is a birth defect in which muscle >  overgrowth blocks the pyloric canal and causes a newborn to  vomit with increased force. To diagnose the condition, a radio-  graph is taken of the area after the infant drinks formula con-  taining a radiopaque barium compound. Surgical splitting of the  muscle blocking the passageway from stomach to small intes-  tine is necessary to enable the infant to eat normally. Pyloric ste-  nosis can also occur later in life as a result of ulcers or cancer.    The mucous membrane that forms the inner lining of the stom-  ach is thick. Its surface is studded with many small openings,  called gastric pits, that are located at the ends of tubular gastric  glands (oxyntic glands) (fig. 17.19). Although their structure and    FIGURE 17.18 Radiograph of a stomach. (Note: A radiopaque compound the patient swallowed appears white in the radiograph.)    FIGURE 17.19 (AP|R) Lining of the stomach. (a) Gastric glands include mucous cells, parietal cells, and chief cells. The mucosa of the stomach is  studded with gastric pits that are the openings of the gastric glands. (b) A light micrograph of cells associated with the gastric glands (60x).    the composition of their secretions vary in different parts of the  stomach, gastric glands generally contain three types of secretory  cells. One type, the mucous cell, found in the necks of the glands  near the openings of the gastric pits, secretes mucus. The other  types, chief cells (peptic cells) and parietal cells (oxyntic cells),  reside in the deeper parts of the glands (fig. 17.19). The chief  cells secrete digestive enzymes, and the parietal cells release a  solution containing hydrochloric acid. The secretions from the  mucous cells, chief cells, and parietal cells together form gastric  juice (gas’trik joos).   Pepsin is by far the most important of the digestive enzymes  in gastric juice. The chief cells secrete pepsin in the form of an  inactive, nonerosive enzyme precursor called pepsinogen. When  pepsinogen contacts the hydrochloric acid from the parietal cells,  it breaks down rapidly and forms the active enzyme called pep-  sin. Pepsin, in turn, can also break down pepsinogen to release  more pepsin.   Pepsin begins the digestion of nearly all types of dietary protein  into polypeptides. This enzyme is most active in an acidic environ-  ment, which is provided by the hydrochloric acid in gastric juice.   Gastric juice contains small quantities of a fat-splitting  enzyme, gastric lipase. Its action is inhibited somewhat by the low  pH of gastric juice.    Much of what we know about the stomach’s functioning comes  from a French-Canadian explorer, Alexis St. Martin, who in 1822  accidentally shot himself in the abdomen. His extensive injuries  eventually healed, but a hole, called a fistula, was left, allow-  ing observers to look at his stomach in action. A U.S. Army  surgeon, William Beaumont, spent eight years watching food  digesting in the stomach, and noted how the stomach lining  changed in the process.   In 1984, our knowledge of digestive function expanded  when medical resident Barry Marshall at Royal Perth Hospital  in western Australia performed a daring experiment. His men-  tor, J. Robin Warren, had hypothesized that a bacterial infec-  tion causes gastritis (inflammation of the stomach lining) and  peptic ulcers (sores in the lining of the esophagus, stomach,  or small intestine). At the time, these conditions were attrib-  uted to poor diet and stress. Marshall drank “swamp water”—  billions of bacteria. He developed gastritis, which, fortunately,  cleared up. A colleague who repeated the experiment devel-  oped an ulcer and required antibiotics. After a decade of  debate, the medical community finally concurred that the bac-  terium Helicobacter pylori, which thrives under acidic condi-  tions, causes many cases of gastritis and peptic ulcers. A short  course of antibiotics and acid-lowering drugs has replaced  lifelong treatments. Marshall and Warren were awarded a  Nobel Prize in 2005 for their discovery.    The mucous cells of the gastric glands (mucous neck cells)  and the mucous cells, associated with the stomach’s inner surface,  release a viscous, alkaline secretion that coats the inside of the stom-  ach wall. This coating is especially important because pepsin can  digest the proteins of stomach tissues, as well as those in foods. The  coating normally prevents the stomach from digesting itself.    Another component of gastric juice is intrinsic factor  (in-trin’sik fak’tor). The parietal cells of the gastric glands secrete  intrinsic factor, which is required for vitamin B,, absorption from  the small intestine. Table 17.5 summarizes the components of gas-  tric juice.    19 Where is the stomach located?  20 What are the secretions of the chief cells and parietal cells?    Gastric juice is produced continuously. However, the rate varies  considerably and is controlled both neurally and hormonally. In  the gastric glands, specialized cells closely associated with the  parietal cells secrete the hormone somatostatin, which inhibits  acid secretion. However, acetylcholine (ACh) released from syn-  aptic knobs in response to parasympathetic impulses arriving on  the vagus nerves suppresses the secretion of somatostatin and  stimulates the gastric glands to secrete abundant gastric juice,  which is rich in hydrochloric acid and pepsinogen. These para-  sympathetic impulses also stimulate certain stomach cells, mainly  in the pyloric region, to release a peptide hormone called gastrin,  which increases the secretory activity of gastric glands (fig.17.20).  Furthermore, parasympathetic impulses and gastrin promote  release of histamine from gastric mucosal cells, which, in turn,  stimulates additional gastric secretion.   Gastric secretion occurs in three stages—the cephalic, gas-  tric, and intestinal phases. The cephalic phase begins before food  reaches the stomach and possibly even before eating. In this stage,  parasympathetic reflexes operating through the vagus nerves stimu-  late gastric secretion at the taste, smell, sight, or thought of food.  The greater the hunger, the greater the gastric secretion.   The gastric phase of gastric secretion, which accounts for  most of the secretory activity, starts when food enters the stomach.  The presence of food and the distension of the stomach wall trig-  ger the stomach to release gastrin, which stimulates production of  more gastric juice.   As food enters the stomach and mixes with gastric juice,  the pH of the contents rises, which enhances gastrin secretion.  Consequently, the pH of the stomach contents drops. As the pH  approaches 3.0, secretion of gastrin is inhibited. When the pH  reaches 1.5, gastrin secretion ceases.   For the stomach to secrete hydrochloric acid, hydrogen ions  are actively transported into the stomach. Negatively charged  chloride ions, attracted by the positively charged hydrogen ions,  move from the blood into the stomach. An equivalent number of  alkaline bicarbonate ions are released into the blood. Following a  meal, the blood concentration of bicarbonate ions increases, and  the urine excretes excess bicarbonate ions. This phenomenon is  called the alkaline tide.   The intestinal phase of gastric secretion begins when food leaves  the stomach and enters the small intestine. When food first contacts  the intestinal wall, it stimulates intestinal cells to release a hormone,  intestinal gastrin, that briefly enhances gastric gland secretion.    Hydrochloric acid Parietal cells of the gastric glands  Mucus Mucous cells    A protein-splitting enzyme that digests nearly all types of dietary protein into  polypeptides    Provides the acid environment needed for production and action of pepsin  Provides a viscous, alkaline protective layer on the stomach’s inner surface    The intestinal phase primarily inhibits gastric juice secretion.  As more food moves into the small intestine, a sympathetic reflex  triggered by acid in the upper part of the small intestine inhibits  secretion of gastric juice from the stomach wall. At the same time,  proteins and fats in this region of the intestine stimulate release  of the peptide hormone cholecystokinin (ko”le-sis”to-ki’nin)  (CCK) from the intestinal wall, which decreases gastric motil-  ity. Similarly, fats in the small intestine stimulate intestinal cells  to release intestinal somatostatin, which inhibits release of gastric  juice. Overall, these actions decrease gastric secretion and motility  as the small intestine fills with food. Table 17.6 summarizes the  phases of gastric secretion.    23 Distinguish among the cephalic, gastric, and intestinal phases of  gastric secretion.    FIGURE 17.20 The secretion of gastric juice is regulated in part  by parasympathetic impulses that stimulate the release of gastric juice  and gastrin.    Gastric enzymes begin breaking down proteins. However, the  stomach wall is not well-adapted to absorb digestive products. The  stomach absorbs only small volumes of water and certain salts, as  well as certain lipid-soluble drugs. Most nutrients are absorbed in  the small intestine. Alcohol, which is not a nutrient, is absorbed  both in the small intestine and stomach.    Mixing and Emptying Actions  Food stretches the smooth muscle layers of the stomach wall. The  stomach may enlarge, but its muscle layers maintain their tone,  and internal pressure of the stomach normally is unchanged. When  a person eats more than the stomach can comfortably hold, the  internal pressure may rise enough to stimulate pain receptors. The  result is a stomachache. Clinical Application 17.2 discusses this  common problem along with its associated indigestion.  Following a meal, the mixing movements of the stomach  wall aid in producing a semifluid paste of food particles and gas-  tric juice called chyme (kim). Peristaltic waves push the chyme  toward the pylorus of the stomach, and as chyme accumulates near  the pyloric sphincter, it begins to relax. Stomach contractions push  chyme a little (5-15 milliliters) at a time into the small intestine.  These stomach contraction waves push most of the chyme back-  ward into the stomach, mixing it further. The lower esophageal  sphincter prevents reflux of stomach contents into the esophagus.  Figure 17.21 illustrates this process.    The sight, taste, smell, or thought of food  triggers parasympathetic reflexes. Gastric juice is  secreted in response.    Food in stomach chemically and mechanically  stimulates release of gastrin, which, in turn,  stimulates secretion of gastric juice; reflex  responses also stimulate gastric juice secretion.    As food enters the small intestine, it stimulates  intestinal cells to release intestinal gastrin, which,  in turn, briefly promotes the secretion of gastric  juice from the stomach wall. This phase primarily  inhibits gastric juice secretion.    If a person eats large amounts of food too quickly, perhaps  because it can take up to 20 minutes for the brain’s hypothala-  mus to sense that the stomach is full, a stomachache can result. A  feeling of fullness becomes abdominal pain and then heartburn,  as stomach contents back up into the esophagus (gastric reflux).  The material from the stomach causes inflammation of the esoph-  agus (esophagitis), but the perception that the pain is from the  heart has given rise to the term “heartburn.”   An antacid product may provide temporary relief from gas-  tric reflux by quickly raising the pH of the stomach contents.  Most antacids include a compound containing sodium, calcium,  magnesium, or aluminum. Some products also contain simethi-  cone, which breaks up gas bubbles in the digestive tract.    The rate at which the stomach empties depends on the fluidity  of the chyme and the type of food. Liquids usually pass through  the stomach rapidly, but solids remain until they are well mixed  with gastric juice. Fatty foods may remain in the stomach three  to six hours; foods high in proteins move through more quickly;  carbohydrates usually pass through more rapidly than either fats  or proteins.   As chyme fills the duodenum (the proximal portion of the small  intestine), internal pressure on the organ increases, stretching the  intestinal wall. These actions stimulate sensory receptors in the wall,  triggering an enterogastric reflex (en-ter-o-gas’trik re’fleks). The  name of this reflex, like those of other digestive reflexes, describes the  origin and termination of reflex impulses. That is, the enterogastric  reflex begins in the small intestine (entero) and ends in the stom-  ach (gastro). As a result of the enterogastric reflex, fewer parasym-  pathetic impulses arrive at the stomach, decreasing peristalsis, and    Avoiding gastric reflux and heartburn is a more health-  ful approach than gorging and then reaching for medication.  Some tips:  e Avoid large meals. The more food, the more acid the stomach  produces.  e Eat slowly so that stomach acid secretion is more gradual.  ¢ Do not lie down immediately after eating. Being upright  enables gravity to help food move along the alimentary canal.  e If prone to indigestion or heartburn, avoid caffeine, which  increases stomach acid secretion.  e Nicotine and alcohol irritate the stomach lining and relax the  lower esophageal sphincter. This makes it easier for gastric  reflux to occur.    intestinal filling slows (fig. 17.22). If chyme entering the intestine is  fatty, the intestinal wall releases the hormone cholecystokinin, which  further inhibits peristalsis.   Vomiting results from a complex reflex that empties the  stomach in the reverse of the normal direction. Irritation or dis-  tension in the stomach or intestines can trigger vomiting. Sensory  impulses travel from the site of stimulation to the vomiting center  in the medulla oblongata. The responses initiated by the vomiting  center include taking a deep breath, raising the soft palate and thus  closing the nasal cavity, closing the opening to the trachea (glot-  tis), relaxing the lower esophageal sphincter, contracting the dia-  phragm so it presses downward over the stomach, and contracting  the abdominal wall muscles to increase pressure inside the abdom-  inal cavity. These motor responses squeeze the stomach from all  sides, forcing its contents upward and out via the open pathway  through the esophagus, pharynx, and mouth.    FIGURE 17.21 Stomach movements. (a) As the stomach fills, its muscular wall stretches, but the pyloric sphincter remains closed. (b) Mixing  movements combine food and gastric juice, creating chyme. (c) Peristaltic waves move the chyme toward the pyloric sphincter, which relaxes and admits    FIGURE 17.22 The enterogastric reflex partially regulates the rate at  which chyme leaves the stomach.    Several types of stimuli can promote activity in the vomiting  center. These include certain drugs (emetics); toxins in contami-  nated foods; rapid changes in body motion; and sensory impulses  from the labyrinths of the inner ears, which can produce motion  sickness. Stimulation of higher brain centers through sights,  sounds, odors, tastes, emotions, or mechanical stimulation of the  back of the pharynx can also trigger vomiting.   Nausea emanates from activity in the vomiting center or in  nerve centers near it. During nausea, stomach movements usually  are diminished or absent, and duodenal contents may move back  into the stomach.    25 How is chyme produced?  26 What factors influence how quickly chyme leaves the stomach?  27 Describe the enterogastric reflex.    The pancreas was discussed as an endocrine gland in chapter 13  (pp. 514-515). It also has an exocrine function—secretion of  a digestive fluid called pancreatic juice (pan”kre-at’ik joos).    The pancreas is closely associated with the small intestine and is  posterior to the parietal peritoneum, or retroperitoneal. It extends  horizontally across the posterior abdominal wall, with its head  in the C-shaped curve of the duodenum (portion of the small  intestine) and its tail against the spleen (fig. 17.23 and reference  plate 19, p. 52).   Pancreatic acinar cells produce pancreatic juice and make  up the bulk of the pancreas. These cells form clusters called acini  (acinus, sing.) around tiny tubes into which they release their  secretions. The smaller tubes unite to form larger ones, which  join a pancreatic duct that extends the length of the pancreas and  transports pancreatic juice to the small intestine. The pancreatic  duct usually connects with the duodenum at the same place where  the bile duct from the liver and gallbladder joins the duodenum,  although divisions and other connections may be present (see  figs. 13.34 on p. 514 and 17.23).   The main pancreatic duct and bile duct join at a short, dilated  tube called the hepatopancreatic ampulla (ampulla of Vater). A  band of smooth muscle, called the hepatopancreatic sphincter  (sphincter of Oddi), surrounds this ampulla. This sphincter controls  the movement of pancreatic juice and bile into the small intestine.    Pancreatic juice contains enzymes that digest carbohydrates, fats,  proteins, and nucleic acids. The carbohydrate-digesting enzyme,  pancreatic amylase, splits molecules of starch or glycogen into  disaccharides. The fat-digesting enzyme, pancreatic lipase,  breaks triglyceride molecules into fatty acids and monoglyc-  erides. (A monoglyceride molecule consists of one fatty acid  bound to glycerol.)   The protein-splitting (proteolytic) enzymes are trypsin,  chymotrypsin, and carboxypeptidase. Each of these enzymes  splits the bonds between particular combinations of amino acids  in proteins. No single enzyme can split all possible amino acid  combinations. Therefore, several enzymes are necessary to com-  pletely digest protein molecules.   The proteolytic enzymes are stored in tiny cellular struc-  tures called zymogen granules. These enzymes, like gastric pep-  sin, are secreted in inactive forms and must be activated by other  enzymes after they reach the small intestine. For example, the  pancreatic cells release inactive trypsinogen, which is activated  to trypsin when it contacts the enzyme enterokinase, which the  mucosa of the small intestine secretes. Trypsin, in turn, activates  chymotrypsin and carboxypeptidase. The need for activation pre-  vents enzymatic digestion of proteins in the secreting cells and  the pancreatic ducts.    Painful acute pancreatitis results when pancreatic enzymes  become active before they are secreted, and digest parts of the  pancreas. Blockage of the release of pancreatic juice can cause  pancreatitis, as can alcoholism, gallstones, certain infections,  traumatic injuries, and the side effects of some drugs.    FIGURE 17.23 (AP|R) The pancreas is closely associated with the duodenum.    Pancreatic juice contains two types of nucleases, which are  enzymes that break down nucleic acid molecules into nucleotides.  A high concentration of bicarbonate ions makes the juice alka-  line, which provides a favorable environment for the actions of the  digestive enzymes and helps neutralize acidic chyme as it arrives  from the stomach. The alkaline environment in the small intestine  also blocks the action of pepsin, which might otherwise damage  the duodenal wall.    The nervous and endocrine systems regulate release of pancreatic  juice, much as they regulate gastric and small intestinal secre-  tions. For example, during the cephalic and gastric phases of gas-  tric secretion, parasympathetic impulses stimulate the pancreas to  release digestive enzymes. A peptide hormone, secretin, stimu-  lates the pancreas to secrete abundant fluid when acidic chyme  enters the duodenum. Secretin is released into the blood from the  duodenal mucous membrane in response to the acid in chyme. The  pancreatic juice secreted at this time contains few, if any, digestive  enzymes but has a high concentration of bicarbonate ions. These  ions neutralize the acid in chyme (fig. 17.24).    Proteins and fats in chyme in the duodenum also stimulate the  release of cholecystokinin from the intestinal wall. As in the case  of secretin, cholecystokinin reaches the pancreas via the blood-  stream. Pancreatic juice secreted in response to cholecystokinin  has a high concentration of digestive enzymes.    30 List the enzymes in pancreatic juice.  31 What are the functions of the enzymes in pancreatic juice?    The liver, the largest internal organ, is located in the right upper  quadrant of the abdominal cavity, just inferior to the diaphragm. A  fold of visceral peritoneum called the coronary ligament attaches  the liver to the diaphragm on its superior surface. The liver is par-  tially surrounded by the ribs and extends from the level of the fifth   stomach stimulates the release of  secretin, which, in turn, stimulates  the release of pancreatic juice.    intercostal space to the lower margin of the ribs. It is reddish brown  in color and well supplied with blood vessels (figs. 17.25 and  17.26 and reference plates 10, 17, and 24, pp. 47, 51, and 55).    A fibrous capsule encloses the liver, and ligaments divide the  organ into a large right lobe and a smaller left lobe. The falciform  ligament is a fold of visceral peritoneum that separates the lobes  and fastens the liver to the abdominal wall anteriorly. The liver  also has two minor lobes, the guadrate lobe, near the gallbladder,  and the caudate lobe, close to the vena cava (fig. 17.26). The area  where the four lobes meet and blood vessels and ducts enter or exit  the liver is the porta hepatis.   Each lobe is separated into many tiny hepatic lobules, which  are the liver’s functional units (fig. 17.27). A lobule consists of  many hepatic cells (hepatocytes) radiating outward from a central  vein. Blood-filled channels called hepatic sinusoids separate plate-  like groups of these cells from each other. Blood from the diges-  tive tract, carried in the hepatic portal vein (see chapter 15, p. 603),  brings newly absorbed nutrients into the sinusoids (fig. 17.28). The  oxygen-rich blood from the hepatic artery mixes freely with the  blood containing nutrients and flows through the liver sinusoids,  which provides oxygen and nourishment to the hepatic cells.   Often blood in the hepatic portal vein contains some bacte-  ria that have entered through the intestinal wall. However, large  Kupffer cells, fixed to the inner lining (endothelium) of the  hepatic sinusoids, remove most of the bacteria from the blood  by phagocytosis. Then the blood passes from the sinusoids into    the central veins of the hepatic lobules and exits the liver via the  hepatic veins.   Within the hepatic lobules are many fine bile canaliculi,  which carry bile secreted by hepatic cells to bile ductules. The  ductules of neighboring lobules unite to form intrahepatic bile  ducts, which then converge to ultimately form the hepatic ducts.  These ducts merge, in turn, to form the common hepatic duct.    The liver carries on many important metabolic activities. From Science  to Technology 17.1 discusses a bioengineered liver. Recall from chap-  ter 13 (p. 514) that the liver plays a key role in carbohydrate metabo-  lism by helping maintain concentration of blood glucose within the  normal range. Liver cells responding to hormones such as insulin and  glucagon lower the blood glucose level by polymerizing glucose to  glycogen and raise the blood glucose level by breaking down glyco-  gen to glucose or by converting noncarbohydrates into glucose.   The liver’s effects on lipid metabolism include oxidizing fatty  acids at an especially high rate (see chapter 18, pp. 697-698);  synthesizing lipoproteins, phospholipids, and cholesterol; and  converting excess portions of carbohydrate molecules into fat mol-  ecules. The blood transports fats synthesized in the liver to adipose  tissue for storage.   The most vital liver functions are probably those related to  protein metabolism. They include deaminating amino acids; forming  urea (see chapter 18, p. 698); synthesizing plasma proteins such as  clotting factors (see chapter 14, pp. 541 and 543); and converting  certain amino acids into other amino acids.    Life without a liver is not possible. Although the liver is capable of  regeneration if even a small part of it (25 - 30%) remains healthy,  a person can survive only a few days once the liver stops function-  ing. For example survival is generally only weeks or a few months  after cancer, spreads to the liver.   Livers are in great demand for transplant, but they are scarce.  Each year in the United States, only about 6,000 of the 16,000 or  so individuals requiring livers survive long enough to undergo a  transplant. A person can receive part of a liver donated by a liv-  ing relative or other close match. The donor lives because only a  portion of the liver is needed for survival, and enough is left by the  procedure to allow regeneration to occur.   A promising solution to the liver shortage is an “extracorpo-  real liver assist device” (ELAD). It can take over the liver’s blood-    FIGURE 17.25 fAP|R) This transverse section of the abdomen reveals the liver and other organs in  the upper part of the abdominal cavity.    Bacteria in the intestine produce ammonia, which is carried in  the blood to the liver, where it reacts to yield urea. When this    liver function fails, concentration of blood ammonia sharply  rises, causing hepatic coma, a condition that can lead to death.    cleansing function until a cadaver organ becomes available, or  enable remaining functional liver tissue to stimulate enough  regeneration to restore health.   An ELAD is a “bioartificial” liver because it has synthetic as  well as biological components. The device consists of four car-  tridges filled with hollow fibers that house millions of human liver  cells (hepatocytes). A patient's plasma is separated from the blood  and passed through the device, where the liver cells remove tox-  ins and add liver-secreted products, such as clotting factors. The  plasma is then reunited with the formed elements of the blood,  and the blood reinfused into the patient. It is clinical trials in the  United States. An ELAD is similar to an artificial kidney used in  hemodialysis (see Clinical Application 20.3 on page 792).    The liver also stores many substances, including glycogen,  iron, and vitamins A, D, and B,,. Extra iron from the blood com-  bines with a protein (apoferritin) in liver cells, forming ferritin.  The iron is stored in this form until blood iron concentration falls,  when some of the iron is released. Thus, the liver is important in  iron homeostasis.    (a) (b)  FIGURE 17.26 (AP|R} Lobes of the liver, viewed (a) anteriorly and (b) inferiorly.    Branch of hepatic portal vein  Branch of hepatic artery  Plates of hepatic cells   Central vein section of a hepatic lobule. (b) Enlarged longitudinal section  of a hepatic lobule. (c) Light micrograph of hepatic lobules  in cross section (17x).    Liver cells help destroy damaged red blood cells and phago-  cytize foreign antigens. The liver removes toxic substances such as  alcohol and certain drugs from the blood (detoxification). The liver  can also serve as a blood reservoir, storing 200 to 400 milliliters of    Storage  Composition of Bile REGEE Tea  Bile (bil) is a yellowish-green liquid that is continuously secreted  from hepatic cells. In addition to water, bile contains bile salts, Detoxification    bile pigments, cholesterol, and electrolytes. Bile salts are the  most abundant and are the only bile components that have a  digestive function.   Hepatic cells use cholesterol to produce bile salts, and in secret-    Polymerizes glucose to glycogen; breaks down  glycogen to glucose; converts noncarbohydrates  to glucose    Oxidizes fatty acids; synthesizes lipoproteins,  phospholipids, and cholesterol; converts excess  portions of carbohydrate molecules into fat molecules    Deaminates amino acids; forms urea; synthesizes  plasma proteins; converts certain amino acids into  other amino acids    Removes damaged red blood cells and foreign  substances by phagocytosis  Removes toxins from the blood    ing these salts, they release some cholesterol into the bile. Cholesterol Jaundice, a yellowing of the skin, sclerae of the eyes, and    by itself has no special function in bile or in the alimentary canal.  Bile pigments (bilirubin and biliverdin) are breakdown prod-   ucts of hemoglobin from red blood cells (see chapter 14, p. 535).    mucous membranes due to accumulation of bile pigments, has  several causes. In obstructive jaundice, bile ducts are blocked,    perhaps by gallstones or tumors. In hepatocellular jaundice, the  liver is diseased, as in cirrhosis or hepatitis. In hemolytic jaun-  dice, red blood cells are destroyed too rapidly, as happens with  skin, sclerae, and mucous membranes of jaundice result from excess an incompatible blood transfusion or a blood infection.    Hepatitis is an inflammation of the liver. It has several causes, but  the various types have similar symptoms.   For the first few days, hepatitis may resemble the flu, producing  mild headache, low fever, fatigue, lack of appetite, nausea and vom-  iting, and sometimes stiff joints. By the end of the first week, more  distinctive symptoms arise: a rash, pain in the right upper quadrant  of the abdomen, dark and foamy urine, and pale feces. The skin and  sclera of the eyes begin to turn yellow (jaundice) due to accumu-  lating bile pigments. Great fatigue may continue for two or three  weeks, and then gradually the person begins to feel better.   This is hepatitis in its most common, least dangerous, acute  form. About half a million people develop hepatitis in the United  States each year, and 6,000 die. In a rare form called fulminant  hepatitis, symptoms are sudden and severe, along with altered  behavior and personality. Medical attention is necessary to pre-  vent kidney or liver failure or coma. Hepatitis that persists for  more than six months is termed chronic.   Only rarely does hepatitis result from alcoholism, autoimmunity,  or the use of certain drugs. Usually, one of several types of viruses  causes hepatitis. Viral types are distinguished by the route of infec-  tion, surface features, and whether the viral genetic material is DNA  or RNA. Hepatitis B virus has DNA; the others have RNA. The viral  types are classified as follows:   Hepatitis A spreads by contact with food or objects contami-  nated with virus-containing feces, including diapers. The course  of hepatitis A is short and mild.    The gallbladder is a pear-shaped sac in a depression on the inferior  surface of the liver. It is connected to the cystic duct, which, in turn,  joins the common hepatic duct (see fig. 17.23 and reference plate  19, p. 52). The gallbladder has a capacity of 30-50 milliliters, is  lined with columnar epithelial cells, and has a strong muscular layer  in its wall. It stores bile between meals, concentrates bile by reab-  sorbing water, and contracts to release bile into the small intestine.   The bile duct (common bile duct) is formed by the union of  the common hepatic and cystic ducts. It leads to the duodenum,  where the hepatopancreatic sphincter muscle guards its exit (see  fig. 17.23). This sphincter normally remains contracted, so as bile  collects in the bile duct it backs up into the cystic duct. When this  happens, the bile flows into the gallbladder, where it is stored.   Bile salts, bile pigments, and cholesterol become increasingly  concentrated as the gallbladder lining reabsorbs water and electro-  lytes. The cholesterol normally remains in solution, but under certain  conditions it may precipitate and form solid crystals. If cholesterol  continues to come out of solution, the crystals enlarge, forming  gallstones (fig. 17.29). This may happen if the bile is too concen-  trated, hepatic cells secrete too much cholesterol, or the gallblad-  der is inflamed (cholecystitis). Gallstones in the bile duct may block  the flow of bile, causing obstructive jaundice and considerable pain.  Clinical Application 17.4 discusses disorders of the gallbladder.    Hepatitis B spreads by contact with virus-containing body  fluids, such as blood, saliva, or semen. It may be transmitted by  blood transfusions, hypodermic needles, or sexual activity.   Hepatitis C accounts for about half of all known cases of hepa-  titis. This virus is primarily transmitted in blood—by sharing razors  or needles, from pregnant woman to fetus, or through blood trans-  fusions or use of blood products. Ten to twenty percent of people  known to be infected with hepatitis C virus develop symptoms.   Hepatitis D occurs in people already infected with the hepa-  titis B virus. It is blood-borne and associated with blood transfu-  sions and intravenous drug use. About 20% of individuals infected  with this virus die from the infection.   Hepatitis E virus is usually transmitted in water contaminated  with feces. It most often affects visitors to developing nations.   Hepatitis G is rare but seems to account for a significant per-  centage of cases of fulminant hepatitis. In people with healthy  immune systems, it produces symptoms so mild that they may not  even be noticed.   Antibiotic drugs, which are effective against bacteria, do  not treat hepatitis because most cases are viral. Usually, the per-  son must just wait out the symptoms. Hepatitis C infection may  resolve on it’s own, or respond to 6 to 12 months treatment with  a form of interferon or any of several new drugs. As many as  300 million people worldwide are hepatitis carriers. They do not  have symptoms but can infect others. Five percent of carriers  eventually develop liver cancer.    Normally, bile does not enter the duodenum until cholecystokinin  stimulates the gallbladder to contract. The intestinal mucosa releases  this hormone in response to proteins and fats in the small intestine.  (Recall from earlier in this chapter, p. 669, that cholecystokinin  also stimulates pancreatic enzyme secretion.) The hepatopancreatic  sphincter usually remains contracted until a peristaltic wave in the    Molly G., an overweight, forty-seven-year-old college administra-  tor and mother of four, had pain in the right upper quadrant of her  abdomen (see fig. 1.25b, p. 31). Sometimes the discomfort seemed  to radiate around to her back and move upward into her right shoul-  der (see fig. 12.2, p. 448). She usually felt this pain after her evening  meal, but it occasionally happened at night, awakening her. After an  episode of severe pain accompanied by sweating (diaphoresis) and  nausea, Molly visited her physician, who discovered tenderness in  the epigastric region (see fig. 1.25a, p. 31). She decided that Molly's  symptoms could indicate acute cholecystitis—an inflammation of  the gallbladder. Ultrasonography of the gallbladder or an X ray of  the gallbladder called a cholecystogram could provide the evidence  required to diagnose the painful problem.   Molly took tablets containing a contrast medium the night  before the X-ray procedure, which allowed time for the small intes-  tine to absorb the substance and for it to reach the liver and be  excreted into the bile. Later, contrast medium would be concen-  trated in the bile and stored in the gallbladder and would make the  contents of the gallbladder opaque to X rays.   Molly's cholecystogram revealed several stones (calculi) in  her gallbladder, a condition called cholelithiasis (see fig. 17.29).  Because Molly's symptoms were worsening, her physician recom-  mended cholecystectomy—surgical removal of the gallbladder.    duodenal wall approaches. Just before the wave hits, the sphincter  relaxes, and bile squirts into the duodenum (fig. 17.30). Table 17.8  summarizes the hormones that control digestion.    Bile salts aid digestive enzymes. Molecules of fats are lipophilic  and tend to clump when in a water solution. Bile salts have both a  water soluble end and a lipid soluble end, and break up fat clumps  by allowing the fat and water to interact, much like the action of soap  or detergent. The result is smaller fat droplets. This process is called    An incision was made in Molly’s right subcostal region and her  gallbladder excised from the liver. Fortunately, the cystic duct and  hepatic ducts did not have stones (see fig. 17.26b). Unfortunately,  Molly’s symptoms persisted following her recovery from surgery.  So her surgeon ordered a cholangiogram—an X-ray series of the  bile ducts. This study showed a residual stone at the distal end of  Molly’s bile duct (see fig. 17.23).   The surgeon extracted the residual stone using a fiberoptic  endoscope, a long, flexible tube passed through the esophagus  and stomach and into the duodenum. This instrument enables a  surgeon to observe features of the gastrointestinal tract directly  through the eyepiece of the endoscope or on a monitor. A sur-  geon can also perform manipulations using specialized tools  passed through the endoscope to its distal end.   In Molly's case, the surgeon performed an endoscopic  papillotomy—an incision of the hepatopancreatic sphincter made  by applying an electric current to a wire extending from the end  of the endoscope (see fig. 17.23). She then removed the exposed  stone by manipulating a tiny basket at the tip of the endoscope.  Many patients undergo only the endoscopic procedure to remove  the gallbladder, performed on an outpatient basis.    emulsification. The smaller fat droplets greatly increase the total sur-  face area of the fatty substance, giving lipase molecules better access  to the fat molecules and resulting in more effective fat digestion.   Bile salts enhance absorption of fatty acids and cholesterol  by forming complexes (micelles) that are very soluble in chyme  and that epithelial cells can more easily absorb. The fat-soluble  vitamins A, D, E, and K are also absorbed in the presence of bile  salts. Lack of bile salts results in poor lipid absorption and vita-  min deficiencies.   The mucous membrane of the small intestine reabsorbs nearly  all of the bile salts, along with fatty acids. The blood carries bile    Increases secretory activity of gastric glands  Increases secretory activity of gastric glands  Inhibits secretion of acid by parietal cells  Inhibits secretion of acid by parietal cells    Decreases secretory activity of gastric glands and inhibits gastric motility;  stimulates pancreas to secrete fluid with a high digestive enzyme  concentration; stimulates gallbladder to contract and release bile    Stimulates pancreas to secrete fluid with a high bicarbonate ion  concentration    @ Cells of the  intestinal mucosa  secrete the hormone  cholecystokinin (CCK)  into the bloodstream    @ Bile passes down the cystic duct  and bile duct to duodenum    FIGURE 17.30 Fatty chyme entering the duodenum stimulates the gallbladder to release bile.    Which other organ, besides the gallbladder, responds to cholecystokinin stimulation, and what is the response of that organ to    salts to the liver, where hepatic cells resecrete them into the bile  ducts. Liver cells synthesize bile salts, which replace the small  amounts lost in the feces.    36 Explain how bile forms.  37 Describe the function of the gallbladder.  38 How is secretion of bile regulated?    The small intestine is a tubular organ that extends from the pyloric  sphincter to the beginning of the large intestine. With its many  loops and coils, the small intestine fills much of the abdominal  cavity (see fig. 17.1 and reference plates 4 and 5, pp. 41-42). The  small intestine is 5.5—6.0 meters (18-20 feet) long in a cadaver    when the muscular wall lacks tone, but it may be only half this  long in a living person.   The small intestine receives chyme from the stomach and  secretions from the pancreas and liver. It completes digestion of  the nutrients in chyme, absorbs the products of digestion, and  transports the remaining material to the large intestine.    The small intestine, shown in figures 17.31 and 17.32 and in refer-  ence plates 12 and 18 (pp. 48 and 51), consists of three portions:  the duodenum, the jejunum, and the ileum.   The duodenum (du”o-de’num), which is about 25 centime-  ters long and 5 centimeters in diameter, lies posterior to the pari-  etal peritoneum (retroperitoneal). It is the shortest and most fixed  portion of the small intestine. The duodenum follows a C-shaped  path as it passes anterior to the right kidney and the upper three  lumbar vertebrae.   The remainder of the small intestine is mobile and lies free in  the peritoneal cavity. The proximal two-fifths of this portion of the    FIGURE 17.31 (APIRI  The three parts of the small Cecum  intestine are the duodenum,  the jejunum, and the ileum.  Veins are not visible from this  view of the small intestine. lleum    Radiograph showing a normal  small intestine containing a  radiopaque substance that the  patient ingested.    small intestine is the jejunum (jé-joo’num), and the remainder is the  ileum (il’e-um). There is no distinct separation between the jejunum  and ileum, but the diameter of the jejunum is typically greater, and  its wall is thicker, more vascular, and more active than that of the  ileum. The ileum has lymph nodules (Peyer’s patches, p. 621) and   The jejunum and ileum are suspended from the posterior  abdominal wall by a double-layered fold of peritoneum called  mesentery (mes’en-ter”e) (fig. 17.33). The mesentery supports the    blood vessels, nerves, and lymphatic vessels that supply the intes-  tinal wall (see fig. 17.31 and reference plate 5, p. 42). Most of the cells within a human body are not actually human—  they are bacterial, constituting our microbiome. The ten trillion  bacteria of the human “gut microbiome” have long been known  to help us digest certain foods. The mouth houses more than  600 species of bacteria, and the large intestine 6,800. One of    A filmy, double fold of peritoneal membrane called the greater  omentum drapes like an apron from the stomach over the transverse  colon and the folds of the small intestine (fig. 17.34). If the wall of  the alimentary canal becomes infected, cells from the omentum may the first microbiome studies examined soiled diapers from  adhere to the inflamed region and help seal it off, lowering the risk babies regularly during their first year. Newborns start out with  that the infection will spread to the peritoneal cavity. clean intestines, but after various bacteria come and go, very   similar species remain from baby to baby by the first birthday.    The inner surface of the small intestine has a velvety appearance  throughout its length, due to many tiny projections of mucous mem-  brane called intestinal villi (figs. 17.35 and 17.36; see fig. 17.3).  These structures are most numerous in the duodenum and the proxi-  mal jejunum. They project into the lumen of the alimentary canal,  contacting the intestinal contents. Villi greatly increase the surface  area of the intestinal lining, aiding absorption of digestive products.  Each villus consists of a layer of simple columnar epithe-  lium and a core of connective tissue containing blood capillaries, a  lymphatic capillary called a lacteal, and nerve fibers (see fig. 17.35).    FIGURE 17.33 fAP|R} Mesentery formed by folds of the peritoneal  membrane suspends portions of the small intestine from the posterior  abdominal wall. Villus 5    FIGURE 17.34 fAP|R) The greater omentum hangs like an apron  over the abdominal organs. FIGURE 17.35 (AP|R) Structure of a single intestinal villus.    At their free surfaces, the epithelial cells have many fine extensions  called microvilli that form a brushlike border and greatly increase  the surface area of the intestinal cells, further enhancing absorption  (fig. 17.37; see fig. 17.3). The blood capillaries and lacteals carry  away absorbed nutrients, and nerve fibers conduct impulses to stim-  ulate or inhibit villus activities.   Between the bases of adjacent villi are tubular intestinal  glands (crypts of Lieberktihn) that dip into the mucous membrane.  The deeper layers of the small intestinal wall are much like those  of other parts of the alimentary canal in that they include the sub-  mucosa, the muscularis, and the serosa layers.   The lining of the small intestine has many circular folds of  mucosa, called plicae circulares, that are especially well devel-  oped in the lower duodenum and upper jejunum (fig. 17.38). With  the villi and microvilli, these folds help increase the surface area  of the intestinal lining.    The epithelial cells that form the lining of the small intes-  tine are continually replaced. New cells form in the intestinal  glands by cell division and migrate outward onto the villus  surface. When the migrating cells reach the tip of the villus,    they are shed. As a result, nearly one-quarter of the bulk of  feces consists of dead epithelial cells from the small intestine.  This cellular turnover renews the small intestine’s epithelial lin-  ing every three to six days.    Mucus-secreting goblet cells are abundant throughout the mucosa  of the small intestine. In addition, many specialized mucus-secreting  glands (Brunner’s glands) in the submucosa in the proximal portion  of the duodenum secrete a thick, alkaline mucus in response to  certain stimuli.   The intestinal glands at the bases of the villi secrete large  volumes of a watery fluid (see fig. 17.35). The villi rapidly reab-  sorb this fluid, which carries digestive products into the villi.    FIGURE 17.37 (AP|R) Intestinal epithelium. (a) Microvilli increase  the surface area of intestinal epithelial cells. (6) Transmission electron  micrograph of microvilli (16,000x).    The fluid the intestinal glands secrete has a nearly neutral pH  (6.5—7.5), and it lacks digestive enzymes. However, the epithe-  lial cells of the intestinal mucosa have digestive enzymes embed-  ded in the membranes of the microvilli on their luminal surfaces.  These enzymes break down food molecules just before absorp-  tion takes place. The enzymes include peptidases, which split    peptides into their constituent amino acids; sucrase, maltase,  and lactase, which split the disaccharides sucrose, maltose, and  lactose into the monosaccharides glucose, fructose, and galac-  tose; and intestinal lipase, which splits fats into fatty acids and  glycerol. Table 17.9 summarizes the sources and actions of the  major digestive enzymes.    circulares Mucus protects the intestinal wall in the same way it protects the  stomach lining. Therefore, mucus secretion increases in response  to mechanical stimulation and the presence of irritants, such as  gastric juice. Stomach contents entering the small intestine stimu-  late the duodenal mucous glands to release mucus.  Direct contact with chyme chemically and mechanically stim-  ulates goblet cells and intestinal glands to secrete their products.  Distension of the intestinal wall activates the nerve plexuses therein    —— Submucosa and stimulates parasympathetic reflexes that also trigger release of  :  eeeenlanns small intestine secretions.  =—- »>  — Circular muscle R ) PRACTICE  Longitudinal muscle 40 Describe the parts of the small intestine.  es 7 Serosa 41 What is the function of an intestinal villus?  (b) 42 Distinguish between intestinal villi and microvilli.  FIGURE 17.38 Section of small intestine. (a) The inner lining of the 43 What is the function of the intestinal glands?  small intestine contains many circular folds, the plicae circulares. (b) A AA List intestinal digestive enzymes.   Pancreatic lipase Pancreas Breaks down fats into fatty acids and glycerol   Trypsin, chymotrypsin Pancreas Breaks down proteins or partially digested proteins into peptides  Carboxypeptidase Pancreas Breaks down peptides into amino acids   Intestinal lipase Mucosal cells Breaks down fats into fatty acids and glycerol    Adults who have lactose intolerance do not produce suf-  ficient lactase to adequately digest lactose, or milk sugar.  Undigested lactose increases osmotic pressure of the intesti-  nal contents and draws water into the intestines. At the same  time, intestinal bacteria metabolize undigested sugar, pro-  ducing organic acids and gases. The overall result is bloating,  intestinal cramps, and diarrhea.   Digestive difficulties following milk drinking have been  noted for thousands of years, but were associated with lactose  only a century ago. Genetic evidence suggests that lactose  intolerance may be the “normal” condition, with the ability to  digest lactose the result of a mutation that occurred recently in  our past and became advantageous when agriculture brought  dairy foods to human populations. The ability to digest lactose  has increased with the increased use of dairy foods.    Villi greatly increase the surface area of the intestinal mucosa,  making the small intestine the most important absorbing organ of  the alimentary canal. The small intestine is so effective in absorb-  ing digestive products, water, and electrolytes, that very little  absorbable material reaches the organ’s distal end.    Carbohydrate digestion begins in the mouth with the activ-  ity of salivary amylase and is completed in the small intestine by  enzymes from the intestinal mucosa and pancreas (fig. 17.39).  The resulting monosaccharides are absorbed by facilitated diffusion    or active transport into the villi and enter blood capillaries (see  chapter 3, pp. 100-101 and 103).   Protein digestion begins in the stomach as a result of pepsin  activity and is completed in the small intestine by enzymes from  the intestinal mucosa and the pancreas (fig. 17.40). Protein mole-  cules are ultimately broken down into amino acids, which are then  absorbed into the villi by active transport and enter the circulation.   Fat molecules are digested almost entirely by enzymes from  the pancreas and intestinal mucosa (fig. 17.41). The resulting fatty  acid molecules are absorbed in the following steps: (1) The fatty  acid molecules dissolve in the epithelial cell membranes of the  villi and diffuse through them. (2) The endoplasmic reticula of  the cells use the fatty acids to resynthesize fat molecules similar  to those previously digested. (3) These fats collect in clusters that  become encased in protein. (4) The resulting large molecules of  lipoprotein are called chylomicrons, and they make their way to  the lacteals of the villi. (5) Periodic contractions of smooth mus-  cle in the villi help empty the lacteals into the cysterna chyli (see  fig. 16.6a, p. 620), which is an expansion of the thoracic duct. The  lymph carries the chylomicrons to the bloodstream (fig. 17.42).   Chylomicrons in the blood transport dietary fats to mus-  cle and adipose cells. Similarly, very-low-density lipoprotein  (VLDL) molecules, produced in the liver, transport triglycerides  synthesized from excess dietary carbohydrates. As VLDL mol-  ecules reach adipose cells, an enzyme, lipoprotein lipase, cata-  lyzes reactions that unload their triglycerides, converting VLDL  to low-density lipoprotein (LDL) molecules. Because most of the  triglycerides have been removed, LDL molecules have a higher  cholesterol content than the original VLDL molecules. Cells in the  peripheral tissues obtain cholesterol by using receptor-mediated  endocytosis to remove LDL particles from plasma (see chapter 3,  pp. 104-105).   Unlike LDL, which delivers cholesterol to tissues, high-  density lipoprotein (HDL) removes cholesterol from tissues and    FIGURE 17.39 Digestion breaks down complex carbohydrates into disaccharides, which are then broken down into monosaccharides, which are small  enough for intestinal villi to absorb. The monosaccharides then enter the bloodstream.    FIGURE 17.40 The amino acids that result from dipeptide digestion are absorbed by intestinal villi and enter the blood.    FIGURE 17.41 Fatty acids and glycerol result from fat digestion. Intestinal villi absorb them, and most are resynthesized into fat molecules before they    delivers it to the liver. The liver produces the basic HDL framework  and secretes HDL molecules into the bloodstream. Circulating HDL  picks up cholesterol from peripheral tissues and returns it to the  liver, where it enters cells by receptor-mediated endocytosis. The  liver disposes of the cholesterol it obtains in this manner by secret-  ing it into bile or by using it to synthesize bile salts.   The intestine reabsorbs much of the cholesterol and bile  salts in bile, which are then transported back to the liver, and the  secretion-reabsorption cycle repeats. During each cycle, some of  the cholesterol and bile salts escape reabsorption, reach the large  intestine, and are excreted as part of the feces.   The intestinal villi also absorb electrolytes and water. Most  electrolyte absorption is by facilitated diffusion and active trans-  port, and water by osmosis. Thus, the intestinal contents may be  hypertonic at first, but as nutrients and electrolytes are absorbed,  the contents become slightly hypotonic to the cells. Then, water  follows the nutrients and electrolytes into the villi by osmosis.  In most cases the electrolytes are absorbed at a steady rate, but  in some cases, as with iron and calcium, absorption will increase  when body stores are low, as long as these substances are present  in the diet. Table 17.10 summarizes the absorption process.    In malabsorption the small intestine digests, but does not  absorb, some nutrients. Symptoms of malabsorption include  diarrhea, weight loss, weakness, vitamin deficiencies, anemia,  and bone demineralization. Causes of malabsorption include  surgical removal or rerouting of a portion of the small intestine,  obstruction of lymphatic vessels due to a tumor, or interference  with the production and release of bile as a result of liver dis-  ease and enzyme deficiency. Another cause of malabsorption  is a reaction to gluten, which is a composite of two types of  proteins that are found in certain grains, such as wheat , barley,  and rye. This condition, called celiac disease, is an autoimmune  response to eating gluten that damages or destroys micro-  villi, reducing the surface area of the small intestine, prevent-  ing adequate absorption of some nutrients. Many gluten-free  products are available for the 1 in 100 people worldwide who  have celiac disease.    Facilitated diffusion of  glycerol; diffusion of fatty acids  into cells or blood capillaries    (a) Most fatty acids are  resynthesized into fats  and incorporated in  chylomicrons    Some fatty acids with  relatively short carbon  chains are absorbed  without being changed  back into fats    »>  hep PRACTICE  45 Which substances resulting from digestion of carbohydrate,  protein, and fat molecules does the small intestine absorb?  46 Which ions does the small intestine absorb?    The small intestine carries on mixing movements and peri-  stalsis, like the stomach. In the major mixing movement—  segmentation—periodic small, ringlike contractions cut the chyme  into segments and move it back and forth. Segmentation also  slows the movement of chyme through the small intestine.    @ Fatty acids are  used to synthesize  fats in endoplasmic  reticulum    Peristaltic waves propel chyme through the small intestine.  These waves are usually weak, and they stop after pushing the  chyme a short distance. Consequently, chyme moves slowly  through the small intestine, taking from three to ten hours to  travel its length.   As might be expected, parasympathetic impulses enhance  both mixing and peristaltic movements, and sympathetic impulses  inhibit them. Reflexes involving parasympathetic impulses to the  small intestine sometimes originate in the stomach. For example,  food in the stomach distends its wall, triggering the gastroenteric  reflex, which greatly increases peristaltic activity in the small  intestine. Another reflex begins when the duodenum fills with  chyme, stretching its wall. This reflex speeds movement through  the small intestine. These reflexes make room for new chyme from  the stomach.   If the small intestine wall becomes overdistended or irri-  tated, a strong peristaltic rush may pass along the organ’s entire  length. This movement sweeps the contents into the large intestine  so quickly that water, nutrients, and electrolytes that would nor-  mally be absorbed are not. The result is diarrhea, characterized by  frequent defecation and watery stools. Prolonged diarrhea causes  dehydration and imbalances in electrolyte concentrations.   At the distal end of the small intestine, the ileocecal sphinc-  ter joins the small intestine’s ileum to the large intestine’s cecum.  Normally, this sphincter remains constricted, preventing the con-  tents of the small intestine from entering the large intestine, and  at the same time keeping the contents of the large intestine from  backing up into the ileum. However, after a meal, a gastroileal  reflex increases peristalsis in the ileum and relaxes the sphincter,  forcing some of the contents of the small intestine into the cecum.    The large intestine is so named because its diameter is greater than  that of the small intestine. This part of the alimentary canal is about  1.5 meters long, and it begins in the lower right side of the abdomi-  nal cavity where the ileum joins the cecum. From there, the large  intestine ascends on the right side, crosses obliquely to the left, and  descends into the pelvis. At its distal end, it opens to the outside of  the body as the anus.   The large intestine absorbs ingested water and electrolytes  remaining in the alimentary canal. Additionally it reabsorbs and  recycles water and remnants of digestive secretions. The large  intestine also forms and stores feces.    The large intestine consists of the cecum, the colon, the rectum, and  the anal canal. Figures 17.43 and 17.44 and reference plates 11, 12,  18, and 25 (pp. 47, 48, 51, and 56) depict the large intestine.   The cecum, at the beginning of the large intestine, is a dilated,  pouchlike structure that hangs slightly inferior to the ileocecal open-  ing. Projecting downward from it is a narrow tube with a closed  end called the appendix. The human appendix has no known  digestive function, but it contains lymphatic tissue. Removal of the    appendix raises the risk of recurrence of certain infections, such as  Clostridium difficile. This evidence suggests that the human appen-  dix may be a storage place for the healthy “gut” microbiome.    In appendicitis, the appendix becomes inflamed. Surgery is often  required to remove the appendix before it ruptures. If it does  rupture, this may allow contents of the large intestine including    any infectious organisms to enter the abdominal cavity and cause  a serious inflammation of the peritoneum called peritonitis.    The colon is divided into four parts—the ascending, transverse,  descending, and sigmoid colons. The ascending colon begins at the  cecum and extends upward against the posterior abdominal wall to a  point just inferior to the liver. There it turns sharply to the left (as the  right colic, or hepatic, flexure) and becomes the transverse colon.  The transverse colon is the longest and most movable part of the  large intestine. It is suspended by a fold of peritoneum and sags in  the middle below the stomach. As the transverse colon approaches  the spleen, it turns abruptly downward (as the left colic, or splenic,  flexure) and becomes the descending colon. At the brim of the pel-    vis, the colon makes an S-shaped curve, called the sigmoid colon,  and then becomes the rectum.   The rectum lies next to the sacrum and generally follows its  curvature. The peritoneum firmly attaches it to the sacrum, and it  ends about 5 centimeters inferior to the tip of the coccyx, where it  becomes the anal canal (fig. 17.45).   The anal canal is formed by the last 2.5 to 4.0 centimeters of the  large intestine. The mucous membrane in the canal is folded into a  series of six to eight longitudinal anal columns. At its distal end, the  canal opens to the outside as the anus. Two sphincter muscles guard  the anus—an internal anal sphincter muscle, composed of smooth  muscle under involuntary control, and an external anal sphincter  muscle, composed of skeletal muscle under voluntary control.    Hemorrhoids are enlarged and inflamed branches of the rectal  vein in the anal columns that cause intense itching, sharp pain, and  sometimes bright red bleeding. The hemorrhoids may be internal    or bulge out of the anus. Causes of hemorrhoids include anything  that puts prolonged pressure on the delicate rectal tissue, includ-  ing obesity, pregnancy, constipation, diarrhea, and liver disease.    FIGURE 17.45 The rectum and the anal canal are at the distal end of  the alimentary canal.    51. What is the general function of the large intestine?  52 Describe the parts of the large intestine.    53 Distinguish between the internal sphincter muscle and the  external sphincter muscle of the anus.    The wall of the large intestine includes the same types of tissues  found in other parts of the alimentary canal but also has some  unique features (fig. 17.46). The large intestinal wall lacks the villi  and plicae circularis characteristic of the small intestine. The longi-  tudinal layer of smooth muscle cells is not uniformly distributed  throughout the large intestinal wall. Instead the smooth muscle  cells are mostly in three distinct bands (taeniae coli) that extend  the entire length of the colon. These bands exert tension length-  wise on the wall, creating a series of pouches (haustra). The large  intestinal wall also has small collections of fat (epiploic append-  ages) in the serosa on its outer surface (see fig. 17.43).    The large intestine has little or no digestive function. This is in  contrast to the small intestine, which secretes digestive enzymes  and absorbs the products of digestion. However, the mucous mem-  brane that forms the inner lining of the large intestine includes  many tubular glands. Structurally, these glands are similar to those  of the small intestine, but they are composed almost entirely of gob-  let cells (fig. 17.47). Consequently, mucus is the large intestine’s  only significant secretion.   Mechanical stimulation from chyme and parasympathetic  impulses control the rate of mucus secretion. In both cases, the  goblet cells respond by increasing mucus production, which, in  turn, protects the intestinal wall against the abrasive action of  materials passing through it. Mucus also holds particles of fecal  matter together, and, because it is alkaline, mucus helps con-  trol the pH of the large intestinal contents. This is important  because acids are sometimes released from the feces as a result of  bacterial activity.   Chyme entering the large intestine usually has few nutrients  remaining in it and mostly consists of materials not digested or  absorbed in the small intestine. It also contains water, electro-  lytes, mucus, and bacteria.   Absorption in the large intestine is normally limited to water  and electrolytes, and this usually occurs in the proximal half  of the tube. Electrolytes such as sodium ions can be absorbed  by active transport, while water follows passively, crossing the    @ Note the many goblet cells in the mucosa of the large  intestine. Why are there so many more of these cells in the  large intestinal wall than in the small intestinal wall?    mucosal layer by osmosis. About 90% of the water that enters  the large intestine is absorbed, and little sodium or water is lost  in the feces.   The many bacteria that normally inhabit the large intestine,  called intestinal flora, break down some of the molecules that  escape the actions of human digestive enzymes. For instance,  cellulose, a complex carbohydrate in food of plant origin, passes  through the alimentary canal almost unchanged, but colon bacteria  can break down cellulose and use it as an energy source. These  bacteria, in turn, synthesize vitamins, such as K, B,,, thiamine, and  riboflavin, which the intestinal mucosa absorbs. Bacterial actions  in the large intestine may produce intestinal gas (flatus).    Intestinal gas contains nitrogen and oxygen taken in while  breathing and eating, plus variable amounts of methane (CH,),  carbon dioxide (CO,), and hydrogen contributed from the  bacterial fermentation of undigested food. The characteristic  odor comes from bacterial action on the nitrogen and sulfur  in proteins, which yields pungent-smelling ammonia (NH,) and  foul hydrogen sulfide (H,S). Most people release a half liter of    intestinal gas a day. Foods rich in sulfur-containing amino acids  make intestinal gas more foul. These foods include beans, broc-  coli, bran, brussels sprouts, cabbage, cauliflower, and onions.    54 How does the structure of the large intestine differ from that of  the small intestine?    The movements of the large intestine—mixing and peristalsis—  are similar to those of the small intestine, although usually slower.  The mixing movements break the fecal matter into segments and  turn it so that all portions are exposed to the intestinal mucosa.  This helps absorb water and electrolytes.   The peristaltic waves of the large intestine are different from  those of the small intestine. Instead of occurring frequently, they  happen only two or three times each day. These waves produce mass  movements in which a large section of the intestinal wall constricts  vigorously, forcing the intestinal contents to move toward the rec-  tum. Typically, mass movements follow a meal, as a result of the  gastrocolic reflex initiated in the small intestine. Irritation of the  intestinal mucosa can also trigger such movements. For instance,  a person suffering from an inflamed colon (colitis) may experience  frequent mass movements. Clinical Application 17.5 examines con-  ditions affecting the large intestine.   When it is appropriate to defecate, a person usually can initi-  ate a defecation reflex by holding a deep breath and contracting the  abdominal wall muscles. This action increases the internal abdomi-  nal pressure and forces feces into the rectum. As the rectum fills, its  wall distends, triggering the defecation reflex, which stimulates per-  istaltic waves in the descending colon. The internal anal sphincter  relaxes. At the same time, other reflexes involving the sacral region  of the spinal cord strengthen the peristaltic waves, lower the dia-  phragm, close the glottis, and contract the abdominal wall muscles.  These actions further increase the internal abdominal pressure and  squeeze the rectum. The external anal sphincter is signaled to relax,  and the feces are forced to the outside. A person can voluntarily  inhibit defecation by contracting the external anal sphincter.    Investigating the gut microbiome can improve health, because  illness can alter the bacterial populations within us. Antibiotic  drugs may cause diarrhea by temporarily changing the gut  microbiome. Probiotics are live microorganisms, such as bacte-  ria and yeasts, that, when ingested, confer a health benefit. For  example, certain Lactobacillus strains added to yogurt help pro-  tect against Salmonella foodborne infection.   Probiotics typically consist of one or a few microbial species.  In contrast, “fecal transplantation” alters hundreds of bacterial  species at once. In the procedure, people with recurrent infec-  tion from Clostridium difficile, which causes severe diarrhea,  receive feces from a healthy donor. The bacteria transferred in  the donated feces reconstitute a healthy gut microbiome, treat-  ing the infection. Fecal transplantation has been performed by  enema in cattle for a century, and since 1958 in humans. A recent  clinical trial introduced the fecal material in a tube through the  nose to the small intestine, but soon the material may be deliv-  ered in a capsule.    Feces (fe’séz) are composed of materials not digested or absorbed,  along with water, electrolytes, mucus, and bacteria. Usually the  feces are about 75% water, and their color derives from bile pig-  ments altered by bacterial action.    The large intestine (colon) is the source of familiar digestive dis-  comforts as well as more serious disorders.    In diverticulosis, parts of the intestinal wall weaken, and the inner  mucous membrane protrudes through, forming small sacs on the  outer intestinal surface. If chyme accumulates in the outpouching  and becomes infected and inflamed (diverticulitis), antibiotics  or surgical removal of the area may become necessary. Lack of  dietary fiber may increase the risk of developing diverticulosis.   Inflammatory bowel disease is a group of disorders that  includes ulcerative colitis and Crohn's disease. The disorders dif-  fer by the site and extent of inflammation and ulceration of the  intestines. In the United States, about 100,000 people suffer the  abdominal cramps and diarrhea of ulcerative colitis, and 500,000  individuals have similar symptoms of Crohn's disease.   Ulcerative colitis affects the mucosa and submucosa of the  distal large intestine and the rectum. In about 25% of cases, the  disease extends no farther than the rectum. Bloody diarrhea and  cramps may last for days or weeks and may recur frequently or  only rarely. The severe diarrhea leads to weight loss and elec-  trolyte imbalances and may develop into colon cancer or affect  other organs, including the skin, eyes, or liver. The inflamed and  ulcerous tissue is continuous.   Crohn's disease is more extensive than ulcerative colitis, infil-  trating the small and large intestines and penetrating all tissue  layers. In contrast to the uniformity of ulcerative colitis, affected  portions of intestine in Crohn's disease are interspersed with  unaffected areas, producing a “cobblestone” effect after many  years. The ileum and cecum are affected in about 40% of indi-  viduals, only the small intestine is involved in 30% of cases, and  only the large intestine is involved in 25% of cases. Rarely, the  disease affects more proximal structures of the gastrointestinal  tract. The diarrhea is often not bloody, and complications such as  cancer are rare.   Overall, about 20% of people with inflammatory bowel dis-  ease have symptoms that fall between the descriptions of ulcer-  ative colitis and Crohn’s disease, and are considered to have  “indeterminate colitis.” Autoimmunity, infection, or a genetic  predisposition may contribute to causing inflammatory bowel dis-  ease. Surgery and drugs that suppress the immune response are  used to treat some cases of inflammatory bowel disease.    Cancer of the large intestine or rectum, known as colorectal can-  cer, is the fourth most prevalent cancer in the United States and  the second most common cause of cancer death. More than  30,000 new cases are diagnosed each year, and more than 56,000  people die of the condition. It tends to run in families.    Diagnostic tests, described in table 17A, may detect colorec-  tal cancer. These tests are of two general types—the fecal occult  blood test performed on a stool sample and imaging the large  intestinal wall. An experimental test screens the DNA from cells in  feces for mutations associated with colorectal cancer.   Fiberoptic colonoscopy is a test commonly performed on  people over age 50, when the risk of colorectal cancer increases.  Under sedation, a flexible lit tube is inserted into the rectum,  and polyps and tumors are identified and removed. People with  a family history of colon cancer should be screened at an earlier  age. Fiberoptic colonoscopy takes less than an hour. A newer pro-  cedure, computed tomographic colonography (virtual colonos-  copy), requires the same preparatory bowel cleansing, but does  not require sedation and is faster. However, if a lesion is detected,  the more invasive approach must be used to remove the suspi-  cious tissue.   Treatment for colorectal cancer removes the affected tissue.  If a large portion of the intestine is removed, surgery is used to  construct a new opening to release feces. The free end of the  intestine is attached to an opening created through the skin of  the abdomen, and a bag is attached to the opening to collect the  fecal matter. This procedure is called a colostomy.   For people who have a certain inherited form of colon cancer  (familial adenomatous polyposis), nonsteroidal anti-inflammatory  drugs (NSAIDs) called Cox-2 inhibitors are used to treat the disease  and may even help to prevent it in those identified by a genetic test  to be at high risk. However, these drugs increase the risk of heart  disease in certain individuals.    Double-contrast barium X-ray exam following ingestion of  enema contrast agent highlights blockages  in large intestine    Mutations associated with colorectal  cancer detected in DNA of cells shed  with feces    The pungent odor of the feces results from a variety of com-  pounds that bacteria produce. These compounds include phenol,  hydrogen sulfide, indole, skatole, and ammonia.    57 How does peristalsis in the large intestine differ from peristalsis  in the small intestine?    Changes to the digestive system associated with the passing years  are slow and slight, so most people can enjoy eating a variety of  foods as they grow older. Maintaining healthy teeth is vital to  obtaining adequate nutrition. This requires frequent dental check-  ups, cleanings, and plaque removal, plus care of the gums. Tooth  loss due to periodontal disease becomes more likely after age  thirty-five.   Despite regular dental care, some signs of aging may affect  the teeth. The enamel often thins from years of brushing, teeth  grinding, and eating acidic foods. Thinning enamel may make  the teeth more sensitive to hot and cold foods. At the same time,  the cementum may thicken. The dentin heals more slowly and  enlarges as the pulp shrinks. Loss of neurons in the pulp may make  it more difficult to notice tooth decay. The gums recede, creating  more pockets to harbor the bacteria whose activity contributes  to periodontal disease. The teeth may loosen as the bones of the  jaw weaken. On a functional level, older people sometimes do not  chew their food thoroughly and swallow larger chunks of food that  may present a choking hazard.   A common complaint of older individuals is “dry mouth,” or  xerostomia. This condition is not a normal part of aging—stud-  ies have shown that the oldest healthy people make just as much  saliva as healthy younger people. Dry mouth is common, however,  because it is a side effect of more than 400 medications, many of  which are more likely to be taken by the elderly. These medica-  tions include antidepressants, antihistamines, and drugs that treat  cancer or hypertension. In addition, radiation and chemotherapy  used to treat cancer can cause mouth sores and tooth decay.   The gastrointestinal tract gradually becomes less efficient  with age. Slowing peristalsis may cause frequent heartburn as food  backs up into the esophagus. The stomach lining thins with age, and    secretion of hydrochloric acid, pepsin, and intrinsic factor decline.  Exit of chyme from the stomach slows. Overall, these changes may  affect the rate at which certain medications are absorbed.   The small intestine is the site of absorption of nutrients, so  it is here that noticeable signs of aging on digestion arise. Subtle  shifts in the microbial species that inhabit the small intestine alter  the rates of absorption of particular nutrients. With age, the small  intestine becomes less efficient at absorbing vitamins A, D, and  K and the mineral zinc. This raises the risk of deficiency symp-  toms—effects on skin and vision due to a lack of vitamin A;  weakened bones from inadequate vitamin D; impaired blood clot-  ting seen in vitamin K deficiency; and slowed healing, decreased  immunity, and altered taste evidenced in zinc deficiency.   Many people who have inherited lactose intolerance begin to  notice the telltale cramping after eating dairy foods in the middle  years. They must be careful that by avoiding dairy products, they  do not also lower their calcium intake. Less hydrochloric acid also  adversely affects the absorption of calcium, as well as iron. Too  little intrinsic factor may lead to vitamin B ,, deficiency anemia.   The lining of the large intestine changes too, thinning and con-  taining less smooth muscle and mucus. A dampening of the respon-  siveness of the smooth muscle to neural stimulation slows peristalsis,  ultimately causing constipation. Compounding this common prob-  lem is a loss of elasticity in the walls of the rectum and declining  strength and responsiveness of the internal and external sphincters.   The accessory organs to digestion age too, but not necessar-  ily in ways that affect health. Both the pancreas and the liver are  large organs with cells to spare, so a decline in their secretion abili-  ties does not usually hamper digestion. Only 10% of the pancreas  and 20% of the liver are required to digest foods. However, the liver  may not be able to detoxify certain medications as quickly as it once  did. The gallbladder becomes less sensitive to cholecystokinin, but  in a classic feedback response, cells of the intestinal mucosa secrete  more of it into the bloodstream. The gallbladder also retains its abil-  ity to contract. The bile ducts widen in some areas, but the end of  the bile duct narrows as it approaches the small intestine. As long  as gallstones do not become entrapped in the ducts, the gallbladder  generally functions well into the later years.    61. Which conditions might be caused by the slowing of peristalsis  in the digestive tract that occurs with aging? Hl    The digestive system ingests, digests, and  absorbs nutrients for use by all body cells.    Vitamin D activated  in the skin plays a  "{ role in absorption  of calcium from    Bones are important  . in mastication.  ( Calcium absorption  is necessary to  maintain bone matrix.    Muscles are important  in mastication,  swallowing, and the  mixing and moving  | of digestion products  y through the  gastrointestinal tract.    The lymphatic  system plays a  major role in the  absorption of fats.    In a woman, nutrition  is essential for  conception and  normal development  of an embryo and  fetus.    (page 650)  Digestion is the process of mechanically and chemically  breaking down foods so that they can be absorbed. The digestive  system consists of an alimentary canal and several accessory  organs that carry out the processes of ingestion, propulsion,  digestion, absorption, and defecation.   (3) The wall of the tube undergoes receptive relaxation  just ahead of a peristaltic wave.   (1) The tube is innervated by branches of the sympathetic  and parasympathetic divisions of the autonomic  nervous system.   (2) Parasympathetic impulses generally increase  digestive activities; sympathetic impulses generally  inhibit digestive activities.   (3) Sympathetic impulses contract certain sphincter  muscles, controlling movement of digesting food  through the alimentary canal.    The mouth is adapted to receive food and begin digestion by  mechanically breaking up solid particles (mastication). It also  serves as an organ of speech and sensory perception.  1. Cheeks and lips  a. Cheeks form the lateral walls of the mouth.  b. Lips are highly mobile and have a variety of sensory  receptors useful in judging the characteristics of food.  2. Tongue  a. The tongue is a thick, muscular organ that mixes food  with saliva and moves it toward the pharynx.  b. The rough surface of the tongue handles food and has  taste buds.  c. Lingual tonsils are located on the root of the tongue.  3. Palate  a. The palate comprises the roof of the mouth and  includes hard and soft portions.  b. The soft palate, including the uvula, closes the opening  to the nasal cavity during swallowing.  c. Palatine tonsils are located on either side of the tongue  in the back of the mouth.  d. Tonsils consist of lymphatic tissues.  4. Teeth  a. Two sets of teeth develop in sockets of the mandibular  and maxillary bones.  b. There are twenty primary and thirty-two secondary teeth.  c. Teeth mechanically break food into smaller pieces,  increasing the surface area exposed to digestive actions.  d. Different types of teeth are adapted to handle foods in  different ways, such as biting, grasping, or grinding.  e. Each tooth consists of a crown and root and is composed  of enamel, dentin, pulp, nerves, and blood vessels.    f. A tooth is attached to the alveolar process by the  periodontal ligament.    Salivary glands secrete saliva, which moistens food,  helps bind food particles, begins chemical digestion of  carbohydrates, makes taste possible, helps cleanse the  mouth, and regulates pH in the mouth.  1. Salivary secretions  a. Salivary glands include serous cells that secrete  salivary amylase and mucous cells that secrete mucus.  b. Parasympathetic impulses stimulate the secretion of a  large volume of watery saliva.  2. Major salivary glands  a. The parotid glands are the largest, and they secrete  saliva rich in amylase.  b. The submandibular glands in the floor of the mouth  produce viscous saliva containing amylase.  c. The sublingual glands in the floor of the mouth  primarily secrete mucus.    The pharynx and esophagus serve as passageways.  1. Structure of the pharynx  a. The pharynx is divided into a nasopharynx,  oropharynx, and laryngopharynx.  b. The muscular walls of the pharynx contain fibers in  circular and longitudinal groups.  2. Swallowing mechanism  a. Swallowing (deglutition) occurs in three stages.  (1) Food is mixed with saliva and forced into the  pharynx.  (2) Involuntary reflex actions move the food into  the esophagus.  (3) Peristalsis transports food in the esophagus to the  stomach.  b. Swallowing reflexes momentarily inhibit breathing.  3. Esophagus  a. The esophagus passes through the mediastinum and  penetrates the diaphragm.  b. The lower esophageal sphincter, at the distal end  of the esophagus, help prevent regurgitation of food  from the stomach.    The stomach receives food, mixes it with gastric juice, carries  on a limited amount of absorption, and moves food into the  small intestine.  1. Parts of the stomach  a. The stomach is divided into the cardia, fundus, body,  and pylorus.  b. The pyloric sphincter serves as a valve between the  stomach and the small intestine.  2. Gastric secretions  a. Gastric glands secrete gastric juice.  b. Gastric juice contains pepsin (begins digestion of  proteins), hydrochloric acid, lipase, and intrinsic factor.  3. Regulation of gastric secretions  a. Parasympathetic impulses and the hormone gastrin  enhance gastric secretion.    b. The three stages of gastric secretion are the cephalic, 4, Gallbladder  gastric, and intestinal phases. a. The gallbladder stores bile between meals.  c. The presence of food in the small intestine reflexly b. A sphincter muscle controls release of bile from the  inhibits gastric secretions. bile duct.  4. Gastric absorption c. Gallstones may form within the gallbladder.  a. The stomach is not well adapted for absorption. 5. Regulation of bile release    b. A few substances such as water and other small  molecules are absorbed through the stomach wall.   a. As the stomach fills, its wall stretches, but its internal  pressure remains unchanged.   b. Mixing movements aid in producing chyme; peristaltic  waves move chyme into the pylorus.   c. The muscular wall of the pylorus regulates chyme  movement into the small intestine.   d. The rate of emptying depends on the fluidity of the  chyme and the type of food present.   e. The upper part of the small intestine fills, and an  enterogastric reflex inhibits peristalsis in the stomach.   f. Vomiting results from a complex reflex that has many  stimuli.    b. The sphincter muscle at the base of the bile duct relaxes  as a peristaltic wave in the duodenal wall approaches.  6. Functions of bile salts  a. Bile salts emulsify fats and aid in the absorption of fatty  acids, cholesterol, and certain vitamins.  b. Bile salts are reabsorbed in the small intestine.    The small intestine extends from the pyloric sphincter to the  large intestine. It receives secretions from the pancreas and  liver, completes digestion of nutrients, absorbs the products of  digestion, and transports the residues to the large intestine.  1. Parts of the small intestine  a. The small intestine consists of the duodenum,  jejunum, and ileum.  b. The small intestine is suspended from the posterior  abdominal wall by mesentery.  2. Structure of the small intestinal wall    17.6 Pancreas (page 668)  The pancreas is closely associated with the duodenum.  1. Structure of the pancreas    b. The pancreatic duct leads to the duodenum.  2. Pancreatic juice a. The wall is lined with villi that greatly increase the    surface area and aid in mixing and absorption.  b. Microvilli on the free ends of epithelial cells increase  the surface area even more.  c. Intestinal glands are located between the villi.  d. Circular folds in the lining of the intestinal wall also  increase its surface area.  3. Secretions of the small intestine  a. Intestinal glands secrete a watery fluid that lacks  digestive enzymes but provides a vehicle for moving  chyme to the villi.  b. Digestive enzymes embedded in the surfaces of  microvilli split molecules of sugars, proteins, and fats.  4. Regulation of small intestinal secretions    a. Pancreatic juice contains enzymes that can split  carbohydrates, proteins, fats, and nucleic acids.   b. Pancreatic juice has a high bicarbonate ion  concentration that helps neutralize chyme and causes  the intestinal contents to be alkaline.   a. Secretin from the duodenum stimulates the release of  pancreatic juice that contains few digestive enzymes but  has a high bicarbonate ion concentration.   b. Cholecystokinin from the intestinal wall stimulates the  release of pancreatic juice that has a high concentration  of digestive enzymes.   reflexes stimulated by distension of the small intestinal wall.  . Absorption in the small intestine    17.7 Liver (page 669)  The liver is located in the upper-right quadrant of the 5  abdominal cavity.  1. Liver structure    a. The liver is a highly vascular organ, enclosed in a  fibrous capsule, and divided into lobes.   b. Each lobe consists of hepatic lobules, the functional  units of the liver.   c. Bile from the lobules is carried by bile ductules to hepatic  ducts that unite to form the common hepatic duct.    a. The liver has many functions. It metabolizes  carbohydrates, lipids, and proteins; stores some  substances; removes toxic substances from the blood  (detoxifies); and secretes bile.   b. Bile is the only liver secretion that directly affects  digestion.    electrolytes.  b. Blood capillaries in the villi absorb monosaccharides and  amino acids.   c. Fatty acids diffuse into small intestinal epithelial cells  where they are processed to form chylomicrons, which  enter the lacteals of the villi.   b. Overdistension or irritation may stimulate a peristaltic  rush and result in diarrhea.   c. The ileocecal sphincter controls movement of the  intestinal contents from the small intestine into the  large intestine.    The large intestine absorbs water and electrolytes and forms  and stores feces.    1. Parts of the large intestine  a. The large intestine consists of the cecum, colon,   b. The colon is divided into ascending, transverse,  descending, and sigmoid portions.   2. Structure of the large intestinal wall  a. The large intestinal wall resembles the wall in other   b. The large intestinal wall has a unique layer of  longitudinal muscle fibers, arranged in distinct bands,  that extend the entire length of the colon.   3. Functions of the large intestine  a. The large intestine has little or no digestive function,   d. Many bacteria inhabit the large intestine, where they  break down some undigestible substances, such as  cellulose, and synthesize vitamins K, B ,, thiamine,  and riboflavin.   List the major parts of the alimentary canal, then separately  list the accessory organs of the digestive system. (p. 650)  Contrast the composition of the four layers in the wall of  the alimentary canal. (p. 650)    4 Distinguish between mixing movements and propelling  movements. (pp. 650-651)  5 Define peristalsis. (p. 651)  6 Explain the relationship between peristalsis and receptive  relaxation. (p. 651)  7 Describe the effects of parasympathetic and sympathetic  impulses on the alimentary canal. (p. 651)  17.2 Mouth  8 Discuss the functions of the mouth and its parts.  (pp. 653-656)  9 Distinguish among lingual, palatine, and pharyngeal tonsils.  (pp. 653-654)  10 Compare the primary and secondary teeth. (pp. 655-656)  11. The teeth best adapted for grasping and tearing food are  the . (p. 656)  a. incisors  b. canines  c. premolars  d. molars  12 Describe the structure of a tooth. (pp. 656-657)  13 Explain how a tooth is anchored in its socket. (pp. 657)  17.3-17.9 Salivary Glands-Large Intestine  14 Discuss the digestive functions of saliva. (p. 659)  15 Describe the locations of the major salivary glands. (p. 659)  16 Explain how secretions of the salivary glands differ. (pp. 659)  17 Name and locate the three major regions of the pharynx.  (p. 660)  18 Discuss the mechanism of swallowing. (pp. 660-661)  692 — UNITS | ABSORPTION AND EXCRETION    4. Movements of the large intestine  a. Movements are similar to those in the small intestine.  b. Mass movements occur two to three times each day.  c. A reflex stimulates defecation.  5. Feces  a. The large intestine forms and stores feces.  b. Feces consist of water, undigested material, mucus,  and bacteria.  c. The color of feces is due to bile pigments that have  been altered by bacterial actions.    1. Older people sometimes do not chew food thoroughly  because thinning enamel makes teeth more sensitive to  hot and cold foods, gums recede, and teeth may loosen.   2. Slowing peristalsis in the digestive tract may cause  heartburn and constipation.   4. Accessory organs to digestion also age, but not necessarily  in ways that affect health.    Explain the function of the esophagus. (p. 661)  Describe the structure of the stomach. (pp. 661 and 663)  List the components of gastric juice, and describe the function  of each component. (pp. 663 and 665)  Explain how gastric secretions are regulated. (pp. 665-661)  Describe the mechanism that controls the emptying of the  stomach. (p. 667)  Describe the enterogastric reflex. (pp. 667)  Explain the mechanism of vomiting. (p. 667)  Describe the location of the pancreas and the pancreatic  duct. (p. 668)  Explain how pancreatic secretions are regulated. (p. 669)  Describe the structure of the liver. (pp. 669-670)  Trace the path of bile from a bile canaliculus to the small  intestine by filling in the blanks: bile canaliculi carry secretions  from hepatic cells to , which unite to form  intrahepatic bile ducts, which converge to become the   that merge to form the common hepatic duct,  which joins the cystic duct to form the , which  empties into the small intestine (duodenum). (pp. 670 and 674)  List the major functions of the liver. (pp. 670-673)  Describe the composition of bile. (jp. 673)  Explain how gallstones form. (p. 674)  Explain the regulation of bile release. (pp. 674-675)  Discuss the functions of bile salts. (p. 675)  Describe the locations of the parts of the small intestine. (p. 676)  Describe the functions of the intestinal villi. (pp. 678-679)  Match the organ or gland with the enzyme(s) it secretes.  Enzymes may be used more than once. An organ or gland  may secrete more than one enzyme. (pp. 658-680)    (1) salivary glands (serous cells) A. peptidase  (2) stomach (chief cells) B. amylase  (3) pancreas (acinar cells) C. nuclease  (4) small intestine D. lipase  (mucosal cells) E. pepsin  F. trypsin, chymotrypsin,  carboxypeptidase  G. sucrase, maltase,    38 Match the enzyme(s) with its (their) function(s). Functions may  be used more than once. (pp. 658-680)    1. Several years ago, an extract from kidney beans was sold in  health-food stores as a “starch blocker.” Advertisements claimed  that one could eat a plate of spaghetti, yet absorb none of it,  because starch-digesting enzyme function would be blocked.  The kidney bean product indeed kept salivary amylase from  functioning. However, people who took the starch blocker  developed abdominal pain, bloating, and gas. Suggest a reason  for these ill effects.    2. How would removal of 95% of the stomach (subtotal  gastrectomy) to treat severe ulcers or cancer affect digestion and  absorption? How would the patients have to alter eating habits?  Why? Do you think that people should have this type of surgery  to treat life-threatening obesity?    39 Explain the regulation of the secretions of the small intestine.  (p. 680)   40 Discuss absorption of amino acids, monosaccharides,  glycerol, fatty acids, electrolytes, and water from substances  in the small intestine. (pp. 681-682)   41 Explain control of the movement of the intestinal contents.  (p. 683)   42 Describe the locations of the parts of the large intestine.  (pp. 683-684)   43 Explain the general functions of the large intestine.  (pp. 685-686)    45 How does digestive function change with age? (p. 688)  46 What are the effects of altered rates of absorption, due to  aging, in the small intestine? (p. 688)    3. What effect is a before-dinner alcoholic cocktail likely to have  on digestion? Why are such beverages inadvisable for people  with ulcers?    4. What type of acid-base imbalance is likely to develop if the  stomach contents are repeatedly lost by vomiting over a  prolonged period? Which acid-base imbalance may develop  as a result of prolonged diarrhea?    5. Why might a person with inflammation of the gallbladder  (cholecystitis) also develop inflammation of the pancreas  (pancreatitis)?    Connect Interactive Questions Reinforce your knowledge  using assigned interactive questions covering the anatomy of the  digestive organs, and the functions of the digestive enzymes.    Connect Integrated Activity Could you help a radiologist  identify organs of the digestive system on a CT scan?    Anatomy & Physiology Revealed Go more in depth into the  human body by exploring the cadaver dissection of the digestive  system, identifying organs on a CT scan, or viewing animations  covering the stomach or liver.    After you have studied this chapter, you should be able to:    List the major sources of carbohydrates, lipids, and  proteins. (pp. 695-699)    Explain the factors that affect an individual’s energy  requirements. (pp. 701-702)    Contrast the physiological impact of positive and  negative energy balance. (p. 702)    List the fat-soluble and water-soluble vitamins and  summarize the general functions of each vitamin.  (pp. 705-711)    Minerals  Distinguish between a vitamin and a mineral. (p. 711)  List the major minerals and trace elements and    List the factors that may lead to inadequate nutrition  later in life. (pp. 723-724)    People can satisfy nutritional requirements in a wide variety of ways.    The human body requires a constant supply of energy, and body  structures must develop, grow, and occasionally be repaired. To  accomplish all of this the body requires fuel as well as materi-  als to serve as building blocks and to drive the body’s metabolic  processes, anabolism and catabolism. Nutrients from a balanced  diet fulfill these requirements.   Nutrients are chemicals obtained from the environment that  an organism requires for survival. There are two major classes  of nutrients. The macronutrients, needed in larger quantities,  are the carbohydrates, lipids, and proteins. Micronutrients are  required in small daily amounts and include vitamins and miner-  als. Nutrients that human cells cannot synthesize and that must  be obtained in the diet, such as certain amino acids, are called  essential nutrients. Water, which the body cannot produce in  sufficient amounts to survive, as well as minerals and oxygen, are  additional examples of essential nutrients.   carot-, carrot: carotene—yellowish plant  pigment that imparts the color of carrots  and other yellowish plant tissues.    Carbohydrates are organic compounds and include the sugars  and starches. The energy held in their chemical bonds is used to  power cellular processes.    Carbohydrates are ingested in a variety of forms. Complex car-  bohydrates include the polysaccharides (“many sugars’), such as  starch from plant foods and glycogen from meats. Most foods con-  taining starch and glycogen have many other nutrients, including  valuable vitamins and minerals. The simple carbohydrates include  disaccharides (“double sugars’’) from milk sugar, cane sugar, beet  sugar, and molasses and monosaccharides (“single sugars”) from  honey and fruits. Digestion ultimately breaks complex carbohy-  drates down to monosaccharides, which are small enough to be  absorbed into the bloodstream.    Sugar substitutes provide concentrated sweetness, so fewer  calories are needed to sweeten a food compared to table  sugar (sucrose). Stevia is extracted from leaves of an herb, and    is 30 times as sweet as table sugar. Aspartame, a dipeptide, is  200 times as sweet; the artificial sweetener saccharin is 300 times  as sweet; and sucralose is 600 times as sweet as sucrose.  Sucralose is derived from sucrose, and includes chloride.    Cellulose is a complex carbohydrate abundant in our food—  it provides the crunch to celery and the crispness to lettuce. We  cannot digest cellulose, and most of it passes through the alimen-  tary canal largely unchanged. However, cellulose provides bulk  (also called fiber or roughage) against which the muscular wall  of the digestive system can push, facilitating the movement of  intestinal contents. Hemicellulose, pectin, and lignin are other  plant carbohydrates that provide fiber.    The monosaccharides absorbed from the digestive tract include  fructose, galactose, and glucose. Liver enzymes catalyze reactions  that convert fructose and galactose into glucose (fig. 18.1). Recall  that glucose is the carbohydrate most commonly oxidized in gly-  colysis for cellular fuel.    Some excess glucose is polymerized to form glycogen (gly-  cogenesis), which the liver and muscles store as a glucose reserve.  Glycogen can be rapidly broken down to yield glucose (glycogenol-  ysis) when it is required to supply energy. However, the body can  store only a certain amount of glycogen, and excess glucose reacts  to form fat (lipogenesis), which is stored in adipose tissue (fig. 18.2).   Many cells can also oxidize fatty acids to obtain energy.  However, some cells, such as neurons, normally require a continu-  ous supply of glucose for survival. (Under some conditions, such  as prolonged starvation, other fuel sources may become available  for neurons.) Even a temporary decrease in the glucose supply    The young woman has decided to have weight loss surgery,  and one of the first steps to prepare for the procedure   is to lose 10% of her body weight. A registered dietitian  (RD) helps the patient do this by discussing the types of  foods that a person with type 2 diabetes mellitus should  and should not eat. The RD uses plastic models of foods to  demonstrate the makeup of appropriate meals, and then  helps the patient develop a meal plan that will start her on  the road to success, and also be enjoyable.   Dietitians work in diverse settings. These include  businesses, hotels, food-service corporations, community  agencies, schools, senior centers, health-care facilities, prisons,  and restaurants. Registered dietitians can also have careers in  research or teaching other health-care professionals, or open  their own businesses. Educating the public about healthful food  choices can be a major part of the job.   Training to become a registered dietitian includes  earning a bachelor’s degree in an accredited program,  completing a supervised practice program typically  lasting six to twelve months, and passing a national exam.  Continuing education courses are necessary throughout the  career of a registered dietitian to stay up to date with new  nutritional findings and medical practices related to diet,  and changing government recommendations.    FIGURE 18.1 Liver enzymes catalyze reactions that convert the  monosaccharides fructose and galactose into glucose.    may seriously impair nervous system function. Consequently, the  body requires a minimum amount of carbohydrate. If foods do not  provide an adequate supply of carbohydrates, the liver may con-  vert some noncarbohydrates, such as amino acids from proteins or  glycerol from fats, into glucose—a process called gluconeogen-  esis. The requirement for glucose has physiological priority over  the need to synthesize certain other substances, such as proteins,  from available amino acids.   Cells also use carbohydrates as starting materials for synthe-  sizing such vital biochemicals as the 5-carbon sugars ribose and  deoxyribose, which are the sugars required for the production of  the nucleic acids RNA and DNA. The disaccharide lactose (milk  sugar) is synthesized when the breasts are actively secreting milk.    Carbohydrates provide the primary source of fuel for cellular pro-  cesses. The need for carbohydrates varies with individual energy  requirements. Physically active individuals require more carbohy-  drates than those who are sedentary. The minimal requirement for  carbohydrates in the human diet is unknown, but getting at least  125 to 175 grams daily is probably necessary to avoid protein  breakdown and to avoid metabolic disorders resulting from excess  fat use. An average diet includes 200 to 300 grams of carbohy-  drates daily.    An adult's liver stores about 100 grams of glycogen, and  muscle tissue stores another 200 grams, providing enough  reserve to meet energy demands for about twelve hours  when the person is resting. Whether these stores are filled  depends on diet. People consume widely varying amounts    of carbohydrates, often reflecting economic conditions. In  the United States, a typical adult’s diet supplies about 50%  of total body energy from carbohydrates. In Asian countries  where rice is a staple, carbohydrates contribute even more  to the diet.    Why do daily requirements for carbohydrates vary from person  to person?    Lipids are organic compounds that include fats, oils, and fat-  like substances such as phospholipids and cholesterol (see chap-  ter 2, pp. 71-72). They supply energy for cellular processes and  help build structures, such as cell membranes. The most common  dietary lipids are the fats called triglycerides (tri-glis’er-idz), con-  sisting of three fatty acid molecules and a glycerol molecule (see  fig. 2.14, p. 71).    Triglycerides are found in plant- and animal-based foods. Saturated  fats contain no double bonds between the carbons of their fatty  acid molecules and are mainly found in foods of animal origin,  such as meat, eggs, milk, and lard, as well as in palm and coconut  oils. Unsaturated fats contain fatty acid molecules with double  bonds in their carbon chains and are in seeds, nuts, and plant oils.  Monounsaturated fats (in which fatty acids contain one double bond),  such as those in olive, peanut, and canola oils, are the healthiest.  Saturated fats in excess are a risk factor for cardiovascular disease.   Cholesterol is abundant in liver and egg yolk and, to a lesser  extent, in whole milk, butter, cheese, and meats. Foods of plant  origin do not contain cholesterol. A label on a plant-based food  claiming that it is “cholesterol-free” states the obvious.    Be wary of claims that a food product is "99% fat-free.” This  usually refers to percentage by weight—not calories, which is  what counts. A 99% fat-free creamy concoction may be largely    air and water, and therefore in that form, fat comprises very little  of it. But when the air and the water are removed, as happens in  the body, the fat percentage may skyrocket.   The lipids in foods are phospholipids, cholesterol, and, most com-  monly, fats (triglycerides). Lipids provide a variety of physiologi-  cal functions; however, fats mainly supply energy. Gram for gram,  fats contain more than twice as much chemical energy as carbohy-  drates or proteins.   Before a triglyceride molecule can release energy, it must  undergo hydrolysis. This happens when digestion breaks triglyc-  erides down into fatty acids and glycerol. After being absorbed,  these products are carried by the lymph to the blood, then on to  tissues. As figure 18.3 shows, some of the resulting fatty acid  portions can then form molecules of acetyl coenzyme A (ace-  tyl CoA) by a series of reactions called beta oxidation, which  occurs in the mitochondria.   In the first phase of beta oxidation, fatty acids are activated.  This change requires energy from ATP and a special group of  enzymes called thiokinases. Each of these enzymes can act upon a  fatty acid that has a particular carbon chain length.   Once fatty acid molecules have been activated, other enzymes  called fatty acid oxidases in mitochondria break them down. This  phase of the reactions removes successive two-carbon segments of  fatty acid chains. In the liver, some of these segments react to pro-  duce acetyl coenzyme A molecules. Excess acetyl CoA molecules    FIGURE 18.3 The body digests fat from foods into glycerol and fatty  acids, which may enter catabolic pathways and provide energy.    can be converted into compounds called ketone bodies, such as  acetone, which later may be changed back to acetyl coenzyme A.  In either case, the resulting acetyl coenzyme A can be oxidized  in the citric acid cycle. The glycerol parts of the triglyceride mol-  ecules can also enter metabolic pathways leading to the citric acid  cycle, or they can be used to synthesize glucose.    When ketone bodies form faster than they can be decomposed,  some of them are eliminated through the lungs and kidneys.  When this happens, the ketone acetone may impart a fruity  odor to the breath and urine. Ketones are released when a per-  son fasts, forcing body cells to metabolize a large amount of  fat. People with diabetes mellitus may develop a serious imbal-  ance in pH called ketoacidosis when acetone and other acidic  ketones accumulate.    Glycerol and fatty acid molecules resulting from the hydrolysis  of fats can also combine to form fat molecules in anabolic reactions  and be stored in fat tissue. Additional fat molecules can be synthe-  sized from excess glucose or amino acids.   The liver can convert fatty acids from one form to another.  However, the liver cannot synthesize certain fatty acids, called  essential fatty acids, which must be obtained in the diet. Linoleic  acid, for example, is an essential fatty acid required to synthesize  phospholipids, which, in turn, are necessary for constructing cell  membranes and myelin sheaths, and for transporting circulating lip-  ids. Good sources of linoleic acid include corn oil, cottonseed oil,  and soy oil. Linolenic acid is another essential fatty acid.   The liver uses free fatty acids to synthesize triglycerides,  phospholipids, and lipoproteins that may then be released into  the bloodstream (fig. 18.4). These lipoproteins are large and con-  sist of a surface layer of phospholipid, cholesterol, and protein  surrounding a triglyceride core. The protein constituents of lipo-  proteins in the outer layer, called apoproteins or apolipoproteins,  can combine with receptors on the membranes of specific target  cells. Lipoprotein molecules vary in the proportions of the lipids  they contain.   Lipids are less dense than proteins. As the proportion of lip-  ids in a lipoprotein increases, the density of the particle decreases.  Conversely, as the proportion of lipids decreases, the density  increases. Lipoproteins are classified on the basis of their densi-  ties, which reflect their composition. Very-low-density lipoproteins  (VLDL) have a high concentration of triglycerides. Low-density  lipoproteins (LDL) have a high concentration of cholesterol and  are the major cholesterol-carrying lipoproteins. High-density lipo-  proteins (HDL) have a relatively high concentration of protein and  a lower concentration of lipids.   In addition to regulating circulating lipids, the liver controls  the total amount of cholesterol in the body by synthesizing and  releasing it into the blood or by removing cholesterol from the  blood and excreting it into the bile. The liver uses cholesterol to  produce bile salts. Cholesterol is not used as an energy source,  but it does provide structural material for cell and organelle mem-  branes, and it furnishes starting materials for the synthesis of cer-  tain sex hormones and hormones produced by the adrenal cortex.    Adipose tissue stores excess triglycerides. If the blood lipid  concentration drops (in response to fasting, for example), some of  these stored triglycerides are hydrolyzed into free fatty acids and  glycerol and are released into the bloodstream.    The lipid content of human diets varies widely. A person who eats  mostly burgers, fries, and shakes may consume 50% or more of total  daily calories from fat. For a vegetarian, the percentage may be far  lower. The USDA and the American Heart Association recommend  that lipid intake not exceed 30% of the total daily calories.    The types and locations of the chemical bonds between car-  bon atoms of fatty acid molecules affect how healthful the fat  is. Monounsaturated fats (such as from avocado and olives)  promote cardiovascular health, whereas saturated fats (such as  those in butter or lard) raise the risk of heart disease. The site of  the double bond that contributes to a fat’s degree of unsatura-  tion is also important. Omega-3 fatty acids, which have double  bonds between the third and fourth carbons, are more health-  ful than omega-é fatty acids, with double bonds between the  sixth and seventh carbons. Omega-3 fatty acids are found in  fish; omega-6 fatty acids are in red meat.    The amounts and types of fats required for health vary with  individuals’ habits, goals, and stage of life. For example, infant for-  mula contains two long-chain polyunsaturated fatty acids (docosa-  hexaenoic acid and arachidonic acid) that are in breast milk and are  vital for development of the infant’s nervous system, particularly the  eyes. Fat intake must be sufficient throughout life to support absorp-  tion and transport of fat-soluble vitamins. Most adults who eat a  variety of foods obtain adequate fats.    Which foods commonly supply lipids?  Which fatty acids are essential nutrients?  What is the role of the liver in the use of lipids?    Proteins are composed of amino acids. They have a wide vari-  ety of functions. When dietary proteins are digested, the resulting  amino acids are absorbed and carrried by the blood to cells. Many  of these amino acids are used to form new protein molecules, as  specified by DNA base sequences. These new proteins include  enzymes that control the rates of metabolic reactions; clotting fac-  tors; the keratins of skin and hair; elastin and collagen of connec-  tive tissue; plasma proteins that regulate water balance; the muscle  components actin and myosin; certain hormones; and the antibod-  ies that protect against infection (fig. 18.5).   Protein molecules may also supply energy. To do this, they  must first be broken down into amino acids. The amino acids then  undergo deamination, a process in the liver that removes the  nitrogen-containing amino groups (—NH,), which then react to  form a waste called urea (u-re’ah) (see fig. 2.17, p. 73). The blood  carries urea to the kidneys, where it is excreted in urine.    Certain kidney disorders impair the removal of urea from the  blood, raising the blood urea concentration. A blood test called  blood urea nitrogen (BUN) determines the blood urea con-  centration and is often used to evaluate kidney function (see  Appendix C, Laboratory Tests of Clinical Importance).    Several pathways decompose the remaining deaminated parts  of amino acids. The specific pathways that are followed depend  upon the particular type of amino acid being dismantled. Some  pathways form acetyl coenzyme A, and others more directly lead  to steps of the citric acid cycle. Most of the energy released from  the cycle is captured in molecules of ATP (fig. 18.6). If energy is  not required immediately, the deaminated parts of the amino acids  may react to form glucose or fat molecules in other metabolic  pathways (see fig. 18.5).   A few hours after a meal, protein catabolism, through the pro-  cess of gluconeogenesis (see chapter 13, p. 514), becomes a major  source of blood glucose. However, metabolism in most tissues soon  shifts away from glucose and toward fat catabolism as a source of  ATP. Thus, energy needs are met in a way that spares proteins for    FIGURE 18.5 Proteins are digested to their constituent amino acids. These amino acids are then linked, following genetic instructions, to build new  proteins. Free amino acids are also used to supply energy under certain conditions.    tissue building and repair, rather than being broken down and reas-  sembled into carbohydrates to supply energy. Using structural pro-  teins to generate energy causes the tissue-wasting of starvation.    Foods rich in proteins include meats, seafood, poultry, cheese,  nuts, milk, eggs, and cereals. Legumes, including beans and peas,  contain less protein.   The human body can synthesize many amino acids (nones-  sential amino acids). However, eight amino acids the adult body  needs (ten required for growing children) cannot be synthesized  sufficiently or at all, and they are called essential amino acids.  This term refers only to dietary intake, because all amino acids are  required for normal protein synthesis. Table 18.1 lists the amino  acids in foods and indicates those that are essential.   All twenty types of amino acids must be in the body at the  same time for growth and tissue repair to occur. In other words, if  the diet lacks one essential amino acid, the cells cannot synthesize  protein. Essential amino acids are not stored. Those not used to  make proteins are oxidized as energy sources or are converted into  carbohydrates or fats.   Proteins are classified as complete or incomplete based on the  amino acid types they provide. Complete proteins have adequate  amounts of the essential amino acids to maintain human body tis-  sues and promote normal growth and development. Certain pro-  teins in milk, meat, and eggs are complete. Incomplete proteins    Alanine Glycine Proline  Arginine (ch) Histidine (ch) Serine  Asparagine Isoleucine (e) Threonine (e)  Aspartic acid Leucine (e) Tryptophan (e)  Cysteine Lysine (e) Tyrosine  Glutamic acid Methionine (e) Valine (e)    Eight essential amino acids (e) cannot be synthesized by human cells and must be provided in the  diet. Two additional amino acids (ch) are essential in growing children.    lack one or more of the essential amino acids, and cannot by  themselves maintain human tissues or support normal growth and  development. Zein in corn, for example, has too little of the essen-  tial amino acids tryptophan and lysine to be complete. A partially  complete protein does not have enough amino acid variety to pro-  mote growth, but it has enough to maintain life. A protein in wheat  called gliadin is a partially complete protein because it has very  little of the amino acid lysine.    Many plant proteins have too little of one or more essen-  tial amino acids to provide adequate nutrition for a person.  However, combining appropriate plant foods can supply an ade-  quate diversity of dietary amino acids. For example, beans are  low in methionine but have enough lysine. Rice lacks lysine but  has enough methionine. A meal of beans and rice offers enough  of both types of amino acids.    9 How do cells use proteins?  10 Which foods are rich sources of protein?  11. Why are some amino acids called essential?    A healthy adult continuously builds up and breaks down proteins.  Proteins are metabolized at different rates in different tissues, but  the overall gain of body proteins equals the loss, producing a state  of dynamic equilibrium (di-nam’ik e’kwi-lib’re-um). Because  proteins have a high percentage of nitrogen, dynamic equilibrium  also brings nitrogen balance (ni’tro-jen bal’ans), in which the  amount of nitrogen taken in equals the amount excreted.   A person who is starving has a negative nitrogen balance  because the amount of nitrogen excreted as a result of amino acid  oxidation exceeds the amount the diet replaces. Conversely, a  growing child, a pregnant woman, or an athlete in training is likely  to have a positive nitrogen balance because more protein is being  built into new tissue and less is being used for energy or excreted.    into amino acids, but must Hydrolysis In addition to supplying essential amino acids, proteins provide  deaminate these smaller nitrogen and other elements for the synthesis of nonessential  molecules before they can be Amino acids   intake of about 0.8 gram per kilogram (0.4 gram per pound) of    people should consume 60-150 grams of protein a day. For a preg-  nant woman, who needs to maintain a positive nitrogen balance,  the recommendation adds 30 grams of protein per day. Similarly, a  nursing mother requires an additional 20 grams of protein per day  to maintain milk production.   Protein deficiency causes tissue wasting and also decreases  the level of plasma proteins, which decreases the colloid osmotic  pressure of the plasma. As a result, fluids collect in the tis-  sues, producing nutritional edema. Table 18.2 summarizes the  sources, requirements, and uses for carbohydrate, lipid, and pro-  tein nutrients.    “ RECONNECT  <4 To Chapter 15, Exchanges in the Capillaries, page 581.    Carbohydrate Primarily from starch and : Oxidized for energy; used in production of Obesity, Metabolic  sugars in foods of plant ribose, deoxyribose, and lactose; stored in liver dental caries, acidosis  origin and from glycogen and muscles as glycogen; converted to fats and nutritional  in meats stored in adipose tissue deficits  225-325 g    Meats, eggs, milk, lard, : Oxidized for energy; production of triglycerides, Obesity, Weight loss,  plant oils phospholipids, lipoproteins, and cholesterol, increased serum __ skin lesions  44-78 g stored in adipose tissue; glycerol portions of fat cholesterol,  molecules may be used to synthesize glucose increased risk of  heart disease    Protein Meats, cheese, nuts, milk, : Production of protein molecules used to build Obesity Extreme  eggs, cereals, legumes cell structure and to function as enzymes or weight loss,  50-175 g hormones; used in the transport of oxygen, wasting,  regulation of water balance, control of pH, anemia,  formation of antibodies; amino acids may growth  be broken down and oxidized for energy or retardation  converted to carbohydrates or fats for storage    “RDA = recommended dietary allowance (based on 2,000 calories per day).    Carbohydrates, fats, and proteins supply energy, which is required  for all metabolic processes and therefore important to cell sur-  vival. If the diet is deficient in energy-supplying nutrients, struc-  tural molecules may gradually be consumed, leading to death. On  the other hand, excess intake of energy-supplying nutrients may  lead to obesity, which also threatens health.    The amount of potential energy a food contains is expressed as  calories (kal’o-réz), which are units of heat. Although a calorie is  defined as the amount of heat required to raise the temperature of  a gram of water by | degree Celsius (°C), the calorie used to mea-  sure food energy is 1,000 times greater. This large calorie (Cal.)  equals the amount of heat required to raise the temperature of a  kilogram (1,000 grams) of water by 1°C (from 14.5°C to 15.5°C)  and is also equal to 4.184 joules. A joule is the international unit of  heat and energy. A large calorie is also called a kilocalorie, but it is  customary in nutritional studies to refer to it as a calorie.   Figure 18.7 shows a bomb calorimeter, which is a device  used to measure the caloric contents of foods. It consists of a metal  chamber submerged in a known volume of water. A food sample is  dried, weighed, and placed in a nonreactive dish inside the cham-  ber. The chamber is filled with oxygen and submerged in the water.  Then, the food is ignited and allowed to completely oxidize. Heat  released from the food raises the temperature of the surrounding  water, and the change in temperature is measured. Because the  volume of the water is known, the amount of heat released from  the food can be calculated in calories.   Caloric values determined in a bomb calorimeter are some-  what higher than the amount of energy that metabolic oxidation    FIGURE 18.7 A bomb calorimeter measures the caloric content of a  food sample.    releases, because nutrients generally are not completely absorbed  from the digestive tract. Also, the body does not completely oxi-  dize amino acids, but excretes parts of them in urea or uses them  to synthesize other nitrogenous substances. When such losses are  considered, cellular oxidation yields on the average about 4.1 calo-  ries from | gram of carbohydrate, 4.1 calories from 1 gram of pro-  tein, and 9.5 calories from | gram of fat. More than twice as much  energy is derived from equal amounts by weight of fats as from  either proteins or carbohydrates. This is one reason why avoiding  fatty foods helps weight loss, if intake of other nutrients does not  substantially increase. Fats encourage weight gain because they  add flavor to food, which can cause overeating. However, fatty  foods satisfy hunger longer than carbohydrate-rich foods.    16 What is the energy value of a gram of carbohydrate? a gram of  protein? a gram of fat?    The amount of energy required to support metabolic activities for  twenty-four hours varies from person to person. The factors that  influence individual energy needs include a measurement called  the basal metabolic rate, the degree of muscular activity, body  temperature, and rate of growth.   The basal metabolic rate (ba’sal met’ah-bol’ik rat), or BMR,  measures the rate at which the body expends energy under basal  conditions—when a person is awake and at rest; after an overnight  fast; and in a comfortable, controlled environment. Tests of thy-  roid function can be used to estimate a person’s BMR.   The amount of oxygen the body consumes is directly propor-  tional to the amount of energy released by cellular respiration. The  BMR indicates the total amount of energy expended in a given  time to support the activities of such organs as the brain, heart,  lungs, liver, and kidneys.   The BMR for an average adult indicates a requirement for  approximately | calorie of energy per hour for each kilogram of  body weight. However, this requirement varies with sex, body  size, body temperature, and level of endocrine gland activity. For  example, because heat loss is directly proportional to the body sur-  face area, and a smaller person has a greater surface area relative  to body mass, he or she will have a higher BMR. Males typically  have higher metabolic rates than females. As body temperature,  blood level of thyroxine, or blood level of epinephrine increase,  so does the BMR. The BMR can also increase when the level of  physical activity increases during the day.   Maintaining the BMR usually requires the body’s greatest  expenditure of energy. The energy required to support voluntary  muscular activity comes next, though this amount varies greatly  with the type of activity (table 18.3). For example, the energy to  maintain posture while sitting at a desk might require 100 calo-  ries per hour above the basal need, whereas running or swim-  ming might require 500-600 calories per hour.   Maintenance of body temperature may require additional  energy expenditure, particularly in cold weather. In this case, extra    energy is expended in involuntary muscular contractions, such as  shivering, or through voluntary muscular actions, such as walking.  Growing children and pregnant women, because their bodies are  actively producing new tissues, also require more calories.    A state of energy balance exists when caloric intake in the form of  foods equals caloric expenditure from the basal metabolic rate and  muscular activities. Under these conditions, body weight remains  constant, except perhaps for slight variations due to changes in  water content.   If, however, caloric intake exceeds expenditure, a positive  energy balance occurs, and tissues store excess nutrients. This  increases body weight because 3,500 excess calories are stored as  a pound of fat. Conversely, if caloric expenditure exceeds input, the  energy balance is negative, and stored materials are mobilized from  the tissues for oxidation, causing weight loss. To maintain weight,  calories in must equal calories expended.    The most obvious and common nutritional disorders reflect cal-  orie imbalances, which may result from societal and geographic  factors. Obesity is prevalent in nations where food is plentiful  and diverse. The tendency to become obese may be a holdover  from thousands of years ago, when the ability to store energy in  the form of fat was a survival advantage when food supplies were  scarce or erratic. Today in many African nations, natural famines  combined with political unrest cause mass starvation. Starvation is  considered later in the chapter.   It is difficult to determine a desirable body weight. In the past,  weight standards were based on average weights and heights in a  certain population, and the degrees of underweight and overweight  were expressed as percentage deviations from these averages.  These standards reflected the gradual gain in weight as people  age. Then medical researchers recognized that such an increase  in weight after the age of twenty-five to thirty years is not nec-  essary and may not be healthy. This lead to developing standards  of desirable weights. Today a measurement termed body mass    Weight in pounds  120 130 140 150 160 170 180 190 200 210 220 230 240 250    «6 BO Bi 84 36 89 47] 43 46 48 61 3 6 58 60  «8° Bi BS 31 34 86 88 40 43 45 47 49 62 61 56  «10 BB G7 29 Bi 84 86 88 40 42 44 46 48 60 52  50" BS 5 27 29 Si $3 85 S7 89 Ai Aa 45 47 49  52° 22 Ba BG Bz BS Sil 83 85 87 88 40 42 44 46  oa” Bi 22 BA BG BS BS Gi GS 84 36 88 40 Ai 4s  56” iS) 2a) 23 4 26 27 29 Bi 82 84 86 87 89 20  58’[18] BO 2a] 23 24 B6 27 29 80 82 84 85 87 G8  5'10°[17| 9 20 22 23 24 26 27 BS 80 82 83 35 36  6o"6][18| iS) 20 22 BS Ba BG Bz BS 80 Si Ss 64  62"[15][17| [18] IS) 2 22 23 24 BG B7 28 80 Si 82  64’[15][16][17|[18] 26 2a] 22 2S 2a Be 27 28 29 80  ee'[14][15][16][17] 9 20 Bi] 22 23 2a 25 27 28 29  es’[13][14]|15]17||18] 18) BO Bi 22 63 Ba Be Be BB    Developed by the National Center for Health Statistics in collaboration with the  National Center for Chronic Disease Prevention and Health Promotion    FIGURE 18.8 Body mass index (BMI). BMI can be calculated. In this  chart the calculations have been done. The uncolored squares indicate  lower than healthy weight according to this index.    What is your body mass index? Based on whether you are  lower than healthy weight, healthy weight, overweight, or  obese, what might you do with regards to your diet and  activity level to achieve/maintain healthy weight?    index (BMD) is used to assess weight considering height, and has  become the basis of classifying a person as underweight, normal  weight, overweight, or obese (fig. 18.8).   Overweight is defined as exceeding desirable weight by 10%  to 20%, or a BMI between 25 and 30. A person more than 20%  above the desired weight or with a BMI over 30, is obese, although  obesity (0-bés’i-te) is more correctly defined as excess adipose  tissue. Therefore, overweight and obesity are not the same. For  example, as figure 18.9 shows, an athlete or a person whose work  requires heavy muscular activity may be overweight, but not  obese. Clinical Application 18.1 discusses obesity.   When a person needs to gain weight, diet can be altered to  include more calories and to emphasize particular macronutri-  ents. For example, a person recovering from a debilitating ill-  ness might consume more carbohydrates, whereas a bodybuilder  might eat extra protein to hasten muscle development. An infant  also needs to gain weight rapidly, best accomplished by drinking  human milk, which has more total carbohydrate than prepared  formulas. The high fat content of human milk is important for  the rapid growth of the infant’s brain, where many neurons are  ensheathed in lipids.    In the United States, obesity is common. Nearly a third of all    adults are obese, defined as 20% above “ideal” weight based on  population statistics considering age, sex, and build, or a body  mass index above 30. Obesity raises risks for type 2 diabetes,  digestive disorders, heart disease, kidney failure, hypertension,  stroke, and cancers of the gallbladder and female reproductive  organs. The body has to support the extra weight—miles of extra  blood vessels are needed to nourish the additional pounds. Obe-  sity is the second leading cause of preventable death, following  cigarette smoking.   Obesity refers to extra pounds of fat. The proportion of fat in  a human body ranges from 5% to more than 50%, with “normal”  for males falling between 12% and 23% and for females between  16% and 28%. An elite athlete may have a body fat level as low as  4%. Fat distribution also affects health. Excess poundage above  the waist is linked to increased risk of heart disease, type 2 diabe-  tes, hypertension, and lipid disorders. The body mass index (BMI)  accounts somewhat for a person’s build (see fig. 18.8). A person  who weighs 170 pounds and is 6 feet tall is slim, whereas a person  of the same weight who is 5 feet tall is obese. The tall person's  BMI is 23; the short person's is 33.5.   Both heredity and the environment contribute to obesity.  Dozens of genes interact to control energy balance and therefore  body weight. The observation that identical twins reared in differ-  ent households can grow into adults of vastly different weights  indicates that environment influences weight too. Even the envi-  ronment before birth can affect body weight later. Individuals born  at full term, but undernourished as fetuses, are at high risk of obe-  sity. Physiological changes that countered starvation in the uterus  cause obesity when they persist.   Certain genes encode proteins that connect sensations in the  gastrointestinal tract with centers in the hypothalamus that con-  trol hunger and satiety. It is how we satisfy those signals—what we  eat—that provides the environmental component to body weight.  A certain set of gene variants may have led to a trim figure in a  human many thousands of years ago, when food had to be hunted  or gathered—and meat was leaner. Today those same gene vari-  ants do not foster slimness in a person who takes in many more  calories than he or she expends.    Diet and Exercise  A pound of fat contains 3,500 calories of energy, so that pound  can be shed by an appropriate combination of calorie cutting and  exercise. This might mean eating 500 fewer calories per day or  exercising to expend an extra 500 calories each day.   The National Heart, Lung, and Blood Institute recommends  that overweight and obese individuals aim to lose 10% of their    body weight over a six-month period. For people with BMIs from  27 to 35, that means a decrease of 300 to 500 calories per day, to  lose one-half to one pound of body weight per week. For people  with BMIs exceeding 35, a decrease of up to 500 to 1,000 calo-  ries per day will translate to a loss of one to two pounds of body  weight per week.   Some physicians recommend drug therapy if the BMI exceeds 30  or if it exceeds 27 and the person also has hypertension, type 2  diabetes mellitus, or hyperlipidemia. Several types of “diet drugs”  are no longer in use because they are dangerous. Amphetamines,  for example, carried the risk of addiction, and the combination of  fenfluramine and phentermine damaged heart valves.   Newer antiobesity drugs target fat in diverse ways.  Tetrahydrolipostatin, marketed as Orlistat and Xenical, inhibits  the function of pancreatic lipase, preventing the digestion and  absorption of about a third of dietary fat, which is eliminated in  loose feces. This effect is not disruptive as long as the person fol-  lows a low-fat diet. Future weight control drugs may manipulate  appetite-control hormones, such as ghrelin and leptin.   For people with BMIs above 40, or above 35 in addition to an  obesity-related disorder, bariatric (weight loss) surgery can lead  to weight loss. Three types of procedures are done. In laparo-  scopic adjustable gastric banding, a silicone band ties off part  of the stomach, limiting its capacity to hold food. The band can  be inflated or deflated in a doctor's office by adding or remov-  ing saline. The band may need to be removed if it slips out of  place, it erodes the stomach lining, the body rejects it, or the  port to add or remove fluid becomes displaced. In the second  type of bariatric surgery, sleeve gastrectomy, a surgeon removes  about 75% of the stomach, leaving a banana-shaped “sleeve.”  This sleeve procedure is irreversible. The third type of bariatric  surgery is gastric bypass, in which part of the stomach is stapled  shut, forming a pouch surgically connected to the jejunum,  bypassing the duodenum.   All three bariatric procedures lead to decreased hunger,  greatly reduced food intake, and some decrease in the absorp-  tion of nutrients. A special diet, liquid at first, must be followed.  Many patients who have had bariatric surgery report improve-  ment in or disappearance of type 2 diabetes, back pain, arthritis,  varicose veins, sleep apnea, and hypertension. However, people  can regain the weight and lose the benefits if they fail to adhere  to the dietary restrictions. From Science to Technology 13.1  (pp. 518-519) discusses the effect of gastric bypass surgery on  blood glucose control.    17 What is the basal metabolic rate?  18 What factors influence the BMR?  19 What is energy balance?    We eat to obtain the nutrients that power the activities of life.  Eating is a complex, finely tuned homeostatic mechanism that bal-  ances nutrient intake with nutrient use. Too few nutrients, and dis-  orders associated with malnutrition result. Too many nutrients, and  obesity is the consequence. Several factors influence food intake,  including smell, taste, and texture of food; neural signals triggered  by stretch receptors in the stomach; stress; and hormones.   Appetite is the drive that compels us to seek food. Several  types of interacting hormones control appetite by affecting part of  the hypothalamus called the arcuate nucleus (table 18.4).   Insulin, secreted from the pancreas, regulates fat stores by  stimulating cells called adipocytes to take up glucose and store fat,  and by stimulating certain other cells to take up glucose and link  it to form glycogen, a storage carbohydrate. Eating stimulates adi-  pocytes to secrete the hormone leptin, which acts on target cells in  the hypothalamus. Leptin secretion suppresses appetite by inhibit-  ing release of the hypothalamic neurotransmitter neuropeptide Y,  which stimulates eating. The interaction between leptin and neuro-  peptide Y is a negative feedback response to ingesting calories.  Leptin also stimulates metabolic rate (fig. 18.10). Low leptin levels  indicate depleted fat stores, a condition in which metabolism slows to    FIGURE 18.9 Weight. (a) An obese person is overweight and has excess adipose  tissue. (b) An athlete may be overweight due to muscle overgrowth but is not  considered obese. Many athletes have very low percentages of body fat.    conserve energy and appetite increases. Inherited leptin deficiency  is very rare, but the resultant loss of this appetite “brake” results  in obesity. In this special case, leptin injections enable these indi-  viduals to reduce their weight.   Conversely, ghrelin, a hormone that the stomach secretes,  enhances appetite by stimulating the release of neuropeptide Y.  Therefore, a compound that blocks ghrelin production or activ-  ity might help people lose weight. Fasting and a low-calorie diet  stimulate ghrelin production. The success of gastric bypass surgery  may be due in part to decreased ghrelin secretion resulting from  loss of stomach tissue.    Adiponectin is a protein hormone synthesized in adipose cells  and secreted into the bloodstream that mediates response to  insulin and regulates fatty acid catabolism. Adiponectin also  has an anti-inflammatory effect. The hormone increases basal  metabolic rate (calories burned at rest) without affecting appe-  tite. Because levels of adiponectin are higher in people who do  not have diabetes and have healthy body weights, some studies  suggest boosting its levels may help in weight loss. Although  companies sell adiponectin in pill form, it is a protein and is  therefore broken down in the digestive tract before it can exert  an effect. The hormone is marketed as a dietary supplement,  not as a drug.    FIGURE 18.10 Appetite control is complex. Illustrated here are the  effects of leptin and ghrelin on appetite.    Vitamins (vi’tah-minz) are organic compounds (other than car-  bohydrates, lipids, and proteins) required in small amounts for  normal metabolism that body cells cannot synthesize in ade-  quate amounts. Vitamins are essential nutrients that must come  directly from foods or indirectly from provitamins, which are  precursor substances.    Vitamins are classified on the basis of whether they are solu-  ble in fats (or fat solvents) or in water. Fat-soluble vitamins are A,  D, E, and K; the water-soluble group includes the B vitamins and  vitamin C. Table 18.5 lists, and corrects, some common miscon-  ceptions about vitamins.    Fat-soluble vitamins dissolve in fats. Therefore they associate  with lipids and are influenced by the same factors that affect lipid  absorption. For example, bile salts in the intestine promote absorp-  tion of fat-soluble vitamins. The fat-soluble vitamins are stored in  moderate quantities in various tissues, which is why excess intake  can lead to overdose. These vitamins resist the effects of heat, so  cooking and food processing do not usually destroy them.    24 How do bile salts affect the absorption of fat-soluble vitamins?    Vitamin A exists in several forms, including retinol and reti-  nal (retinene). Body cells synthesize this vitamin from a group of  yellowish plant pigments, which are provitamins called carotenes  (fig. 18.11). Excess vitamin A or its precursors are mainly stored  in the liver, which regulates their concentration in the body. An    Too much of a water-soluble vitamin  results in excretion of the vitamin through  urination; too much of a fat-soluble vitamin  can harm health    Many people do benefit from vitamin  supplements, particularly pregnant and  breast-feeding women    Vitamins do not directly supply energy;  they aid in the release of energy from  carbohydrates, fats, and proteins    FIGURE 18.11 A molecule of beta carotene can react to form two molecules of retinal, which, in turn, can react to form retinol.    adult’s liver stores enough vitamin A to supply body requirements  for a year. Infants and children usually lack such reserves and are  therefore more likely to develop vitamin A deficiencies if their  diets are inadequate.   Vitamin A is relatively stable to the effects of heat, acids, and  bases. However, it is readily destroyed by oxidation and is unsta-  ble in light.   Vitamin A is important in vision. Retinal is used to synthesize  rhodopsin (visual purple) in the rods of the retina and light-sensitive  pigments in the cones (pp. 479-480). The vitamin also functions in  the synthesis of mucoproteins and mucopolysaccharides, in devel-  opment of normal bones and teeth, and in maintenance of epithelial  cells in skin and mucous membranes. Vitamin A and beta carotenes  also act as antioxidants (an’ti-ok’si-dant) by readily combining  with oxygen and certain oxygen-containing molecules that have  unshared electrons, which makes them highly reactive and dam-  aging to cellular structures. These unstable molecules are called  oxygen free radicals, and they accumulate in certain diseases and  with age.    ~ RECONNECT  « To Chapter 2, Bonding of Atoms, page 64.    Only foods of animal origin such as liver, fish, whole milk,  butter, and eggs are sources of vitamin A. However, the vitamin’s  precursor, carotene, is widespread in leafy green vegetables and in  yellow or orange vegetables and fruits.   Excess vitamin A produces the peeling skin, hair loss, nausea,  headache, and dizziness of hypervitaminosis A. Chronic overdoses  of the vitamin may inhibit growth and break down bones and  joints. “Megadosing” on fat-soluble vitamins is particularly dan-  gerous during pregnancy. Some forms of vitamin A, in excess, can  cause birth defects.   A deficiency of vitamin A causes night blindness, in which  a person cannot see normally in dim light. Xeropthalmia, a dry-  ness of the conjunctiva and cornea, is due to vitamin A deficiency.  Vitamin A deficiency also causes degenerative changes in certain  epithelial tissues, and the body becomes more susceptible to infection.    25 Which chemical in the body is the precursor to vitamin A?    Vitamin D is a group of steroids that have similar properties.  One of these substances, vitamin D, (cholecalciferol), is found  in foods such as milk, egg yolk, and fish liver oils. Vitamin D,  (ergocalciferol) is commercially produced by exposing a steroid  obtained from yeasts (ergosterol) to ultraviolet light. Vitamin D  can also be synthesized from dietary cholesterol that has been  metabolized to provitamin D by intestinal enzymes, then stored in  the skin and exposed to ultraviolet light (see chapter 6, p. 189 and  fig. 13.26 on p. 508).   Like other fat-soluble vitamins, vitamin D resists the effects  of heat, oxidation, acids, and bases. It is primarily stored in the  liver and is less abundant in the skin, brain, spleen, and bones.   Vitamin D stored in the form of hydroxycholecalciferol is  released as needed into the blood. When parathyroid hormone is  present, this form of vitamin D is converted in the kidneys into an  active form of the vitamin (dihydroxycholecalciferol). This sub-  stance, in turn, is carried as a hormone in the blood to the intes-  tines where it stimulates production of calcium-binding protein.  Here, it promotes absorption of calcium and phosphorus, ensuring  that adequate amounts of these minerals are available in the blood  for tooth and bone formation and metabolic processes.   Natural foods are poor sources of vitamin D, so the vitamin  is often added to them during processing. For example, homog-  enized, nonfat, and evaporated milk are typically fortified with  vitamin D. Fortified means essential nutrients have been added to a  food where they originally were absent or scarce. Enriched means  essential nutrients have been partially replaced in a food that has  lost nutrients during processing.   Excess vitamin D, or hypervitaminosis D, produces diarrhea,  nausea, and weight loss. Over time too much of this vitamin may  calcify certain soft tissues and irreversibly damage the kidneys.   In children, vitamin D deficiency results in rickets, in which  the bones, teeth, and abdominal muscles do not develop normally    (fig. 18.12). In adults or in the elderly who have little exposure to  sunlight, vitamin D deficiency may lead to osteomalacia, in which  the bones decalcify and weaken due to disturbances in calcium  and phosphorus metabolism. Just five minutes of sun exposure two  to three times a week can maintain skeletal health without elevat-  ing skin cancer risk. Because many older people stay indoors, the  Institute of Medicine suggests that daily vitamin D intake increase  with age (table 18.6).    Vitamin E includes a group of compounds, the most active of  which is alpha-tocopherol. This vitamin is resistant to the effects  of heat, acids, and visible light but is unstable in bases and in  the presence of ultraviolet light or oxygen. Vitamin E is a strong  antioxidant.   Vitamin E is found in all tissues but is primarily stored in the  muscles and adipose tissue. It is also highly concentrated in the  pituitary and adrenal glands.   The precise functions of vitamin E are unknown, but it is  thought to act as an antioxidant by preventing oxidation of vitamin  A and polyunsaturated fatty acids in the tissues. It may also help  maintain the stability of cell membranes.   Vitamin E is widely distributed among foods. Its richest sources  are oils from cereal seeds such as wheat germ. Other good sources  are salad oils, margarine, shortenings, fruits, nuts, and vegetables.  Excess vitamin E may cause nausea, headache, fatigue, easy bruis-  ing and bleeding, and muscle weakness. This vitamin is so easily  obtained that deficiency conditions are rare.   Vitamin K, like the other fat-soluble vitamins, is in several  chemical forms. One of these, vitamin K, (phylloquinone), is  found in foods, whereas another, vitamin K,, is produced by bac-  teria (Escherichia coli) that normally inhabit the human intestinal  tract. These vitamins resist the effects of heat but are destroyed by  oxidation or by exposure to acids, bases, or light. The liver stores  them to a limited degree.   Vitamin K primarily functions in the liver, where it is nec-  essary for the formation of several proteins needed for blood  clotting, including prothrombin (see chapter 14, pp. 543-544).  Consequently, deficiency of vitamin K prolongs blood clotting  time and may increase risk of hemorrhage. Excess vitamin K may  occur in formula-fed infants, causing jaundice, hemolytic anemia,  and hyperbilirubinemia.    The richest sources of vitamin K are leafy green vegetables.  Other good sources are egg yolk, pork liver, soy oil, tomatoes, and  cauliflower. Table 18.7 summarizes the fat-soluble vitamins and  their properties.    About 1 in every 200 to 400 newborns develops vitamin K  deficiency because of an immature liver, poor transfer of  vitamin K through the placenta, or lack of intestinal bacteria  that can synthesize this vitamin. The deficiency causes “hem-  orrhagic disease of the newborn,” in which abnormal bleed-    ing occurs two to five days after birth. Injections of vitamin K    shortly after birth prevent this condition. Adults may develop  vitamin K deficiency if they take antibiotic drugs that kill the  intestinal bacteria that manufacture the vitamin. People with  cystic fibrosis may develop vitamin K deficiency, and/or defi-  ciency of other fat-soluble vitamins, because they cannot  digest fats well.    Exists in several forms;  synthesized from carotenes;  stored in liver; stable in  heat, acids, and bases;  unstable in light    A group of steroids;  resistant to heat, oxidation,  acids, and bases; stored in  liver, skin, brain, spleen, and  bones    A group of compounds;  resistant to heat and visible  light; unstable in presence  of oxygen and ultraviolet  light; stored in muscles and  adipose tissue    Exists in several forms;  resistant to heat but  destroyed by acids, bases,    Liver, fish, whole milk,  butter, eggs, leafy green  vegetables, yellow and  orange vegetables and  fruits    Produced in skin exposed  to ultraviolet light; in  milk, egg yolk, fish liver  oils, fortified foods    Oils from cereal seeds,  salad oils, margarine,  shortenings, fruits, nuts,  and vegetables    Leafy green vegetables,  egg yolk, pork liver, soy  oil, tomatoes, cauliflower   30 Which foods are good sources of vitamin E?  31 Name two sources of vitamin K.    The water-soluble vitamins include the B vitamins and vitamin C.  Cooking and food processing destroy some of them. The B vitamins  are several compounds essential for normal cellular metabolism.  They help oxidize (remove electrons from) carbohydrates, lipids,  and proteins during cellular respiration. The B vitamins are usually in  the same foods, so they are called the vitamin B complex. Members  of this group differ chemically and functionally.  The B-complex vitamins include the following:    1. Thiamine, or vitamin B,, in its pure form is a crystalline  compound called thiamine hydrochloride. Exposure to heat  and oxygen destroys it, especially in alkaline environments.  (See fig. 18.19 for its molecular structure.)   Thiamine is part of a coenzyme called cocarboxylase,  which oxidizes carbohydrates. Specifically, thiamine is required  for pyruvic acid to enter the citric acid cycle (see chapter 4,  p. 129). Without this vitamin, pyruvic acid accumulates in the  blood. Thiamine also functions as a coenzyme in the synthesis  of the sugar ribose, which is part of the nucleic acid RNA.    Thiamine is primarily absorbed through the wall of the  duodenum and is transported by the blood to body cells. Only  small amounts are stored in the tissues, and excess is excreted  in the urine.   Vitamin B, oxidizes carbohydrates, and therefore cellular  requirements vary with caloric intake. The recommended daily  allowance (RDA) for adults is 1.2 milligrams (mg). Good  sources of thiamine are lean meats, liver, eggs, whole-grain  cereals, leafy green vegetables, and legumes.   Excess thiamine is not as common as excesses of fat-  soluble vitamins, due to the excretion of thiamine in urine.  Toxicity effects include vasodilation, cardiac dysrhythmias,  headache, weakness, and convulsions.   A mild deficiency of thiamine produces loss of appetite,  fatigue, and nausea. Prolonged deficiency leads to a disease  called beriberi, which causes gastrointestinal disturbances,  mental confusion, muscular weakness and paralysis, and heart  enlargement. In severe cases, the heart may fail.    alcohol, people with alcoholism are particularly likely to develop  a thiamine deficiency.    2. Riboflavin, or vitamin B., is a yellowish brown crystalline  substance that is relatively stable to the effects of heat, acids,  and oxidation but is destroyed by exposure to bases and ultra-  violet light. This vitamin is part of several enzymes and coen-  zymes known as flavoproteins. One such coenzyme, FAD, is  an electron carrier in the citric acid cycle and electron transport  chain of aerobic respiration. Flavoproteins are essential for the  oxidation of glucose and fatty acids and for cellular growth. An  active transport system controls the amount of riboflavin enter-  ing the intestinal mucosa. Riboflavin is carried in the blood  combined with proteins called albumins. Excess riboflavin in  the blood is excreted in the urine, turning it yellow-orange, and  any that remains unabsorbed in the intestine is lost in the feces.   The amount of riboflavin the body requires varies with  caloric intake. About 1.3 mg is sufficient to meet daily cellular  requirements.   Riboflavin is widely distributed in foods, and rich sources  include meats and dairy products. Leafy green vegetables,  whole-grain cereals, and enriched cereals provide lesser  amounts. Vitamin B, deficiency produces dermatitis and  blurred vision.   3. Niacin or vitamin B,, also known as nicotinic acid, is in  plant tissues and is stable in the presence of heat, acids, and  bases. After ingestion, it is converted to a physiologically  active form called niacinamide (fig. 18.13). Niacinamide is  the form of niacin in foods of animal origin.   Niacin functions as part of two coenzymes (coenzyme I,  also called NAD [fig. 18.14], and coenzyme II, called NADP)  essential in glucose oxidation. These coenzymes are electron  carriers in glycolysis, the citric acid cycle, and the electron    FIGURE 18.13 Enzymes catalyze reactions that convert niacin from  foods into physiologically active niacinamide.    transport chain, as well as in the synthesis of proteins and fats.  They are also required for the synthesis of the sugars (ribose  and deoxyribose) that are part of nucleic acids.   Niacin is readily absorbed from foods, and human  cells synthesize it from the essential amino acid tryptophan.  Consequently, the daily requirement for niacin varies with  tryptophan intake. The RDA for niacin is 14 mg for women  and 16 mg for men.   Rich sources of niacin (and tryptophan) include liver, lean  meats, peanut butter, and legumes. Milk is a poor source of  niacin but a good source of tryptophan.   Excess niacin can cause acute toxicity with effects such  as flushing, wheezing, vasodilation, headache, diarrhea, and  vomiting. Chronic toxicity effects include liver problems.   Historically, niacin deficiencies have been associated with  diets based on corn and corn products, which are very low in  niacin and lack tryptophan. Niacin deficiency causes pellagra,  which produces dermatitis, inflammation of the digestive tract,  diarrhea, and mental disorders.   Pellagra is rare today, but it was a serious problem in the  rural South of the United States in the early 1900s. Pellagra is  less common in cultures that extensively treat corn with lime  (CaCO,) to release niacin bound to protein. Like beriberi, pel-  lagra affects people who consume alcoholic beverages instead  of food.    . Pantothenic acid, or vitamin B,, is a yellowish oil destroyed    by heat, acids, and bases. It functions as part of a complex  molecule called coenzyme A, which, in turn, reacts with inter-  mediate products of carbohydrate and fat metabolism to yield  acetyl coenzyme A, which enters the citric acid cycle. Panto-  thenic acid is therefore essential to cellular energy release.   A daily adult intake of 5 mg of pantothenic acid is ade-  quate. Most diets provide sufficient amounts, and therefore  deficiencies are rare. Good sources of pantothenic acid include  meats, whole-grain cereals, legumes, milk, fruits, and veg-  etables.    pyridoxal, and pyridoxamine, which are chemically similar  (fig. 18.15). These compounds have similar actions and are  fairly stable in the presence of heat and acids. Oxidation or  exposure to bases or ultraviolet light destroys them. The vita-  min B, compounds function as coenzymes essential in several  metabolic pathways, including those that synthesize proteins,  amino acids, antibodies, and nucleic acids, as well as the reac-  tion of tryptophan to produce niacin.   Vitamin B, functions in the metabolism of nitrogen-  containing substances. Thus, the requirement for this vitamin  varies with the protein content of the diet rather than with  caloric intake. The RDA for vitamin B, ranges from 1.3 to  1.7 mg depending upon age, but because it is so abundant in  foods, deficiency is rare. Good sources of vitamin B, include  liver, meats, bananas, avocados, beans, peanuts, whole-grain  cereals, and egg yolk. Excess vitamin B, produces burning  pains, numbness, clumsiness, diminished reflexes, and paralysis.    . Biotin, or vitamin B., is a simple compound that is unaffected    by heat, acids, and light but may be destroyed by oxidation or  bases. (See fig. 18.19 for the molecular structure of biotin.) It    is a coenzyme in metabolic pathways for amino acids and fatty the effects of heat but is inactivated by light or strong acids or  acids. It also plays a role in the synthesis of the purine nitrog- strong bases.  enous bases of nucleic acids (adenine and guanine). Secretion of intrinsic factor from the parietal cells of the gas-  Metabolically active organs such as the brain, liver, and tric glands regulates cyanocobalamin absorption. Intrinsic factor  kidneys store some biotin. Bacteria that inhabit the intestinal combines with cyanocobalamin and facilitates its transfer through  tract synthesize biotin. The vitamin is widely distributed in the epithelial lining of the small intestine and into the blood.  foods, and dietary deficiencies are rare. Good sources include Calcium ions must be present for the process to take place.  liver, egg yolk, nuts, legumes, and mushrooms. Excess biotin  does not produce toxic effects. , >  7. Folacin or vitamin B,, also known as folic acid, is a yellow Inability of the gastric glands to secrete adequate amounts  crystalline compound that exists in several forms. It is easily of intrinsic factor impairs vitamin B,, absorption. This leads to  oxidized in an acid environment and is destroyed by heat in pernicious anemia, which produces abnormally large red blood  alkaline solutions; consequently, this vitamin may be lost in cells, called macrocytes, when bone marrow cells do not divide  stored or cooked foods. properly because of defective DNA synthesis.  Folacin is readily absorbed from the digestive tract and is e ey    stored in the liver, where it is converted to a physiologically  active substance called folinic acid. Folinic acid functions as a  coenzyme necessary for the metabolism of certain amino acids CH,—CONH,  and for the synthesis of DNA. It also acts with cyanocobalamin |  in producing normal red blood cells. CH CH3 CH3   Good sources of folacin include liver, leafy green CH,—CONH,  vegetables, whole-grain cereals, and legumes. Because excess NH,CO — CH,  folacin is excreted in the urine, toxicity is rare. Folacin deficiency CHs  leads to megaloblastic anemia, in which the number of normal  red blood cells is reduced and large, nucleated red cells appear.  Folacin deficiency has been linked to neural tube defects, in  which the tube that becomes the central nervous system in a  fetus does not completely close. Neural tube defects include  spina bifida and anencephaly. Taking synthetic folic acid  supplements just before and during pregnancy can greatly  reduce the risk of a neural tube defect.    Naturally occurring folate is a mixture of compounds that col-  lectively have the same activity as synthetic folic acid, also called CH—CH;  pteroylmonoglutamic acid. However, synthetic folic acid is much re)  more stable and enters the bloodstream much more readily.  This difference has led to confusion. For example, 200 micro-  grams of synthetic folic acid is prescribed to treat anemia, but  the same effect requires 400 micrograms of folate from foods.  Synthetic folic acid used to enrich grain foods has a greater  effect on health than folate.    8. Cyanocobalamin, or vitamin B,,, has a complex molecu- IESE yes yen EEO belemnin)    lar structure, including a single atom of the element cobalt FIGURE 18.16 Vitamin B,,, which has the most complex molecular  (fig. 18.16). In its pure form, this vitamin is red. It is stable to structure of the vitamins, contains cobalt (Co).    Various tissues store cyanocobalamin, particularly  those of the liver. An average adult has a reserve sufficient to  supply cells for three to five years. This vitamin is essential  for the functions of all cells. It is part of coenzymes required  for the synthesis of nucleic acids and the metabolism of  carbohydrates and fats. Vitamin B ,, is important to erythro-  cyte production. Cyanocobalamin also helps form myelin in  the central nervous system.   Only foods of animal origin contain cyanocobalamin.  Good sources include liver, meats, milk, cheese, and eggs.  Excessive intake does not appear to be toxic. In most countries,  dietary lack of this vitamin is rare, although strict vegetarians  may develop a deficiency.    33 Which biochemicals comprise the vitamin B complex?  34 Which foods are good sources of vitamin B complex?    35 What is the general function of each member of the vitamin B  complex?    Vitamin C, or ascorbic acid, is a crystalline compound that  has six carbon atoms. Chemically, it is similar to the monosaccha-  rides (fig. 18.17). Vitamin C is one of the least stable vitamins in  that oxidation, heat, light, or bases destroy it. However, vitamin C  is fairly stable in acids.   Ascorbic acid is necessary for the production of the connec-  tive tissue protein collagen, for conversion of folacin to folinic acid,  and in the metabolism of certain amino acids. It also promotes iron  absorption and synthesis of certain hormones from cholesterol.   Overall, vitamin C is not stored in any great amount, but the adre-  nal cortex, pituitary gland, and intestinal glands contain high concen-  trations of it. Excess vitamin C is excreted in the urine or oxidized.   Individual requirements for ascorbic acid may vary. Ten mg  per day is sufficient to prevent deficiency symptoms, and 80 mg  per day saturates the tissues within a few weeks. The RDA for  vitamin C is 75 mg for women and 90 mg for men.   Ascorbic acid is fairly widespread in plant foods, with high  concentrations in citrus fruits and tomatoes. Leafy green vegeta-  bles are also good sources.   Prolonged deficiency of ascorbic acid leads to scurvy, which  is more likely to affect infants and children. Scurvy impairs bone    FIGURE 18.17 Vitamin C is  chemically similar to some  6-carbon monosaccharides.    development and causes swollen, painful joints. The gums may  swell and bleed easily, resistance to infection is lowered, and  wounds heal slowly (fig. 18.18). If a woman takes large doses of  ascorbic acid during pregnancy, the newborn may develop symp-  toms of scurvy when the daily dose of the vitamin drops after birth  because it is no longer delivered through the placenta. Table 18.8  summarizes the water-soluble vitamins and their characteristics.    Millions of Americans regularly take vitamin supplements.  Consumer spending on vitamins and minerals is well into the  billions of dollars annually. This practice has led to clinical signs    of excess vitamin and mineral toxicity. lron-containing vitamins  are the most toxic, especially in acute pediatric ingestions.    Carbohydrates, lipids, proteins, and vitamins are organic com-  pounds. In contrast, dietary minerals are inorganic elements  essential in human metabolism. Most plants extract minerals from  soil, and humans obtain them from plant foods or from animals  that have eaten plants.    Minerals contribute about 4% of body weight and are most con-  centrated in the bones and teeth. The minerals calcium and phos-  phorus are very abundant in these tissues.   Minerals are usually incorporated into organic molecules.  Examples include phosphorus in phospholipids, iron in hemo-  globin, and iodine in thyroxine. However, some minerals are part of  inorganic compounds, such as the calcium phosphate of bone. Other  minerals are free ions, such as sodium, chloride, and calcium ions in  the blood.    FIGURE 18.18 Vitamin C deficiency causes bleeding gums and other  symptoms of scurvy.    Stable to heat, acids, and  oxidation; destroyed by  bases and ultraviolet light    Stable to heat, acids,  and bases; converted  to niacinamide by  cells; synthesized from  tryptophan    Group of three  compounds; stable to  heat and acids; destroyed  by oxidation, bases, and  ultraviolet light    Stable to heat, acids,  and light; destroyed by  oxidation and bases   in an acid environment  or by heat in an alkaline  environment; stored in  liver where it is converted  into folinic acid    Complex, cobalt-  containing compound;  stable to heat; inactivated  by light, strong acids, and  strong bases; absorption  regulated by intrinsic  factor from gastric  glands; stored in liver    Chemically similar to  monosaccharides; stable  in acids but destroyed by  oxidation, heat, light, and  bases    Part of coenzyme required for  oxidation of carbohydrates;  coenzyme required for ribose  synthesis    Part of enzymes and coenzymes  such as FAD, required for  oxidation of glucose and fatty  acids and for cellular growth    Part of coenzymes NAD and  NADP required for oxidation of  glucose and synthesis of proteins,  fats, and nucleic acids    Part of coenzyme A required for  oxidation of carbohydrates and  fats    Coenzyme required for synthesis of  proteins and various amino acids,  for conversion of tryptophan to  niacin, for production of antibodies,  and for nucleic acid synthesis    Coenzyme required for  metabolism of amino acids and  fatty acids and for nucleic acid  synthesis    Coenzyme required for  metabolism of certain amino acids  and for DNA synthesis; promotes  production of normal red blood  cells    Part of coenzyme required for  synthesis of nucleic acids and for  metabolism of carbohydrates;  plays role in myelin synthesis;  required for normal red blood cell  production    Required for collagen production,  conversion of folacin to folinic  acid, and metabolism of certain  amino acids; promotes absorption  of iron and synthesis of hormones  from cholesterol    Lean meats, liver,  eggs, whole-grain  cereals, leafy green  vegetables, legumes  1.2 mg    Citrus fruits,  tomatoes, leafy  green vegetables  75 mg for females  90 mg for males    Minerals compose parts of the structural materials of all body  cells. They also constitute portions of enzyme molecules, contrib-  ute to the osmotic pressure of body fluids, and play vital roles in  impulse conduction in neurons, muscle fiber contraction, blood  coagulation, and maintenance of the pH of body fluids. The physi-  ologically active form of minerals is the ionized form, such as Ca”.   Homeostatic mechanisms regulate the concentrations of min-  erals in body fluids so that excretion of minerals matches intake.  Mineral toxicity may result not only from consumption of too  much of a mineral, but also from overexposure to industrial pollut-  ants, household chemicals, or certain drugs. Certain diseases lead  to mineral toxicity. Hemochromatosis, for example, is an inherited  form of “iron overload” resulting from excess iron absorption.  Injuries may also lead to mineral toxicity, such as severe trauma  causing hyperkalemia (high plasma potassium).    Calcium and phosphorus account for nearly 75% by weight of  the mineral elements in the body. Therefore, they are considered  major minerals (macrominerals). Other major minerals, each of  which accounts for 0.05% or more of body weight, include potas-  sium, sulfur, sodium, chlorine, and magnesium. Descriptions of  the major minerals follow:    1. Calcium (Ca) is widely distributed in cells and body fluids,  even though 99% of the body’s supply is in the inorganic  salts of the bones and teeth. It is essential for neurotransmitter  release, muscle fiber contraction, the cardiac action potential,  and blood coagulation. Calcium also activates certain enzymes.   The amount of calcium absorbed varies with a number  of factors. For example, the proportion of calcium absorbed  increases as the body’s need for calcium increases. Vitamin D  and high protein intake promote calcium absorption. Increased  motility of the digestive tract or an excess intake of fats  decreases absorption. Daily intake of 1,000 to 1,200 mg  of calcium covers adult requirements even with variations  in absorption.   Only a few foods contain significant amounts of calcium.  Milk and milk products and fish with bones, such as salmon  or sardines, are the richest sources. Leafy green vegetables,  such as mustard greens, turnip greens, and kale, are good  sources, but because very large servings of these vegetables  are necessary to obtain sufficient minerals, most people must  regularly consume milk or milk products to get enough calcium.   Calcium toxicity is rare, but overconsumption of calcium  supplements can deposit calcium phosphate in soft tissues.  Calcium deficiency in children causes stunted growth, mis-  shapen bones, and enlarged wrists and ankles. In adults, such  a deficiency may remove calcium from the bones, thinning  them and raising risk of fracture. Calcium is required for nor-  mal closing of the sodium channels in nerve cell membranes.    Because of this, too little calcium (hypocalcemia) can cause  tetany. Extra calcium demands in pregnancy can cause cramps.  2. Phosphorus (P) accounts for about 1% of total body weight,  most of it in the calcium phosphate of bones and teeth. The  remainder serves as structural components and plays impor-  tant roles in nearly all metabolic reactions. Phosphorus is a  constituent of nucleic acids, many proteins, some enzymes,  and some vitamins. It is also in the phospholipids of cell mem-  branes, in the energy-carrying molecule ATP, and in the phos-  phates of body fluids that regulate pH. (Review the molecular  structure of ATP in fig. 4.7, p. 126.)  The recommended daily adult intake of phosphorus  is 700 mg, and because this mineral is abundant in protein  foods, diets adequate in proteins are also adequate in phos-  phorus. Phosphorus-rich foods include meats, cheese, nuts,  whole-grain cereals, milk, and legumes.    40 Which are the most abundant minerals in the body?  41 What are the functions of calcium?  42 What are the functions of phosphorus?    3. Potassium (K) is widely distributed throughout the body  and is concentrated inside cells rather than in extracellular  fluids. On the other hand, sodium, which has similar chemi-  cal properties, is concentrated outside cells. The ratio of  potassium to sodium in a cell is 10:1, whereas the ratio  outside the cell is 1:28.   Potassium helps maintain intracellular osmotic pressure  and pH. It is a cofactor for enzymes that catalyze reactions  of carbohydrate and protein metabolism. Potassium is vital  in establishing the membrane potential and in impulse  conduction in neurons.   Nutritionists recommend a daily adult intake of 4.7 grams  (4,700 mg) of potassium. This mineral is in many foods, so a  typical adult diet provides between 2 and 6 grams each day.  Excess potassium in the blood is uncommon because of the  uptake of potassium by body cells and the excretion of potas-  sium in urine. Potassium deficiency due to diet is rare, but it  may occur for other reasons. For example, when a person  has diarrhea, the intestinal contents may pass through the  digestive tract so rapidly that potassium absorption is greatly  reduced. Vomiting or using diuretic drugs may also deplete  potassium. Such losses may cause muscular weakness,  cardiac abnormalities, and edema.   Foods rich in potassium are avocados, dried apricots,  meats, milk, peanut butter, potatoes, and bananas. Citrus  fruits, apples, carrots, and tomatoes provide lesser amounts.    44 How is potassium distributed in the body?  45 What is the function of potassium?    4. Sulfur (S) is responsible for about 0.25% of body weight toxicity, which shrinks cells, including those of the brain,    and is widely distributed throughout tissues. It is abundant requires unusual ingestion of additional sodium, such as   in skin, hair, and nails. Most sulfur is part of the amino acids drinking ocean water. Sodium may be lost as a result of   methionine and cysteine. Other sulfur-containing compounds diarrhea, vomiting, kidney disorders, sweating, or using   include thiamine, insulin, and biotin (fig. 18.19). In addition, diuretics. Sodium loss may cause a variety of symptoms,   sulfur is a constituent of mucopolysaccharides in cartilage, including nausea, cramps, and convulsions.   tendons, and bones and of sulfolipids in the liver, kidneys, The amount of sodium naturally present in foods varies   salivary glands, and brain. greatly, and it is commonly added to foods in the form of table  No daily requirement for sulfur has been established. salt. In some geographic regions, drinking water contains   However, a diet providing adequate amounts of protein significant concentrations of sodium. Foods high in sodium   will also likely meet the body’s sulfur requirement. Good include cured ham, sauerkraut, and cheese.   food sources of this mineral include meats, milk, eggs, and ry   5. Sodium (Na) makes up about 0.15% of adult body weight, r “ PRACTICE  and is widely distributed throughout the body. Only about 47 |In which compounds and tissues of the body is sulfur found?  10% of this mineral is inside cells, and about 40% is in the 48 What are the functions of sodium?    extracellular fluids. The remainder is bound to the inorganic  salts of bone.   Active transport readily absorbs sodium from foods.  The kidneys regulate the blood concentration of sodium  under the influence of the adrenal cortical hormone aldo-  sterone, which causes the kidneys to reabsorb sodium while  expelling potassium.   Sodium makes a major contribution to the solute  concentration of extracellular fluids and thus helps regulate carbon dioxide by red blood cells.  water movement between cells and their surroundings. It is Chlorine and sodium are usually ingested in table salt,  necessary for impulse conduction in neurons and helps to and as in the case for sodium, an ordinary diet usually pro-  move substances, such as chloride ions, through cell mem- vides considerably more chlorine than the body requires.  branes (see chapter 21, p. 809). Vomiting, diarrhea, kidney disorders, sweating, or using   The usual human diet probably provides more than diuretics can deplete chlorine in the body.    enough sodium to meet the body’s requirements. Sodium 7. Magnesium (Mg) is responsible for about 0.05% of body  weight and is found in all cells. It is particularly abundant in   Magnesium is important in ATP-forming reactions in  mitochondria, as well as in breaking down ATP to ADP.  Therefore, it is important in providing energy for cellular  processes.   Magnesium absorption in the intestinal tract adapts  to dietary intake of the mineral. When the intake of mag-  nesium is high, a smaller percentage is absorbed from the  intestinal tract, and when the intake is low, a larger percent-  age is absorbed. Absorption increases as protein intake  increases, and decreases as calcium and vitamin D intake  increase. Bone tissue stores a reserve supply of magnesium,  and excess is excreted in the urine.   (vitamin B;) 310 to 420 mg, with higher amounts for males. A typical  diet usually provides only about 120 mg of magnesium for  every 1,000 calories, barely meeting the body’s needs. Good  sources of magnesium include milk and dairy products  (except butter), legumes, nuts, and leafy green vegetables.  Table 18.9 summarizes the major minerals.    6. Chlorine (Cl) in the form of chloride ions is found throughout  the body and is most highly concentrated in cerebrospinal fluid  and in gastric juice. With sodium, chlorine helps to regulate pH  and maintain electrolyte balance and the solute concentration  of extracellular fluids. Chlorine is also essential for the forma-  tion of hydrochloric acid in gastric juice and in the transport of    Mineral Distribution Functions  | Calcium Mostly in the inorganic Structure of bones and teeth;   (Ca) salts of bones and teeth essential for neurotransmitter  release, muscle fiber contraction, the  cardiac action potential, and blood  coagulation; activates certain enzymes   Phosphorus __ Mostly in the inorganic Structure of bones and teeth;   (P) salts of bones and teeth = component of nearly all metabolic  reactions; in nucleic acids, many  proteins, some enzymes, and some  vitamins; in cell membrane, ATP, and  phosphates of body fluids   and nails mucopolysaccharides  | Sodium Widely distributed; Helps maintain osmotic pressure of  (Na) mostly in extracellular extracellular fluids; regulates water  fluids and bound to movement; plays a role in impulse  inorganic salts of bone conduction in neurons; regulates pH  and transport of substances across cell  membranes  Chlorine Closely associated Helps maintain osmotic pressure of  (Cl) with sodium; most extracellular fluids, regulates pH;  highly concentrated in maintains electrolyte balance; forms  cerebrospinal fluid and hydrochloric acid; aids transport of  gastric juice carbon dioxide by red blood cells    Milk, milk products,  leafy green vegetables  1,000 mg <50 yrs  1,200 mg >50 yrs    Trace elements (microminerals) are essential minerals found in  minute amounts, each making up less than 0.005% of adult body  weight. They include iron, manganese, copper, iodine, cobalt,  zinc, fluorine, selenium, and chromium.   Iron (Fe) is most abundant in the blood, but is stored in the  liver, spleen, and bone marrow and is found to some extent in all  cells. Iron enables hemoglobin molecules in red blood cells to  carry oxygen (fig. 18.20). Iron is also part of myoglobin, which  stores oxygen in muscle cells. In addition, iron assists in vita-  min A synthesis, is incorporated into a number of enzymes, and  is included in the cytochrome molecules that participate in ATP-  generating reactions.   An adult male requires from 0.7 to | mg of iron daily, and a  female needs 1.2 to 2 mg. A typical diet supplies about 10 to 18 mg    of iron each day, but only 2% to 10% of the iron is absorbed. For  some people, this may not be enough iron. Eating foods rich in  vitamin C along with iron-containing foods can increase absorp-  tion of this important mineral.   Liver is the only rich source of dietary iron, and because liver  is not a popular food, iron is one of the more difficult nutrients  to obtain from natural sources in adequate amounts. Foods that  contain some iron include lean meats, dried apricots, raisins, and  prunes, enriched whole-grain cereals, legumes, and molasses.    Pregnant women require extra iron to support the formation of  a placenta and the growth and development of a fetus. lron is  required for the synthesis of hemoglobin in a fetus as well as in  a pregnant woman, whose blood volume increases by a third.    FIGURE 18.20 Iron in hemoglobin. (a) A hemoglobin molecule  contains four heme groups, each of which houses a single iron atom   (Fe) that can combine with oxygen. The red blood cells in (b) are normal  (1,250x), but many of those in (c) are small and pale (1,250x). They contain  too little hemoglobin, which may be the result of a diet lacking in iron.    Manganese (Mn) is most concentrated in the liver, kidneys,  and pancreas. It is necessary for normal growth and development  of skeletal structures and other connective tissues. Manganese is  part of enzymes essential for the synthesis of fatty acids and cho-  lesterol, for urea formation, and for the normal functions of the  nervous system.   The daily requirement for manganese is 2.5 to 5 mg. The rich-  est sources include nuts, legumes, and whole-grain cereals. Leafy  green vegetables and fruits are good sources of manganese too.    Copper (Cu) is in all body tissues but is most highly concen-  trated in the liver, heart, and brain. It is essential for hemoglobin  synthesis, bone development, melanin production, and formation  of myelin in the nervous system.   A daily intake of 0.9 to 3 mg of copper is sufficient to supply  cells. A typical adult diet has about 2 to 5 mg of this mineral, so adults  seldom develop copper deficiencies. Foods rich in copper include  liver, oysters, crabmeat, nuts, whole-grain cereals, and legumes.   Iodine (I) is highly concentrated in the thyroid gland, but is  found in very small quantities in other tissues. Its only known func-  tion is as an essential component of thyroid hormones. (Fig. 13.20  on p. 505 shows the molecular structures of these hormones, thyrox-  ine and triiodothyronine.)   A daily intake of 0.15 mg of iodine is adequate for most adults.  The iodine content of foods varies with the iodine content of soils  in different geographic regions. In many places, people use iodized  table salt to season foods, which prevents iodine deficiency.   Cobalt (Co) is widely distributed in the body because it is an  essential part of cyanocobalamin (vitamin B.,). It is also necessary  for the synthesis of several important enzymes.   The amount of cobalt required in the daily diet is unknown.  This mineral is found in a great variety of foods, and the quantity  in the average diet is apparently sufficient. Good sources of cobalt  include liver, lean meats, and milk.   Zinc (Zn) is most concentrated in the liver, kidneys, and  brain. It is part of many enzymes involved in digestion, respiration,  and bone and liver metabolism. It is also necessary for normal  wound healing and for maintaining the integrity of the skin.   The daily requirement for zinc is about 11 to 15 mg, and  most diets provide enough. Only some may be absorbed, so zinc  deficiencies may occur. Meat provides the most zinc. Cereals,  legumes, nuts, and vegetables provide lesser amounts.   Fluorine (F), as part of the compound fluoroapatite, replaces  hydroxyapatite in teeth, strengthening the enamel and preventing  dental caries. Selenium (Se) is stored in the liver and kidneys. It  is a constituent of certain enzymes and participates in heart func-  tion. This mineral is found in lean meats, whole-grain cereals,    and onions. Chromium (Cr) is widely distributed throughout the  body and regulates glucose use. It is found in liver, lean meats,  yeast, and pork kidneys. Table 18.10 summarizes the characteristics    Part of hemoglobin molecule; assists in  vitamin A synthesis; incorporated into a  number of enzymes    Part of enzymes required for fatty acids  and cholesterol synthesis, urea formation,  and normal functioning of the nervous  system    Essential for hemoglobin synthesis, bone  development, melanin production, and  myelin formation    Component of enzymes involved in  digestion, respiration, bone metabolism,  liver metabolism; necessary for normal    A compulsive disorder that may result from mineral deficiency  is pica, in which people consume large amounts of nondietary  substances such as ice chips, soil, sand, laundry starch, clay and  plaster, and even hair, toilet paper, matchheads, inner tubes,  mothballs, and charcoal. The condition is named for the magpie  bird, Pica pica, which eats a range of odd things.   Pica affects people of all cultures and was noted as early  as 40 B.c. The connection to dietary deficiency stems from the  observation that slaves suffering from pica in the colonial United  States recovered when their diets improved, particularly when    Displayed prominently among the standard  vitamin and mineral preparations in the  pharmacy or health food store is a dizzying  collection of products (fig. 18A). Some obvi-  ously come from organisms (bee pollen and  shark cartilage), some have chemical names  (glucosamine with chondroitin), and some  names are historical or cultural (St. John’s  wort). These “dietary supplements” are clas-  sified as neither food nor drug, but despite  regulatory language, they may contain active  compounds that function as pharmaceuticals  in the human body.   By United States law dietary supplements  include: “a product (other than tobacco) that is  intended to supplement the diet that bears or  contains one or more of the following dietary  ingredients: a vitamin, a mineral, an herb or  other botanical, an amino acid, a dietary sub-  stance for use by man to supplement the diet  by increasing the total daily intake, or a con-  centrate, metabolite, constituent, extract, or  combinations of these ingredients.”   Labels cannot claim that a dietary sup-  plement diagnoses, prevents, mitigates,  treats, or cures any specific disease. Instead,  the language is positive and guarded, as in  claims that valerian root “promotes restful  sleep” and that echinacea and goldenseal  “may help support the immune system.” The  U.S. Food and Drug Administration (FDA)    An adequate diet provides sufficient energy (calories), essen-  tial fatty acids, essential amino acids, vitamins, and minerals to  support optimal growth and to maintain and repair body tissues.  Because individual nutrient requirements vary greatly with age,  sex, growth rate, level of physical activity, and stress, as well  as with genetic and environmental factors, it is not possible to  design a diet adequate for everyone. However, nutrients are so  widely found in foods that consuming satisfactory amounts and  combinations is usually possible despite individual food prefer-  ences, assuming that foods are available.   In countries with adequate food supplies, most healthy individ-  uals can obtain nourishment by eating a variety of foods and limiting  fat intake. People who do not eat meat products can also be well-  nourished, but they must pay more attention to food choices to avoid    FIGURE 18A Some dietary supplements are natural substances that function as drugs in the  human body.    developing nutrient deficiencies. For example, eliminating red meat  also means eliminating an excellent source of iron, copper, zinc, and  vitamin B,. The fiber that often makes up much of a vegetarian’s  diet, although very healthful in many ways, also decreases absorp-  tion of iron. Therefore, a vegetarian must obtain sufficient iron from  nonmeat sources. It is easy for a vegetarian to receive proper nutri-  tion (adequate nutrients) by being aware of the sources, actions, and  interactions of nutrients. Fortified foods, green leafy vegetables, and  whole grains provide many of the nutrients that are also in meat.  Table 18.11 lists types of vegetarian diets.   It is difficult to track the different nutrients in a diet and be  certain that an adequate amount of each is consumed daily.  Nutritionists have devised several ways to help consumers make  healthy food choices, recognizing that people can meet dietary  requirements in many and diverse ways. Most familiar is the RDA  guideline that has appeared on several tables in the chapter. RDA    allows only certain specific food and health claims that are sup-  ported by evidence. These include:   ¢ A diet low in saturated fat and cholesterol lowers the risk  of coronary heart disease.   e Fruits and vegetables reduce the risk of cancers and heart  disease.    Some dietary supplements are of uncertain value. Pyruvic acid  and ATP, which are marketed to boost energy levels, for exam-  ple, are abundant in the cellular respiration pathways—a person  doesn’t need to take more. DNA sold in a form that is merely  expensive brewer's yeast is unnecessary because any food con-  sisting of cells is packed with DNA.   Taking dietary supplements may be dangerous if their active  ingredients interact with certain drugs. An example is the active  ingredient in St. John’s wort, hypericin, which affects levels of nearly  half of all prescription drugs by either decreasing or increasing  their effectiveness, or making side effects more likely.   The FDA does not require clinical trials to demonstrate that  dietary supplements are safe and effective, as the agency does for  drugs. The FDA can act only after a dietary supplement has been  linked to illness, injury, or death. This was the case for a supple-  ment marketed to boost energy in athletes that initially caused  97 cases of liver failure, including one death, in Hawaii, but the  effects of that product may be much more widespread. The  agency has investigated more than 500 dietary supplements and  found that many contain drugs, including stimulants and steroids,  that have never been tested in humans!    stands for United States Recommended Daily Allowance. An RDA  is the upper limit of another measurement, the Recommended  Dietary Allowance, which lists optimal calorie intake for each sex  at various ages, and the amounts of vitamins and minerals needed  to avoid deficiency or excess conditions. The RDA values on food  packages are set high, ensuring that most people who follow them  receive sufficient amounts of each nutrient. Government panels  meet every five years to evaluate the RDAs in light of new data.  Placing foods into groups is a simpler way to follow a healthy  diet. For years, diagrams called food pyramids organized foods  according to suggested proportions in the diet, often in serv-  ing sizes. One food pyramid developed by the United States  Department of Agriculture (USDA) dominated, but other pyra-  mids offered more specific suggestions geared to age, health,  ethnicity, food preferences such as vegetarianism, or weight loss  goals. Past pyramids can seem strange in light of today’s MyPlate    In the United States, people use more than 85,000 combina-  tions of ingredients marketed as dietary supplements, and spend  more than $32 billion a year on them. Be certain to tell your health-  care provider about the dosage and frequency of use of any and  all dietary supplements you take. These are powerful chemicals  that affect physiology. Table 18A lists some medical conditions    Bishop's weed, chrysanthemum,  echinacea, fenugreek, guggul,  St. John’s wort, willow bark    (developed by the USDA) replacement, depicted in figure 18.21.  Clinical Application 18.3 discusses some ways that understanding  nutrition can help athletic performance.    An endurance athlete and a sedentary individual have different  nutritional requirements. A diet that is 60% or more carbohydrate,  18% protein, and 22% fat supports a lifestyle that includes fre-  quent, strenuous activity.    Athletes should get the bulk of their carbohydrates from vegetables  and grains to avoid cholesterol. They should eat frequently, because  the muscles can store only 1,800 calories worth of glycogen.   Athletes need to consume only 25% more protein than less-  active individuals. The American Dietetic Association suggests  that athletes eat 1 gram of protein per kilogram of weight per day,  compared to 0.8 gram for nonathletes. Athletes should not rely  solely on meat for protein, because these foods can be high in fat.  Protein supplements may be necessary for young athletes at the  start of training, under a doctor's supervision. Too little protein in  an athlete is linked to “sports anemia,” in which hemoglobin levels  decline and blood may appear in the urine.   A sedentary person loses a quart of water a day as sweat; an ath-  lete may lose 2 to 4 quarts of water an hour! To stay hydrated, ath-  letes should drink 3 cups of cold water two hours before an event,  then 2 more cups fifteen minutes before the event, and small  amounts every fifteen minutes during the event. They should  drink afterward too. Another way to determine water needs is to  weigh in before and after training. For each pound lost, athletes  should drink a pint of water. They should avoid alcohol, which  increases fluid loss. However, athletes should also avoid drinking  too much water during competition, which can cause hyponatre-  mia (too little sodium in the bloodstream, see Clinical Applica-  tions 21.1 and 21.2, on pp. 810-811 and 813, respectively).    If an athlete eats an adequate, balanced diet, vitamin supplements  are not needed. Supplements of sodium and potassium are usu-    Malnutrition (mal”nu-trish’un) is poor nutrition that results from  a lack of essential nutrients or an inability to utilize them. It may  result from undernutrition and produce the symptoms of deficiency  diseases, or it may be due to overnutrition arising from excess  nutrient intake.    ally not needed either, because the active body naturally con-  serves these nutrients. To be certain of enough sodium, athletes  may want to salt their food; to get enough potassium, they can eat  bananas, dates, apricots, oranges, or raisins.   A healthy pregame meal should be eaten two to five hours  before the game, provide 500 to 1,500 calories, and include 4  or 5 cups of fluid. It should also be high in carbohydrates, which  taste good, provide energy, and are easy to digest.    Creatine  Creatine is advertised to increase energy stores and provide a safe  alternative to steroids for bulking up muscles. This is deceptive.   Creatine may be obtained from foods, through supple-  ments, or by synthesis from the amino acids arginine, glycine,  and methionine. Creatine, in the form of creatine phosphate,  provides energy to muscle cells by phosphorylating ADP to gen-  erate ATP. Creatine is converted to its metabolite, creatinine, at  such a constant rate that the excretion of creatinine in the urine  is used as a marker for normal kidney function.   Do creatine supplements enhance performance? The  emerging picture suggests that during peak exertion, especially  repetitive peak exertion (such as multiple sprints), conditions in  which creatine levels may become depleted, supplemental cre-  atine may be advantageous very briefly. However, muscle mass  may appear to increase in athletes taking creatine supplements  because creatine draws water into muscle cells by osmosis, not  because new muscle tissue forms. Creatine use may be danger-  ous. The disturbance in water distribution may create problems  if the athlete encounters extreme heat—sweating becomes  inadequate to effectively cool the body. Swelled muscle cells  may burst, causing a potentially fatal condition called rhabdo-  myolysis. The Food and Drug Administration has received many  adverse event reports of muscle cramps, seizures, diarrhea, loss  of appetite, muscle strains, dehydration and even deaths, associ-  ated with creatine use among athletes.    A variety of factors can lead to malnutrition. For example, a  deficiency condition may stem from lack of availability or poor  quality of food. On the other hand, malnutrition may result from  overeating or taking too many vitamin supplements. Malnutrition  from diet alone is called primary malnutrition.   Secondary malnutrition occurs when an individual’s char-  acteristics make a normally adequate diet insufficient. For exam-  ple, a person who does not secrete enough bile salts is likely to  develop a deficiency of fat-soluble vitamins, because bile salts  promote absorption of fats. Severe and prolonged emotional stress  may lead to secondary malnutrition, because stress can change  hormonal concentrations in ways that break down amino acids or  excrete nutrients, and affect appetite.    FIGURE 18.21 MyPlate, developed by the United States Department of Agriculture, depicts the foods and appropriate proportions that should make    A healthy human can stay alive for fifty to seventy days without  food. In prehistoric times, this margin allowed survival during sea-  sonal famines. In some areas of Africa today, famine is not a sea-  sonal event but a constant condition, and millions of people have  starved to death. Starvation is also seen in hunger strikers, in pris-  oners of concentration camps, and in sufferers of psychological  eating disorders such as anorexia nervosa and bulimia.   Whatever the cause, the starving human body begins to digest  itself. After only one day without eating, the body’s reserves of  sugar and starch are gone. Next, the body extracts energy from  fat and then from muscle protein. By the third day, hunger ceases  as the body uses energy from fat reserves. Gradually, metabolism  slows to conserve energy, blood pressure drops, the pulse slows,  and chills set in. Skin becomes dry and hair falls out as the pro-  teins in these structures are broken down to release amino acids  used for the more vital functioning of the brain, heart, and lungs.  When the immune system’s antibody proteins are dismantled for  their amino acids, protection against infection declines. Mouth  sores and anemia develop, the heart beats irregularly, and bone  begins to degenerate. After several weeks without food, coordina-  tion is gradually lost. Near the end, the starving human is blind,  deaf, and emaciated.    Marasmus (mah-raz’mus) is a form of starvation resulting from  undernourishment with a lack of calories and protein. It causes  people to lose so much weight that they resemble living skeletons  (fig. 18.22a). Children under the age of two with marasmus may  die of measles or other infectious diseases as their immune systems  become too weakened to fight off normally mild viral illnesses.    Some starving children have protruding bellies. These young-  sters suffer from a form of protein starvation called kwashiorkor  (kwash”-e-or’kor), which in the language of Ghana means “the  evil spirit which infects the first child when the second child is  born” (fig. 18.225). Kwashiorkor typically appears in a child who  has recently been weaned from the breast, usually because of the  birth of a sibling. The switch from protein-rich breast milk to the  protein-poor gruel that is the staple of many developing nations  is the source of this protein deficiency. The skin of children with  kwashiorkor may develop lesions. The children’s bellies swell  with filtered fluid that is not reabsorbed by capillaries due to lack  of plasma proteins. This swelling is called ascites (ah-si’téz).  Infections overwhelm the body as the immune system becomes  depleted of its protective antibodies.   Anorexia nervosa (an”o-rek’se-ah ner’vo-sah) is self-imposed  starvation. The condition is reported to affect 1 out of 250 ado-  lescents, most of them female, although the true number among  males is not known and may be higher than has been thought. The  sufferer, typically a well-behaved adolescent girl from an affluent  family, perceives herself to be overweight and eats barely enough  to survive (fig. 18.23). She is terrified of gaining weight and usu-  ally loses 25% of her original body weight. In addition to eating  only small amounts of low-calorie foods, she may further lose  weight by vomiting, taking laxatives and diuretics, or exercising  intensely. Her eating behavior is often ritualized. She may meticu-  lously arrange her meager meal on her plate or consume only a  few foods. She develops low blood pressure, a slowed or irregular  heartbeat, constipation, and constant chilliness. She stops men-  struating as her body fat level plunges. Like any starving person,  the hair becomes brittle and the skin dries out. To conserve body    FIGURE 18.22 Two types of starvation in the young. (a) This child, suffering from marasmus, did not have adequate nutrition as an infant. (b) This child  suffers from kwashiorkor. Although he may have received adequate nourishment from breast milk early in life, he became malnourished when his diet  switched to a watery, white extract from cassava that looks like milk but has very little protein. The lack of protein in the diet causes edema and the ascites    FIGURE 18.23 Perceiving herself overweight, this young woman is  tying the measuring tape extraordinarily tight around her waist to have a  waist measurement as small as possible.   When the person with anorexia reaches an obviously emaci-  ated state, her parents usually have her hospitalized, where she is  fed intravenously so that she does not starve to death or die sud-  denly of heart failure due to an electrolyte imbalance. She also  receives psychotherapy and nutritional counseling. Despite these  efforts, 15% to 21% of people with anorexia die.   What causes anorexia nervosa is unknown. One hypoth-  esis is that the person is rebelling against approaching woman-  hood. Indeed, her body is astonishingly childlike, and she has  often ceased to menstruate. She typically has low self esteem  and believes that others, particularly her parents, are controlling  her life. Her weight is something that she can control. Genetics  and chemical imbalances in the brain may also elevate the risk  of developing anorexia. Cases of anorexia nervosa are increas-  ing in the elderly, possibly as a result of diminished smell and  taste sensations, as well as difficulties chewing and swallowing.  This eating disorder can be a onetime, short-term experience or a  lifelong obsession.   A person suffering from bulimia (bu-lim’e-ah) is often of normal  weight. She eats whatever she wants, often in huge amounts, but  she then rids her body of the thousands of extra calories by vom-  iting, taking laxatives, or exercising frantically. For an estimated  one in five college students, the majority of them female, “binge-  ing and purging” appears to be a way of coping with stress.   A dentist, who can observe the tooth decay caused by fre-  quent vomiting, may be the first to spot bulimia. The backs of the  hands of a person with bulimia may bear telltale scratches from  efforts to induce vomiting. In addition, the throat is raw and the    esophageal lining ulcerated from the stomach acid forced forward  by vomiting. The binge and purge cycle is hard to break, even with  psychotherapy and nutritional counseling.    59 What is primary malnutrition? Secondary malnutrition?  60 What happens to the body during starvation?  61 How do marasmus and kwashiorkor differ?    Dietary requirements remain generally the same throughout life,  but the ability to acquire nutrients may change. The basal meta-  bolic rate (BMR) changes with age. It rises from birth to about  age five and then declines until adolescence, when it peaks again.  During adulthood, the BMR drops in parallel to decreasing activity  levels and shrinking muscle mass. In women, it may spike during  pregnancy and breastfeeding, when caloric requirements likewise  increase. Table 18.12 shows changes in energy requirements for  adults who are healthy and engage in regular, light exercise.   People of all ages gain weight when energy intake exceeds  energy output, and lose weight when energy output exceeds energy  intake. Age fifty seems to be a key point in energy balance. Before  this age, most adults have a positive energy balance and main-  tain a constant weight, but after fifty their weight may creep up.  However, being aware of a decrease in activity and curbing food  consumption enables many people over the age of fifty to maintain  their weight.   Changing nutrition with age often reflects effects of medical  conditions, many of which are more common among older people,  and social and economic circumstances. Medications can dampen  appetite directly through side effects such as nausea or altered taste  perception or affect a person’s mood in a way that prevents eat-  ing. Poverty may take a greater nutritional toll on older people who  either cannot get out to obtain food or who give whatever is avail-  able to younger people.   Medical conditions that affect the ability to obtain adequate  nutrition include depression, tooth decay and periodontal disease,  diabetes mellitus, lactose intolerance, and alcoholism. These con-  ditions may lead to deficiencies that are not immediately obvious.  Vitamin A deficiency, for example, may take months or years to    become noticeable because the liver stores this fat-soluble vitamin.  Calcium depletion may not produce symptoms, even as the min-  eral is taken from bones. The earliest symptom of malnutrition,  fatigue, may easily be attributed to other conditions or ignored.  Evidence for vitamin D deficiency related to sun avoidance  has a long history. The link between lack of sunlight and develop-  ment of rickets was noted in 1822, and a century later, researchers  realized that sun exposure helps reverse the disease in children.    Carbohydrates are organic compounds primarily used to  supply cellular energy.  1. Carbohydrate sources   c. Cellulose is a polysaccharide that human enzymes  cannot digest, but it provides bulk that facilitates  movement of intestinal contents.   2. Carbohydrate use  a. Carbohydrates are absorbed as monosaccharides.  b. Enzymes in the liver catalyze reactions that convert  fructose and galactose into glucose.  Oxidation releases energy from glucose.  d. Excess glucose is stored as glycogen or combined to  produce fat.  e Some cells, such as neurons, require a continuous  supply of glucose to survive.  f. If glucose is scarce, amino acids may react to produce  glucose.  g. Most carbohydrates supply energy; some are used to  produce sugars (ribose, deoxyribose, lactose).  3. Carbohydrate requirements  a. Humans survive with a wide range of carbohydrate  intakes.  b. Poor nutritional status is usually related to low intake  of nutrients other than carbohydrates.    Lipids are organic compounds that supply energy and are used  to build cell structures. They include fats, phospholipids, and  cholesterol.    1. Lipid sources  a. Triglycerides are obtained from foods of plant and  animal origins.  b. Cholesterol is mostly obtained in foods of animal  origin.  2. Lipid use  a. Before fats can be used as an energy source, they must  be broken down into glycerol and fatty acids.  b. Beta oxidation decomposes fatty acids.  (1) Beta oxidation activates fatty acids and breaks them  down into segments of two carbon atoms each.  (2) Fatty acid segments are converted into acetyl  coenzyme A, which can then be oxidized in the  citric acid cycle.    Other evidence comes from diverse sources, such as women who  wear veils and naval personnel serving three-month tours of duty  on submarines.   d. Liver enzymes can alter the molecular structures of  fatty acids.   e. Linoleic acid and linolenic acid are essential fatty  acids which must be obtained through the diet.   f. The liver regulates cholesterol level by synthesizing or  excreting it.   b. The amounts and types of lipids needed for health are  unknown.   c. Fat intake must be sufficient to support absorption and  transport of fat-soluble vitamins.    Proteins are broken down in digestion. The resulting amino  acids can be used to form new protein molecules such as  enzymes, clotting factors, keratin, elastin, collagen, actin,  myosin, hormones, and antibodies, or can be used as energy  sources. Before amino acids can be used as energy sources,  they must be deaminated, forming the waste urea. During  starvation, tissue proteins may be used as energy sources,  causing the tissues to waste away.   a. Proteins are mainly obtained from meats, dairy  products, cereals, and legumes.   b. Eight amino acids are essential for adults, whereas ten  are essential for growing children.   c. All essential amino acids must be present at the same  time for growth and repair of tissues to take place.   d. Complete proteins contain adequate amounts of all  the essential amino acids needed to maintain the tissues  and promote growth.   e. Incomplete proteins lack adequate amounts of one or  more essential amino acids.   a. In healthy adults, the gain of protein equals the loss of  protein, and a nitrogen balance exists.   a growing child, a pregnant woman, or an athlete in  training usually has a positive nitrogen balance.  3. Protein requirements   a. Proteins and amino acids are needed to supply essential  amino acids and nitrogen for the synthesis of nitrogen-  containing molecules.   b. The consequences of protein deficiencies are  particularly severe among growing children.    Energy is of prime importance to survival and may be obtained  from carbohydrates, fats, or proteins.   When energy losses due to incomplete absorption  and incomplete oxidation are taken into account,   1 gram of carbohydrate or 1 gram of protein yields  about 4 calories, whereas | gram of fat yields about  9 calories.   Factors that influence energy requirements include  basal metabolic rate, muscular activity, body  temperature, and nitrogen balance.   If energy balance is positive, body weight increases;  if energy balance is negative, body weight decreases.   Average weights of persons 25-30 years of age are  desirable for older persons as well.    account.  A BMI between 25 and 30 indicates overweight, and  above 30, obesity.    Appetite is the drive that compels us to eat. Food powers  the activities of life.    Hormones control appetite by affecting the arcuate  nucleus, a part of the hypothalamus.    Vitamins are organic compounds (other than carbohydrates,  lipids, and proteins), that cannot be synthesized by body cells  in adequate amounts and are essential for normal metabolic  processes.   (1) Fat-soluble vitamins are carried in lipids and are  influenced by the same factors that affect lipid  absorption.   (2) They resist the effects of heat; thus, they are not  destroyed by cooking or food processing.   (1) Vitamin A exists in several forms, is synthesized  from carotenes, and is stored in the liver.    (2) Itis found in certain foods and is produced  commercially; it can also be synthesized in the skin.   (3) When needed, vitamin D is converted by the  kidneys to an active form that functions as a  hormone and promotes the intestine’s absorption  of calcium and phosphorus.   (3) It prevents breakdown of polyunsaturated fatty  acids and stabilizes cell membranes.   (1) Vitamin K is in foods and is produced by intestinal  bacteria.   (2) Cooking or processing food destroys some water-  soluble vitamins.  (3) B vitamins make up a group called the vitamin   (a) Thiamine functions as part of coenzymes that  oxidize carbohydrates and synthesize ribose.   (b) Small amounts are stored in the tissues; excess  is excreted in the urine.   (a) Riboflavin functions as part of several  enzymes and coenzymes essential to the  oxidation of glucose and fatty acids.   (b) Its absorption is regulated by an active transport  system; excess is excreted in the urine.   (a) Niacin functions as part of coenzymes  required for the oxidation of glucose and for  the synthesis of proteins and fats.   (b) It can be synthesized from tryptophan; daily  requirement varies with the tryptophan intake.   (a) Pantothenic acid functions as part of  coenzyme A; thus, it is essential for energy-  releasing mechanisms.   (a) Vitamin B, is a group of compounds that  function as coenzymes in metabolic pathways  that synthesize proteins, certain amino acids,  antibodies, and nucleic acids.   (a) Biotin is acoenzyme required for the metabolism  of amino acids and fatty acids, and for nucleic  acid synthesis.    (b) It is stored in metabolically active organs,  including the brain, liver, and kidneys.  (7) Folacin (vitamin B, or folic acid)  (a) Liver enzymes catalyze reactions that convert  folacin to physiologically active folinic acid.  (b) It is acoenzyme needed for the metabolism of  certain amino acids, DNA synthesis, and the  production of normal red blood cells.  (8) Cyanocobalamin (vitamin B,,)    (b) Its absorption is regulated by the secretion of  intrinsic factor from the gastric glands.   (c) It functions as part of coenzymes needed for  nucleic acid synthesis and for the metabolism  of carbohydrates and fats.   (d) Itis important to erythrocyte production and  myelin formation in the central nervous system.   (2) Itis required for collagen production, the metabolism  of certain amino acids, and iron absorption.   (3) Itis not stored in large amounts; excess is excreted  in the urine.    a. Minerals account for about 4% of body weight.  b. Minerals are usually incorporated into organic    molecules, although some are in inorganic compounds  or are free ions.   They compose structural materials, function in  enzymes, and play vital roles in various metabolic  processes.    (1) Calcium is essential for forming bones and teeth,  neurotransmitter release, contracting muscle fibers,  the cardiac action potential, clotting blood, and  activating various enzymes.   (2) Existing calcium concentration, vitamin D, protein  intake, and motility of the digestive tract affect  calcium absorption.    (1) Phosphorus is incorporated into the salts of bones  and teeth.   (2) It participates in nearly all metabolic reactions  as a constituent of nucleic acids, proteins, and  some vitamins.   (3) It also is in the phospholipids of cell membranes,  in ATP, and in phosphates of body fluids.   (2) It maintains osmotic pressure, regulates pH, and  plays a role in impulse conduction in neurons.   (1) Sulfur is incorporated into two of the twenty  amino acids.   (1) Most sodium is in extracellular fluids or is bound  to the inorganic salts of bone.   (2) The kidneys, under the influence of aldosterone,  regulate the blood concentration of sodium.   (4) Itis essential for impulse conduction in neurons  and moving substances through cell membranes.   (2) It acts with sodium to help maintain osmotic  pressure, regulate pH, and maintain electrolyte  balance.   (3) Chlorine is essential for hydrochloric acid  formation and for carbon dioxide transport by  red blood cells.   (1) Magnesium is abundant in the bones as phosphates  and carbonates.   (2) It functions in ATP production and in the breakdown  of ATP to ADP.   (3) A reserve supply of magnesium is stored in the  bones; excesses are excreted in the urine.   (1) Iron is part of hemoglobin in red blood cells and  myoglobin in muscles.   (2) A reserve supply of iron is stored in the liver,  spleen, and bone marrow.   (3) Itis required to catalyze vitamin A formation; it  is also incorporated into various enzymes and the  cytochrome molecules.   (1) Most manganese is concentrated in the liver,  kidneys, and pancreas.   (2) Itis necessary for normal growth and development  of skeletal structures and other connective tissues;  it is essential for the synthesis of fatty acids,  cholesterol, and urea.   (1) Most copper is concentrated in the liver, heart,  and brain.   (2) Itis required for hemoglobin synthesis, bone  development, melanin production, and myelin  formation.   (2) Itis an essential part of cyanocobalamin and is  required for the synthesis of several enzymes.    f. Zinc  (1) Zinc is most concentrated in the liver, kidneys,  and brain.  (2) Itis acomponent of several enzymes that take part  in digestion, respiration, and metabolism.  (3) Itis necessary for normal wound healing.  g. Fluorine  (1) The teeth concentrate fluorine.  (2) Itis incorporated into enamel and prevents  dental caries.  h. Selenium  (1) The liver and kidneys store selenium.  (2) Itis acomponent of certain enzymes.  i. Chromium  (1) Chromium is widely distributed throughout  the body.  (2) Itregulates glucose use.    1. An adequate diet provides sufficient energy and  essential nutrients to support optimal growth, as well as  maintenance and repair, of tissues.   2. Individual needs vary so greatly that it is not possible to  design a diet adequate for everyone.   3. Devices to help consumers make healthy food choices  include Recommended Daily Allowances, Recommended  Dietary Allowances, food group plans such as “MyPlate,”  and food labels.    Identify dietary sources of carbohydrates. (p. 695)  Summarize the importance of cellulose in the diet. (p. 695)  Explain what happens to excess glucose in the body. (p. 695)  Explain why a temporary drop in blood glucose concentration  may impair nervous system functioning. (pp. 695-696)   Define deamination, and explain its importance. (p. 698)  Identify dietary sources of proteins. (p. 699)   Explain why all of the essential amino acids must be present  for growth. (p. 699)   a. Poor nutrition is due to lack of foods or failure to wisely  use available foods.   c. Secondary malnutrition is due to an individual  characteristic that makes a normal diet inadequate.   a. A person can survive fifty to seventy days without food.   b. A starving body digests itself, starting with  carbohydrates, then fats, then proteins.   c. Symptoms include low blood pressure, slow pulse,  chills, dry skin, hair loss, and poor immunity. Finally,  vital organs cease to function.   d. Marasmus is undernutrition involving a lack of  calories and protein.   Anorexia nervosa is a self-starvation eating disorder.  g. Bulimia is an eating disorder characterized by bingeing  and purging.    1. Basal metabolic rate rises in early childhood, declines,  then peaks again in adolescence, with decreasing activity  during adulthood.   2. Weight gain, at any age, occurs when energy in exceeds  energy out, and weight loss occurs when energy out  exceeds energy in.   3. Changing nutrition with age reflects medical conditions  and social and economic circumstances.    is when the amount of nitrogen taken  in is equal to the amount excreted. (p. 699)    Define calorie. (p. 701)  Explain how the caloric values of foods are determined.  (p. 701)  Define basal metabolic rate. (p. 701)  List some of the factors that affect the BMR. (p. 701)   exists when caloric intake in the form of  foods equals caloric output from basal metabolic rate and  muscular activities. (p. 702)  Distinguish among underweight, desirable weight,  overweight, and obesity. (p. 702)   Identify the part of the brain where hormones act, controlling  appetite. (p. 704)    if the vitamin is fat-soluble or water-soluble. Functions may  be used more than once, and more than one function may  be applied to a vitamin. (pp. 706-711)    (1) vitamin A A. part of coenzyme A in  (2) vitamin B, (thiamine) oxidation of carbohydrates  (3) vitamin B, (riboflavin) B. coenzyme in ribose synthesis  (4) vitamin B, (niacin) C. necessary for synthesis of  (5) vitamin B, visual pigments  (pantothenic acid) D. required for synthesis of  (6) vitamin B, prothrombin  (7) vitamin B, (biotin) E. required to produce collagen  (8) vitamin B, (folacin) F. required to synthesize  (9) vitamin B,, nucleic acids  (cyanocobalamin) G. promotes normal red  (10) vitamin C blood cell production  (ascorbic acid) H. plays a role in myelin  (11) vitamin D synthesis  (12) vitamin E |. antioxidant, helps stabilize  (13) vitamin K cell membranes    Match the minerals/elements with their functions, and  indicate whether each is a major mineral or a trace element  required for nutrition. Functions may be used more than  once, and more than one function may be applied to a  mineral or trace element. (pp. 713-717)    (1) calcium A. essential for the use of glucose  (2) chlorine B. component of certain enzymes  (3) chromium C. component of tooth enamel  (4) cobalt D. component of teeth and bones  (5) copper E. helps maintain intracellular osmotic  (6) fluorine pressure  (7) iodine F. essential part of certain amino acids  (8) iron G. helps maintain extracellular fluid  (9) magnesium osmotic pressure  (10) manganese H. necessary for normal wound healing  (11) phosphorus |. component of cyanocobalamin  (12) potassium J. essential for synthesis of thyroid  (13) selenium hormones  (14) sodium K. required in metabolic reactions  (15) sulfur associated with ATP production  (16) zinc L. component of hemoglobin   Contrast primary and secondary malnutrition. (p. 720)  Discuss bodily changes during starvation. (p. 722)   Factors that may lead to inadequate nutrition later in life  include . (p. 723)   Name some medical conditions that affect the ability to  obtain adequate nutrition as a person ages. (pp. 723-724)    Outcomes 4.4, 9.3, 18.1, 18.2, 18.3, 18.4, 18.8 Outcomes 18.1, 18.2, 18.3, 18.4, 18.5, 18.6,    1. Which of the diets described in the following chart would be 18.7, 18.8, 18.9  most appropriate for an athlete training fora triathlon (biking, 5. How do you think the nutritional requirements of a healthy  swimming, running event)? What is a problem with all of these twelve-year-old boy, a twenty-four-year-old pregnant woman,  diets for such a person? and a healthy sixty-year-old man differ?  Diet Total Calories/Day % Fat % Carbohydrate —_% Protein  1,450 10-20 70 17 Outcomes 18.1, 18.2, 18.3, 18.6, 18.7  Ul 1,450 25 60 15 6. Examine the label information on the packages of a variety  TH 1,400 60 10 30 of breakfast cereals. Which types of cereals provide the best  sources of carbohydrates, lipids, proteins, vitamins, and  . 5 Ai . : naar .  Outcomes 4.4, 18.1, 18.2, 18.3, 18.4, 18.6 minerals? Which major nutrients are lacking in these cereals?    2. Ayoung man takes several vitamin supplements each day,  claiming that they give him energy. Is he correct? Why or why not? Outcome 18.3    Outcomes 13.8, 18.1, 18.2, 18.3, 18.4, 18.5 eee ere ee eo ea  3. Why does the blood sugar concentration of a person whose diet    4. Using nutrient tables, calculate the number of grams of  carbohydrate, lipid, and protein that you eat in a typical day, and  the total calories in these foods. Suggest ways to improve your diet.    After you have studied this chapter, you should be able to:    Explain why respiration is necessary for cellular survival.  (p. 731)  Organs of the Respiratory System    Name and describe the locations of the organs of the  respiratory system. (pp. 732-741)    Describe the functions of each organ of the respiratory  system. (pp. 732-741)  Breathing Mechanism    Describe each of the respiratory air volumes and  capacities. (pp. 747-748)    Show how alveolar ventilation rate is calculated. (p. 749)  List several nonrespiratory air movements, and explain  how each occurs. (p. 749)    Locate the respiratory areas, and explain control of  normal breathing. (pp. 750-751)    Discuss how various factors affect breathing.  (pp. 752-753)  Alveolar Gas Exchanges    Describe the structure and function of the respiratory  membrane. (pp. 754-755)    Explain the importance of partial pressure in diffusion of  gases. (pp. 755-756)  Gas Transport    Explain how the blood transports oxygen and carbon  dioxide. (pp. 758-760)    Describe gas exchange in the pulmonary and systemic  circuits. (pp. 758-760)  Life-Span Changes    Describe the effects of aging on the respiratory  system. (p. 762)    Falsely colored scanning electron micrograph of the trachea lining  consisting of mucous-secreting goblet cells (brown) amid ciliated epithelium  (red) (3,700x).    The respiratory system uses skeletal muscles, which are under  voluntary control, but unless you are blowing up party balloons  or playing a wind instrument, you may not be aware of the air  moving in and out of your lungs. Parts of the brainstem control  breathing automatically, constantly bringing in oxygen to sup-  port aerobic production of ATP and constantly eliminating just  the right amount of carbon dioxide to maintain homeostasis.    The respiratory system consists of passages that filter incoming  air and transport it into the body, into the lungs, and to the many  microscopic air sacs where gases are exchanged. The entire pro-  cess of exchanging gases between the atmosphere and body cells  is called respiration (res”pi-ra’shun). It consists of several events:    * movement of air in and out of the lungs, commonly called  breathing, or ventilation   ¢ exchange of gases between the air in the lungs and the blood,  called external respiration   * transport of gases by the blood between the lungs and  body cells   ¢ exchange of gases between the blood and the body cells,  also called internal respiration   * oxygen (O,) use and production of carbon dioxide (CO,) by  body cells as part of the process of cellular respiration    Respiration occurs on a macroscopic level—it is a function  of an organ system. However, the reason that body cells must  exchange gases—take up oxygen and release carbon dioxide—is  apparent at the cellular and molecular levels.    Cellular respiration enables cells to harness energy held in  the chemical bonds of nutrient molecules. In aerobic reactions,  cells liberate energy from these molecules by removing elec-  trons and channeling them through a series of carriers called the  electron transport chain, yielding ATP. At the end of this chain,  electrons bind oxygen atoms and hydrogen ions to produce water  molecules. Without oxygen, these reactions cease.   The aerobic reactions also produce CO,. CO, is a metabolic  waste that combines with water to form carbonic acid, helping to  maintain blood pH. Too much CO,, however, lowers blood pH,  compromising homeostasis. The respiratory system both provides  oxygen for aerobic reactions and eliminates CO, at the appropriate  rate to maintain the pH of the internal environment.    The organs of the respiratory system can be divided into two  groups, or tracts. The upper respiratory tract includes the nose,  nasal cavity, sinuses, and pharynx. The lower respiratory tract  includes the larynx, trachea, bronchial tree, and lungs (fig. 19.1).    The teachers welcome an education session from the local  hospital's respiratory therapist. Several children in the  elementary school have asthma, and the teachers have  requested this visit so that they can better understand the  condition. After the respiratory therapist’s presentation, the  teachers feel more confident that they can help the students,  and also explain to their classmates what is happening.   Respiratory therapists assess patients who are  experiencing breathing problems and treat them, under  supervision of a physician. They work in a variety of  situations. A respiratory therapist might help a patient  breathe on his or her own following anesthesia, instruct a  patient newly diagnosed with emphysema on how to use  supplemental oxygen, check on how patients on a hospital  floor are breathing, or teach parents of a young child with  cystic fibrosis how to apply pressure to the child’s chest to  shake free the thick mucus that builds up in the child’s lungs.  The overall goal is to help patients on breathing assistance  be as independent as possible.   A respiratory therapist is an expert in how the heart and  lungs function. Educational requirements include an associates  degree and certification, plus continuing education.    The respiratory structures that air passes through face the outside  environment, and except for the parts where exchange of gases    The nose is covered with skin and is supported internally by mus-  cle, bone, and cartilage. Its two nostrils (external nares) provide  openings through which air can enter and leave the nasal cavity.  Many internal hairs in these openings prevent entry of large par-    The nasal cavity, a hollow space behind the nose, is divided  medially into right and left portions by the nasal septum. This  cavity is separated from the cranial cavity by the cribriform plate    of the ethmoid bone and from the oral cavity by the hard palate.    The nasal septum may bend during birth or shortly before ado-  lescence. Such a deviated septum may obstruct the nasal cavity,    As figure 19.2 shows, nasal conchae (turbinate bones) curl  out from the lateral walls of the nasal cavity on each side, form-  ing passageways called the superior, middle, and inferior meatuses  (see chapter 7, pp. 220 and 222). The nasal chonchae support the  mucous membrane that lines the nasal cavity and help increase its  surface area.   The upper posterior portion of the nasal cavity, below the  cribriform plate, is slitlike, and its lining contains the olfactory  receptors that provide the sense of smell. The remainder of the  cavity conducts air to and from the nasopharynx.   The mucous membrane lining the nasal cavity has pseu-  dostratified ciliated epithelium rich in mucous-secreting goblet  cells (see chapter 5, pp. 153-154). It also includes an extensive  network of blood vessels and normally appears pinkish. As air  passes over the membrane, heat radiates from the blood and warms  the air, adjusting its temperature to that of the body. At the same  time, evaporation of water from the mucous lining moistens the    Nostril ,  Nasopharynx  Hard palate ’ pa | Pharyngeal tonsil  a On Qe . “A Opening of  Uvula } I auditory tube  Y,  Tongue i/l Palatine tonsil  i - Oropharynx  4 Lingual tonsil  = 3 Epiglottis  Hyoid bone Laryngopharynx  Larynx  Esophagus  Trachea i,    air. The sticky mucus secreted by the mucous membrane entraps  dust and other small particles entering with the air.   As the cilia of the epithelial cells move, they push a thin layer  of mucus toward the pharynx (fig. 19.3), where the mucus and  any entrapped particles are swallowed. In the stomach, gastric  juice destroys microorganisms in the mucus, including pathogens.  In this way, the mucous membrane keeps particles from reaching  the lower air passages, preventing respiratory infections. Clinical  Application 19.1 discusses how cigarette smoking impairs the func-  tion of the respiratory system, beginning with the mucus and cilia.    3 > What is the function of the mucous membrane that lines the  nasal cavity?    4 What is the function of the cilia on the cells that line the nasal cavity?    Recall from chapter 7 (pp. 218, 220, and 221) that the sinuses  (paranasal sinuses) are air-filled spaces in the frontal, sphenoid,  ethmoid, and maxillary bones of the skull (fig. 19.4). The sinuses  reduce the weight of the skull. They also serve as resonant cham-  bers that affect the quality of the voice. The sinuses open into the  nasal cavity and are lined with mucous membranes that are contin-  uous with the lining of the nasal cavity, allowing mucus secretions  to drain from the sinuses into the nasal cavity. Membranes that are  inflamed and swollen because of nasal infections or allergic reac-  tions (sinusitis) may block this drainage, increasing pressure in a  sinus and causing headache.   The sinuses reduce the weight of the skull. They also serve as  resonant chambers that affect the quality of the voice.    It is possible to illuminate a person’s frontal sinus in a darkened  room by holding a small flashlight just beneath the eyebrow.    Similarly, holding the flashlight in the mouth illuminates the  maxillary sinuses.    The pharynx (far’inks) is posterior to the nasal cavity, oral cavity,  and larynx. It is a passageway for food moving from the oral cav-  ity to the esophagus and for air passing between the nasal cavity  and the larynx. The pharynx also aids in producing the sounds of  speech. It can be divided into the nasopharynx, the oropharynx,  and the laryngopharynx (see fig. 19.2):    1. The nasopharynx (na”zo-far’inks) is superior to the soft pal-  ate. It communicates with the nasal cavity and provides a pas-  sageway for air during breathing. The auditory tubes, which  connect the pharynx with the middle ears, open through the  walls of the nasopharynx (see chapter 12, p. 459).   2. The oropharynx (0”ro-far’inks) is posterior to the mouth and  soft palate and inferior to the nasopharynx, projecting down-  ward to the upper border of the epiglottis. It is a passageway  both for food moving downward from the mouth and for air  moving to and from the nasal cavity.   3. The laryngopharynx (lah-ring” go-far’inks) is just inferior  to the oropharynx. It extends from the upper border of the  epiglottis downward to the lower border of the cricoid car-  tilage of the larynx. The laryngopharynx is continuous with  both the esophagus and the larynx.    Larynx  The larynx (lar’inks) is an enlargement in the airway superior to  the trachea (see reference plates 9 and 21, pp. 46 and 53). It isa  passageway for air moving in and out of the trachea and prevents  foreign objects from entering the trachea. The larynx also houses  the vocal cords.   The larynx is composed of a framework of muscles and carti-  lages bound by elastic tissue. The largest of the cartilages are the thy-  roid, cricoid, and epiglottic cartilages (fig. 19.5). These structures are    FIGURE 19.3 fAP|R) Mucus movement in the respiratory tract. (a) Cilia move mucus and trapped particles from the nasal cavity to the pharynx.    single. The other laryngeal cartilages—the arytenoid, corniculate,  and cuneiform cartilages—are paired.   The thyroid cartilage was named for the thyroid gland that  covers its lower area. This cartilage is the shieldlike structure that  protrudes in the front of the neck and is also called the “Adam’s  apple.” The protrusion typically is more prominent in males than  in females because of an effect of male sex hormones on the devel-  opment of the larynx.   The cricoid cartilage lies inferior to the thyroid cartilage. It  marks the lowermost portion of the larynx.   The epiglottic cartilage, the only one of the laryngeal carti-  lages that is elastic, not hyaline, cartilage, is attached to the upper  border of the thyroid cartilage and is the central part of a flap-  like structure called the epiglottis. The epiglottis usually stands  upright and allows air to enter the larynx. During swallowing,  muscular contractions raise the larynx, and the base of the tongue  presses the epiglottis downward, partially covering the opening  into the larynx, helping to prevent foods and liquids from entering  the air passages.   Posteriorly on the larynx, the pyramid-shaped arytenoid  cartilages are superior to and on either side of the cricoid carti-  lage. Attached to the tips of the arytenoid cartilages are the tiny,  conelike corniculate cartilages. These cartilages are attachments  for muscles that help regulate tension on the vocal cords during  speech and aid in closing the larynx during swallowing.   The cuneiform cartilages are small, cylindrical structures in the  mucous membrane between the epiglottic and the arytenoid carti-  lages. They stiffen the soft tissues in this region.    FIGURE 19.4 Radiograph of a skull (a) anterior view and (b) lateral  view, showing air-filled sinuses (arrows) within the bones. Sinuses include:  maxillary sinuses in (a); sohenoidal, ethmoidal, and frontal sinuses in (b).    (b)  FIGURE 19.5 fAP|R} Larynx. (a) Anterior and (b) posterior views of    Damage to the respiratory system from cigarette smoking is slow,  progressive, and potentially deadly. A healthy respiratory system  is continuously cleansed. The mucus produced by the respira-  tory tubes traps dirt and pathogens, which cilia sweep toward the  mouth, where they can be eliminated. Smoking greatly impairs  this action. With the first inhalation of smoke, the beating of cilia  slows. With time, the cilia become paralyzed and, eventually,  degenerate, leading to “smoker's cough” when the cilia no longer  effectively remove mucus, which must be coughed up. Coughing  is usually worse in the morning because mucus has accumulated  during sleep.   Smokers produce excess mucus and it accumulates, clogging  the air passageways. Pathogens normally removed now have easier  access to the respiratory surfaces, and the resulting lung congestion  favors their growth. This is why smokers have respiratory infections  more often than nonsmokers. A lethal chain reaction begins. Cough  leads to chronic bronchitis, and increased mucus production and  bronchial lining thickening compromises breathing, especially expi-  ration (exhalation). As expiration becomes more difficult, air gets  trapped in the alveoli (microscopic air sacs in the lungs). Alveolar  walls may be destroyed. This is the beginning of smoking-induced  emphysema, which is fifteen times more common among individu-    lung on the right, taking up much of the lung space.    Inside the larynx, two pairs of horizontal folds composed of  muscle tissue and connective tissue with a covering of mucous  membrane extend inward from the lateral walls. The upper folds  (vestibular folds) are called false vocal cords because they do not    als who smoke a pack of cigarettes a day than among nonsmokers.   Cellular changes induced by smoking set the stage for the  development of lung cancer. First, cells in the outer border of the  bronchial lining begin to divide more rapidly than usual. Eventually,  these cells displace the ciliated cells. Their nuclei begin to resemble  those of cancerous cells—large and distorted with abnormal num-  bers of chromosomes. Up to this point, the damage can be repaired  if smoking ceases. If smoking continues, these cells may eventually  break through the basement membrane and begin dividing within  the lung tissue, forming a tumor with the potential of spreading  throughout lung tissue (figs. 19A and 19B) and beyond, such as to  the brain or bones. While more than 80% of lung cancer cases are  due to cigarette smoking, only 20% of smokers develop the cancer.  Genes may influence which smokers develop cancer.   Smoking endangers more than the smoker. Exposure to  environmental tobacco smoke (ETS)—also called secondhand  smoke—may be as dangerous as smoking. ETS has two sources:  sidestream smoke comes from lit cigarettes, cigars, or pipes, and  mainstream smoke is exhaled by smokers. The smoke contains  more than 4,000 chemical compounds, including irritants, carcino-  gens, mutagens, and many toxins.    FIGURE 19A The lung on the left is normal. A cancerous tumor has invaded the a tiny tumor (orange) growing in an alveolus,   The lower folds of the larynx are the true vocal cords. They  have elastic fibers and are responsible for vocal sounds, which are    created when air is forced between these folds, vibrating them. This  action generates sound waves, which are formed into words by  changing the shapes of the pharynx and oral cavity and by using the  tongue and lips. Figure 19.6 shows both pairs of cords.   Changing tension on the vocal cords, by contracting or relax-  ing laryngeal muscles, controls pitch (musical tone) of the voice.  Increasing the tension produces a higher pitch, and decreasing the  tension creates a lower pitch.   The intensity (loudness) of a vocal sound depends upon the  force of the air passing over the vocal cords. Stronger blasts of air  result in greater vibration of the vocal cords and louder sound.   The true vocal cords and the opening between them form the  glottis (glot’is). During normal breathing the vocal cords remain  relaxed, and the glottis is an open triangular slit. When a person  swallows food or liquid, muscles in the false vocal folds close the    (b)  FIGURE 19.6 fAP|R) Larynx. (a) Frontal section and (b) sagittal    glottis. Along with the epiglottis pressing downward to partially  cover the glottis, this action helps prevent food or liquid from  entering the trachea (fig. 19.7). The mucous membrane that lines  the larynx continues to filter incoming air by entrapping particles  as waving cilia move them toward the pharynx by ciliary action.    >  he i PRACTICE  7 What part of the respiratory tract is shared with the alimentary  canal?  Describe the structure of the larynx.  How do the vocal cords produce sounds?    10 What is the function of the epiglottis? Of the glottis?    of tongue  False vocal  cord  True vocal  Glottis cord  Cuneiform  Corniculate cartilage  cartilage  (a)    FIGURE 19.7 The vocal cords as viewed from above with the  glottis (a) closed and (b) open. (c) Photograph of the glottis (open)  and vocal cords.    The trachea (windpipe) is a flexible cylindrical tube about 2.5  centimeters in diameter and 12.5 centimeters in length. It extends  downward anterior to the esophagus and into the thoracic cavity,  where it splits into right and left main bronchi (fig. 19.8 and ref-  erence plate 9, p. 46).   The inner wall of the trachea is lined with a ciliated mucous  membrane that has many goblet cells. This membrane continues  to clean the incoming air and to move entrapped particles upward  into the pharynx where the mucus can be swallowed.   Within the tracheal wall are about twenty C-shaped pieces  of hyaline cartilage, one above the other. The open ends of these  incomplete rings are directed posteriorly, and the gaps between  their ends are filled with smooth muscle and connective tissues  (figs. 19.9 and 19.10). These cartilaginous rings prevent the tra-  chea from collapsing and blocking the airway. At the same time,  the soft tissues that complete the rings in the back allow the nearby  esophagus to expand as food moves through it on the way to  the stomach.   A blocked trachea can cause asphyxiation in minutes. If swol-  len tissues, excess secretions, or a foreign object obstruct the tra-  chea, making a temporary, external opening in the trachea, so that  a tube can be inserted to bypass the obstruction, can be lifesaving.  This procedure, shown in figure 19.11, is called a tracheostomy.    The bronchial tree (brong’ke-al tré) consists of branched air-  ways leading from the trachea to the microscopic air sacs in the  lungs. Its branches begin with the right and left main (primary)  bronchi, which arise from the trachea at the level of the fifth tho-  racic vertebrae. A ridge of cartilage called the carina separates  the openings of the main bronchi (see fig. 19.8). Each bronchus,  accompanied by large blood vessels, enters its respective lung.    FIGURE 19.9 Cross section of the trachea. Note the C-shaped ring of  hyaline cartilage in the wall. The cartilage is absent in the posterior part of  the tracheal wall.    FIGURE 19.10 (AP|R) Light micrograph of a section of the tracheal  wall (100x).    FIGURE 19.11 A tracheostomy may be performed to allow insertion  of a tube to bypass an obstruction.    Each main bronchus divides into lobar, or secondary, bronchi  (two on the left and three on the right) a short distance from its  origin. The secondary bronchi branch repeatedly. The airways    appear as an upside-down tree when stripped of their associated  blood vessels and tissues (figs. 19.12 and 19.13). The successive  divisions of these branches from the trachea to the microscopic air  sacs are as follows:    . Right and left main (primary) bronchi branch directly off  the trachea.   . Three lobar (secondary) bronchi branch from the right  main bronchus, and two branch from the left.   . Segmental (tertiary) bronchi supply portions of the lungs  called bronchopulmonary segments. In most individuals  ten such segments are in the right lung and eight are in the  left lung.   . Intralobular bronchioles are small branches of the segmen-  tal bronchi that enter the basic units of the lung—the Jobules.   . Terminal bronchioles branch from an intralobular bronchi-  ole. Fifty to eighty terminal bronchioles occupy a lobule of  the lung.   . Two or more respiratory bronchioles branch from each  terminal bronchiole. These structures, which are short and  about 0.5 millimeter in diameter, are called “respiratory”  because a few air sacs bud from their sides, enabling them  to take part in gas exchange.    FIGURE 19.12 The bronchial tree consists of the passageways that  connect the trachea and the alveoli. The alveolar ducts and alveoli  are enlarged to show their locations.   8. Alveolar sacs are thin-walled, closely packed outpouchings  of the alveolar ducts (fig. 19.14).   9. Alveoli (al-ve’o-li) are thin-walled, microscopic air sacs  that open to an alveolar sac. Air can diffuse freely from the  alveolar ducts, through the alveolar sacs, and into the alveoli.  The alveoli are the site of gas exchange between the inhaled  air and the bloodstream (fig. 19.15).    Dust particles, asbestos fibers, and other pollutants travel at  speeds of 200 centimeters per second in the trachea but slow to  1 centimeter per second when deep in the lungs. Gravity deposits  such particles, particularly at branchpoints in the respiratory tree.  It is a little like traffic backing up at an exit from a highway.    In severe cases of the inherited illness cystic fibrosis, airways  become clogged with thick, sticky mucus, which attracts bac-  teria. As damaged white blood cells accumulate at the infec-  tion site, their DNA may leak out and further clog the area.  A treatment that moderately eases breathing is deoxyribo-  nuclease (DNase), an enzyme that degrades accumulating    © Why is the pulmonary arteriole  colored blue in this figure?   The structure of a main bronchus is similar to that of the trachea,  but the C-shaped cartilaginous rings are replaced with cartilagi-  nous plates where the main bronchus branches. These plates are  irregularly shaped and completely surround the tube. However,  as the branching tubes become thinner, the amount of cartilage  decreases. It finally disappears in the bronchioles, which have  diameters of about | millimeter. Also as the tubes thin, layers of  surrounding smooth muscle just beneath the mucosa become more  prominent. This muscular layer persists in the walls to the ends of  the respiratory bronchioles, and only a few muscle fibers are in the  walls of the alveolar ducts.   Elastic fibers are scattered among the smooth muscle cells  and are abundant in the connective tissue that surrounds the respi-  ratory tubes. These fibers play an important role in breathing, as is  explained later in this chapter (p. 746).   As the tubes become smaller in diameter, the type of cells  that line them changes. The lining of the larger tubes consists  of pseudostratified, ciliated columnar epithelium and mucus-  secreting goblet cells. However, along the way, the number of  goblet cells and the height of the other epithelial cells decline, and  cilia become scarcer. In the finer tubes, beginning with the respira-  tory bronchioles, the lining is cuboidal epithelium; in the alveoli,  it is simple squamous epithelium closely associated with a dense  network of capillaries. The mucous lining gradually thins, until  none appears in the alveoli.    A flexible optical instrument called a fiberoptic bronchoscope is  used to examine the trachea and bronchial tree. This procedure    (bronchoscopy) is used in diagnosing tumors or other pulmo-  nary diseases and to locate and remove aspirated foreign bod-  ies in the air passages.   The branches of the bronchial tree are air passages, whose mucous  membranes continue to filter incoming air and distribute it to the  alveoli in all parts of the lungs. The alveoli, in turn, provide a large  surface area of thin epithelial cells through which gas exchanges    can occur (fig. 19.16). The 300 million alveoli in two human lungs  have a combined surface area of 70-80 square meters—nearly half  the area of a tennis court.   During gas exchange, oxygen diffuses through the alveolar  walls and capillary walls to enter the blood. Carbon dioxide dif-  fuses from the blood through these walls and enters the alveoli  (figs. 19.17 and 19.18).    FIGURE 19.17 fAP|R) Oxygen (O,,) diffuses from the air in the  alveolus into the capillary, while carbon dioxide (CO, diffuses from blood  in the capillary into the alveolus.    FIGURE 19.18 Falsely colored scanning electron micrograph of casts  of alveoli and associated capillary networks. These casts were prepared  by filling the alveoli and blood vessels with resin and later removing the  soft tissues by digestion, leaving only the resin casts (420x). Tissues and  Organs: A Text-Atlas of Scanning Electron Microscopy, by Richard G.  Kessel and Randy Kardon. © 1979 W. H. Freeman and Company.    Several techniques enable a person who has stopped breathing  to survive. In artificial respiration, a person blows into the mouth  of a person who has stopped breathing. The oxygen in the res-  cuer’s exhaled breath can keep the victim alive.   In extracorporeal membrane oxygenation, blood is pumped  out of the body and across a gas-permeable membrane that adds  oxygen and removes CO,, simulating lung function. Such a device  can keep a person alive until he or she recovers from other prob-  lems, but is too costly and cumbersome to maintain life indefinitely.   A lung assist device, called an intravascular oxygenator,  consists of hundreds of tiny porous hair-thin fibers surgically  implanted in the inferior vena cava. Here, deoxygenated blood  returning to the heart receives oxygen and is rid of CO,—but  only at about 30% the capacity of a healthy respiratory system.    11. What is the function of the cartilaginous rings in the tracheal wall?  12 How do the right and left bronchi differ in structure?  13 List the branches of the bronchial tree.    14 Describe structural changes in the respiratory tubes as their  diameters decrease.    The lungs are soft, spongy, cone-shaped organs in the thoracic  cavity. The right and left lungs are separated medially by the heart    and the mediastinum, and they are enclosed by the diaphragm and  the thoracic cage (see fig. 1.10 on p. 19, fig. 19.19, and reference  plates 16, 17, and 21 on pp. 50, 51, and 53).   Each lung occupies most of the thoracic space on its side and  is suspended in the cavity by a bronchus and some large blood ves-  sels. These tubular structures enter the lung on its medial surface  through a region called the hilum. A layer of serous membrane,  the visceral pleura, is firmly attached to the surface of each lung,  and this membrane folds back at the hilum to become the parietal  pleura. The parietal pleura, in turn, forms part of the mediastinum  and lines the inner wall of the thoracic cavity (fig. 19.20).   No significant space exists between the visceral and parietal  pleurae, because they are essentially in contact with each other.  The potential (possible) space between them, called the pleural  cavity, contains only a thin film of serous fluid that lubricates the  adjacent pleural surfaces, reducing friction as they move against  one another during breathing. This fluid also helps hold the pleural  membranes together.   The right lung is larger than the left lung. Fissures divide the  right lung into three parts, the superior, middle, and inferior lobes.  The left lung is divided into two parts, a superior lobe and an infe-  rior lobe.   A lobar bronchus of the bronchial tree supplies each lobe. A  lobe also has connections to blood and lymphatic vessels and is  enclosed by connective tissues. Connective tissue further subdi-  vides a lobe into lobules, each of which contains terminal bron-  chioles together with their alveolar ducts, alveolar sacs, alveoli,  nerves, and associated blood and lymphatic vessels.   Table 19.1 summarizes the characteristics of the major parts  of the respiratory system. Clinical Application 19.2 considers sub-  stances that irritate the lungs.    16 Where are the lungs located?  17 What is the function of the serous fluid in the pleural cavity?    18 How does the structure of the right lung differ from that of the  left lung?    Breathing, also called ventilation, is the movement of air from  outside the body into the bronchial tree and alveoli, followed by a  reversal of this air movement. The actions responsible for these air  movements are termed inspiration (in’spi-ra’shun), or inhalation,  and expiration (ek”spi-ra’shun), or exhalation. One inspiration  plus the following expiration is called a respiratory cycle.    Atmospheric pressure, the pressure of the air around us, is the force  that moves air into the lungs. At sea level, this pressure is sufficient  to support a column of mercury about 760 millimeters high in a  tube. Therefore, normal air pressure equals 760 millimeters (mm)  of mercury (Hg). (Units in common usage include: 760 mm Hg =  760 Torr = | atmosphere.)    FIGURE 19.19 (AP|R) Location of the lungs in the thoracic cavity.    FIGURE 19.20 The potential spaces between the pleural membranes, called the left and right pleural cavities, are shown here as actual spaces.    The lungs are sensitive to inhaled particles. Such exposures can  cause a variety of symptoms, both acute and chronic, that range  in severity from a persistent cough to cancer.    Asbestos, a naturally occurring mineral, was once widely used in  buildings and in various products because it resists burning and  chemical damage. Asbestos easily crumbles into fibers, which,  when airborne, can enter human respiratory passages. Asbestos-  related problems include asbestosis (shortness of breath resulting  from scars in the lungs), lung cancer, and mesothelioma (a cancer  of the pleural membrane).   Asbestos fibers longer than 5 micrometers (0.0002 inch)  and thinner than 2 micrometers (0.00008 inch) can cause illness  when inhaled. Because asbestos causes illness only if the fibers  are airborne, in some situations it is safer to encapsulate asbestos  in a building and leave it in place than to remove it. The risk of  becoming ill rises with duration of exposure to asbestos.   Beryllium is an element used in fluorescent powders, metal alloys,  and in the nuclear power industry. A small percentage of workers  exposed to beryllium dust or vapor develop an immune response  that damages the lungs. Symptoms include cough, shortness of  breath, fatigue, loss of appetite, fevers and night sweats, and  weight loss. Radiographs show granuloma scars in the lungs, and  pulmonary function tests and listening to breath sounds with a  stethoscope reveal impaired breathing.   Symptoms of berylliosis typically begin about a decade  after the first exposure. A blood test that detects antibodies to  beryllium distinguishes the condition from other lung ailments.  Workers who do not have symptoms but know that they were  exposed to beryllium can have periodic blood tests and chest  radiographs to detect the condition early. The steroid drug pred-  nisone is used to control symptoms.    Repeatedly inhaling dust of organic origin can cause a lung irri-  tation called extrinsic allergic alveolitis. An acute form of this  reaction impairs breathing and causes a fever a few hours after  encountering dust. In the chronic form, lung changes occur gradu-  ally over several years. The condition is associated with several  occupations and has a variety of colorful names, including bathtub  refinisher’s lung, maple bark stripper disease, popcorn worker's  lung, and wheat weevil disease.    Air pollution threatens health when the particles are small enough  to penetrate deeply into the lower respiratory system. Through  sneezes and coughs the human respiratory tract easily ejects par-    ticles larger than 10 micrometers in diameter. But particles 2.5 to  10 micrometers in diameter can enter the airways, and the finest  particulates, with diameters 0.09 to 0.24 micrometers, pass the  respiratory system’s initial barriers and may reach the alveoli.   The World Health Organization (WHO) recommends a safe  upper limit for 2.5-micrometer particulates (called microfine air-  borne pollutants) of 25 micrograms per cubic meter. One of the  most heavily polluted cities is Beijing, China, where the level  regularly exceeds the WHO air quality index’s maximum of 500.  In China the source of the microfine airborne pollutants is largely  soot from diesel engines and industrial operations, but these par-  ticulates also are in cigarette smoke. Indoor exposure is mostly  from wood-burning stoves. Cities in Iran, India, and Pakistan top  the WHO's list of most-polluted cities. In the United States the  top three most polluted cities are Bakersfield and Los Angeles in  California, and Phoenix, Arizona.   Exposure to microfine airborne pollutants worsens asthma  and irritates the eyes and lungs. It is also associated with increased  risk of heart disease and lung cancer. WHO estimates that breath-  ing polluted air, either outdoors or indoors, kills more than seven  million people a year. The U.S. Environmental Protection Agency  advises that for microfine airborne pollutant levels above 200 on  the air quality index, “people with heart or lung disease, older  adults, and children should avoid all physical activity outdoors.  Everyone else should avoid prolonged or heavy exertion.”    FIGURE 19C Urban aerosols may compromise lung function, at  least temporarily. This image highlights the sources of some of the  debris that covered lower Manhattan after the September 11, 2001  attacks. Red and yellow represent concrete dust, and purple indicates  a mineral, gypsum, found in wallboard.    Part of the face centered above the mouth  and inferior to the space between the eyes    Soft, cone-shaped organs that occupy a  large portion of the thoracic cavity    Air pressure is exerted on all surfaces in contact with the air, and  because people breathe air, the inside surfaces of their lungs are also  subjected to pressure. In other words, when the respiratory muscles  are at rest, the pressures on the inside of the lungs and alveoli and on  the outside of the thoracic wall are about the same (fig. 19.21).   Pressure and volume are related in an opposite, or inverse, way  (this is known as Boyle’s law). For example, pulling back on the  plunger of a syringe increases the volume inside the barrel, lower-  ing the air pressure inside. Atmospheric pressure then pushes out-  side air into the syringe (fig. 19.22a). In contrast, pushing on the  plunger of a syringe reduces the volume inside the syringe, increas-  ing the pressure inside and forcing air out of the syringe into the  atmosphere (fig. 19.22). Air moves into and out of the lungs in  much the same way.    FIGURE 19.21 When the lungs are at rest, the pressure on the inside  of the lungs is equal to the pressure on the outside of the thorax.    Nostrils provide entrance to nasal cavity; internal hairs begin to filter incoming air    Passageway for air moving from nasal cavity to larynx and for food moving from  oral cavity to esophagus    Passageway for air; prevents foreign objects from entering trachea; houses vocal cords    Passageway for air; mucous lining continues to filter air  Conducts air to the alveoli; mucous lining continues to filter incoming air    Contain the air passages, alveoli, blood vessels, connective tissues, lymphatic  vessels, and nerves of the lower respiratory tract    If the pressure inside the lungs and alveoli (intra-alveolar  pressure) decreases, atmospheric pressure pushes outside air into  the airways. This happens during resting inspiration, and it uses  muscle fibers in the dome-shaped diaphragm.   The diaphragm is just inferior to the lungs. It consists of an  anterior group of skeletal muscle fibers (costal fibers) that origi-  nate from the ribs and sternum, and a posterior group of skeletal  muscle fibers (crural fibers) that originate from the vertebrae. Both  groups of muscle fibers are inserted on a tendinous central portion  of the diaphragm (reference plate 21, p. 53).   The muscle fibers of the diaphragm are stimulated to contract  by impulses conducted on the phrenic nerves, which are associated  with the cervical plexuses. When this happens, the diaphragm moves  downward, the thoracic cavity enlarges, and the intra-alveolar pres-    FIGURE 19.22 Moving the plunger of a syringe causes air to move  (a) in or (b) out of the syringe. Air movements in and out of the lungs  occur in much the same way.    sure falls about 2 mm Hg below atmospheric pressure. In response  to this decreased intra-alveolar pressure, atmospheric pressure  forces air into the alveoli (fig. 19.23).   While the diaphragm is contracting and moving downward, the  external (inspiratory) intercostal muscles and certain thoracic mus-  cles may be stimulated to contract. This action elevates the ribs and  the sternum, increasing the size of the thoracic cavity even more.  The intra-alveolar pressure falls further, and atmospheric pressure  forces more air into the alveoli.   Lung expansion in response to movements of the diaphragm  and chest wall depends on movements of the pleural membranes.  Any separation of the pleural membranes decreases pressure in the  intrapleural space, resisting further separation and holding these  membranes together. In addition, only a thin film of serous fluid  separates the parietal pleura on the inner wall of the thoracic cav-  ity from the visceral pleura attached to the surface of the lungs. The  water molecules in this fluid greatly attract the pleural membranes  and each other, helping to hold the moist surfaces of the pleural  membranes tightly together, much as a wet coverslip sticks to a  microscope slide. As a result of these factors, when the intercostal  muscles move the thoracic wall upward and outward, the parietal  pleura moves too, and the visceral pleura follows it. These move-  ments help expand the lung in all directions.   Although the moist pleural membranes help expand the lungs,  the moist inner surfaces of the alveoli have the opposite effect. In  the alveoli, the attraction of water molecules to each other creates  a force called surface tension that makes it difficult to inflate the  alveoli and may collapse them. Certain alveolar cells, however,  synthesize a mixture of lipoproteins called surfactant, which is  secreted continuously into alveolar air spaces. Surfactant reduces  the alveoli’s tendency to collapse, especially when lung vol-  umes are low, and eases inspiratory efforts to expand the alveoli.  Table 19.2 summarizes the steps of inspiration.    . Impulses are conducted on phrenic nerves to muscle fibers in  the diaphragm, contracting them.    . As the dome-shaped diaphragm moves downward, the  thoracic cavity expands.    . Atthe same time, the external intercostal muscles may contract,  raising the ribs and expanding the thoracic cavity further.    . Atmospheric pressure, greater than intra-alveolar pressure,  forces air into the respiratory tract through the air passages.    Surfactant is particularly important in the minutes after birth,  when the newborn’s lungs inflate for the first time. Premature  infants often suffer respiratory distress syndrome because  they do not produce sufficient surfactant. Physicians inject  synthetic surfactant into the tiny lungs through an endotra-  cheal tube. A ventilator especially geared to an infant’s size  assists breathing.    If a person needs to take a deeper than normal breath, the dia-  phragm and external intercostal muscles contract more forcefully.  Additional muscles, such as the pectoralis minors, sternocleido-  mastoids, and the scalenes, can also pull the thoracic cage farther  upward and outward, enlarging the thoracic cavity and decreasing  intra-alveolar pressure even more (fig. 19.24).    FIGURE 19.23 (AP|R} Normal inspiration. (a) Prior to inspiration, the intra-alveolar pressure is 760 mm Hg. (b) The intra-alveolar pressure  decreases to about 758 mm Hg as the thoracic cavity enlarges, and atmospheric pressure forces air into the airways.    FIGURE 19.24 (APIR)  Maximal inspiration. (a) Shape of  the thorax at the end of normal  inspiration. (b) Shape of the thorax  at the end of maximal inspiration,  aided by contraction of the  sternocleidomastoid and pectoralis  minor muscles.    The ease with which the lungs can expand as a result of pres-  sure changes during breathing is called compliance (distensibility).  In a normal lung, compliance decreases as lung volume increases,  because an inflated lung is more difficult to expand than a lung at  rest. Conditions that obstruct air passages, destroy lung tissue, or  impede lung expansion in other ways also decrease compliance.    The forces responsible for normal resting expiration come from  elastic recoil of lung tissues and abdominal organs and from sur-  face tension. The lungs contain a considerable amount of elastic  tissue, which stretches as the lungs expand during inspiration.  When the diaphragm lowers, the abdominal organs inferior to it are  compressed. As the diaphragm and the external intercostal mus-  cles relax following inspiration, the elastic tissues cause the lungs  to recoil, and they return to their original shapes. Similarly, elastic  tissues cause abdominal organs to spring back into their previous  shapes, pushing the diaphragm upward. At the same time, surface  tension that develops between the moist surfaces of the alveolar  linings shrinks alveoli. Each of these factors increases the intra-  alveolar pressure about 1 mm Hg above atmospheric pressure,  forcing the air inside the lungs out through the respiratory pas-  sages. Normal resting expiration occurs passively without the con-  traction of muscles.   The recoil of elastic fibers in lung tissues reduces pressure in  the pleural cavity. Consequently, the pressure between the pleural  membranes (intrapleural pressure) is typically about 4 mm Hg less  than atmospheric pressure.    The visceral and parietal pleural membranes are held closely  together because of the low intrapleural pressure, and no sig-  nificant space normally separates them in the pleural cavity.  However, if the thoracic wall is punctured, atmospheric air may  enter the pleural cavity and intrapleural pressure becomes equal  to atmospheric pressure. This condition, called pneumothorax,  can collapse the lung on the affected side because of the lung’s    elasticity, creating a substantial space between the parietal and  visceral pleural membranes.   Pneumothorax may be treated by covering the chest wound  with an impermeable bandage, passing a tube (chest tube)  through the thoracic wall into the pleural cavity, and applying  suction to the tube. The suction reestablishes negative pressure  in the cavity and the collapsed lung expands.    A person can exhale more air than normal by contracting the  posterior internal (expiratory) intercostal muscles. These mus-  cles pull the ribs and sternum downward and inward, increas-  ing the air pressure in the lungs, forcing more air out. Also, the  abdominal wall muscles, including the external and internal  obliques, the transversus abdominis, and the rectus abdominis,  squeeze the abdominal organs inward. In this way, the abdomi-  nal wall muscles can increase pressure in the abdominal cavity  and force the diaphragm still higher against the lungs, pushing  additional air out of the lungs (fig. 19.25). Table 19.3 summa-  rizes the steps in expiration.    2. Elastic tissues of the lungs, stretched during inspiration,  suddenly recoil, and surface tension pulls in on alveolar walls.    21 How does surface tension aid in expanding the lungs during  inspiration?    Different volumes of air, called respiratory volumes, can be  moved in or out of the lungs. The measurement of such air vol-  umes is called spirometry and uses a device called a spirometer  (fig. 19.26). Three distinct respiratory volumes can be measured  using spirometry, and a fourth (residual volume) cannot.   The tidal volume is the volume of air that enters or leaves the  airways and alveoli during a respiratory cycle. About 500 millili-    FIGURE 19.25 Expiration. (a) Normal resting  expiration is due to elastic recoil of the lung tissues  and the abdominal organs. (b) Contraction of the  abdominal wall muscles and posterior internal  intercostal muscles aids maximal expiration.    Posterior internal  intercostal muscles  pull ribs down and  inward (External  intercostals have  been removed to  reveal underlying  internal intercostals)    Abdominal wall  muscles contract  and compress  abdominal organs,  forcing the  diaphragm higher    ters (mL) of air enter during a normal, resting inspiration. On the  average, the same volume leaves during a normal, resting expira-  tion. Thus, the resting tidal volume is about 500 mL (fig. 19.27).  During forced maximal inspiration, a volume of air in addition  to the resting tidal volume, called the inspiratory reserve volume  (complemental air), enters the lungs. It equals about 3,000 mL.  During a maximal forced expiration, about 1,100 mL of air in  addition to the resting tidal volume can be expelled from the lungs.  This volume is called the expiratory reserve volume (supplemental    air). However, even after the most forceful expiration, about 1,200 mL  of air remains in the lungs. This is the residual volume and can only  be measured using special gas dilution techniques.   As figure 19.27 depicts, each resting inspiration adds about  500 mL of air to about 2,300 mL of air already in the lungs.  Normally, this newly inhaled air mixes completely with air  already in the lungs. This mixing prevents the oxygen and carbon  dioxide concentrations in the alveoli from fluctuating greatly with  each breath.   Four respiratory capacities can be calculated by combining  two or more of the respiratory volumes. If the inspiratory reserve  volume (3,000 mL) is combined with the tidal volume (500 mL)  and the expiratory reserve volume (1,100 mL), the total is termed  the vital capacity (4,600 mL). This capacity is the maximum volume  of air a person can exhale after taking the deepest breath possible.   The tidal volume (500 mL) plus the inspiratory reserve vol-  ume (3,000 mL) gives the inspiratory capacity (3,500 mL). This  is the maximum volume of air a person can inhale following a rest-  ing expiration. Similarly, the expiratory reserve volume (1,100 mL)  plus the residual volume (1,200 mL) equals the functional residual    capacity (2,300 mL), which is the volume of air that remains in the  lungs following a resting expiration.   The vital capacity plus the residual volume equals the total  lung capacity (about 5,800 mL) (fig. 19.27). This total varies with  age, sex, and body size.   A spirometer can be used to evaluate the course of respiratory  illnesses, such as emphysema, pneumonia, lung cancer, and bron-  chial asthma (see fig. 19.26). Table 19.4 summarizes respiratory  air volumes and capacities.   Some of the air that enters the respiratory tract during breath-  ing does not reach the alveoli. This volume (about 150 mL)  remains in the passageways of the trachea, bronchi, and bronchi-  oles. Gases are not exchanged through the walls of these passages,  so this air is said to occupy anatomic dead space.   Occasionally, alveoli in some regions of the lungs do not func-  tion, due to poor blood flow in the adjacent capillaries. This cre-  ates alveolar dead space. The anatomic and alveolar dead space  volumes combined equal physiologic dead space. In normal lungs,  the anatomic and physiologic dead spaces are essentially the same  (about 150 mL).   Tidal volume (TV) 500 mL ~~ Volume of air moved in or out of the lungs during a respiratory cycle   Inspiratory reserve volume (IRV) 3,000 mL =Maximum volume of air that can be inhaled in addition to resting tidal volume   Expiratory reserve volume (ERV) 1,100 mL Maximum volume of air that can be exhaled in addition to resting tidal volume   Residual volume (RV) 1,200 mL ~~ Volume of air that remains in the lungs even after a maximal expiratory effort   Inspiratory capacity (IC) 3,500 mL Maximum volume of air that can be inhaled following exhalation of resting tidal volume:  IC = TV + IRV   Functional residual capacity (FRC) 2,300 mL ~~ Volume of air that remains in the lungs following exhalation of resting tidal volume:  FRC = ERV + RV   Vital capacity (VC) 4,600 mL Maximum volume of air that can be exhaled after taking the deepest breath possible:  VC = TV + IRV + ERV   Total lung capacity (TLC) 5,800 mL Total volume of air that the lungs can hold: TLC = VC + RV    23 What is tidal volume?  24 Distinguish between inspiratory and expiratory reserve volumes.  25 How is vital capacity measured?    The volume of air moved into the respiratory passages each minute  is called the minute ventilation. It equals the tidal volume multiplied  by the breathing rate. For example, if the tidal volume is 500 mL  and the breathing rate is 12 breaths per minute, the minute ventila-  tion is 500 mL x 12, or 6,000 mL per minute. However, for each  breath much of the new air remains in the physiologic dead space.   For each respiratory cycle, the volume of new air that does  reach the alveoli and is available for gas exchange (in this example)  is calculated by subtracting the physiologic dead space (150 mL)  from the tidal volume (500 mL). The resulting volume (350 mL)  multiplied by the breathing rate (12 breaths per minute) is the  alveolar ventilation rate (4,200 mL per minute). This is the more  important value physiologically because it affects the concentra-  tions of oxygen and carbon dioxide in the alveoli and thus avail-  able for gas exchange with the blood.   Increasing respiratory rate by itself will increase alveolar  ventilation, but each respiratory cycle must fill the dead space  before new air reaches the alveoli. The expiratory reserve vol-  ume and especially the large inspiratory reserve volume allow for  an increase in tidal volume, and therefore an increase in alveolar  ventilation independently of dead space. This becomes important  at times when increased gas exchange is needed, as during exer-  tion. Clinical Application 19.3 discusses respiratory problems that  affect ventilation.    Air movements other than breathing are called nonrespiratory  movements. They clear air passages (coughing, sneezing) or express  emotions (laughing, crying).   Nonrespiratory movements usually result from reflexes,  although sometimes they are initiated voluntarily. A cough, for  example, can be produced through conscious effort or may be trig-  gered by a foreign object in an air passage.   Coughing involves taking a deep breath, closing the glottis,  and forcing air upward from the lungs against the closure. Then  the glottis suddenly opens, and a blast of air is forced upward from  the lower respiratory tract. Usually this rapid rush of air is of suf-  ficient force to dislodge the object that triggered the reflex.    The most sensitive areas of the air passages are in the lar-  ynx, the carina, and in regions near the branches of the major  bronchi. The distal portions of the bronchioles (respiratory  bronchioles), alveolar ducts, and alveoli do not have a nerve  supply. Consequently, before any material in these parts can  trigger a cough reflex, it must be moved into the larger pas-  sages of the respiratory tract.    A sneeze is much like a cough, but it clears the upper respira-  tory passages rather than the lower ones. Usually a mild irritation  in the lining of the nasal cavity forces a blast of air up through the  glottis. The air is directed into the nasal passages by depressing the  uvula, closing the opening between the pharynx and the oral cavity.   In /aughing, a person takes a breath and releases it in a series  of short expirations. Crying consists of similar movements, and  sometimes it is necessary to note a person’s facial expression to  distinguish laughing from crying.   A hiccup is caused by sudden inspiration due to a spasmodic  contraction of the diaphragm while the glottis is closed. Air strik-  ing the vocal folds causes the sound of the hiccup. We do not know  the function, if any, of hiccups.   Yawning is familiar to everyone, yet its significance and con-  tagiousness remain poorly understood. Evidence points away from  a role in increasing oxygen intake. Yawning, and its effect of get-  ting others yawning, may be rooted in brainstem mechanisms that  maintain alertness. Table 19.5 summarizes the characteristics of  nonrespiratory air movements.    27 How is the minute ventilation calculated? The alveolar  ventilation rate?    28 Which nonrespiratory air movements help clear the air passages?  29 Which nonrespiratory air movements are used to express emotions?    Coughing Deep breath is taken, Clears lower  glottis is closed, and air is respiratory  forced against the closure; passages  suddenly the glottis is  opened, and a blast of  air passes upward    larynx, causing vocal cords  to vibrate; actions of lips,  tongue, and soft palate  form words    Injuries to the respiratory center or to spinal tracts that conduct respiratory infections, as well as children raised with cats or dogs, are    motor impulses may paralyze breathing muscles. Paralysis may less likely to develop asthma than are children who do not have these  also be due to a disease that affects the central nervous system exposures. This association of a primed immune system with lower  and injures motor neurons, such as poliomyelitis. Sometimes, risk of developing asthma is called the “hygiene hypothesis.”  other muscles, by increasing their responses, can compensate Emphysema is a progressive, degenerative disease that  for functional losses of a paralyzed muscle. Otherwise, mechani- destroys alveolar walls. As a result, clusters of small air sacs merge  cal ventilation is necessary. More common disorders that decrease into larger chambers, which greatly decreases the total surface  ventilation are bronchial asthma and emphysema. area of the alveoli, thereby reducing the volume of gases that can  Bronchial asthma is usually an allergic reaction to foreign be exchanged across their walls. At the same time, the alveolar  antigens in the airways, such as from inhaled pollen or material walls lose their elasticity, and the capillary networks associated  on dust mites. Normally, cells of the larger airways secrete abun- with the alveoli diminish (fig. 19D).  dant mucus, which traps allergens. Ciliated columnar epithelial A person with emphysema finds it increasingly difficult to  cells move the mucus up and out of the bronchi, then up and exhale because of the loss of tissue elasticity. Abnormal muscular  out of the trachea. However, in the smaller airways, mucus and efforts are required to compensate for the lack of elastic recoil  edematous secretions resulting from the allergic response accu- that normally contributes to expiration.  mulate because fewer cells are ciliated. The allergens and secre- Only 3% of the 2 million people in the United States who have  tions irritate airway smooth muscle, causing bronchoconstriction. emphysema inherit the condition; most of that minority has a defi-  Breathing becomes increasingly difficult, and inhalation produces ciency of an enzyme, alpha-1 antitrypsin. The majority of the other  a characteristic wheezing sound as air moves through narrowed cases are due to smoking or exposure to other respiratory irritants.  and partially clogged passages. Emphysema is a type of chronic obstructive pulmonary disease  A person with asthma usually finds it harder to force air (COPD). The other major form of COPD is chronic bronchitis.  out of the lungs than to bring it in. This is because inspiration Drug combinations treat emphysema by relaxing the mus-  expands the lungs opening the air passages. Expiration, on the cles associated with the airways. An experimental treatment for  other hand, is due to elastic recoil of stretched tissues which severe emphysema is lung volume reduction surgery. As its name  compresses the airways, further impairing air movement through suggests, the procedure reduces lung volume, by removing  the narrowed air passages. 20 to 35% of the most damaged areas of each lung. The treat-  Increase in the prevalence of asthma in the United States may be ment opens collapsed airways in the remaining parts of the lung  due to a too-clean environment, especially for children. Many stud- and eases breathing. So far, it seems to noticeably improve lung  ies have shown that children who are with others and contract minor function and quality of life for many patients.    FIGURE 19D Comparison of lung tissues. (a) Normal lung tissue (100x). (b) As emphysema develops, alveoli coalesce, forming larger  chambers (100x).    Normal breathing is a rhythmic, involuntary act that continues Groups of neurons in the brainstem comprise the respiratory  when a person is unconscious. However, the respiratory muscles areas, which control breathing. These areas periodically initiate  can be voluntarily controlled too (Take a deep breath and con- impulses that travel on cranial and spinal nerves to breathing mus-  sider this!). cles, causing inspiration and expiration. The respiratory areas also    adjust the rate and depth of breathing to meet cellular requirements  for supply of oxygen and removal of CO,, even during strenuous  physical exercise.   The components of the respiratory areas are widely scattered  throughout the pons and medulla oblongata. However, two parts of the  respiratory areas are of special interest. They are the respiratory center  of the medulla and the respiratory group of the pons (fig. 19.28).   The medullary respiratory center includes two bilateral  groups of neurons that extend throughout the length of the medulla  oblongata. They are called the ventral respiratory group and the  dorsal respiratory group.   Current evidence suggests that the basic rhythm of breathing  arises from the ventral respiratory group. Two different popula-  tions of neurons in this area have been implicated in maintaining  inspiration and expiration, depending on the experimental condi-  tions. Indeed, it has been suggested that such an important physi-  ological process might occur in more than one way.   The dorsal respiratory group stimulates the inspiratory mus-  cles, primarily the diaphragm. The dorsal respiratory group also  helps process sensory information related to the respiratory sys-    FIGURE 19.28 The respiratory areas are located in the pons and the  medulla oblongata.    tem and may play a role in certain cardiopulmonary reflexes that  affect respiratory rhythm.   Neurons in another part of the brainstem, the pons, form the  pontine respiratory group (formerly called the pneumotaxic cen-  ter). They may contribute to the rhythm of breathing by limiting  inspiration (fig. 19.29).    A condition called sleep apnea causes one to momentarily  stop breathing while sleeping. In infants, apnea is usually cen-  tral, due to a problem with respiratory control centers and is  responsible for some cases of sudden infant death. In adults,  apnea is usually obstructive, caused by airway blockage, and is  often associated with snoring.   Babies who have difficulty breathing just after birth are sent  home with monitoring devices, which sound an alarm when the  child stops breathing, alerting parents to resuscitate the infant.  The position in which the baby sleeps seems to affect the risk of  sleep apnea—sleeping on the back or side is safest during the  first year of life.   Adults with sleep apnea may cease breathing for ten to  twenty seconds, hundreds of times a night. The frequent ces-  sation in breathing is associated with snoring. Sleep apnea in  adults causes fatigue, headache, depression, and drowsiness  during waking hours.   Sleep apnea is diagnosed in a sleep lab, where breathing  during slumber is monitored for several consecutive hours. One  treatment for obstructive sleep apnea, nasal continuous posi-  tive airway pressure, straps a device onto the nose at night that  maintains air flow into the respiratory system.    32 Describe how the respiratory areas maintain a normal breathing  rhythm.    FIGURE 19.29 The medullary respiratory center and the pontine  respiratory group control breathing.    In a mixture of gases such as air, each gas accounts for a portion  of the total pressure the mixture produces. The amount of pres-  sure each gas contributes is called the partial pressure of that gas  and is proportional to its concentration. For example, because air  is 21% oxygen, oxygen accounts for 21% of the atmospheric pres-  sure (21% of 760 Hg), or 160 mm Hg (.21 x 760 = 160). Thus,  the partial pressure of oxygen, symbolized P, , in atmospheric air  is 160 mm Hg. Similarly, the partial pressure of carbon dioxide  (Peo,) in air is 0.3 mm Hg.   Gas molecules from the air may enter, or dissolve, in liquid.  This is what happens when CO, is added to a carbonated bever-  age or when inspired gases dissolve in the blood in the alveolar  capillaries. Using partial pressures simplifies the calculation of the  concentration of a dissolved gas. The partial pressure of a gas dis-  solved in a liquid equals the partial pressure of that gas in the air  with which the liquid has equilibrated. For example, the P, ina  glass of water that has been on a desk for a while must be 160 mm  Hg, the same as in the air around it. Instead of referring to concen-  trations of oxygen and carbon dioxide in the body fluids, we will  refer to Py and Po.    A number of factors influence breathing rate and depth. These  include P, and P.,, in body fluids, the degree to which lung tissues  are stretched, emotional state, and level of physical activity. The  receptors involved include mechanoreceptors that sense stretch as  well as central and peripheral chemoreceptors.   Under normal circumstances the main control of respiratory  activity is not the level of oxygen in the blood. The limited role of  P,, may be surprising, considering the importance of oxygen for  sustaining life. However, most blood oxygen is carried bound to the  hemoglobin molecules in red blood cells, and so-called oxygen-  poor systemic venous blood still has, on average, 75% of the oxygen  it had when it was fully oxygenated.   Usually this large excess of oxygen “frees up” respiratory  control from responding to blood oxygen levels. Thus, the respira-  tory system responds predominantly to blood P.,, and hydrogen  ion concentration, which are important in maintaining the pH of  the internal environment, especially in the brain. The receptors  that respond to P, and P.o, are chemoreceptors, and they fall into  two categories, central and peripheral.    Low blood Pg has little effect on the central chemoreceptors.  They are in the ventral portion of the medulla oblongata, where  they primarily monitor the pH of the brain. The central chemore-  ceptors also respond to changes in blood pH, but only indirectly,  because hydrogen ions do not easily cross the blood-brain barrier  and therefore do not have access to this area.   co, can cross the blood-brain barrier, and as a result CO_ in the  brain is in equilibrium with CO_ in the blood. If plasma P.o rises, the  CO, easily diffuses into the brain, where it combines with water in  the cerebrospinal fluid to form carbonic acid (H,CO,):    The carbonic acid quickly ionizes, releasing hydrogen ions (H*)  and bicarbonate ions (HCO, ):    The central chemoreceptors respond to the released hydrogen  ions, not to the CO,. However, because Co, and H* are so closely  linked, it may help to think of them as equivalent in terms of acid-  ity in the body. Breathing rate and tidal volume increase when a  person inhales air rich in CO, or when body cells produce excess  CO,. These changes increase alveolar ventilation, exhaling more  CG; and the blood P,,., and hydrogen ion concentration return  toward normal.    Adding CO, to air can stimulate the rate and depth of breath-  ing. Ordinary air is about 0.04% CO.,,. If a person inhales air con-  taining 4% CO,, breathing rate usually doubles.    Peripheral chemoreceptors primarily sense changes in the blood  P,,, in specialized structures called the carotid bodies and aortic  bodies, which are in the walls of the carotid sinuses and aortic arch  (fig. 19.30). Here the chemoreceptors are well positioned to moni-  tor oxygen that will reach the brain and the rest of the body. When  decreased P,, stimulates these peripheral receptors, they send  impulses to the respiratory center, and breathing rate and tidal vol-  ume rise, increasing alveolar ventilation. This mechanism does not  usually play a major role until the P, decreases to about 50% of  normal. Therefore, oxygen has only a minor influence on the con-  trol of normal respiration.   Changes in blood pH stimulate the peripheral chemoreceptors  of the carotid and aortic bodies. These chemoreceptors become  important when the pH of the blood changes and CO, does not. For  example, under conditions of strenuous exercise, lactic acid pro-  duction may threaten to lower pH. Should this happen, the periph-  eral chemoreceptors signal the respiratory centers to increase  alveolar ventilation. Recall that in the body, with respect to their  impact on blood pH, hydrogen ions and CO, can be considered  equivalent. By stimulating the respiratory centers to exhale more  CO,, the peripheral chemoreceptors effectively stabilize blood pH  in the presence of excess lactic acid. Gradually the kidneys elimi-  nate the extra hydrogen ions, and blood CO, returns to normal.    Patients who have COPD gradually adapt to high levels of car-  bon dioxide. For them, low oxygen levels may serve as a nec-  essary respiratory stimulus. If such a patient is placed on 100%  oxygen, the low arterial Po may be corrected sufficiently to  remove the stimulus. As a result, breathing may be suppressed  or even stopped.    An inflation reflex (Hering-Breuer reflex) helps regulate the  depth of breathing. This reflex occurs when stretch receptors in  the visceral pleura, bronchioles, and alveoli are stimulated as    FIGURE 19.30 Decreased Po, stimulates peripheral chemoreceptors  in the carotid and aortic bodies.    lung tissues are stretched. The sensory impulses of the reflex travel  via the vagus nerves to the respiratory areas in the brainstem and  shorten the duration of inspiratory movements. This action prevents  overinflation of the lungs during forceful breathing (fig. 19.31).  Emotional upset or strong sensory stimulation may alter the  normal breathing pattern. Gasping and rapid breathing are famil-  iar responses to fear, anger, shock, excitement, horror, surprise,  sexual stimulation, or even the chill of stepping into a cold shower.  Because control of the respiratory muscles is voluntary, we can  alter our breathing pattern consciously or stop it for a short time.    During childbirth, for example, concentration on controlling her  breathing can distract the mother from her pain.   Holding one’s breath makes the blood concentrations of  carbon dioxide and hydrogen ions rise and the concentration of  oxygen fall. These changes (primarily the increased CO,) stimu-  late the chemoreceptors, and soon the need to inhale overpow-  ers the desire to hold the breath—much to the relief of parents  when young children threaten to hold their breath until they turn  blue! However, a person can increase the breath-holding time by  breathing rapidly and deeply in advance. (This could be danger-  ous, see box that follows.) This action, termed hyperventilation  (hi’per-ven”ti-la’shun), is specifically breathing that lowers the  blood CO, concentration below normal. Following hyperventila-  tion, it takes longer than usual for the carbon dioxide concentra-  tion to reach the level needed to override the conscious effort of  breath holding.    A person who is emotionally upset may hyperventilate, become  dizzy, and lose consciousness. This is due to a lowered CO, con-  centration followed by a rise in pH (respiratory alkalosis) and a  localized vasoconstriction of cerebral arterioles, decreasing    blood flow to nearby brain cells. Hampered oxygen supply to the  brain causes fainting. A person should never hyperventilate to  help hold the breath while swimming, because the person may  lose consciousness under water and drown.    The tubelike parts of the respiratory system move air in and out of  the air passages. The alveoli are the sites of the vital process of gas  exchange between the air and the blood.    Chemoreceptors in carotid and aortic bodies  Chemosensitive areas of the respiratory center    Moderate to heavy exercise greatly increases the amount of oxy-  gen skeletal muscles use. A young man at rest uses about 250 mil-  liliters of oxygen per minute but may require 3,600 milliliters per  minute during maximal exercise. While oxygen use is increasing,  CO, production increases also. Because decreased blood oxygen  and increased blood CO, concentrations stimulate the respiratory  centers, exercise would be expected to increase breathing rate.  Studies reveal, however, that blood oxygen and carbon dioxide  levels do not change significantly during exercise, but breathing  rate does.   The cerebral cortex and the proprioceptors associated with  muscles and joints cause much of the increased breathing rate  associated with exercise (see chapter 12, pp. 449-451). The cortex    Alveoli are microscopic air sacs clustered at the distal ends of the  finest respiratory tubes—the alveolar ducts. Each alveolus is a tiny  space within a thin wall that separates it from adjacent alveoli. Tiny  openings, called alveolar pores, in the walls of some alveoli may  permit air to pass from one alveolus to another (fig. 19.32). The  pores provide alternate air pathways if the passages in some parts of  the lung become obstructed.    sends stimulating impulses to the respiratory center whenever it  signals the skeletal muscles to contract. At the same time, muscular  movements stimulate the proprioceptors, triggering a joint reflex.  In this reflex, sensory impulses are conducted from the propriocep-  tors to the respiratory center, and the respiratory rate increases.   Exercise increases not only the breathing rate, but also the  demand of exercising muscles for blood flow. In this way, exer-  cise taxes both the respiratory and the cardiovascular systems. If  either of these systems does not keep pace, the person will begin  to feel short of breath. This sensation, however, is usually due to  the inability of the cardiovascular system to move enough blood  between the lungs and the cells, rather than to the inability of the  respiratory system to provide enough air.    Phagocytic cells called alveolar macrophages are in alveoli  and in the pores. These macrophages phagocytize airborne agents,  including bacteria, thereby cleaning the alveoli (fig. 19.33).    Part of the wall of an alveolus is made up of cells (type II cells)  that secrete pulmonary surfactant, described earlier. However, the  bulk of the wall of an alveolus consists of a layer of simple squamous    FIGURE 19.31 In the process of inspiration, motor impulses travel from the respiratory center to the diaphragm and external intercostal muscles,  which contract and cause the chest and lungs to expand. This expansion stimulates stretch receptors in the lungs to send inhibiting impulses to the    epithelium (type I cells). Each alveolus is associated with a dense  network of capillaries with walls of simple squamous epithelial  cells (fig. 19.33). Thin basement membranes separate the walls  of the alveoli from the walls of the capillaries, and in the spaces  between them elastic and collagen fibers help support the alveo-  lar walls. Thus, two thicknesses of epithelial cells and basement  membranes separate the air in an alveolus and the blood in a capil-  lary. These layers make up the respiratory membrane (alveolar-  capillary membrane), through which gas exchange occurs between  the alveolar air and the blood (figs. 19.34 and 19.35).    Solutes diffuse from regions where they are in higher concen-  tration toward regions where they are in lower concentration.  Therefore, to determine the direction of diffusion of a solute, we  must know the concentration gradient. For dissolved gases, it is  necessary to think in terms of partial pressure gradients. A gas will  diffuse from an area of higher partial pressure to an area of lower  partial pressure.    When a mixture of gases dissolves in blood, the resulting con-  centration of each dissolved gas is proportional to its partial pres-  sure. Each gas diffuses between blood and its surroundings from  areas of higher partial pressure to areas of lower partial pressure  until the partial pressures in the two regions reach equilibrium. For  example, the P.,, of blood entering the pulmonary capillaries is  45 mm Hg, but the Poo, in alveolar air is 40 mm Hg. Because of the  difference in these partial pressures, carbon dioxide diffuses from  blood, where its partial pressure is higher, across the respiratory  membrane and into alveolar air. When blood leaves the lungs, its  Poo, is 40 mm Hg, the same as the Pyo, of alveolar air. Similarly,  the P, of blood entering the pulmonary capillaries is 40 mm Hg,  but reaches 104 mm Hg as oxygen diffuses from alveolar air into    FIGURE 19.32 Alveolar pores (arrow) allow air to pass from one  alveolus to another (300x).    the blood. Because of the large volume of air always in the lungs,  and the oxygen added as long as breathing continues, alveolar P,,  stays relatively constant at 104 mm Hg. Reaching equilibrium,  blood leaves the alveolar capillaries with a Py of 104 mm Hg. (In  an exception to the usual pattern, some systemic venous blood  draining the bronchi and bronchioles mixes with this blood before  returning to the heart. This contributes to lowering the P, of left  atrial, left ventricular, and systemic arterial blood to 95 mm Hg.)  Clinical Application 19.5 looks at a respiratory effect that occurs  under specific conditions—high altitude.   The respiratory membrane is normally thin (about 1 microm-  eter thick), and gas exchange is rapid. However, a number of fac-  tors may affect diffusion across the respiratory membrane. More    FIGURE 19.33 The respiratory membrane consists of the walls of the  alveolus and the capillary.    Every year, about 100,000 mountain climbers experience varying  degrees of altitude sickness, because at high elevations, the pro-  portion of oxygen in air remains the same (about 21%), but the  Po, decreases. When a person ascends rapidly, oxygen diffuses  more slowly from the alveoli into the blood, and the hemoglo-  bin becomes less saturated with oxygen. In some individuals, the  body's efforts to get more oxygen—increased breathing and heart  rate and enhanced red blood cell and hemoglobin production—  cannot keep pace with the plummeting oxygen supply.   Severe altitude sickness includes a condition called high-  altitude pulmonary edema (HAPE). Symptoms are sudden severe  headache, nausea and vomiting, rapid heart rate and breathing,  and a cyanotic (blue) cast to the skin, often first apparent under  the fingernails.   The hypoxia (low blood oxygen) associated with high altitude  can vasoconstrict pulmonary blood vessels. In some people, this    surface area, shorter distance, greater solubility of gases, and  a steeper partial pressure gradient all favor increased diffusion.  Diseases that harm the respiratory membrane, such as pneumonia,    shunts blood under high pressure through less constricted vessels  in the pulmonary circuit, raising capillary pressure and filtering  fluid from the blood vessels into the alveoli, causing the edema.  People with severe HAPE also commonly develop high-altitude  cerebral edema (HACE).   HAPE is treated by giving oxygen and coming down from the  mountain. Delay may prove fatal. Exertion may worsen the symp-  toms, and victims often need to be carried. Some prescription  vasodilators, such as nifedipine, may help reduce the pulmonary  hypertension, but they can be dangerous without proper medical  attention.   Mountain climbing is an extreme activity that endangers the  respiratory system. Regularly exercising at moderately high alti-  tude, however, can strengthen the system. Distance runners, too,  often train at high altitudes because of beneficial effects on fit-  ness and performance.    or reduce the surface area for diffusion, such as emphysema,  impair gas exchange. These conditions may require increased P,,  for treatment. Clinical Application 19.6 examines illnesses that  result from impaired gas exchange.   The respiratory membrane is normally so thin that certain  soluble chemicals other than CO, may diffuse into alveolar air and  be exhaled. This is why breath analysis can reveal alcohol in the  blood or acetone can be smelled on the breath of a person who  has untreated diabetes mellitus. Breath analysis may also detect  substances associated with kidney failure, certain digestive distur-  bances, and liver disease.    An optical tool called “frequency combs” can detect trace  amounts of many different compounds in an exhaled breath.  The sets of chemicals detected and their concentrations can  provide clues to health. A special laser sends short pulses of  light into a device holding an exhaled breath. An algorithm  uses the pattern of light wavelengths absorbed to identify spe-  cific chemical compounds that may serve as biomarkers. For  example, a signature of nitric oxide, carbon monoxide, nitrites,  nitrates, pentane, ethane, and hydrogen peroxide indicates  asthma, but a different set of compounds in exhaled breath  indicates cystic fibrosis.    39 What causes oxygen and carbon dioxide to move across the  respiratory membrane?    Five-year-old Carly became ill very quickly. After twelve hours  of flulike symptoms, her temperature soared, her chest began  to hurt, and her breathing became rapid and shallow. A chest  radiograph indicated that she had pneumonia. The bacteria that  had caused a mild upper respiratory infection in her sisters had  infected Carly's lower respiratory structures.   Antibiotics treated Carly’s pneumonia. Many of the 50 mil-  lion people who died in the 1918 influenza pandemic were not so  lucky, in that era before antibiotics. Although viruses can cause  pneumonia, most of the flu deaths were actually caused by sec-  ondary bacterial infections. Bacteria that normally inhabit upper  respiratory structures easily moved downward to the lungs made  vulnerable by the viral infection. Fungi can also cause pneumo-  nia, such as the fungus Pneumocystis jirovecii that affects people  with AIDS.   For all types of pneumonia, events in the infected lung are  similar: alveolar linings swell with edema and become abnormally  permeable, allowing fluids and white blood cells to accumulate in  the air sacs. As the alveoli fill, the surface area available for gas  exchange diminishes. Breathing becomes difficult. Untreated,  pneumonia can kill.   Tuberculosis is a different type of lung infection, caused by  the bacterium Mycobacterium tuberculosis. Fibrous connective  tissue develops around the sites of infection, forming structures  called tubercles (fig. 19E). By walling off the bacteria, the tuber-  cles help stop their spread. Sometimes this protective mecha-  nism fails, and the bacteria flourish throughout the lungs and  may spread to other organs. In the later stages of infection, other  types of bacteria may cause secondary infections. As lung tissue  is destroyed, the surface area for gas exchange decreases. In  addition, the widespread fibrous tissue thickens the respiratory  membrane, further restricting gas exchange. A variety of drugs  are used to treat tuberculosis, but in recent years, “multidrug   Another type of condition that impairs gas exchange is atelec-  tasis. This is the collapse of a lung, or some part of it, with the  collapse of the blood vessels that supply the affected region.  Obstruction of a respiratory tube, such as by an inhaled foreign  object or excess mucus secretion, may cause atelectasis. The air  in the alveoli beyond the obstruction is absorbed, and as the air  pressure in the alveoli decreases, their elastic walls collapse, and  they can no longer function. Fortunately, after a portion of a lung  collapses, the functional regions that remain are often able to  carry on enough gas exchange to sustain the body cells.   In acute respiratory distress syndrome (ARDS), which is a spe-  cial form of atelectasis, alveoli collapse. Causes include pneumo-  nia and other infections, near drowning, shock, sepsis, aspiration  of stomach acid into the respiratory system, or physical trauma  to the lungs from an injury or surgical procedure. Anesthetic  drugs can cause ARDS by suppressing surfactant production. In  response the tiny air sacs collapse. Blood vessels and airways nar-  row. Delivery of oxygen to tissues is seriously impaired. ARDS is  fatal about 60% of the time. (It was until recently called adult respi-  ratory distress syndrome.)   New virally caused acute respiratory disorders have appeared.  Severe acute respiratory syndrome (SARS) is a disease caused by  a virus (SARS-coronavirus) that infects lower respiratory structures.  The disease swept through two dozen nations from winter 2002  until spring 2003, infecting more than 8,000 people and killing  about 800 of them. China, Hong Kong, and Taiwan were the hard-  est hit. Since then the disease has mysteriously vanished.   In 2012 another acute respiratory condition caused by a coro-  navirus appeared in six nations near the Arabian peninsula. MERS-  coronavirus causes the fever, cough, and shortness of breath of  Middle Eastern respiratory syndrome (MERS).    FIGURE 19E Healthy lungs appear dark and clear on a radiograph (above on the left). Lungs with tuberculosis have cloudy areas where  fibrous tissue grows, walling off infected areas (radiograph above on the right).    FIGURE 19.35 fAP|R) Gases are exchanged between alveolar air and capillary blood because of differences in partial pressures.    The blood carries oxygen and carbon dioxide between the lungs  and the body cells. As these gases enter the blood, they dissolve in  the liquid portion, the plasma, or combine chemically with other  atoms or molecules.    Almost all the oxygen (over 98%) is carried in the blood bound  to the protein hemoglobin in red blood cells. The oxygen bound  to iron in hemoglobin provides the color of these blood cells. The  remainder of the oxygen is dissolved in the blood plasma.   Hemoglobin consists of two types of components called  heme and globin (see chapter 18, pp. 715-716). Globin is a pro-  tein of 574 amino acids in four polypeptide chains. Each chain is  associated with a heme group, and each heme group surrounds  an atom of iron. Each iron atom can loosely bind an oxygen mol-  ecule. As oxygen dissolves in blood, it rapidly combines with  hemoglobin, forming a new compound called oxyhemoglobin  (ok”si-he”mo-glo’bin). Each hemoglobin molecule can bind up  to four oxygen molecules.   The P,, determines the amount of oxygen that hemoglobin  binds. The greater the P,,, the more oxygen binds until the hemo-  globin molecules are completely loaded with oxygen, or saturated  (fig. 19.36). At normal arterial Po, (95 mm Hg), hemoglobin is  essentially completely saturated.   The chemical bonds between oxygen and hemoglobin mol-  ecules can break. As the P, decreases, oxyhemoglobin releases  oxygen molecules (fig. 19. 36). This happens in tissues in which  cells have used oxygen in respiration. The free oxygen diffuses  from the blood into nearby cells, as figure 19.37 shows.   Increasing the blood level of carbon dioxide (Pco,)s acidity,  and temperature all increase the amount of oxygen that oxyhemo-  globin releases (figs. 19.38, 19.39, and 19.40). These influences  help release more oxygen from the blood to the skeletal muscles  during exercise. The increased muscular activity accompanied by  increased oxygen use increases the P,,.,, decreases the pH, and  raises the local temperature. At the same time, less-active cells  receive the usual amount of oxygen.    As described earlier, respiratory control under most circum-  stances is responding to plasma P,,, and pH, not P,,, despite the  central role of oxygen in cellular metabolism. Notice, however, in  figures 19.36 and 19.37, that the ““oxygen-poor” systemic venous  blood retains 75% of the oxygen it had when it was “oxygen-rich.”  This safety margin for O, makes it possible for the respiratory  system to safely adjust CO, levels, and thereby the pH, of the  internal environment.    Carbon monoxide (CO) is a toxic gas produced in gasoline  engines and some stoves as a result of incomplete combustion  of fuels. It is also a component of tobacco smoke. Carbon mon-  oxide is toxic because it binds hemoglobin in a way that pre-  vents hemoglobin from delivering oxygen to tissues. It may also  inhibit aerobic respiration at the cellular level. Treatment for car-  bon monoxide poisoning is to administer oxygen at high partial    pressure to increase the amount of oxygen available for delivery  to the tissues. Carbon dioxide (CO,) is usually given simultane-  ously to stimulate the respiratory center, which, in turn, increases  breathing rate. Rapid breathing, once the carbon monoxide  source has been removed, helps reduce the partial pressure  of carbon monoxide in the alveoli, favoring diffusion of carbon  monoxide out of the blood.    Cellular metabolism constantly generates CO,, which diffuses into  the systemic capillaries. This CO, is carried to the lungs in one of  three forms: as CO, dissolved in plasma, as part of a compound  formed by bonding to hemoglobin, or as part of bicarbonate ions  (fig. 19.41).    100  90 -  80-  70-  60 -  50-  40+  30 -  20-  10;    | | ! ! ! I I I I I I I I |  0 10 20 30 40 50 60 70 80 90 100 110 120 130 140  Po, (mm Hg)  Oxyhemoglobin dissociation at 38°C    FIGURE 19.36 Hemoglobin is completely saturated at normal systemic  arterial Po, but readily releases oxygen at the Po, of the body tissues.    The amount of carbon dioxide that dissolves in plasma is  determined by its partial pressure. The higher the Poo, of the tis-  sues, the more carbon dioxide dissolves. However, only about 7%  of the carbon dioxide that enters the blood is carried in this form.    FIGURE 19.37 Blood carries oxygen.  Oxygen molecules, entering the blood from  the alveolus, bond to hemoglobin, forming  oxyhemoglobin. In the regions of the body  cells, oxyhemoglobin releases oxygen.  Much oxygen is still bound to hemoglobin  at the Po, of systemic venous blood.   Po, = 40 mm Hg  Tissue  Po, = 40 mm Hg    Unlike oxygen, which binds the iron atoms of hemoglobin  molecules, carbon dioxide bonds with the amino groups (—NH,)  of these molecules. Consequently, oxygen and carbon dioxide do  not directly compete for binding sites—a hemoglobin molecule can  transport both gases at the same time.   Carbon dioxide binding hemoglobin forms a loosely bound  compound called carbaminohemoglobin (kar-bam” i-no-he”mo-  globin). This molecule readily decomposes in regions where the  Pyo, is low, releasing its carbon dioxide. Although this method of  transporting carbon dioxide is theoretically quite effective, carb-  aminohemoglobin forms relatively slowly. About 15% to 25% of  the CO, that enters the blood is carried this way.   In the most important CO, transport mechanism bicarbon-  ate ions (HCO,>) form. Recall that carbon dioxide reacts with  water to form carbonic acid (H,CO,). This reaction occurs slowly  in the blood plasma, but much of the CO, diffuses into the red  blood cells. These cells contain an enzyme, carbonic anhydrase  (kar-bon’ik an-hi’dras), which speeds the reaction between CO,  and water.   The resulting carbonic acid dissociates almost immediately,  releasing hydrogen ions (H*) and bicarbonate ions (HCO, ):   Po, = 95 mm Hg  Tissue  Po, = 40 mm Hg    60 PCO,=  20 mm Hg  40 mm Hg  40 80 mm Hg    FIGURE 19.38 The amount of oxygen released from oxyhemoglobin  increases as the Peo, increases.    100 -  90  80  70  60  50  40  30  20  10    se ae ee ae  0 10 20 30 40 50 60 70 80 90 100 110 120 130 140    FIGURE 19.39 The amount of oxygen released from oxyhemoglobin  increases as the blood pH decreases.    SS a a a a a a  0 10 20 30 40 50 60 70 80 90 100 110 120 130 140    FIGURE 19.40 The amount of oxygen released from oxyhemoglobin  increases as the blood temperature increases.    These new hydrogen ions might be expected to lower blood pH,  but this reaction occurs in the systemic capillaries, where deoxy-  hemoglobin is generated. Deoxyhemoglobin is an excellent buf-  fer because hydrogen ions readily bind it. The bicarbonate ions  diffuse out of the red blood cells and enter the blood plasma. As  much as 70% of the carbon dioxide that enters the blood is carried  in this form.   As the bicarbonate ions leave the red blood cells and enter the  plasma, chloride ions, which also have negative charges, are elec-  trically repelled, and they move from the plasma into the red blood  cells. This exchange in position of the two negatively charged  ions, shown in figure 19.42, maintains the ionic balance between  the red blood cells and the plasma. It is termed the chloride shift.   As blood passes through the capillaries of the lungs, the dis-  solved carbon dioxide diffuses into the alveoli, in response to the  relatively low P.,, of the alveolar air. As the plasma P,o, drops,  hydrogen ions and bicarbonate ions in the red blood cells recom-  bine to form carbonic acid, and under the influence of carbonic  anhydrase, the carbonic acid quickly yields new molecules of CO,  and water:    Note that this is the reverse of the reaction described above.  Carbonic anhydrase catalyzes this reaction in either direction,  depending on the levels of CO, and H*.   Carbaminohemoglobin also releases its Co,, and both of  these events contribute to the P.,, of the alveolar capillary blood.  CO, diffuses out of the blood until an equilibrium is established  between the P.,, of the blood and the P,, of the alveolar air.  Figure 19.43 summarizes this process, and table 19.7 summarizes  the transport of blood gases.   The actual percentages vary somewhat between arterial and  venous blood, but in either case the vast majority of blood CO, is  in the form of bicarbonate ion. This is important, since bicarbon-  ate ion plays a major role in controlling the pH of the blood, as  chapter 21 (p. 814) explains.    FIGURE 19.41 Carbon dioxide produced by  cells is carried in the blood plasma in a dissolved  state, bound to hemoglobin, or in the form of  bicarbonate ions (HCO,).    42 Describe three ways carbon dioxide can be transported from  cells to the lungs.    43 How can hemoglobin carry oxygen and carbon dioxide at the  same time?    44 How do bicarbonate ions help buffer the blood (maintain its pH)?  45 What is the chloride shift?    46 How is carbon dioxide released from the blood into the lungs?    Changes in the respiratory system over a lifetime reflect both the  accumulation of environmental influences and the effects of aging  in other organ systems. The lungs and respiratory passageways  of a person who has breathed only clean air are pinker and can  exchange gases much more efficiently as the years pass than can  the respiratory system of a person who has breathed polluted air  and smoked for many years. Individuals who have been exposed to  foul air are more likely to develop chronic bronchitis, emphysema,  and/or lung cancer than people fortunate enough to breathe fresh  air. Long-term exposure to particulates in the workplace can also  raise the risk of developing respiratory illnesses. Still, many age-  associated changes in the respiratory system are unavoidable.   With age, protection of the lungs and airways falters, as cili-  ated epithelial cells become fewer, and their cilia less active or  gone. At the same time, mucus thickens; the swallowing, gag-  ging, and coughing reflexes slow; and macrophages lose their  efficiency in phagocytizing bacteria. These changes combine to  slow the clearance of pathogens from the lungs and respiratory  passages, which increases susceptibility to and the severity of  respiratory infections.   Several changes contribute to an overall increase in the effort  required to breathe that accompanies aging. Cartilage between the  sternum and ribs calcifies and stiffens, and skeletal shifts change  the shape of the thoracic cavity as posture changes with age. In    The respiratory system includes the passages that transport  air to and from the lungs and the air sacs in which gas  exchanges occur.    a. Respiration is the entire process by which gases are  exchanged between the atmosphere and the body cells.   b. Respiration is necessary because cells require oxygen to  extract maximal energy from nutrient molecules and release  carbon dioxide, a metabolic waste.    the bronchioles, fibrous connective tissue replaces some smooth  muscle, decreasing the ability to dilate. As muscles lose strength,  breathing comes to depend more upon the diaphragm. The vital  capacity, which reaches a maximum by age forty, may drop by a  third by the age of seventy years.   Keeping fresh air in the lungs becomes more difficult with  age. As the farthest reaches of the bronchiole walls thin, perhaps  in response to years of gravity, they do not stay as open as they  once did, trapping residual air in the lower portions of the lungs.  Widening of these bronchioles and alveolar ducts increases the  volume of air that is dead space. In addition, the maximum minute  ventilation begins to decrease at around age thirty.   Aging-associated changes occur at the microscopic level too.  The number of alveoli is about 24 million at birth, reaching 480  million by adulthood, which translates to about 170 alveoli per  cubic millimeter of lung tissue. With advancing age, alveolar walls  thin and alveoli may coalesce, decreasing the surface area avail-  able for gas exchange. One study estimated that one square foot  of respiratory membrane is lost per year after age thirty. Also, an  increase in the proportion of collagen to elastin and a tendency of  the collagen to cross-link impair the ability of alveoli to expand  fully. Oxygen transport from the alveoli to the blood, as well as  oxygen loading onto hemoglobin in red blood cells, becomes less  efficient. Diffusion of CO, out of the blood and through the alveo-  lar walls slows too.   As with other organ systems, the respiratory system undergoes  specific changes, but these may be unnoticeable at the whole-body  level. A person who is sedentary or engages only in light activity  would probably not be aware of the slowing of air flow in and out  of the respiratory system. Unaccustomed exercise, however, would  quickly reveal how difficult breathing has become with age.    47 How does the environment influence the effects of aging on the  respiratory system?    The respiratory system is divided into two tracts. The upper  respiratory tract includes the nose, nasal cavity, sinuses,  and pharynx; the lower respiratory tract includes the larynx,  trachea, bronchial tree, and lungs.  1. Nose  a. Bone and cartilage support the nose.  b. Nostrils provide entrances for air.  2. Nasal cavity  a. The nasal cavity is a space posterior to the nose.  b. The nasal septum divides it medially.    Hormonelike  substances control  the production of  red blood cells that  transport oxygen    The respiratory system provides oxygen for the  internal environment and excretes carbon dioxide.    As the heart pumps  blood through the  lungs, the lungs  oxygenate the blood  and excrete carbon  dioxide.    Cells of the immune  system patrol the  lungs and defend  against infection.    The digestive  system and  respiratory system  share openings to  the outside.   e. Particles trapped in the mucus are carried to the  pharynx by ciliary action and are swallowed.    a. Sinuses are spaces in the bones of the skull that open  into the nasal cavity.   b. They are lined with mucous membrane that is  continuous with the lining of the nasal cavity.   a. The pharynx is posterior to the mouth, between the  nasal cavity and the larynx.   a. The larynx is an enlargement at the top of the trachea.   b. Itis a passageway for air and helps prevent foreign  objects from entering the trachea.   c. Itis composed of muscles and cartilages; some of these  cartilages are single, whereas others are paired.   d. It contains the vocal cords, which produce sounds by  vibrating as air passes over them.  (1) The pitch of a sound is related to the tension on   the cords.  (2) The intensity of a sound is related to the force of  the air passing over the cords.    a. The trachea extends into the thoracic cavity anterior to  the esophagus.    a. The bronchial tree consists of branched air passages  that connect the trachea to the air sacs.   b. The branches of the bronchial tree include main  bronchi, lobar bronchi, segmental bronchi,  intralobular bronchioles, terminal bronchioles,  respiratory bronchioles, alveolar ducts, alveolar  sacs, and alveoli.   c. Structure of the respiratory tubes  (1) As tubes branch, the amount of cartilage in the   walls decreases, and the muscular layer persists  to the ends of the respiratory bronchioles.   (3) The epithelial lining changes from pseudostratified  and ciliated to cuboidal and then to simple  squamous as the tubes become progressively  smaller.   d. Functions of the respiratory tubes and alveoli include  distribution of air and exchange of gases between the  alveolar air and the blood.    a. The left and right lungs are separated by the  mediastinum and are enclosed by the diaphragm and  the thoracic cage.   b. The visceral pleura is attached to the surface of the  lungs; parietal pleura lines the thoracic cavity.    c. The right lung has three lobes, and the left lung has two.   d. Each lobe is composed of lobules that contain alveolar  ducts, alveolar sacs, alveoli, nerves, blood vessels,  lymphatic vessels, and connective tissues.    Inspiration and expiration movements are accompanied  by changes in the size of the thoracic cavity. One inspiration  followed by one expiration is a respiratory cycle.   c. The intra-alveolar pressure is reduced when the  diaphragm moves downward and the thoracic cage  moves upward and outward.   a. The forces of expiration come from the elastic recoil of  tissues and from surface tension in the alveoli.   b. Expiration can be aided by thoracic and abdominal  wall muscles that pull the thoracic cage downward and  inward and compress the abdominal organs inward and  upward.   a. The amount of air that moves in or out during a  respiratory cycle is the tidal volume.   b. Additional air that can be inhaled is the inspiratory  reserve volume; additional air that can be exhaled is  the expiratory reserve volume.   c. Residual air remains in the lungs and is mixed with  newly inhaled air.   e. The vital capacity is the maximum amount of air  a person can exhale after taking the deepest breath  possible.   f. The inspiratory capacity is the maximum volume of  air a person can inhale following exhalation of the tidal  volume.   g. The functional residual capacity is the volume of air  that remains in the lungs following the exhalation of the  tidal volume.   h. The total lung capacity is equal to the vital capacity  plus the residual volume.   i. Air in the anatomic and alveolar dead spaces is not  available for gas exchange.   b. Alveolar ventilation rate is the physiologic dead  space subtracted from the tidal volume multiplied by  breathing rate.   c. The alveolar ventilation rate is a major factor affecting  gas exchange between the alveolar air and the blood.    2. Respiratory membrane  a. The respiratory membrane consists of the alveolar  and capillary walls.  b. Gas exchange takes place through these walls.  3. Diffusion through the respiratory membrane    Normal breathing is rhythmic and involuntary, although the  respiratory muscles can be controlled voluntarily.  1. Respiratory areas  a. The respiratory areas are in the brainstem and include  parts of the medulla oblongata and pons.  b. The medullary respiratory center includes two  groups of neurons.   (1) The ventral respiratory group provides the basic  rhythm of breathing.   (2) The dorsal respiratory group stimulates inspiratory  muscles and processes sensory information  regarding the respiratory system. It may play a role  in certain cardiopulmonary reflexes.   c. The pontine respiratory group may contribute to the  rhythm of breathing by limiting inspiration.  2. Partial pressure b.  a. The partial pressure of a gas is determined by the    a. Gases diffuse from regions of higher partial pressure  toward regions of lower partial pressure.   b. Oxygen diffuses from the alveolar air into the blood;  CO, diffuses from the blood into the alveolar air.   a. Oxygen is mainly transported bound to hemoglobin  molecules.  The resulting oxyhemoglobin is unstable and releases  its oxygen in regions where the P, is low.    concentration of that gas in a mixture of gases or the  concentration of gas dissolved in a liquid.  The partial pressure of a gas dissolved in a liquid equals    More oxygen is released as the plasma P.o, increases,  as the blood becomes more acidic, and as the blood  temperature increases.    the partial pressure of that gas in the air with which the  liquid has equilibrated.  3. Factors affecting breathing.  a. Chemicals, lung tissue stretching, and emotional state  affect breathing.  b. Chemosensitive areas (central chemoreceptors) are  associated with the respiratory center.  (1) CO, combines with water to form carbonic acid,  which, in turn, releases hydrogen ions in the CSF.  (2) Stimulation of these areas increases alveolar  ventilation.  c. Peripheral chemoreceptors are in the carotid bodies  and aortic bodies of certain arteries.  (1) These chemoreceptors sense low oxygen levels as  well as excess hydrogen ions.  (2) When oxygen levels are low or blood pH drops,  alveolar ventilation increases.  d. Stretching the lung tissues triggers an inflation reflex.  (1) This reflex reduces the duration of inspiratory   a. CO, may be carried either as dissolved CO, in solution,  CO, bound to hemoglobin, or as a bicarbonate ion.   c. Carbonic anhydrase speeds the reaction between  CO, and water to form carbonic acid as well as the  reverse reaction to breakdown carbonic acid into CO,  and water. :   d. Carbonic acid dissociates to release hydrogen ions and  bicarbonate ions.    The lungs, respiratory passageways, and alveoli undergo aging-  associated changes exacerbated by exposure to polluted air.  However, the increased work required to breathe with age is  typically not noticeable unless one engages in vigorous exercise.    movements. the risk of developing diseases of the respiratory system.  (2) This prevents overinflation of the lungs during 2. Loss of cilia, thickening of mucus, and impaired  forceful breathing. macrophages raise the risk of infection.  e. Hyperventilation decreases CO, levels below normal, 3. Calcified cartilage, skeletal changes, altered posture, and    19.5 Alveolar Gas Exchanges (page 753) 4. Physiologic dead space increases.  Gas exchange between the air and the blood occurs in the alveoli. 5. Alveoli coalesce, decreasing the surface area available for  1. Alveoli gas exchange.    a. The alveoli are tiny sacs clustered at the distal ends of  the alveolar ducts.   b. Some alveoli open into adjacent air sacs through  alveolar pores that provide alternate pathways for air  when passages are obstructed.    List the general functions of the respiratory system. (p. 731)  Explain why oxygen is required at the cellular level. (p. 731)   Explain how the nose and nasal cavity filter incoming air.  (p. 732)   Name and describe the locations of the major sinuses.  (p. 733)   Name and describe the functions of the cartilages of the  larynx. (p. 734)    Name the successive branches of the bronchial tree, from  the main bronchi to the alveoli, and identify their functions.  (pp. 738-739)   Describe how the structure of the respiratory tubes changes  as the branches become finer. (p. 740)   Distinguish between the visceral pleura and the parietal  pleura. (p. 741)    Compare the muscles used in a resting inspiration with those  used in a forced inspiration. (p. 745)   Define surface tension, and explain how it works against the  breathing mechanism. (p. 745)   Compare the muscles used (if any) in a resting expiration  with those used in a forced expiration. (p. 746)    D. volume of air, in addition to resting  tidal volume, that can be expelled  from the lungs   Calculate both minute ventilation and alveolar ventilation  given the following: (p. 749)   Explain the mechanisms of coughing and sneezing, and give  the functions of each. (p. 749)    Locate the respiratory areas and name their major  components. (pp. 750-751)   Explain control of the basic rhythm of breathing. (p. 751)  What is the partial pressure of pure oxygen at sea level?  (p. 752)   Describe the response of the peripheral chemoreceptors  in the carotid and aortic bodies to both CO, and hydrogen  ions. (p. 752)   Describe the effects of emotions on breathing. (p. 753)  Hyperventilation is which one of the following? (p. 753)   b. an increase in breathing that brings in oxygen too quickly  c. an increase in breathing that eliminates CO, too quickly  d. an increase in breathing that has no effect on blood gases   Explain the relationship between the partial pressure of a gas  and its rate of diffusion. (p. 755)   Summarize the exchange of oxygen and CO, across the  respiratory membrane. (p. 755)   List three factors that increase the release of oxygen from  hemoglobin. (p. 758)   Give the percentages of the three ways CO, is transported in  blood. (pp. 758-760)    Describe the changes that make it harder to breathe with  advancing years. (p. 762)    1. Describe the following structures that are part of the respiratory  tubes and state their locations.    2. Patients experiencing asthma attacks are often advised to  breathe through pursed (puckered) lips. How might this help  reduce the symptoms of asthma?    3. What changes would you expect to occur in the levels of blood  oxygen and carbon dioxide in a patient who breathes rapidly  and deeply for a prolonged time?    4. Ifatracheostomy bypasses the upper respiratory passages, how  might the air entering the trachea differ from air normally passing    through this tube? What problems might this cause for the patient?    5. Certain respiratory disorders, such as emphysema, reduce the  capacity of the lungs to recoil elastically. Which respiratory volumes  will this condition affect? Explain the impact on gas exchange.    6. Ifaperson is receiving supplemental oxygen to restore blood  oxygen levels, why might it be better to administer a combination  of oxygen and carbon dioxide rather than pure oxygen?    7. Why is it impossible, under normal circumstances, for a person to  hold the breath long enough to pass out?    8. What problem might a person with a serious respiratory  disorder encounter flying in the passenger compartment of a  commercial aircraft that has an air pressure equivalent to an  altitude of 8,000 feet?    Connect Interactive Questions Reinforce your knowledge using  assigned interactive questions covering respiratory structures, the  mechanics of breathing, and the process of gas transport to and  from tissues.    Anatomy & Physiology Revealed Go more in depth into the  human body by exploring the upper respiratory tract and lower  respiratory tract structures. Also view animations on the process  of breathing.    After you have studied this chapter, you should be able to:    Name the organs of the urinary system and list their  general functions. (p. 769)   Trace the pathway of blood flow through the major  vessels within a kidney. (p. 772)   Describe a nephron and explain the functions of its major  parts. (pp. 775-776)   Explain how glomerular filtrate is produced and describe  its composition. (p. 779)   Explain how various factors affect the rate of glomerular  filtration and identify ways that this rate is regulated.   Explain tubular reabsorption, and its role in urine  formation. (pp. 783-786)   Identify the changes in the osmotic concentration of the  glomerular filtrate as it passes through the renal tubule.  (pp. 783-788)   Explain tubular secretion, and its role in urine formation.  (pp. 787-788)   Identify the characteristics of a countercurrent  mechanism, and explain its role in concentrating the  urine. (p. 789)   Explain how the final composition of urine contributes to  homeostasis. (pp. 791-792)    Describe the structures of the ureters, urinary bladder,  and urethra. (pp. 791-794)    Explain how micturition occurs, and how it is controlled.  (pp. 795-796)   Describe how the components of the urinary system  change with age. (pp. 797-798)    A falsely colored, scanning electron micrograph of part of the kidney shows  one of the million or so glomeruli, which is a tangle of capillaries (red),  where filtration of plasma begins urine formation (1,200x).    The main theme in anatomy and physiology is the maintenance  of a stable internal environment. Consider how many substances  we add to our internal environments every day: the complex of  chemicals called “food,” medications, or simply water. Despite  all of these challenges to maintaining a constant internal envi-  ronment, the composition of our body fluids remains remarkably  steady, thanks largely to the urinary system.   The urinary system is amazingly reliable. The kidneys excrete  exactly the right amounts of whatever we take in to ensure that  the composition and even the total volume of body fluids stay  in a range compatible with life. Each substance is handled sepa-  rately. If we eat heavily salted French fries, the urine later that  day contains more salt than usual. If we don’t drink enough  water, the microscopic tubules that compose the kidneys retain  water, decreasing urine volume. The kidneys are working con-  stantly, yet except for an occasional trip to empty the bladder,  we are unaware from moment to moment of all that they do.    A major part of homeostasis is maintaining the composition, pH,  and volume of body fluids within normal ranges. The urinary  system accomplishes this task. It removes metabolic wastes and  excess biochemicals, yet does not deplete the body of essential  substances. The urinary system also excretes foreign substances,  such as drugs and their metabolites that can be toxic if they remain  in the body fluids after they have exerted their therapeutic effects.   The urinary system consists of a pair of kidneys, which remove  substances from the blood, form urine, and help regulate certain  metabolic processes by secreting hormones; a pair of tubular ure-  ters, which transport urine from the kidneys; a saclike urinary blad-  der, which collects urine from the ureters and serves as a urine  reservoir; and a tubular urethra, which conveys urine to the outside  of the body. Figures 20.1 and 20.2 show these organs.    A kidney is a reddish brown, bean-shaped organ with a smooth  surface. It is about 12 centimeters long, 6 centimeters wide, and 3  centimeters thick in an adult, and it is enclosed in a tough, fibrous  capsule (tunic fibrosa).    The kidneys lie on either side of the vertebral column in a depres-  sion high on the posterior wall of the abdominal cavity. The upper  and lower borders of the kidneys are generally at the levels of the  twelfth thoracic and third lumbar vertebrae, respectively, although  the positions of the kidneys may vary slightly with changes in pos-  ture and with breathing movements (see fig. 20.1). The left kidney  is typically about 1.5 to 2 centimeters higher than the right one.   The kidneys are positioned retroperitoneally (re”tro-per’ I-  to-ne’al-le); they are posterior to the parietal peritoneum and  against the deep muscles of the back. Connective tissue (renal  fascia) and masses of adipose tissue (renal fat) surrounding the  kidneys hold them in place (fig. 20.3 and reference plates 18, 19  on pp. 51 and 52).    The main function of the kidneys is to regulate the volume and  composition of body fluids. In the process, the kidneys remove  metabolic wastes as well as excess water and electrolytes from  the blood and, along with the ureters, urinary bladder, and urethra,  excrete them to the outside as urine. These wastes include nitrog-  enous and sulfur-containing products of protein metabolism, such  as certain metabolic acids.   The kidneys also help control the rate of red blood cell for-  mation by secreting the hormone erythropoietin (see chapter 14,  p. 533), regulate blood pressure by secreting the enzyme renin (see  chapter 13, p. 511), and regulate absorption of calcium ions by  activating vitamin D (see chapter 18, p. 706).    The 83-year-old woman's kidneys have been slowly failing  for several years. Now, with her kidneys working at less than  10% of normal, she requires hemodialysis to cleanse her blood  of toxins and wastes and remove excess fluid. A nephrologist  has prescribed dialysis three times a week, for three to four  hours per session, to treat her chronic kidney disease.   A dialysis technician performs the tasks of hemodialysis,  including:  e Setting up, cleaning, sterilizing, and operating the dialysis    Dialysis technicians work in hospitals and dialysis  centers, as well as assist patients performing peritoneal  dialysis in their homes. Training programs typically take two  semesters, leading to a written exam for certification and  national licensure. Students learn anatomy and physiology,  nutrition, transplantation, pharmacology, health information  management, medical terminology, and clinical skills related  to performing dialysis.    FIGURE 20.1 (AP|R) The urinary system includes the kidneys, FIGURE 20.2 fAP|R) Structures of the urinary system    ureters, urinary bladder, and urethra. Notice the relationship of these  structures to the major blood vessels.    Medical technology can take over some of the roles of a kid-  ney. In hemodialysis, a person’s blood is rerouted across an artifi-  cial membrane that “cleanses” it, removing substances that would  normally be excreted in the urine, and adding some substances  that the kidney normally produces.    The lateral surface of each kidney is convex, but its medial side  is deeply concave. The resulting medial depression leads into  a hollow chamber called the renal sinus (fig. 20.4). Through  the entrance to this sinus, termed the hilum, pass blood vessels,  nerves, lymphatic vessels, and the ureter (fig. 20.5, see fig. 20.1).   The superior end of the ureter expands to form a funnel-  shaped sac called the renal pelvis, which is located mostly inside  the renal sinus and directs the urine formed by the kidney toward  the ureter. The pelvis is formed by the convergence of two or  three tubes, called major calyces (sing., calyx), and they, in turn,  are formed by the convergence of seven to twenty minor calyces  (see fig. 20.4). At least one small projection called a renal papilla  extends into each minor calyx.   The kidney includes two distinct regions: an inner medulla  and an outer cortex. The renal medulla (re’nal mé-dul’ah) is com-  posed of conical masses of tissue called renal pyramids. Their  bases orient toward the convex surface of the kidney, and their  apexes form the renal papillae. The tissue of the medulla appears  striated because it consists of microscopic tubules that lead from  the cortex to the renal papillae.   The renal cortex (re’nal kor’teks), which appears somewhat  granular, forms a shell around the medulla. It dips into the medulla    between the renal pyramids, forming renal columns. The renal  capsule is a fibrous membrane that surrounds the cortex and helps  maintain the shape of the kidney. It also is protective (see fig. 20.4).   Certain organs, such as the kidneys, can be broken down  into subunits, each of which performs the functions of the organ  as a whole. In the kidneys, these functional units are called  nephrons (nef’ronz), and each kidney contains about | million  of them. Each nephron in turn consists of a renal corpuscle  (re’nal kor’pusl) and a renal tubule (re’nal tu’bil) (see fig. 20.4).  Nephrons are responsible for urine formation, and will be dis-  cussed in detail later in this chapter.    1 Where are the kidneys located?  2 What are the general functions of the kidneys?    About two in every ten patients with renal failure can use a pro-  cedure that can be done at home called continuous ambulatory  peritoneal dialysis instead of hemodialysis. The patient infuses  a solution into the abdominal cavity through a permanently  implanted tube. The solution stays in for four to eight hours,  while it takes up substances that would normally be excreted  into urine. Then the patient drains the waste-laden solution out  of the tube, replacing it with clean fluid. Infection is a risk associ-  ated with this procedure.    FIGURE 20.3 The kidneys are located retroperitoneally. (a) Transverse section through the posterior abdominal cavity including the kidneys, behind the  parietal peritoneum. Adipose and other connective tissues surround and support the kidneys. (b) Sagittal section through the posterior abdominal cavity    The renal arteries, which arise from the abdominal aorta, trans-  port a large volume of blood to the kidneys (fig. 20.5). When a  person is at rest, the renal arteries usually carry 15% to 30% of the  total cardiac output into the kidneys, although the kidneys account  for less than 1% of body weight. This disproportionately large  blood flow reflects the kidney’s role in maintaining the volume and  composition of the body fluids.   A renal artery enters a kidney through the hilum and gives  off several branches, called the interlobar arteries, which pass  between the renal pyramids. At the junction between the medulla    and the cortex, the interlobar arteries branch to form a series of  incomplete arches, the arcuate arteries (arciform arteries), which  in turn give rise to cortical radiate arteries (interlobular arteries).  The final branches of the cortical radiate arteries, called afferent  arterioles (af’er-ent ar-te’re-G1z), lead to the nephrons, the func-  tional units of the kidneys. Each afferent arteriole gives rise to a  tuft of capillaries within the renal corpuscle called the glomerulus  (glomerular capillaries).   Blood passes through the glomerular capillaries, and then  (minus any filtered fluid) enters an efferent arteriole. (This is  different from entering a venule, which is the usual circulatory    FIGURE 20.4 (AP|R} The kidney. (a) Longitudinal section of a kidney. (b) A renal pyramid containing nephrons. (c) A single nephron.    FIGURE 20.5 Blood vessels are associated with the kidneys and adrenal glands. Note their relationship with the renal pelvis and ureters.    FIGURE 20.6 (AP|R]  Renal blood vessels. (a) a  simplified diagram showing  the relationship between the    route.) The efferent arterioles typically lead to complex networks  of capillaries in the renal cortex that surround the renal tubules,  called the peritubular capillaries (per’i-tu’bu-lar kap’i-ler’es)  that empty into the venous system of the kidney.   Only 10% to 15% of the renal blood flow reaches the medulla.  A small fraction of efferent arterioles form relatively straight, par-  allel bundles of blood vessels that descend into the renal medulla,  form capillary loops, and then ascend back to the cortex. These  bundles are called the vasa recta. After blood flows through the  vasa recta it returns to the renal cortex, where it enters the venous  system of the kidney.   Venous blood returns through a series of vessels that gener-  ally correspond to the arterial pathways. For example, the venous  blood passes through cortical radiate, arcuate, interlobar, and renal  veins. The renal vein then joins the inferior vena cava as it courses  through the abdominal cavity. Figure 20.6 shows branches of the  renal arteries and veins. Figure 20.7 shows detail of the blood ves-  sels and other structures associated with the nephrons.   Figure 20.8 summarizes the pathway that blood follows as it  passes through the blood vessels of the kidney. Blood circulating  through two capillaries as it moves through the kidney is another  example of a portal system (see fig. 15.55, p. 605). (b)    FIGURE 20.7 Blood vessels associated with nephrons. (a) A scanning electron micrograph of a cast of the renal blood vessels associated with the  glomeruli (200x). (b) A scanning electron micrograph of a glomerular capsule surrounding a glomerulus (480x). Tissues and Organs: A Text-Atlas of  Scanning Electron Microscopy, by R. G. Kessel and R. H. Kardon. ©1979 W. H. Freeman and Company.    To Chapter 13, Portal system, pages 498-499.  To Chapter 17, Portal system, page 670.    rons. Each nephron in turn consists of a renal corpuscle and a  renal tubule (see fig. 20.4).    A renal corpuscle consists of a filtering unit composed of a  tangled cluster of blood capillaries called a glomerulus (glo-  mer’u-lus) and a surrounding thin-walled, saclike structure called  a glomerular (Bowman’s) capsule. An afferent arteriole gives rise  to these capillaries, which lead to an efferent arteriole (ef’er-ent  ar-te’re-61) (see fig. 20.7).   Filtration of fluid from the glomerular capillaries is the first  step in urine formation. The glomerular capsule is an expansion  at the end of a renal tubule that receives the fluid filtered at the  glomerulus. The capsule is composed of two layers of epithelial  cells: a visceral layer that closely covers the glomerulus and an  outer parietal layer that is continuous with the visceral layer and  with the wall of the renal tubule (fig. 20.9a).   The cells of the parietal layer are typical squamous epithelial  cells, but those of the visceral layer are highly modified epithelial  cells called podocytes. Each podocyte has several primary processes  extending from its cell body, and these processes, in turn, bear  numerous secondary processes, called pedicels (foot processes).  The pedicels of each cell interdigitate with those of adjacent podo-  cytes, and the clefts between them form a complicated system of slit  pores (fig. 20.9b).    , a  A cascade of cell-to-cell communication forms glomeruli in the  embryo. Podocyte precursor cells give rise to podocytes, but  also secrete vascular endothelial growth factor (VEGF), which  attracts the squamous epithelium that forms the parietal layer.  These epithelial cells then produce platelet-derived growth  factor (PDGF) and extracellular matrix proteins, which in turn  signal certain cells to specialize as mesangial cells. These cells  are closely associated with the capillary tuft, and can contract,  which decreases the rate at which the glomerulus filters plasma.  Mesangial cells also provide structural support to the glomeru-  lus and phagocytize debris.    FIGURE 20.9 (AP|R) (a) The glomerular capsule has a visceral layer and a parietal layer. (b) Scanning electron micrograph of a portion of a    Filtered fluid enters the renal tubule, which leads away from  the glomerular capsule and becomes highly coiled. This coiled  portion is the proximal convoluted tubule. Following it is the  nephron loop (loop of Henle). The proximal convoluted tubule  dips toward the renal pelvis to become the descending limb of the  nephron loop. The tubule then curves back toward its renal corpus-  cle and forms the ascending limb of the nephron loop. The ascend-  ing limb returns toward its renal corpuscle of origin, where it  becomes the distal convoluted tubule (fig. 20.10a). This distal por-  tion is shorter and somewhat less coiled than the proximal tubule.   Several distal convoluted tubules merge in the renal cortex  to form a collecting duct (collecting tubule), which is technically  not part of any one nephron but instead collects fluid from mul-  tiple nephrons. The collecting duct passes into the renal medulla,  widening as it joins other collecting ducts. The resulting tube  empties into a minor calyx through an opening in a renal papilla  (see figure 20.6). Figures 20.10 and 20.11 show the parts of a  nephron. Figure 20.12 lists the structures involved in urine for-  mation and excretion. Clinical Application 20.1 examines glo-  merulonephritis, an inflammation of the glomeruli.   Most nephrons have renal corpuscles in the renal cortex near the  surface of the kidney. These are called cortical nephrons and gen-  erally have short loops that extend only part way into the renal  medulla. Another group of nephrons, called juxtamedullary neph-  rons, have corpuscles located deep in the cortex, close to the renal  medulla. Their loops extend well into the medulla (see fig. 20.6).  Although juxtamedullary nephrons represent only a small fraction    of the total, they are important in regulating water balance and are  discussed in more detail later in this chapter.   At the end of the nephron loop, before it becomes the distal con-  voluted tubule, the ascending limb passes between the afferent  and efferent arterioles of its own glomerulus and contacts them.  Here, the epithelial cells of the ascending limb are tall and densely  packed, composing a structure called the macula densa.   Close by, in the wall of the afferent arteriole near its attach-  ment to the glomerulus, are large, vascular smooth muscle cells  called juxtaglomerular cells. Together with the cells of the macula  densa, they constitute the juxtaglomerular apparatus (juks”tah-  glo-mer’u-lar ap”ah-ra’tus). This structure plays a role in regulat-  ing the secretion of renin (fig. 20.13; see chapter 13, p. 511).    The main function of the nephrons and collecting ducts is to con-  trol the composition of body fluids and remove wastes from the  blood. The product is urine, which is excreted from the body.    FIGURE 20.10 (AP|R) A nephron. (a) Structure of a nephron plus the afferent and efferent arterioles. (b) Schematic representation of a nephron  and the blood vessels associated with it.    Nephritis is an inflammation of the kidney. Glomerulonephritis is  an inflammation of the glomeruli, and it may be acute or chronic  and can lead to renal failure.   Acute glomerulonephritis (AGN) can result from an abnor-  mal immune reaction that develops one to three weeks follow-  ing bacterial infection by beta-hemolytic Streptococcus. The  infection is not in the kidneys, but bacterial antigens trigger  production of antibodies that form insoluble immune com-  plexes (see chapter 16, p. 638) that travel in the bloodstream  and lodge in the kidneys. The antigen-antibody complexes  are deposited in and block the glomerular capillaries, which  become further obstructed as the inflammatory response sends  white blood cells to the region. Capillaries remaining open may    become abnormally permeable, allowing plasma proteins and  red blood cells to enter the urine.   Most acute glomerulonephritis patients eventually regain  normal kidney function. However, in severe cases, renal functions  may fail completely. Without treatment, the disease is usually  fatal within a week or so.   Chronic glomerulonephritis is a progressive disease in which  more and more nephrons are damaged until the kidneys are unable  to function. The cause of this condition is not fully understood, but  it may also involve formation of antigen-antibody complexes that  precipitate and accumulate in the glomeruli. The resulting inflamma-  tion is prolonged, and fibrous tissue replaces glomerular membranes,  permanently disabling the nephrons. Eventually the kidneys fail.    FIGURE 20.11 fAP|R) Microscopic view of the kidney. (a) Light micrograph of a section of the human renal cortex (220x). (b) Light micrograph of  the renal medulla (80x).    Urine formation begins when the glomerular capillaries filter  plasma, a process called glomerular filtration (glo-mer’u-lar fil-  tra’shun). Recall from chapter 15 (p. 581) that the force of blood  pressure drives filtration at capillaries throughout the body. Most  of this fluid is reabsorbed into the bloodstream by the colloid  osmotic pressure of the plasma, leaving only a small volume of  interstitial fluid (fig. 20.14a).    Urine contains wastes, along with excess water and electrolytes.  Urine formation involves three steps, which are discussed in the  following paragraphs:    FIGURE 20.12 A summary of the sequence of the structures involved  in the formation and elimination of urine.    Nephrons take filtration and reabsorption to another level,  using two capillary beds working in series. The first capillary bed  is specialized only to filter. However, instead of forming intersti-  tial fluid, the filtered fluid (filtrate) moves into the renal tubule  as tubular fluid, where some of it is destined to become urine  (fig. 20.145).   Glomerular filtration produces 180 liters of fluid, more than  four times the total body water, every 24 hours. Obviously this  output could not continue for long unless most of this filtered fluid  were returned to the internal environment. The kidney accom-  plishes this by the process of tubular reabsorption (too’bu-lar  re-ab-sorp’shun), selectively reclaiming just the right amounts of  substances, such as water, electrolytes, and glucose, that the body  requires (fig. 20.14). Waste products and substances in excess  are allowed out of the body.    within the peritubular capillary system into the renal tubule.  Tubular secretion removes some substances that the body must  eliminate, such as hydrogen ions and certain toxins, faster than  filtration alone (fig. 20.145).   Overall, the following relationship determines the volume of  substances excreted in the urine:    Urine formation begins when glomerular filtration filters water  and other small dissolved molecules and ions out of the glomerular  capillary plasma and into the glomerular capsules. Large mol-  ecules, such as proteins, are restricted primarily because of their  size. The filtration of these materials through the capillary walls  is much like the filtration at the arteriolar ends of other capillar-  ies throughout the body. The glomerular capillaries, however, are  many times more permeable to small molecules than are the capil-  laries in other tissues, due to the many tiny openings (fenestrae) in  their walls (fig. 20.15).    ® RECONNECT  “ To Chapter 15, Exchanges in the Capillaries, page 581.    The glomerular capsule receives the resulting glomerular  filtrate, which has about the same composition as the filtrate that  becomes tissue fluid elsewhere in the body. Glomerular filtrate is  mostly water and the same solutes as in blood plasma, except for  the larger protein molecules. More specifically, glomerular filtrate  includes water, glucose, amino acids, urea, uric acid, creatine, cre-  atinine, sodium, chloride, potassium, calcium, bicarbonate, phos-  phate, and sulfate ions.    The concentrations of certain components of the blood plasma  can be used to evaluate kidney functions. For example, if the  kidneys are functioning inadequately, the plasma concentra-  tions of urea (a nitrogenous waste) indicated by a blood urea  nitrogen (BUN) test and creatinine may increase as much as ten-  fold above normal (see Appendix C, Common Tests Performed  on Urine).    The main force that moves substances by filtration through the  glomerular capillary wall, as in other capillaries, is the hydrostatic  pressure of the blood inside. The afferent arterioles have diameters  larger than the efferent arterioles. The greater resistance to blood  flow of the efferent arteriole causes blood to back up into the glo-  merular capillaries. This raises the blood pressure in the glomeru-  lar capillaries, favoring filtration.    FIGURE 20.13 Juxtaglomerular apparatus. (a) Location of and (b) enlargement of a section of the juxtaglomerular apparatus, which consists of the  macula densa and the juxtaglomerular cells.    The colloid osmotic pressure of the plasma caused by plasma Net . ;  proteins and the hydrostatic pressure inside the glomerular capsule filtration: = force favoring = forces SPposine  also influence glomerular filtration. The plasma colloid osmotic pressure filtration filtration  pressure is always higher than that of the glomerular filtrate (except F :   The result of these forces is called net filtration pressure,  and it is normally positive, favoring filtration at the glomerulus.  Net filtration pressure is calculated as follows:    FIGURE 20.14 Compared to most  capillaries in the (a) systemic circulation,  those in the (b) kidneys are highly  specialized for filtration.    (a) In most systemic capillaries, filtration predominates at the arteriolar end  and osmotic reabsorption predominates at the venular end.    (b) In the kidneys, the glomerular capillaries are specialized for filtration. The renal tubule is  specialized to control movements of substances back into the blood of the peritubular  capillaries (tubular reabsorption) or from the blood into the renal tubule (tubular secretion).    FIGURE 20.15 Glomerular filtration. (a) The first step in urine formation is filtration of substances out of glomerular capillaries and into the glomerular  capsule. (b) Glomerular filtrate passes through the fenestrae of the capillary endothelium.    Outward force, glomerular hydrostatic pressure =  Inward force of plasma colloid osmotic pressure =  Inward force of capsular hydrostatic pressure =) 16mm    FIGURE 20.16 Normally the glomerular net filtration pressure is  positive, causing filtration. The responsible forces include the hydrostatic  and osmotic pressure of the plasma and the hydrostatic pressure of the  fluid in the glomerular capsule.    At rest, the kidneys receive approximately 25% of the cardiac out-  put, and about 20% of the blood plasma is filtered as it flows through  the glomerular capillaries. This means that in an average adult, the  glomerular filtration rate for the nephrons of both kidneys is about  125 milliliters per minute, or 180,000 milliliters (180 liters) in twenty-  four hours. Estimating the blood plasma volume at about 3 liters, the  production of 180 liters of filtrate in twenty-four hours means that  an amount equivalent to the entire plasma volume must be filtered  through the glomeruli about sixty times each day. Clearly not all of it  is excreted as urine (fig. 20.17). Instead, most of the fluid that passes  through the renal tubules is reabsorbed and reenters the plasma.   The glomerular filtration rate (GFR) is directly proportional  to the net filtration pressure. If the net filtration pressure increases,  GFR goes up, and if net filtration pressure decreases, GFR goes  down. Consequently, the factors that affect the glomerular hydro-  static pressure, glomerular plasma colloid osmotic pressure, or  hydrostatic pressure in the glomerular capsule also affect the rate  of filtration (see fig. 20.16). GFR is the most commonly measured  index of kidney function.   Normally, glomerular hydrostatic pressure is the most important  factor determining net filtration pressure and GFR. Because each glo-  merular capillary lies between two arterioles—the afferent and effer-  ent arterioles—any change in the diameters of these vessels is likely  to change glomerular hydrostatic pressure, affecting glomerular fil-  tration rate. If the afferent arteriole (through which blood enters the  glomerulus) constricts, filtration pressure will decrease. In contrast,    180 +  170 +  160 +  150 +  140 b  130 +  120+  110 F  100 +    FIGURE 20.17 Relative volumes of (a) glomerular filtrate and (b) urine  formed in twenty-four hours.    if the efferent arteriole (through which blood leaves the glomerulus)  constricts, blood backs up into the glomerulus and filtration pressure  rises. Vasodilation of these vessels produces opposite effects.   The colloid osmotic pressure of the glomerular plasma also  influences net filtration pressure and the rate of filtration. In other  systemic capillaries, filtration occurs at the beginning of the capil-  lary, but the osmotic effect of the plasma proteins predominates at  the end of the capillary, and most filtered fluid is thus reabsorbed.  The small excess remaining eventually becomes lymph.   Much more fluid is filtered by glomerular capillaries than by  capillaries elsewhere because of the relatively high hydrostatic pres-  sure in the glomerular capillaries. In fact, as filtration occurs through  the capillary wall, proteins remaining in the plasma raise the colloid  osmotic pressure within the glomerular capillaries. Despite this, the  glomerular capillary hydrostatic pressure is sufficiently great that  the net filtration pressure is normally positive. That is, the forces  favoring filtration in the glomerular capillaries always predominate.  Of course, conditions that lower plasma colloid osmotic pressure,  such as a decrease in plasma protein concentration, would increase  filtration rate.   The hydrostatic pressure in the glomerular capsule is another  factor that may affect net filtration pressure and GFR. This capsular    pressure can change as a result of an obstruction, such as a stone in  a ureter or an enlarged prostate gland pressing on the urethra. If this  occurs, fluids may back up into the renal tubules and raise the hydro-  static pressure in the glomerular capsules. Any increase in capsular  pressure opposes glomerular filtration, so filtration rate may signifi-  cantly decrease.   The volume of plasma the kidneys filter also depends on the  large surface area of the glomerular capillaries. This surface area  is estimated to be about 2 square meters—approximately equal to  the surface area of an adult’s skin.    In general, glomerular filtration rate remains relatively constant  through a process called autoregulation. However, certain con-  ditions override autoregulation. GFR may increase, for example,  when body fluids are in excess and decrease when the body must  conserve fluid.   Recall from chapter 15 (p. 577) that the sympathetic nervous  system controls the vascular smooth muscle of arterioles. Reflexes  responding to changes in blood pressure and volume control sym-  pathetic activity. If blood pressure drops, vasoconstriction of both  the afferent and efferent arterioles results. Afferent arteriole con-  striction helps maintain peripheral resistance and systemic pressure,  but would lower filtration pressure. Simultaneous constriction of the  efferent arteriole counteracts this effect on filtration pressure. Thus,  systemic pressure is protected, but GFR remains relatively constant.    If arterial blood pressure drops greatly, such as during shock, the  resulting increase in sympathetic stimulation may cause so much  afferent arteriolar constriction that glomerular hydrostatic pressure  falls below the level required for filtration, leading to acute renal  failure. At the same time, the epithelial cells of the renal tubules  may not receive sufficient nutrients to maintain their high rates of  metabolism. Cells may die (tubular necrosis), and renal functions  may be lost permanently, resulting in chronic kidney disease.    A second control of GFR is the hormonelike renin-angiotensin  system. The juxtaglomerular cells of the afferent arterioles secrete  an enzyme, renin, in response to stimulation from sympathetic  nerves and pressure-sensitive cells, called renal baroreceptors,  in the afferent arteriole. These factors stimulate renin secretion if  blood pressure drops. The macula densa also controls renin secre-  tion. Cells of the macula densa sense the numbers of sodium, potas-  sium, and chloride ions in the ascending limb of the nephron loop.  Decreasing levels of these ions stimulate renin secretion.   Once in the bloodstream, renin reacts with the plasma protein  angiotensinogen to form angiotensin I. An enzyme, angiotensin-    converting enzyme (ACE), on capillary endothelial cells (particu-  larly in the lungs), rapidly converts angiotensin I to angiotensin IT  (fig. 20.18).   Angiotensin II has a number of renal effects that help main-  tain sodium balance, water balance, and blood pressure. As a  vasoconstrictor, angiotensin II affects both the afferent and effer-  ent arterioles. Although afferent arteriolar constriction decreases  GFR, efferent arteriolar constriction minimizes the decrease, thus  contributing to autoregulation of GFR. Angiotensin II has a major  effect on the kidneys through the adrenal cortical hormone aldoste-  rone, which stimulates sodium reabsorption in the distal convoluted  tubule. By stimulating aldosterone secretion, angiotensin II helps to  reduce the amount of sodium excreted in the urine. Angiotensin II  also stimulates ADH secretion, helping to retain water.   Two cardiac hormones, atrial natriuretic peptide (ANP) and  ventricular natriuretic peptide (BNP) increase sodium excretion.  ANP is secreted when blood volume increases and BNP when blood  pressure increases. Both inhibit the renin-angiotensin system.    Eating raw spinach or undercooked hamburger, drinking unpas-  teurized apple cider, and petting animals at country fairs have all  led to hemolytic uremic syndrome (HUS). The direct cause is a  poison called shigatoxin that a certain strain of E. coli (bacteria)  produces. Humans encounter the toxin through excrement—in  the water used to grow spinach, in beef contaminated during  processing, from apples that fell into droppings, and from tiny  hands unwashed after petting animals. Food poisoning from  toxin-producing E. coli begins with sharp abdominal pain and  bloody diarrhea, and about 16% of the time HUS develops.  About 5% of HUS cases are fatal.   Shigatoxin causes fibrin to form thrombi that obstruct the  narrow glomerular capillaries. Platelets join the clumping, deplet-  ing the circulation of these cell fragments (thrombocytopenia).  Red blood cells in the blocked glomerular capillaries break apart,  causing hemolytic anemia. As GFR plummets, the person, typi-  cally a child, goes into acute renal failure.    If the composition of the glomerular filtrate entering the renal  tubule is compared with that of urine, it is apparent that the fluid  changes as it passes through the tubule. Table 20.1 compares the  concentrations of some of the substances in the blood plasma, glo-  merular filtrate, and urine. For example, glucose is present in the  filtrate but absent in the urine. Such a change in fluid composition  is largely the result of tubular reabsorption, the process by which  substances are transported out of the tubular fluid, through the  epithelium of the renal tubule, and into the interstitial fluid. These  substances then diffuse into the peritubular capillaries or the vasa  recta (fig. 20.19).   In contrast, other substances are more concentrated in urine  than they are in the glomerular filtrate (see table 20.1). This differ-  ence reflects tubular secretion of certain substances as well as the  reabsorption of water from the renal collecting ducts, described in  detail later.    FIGURE 20.18 The formation of angiotensin II in the bloodstream  involves several organs and results in multiple actions that conserve  sodium and water.    Tubular reabsorption returns substances to the internal envi-  ronment. The term tubular is used because this process is carried  out by the epithelial cells that make up the renal tubules and col-  lecting ducts. In tubular reabsorption, substances must first cross  the cell membrane facing the inside of the tubule (mucosal sur-  face) and then the cell membrane facing the interstitial fluid (sero-  sal surface).   The basic rules for movements across cell membranes apply  to tubular reabsorption. Substances moving down a concentra-  tion gradient must either be lipid soluble or there must be a carrier  or channel for that substance. Active transport, requiring ATP,  may move substances uphill against a concentration gradient.  If active transport is involved at any step of the way, the over-  all process is considered active. In all other cases, the process is  considered passive.    “ To Chapter 3, Movements Into and Out of the Cell,  pages 98-104.    Peritubular capillary blood is under relatively low pressure  because it has already passed through two arterioles and a capil-  lary bed. Also, the wall of the peritubular capillary is more perme-  able than that of other capillaries. Finally, the relatively high rate  of glomerular filtration has increased the protein concentration  and, thus, the colloid osmotic pressure of the peritubular capillary  plasma. These factors enhance the rate of fluid reabsorption from  the renal tubule.    TABLE 20.1 Relative Concentrations of Plasma, Glomerular Filtrate, and Urine Components    Substance Plasma  Sodium (Na*) 142  Potassium (K*) 5)  Calcium (Ca*?) 4  Magnesium (Mg*) 3  Chloride (CF) 103  Bicarbonate (HCO, ) 27  Sulfate (SO,*) 1  Phosphate (PO, *) 2    (mEq/L [milliequivalents per liter] is a commonly used measure of concentration based on how many charges an ion carries. For a substance with a    charge of 1, such as CI, a milliequivalent is equal to a millimole.)    (mg% [mg of a substance per 100 mL of solution] is a commonly used measure of concentration of solute. It is equivalent to mg/deciliter [mg/dL].)    FIGURE 20.19 (AP|R) Two processes in addition to glomerular filtration help to form urine. Tubular reabsorption transports substances from the  glomerular filtrate into the blood in the peritubular capillary. Tubular secretion transports substances from the blood in the peritubular capillary into the    4  © Which of the three processes (glomerular filtration, tubular reabsorption, tubular secretion), if increased for a substance, would    Tubular reabsorption occurs throughout the renal tubule.  However, most of it occurs in the proximal convoluted portion.  The epithelial cells in this area have many microvilli that form a  “brush border” on their free surfaces facing the tubular lumen.  These tiny extensions greatly increase the surface area exposed to  the glomerular filtrate and enhance reabsorption.   Segments of the renal tubule are adapted to reabsorb specific  substances, using particular modes of transport. Glucose reabsorp-  tion, for example, takes place through the walls of the proximal  convoluted tubule by active transport. Water also is rapidly reab-  sorbed through the epithelium of the proximal convoluted tubule  by osmosis; however, portions of the distal convoluted tubule and  collecting duct may be almost impermeable to water. This char-  acteristic of the distal convoluted tubule and collecting duct is  important in the regulation of urine concentration and volume, as  described in a subsequent section.   Recall that active transport requires carrier proteins in a cell  membrane. The molecule to be transported binds to the carrier.  The carrier changes shape, releases the transported molecule on  the other side of the cell membrane, and then returns to its origi-  nal shape and repeats the process. Such a mechanism has a limited  transport capacity. That is, it can transport only a certain number of  molecules in a given time because the number of carriers is limited.   Usually all of the glucose in the glomerular filtrate is reab-  sorbed because there are enough carrier molecules to transport  it. When the plasma glucose concentration increases to a critical    level, called the renal plasma threshold, more glucose molecules  are in the filtrate than the active transport mechanism can handle.  As a result, some glucose remains in the filtrate and is excreted in  the urine. This overwhelming of the active transport mechanism  for glucose reabsorption explains why the elevated blood glucose  of diabetes mellitus results in glucose in the urine.   An increase in urine volume is called diuresis. Nonreabsorbed  glucose in the tubular fluid increases the osmotic concentration of  the tubular fluid, which reduces the volume of water reabsorbed by  osmosis from the proximal tubule and collecting duct. The resul-  tant increase in urine volume is called an osmotic diuresis.   Amino acids enter the glomerular filtrate and are reabsorbed  in the proximal convoluted tubule. Three active transport mecha-  nisms reabsorb different types of amino acids with similar struc-  tures. Normally only a trace of amino acids remains in the urine.   The glomerular filtrate is nearly free of protein, but a num-  ber of smaller protein molecules, such as albumin, may squeeze  through the glomerular capillaries. These proteins are transported  by endocytosis through the brush border of epithelial cells lining  the proximal convoluted tubule. Once inside an epithelial cell, the  proteins are degraded to amino acids, which are moved into the  blood of the peritubular capillary.   The epithelium of the proximal convoluted tubule also reab-  sorbs lactic, citric, uric, and ascorbic (vitamin C) acids; and  phosphate, sulfate, calcium, potassium, and sodium ions. Active  transport mechanisms with limited transport capacities reabsorb    The nephrotic syndrome is a set of symptoms that often appears  in patients with renal diseases. Considerable loss of plasma pro-  teins into the urine (proteinuria) results in widespread edema and  increased susceptibility to infection.   Plasma proteins enter the urine because of increased per-  meability of the glomerular membranes, which accompanies  renal disorders such as glomerulonephritis. As a consequence of  a decreasing plasma protein concentration (hypoproteinemia),  the plasma colloid osmotic pressure falls, increasing net filtra-  tion pressure in capillaries throughout the body. This may lead to  widespread accumulation of fluid in interstitial spaces in tissues  (edema) and in body spaces such as the abdominal cavity (asci-  tes), pleural cavity, pericardial cavity, and joint cavities.    all of these chemicals. The amounts of substances in the urine will  increase if their concentrations in the glomerular filtrate exceed their  respective renal plasma thresholds. Clinical Application 20.2 dis-  cusses how plasma proteins enter the urine in nephrotic syndrome.    Glucose in the urine is called glucosuria. It may follow intrave-  nous administration of glucose, or eating candy, or it may occur  in a person with diabetes mellitus. In type 1 diabetes, blood glu-  cose concentration rises because of insufficient insulin secretion  from the pancreas (see Clinical Application 13.4, page 516).   One in three people who have diabetes mellitus sustains  kidney damage (nephropathy). In the past, large amounts of the  protein albumin in the urine indicated high risk of developing  kidney damage. Recent studies show that small amounts of allbu-  min (microalbuminuria) predict kidney damage in people with  type 1 diabetes. Following a low-protein diet can slow the loss of  kidney function.    Water reabsorption occurs passively by osmosis, primarily in  the proximal convoluted tubule, and is closely associated with  the active reabsorption of sodium ions. In the proximal convo-  luted tubule, if sodium reabsorption increases, water reabsorption  increases; if sodium reabsorption decreases, water reabsorption  decreases also.   In addition to active mechanisms, reabsorption of some sol-  utes is passively linked to active reabsorption of sodium ions.  When the positively charged sodium ions (Na*) are moved through  the tubular wall, negatively charged ions, including chloride ions  (Cl) and phosphate ions (PO es two abundant plasma anions,  accompany them. This movement of negatively charged ions is  due to the electrochemical attraction between particles of opposite    As edema and other fluid accumulation develops, blood vol-  ume decreases and blood pressure drops. These changes may  activate the renin-angiotensin system, stimulating the adrenal  cortex to release aldosterone (see chapter 13, p. 511) and the  posterior pituitary to release antidiuretic hormone (see chap-  ter 13, p. 503), which in turn stimulates the kidneys to conserve  sodium ions and water. This action helps to restore blood volume  and may aggravate the edema.   The nephrotic syndrome sometimes appears in young chil-  dren who have lipoid nephrosis. The cause of this condition is  unknown, but it alters the epithelial cells of the glomeruli so that  the glomerular membranes enlarge and distort, allowing proteins  to be filtered.    electrical charge. Although this movement of negatively charged  ions depends on active transport of sodium, it is considered a pas-  sive process because it does not require a direct expenditure of cel-  lular energy. Active transport also reabsorbs some negative ions  directly, such as bicarbonate (HCO,_) and phosphate.   As more sodium ions are reabsorbed into the peritubular  capillary along with negatively charged ions, the concentration  of solutes in the peritubular blood might be expected to increase.  However, because water moves by osmosis through cell mem-  branes from regions of lesser solute concentration (hypotonic)  toward regions of greater solute concentration (hypertonic), water  is also reabsorbed, following the ions from the renal tubule into  the peritubular capillary.   The proximal convoluted tubule reabsorbs about 70% of the  filtered sodium, other ions, and water. By the end of the proxi-  mal convoluted tubule, osmotic equilibrium is reached, and the  remaining tubular fluid is isotonic (fig. 20.20).   Active transport continues to reabsorb sodium ions as the  tubular fluid moves through the nephron loop, the distal convo-  luted tubule, and the collecting duct. Consequently, almost all of  the sodium and water (97% to 99%) that enters the renal tubules as  part of the glomerular filtrate may be reabsorbed before the urine  is excreted. However, aldosterone controls sodium reabsorption,  and antidiuretic hormone controls water reabsorption. Under the  influence of these hormones, reabsorption of sodium and water can  change to keep conditions in the body fluids constant. Chapter 21  (pp. 808 and 809) discusses the specific effects of antidiuretic hor-  mone and aldosterone, respectively.   Recall that the kidneys filter an extremely large volume of  fluid (180 liters) each day. If 99% of the glomerular filtrate is  reabsorbed, the remaining 1% excreted includes a relatively large  amount of sodium and water (table 20.2). On the other hand, if  sodium and water reabsorption decrease to 97% of the amount fil-  tered, the amount excreted triples! Therefore, small changes in the  tubular reabsorption of sodium and water result in large changes in  urinary excretion of these substances.    FIGURE 20.20 In the proximal part of the renal tubule, osmosis reabsorbs water in response to reabsorption of sodium and other solutes.    12 Which substances in glomerular filtrate are not normally present  in urine?    In tubular secretion, certain substances move from the plasma  of the peritubular capillary into the fluid of the renal tubule (see  20.19). Because of tubular secretion, the amount of a particular  chemical excreted in the urine may exceed the amount filtered  from the plasma in the glomerulus (see table 20.1). This process  can be so thorough that in the case of some substances virtually    none can be detected in the blood leaving through the renal vein.  The term tubular is used because the epithelial cells of the renal  tubules carry out the process, as they do in tubular reabsorption.   Active transport mechanisms similar to those that function  in reabsorption secrete some substances. However, the secre-  tory mechanisms transport substances in the opposite direction.  For example, the epithelium of the proximal convoluted tubules  actively secretes certain organic compounds, including penicillin  and histamine, into the tubular fluid.   Hydrogen ions are actively secreted throughout the entire  renal tubule. Urine is usually acidic by the time it is excreted,  although the urinary pH can vary considerably. The secretion of  hydrogen ions is important in regulating the pH of body fluids, as  chapter 21 (p. 816) explains.    The kidneys respond to certain chemicals, including antibiot-  ics, by eliminating them from the body as rapidly as possible.  In some cases, such as elimination of toxins, this is benefi-  cial. In the case of helpful drugs, however, it is undesirable.  The drug probenecid is given with certain antibiotics to block    their tubular secretion, increasing their levels in the plasma.  For example, by blocking tubular secretion of penicillin, pro-  benecid increases plasma concentration of penicillin two to  four fold. It also acts on ampicillin, methicillin, and certain  other drugs in the penicillin family, as well as certain cephalo-  sporin antibiotics.    Most of the potassium ions in the glomerular filtrate are  actively reabsorbed in the proximal convoluted tubule, but con-  trol of potassium excretion depends on potassium secretion in the  distal convoluted tubule and collecting duct. During this process,  the active reabsorption of sodium ions out of the tubular fluid  under the influence of aldosterone produces a negative electrical  charge in the tubule. Positively charged potassium ions (K*) move  through channels activated by the negative charge in the tubule  and enter the tubular fluid (fig. 20.21).   ¢ tubular reabsorption of substances, including glucose;  water; urea; proteins; amino, lactic, citric, and uric acids; and  phosphate, sulfate, calcium, potassium, and sodium ions   ¢ tubular secretion of substances, including penicillin, histamine,  phenobarbital, hydrogen ions, ammonia, and potassium ions    18 How does the reabsorption of sodium affect the secretion of  potassium?    Hormones such as aldosterone and cardiac natriuretic polypep-  tides affect the solute concentration of urine, particularly sodium.    However, the ability of the kidneys to maintain the internal envi-  ronment is largely due to their reabsorbing large volumes of water,  which concentrates the urine.   In contrast to conditions in the proximal convoluted tubule,  the tubular fluid reaching the distal convoluted tubule is hypo-  tonic because of changes that occur through the loop segment of  each nephron. The cells lining the distal convoluted tubule and  the collecting duct that follows continue to reabsorb sodium ions  (chloride ions follow passively) under the influence of aldoste-  rone, which the adrenal cortex secretes (see chapter 13, p. 511).  In addition, the interstitial fluid surrounding the collecting ducts  is hypertonic, particularly in the medulla. These might seem to  be ideal conditions for water reabsorption as well. However, the  cells lining the later portion of the distal convoluted tubule and  the collecting duct are impermeable to water unless antidiuretic  hormone (ADH) is present. Thus, water inside the tubule may be  excreted, forming dilute urine.   Neurons in the hypothalamus produce ADH, as chapter 13  discussed (p. 503). The posterior lobe of the pituitary gland  releases ADH in response to decreasing concentration of water  in the body fluids or to decreasing blood volume and blood  pressure. When ADH reaches the kidney, it stimulates cells in  the distal convoluted tubules and collecting ducts to insert pro-  teins called aquaporins into their cell membranes, which form  water channels. These channels greatly increase permeability to  water. Consequently, water rapidly moves out of these structures  by osmosis, especially where the distal tubules and collecting  ducts pass through the extremely hypertonic medulla. The urine  becomes more concentrated, and water is retained in the internal  environment (fig. 20.22).    distal convoluted tubule,  potassium ions are secreted  in response to the active  reabsorption of sodium ions.    FIGURE 20.22 Urine concentrating mechanism. (a) The distal convoluted tubule and collecting duct are impermeable to water, so water may be  excreted as dilute urine. (b) If ADH is present, however, these segments become permeable, and water is reabsorbed by osmosis into the hypertonic    Most nephrons in humans are cortical nephrons, but it is the  juxtamedullary nephrons that are most important in regulating  water reabsorption. These nephrons set up an osmotic gradient  between the collecting duct and the interstitial fluid in the renal  medulla that enables water to be reabsorbed.   A countercurrent mechanism in the nephron loops of the  juxtamedullary nephrons ensures that the medullary interstitial  fluid becomes hypertonic. This mechanism is possible because the  descending and ascending limbs of the nephron loops lie parallel  and close to one another. The mechanism is named partly for the  fact that fluid moving down the descending limb results in a current  that is counter to that of the fluid moving up in the ascending limb.   The different parts of the nephron loop have important func-  tional distinctions. For example, the epithelial lining in the thick  upper portion of the ascending limb (thick ascending limb, or  thick segment) is relatively impermeable to water. However, this  part of the nephron loop does actively reabsorb sodium and chlo-  ride ions (some potassium is actively reabsorbed as well). As these  solutes accumulate outside the ascending limb, the interstitial fluid  becomes hypertonic, while the tubular fluid inside becomes hypo-  tonic because it is losing solute.   In contrast to the ascending limb, the epithelium of the  descending limb (thin segment) is permeable to water, but relatively  impermeable to solutes. This segment is surrounded by hypertonic  fluid created by the thick ascending limb, so water tends to leave the  descending limb by osmosis. The contents of the descending limb  become more concentrated, or hypertonic (fig. 20.23).   The very concentrated tubular fluid now moves into the  ascending limb, and sodium chloride (NaCl) is again actively reab-  sorbed into the medullary interstitial fluid, raising the interstitial  NaCl concentration further. With the increased interstitial fluid sol-    ute concentration, even more water diffuses out of the descending  limb, further increasing the salt concentration of the tubular fluid.  Each time this circuit is completed, the concentration of NaCl in  the ascending limb increases, or multiplies. For this reason, the  mechanism is called a countercurrent multiplier. The countercur-  rent multiplier is dependent not only on the countercurrent flow in  the nephron loops, but also on the active reabsorption of solute in  the thick ascending limbs of the loops.   The descending limb of the loop is permeable to water, so  the interstitial fluid at any level of the loop is essentially in equi-  librium with the fluid in the tubule. Thus, the concentration gra-  dient in the loop is also found in the interstitial fluid. The solute  concentration of both tubular and interstitial fluids progressively  increases toward the deeper parts of the renal medulla (fig. 20.23).   In addition to sodium chloride, urea contributes to the high  solute concentration of the renal medulla. Urea is a waste prod-  uct of protein catabolism and is filtered at the glomerulus. Before  it is excreted, however, as much as 80% of the urea in the tubular  fluid is reabsorbed by the collecting duct and enters the medullary  interstitial fluid. This urea eventually is secreted into the ascend-  ing limb of the nephron loop and again reaches the collecting duct.  This urea “cycle” excretes about 20% of the filtered urea in the  urine, but newly filtered urea constantly replaces what is lost. As  a result, there is always a significant concentration of urea in the  renal medulla contributing to the osmotic gradient for water reab-  sorption. In humans, these mechanisms create a tubular and inter-  stitial fluid solute concentration near the tip of the loop more than  four times the solute concentration of plasma (fig. 20.23).   The vasa recta, another example of a countercurrent mecha-  nism called a countercurrent exchanger, prevent blood flow from  carrying away the solute concentrated in the renal medulla by the    FIGURE 20.23 The countercurrent  multiplier. (a) Active solute reabsorption  from the ascending limb increases solute  concentration in the interstitial fluid of  the medulla. The solute concentration of  interstitial fluid in the medulla equilibrates  with tubular fluid, which loses water in    the ascending limb and again active solute  reabsorption occurs causing even more  water loss from the descending limb as  tubular fluid continues to flow. (b) The  countercurrent multiplier progressively  increases the solute concentration of the  interstitial fluid, up to a maximum near  the tip of the loop more than four times  that of plasma.    countercurrent multiplier. Recall that the vasa recta are bundles of  parallel blood vessels connected by capillary loops and extend-  ing deep into the medulla (see figure 20.6). The vasa recta do not  actively transport NaCl, so they do not contribute to establishing  the high solute concentration in the renal medulla. Rather, they  preserve the NaCl gradient established by the countercurrent mul-  tiplier despite blood flowing through the renal medulla. As blood  flows down the descending portion of the vasa recta, NaCl enters.  Then, as the blood flows back up toward the renal cortex, NaCl  leaves to reenter the medullary interstitial fluid. Consequently, the  bloodstream carries away little of the NaCl, thus preserving the  osmotic gradient for water reabsorption. At the same time the vasa  recta carry away water reabsorbed from the collecting ducts in the  medulla (fig. 20.24).   To summarize, the countercurrent multiplier creates a large  osmotic gradient for water reabsorption in the interstitial fluid sur-  rounding the distal convoluted tubules and the collecting ducts of  the nephron. The epithelial lining of these structures is imperme-  able to water, unless ADH is present. The higher the blood lev-  els of ADH, the more permeable the epithelial lining becomes,  increasing water reabsorption and concentrating the urine. In this  way, soluble wastes and other substances are excreted in minimal  water, preserving body water when dehydration is a threat. If the  body fluids contain excess water, ADH secretion decreases and the  epithelial linings of the distal convoluted tubule and the collecting  duct become less permeable to water. Less water is reabsorbed,  and the urine becomes more dilute. Table 20.3 summarizes the  role of ADH in urine production. Table 20.4 summarizes the func-  tions of parts of the nephron.    Urea is a by-product of amino acid catabolism in the liver.  Therefore, the amount of urea that must be eliminated in the urine  reflects the amount of protein in the diet. As described earlier, urea  enters the renal tubule by filtration and is both reabsorbed and  secreted by different portions of the renal tubule. The net effect of  these processes is that up to 80% of the filtered urea is reabsorbed,  and the remaining 20% is excreted in the urine.   Uric acid is a product of the metabolism of certain nucleic  acid bases (the purines adenine and guanine). Active transport  completely reabsorbs the filtered uric acid. The approximately  10% of the filtered uric acid excreted in the urine reflects secretion  into the renal tubule.    . Increase in the osmotic pressure of body fluids stimulates  osmoreceptors in the hypothalamus.    . ADH causes the distal convoluted tubules and collecting  ducts to increase water reabsorption by osmosis.    FIGURE 20.24 A countercurrent mechanism in the vasa recta helps  maintain the NaCl concentration gradient in the medullary interstitial fluid.    Excess uric acid may precipitate in the plasma and be deposited  as crystals in joints, causing the inflammation and extreme pain  of gout, particularly in the digits and especially in the great toe.  Gout has had an interesting history. Hippocrates mentioned it.  King Charles | of Spain gave up his vast empire in 1556 due to  the painful condition. In 2006, Spanish researchers confirmed the  diagnosis by detecting uric acid deposits in the terminal joint of a    finger that, for reasons unknown, had been preserved in a small  box apart from the rest of the king. Today, gout is treated with  drugs that inhibit uric acid reabsorption or block an enzyme in the  biosynthetic pathway for uric acid. Limiting foods rich in uric acid,  such as meats and seafood, and drinking more water to dilute  the urine can help. Gout is inherited, but an attack may not occur  unless the person eats large amounts of the offending foods.    Reabsorption of glucose; amino acids;  creatine; lactic, citric, uric, and ascorbic  acids; phosphate, sulfate, calcium,  potassium, and sodium ions by active  transport    Reabsorption of chloride ions and  other negatively charged ions by  electrochemical attraction    Active secretion of substances such as  penicillin, histamine, creatinine, and  hydrogen ions    ‘The collecting duct is not anatomically part of the nephron, but it is functionally linked in the pro-  cess of urine formation.    Urine composition varies depending on the volumes of water and  solutes that the kidneys must eliminate from the body or retain in the  internal environment to maintain homeostasis. Urinary excretion of  any solute may increase at one time and decrease at another. Water  excretion is independent of solute excretion. Urine composition var-  ies considerably from time to time because of differences in dietary  intake and physical activity. Urine is typically about 95% water  and usually also contains urea and uric acid from the catabolism of  amino acids and nucleic acids, and creatinine from metabolism of  creatine. Urine also contains various ions whose concentrations vary  with the diet and may contain a trace of amino acids (see table 20.1).  Appendix C, Common Tests Performed on Urine lists the nor-  mal concentrations of urine components.    Not all abnormal constituents of urine indicate illness. Glucose  may enter urine after a sugary meal or toward the end of preg-  nancy; protein may appear in the urine following vigorous physi-  cal exercise; ketones are in urine during a prolonged fast or when  a person follows a very low-calorie or low-carbohydrate diet.    The volume of urine produced usually varies between 0.6  and 2.5 liters per day. Such factors as fluid intake; environmental  temperature; relative humidity of the surrounding air; and a per-  son’s emotional condition, respiratory rate, and body temperature  influence the exact urine volume. An output of 50-60 milliliters  of urine per hour is considered normal, and an output of less than  30 milliliters per hour may indicate kidney failure.    a  The kidneys of infants and young children are unable to concen-  trate urine and conserve water as effectively as those of adults.  As a result, they can lose water rapidly, which may lead to dehy-  dration. A 20-pound infant can lose a pound in just a day of an  acute viral illness, and this is a sufficiently significant proportion  of body weight to warrant hospitalization. Intravenous fluids  may be required to restore water and electrolyte balance (see  chapter 21, p. 804).    The rate at which a chemical is removed from the plasma is called  the renal clearance of that substance. Tests of renal clearance  detect glomerular damage or monitor the progression of renal  disease. One such test, the inulin clearance test, uses inulin (not  to be confused with insulin), which is a complex polysaccharide  found in certain plant roots. In the test, a known amount of inulin  is infused into the blood at a constant rate. The inulin passes freely  through the glomerular membranes, so its concentration in the glo-  merular filtrate equals that in the plasma. In the renal tubule, inu-  lin is not reabsorbed to any significant degree, nor is it secreted.  Consequently, the rate at which inulin appears in the urine can be  used to calculate the rate of glomerular filtration.   The kidneys also remove creatinine from the blood. Creatinine  is produced at a constant rate during muscle metabolism. Like inu-  lin, creatinine is filtered but neither reabsorbed nor secreted by the  kidneys. The creatinine clearance test, which compares a patient’s  blood and urine creatinine concentrations, can also be used to cal-  culate the GFR. A significant advantage of this test over the inu-  lin clearance test is that the bloodstream normally has a constant  level of creatinine. Therefore, a single measurement of plasma  creatinine levels provides a rough index of kidney function. For  example, significantly elevated plasma creatinine levels suggest  that GFR is greatly reduced. Because nearly all of the creatinine  that the kidneys filter normally appears in the urine, a decrease in  the rate of creatinine excretion may indicate renal failure.   Another plasma clearance test uses para-aminohippuric acid  (PAH), which filters freely through the glomerular membranes.    However, unlike inulin, any PAH remaining in the peritubular  capillary plasma after filtration is secreted into the proximal con-  voluted tubules. Therefore, essentially all PAH passing through  the kidneys appears in the urine. For this reason, the rate of PAH  clearance can be used to calculate the rate of plasma flow through  the kidneys. Then, if the hematocrit is known (see chapter 14,  p. 529), the rate of total blood flow through the kidneys can also be  calculated. Clinical Application 20.3 describes some of the causes  and treatments of chronic kidney disease.    23 What is the normal hourly output of urine? The minimal hourly  output?    After urine forms along the nephrons and collecting ducts, it  passes through openings in the renal papillae and enters the minor  and major calyces of the kidney. From there it passes through the  renal pelvis, into a ureter, and into the urinary bladder. The urethra  delivers urine to the outside.    Each ureter is a tubular organ about 25 centimeters long, which  begins as the funnel-shaped renal pelvis. It extends downward  posterior to the parietal peritoneum and parallel to the vertebral  column. In the pelvic cavity, each ureter courses forward and  medially to join the urinary bladder from underneath.   The wall of a ureter is composed of three layers. The inner layer,  or mucous coat, includes several thicknesses of transitional epithelial  cells and is continuous with the linings of the renal tubules and the uri-  nary bladder. The middle layer, or muscular coat, consists largely of  smooth muscle fibers in circular and longitudinal bundles. The outer  layer, or fibrous coat, is composed of connective tissue (fig. 20.25).   Muscular peristaltic waves, originating in the renal pelvis, help  move the urine along the length of the ureter. The presence of urine  in the renal pelvis initiates these waves, whose frequency keeps pace    Charles B., a forty-three-year-old construction worker, had been feel-  ing unusually tired for several weeks, with occasional dizziness and  difficulty sleeping. More recently he had noticed a burning pain in  his lower back, just below his rib cage, and his urine had darkened. In  addition, his feet, ankles, and face were swollen. His wife suggested  that he consult their family physician.   Charles had elevated blood pressure (hypertension) and the  regions of his kidneys were sensitive to pressure. His urine had  excess protein (proteinuria) and blood (hematuria), and his blood  had elevated blood urea nitrogen (BUN), elevated serum creatinine,  and decreased serum protein (hypoproteinemia) concentrations.   Charles had chronic glomerulonephritis, an inflammation of  the capillaries in the glomeruli of the nephrons. It is a progressive  degeneration with no direct treatment, although drugs can help to  control blood pressure. Microscopic examination of a small sample  of kidney tissue (biopsy) confirmed the diagnosis.   Despite antihypertensive drugs and careful attention to his diet,  Charles’s condition deteriorated rapidly. When it appeared that  most of his kidney function had been lost (end-stage renal disease,  or ESRD), he was offered artificial kidney treatments (hemodialysis).   To prepare Charles for hemodialysis, a vascular surgeon created a  fistula in his patient's left forearm by surgically connecting an artery to  a vein. The greater pressure of the blood in the artery that now flowed  directly into the vein swelled the vein, making it more accessible.   During hemodialysis, a hollow needle was inserted into the vein  of the fistula near its arterial connection. This allowed the blood to    with the rate of urine formation. If urine forms quickly, a peristaltic  wave may pass every few seconds; if it forms more slowly, a wave  may pass every few minutes.   When a peristaltic wave reaches the urinary bladder, a jet of  urine spurts through a fold of mucous membrane that surrounds  the opening, and the urine enters. Because of the angle at which  the ureters enter the bladder, the bladder wall acts as a valve,  allowing urine to enter the bladder from the ureters but preventing  it from flowing backward as the bladder fills.   If a ureter becomes obstructed, such as by a small kidney  stone (renal calculus) in its lumen, strong peristaltic waves begin  in the proximal part of the tube, which may help move the stone  into the bladder. The presence of a stone usually also stimulates  a sympathetic reflex (ureterorenal reflex) that constricts the renal  arterioles and reduces urine production in the affected kidney.  Clinical Application 20.4 describes kidney stones.    24 Describe the structure of a ureter.  25 Howis urine moved from the renal pelvis to the urinary bladder?    26 What prevents urine from backing up from the urinary bladder  into the ureters?    27 How does an obstruction in a ureter affect urine production?    flow, with the aid of a blood pump, through a tube leading to the  blood compartment of a dialysis machine, where the blood passed  over a selectively permeable membrane. On the opposite side of  the membrane was a dialysate solution with a controlled composi-  tion. Negative pressure on the dialysate side of the membrane, cre-  ated by a vacuum pump, increased the movement of fluid through  the membrane. At the same time, waste and excess electrolytes dif-  fused from the blood through the membrane and entered the dialy-  sate solution. The blood was then returned through a tube to the  vein of the fistula.   To maintain favorable blood concentrations of waste, electro-  lytes, and water, Charles had to undergo hemodialysis three times  per week, with each treatment lasting three to four hours. Each  time he took an anticoagulant to prevent blood clotting, an antibi-  otic drug to control infections, and an antihypertensive drug.   Charles had to carefully control his intake of water, sodium,  potassium, proteins, and total calories between treatments. He was a  candidate for a kidney transplant, which could free him from depen-  dence on hemodialysis.   In a transplant, a kidney from a living donor or a cadaver,  whose tissues are antigenically similar (histocompatible) to those  of the recipient, is placed in the depression on the medial surface  of the right or left ilium (iliac fossa). The renal artery and vein of  the donor kidney are connected to the recipient's iliac artery and  vein, respectively, and the kidney’'s ureter is attached to the dome  of the recipient's urinary bladder.    The urinary bladder is a hollow, distensible, muscular organ in  the pelvic cavity, posterior to the pubic symphysis and inferior to  the parietal peritoneum (fig. 20.26 and reference plate 8, p. 45). In  a female, the bladder contacts the anterior walls of the uterus and  vagina, and in a male, the bladder lies posteriorly against the rectum.   The pressure of surrounding organs alters the spherical shape  of the bladder. When the bladder is empty, its inner wall forms many  folds, but as it fills with urine, the wall becomes smoother. At the same  time, the superior surface of the bladder expands upward into a dome.   When greatly distended, the bladder pushes above the pubic  crest and into the region between the abdominal wall and the pari-  etal peritoneum. The dome can reach the level of the umbilicus and  press against the coils of the small intestine.   The internal floor of the bladder includes a triangular area  called the trigone, which has an opening at each of its three angles  (fig. 20.27). Posteriorly, at the base of the trigone, the openings  are those of the ureters. Anteriorly, at the apex of the trigone, is  a short, funnel-shaped extension called the neck of the bladder,  which contains the opening into the urethra. The trigone generally  remains in a fixed position, even though the rest of the bladder dis-  tends and contracts.   The wall of the urinary bladder consists of four layers. The  inner layer, or mucous coat, includes several thicknesses of tran-    Kidney stones, which are usually composed of uric acid, calcium  oxalate, calcium phosphate, or magnesium phosphate, can form in  the collecting ducts and renal pelvis (fig. 20A). Such a stone passing  into a ureter causes sudden, severe pain that begins in the region of  the kidney and radiates into the abdomen, pelvis, and lower limbs.  It may also cause nausea and vomiting, and blood in the urine.   About 60% of kidney stones pass from the body on their  own. Other stones were at one time removed surgically but  are now shattered with intense sound waves. In this procedure,  called extracorporeal shock-wave lithotripsy (ESWL), the patient  is placed in a stainless steel tub filled with water. A spark-gap  electrode produces underwater shock waves, and a reflector con-  centrates and focuses the shock-wave energy on the stones. The  resulting sandlike fragments then leave in urine.   The tendency to form kidney stones is inherited, particularly  the stones that contain calcium, which account for more than  half of all cases. Eating calcium-rich foods does not increase the  risk, but taking calcium supplements can. People who have cal-  cium oxalate stones can reduce the risk of recurrence by avoiding  specific foods: chocolate, coffee, wheat bran, cola, strawberries,  spinach, nuts, and tea. Other causes of kidney stones include  excess vitamin D, blockage of the urinary tract, or a complication  of a urinary tract infection.    sitional epithelial cells similar to those lining the ureters and the  upper portion of the urethra. The thickness of this tissue changes  as the bladder expands and contracts. During distension, the tissue  appears to be only two or three cells thick, but during contraction,  it appears to be five or six cells thick (see fig. 5.11, p. 157).   The second layer of the bladder wall is the submucous coat. It  consists of connective tissue and has many elastic fibers.    It is very helpful for a physician to analyze the composition of  the stones, because certain drugs can prevent recurrence. Stones  can be collected during surgery or by the person, using a special  collection device.    FIGURE 20A This kidney stone is small, held against this fingertip,  but it is large enough to cause severe pain.    The third layer of the bladder wall, the muscular coat, is  primarily composed of coarse bundles of smooth muscle. These  bundles are interlaced in all directions and at all depths, and  together they comprise the detrusor muscle (de-truz’or mus’1).  The portion of the detrusor muscle that surrounds the neck of the  bladder forms an internal urethral sphincter. Sustained contrac-  tion of this sphincter muscle prevents the bladder from emptying    FIGURE 20.26 fAP|R) The urinary bladder is in the pelvic cavity and behind the pubic symphysis. (a) In a female, it contacts the uterus and vagina.    FIGURE 20.27 (AP|R) A male urinary bladder. (a) Longitudinal section. (b) Posterior view.    until the pressure within it increases to a certain level. The detru-  sor muscle has parasympathetic nerve fibers that function in the  reflex that passes urine.   The outer layer of the wall, the serous coat, consists of the  parietal peritoneum. It is found only on the upper surface of the  bladder. Elsewhere, the outer coat is composed of fibrous con-  nective tissue (fig. 20.28). From Science to Technology 5.2 on  page 172 discusses a tissue-engineered replacement bladder.    28 Describe the trigone of the urinary bladder.  29 Describe the structure of the bladder wall.    The urethra is a tube that conveys urine from the urinary bladder  to the outside of the body. Its wall is lined with mucous membrane  and has a thick layer of longitudinal smooth muscle fibers. The  urethral wall also has many mucous glands, called urethral glands,  which secrete mucus into the urethral canal (fig. 20.29).   In a female, the urethra is about 4 centimeters long. It passes  forward from the bladder, courses below the pubic symphysis, and  empties between the labia minora. Its opening, the external ure-  thral orifice (urinary meatus), is anterior to the vaginal opening and  is about 2.5 centimeters posterior to the clitoris (fig. 20.30a).   In a male, the urethra, which functions both as a urinary canal  and a passageway for cells and secretions from the reproductive  organs, can be divided into three sections: the prostatic urethra, the  intermediate part of urethra, and the spongy urethra (see fig. 20.30b  and reference plate 20, p. 52).    The prostatic urethra is about 2.5 centimeters long and  passes from the urinary bladder through the prostate gland,  located just below the bladder. Ducts from reproductive structures  join the urethra in this region.   The intermediate part of urethra, or membranous urethra,  is about 2 centimeters long. It originates just distal to the prostate  gland, passes through the urogenital diaphragm, and is surrounded  by the fibers of the external urethral sphincter muscle.   The spongy urethra is about 15 centimeters long and passes  through the corpus spongiosum of the penis, within erectile tissue.  This portion of the urethra terminates with the external urethral  orifice at the tip of the penis.    The urgent need to urinate and the burning pain of urination  may signal inflammation or infection of the bladder and/or ure-  ters. Inflammation of the bladder (cystitis) is more common in  women because the urethral pathway is shorter than in men, and  bacteria from the external environment may more readily enter  the bladder. Inflammation of the ureters is called ureteritis.   In a urinary tract infection (UTI), bacteria ascend from the  bladder to the ureters on the continuous linings. Urination is fre-  quent, painful, scant, and may be bloody, with accompanying  abdominal pain. Usually pathogenic bacteria in the urinary tract  remain outside the cells and are easily killed with antibiotic drugs  or prevented from attaching to ureter lining cells by exposure  to compounds in cranberry and blueberry juices that the person  drinks. However, certain bacteria, such as Escherichia coli, enter  the lining cells, forming “intracellular bacterial communities.”  The microbes can emerge and start new infections, explaining  why some people experience frequent UTIs.    Muscular coat Mucous coat coat .  ——— : Ureter  Urinary  bladder  Trigone  Urethra  FIGURE 20.28 (AP|R} Light micrograph of the human urinary  bladder wall (6x).  External  urethral orifice  (a)  Ureter  Urethral glands  Muscle layer Urinary  bladder  Lumen of Trigone  urethra  Mucous  membrane Prostatic Prostate  urethra gland  Bulbourethral  gland  Intermediate  part of  urethra  FIGURE 20.29 Cross section through the urethra (10x).  Spongy  xy a urethra Penis  31 Describe the structure of the urethra.  32 How does the urethra of a male differ from that of a female?  Micturition External —  : ; ; oe : urethral orifice  Urine leaves the urinary bladder by the micturition (mik”tu- (b)  rish’un) or urination reflex. The detrusor muscle contracts, and  contractions of muscles in the abdominal wall and pelvic floor FIGURE 20.30 Urinary bladder and urethra (a) of the female  may help, as well as fixation of the thoracic wall and diaphragm. (longitudinal section) and (b) of the male (longitudinal section).    In micturition, the external urethral sphincter also relaxes. This  muscle, part of the urogenital diaphragm (see chapter 9, pp. 325  and 327-328), surrounds the urethra about 3 centimeters from the  bladder and is composed of voluntary skeletal muscle tissue.    Incontinence is the loss of control of micturition. Stress incon-  tinence, caused by pressure on the bladder, is particularly  common among women who have had children, especially if  they have gained weight. An effective treatment is at least  two months of doing Kegel exercises, in which a woman con-  tracts the muscles that support the bladder, several times  daily. Treatments for severe cases include a tamponlike cone  inserted into the vagina to raise the pelvic floor; a small foam  pad placed over the urethra to catch small amounts of urine;  collagen injections around the urethra to tighten it; and sur-  gery. Many people use absorbent pads.   Nighttime bedwetting was noted as long ago as 1500 B.c.  Treatments have ranged from blocking the urethra at night to  punishment and ridicule. In many cases, this nocturnal enure-  sis is inherited. Drug treatment and pads to absorb urine  help to manage the problem in children, who usually outgrow  the condition.    Distension of the bladder wall as it fills with urine stimu-  lates the urge to urinate. The wall expands, stimulating stretch  receptors, which eventually triggers the micturition reflex. The  effectors of the reflex include the detrusor muscle and the internal  urethral sphincter. Conscious control of the external sphincter also  plays a role.   The micturition reflex center is in the sacral portion of the spi-  nal cord. When sensory impulses from the stretch receptors signal  the reflex center, parasympathetic motor impulses travel out to the  detrusor muscle, which contracts rhythmically in response. A sen-  sation of urgency accompanies this action.   The urinary bladder may hold up to 600 milliliters of urine. The  desire to urinate usually begins when it contains about 150 millili-  ters. Then, as urine volume increases to 300 milliliters or more, the  sensation of fullness becomes increasingly uncomfortable.   As the bladder fills with urine and its internal pressure  increases, contractions of its wall intensify. When these contrac-  tions become strong enough to force the internal urethral sphinc-  ter to open slightly and admit some urine into the urethra, another  reflex signals the external urethral sphincter to relax, and the blad-  der may empty. However, because the external urethral sphinc-  ter is composed of skeletal muscle, it is under conscious control,  and therefore usually remains contracted until a person decides  to urinate. Nerve centers in the brainstem and cerebral cortex that  inhibit the micturition reflex aid this control.   When a person decides to urinate, the external urethral  sphincter relaxes and inhibition of the micturition reflex lifts.  Neural centers in the pons and the hypothalamus heighten the  micturition reflex. The detrusor muscle contracts, the internal  urethral sphincter relaxes, and urine is excreted through the ure-  thra. Subsequently, the micturition reflex subsides, the detrusor  muscle relaxes, the internal urethral sphincter contracts, and the  bladder begins to fill with urine again. Table 20.5 outlines the  micturition process, and Clinical Application 20.5 discusses uri-  nalysis and health. Table 20.6 lists conditions that result from  abnormal development of part of the urinary system. About | in  500 newborns has a birth defect affecting the urinary system.    Damage to the spinal cord above the sacral region may abolish  voluntary control of urination. However, if the micturition reflex  center and its sensory and motor fibers are uninjured, micturi-  tion may continue to occur reflexively. In this case, the bladder  collects urine until its walls stretch enough to trigger a micturi-  tion reflex, and the detrusor muscle contracts and the internal  urethral sphincter relaxes in response. This condition is called  an automatic bladder.    2. Stretch receptors in the bladder wall are stimulated, and they  signal the micturition center in the sacral spinal cord.    3. Parasympathetic nerve impulses travel to the detrusor  muscle, which responds by contracting rhythmically.    5. Voluntary contraction of the external urethral sphincter  and inhibition of the micturition reflex by impulses from the  brainstem and the cerebral cortex prevent urination.    6. Following the decision to urinate, the external urethral  sphincter is relaxed, and impulses from the pons and the  hypothalamus facilitate the micturition reflex.    7. The detrusor muscle contracts, the internal urethral sphincter  relaxes, and urine is expelled through the urethra.    8. The micturition reflex subsides, the detrusor muscle relaxes, the  internal urethral sphincter contracts, and the bladder begins to  fill with urine again.   Horseshoe kidney Fusion of kidneys at one pole, usually lower,  with most of each kidney on opposing side  of midline    Urine has long fascinated medical minds. As a folk remedy, urine  has been used as a mouthwash, toothache treatment, and a cure  for sore eyes. Hippocrates (460-377 Bc) was the first to observe  that the condition of the urine can provide clues to health, noting  that frothy urine denoted kidney disease. During the Middle Ages,  health practitioners consulted charts that matched urine colors to  diseases. In the seventeenth century, British physicians diagnosed  diabetes by having their medical students taste sugar in patients’  urine. Today, urine composition is still used as a window on health  and also to check for illicit drug use.   Certain inherited disorders can noticeably alter urine. The name  maple syrup urine disease vividly describes what this inborn error  of metabolism does to the urine. This condition, which causes intel-  lectual disability, results from a block in the breakdown pathways    34 How is it possible to consciously inhibit the micturition reflex?    The urinary system has sufficient reserve, in both structure and  function, to mask aging-related changes. However, the kidneys  become slower to remove nitrogenous wastes and toxins and to  compensate for changes that might alter homeostasis.   From the outside, the kidneys change with age, appearing  scarred and grainy as arterioles serving the cortex constrict and  fibrous connective tissue accumulates around the capsules. On the  inside, kidney cells begin to die as early as age twenty years, but the  gradual shrinkage is not generally noticeable until after age forty.  By eighty years, the kidneys have lost about a third of their mass.   Kidney shrinkage is mostly due to the gradual loss of glomer-  uli. They may atrophy, cease functioning, become blocked with  fibrous connective tissue, or untwist. About 5% of glomeruli are  abnormal by age forty; 37% are abnormal by age ninety. The pro-  gressive shutdown of glomeruli decreases the surface area for fil-  tration, and as a result, glomerular filtration rate (GFR) begins to  drop in the fourth decade. By age seventy-five, GFR is about half  that in a young adult, falling from about 125 milliliters/minute to  about 60. With this decline, proteins are more likely to enter the  urine. About a third of the elderly have proteinuria.   Further along the nephron, renal tubules thicken, accumulat-  ing fatty coats. They may shorten, forming small outpouches as  cell death disrupts their sleek symmetry. Urine may become more  dilute as reabsorption of sodium and glucose and other molecules  becomes less efficient. The renal tubules also slow in processing  certain drugs, which remain in the circulation longer. It becomes    for certain amino acids. In alkaptonuria, urine turns black when it  is left to stand. This condition also produces painful arthritis and  blackened ear tips. People with Wilson disease have an inherited  inability to excrete copper. If they are properly diagnosed and given  the drug penicillamine, their urine becomes the color of copper.   Other genetic conditions alter urine without causing health  problems. People with beeturia excrete dark pink urine after they  eat beets. The problem for people with urinary excretion of odor-  iferous component of asparagus is obvious. Parents of newborns  who have inherited blue diaper syndrome are shocked when they  change their child’s first diaper. Due to a defect in transport of the  amino acid tryptophan in the small intestine, bacteria degrade the  unabsorbed tryptophan, producing a compound that turns blue  on contact with oxygen.    harder to clear nonsteroidal anti-inflammatory drugs such as aspi-  rin, as well as opiates, antibiotics, urea, uric acid, creatinine, and  various toxins. Slowing kidney function is one reason why a per-  son’s age should be considered when prescribing drugs.   Cardiovascular changes slow the journey of blood through  the kidneys. A college student’s kidneys may process about a  fourth of the cardiac output, or about 1,200 milliliters, per minute.  Her eighty-year-old grandfather’s kidneys can handle about half  that volume. Starting at about age twenty, renal blood flow rate  diminishes by about 1% per year. The blood vessels that serve the  kidneys become slower to dilate or constrict in response to body  conditions. The kidneys’ release of renin declines, hampering  control of blood pressure and sodium and potassium ion concen-  trations in the blood. The kidneys also become less able to acti-  vate vitamin D, which may contribute to the higher prevalence of  osteoporosis among the elderly.   The urinary bladder, ureters, and urethra lose elasticity and  recoil with age. In the later years, the bladder holds less than half  of what it did in young adulthood, and may retain more urine after  urination. In the elderly, the urge to urinate may become delayed,  so when it does happen, it is sudden. Older individuals have to uri-  nate at night more than younger people.   Controlling bladder function is a challenge at the beginning of  life and much later too. A child usually learns to control urination  by about age two or three years. Incontinence, the uncontrolled  leakage of urine, becomes more common in advanced years,  although it is not considered a normal part of aging. It results  from loss of muscle tone in the bladder, leading to increased blad-  der volume, and in the sphincters, which fail to close normally.  Incontinence affects 15% to 20% of women over sixty-five and  half of all men. In women, incontinence may develop from the  stresses of childbirth and the effects of less estrogen during meno-  pause. In males, incontinence usually is a response to an enlarged  prostate gland pressing on the urethra and bladder.    How do the kidneys change in appearance with advancing years?  What happens to glomeruli as a person ages?  How does kidney function change with age?    How do aging-related changes in the cardiovascular system  affect the kidneys?    How do the urinary bladder, ureters, and urethra change with age? li    The urinary system maintains homeostasis by regulating the  composition, pH, and volume of body fluids. It does this by  producing urine. The urinary system includes the kidneys,  ureters, urinary bladder, and urethra.   a. The kidneys are bean-shaped organs on either side of  the vertebral column, high on the posterior wall of the  abdominal cavity.   b. They are posterior to the parietal peritoneum and  anchored by adipose and connective tissues.   a. The kidneys remove metabolic wastes from the blood  and excrete them.   b. They also help regulate red blood cell production, blood  pressure, calcium ion absorption, and the volume,  composition, and pH of the blood.   b. The ureter expands into the renal pelvis, which, in turn,  leads to the major and minor calyces.   d. Kidney tissue is divided into a medulla and a cortex.   a. Arterial blood flows through the renal artery,  interlobar arteries, arcuate arteries, cortical radiate  arteries, afferent arterioles, glomerular capillaries,  efferent arterioles, and peritubular capillaries.   b. Venous blood returns through a series of vessels that  correspond to those of the arterial pathways.   a. Structure of a nephron  (1) A nephron is the functional unit of the kidney.   (2) It consists of a renal corpuscle and a renal tubule.   (a) The corpuscle consists of a glomerulus and a  glomerular capsule.   (b) Parts of the renal tubule include the proximal  convoluted tubule, the nephron loop  (ascending and descending limbs), and the  distal convoluted tubule.   (3) The nephron joins a collecting duct, which empties  into a minor calyx.   b. Cortical and juxtamedullary nephrons  (1) Cortical nephrons are the most numerous and have   (1) The juxtaglomerular apparatus is between  the ascending limb of the nephron loop and the  afferent and efferent arterioles.   (2) It consists of the macula densa and the  juxtaglomerular cells.    Nephrons remove wastes from the blood and regulate water and  electrolyte concentrations. Urine is the product of glomerular  filtration, tubular reabsorption, and tubular secretion.    Urine formation begins when water and dissolved  materials are filtered out of the glomerular capillaries.  The glomerular capillaries are much more permeable  than the capillaries in other tissues.   Filtration is mainly due to hydrostatic pressure inside  the glomerular capillaries.   The osmotic pressure of the blood plasma and  hydrostatic pressure in the glomerular capsule also  affect filtration.   Filtration pressure is the net force moving material out  of the glomerulus and into the glomerular capsule.  The composition of the filtrate is similar to that of  tissue fluid.   The rate of filtration varies with the filtration pressure.  Filtration pressure changes with the diameters of the  afferent and efferent arterioles.   As the hydrostatic pressure in a glomerular capsule  increases, the filtration rate decreases.   The kidneys produce about 125 milliliters of  glomerular fluid per minute; most is reabsorbed.   The volume of filtrate varies with the surface area of  the glomerular capillaries.    constant but may increase or decrease with need.  Autoregulation is the ability of an organ or   tissue to maintain a constant blood flow under  certain conditions when the arterial blood pressure  is changing.   When tubular fluid NaCl concentration decreases,  the macula densa causes the juxtaglomerular cells  to release renin. This triggers a series of changes  leading to vasoconstriction, which may affect GFR,  and secretion of aldosterone, which stimulates tubular  sodium reabsorption.    The kidneys and  the lungs work  together to control  the pH of the  internal  environment.    The urinary system in  males shares organs  with the reproductive  system. The kidneys   (1) Negatively charged ions accompany positively  charged sodium ions out of the filtrate.   (2) Water is passively reabsorbed by osmosis as  sodium ions are actively reabsorbed.   (1) Sodium and chloride ions are actively reabsorbed  in the ascending limb.   (2) Tubular fluid in the ascending limb becomes  hypotonic as it loses solutes.   (4) Tubular fluid in the descending limb becomes  hypertonic as it loses water.   (5) As this process repeats, the NaCl concentration in  the medulla increases.   (1) Itis reabsorbed and secreted by different portions  of the renal tubule.    Urine is about 95% water, and it usually contains urea,  uric acid, and creatinine.    It may contain a trace of amino acids and varying  amounts of electrolytes, depending upon diet.   The volume of urine varies with the fluid intake, with  certain environmental factors, and a person’s emotional  condition, respiratory rate, and body temperature.    Renal clearance is the rate at which a chemical is  removed from the plasma.   The inulin clearance test, creatinine clearance test,  and para-aminohippuric acid test can be used to  calculate GFR.    The ureter is a tubular organ that extends from each  kidney to the urinary bladder.    Peristaltic waves in the ureter force urine to the urinary  bladder.   Obstruction in the ureter stimulates strong peristaltic  waves and a reflex that decreases urine production.    The urinary bladder is a distensible organ that stores  urine and forces it into the urethra.   The ureters and urethra open at the three angles of the  trigone in the floor of the urinary bladder.   Muscle fibers in the wall form the detrusor muscle.  A portion of the detrusor muscle forms an internal  urethral sphincter.    The urethra conveys urine from the urinary bladder to  the outside.   (1) Three portions of the male urethra are the prostatic  urethra, the intermediate part of the urethra,  and the spongy urethra.   (2) The micturition reflex center in the sacral portion  of the spinal cord sends parasympathetic motor  impulses to the detrusor muscle.   (3) As the urinary bladder fills, its internal pressure  increases, forcing the internal urethral sphincter  open.   (4) A second reflex relaxes the external urethral  sphincter, unless its contraction is voluntarily  controlled.   (5) Nerve centers in the brainstem and cerebral  cortex aid control of urination.    The kidneys, ureters, and urethra change with age, but nephrons  are so numerous that a healthy person is usually unaware of  kidney shrinkage and slowed cleansing of the blood.   3. Renal tubules accumulate fat on their outsides and become  asymmetric. Reabsorption and secretion may slow or  become impaired. Drugs remain longer in the circulation  as a person ages.    Explain why the urinary system is necessary for survival. (p. 769)  Identify the organs of the urinary system and list their  general functions. (p. 769)   Describe the external and internal structure of a kidney.  (pp. 770-771)   List in correct order the vessels through which blood passes  as it travels from the renal artery to the renal vein. (p. 772)  Distinguish between a renal corpuscle and a renal tubule.  (pp. 775-776)   Describe the location and structure of the juxtaglomerular  apparatus. (p. 776)    Distinguish among filtration, tubular reabsorption, and  tubular secretion as they relate to urine formation.   Explain how the diameters of the afferent and efferent  arterioles affect the rate of glomerular filtration. (p. 781)  Explain how changes in the osmotic pressure of blood  plasma affect the glomerular filtration rate. (p. 781)   Explain how the hydrostatic pressure of a glomerular capsule  affects the rate of glomerular filtration. (pp. 781-782)   Describe the two mechanisms by which the body regulates  glomerular filtration rate. (p. 782)   Which one of the following is abundant in blood plasma, but  present only in small amounts in glomerular filtrate? (p. 782)  a. sodium ions    Explain how the peritubular capillary is adapted for tubular  reabsorption. (p. 783)   Explain how epithelial cells of the proximal convoluted  tubule are adapted for tubular reabsorption. (p. 784)  Discuss how tubular reabsorption is selective. (p. 784)  Explain why active transport mechanisms have limited  transport capacities. (p. 784)   Define renal plasma threshold, and explain its significance in  tubular reabsorption. (p. 784)    4. Changes in the cardiovascular system slow the rate of  processing through the urinary system. The kidneys slow  in their response to changes, and are less efficient at  activating vitamin D.   5. The urinary bladder, ureters, and urethra lose elasticity,  with effects on the urge and timing of urination.    Explain how amino acids and proteins are reabsorbed. (p. 784)  Describe the effect of sodium reabsorption on the  reabsorption of negatively charged ions. (p. 785)  Explain how sodium reabsorption affects water reabsorption.  (p. 785)  Explain how the renal tubule is adapted to secrete hydrogen  ions. (p. 786)  Explain how potassium ions may be passively secreted.  (p. 787)  The major action of ADH on the kidneys is to increase   . (p. 787)  a. water reabsorption by the proximal convoluted tubule  b. glomerular filtration rate  c. water reabsorption by the collecting duct  d. potassium excretion  Explain how hypotonic fluid is produced in the ascending  limb of the nephron loop. (p. 788)  Explain why fluid in the descending limb of the nephron loop  is hypertonic. (p. 788)  Explain how urine may become concentrated as it moves  through the collecting duct. (p. 789)  Compare the processes by which urea and uric acid are  excreted. (p. 789)  List the common constituents of urine and their sources.  (p. 790)  List some of the factors that affect the daily urine volume.  (p. 791)    Describe the structure and function of a ureter. (p. 791)  Explain how the muscular wall of the ureter helps move  urine. (pp. 791-792)   Describe the location and structure of the urinary bladder.  (pp. 792-793)   Distinguish between the internal and external urethral  sphincters. (pp. 793 and 795)    1. Why are people with the nephrotic syndrome, in which plasma  proteins are lost into the urine, more susceptible to infection?    2. Ifthe blood pressure of a patient in shock as a result of a severe  injury decreases greatly, how would you expect the volume of  urine to change? Why?    3. Ifa patient who has had major abdominal surgery receives  intravenous fluids equal to the volume of blood lost during  surgery, would you expect the volume of urine produced to be  greater than or less than normal? Why?    Outcomes 15.6, 15.7, 17.2, 17.4, 17.5, 17.7,  17.8, 20.2, 20.3, 20.4    4. Aphysician prescribes oral penicillin therapy for a patient with an  infection of the urinary bladder. How would you describe for the  patient the route the drug follows to reach the bladder?    5. Inflammation of the urinary bladder is more common in women  than in men. What anatomical differences between the female  and male urethra explain this observation?    6. What effect would being born with narrowed renal arteries have  on the volume and composition of urine?    Connect Interactive Questions Reinforce your knowledge using  assigned interactive questions covering the anatomy of the kidney  and the process of urine formation.    Connect Integrated Activity Can you predict the differences in  urine composition associated with different factors such as diet  and health status?    Anatomy & Physiology Revealed Go more in depth into the  human body by exploring cadaver dissections of the organs of the  urinary system, as well as viewing an animation about urine formation.    Falsely colored scanning electron micrograph of glomerular podocytes  involved in the filtration of water and electrolytes (5,700x).    Each of the cells that make up the body has water inside it. In  fact, approximately two-thirds of the water in the body is inside  cells. Outside the cells is the internal environment of the body,  including the interstitial fluid and the plasma of the blood. The  synovial fluid of the joints, fluids in the eyes, serous fluids, and  others are also on the list of body fluids.   If the internal environment is to remain constant, what hap-  pens to the salt, water, and solutes that are ingested at every  meal? How does the body compensate for water lost when we  sweat, urinate, defecate, and even just exhale? The answer is  the concept of balance, and it is a simple equation: What goes in  must equal what goes out.    After you have studied this chapter, you should be able to:   Explain how fluid composition varies among compartments  and how fluids move from one compartment to another.  (pp. 805-806)   List the routes by which water enters and leaves the  body. (pp. 806-807)   Explain the regulation of water input and water output.  (pp. 806-808)   List the routes by which electrolytes enter and leave the  body. (p. 809)   Explain the regulation of the input and output of  electrolytes. (pp. 809-812)   Identify how pH number describes the acidity and  alkalinity of a body fluid. (p. 812)   Distinguish between strong acids and weak acids. (p. 813)  Explain how chemical buffer systems, the respiratory  center, and the kidneys keep the pH of body fluids  relatively constant. (pp. 814-816)    Describe the causes and consequences of increase or  decrease in body fluid pH. (pp. 817-818)   For each of the four main types of acid-base imbalance,  explain which system(s)—renal, respiratory, or both—  would help to return blood pH toward normal. (p. 819)   -emia, a blood condition: hypoprotein-  emia—abnormally low concentration of  blood plasma proteins.    The term balance suggests a state of constancy. For water and  electrolytes, balance means that the quantities entering the body  equal the quantities leaving. Mechanisms that replace lost water  and electrolytes and excrete excesses maintain this balance. As a  result, the levels of water and electrolytes in the body remain rela-  tively stable at all times, helping to maintain homeostasis.    Water balance and electrolyte balance are interdependent,  because electrolytes are dissolved in the water of body fluids.  Consequently, anything that alters the concentrations of the elec-  trolytes will alter the concentration of the water by adding sol-  utes to it or by removing solutes from it. Likewise, anything that  changes the concentration of the water will change the concentra-  tions of the electrolytes by concentrating or diluting them.    Body fluids are not uniformly distributed. Instead, they occupy  regions, or compartments, of different volumes that contain fluids  of varying compositions. The movement of water and electrolytes  between these compartments is regulated to stabilize the distribu-  tion and the composition of body fluids.    The body of an average adult female is about 52% water by weight  and that of an average male is about 63% water by weight. This  difference between the sexes is because females generally have  more adipose tissue, which has little water. Males generally have  more muscle tissue, which contains a great deal of water. Water in  the body (about 40 liters), with its dissolved electrolytes, is distrib-  uted into two major compartments: an intracellular fluid compart-  ment and an extracellular fluid compartment (fig. 21.1).   The intracellular (in’trah-sel’u-lar) fluid compartment  includes all the water and electrolytes that cell membranes enclose.    In other words, intracellular fluid is the fluid inside cells. In an adult,  it accounts for about 63% by volume of total body water.   The extracellular (ek”strah-sel’u-lar) fluid compartment  includes all the fluid outside cells—in tissue spaces (interstitial fluid),  blood vessels (plasma), and lymphatic vessels (lymph). Epithelial lay-  ers separate a specialized fraction of the extracellular fluid from other  extracellular fluids. This transcellular (trans-sel’ular) fluid includes  cerebrospinal fluid of the central nervous system, aqueous and vitre-  ous humors of the eyes, synovial fluid of the joints, and serous fluid in  the body cavities. The fluids of the extracellular compartment consti-  tute about 37% by volume of the total body water (fig. 21.2).    FIGURE 21.1 Of the 40 liters of water in the body of an average  adult, about two-thirds is intracellular and about one-third is extracellular.    All of the body fluids are solutions of electrolytes in water. They  also include dissolved gases, proteins, and other substances to  varying degrees (see chapter 14, p. 529) Extracellular fluids gen-  erally are similar in composition, including high concentrations of  sodium, chloride, calcium, and bicarbonate ions and lesser con-  centrations of potassium, magnesium, phosphate, and sulfate ions.  The blood plasma portion of extracellular fluid has considerably  more protein than do either interstitial fluid or lymph.   Intracellular fluid has high concentrations of potassium,  phosphate, and magnesium ions. It includes a greater concentra-  tion of sulfate ions and lesser concentrations of sodium, chloride,  and bicarbonate ions than does extracellular fluid. Intracellular  fluid also has a greater concentration of protein than plasma.  Figure 21.3 shows these relative concentrations.    3. Which electrolytes are in higher concentrations in extracellular  fluids? In intracellular fluid?    4 How does the concentration of protein vary in body fluids?    Two major factors regulate the movement of water and electro-  lytes from one fluid compartment to another: hydrostatic pressure  and osmotic pressure. For example, as explained in chapter 15  (p. 581), fluid leaves the plasma at the arteriolar ends of capillar-  ies and enters the interstitial spaces because of the net outward  force of hydrostatic pressure (blood pressure). Fluid returns to the  plasma from the interstitial spaces at the venular ends of capillar-  ies because of the net inward force of colloid osmotic pressure  due to the plasma proteins. Likewise, as mentioned in chapter 16  (p. 620), fluid leaves the interstitial spaces and enters the lymph  capillaries due to the hydrostatic pressure of the interstitial fluid.  The circulation of lymph returns interstitial fluid to the plasma.  Hydrostatic pressure in the cells and surrounding interstitial fluid  is ordinarily equal and remains stable. Therefore, any net fluid move-  ment is likely to result from changes in osmotic pressure (fig. 21.4).  Recall that osmotic pressure is due to impermeant solutes on one side  of a cell membrane. Sodium (extracellular) and potassium (intra-    cellular) ions function as impermeant solutes and create an osmotic  pressure because of the Na*/K* pump. For example, because most  cell membranes in the body are freely permeable to water, a decrease  in extracellular sodium ion concentration causes a net movement of  water from the extracellular compartment into the intracellular com-  partment by osmosis. The cell swells. Conversely, if the extracellular  sodium ion concentration increases, cells shrink as they lose  water by osmosis. Although the solute composition of body fluids    A medical technologist is the behind-the-scenes professional  who tests cells and tissues from patients, enabling physicians  to diagnose disease. The tests fall into five areas: immunology,  microbiology, chemistry, blood banking, and hematology.   Microbiology skills are used to culture bacteria, fungi,  and parasites in body fluids. The polymerase chain reaction  amplifies the genetic material of viruses. Flow cytometry can  reveal the abnormal proportions of blood cells that underlie  an anemia, clotting disorder, mononucleosis, or cancer.  Other tests can confirm a pregnancy, detect illicit drug  use, or measure levels of substances in body fluids such  as cholesterol, glucose, or hormones.   In addition to deep knowledge of microscopic and  macroscopic anatomy and physiology, a medical technologist  must be comfortable and adept at working with a great  variety of instruments and devices, be able to focus on  details, be able to stand for long periods, and perhaps most  important, be a problem solver. Excellent communication  skills and the ability to recognize errors and work efficiently  under stress are also important skills.   Medical technologists work in many places, including  clinics, hospitals, commercial and government testing  laboratories, public health facilities, biotechnology and  pharmaceutical companies, in vitro fertilization facilities,  and research laboratories.   The educational requirement is a bachelor’s degree in  medical technology approved by the National Accrediting  Agency for Clinical Laboratory Sciences or in a related field  such as biology or clinical laboratory science plus medical  technology training. The Board of Registry of the American  Society for Clinical Pathology offers national certification after  passing an exam. Licensing requirements vary by state.    FIGURE 21.3 Extracellular fluids have relatively high concentrations  of sodium (Na‘*), calcium (Ca*), chloride (Ch), and bicarbonate (HCO,)  ions. Intracellular fluid has relatively high concentrations of potassium (K*),  magnesium (Mg*), phosphate (PO,*), and sulfate (SO,*) ions.    @ According to this graph, which cation is most abundant in  the extracellular fluid?    varies between intracellular and extracellular compartments, water  will “follow salt” and distribute by osmosis such that the water con-  centration (and total solute concentration) is essentially equal inside  and outside cells.    Different substances distribute to different compartments. Sodium  is largely kept out of cells by sodium pumps in cell membranes.  Because water follows trapped solute by osmosis, a liter of iso-  tonic saline (9 grams of NaCl per 1,000 mL of solution) distributes  throughout the extracellular space. Glucose, on the other hand, is    metabolized by cells. A 5% glucose solution (5 grams of glucose  per 100 mL of solution) can be infused slowly intravenously with-  out hemolyzing red blood cells, but as the glucose is metabolized,  eventually only the water remains, and water distributes through-  out both the intracellular and extracellular compartments.   @ Fluid returns to  plasma at venular  ends of the  capillaries  because the  inward force of  colloid osmotic  pressure  predominates    @ Hydrostatic  pressure within  interstitial spaces  forces fluid into  lymph capillaries    @ Interstitial fluid is  in equilibrium with  transcellular and  intracellular fluids    FIGURE 21.4 Net movements of fluid between compartments result  from differences in hydrostatic and osmotic pressures.    5 Which factors control the movement of water and electrolytes  from one fluid compartment to another?    6 How does the sodium ion concentration in body fluids affect the  net movement of water between the compartments?    Water balance exists when water intake (and production by  metabolism) equals water output. Homeostasis requires control of  both water intake and water output. Ultimately, maintenance of the  internal environment depends on thirst centers in the brain to vary  water intake and on the kidneys’ ability to vary water output.    The volume of water gained each day varies among individuals.  An average adult living in a moderate environment takes in about  2,500 milliliters daily. Probably 60% is obtained from drinking  water or beverages, and another 30% comes from moist foods.  The remaining 10% is a by-product of the oxidative metabolism of  nutrients, called water of metabolism (fig. 21.5a).    The primary regulator of water intake is thirst. The intense feeling  of thirst derives from a change in either the volume or the osmotic  pressure of extracellular fluids and both neural and hormonal input  to the brain.    ‘ — Water of  metabolism  (250 mL or 10%)  Water in  moist food  (750 mL or 30%)  Total intake  (2,500 mL)  FIGURE 21.5 Water Water in  balance. (a) Major sources beverages  of body water. (b) Routes by (1,500 mL or 60%)  which the body loses water.  Urine production is most  important in the regulation v    Recall from chapter 2 (pp. 64-65) that water molecules are  polar. Molecules that have polar regions, such as carbohydrates  and proteins, dissolve in water but remain intact. In contrast, elec-  trolytes dissociate in water to release ions. Intact or dissociated, all  of these dissolved particles are solutes.   The total solute concentration of a body fluid determines its  osmolarity. One molecule of glucose yields one dissolved particle,  and one molecule of sodium chloride yields two, a sodium ion and  a chloride ion. The total number of dissolved particles determines  the osmolarity of body solutions, irrespective of the source, so  the term osmoles is used. Thus, one mole of glucose yields one  osmole of dissolved particles, and one mole of sodium chloride  yields two osmoles. The total number of osmoles per liter gives  the osmolarity of the solution.    a ™  The units for osmolarity are milliosmoles per liter of solution  (mOsm/L). Osmolality is a closely related term that is measured  clinically, with units of milliosmoles per kilogram of water (mOsm/  kg H,O). In the body fluids the two are approximately equivalent.    Osmolarity and osmotic pressure sound alike but are signifi-  cantly different. Osmolarity (and osmolality) are measures of the  total solute concentration of a solution. Osmotic pressure is due  only to the solutes in a solution that are impermeant, unable to  cross the cell membrane, which cause osmosis. The osmorecep-  tors are sensitive to the osmotic pressure of the body fluids.   As the body loses water, the osmotic pressure of the extracel-  lular fluids increases. Such a change stimulates osmoreceptors  (oz”mo-re-sep’torz) in the hypothalamus, and in response, the per-  son feels thirsty and seeks water. A thirsty person usually has a  dry mouth, caused by loss of extracellular water and the resulting  decreased flow of saliva.   The thirst mechanism is normally triggered whenever the  total body water decreases by as little as 1%. The act of drinking    and the resulting distension of the stomach wall trigger impulses  that inhibit the thirst mechanism. In this way, drinking stops long  before the swallowed water is absorbed. This inhibition helps pre-  vent the person from drinking more than is required to replace the  volume lost, avoiding development of an imbalance. Table 21.1  summarizes this mechanism.   Another mechanism of stimulating thirst responds to volume  loss that occurs as a result of hemorrhage. Stretch receptors in certain  parts of the cardiovascular system (volume receptors) stimulate the  thirst center directly. In addition, if blood pressure drops sufficiently,  the renin-angiotensin system may be activated, and one action of  angiotensin II is to stimulate thirst. These mechanisms are not as  sensitive as the response to changing osmolality, and they do not act  until blood volume and blood pressure decrease by 10% or more.    7 What is water balance?  8 Where is the thirst center?  9 What stimulates fluid intake? What inhibits it?    1. The body loses as little as 1% of its water.    2. Anincrease in the osmotic pressure of extracellular fluid due  to water loss stimulates osmoreceptors in the hypothalamus.    3. Activity in the hypothalamus causes the person to feel thirsty  and to seek water.    4. Drinking and the resulting distension of the stomach by water  stimulate impulses that inhibit the thirst center.    5. Water is absorbed through the walls of the stomach and small  intestine.    Water normally enters the body only through the mouth, but it  can be lost by a variety of routes. These include obvious losses in  urine, feces, and sweat (sensible perspiration), as well as evapora-  tion of water from the skin (insensible perspiration) and from the  lungs during breathing.   If an average adult takes in 2,500 milliliters of water each  day, then 2,500 milliliters must be eliminated to maintain water  balance. Of this volume, perhaps 60% will be lost in urine, 6%  in feces, and 6% in sweat. About 28% will be lost by evaporation  from the skin and lungs (fig. 21.5b). These percentages vary with  such environmental factors as temperature and relative humidity  and with physical exercise.    Heatstroke is a result of exposure to extreme environmen-  tal heat combined with a failure of normal body temperature  control that can be quickly fatal. It occurs when the body is  exposed to a heat index (heat considering humidity) of more  than 105°F and body temperature reaches 104°F. Under these  conditions, evaporation of sweat becomes less effective at  cooling the body, and organs begin to fail.   The symptoms of heatstroke happen in a sequence. First  come headache, dizziness, and exhaustion. Sweating is profuse,  then stops, as the skin becomes dry, hot, and red. Respiratory  rate rises and the pulse may race up to 180 beats per minute.  If the person isn’t cooled, neurological symptoms may begin,  including disorientation, hallucinations, and odd behavior.  Kidney failure and/or heart arrhythmia can prove fatal.   During heat waves, the very young and the very old are  more susceptible to heatstroke because their body tempera-  ture control mechanisms may be poor. However, heatstroke  also affects two groups of young, otherwise healthy indi-  viduals—athletes who work out in extreme heat and soldiers  deployed to hot climates. For this reason, soldiers must carry  drinking water with them at all times and drink throughout the  day, whether they feel thirsty or not.    If water intake is insufficient, water output must be reduced  to maintain balance. Water lost in sweat is a necessary part of the  body’s temperature control mechanism; water lost in feces accom-  panies the elimination of undigested food materials; and water  lost by evaporation is largely unavoidable. Therefore, the primary  means of regulating water output is control of urine production.    The renal distal convoluted tubules and collecting ducts are the  effectors of the mechanism that regulates the volume of water  excreted in the urine. The epithelium that forms these segments  of the renal tubule remains relatively impermeable to water unless  antidiuretic hormone (ADH) is present.   Recall from chapter 13 (p. 503) that osmoreceptors in the  hypothalamus help control release of ADH. If the blood plasma  becomes more concentrated because of excessive water loss, the  osmoreceptors lose water by osmosis and shrink. This change trig-  gers impulses that signal the posterior pituitary gland to release  ADH into the bloodstream. When ADH reaches the kidneys, it  increases the permeability of the distal convoluted tubules and  collecting ducts to water, increasing water reabsorption, which  conserves water. This action resists further osmotic change in the  plasma. The osmoreceptor-ADH mechanism can reduce a normal  urine production of 1,500 milliliters per day to about 500 millili-  ters per day when the body is dehydrated.   If a person drinks too much water, the plasma becomes less  concentrated, and the osmoreceptors swell as they gain extra water  by osmosis. In this instance, ADH release is inhibited, and the dis-  tal convoluted tubules and collecting ducts remain impermeable  to water. Consequently, less water is reabsorbed and more urine  is produced. Table 21.2 summarizes this mechanism. Clinical  Application 21.1 discusses disorders resulting from water imbalance.   Just as in the case of stimulating thirst, volume receptors also  control ADH. Too much volume will inhibit and too little volume  will stimulate ADH secretion. In addition, if blood pressure drops  sufficiently due to the loss of volume, the renin-angiotensin sys-  tem may be activated, and one action of angiotensin II is to stimu-  late ADH secretion.    . Osmoreceptors in the hypothalamus are stimulated by the  increase in the osmotic pressure of body fluids.    . The hypothalamus signals the posterior pituitary gland to  release ADH into the blood.    . ADH causes the distal convoluted tubules and collecting ducts  to increase water reabsorption.   . This change stimulates osmoreceptors in the hypothalamus.  . The posterior pituitary gland decreases ADH release.    Diuretics are chemicals that promote urine production. They  act in different ways. Alcohol and certain narcotic drugs pro-  mote urine formation by inhibiting ADH release. A drug called  mannitol is an osmotic diuretic. It gets filtered by the kidneys,  but is not reabsorbed, so it draws water into the renal tubules  by osmosis. Mannitol is used in some patients to increase uri-  nary excretion of toxins.    10 By what routes does the body lose water?  11. What is the primary regulator of water loss?  12 What types of water loss are unavoidable?    An electrolyte balance (e-lek’tro-lit bal’ans) exists when the  quantities of electrolytes (molecules that release ions in water) the  body gains equal those lost (fig. 21.6).    The electrolytes of greatest importance to cellular functions release  sodium, potassium, calcium, magnesium, chloride, sulfate, phos-  phate, bicarbonate, and hydrogen ions. These electrolytes are pri-  marily obtained from foods, but they may also be found in drinking  water and other beverages. In addition, some electrolytes are by-  products of metabolic reactions.    Ordinarily, a person obtains sufficient electrolytes by responding  to hunger and thirst. However, a severe electrolyte deficiency may  cause salt craving, which is a strong desire to eat salty foods.    The body loses some electrolytes by perspiring (sweat has about half  the solute concentration of plasma). The quantities of electrolytes    FIGURE 21.6 Electrolyte balance exists when the intake of  electrolytes from all sources equals the output of electrolytes.    leaving vary with the amount of perspiration. More electrolytes are  lost in sweat on warmer days and during strenuous exercise. Varying  amounts of electrolytes are lost in the feces. The greatest electro-  lyte output occurs as a result of kidney function and urine produc-  tion. The kidneys alter renal electrolyte losses to maintain the proper  composition of body fluids, thereby promoting homeostasis.    The concentrations of positively charged ions (cations), such as  sodium (Na*), potassium (K*), and calcium (Ca*’), are particu-  larly important. Certain concentrations of these ions are vital for  impulse conduction along an axon, muscle fiber contraction, and  maintenance of cell membrane permeability. Potassium is espe-  cially important in maintaining the resting potential of nerve and  cardiac muscle cells, and abnormal potassium levels may disrupt  the functioning of these cells.   Sodium ions account for nearly 90% of the positively charged  ions in extracellular fluids. The kidneys and the hormone aldo-  sterone primarily regulate these ions. Aldosterone, which the  adrenal cortex secretes, increases sodium ion reabsorption in the  distal convoluted tubules and collecting ducts of the nephrons.  A decrease in sodium ion concentration in the extracellular fluid  stimulates aldosterone secretion via the renin-angiotensin system,  as described in chapter 20 on page 782 (see fig. 20.18, p. 783).   Aldosterone also regulates potassium ions. An important  stimulus for aldosterone secretion is a rising potassium ion con-  centration, which directly stimulates cells of the adrenal cortex.  This hormone enhances the renal tubular secretion of potassium  ions at the same time that it stimulates renal tubular reabsorption  of sodium ions (fig. 21.7).    Renal tubules increase  reabsorption of sodium ions  and increase secretion of  potassium ions    Sodium ions are  conserved and potassium  ions are excreted in the  urine    FIGURE 21.7 If the potassium ion concentration increases, the  kidneys conserve sodium ions and excrete potassium ions.    Among the more common disorders involving an imbalance in the  water of body fluids are dehydration, water intoxication, and edema.    Dehydration is a deficiency condition that occurs when output of  water exceeds intake. It is a great problem for athletes, military per-  sonnel, and certain industrial workers. Dehydration may develop  following excessive sweating or as a result of prolonged water  deprivation accompanied by continued water output. In either case,  as water is lost, the extracellular fluid becomes more concentrated,  and water leaves cells by osmosis (fig. 21A). Dehydration may  also accompany illnesses in which prolonged vomiting or diarrhea  depletes body fluids, such as the bacterial infection cholera.   During dehydration, the skin and mucous membranes of the  mouth feel dry, and body weight drops. Severe hyperthermia may  develop as the body temperature regulating mechanism falters  due to lack of water for sweat. In severe dehydration, as waste  products accumulate in the extracellular fluid, symptoms of cere-  bral disturbances, including mental confusion, delirium, and coma,  may develop. Dehydration is responsible for some of the symp-  toms of heatstroke.   Infants are more likely to become dehydrated because their  kidneys are less efficient at conserving water than those of adults.  Elderly people are also especially susceptible to developing water  imbalances because the sensitivity of their thirst mechanisms  decreases with age, and physical disabilities may make it difficult to  obtain adequate fluids.   The treatment for dehydration is to replace the lost water and  electrolytes. If only water is replaced, the extracellular fluid may    Recall from chapter 13 (pp. 507-508) that the plasma calcium  ion concentration dropping below normal directly stimulates the  parathyroid glands to secrete parathyroid hormone. Parathyroid  hormone increases activity in bone-resorbing cells (osteoclasts),  which increases the concentrations of both calcium and phosphate  ions in the extracellular fluids. Parathyroid hormone also indirectly  stimulates calcium absorption from the intestine. Concurrently,    become more dilute than normal, causing cells to swell (fig. 21B).  This may produce a condition called water intoxication.    Until recently, runners were advised to drink as much fluid as they  could while running, particularly in long events. The death of a  young woman in a marathon from low blood sodium (hyponatre-  mia, “water intoxication”) due to excessive fluid intake inspired  further study and a reevaluation of this advice. Researchers from  Harvard Medical School studied 488 runners from the race, and  found that 13% of them developed hyponatremia. The tendency  to develop the condition was associated with longer race time,  high or low body mass index, and significant weight gain during  the race. Drinking sports drinks instead of water does not make a  difference because these beverages are mostly water.   In recognition of the possibility of hyponatremia, USA Track  and Field, the national governing body for the sport, offers on  their website instructions for runners to determine exactly how  much to consume during a one-hour training run. The goal is to  replace exactly what is lost.    Edema is an abnormal accumulation of extracellular fluid in the intersti-  tial spaces (fig. 21B). Causes include a decrease in the plasma protein  concentration (hypoproteinemia), obstructions in lymphatic vessels,  increased venous pressure, and increased capillary permeability.  Hypoproteinemia may result from failure of the liver to syn-  thesize plasma proteins; kidney disease (glomerulonephritis) that  damages glomerular capillaries, allowing proteins to enter the    this hormone causes the kidneys to conserve calcium ions (through  increased tubular reabsorption) and increases the urinary excretion  of phosphate ions. The increased phosphate excretion offsets the  increased plasma phosphate. Thus, the net effect of the hormone is  to return the calcium ion concentration of the extracellular fluid to  normal levels but to maintain a normal phosphate ion concentra-  tion (fig. 21.8).    urine; or starvation, in which amino acid intake is insufficient to  support synthesis of plasma proteins. In each of these instances,  the plasma protein concentration is decreased, which decreases  plasma colloid osmotic pressure, reducing the normal return of  tissue fluid into the venular ends of capillaries. Consequently, tis-  sue fluid accumulates in the interstitial spaces.   Lymphatic obstructions may result from surgery or from parasitic  infections of lymphatic vessels, as chapter 16 (1p. 621) discussed. Back  pressure develops in the lymphatic vessels, which interferes with the  normal movement of tissue fluid into them. At the same time, pro-  teins that the lymphatic circulation ordinarily removes accumulate in  the interstitial spaces, raising osmotic pressure of the interstitial fluid.  This effect attracts still more fluid into the interstitial spaces.    If the outflow of blood from the liver into the inferior vena  cava is blocked, the venous pressure in the liver and portal vein  greatly increases. This, in turn, raises pressure in liver sinusoids  and intestinal capillaries, increasing filtration. Fluid is filtered into  the peritoneal cavity. This condition, called ascites, distends the  abdomen. It is painful.   Edema may also result from increased capillary perme-  ability accompanying inflammation. Recall that inflammation is a  response to tissue damage and usually releases chemicals such as  histamine from damaged cells. Histamine causes vasodilation and  increased capillary permeability, so fluid leaks out of the capillary  and enters the interstitial spaces. Table 21A summarizes the fac-  tors that result in edema.    Liver disease and failure to synthesize  proteins; kidney disease and loss of proteins in  urine; lack of proteins in diet due to starvation    Abnormal increases in blood calcium (hypercalcemia) can result  from hyperparathyroidism, in which excess secretion of PTH  increases bone resorption. Hypercalcemia may also be caused  by cancers, particularly those originating in the bone marrow,  breasts, lungs, or prostate gland. Usually the increase in calcium  occurs when cancer causes bone tissue to release calcium ions.  Symptoms of cancer-induced hypercalcemia include weakness and  fatigue, impaired mental function, headache, nausea, increased  urine volume (polyuria), and increased thirst (polydipsia).    Plasma osmotic pressure decreases; less fluid reabsorbed at venular  ends of capillaries by osmosis    Back pressure in lymph vessels interferes with movement of fluid  from interstitial spaces into lymph capillaries    Back pressure in veins increases capillary filtration and interferes with  return of fluid from interstitial spaces into venular ends of capillaries    Abnormal decreases in blood calcium (hypocalcemia) may  result from reduced availability of PTH following removal of  the parathyroid glands, or from vitamin D deficiency. It may  also result from decreased calcium absorption following gas-  trointestinal surgery or excess calcium excretion due to kidney  disease. Hypocalcemia may cause muscle spasms in the air-  ways or cardiac arrhythmias. Administering calcium salts and  high doses of vitamin D to promote calcium absorption may  correct this condition.    FIGURE 21.8 Ifthe plasma concentration of  calcium ions decreases, parathyroid hormone works  to increase the calcium ion concentration back to  normal. Increased urinary phosphate excretion  offsets bone resorption of phosphates (which  increases blood phosphate levels) to maintain a  normal concentration of phosphate ions.    Generally, the regulatory mechanisms that control posi-  tively charged ions secondarily control the concentrations of  negatively charged ions (anions). For example, chloride ions  (Cl), the most abundant negatively charged ions in the extra-  cellular fluids, are passively reabsorbed from the renal tubules  in response to the active reabsorption of sodium ions. That is,  the negatively charged chloride ions are electrically attracted to  the positively charged sodium ions and accompany them as they  are reabsorbed.   Some negatively charged ions, such as phosphate ions (PO,*)  and sulfate ions (SO,”), also are partially regulated by active  transport mechanisms that have limited transport capacities. For  example, if the extracellular phosphate ion concentration is low,  the phosphate ions in the renal tubules are conserved. On the other  hand, if the renal plasma threshold is exceeded, excess phosphate  will be excreted in the urine. Clinical Application 21.2 discusses  symptoms associated with sodium and potassium imbalances.    Renal tubules conserve  calcium ions and increase  secretion of phosphate ions    Electrolytes that release hydrogen ions are acids, as chapter 2  discussed (p. 66). Substances that release ions that combine with  hydrogen ions are bases. Acid-base balance entails regulation of  the hydrogen ion concentration of body fluids. This is important  because slight changes in hydrogen ion concentrations can alter  the rates of enzyme-controlled metabolic reactions, shift the dis-  tribution of other ions, or modify hormone actions. Recall from  chapter 2 (pp. 67-68) that pH number indicates the degree to  which a solution is acidic or basic (alkaline). The more acid the  solution, the lower its pH, and vice versa. The internal environ-  ment is normally maintained between pH 7.35 and 7.45.    Most of the hydrogen ions in body fluids originate as by-products  of metabolic processes, although the digestive tract may directly  absorb some hydrogen ions. The major metabolic sources of  hydrogen ions include the following. (These are reversible  reactions but, for clarity, are presented as the net reaction only.  Remember, it is the concentration of H* at equilibrium that deter-  mines the pH.)    1. Aerobic respiration of glucose. This process produces car-  bon dioxide and water. Carbon dioxide diffuses out of the    Sodium is the most abundant cation in extracellular fluid, and  potassium is the most abundant in intracellular fluid. The renal reg-  ulation of sodium is closely related to that of potassium because  active reabsorption of sodium (under the influence of aldosterone)  is accompanied by secretion (and excretion) of potassium. Thus, it  is not surprising that conditions that alter sodium ion balance also  affect potassium ion balance. Such disorders can be summarized  as follows:    1. Low blood sodium concentration (hyponatremia) Possible  causes of hyponatremia include prolonged sweating,  vomiting, or diarrhea; renal disease in which sodium is  inadequately reabsorbed; adrenal cortex disorders in  which aldosterone secretion is insufficient to promote the  reabsorption of sodium (Addison disease); and drinking too  much water.   Possible effects of hyponatremia include the  development of extracellular fluid that is hypotonic and  promotes the movement of water into the cells by osmosis.  This is accompanied by the symptoms of water intoxication  described in Clinical Application 21.1 on page 810.   2. High blood sodium concentration (hypernatremia) Possible  causes of hypernatremia include excessive water loss by  evaporation and diffusion, as may occur during high fever, or    cells and reacts with water in the extracellular fluids to form  carbonic acid:    The resulting carbonic acid then ionizes to release hydrogen  ions and bicarbonate ions:    2. Anaerobic respiration of glucose. Glucose metabolized  anaerobically produces lactic acid, which adds hydrogen ions  to body fluids.   3. Incomplete oxidation of fatty acids. The incomplete oxi-  dation of fatty acids produces acidic ketone bodies, which  increase hydrogen ion concentration.   4. Oxidation of amino acids containing sulfur. The oxidation  of sulfur-containing amino acids yields sulfuric acid (H,SO,),  which ionizes to release hydrogen ions.   5. Hydrolysis of phosphoproteins and nucleic acids.  Phosphoproteins and nucleic acids contain phosphorus.  Their oxidation produces phosphoric acid (H,PO,), which  ionizes to release hydrogen ions.    The acids resulting from metabolism vary in strength (fig. 21.9).  Thus, their effects on the hydrogen ion concentration of body  fluids vary.    increased water loss accompanying diabetes insipidus (not  to be confused with diabetes mellitus), in one form of which  ADH secretion is insufficient to maintain water conservation  by the renal tubules and collecting ducts. Possible effects of  hypernatremia include disturbances of the central nervous  system, such as confusion, stupor, and coma.   3. Low blood potassium concentration (hypokalemia) Possible  causes of hypokalemia include use of diuretic drugs that  promote potassium excretion; kidney disease; and a drop  in extracellular hydrogen ion concentration. Possible effects  of hypokalemia include muscular weakness or paralysis,  respiratory difficulty, and severe cardiac disturbances, such as  atrial or ventricular arrhythmias.   4. High blood potassium concentration (hyperkalemia)  Possible causes of hyperkalemia include renal disease, which  decreases potassium excretion; use of drugs that promote  renal conservation of potassium; insufficient secretion of  aldosterone by the adrenal cortex (associated with Addison  disease); or a shift of potassium from the intracellular fluid  to the extracellular fluid, a change that accompanies an  increase in plasma hydrogen ion concentration (acidosis) as  hydrogen ions begin to move into cells. Possible effects of  hyperkalemia include paralysis of the skeletal muscles and  severe cardiac disturbances, such as cardiac arrest.    Acids that ionize more completely (release more H*) are strong  acids, and those that ionize less completely are weak acids. For  example, the hydrochloric acid (HCl) of gastric juice is a strong  acid and dissociates completely to release a lot of H*, but the car-  bonic acid (H,CO,) produced when carbon dioxide reacts with  water is weak and dissociates less completely to release less H*.   Bases release ions, such as hydroxide ions (OH), which can  combine with hydrogen ions, thereby lowering their concentra-  tion. Sodium hydroxide (NaOH), which releases hydroxide ions,  and sodium bicarbonate (NaHCO,), which releases bicarbonate  ions (HCO,>), are bases. Strong bases dissociate to release more  OK or its equivalent than do weak bases. Often, the negative ions  themselves are called bases. For example, HCO, acting as a base  combines with H* from the strong acid HCl to form the weak acid  carbonic acid (H,CO,).    Either an acid shift or an alkaline (basic) shift in the body fluids  could threaten the internal environment. However, normal meta-  bolic reactions generally produce more acid than base. These  reactions include cellular metabolism of glucose, fatty acids, and  amino acids. Consequently, the maintenance of acid-base balance    usually eliminates acid. This is accomplished in three ways: acid-  base buffer systems; respiratory excretion of carbon dioxide; and  renal excretion of hydrogen ions.    20 Explain why the regulation of hydrogen ion concentration is so  important.    21 What are the major sources of hydrogen ions in the body?   Chemical buffer systems are in all body fluids and are based on  chemicals that combine with excess acids or bases. Buffers are  substances that stabilize the pH of a solution, despite the addition  of an acid or a base. More specifically, the chemical components  of a buffer system can combine with strong acids to convert them  into weak acids. Likewise, these buffers can combine with strong  bases to convert them into weak bases. Such reactions help mini-  mize pH changes in the body fluids. The three most important buf-  fer systems in body fluids are the bicarbonate buffer system, the  phosphate buffer system, and the protein buffer system.   In the following discussion, associated anions and cations  have been omitted for clarity. For example, the weak base sodium  bicarbonate (NaHCO,) is represented by bicarbonate (HCO,).  Sodium is also the cation associated with the phosphate ions.    1. Bicarbonate buffer system. In the bicarbonate buffer sys-  tem, present in both intracellular and extracellular fluids, the  bicarbonate ion (HCO,,) acts as a weak base, and carbonic  acid (H,CO,) acts as a weak acid. In the presence of excess  hydrogen ions, bicarbonate ions combine with hydrogen ions  to form carbonic acid, minimizing any increase in the hydro-  gen ion concentration of body fluids:    H* + HCO, — H,Co,  On the other hand, if conditions are basic or alkaline, carbonic  acid dissociates to release bicarbonate ion and hydrogen ion:  H,CO, > H* + HCO,  Although this reaction releases bicarbonate ion, it is the    increase of free hydrogen ions at equilibrium that is important  in minimizing the shift toward a more alkaline pH.    2. Phosphate buffer system. The phosphate buffer system is  also present in both intracellular and extracellular fluids. How-  ever, it is particularly important in the control of hydrogen  ion concentration in the intracellular fluid and in renal tubular  fluid and urine. This buffer system consists of two phosphate  ions, dihydrogen phosphate (H,PO,”) and monohydrogen  phosphate (HPO, *).   In the presence of excess hydrogen ions, monohydrogen  phosphate ions act as a weak base, combining with hydrogen  ions to form dihydrogen phosphate, minimizing increase in  the hydrogen ion concentration of body fluids.    On the other hand, if conditions are basic or alkaline, dihydro-  gen phosphate, acting as a weak acid, dissociates to release  hydrogen ion:    3. Protein buffer system. The protein acid-base buffer system  consists of the plasma proteins, such as albumins, and certain  proteins in cells, including hemoglobin in red blood cells.   Recall from chapter 2 (p. 73) that proteins are chains  of amino acids. Some of these amino acids have freely  exposed groups of atoms, called carboxyl groups. If the  H* concentration drops, a carboxyl group (—COOH) can  become ionized, releasing a hydrogen ion, thus resisting  the pH change:   which it is reversible depends on the particular amino acids.)  In the presence of excess hydrogen ions, the —COO™ parts   of the protein molecules accept hydrogen ions and become  —COORH groups again. This action decreases the number of  free hydrogen ions in the body fluids and again minimizes the  pH change.   Some of the amino acids of a protein molecule also have  freely exposed amino groups (—NH.,). If the H* concentration  rises, these amino groups can accept hydrogen ions in another  reversible reaction (Once again, the degree to which it is  reversible depends on the particular amino acids.):    In the presence of excess hydroxyl ions (OH), the —NH,*  groups of protein molecules give up hydrogen ions and  become —NH, groups again. These hydrogen ions then  combine with hydroxyl ions to form water molecules. Once  again, pH change is minimized. The “R”-groups of certain  amino acids (histidine and cysteine) can also function as  buffers. Thus, protein molecules can function as acids by  releasing hydrogen ions under alkaline conditions or as  bases by accepting hydrogen ions under acid conditions.  This special property allows protein molecules to operate  as an acid-base buffer system.   Hemoglobin is an especially important protein that  buffers hydrogen ions. Recall from chapter 19 (p. 759) that  carbon dioxide, produced by cellular oxidation of glucose, dif-  fuses through the capillary wall and enters the plasma and then  the red blood cells. The red blood cells contain an enzyme,  carbonic anhydrase, that speeds the reaction between carbon  dioxide and water, producing carbonic acid:    The carbonic acid quickly dissociates, releasing hydrogen ions  and bicarbonate ions:    In the peripheral tissues, where CO, is generated, oxygen is used  in the metabolism of glucose. Hemoglobin gives up much of its  oxygen and is in the form of deoxyhemoglobin. In this form,  hemoglobin can bind the hydrogen ions generated in red blood  cells, acting as a buffer to minimize the pH change that would  otherwise occur.   The above two reactions can be written as a single revers-  ible reaction:    In the peripheral tissues, where CO, levels are high, the  reaction equilibrium shifts to the right. This generates   H*, which is buffered by hemoglobin, and HCO,,, which  becomes a plasma electrolyte. In the lungs, where oxygen  levels are high, hemoglobin is no longer a good buffer,  and it releases its H*. However, the released H* combines  with plasma HCO,, shifting the reaction equilibrium to the  left, generating carbonic acid, which quickly dissociates to  form CO, and water. The water is added to the body fluids,  and the CO, is exhaled. These shifts occur rapidly because  carbonic anhydrase catalyzes the reactions in both direc-  tions. Carbonic acid is sometimes called a volatile acid  because of this relationship to CO, (see figs. 19.41 and  19.43, p. 761).   Individual amino acids in body fluids can also function  as acid-base buffers by accepting or releasing hydrogen ions.  This is possible because every amino acid has an amino group  (—NH,) and a carboxyl group (—COOH).    To summarize, acid-base buffer systems take up hydrogen  ions when body fluids are becoming more acidic and give up  hydrogen ions when the fluids are becoming more basic (alkaline).  Buffer systems convert stronger acids into weaker acids or convert  stronger bases into weaker bases, as table 21.3 summarizes.    In addition to minimizing pH fluctuations, acid-base buffer  systems in body fluids buffer each other. Consequently, when-  ever the hydrogen ion concentration begins to change, the chemi-  cal balances in all of the buffer systems change too, resisting the  drift in pH.    22 What is the difference between a strong acid or base anda  weak acid or base?    23 How does a chemical buffer system help regulate pH of body fluids?  24 List the major buffer systems of the body.    Chemical buffer systems only temporarily solve the problem  of acid-base balance. Ultimately, the body must eliminate excess  acid or base. The lungs (controlled by the respiratory center) and  the kidneys accomplish this task.    The respiratory center in the brainstem helps regulate hydrogen  ion concentrations in the body fluids by controlling the rate and  depth of breathing. If body cells increase their production of car-  bon dioxide, carbonic acid production increases. As the carbonic  acid dissociates, the concentration of hydrogen ions increases, and  the pH of the internal environment begins to drop (see chapter 19,  p. 752). Such an increasing concentration of carbon dioxide in the  central nervous system and the subsequent increase in hydrogen  ion concentration in the cerebrospinal fluid stimulate chemo-  sensitive areas in the respiratory center.   In response to stimulation, the respiratory center increases the  depth and rate of breathing so that the lungs excrete more carbon  dioxide. Hydrogen ion concentration in body fluids returns toward  normal, because the released carbon dioxide is in equilibrium with  carbonic acid (fig. 21.10):    system (HCO,) acid into a weak acid  Carbonic acid Converts a strong  (H,CO,) base into a weak base  Phosphate Monohydrogen Converts a strong  system phosphate ion acid into a weak acid  (HPO,”)    Conversely, if body cells are less active, concentrations  of carbon dioxide and hydrogen ions in body fluids may begin  to decrease. In response to the change, the respiratory center  decreases breathing rate and depth. This increases the carbon  dioxide level in the body fluids, returning the pH toward normal. If  the pH drops below normal, the respiratory center is stimulated to  increase the rate and depth of breathing.   Activity of the respiratory center, therefore, changes in  response to shifts in the pH of the body fluids, reducing these  shifts to a minimum. Because most of the hydrogen ions in the  body fluids originate from carbonic acid produced when carbon  dioxide reacts with water, the respiratory regulation of hydrogen  ion concentration is important.   Nephrons help regulate the hydrogen ion concentration of body  fluids by excreting hydrogen ions in the urine. Recall from chap-  ter 20 (p. 786) that the epithelial cells of the proximal and distal    convoluted tubules and the collecting ducts secrete these ions into  the tubular fluid. The tubular secretion of hydrogen ions is linked  to tubular reabsorption of bicarbonate ions. In this way, the kid-  neys also regulate the concentration of bicarbonate ions in body  fluids. These mechanisms also help balance the sulfuric acid,  phosphoric acid, and organic acids that appear in body fluids as  by-products of metabolic processes.   The metabolism of certain amino acids, for example, pro-  duces sulfuric and phosphoric acids. Consequently, a diet high in  proteins may form excess acid. The kidneys compensate by alter-  ing the tubular secretion of hydrogen ions, thus resisting a shift  in the pH of body fluids (fig. 21.11). Once hydrogen ions are  secreted, phosphates filtered into the fluid of the renal tubule buf-  fer them, aided by ammonia (NH,).   Through deamination of certain amino acids, the cells of the  renal tubules produce ammonia, which diffuses readily through  cell membranes and enters the renal tubules. When increase in the  hydrogen ion concentration of body fluids is prolonged, the renal  tubules increase ammonia production. Ammonia is a weak base,  so it can accept hydrogen ions to form ammonium ions (NH,,"*):    Cell membranes are impermeable to ammonium ions, which  are trapped in the renal tubules as they form and are excreted  with the urine. This mechanism helps to transport excess hydro-  gen ions to the outside and helps prevent the urine from becom-  ing too acidic.    The various regulators of hydrogen ion concentration operate at  different rates. Acid-base buffers function rapidly and can convert  strong acids or bases into weak acids or bases almost immediately.  For this reason, these chemical buffer systems are called the body’s  first line of defense against shifts in pH.   Physiological buffer systems, such as the respiratory and renal  mechanisms, function more slowly and constitute the second line  of defense. The respiratory mechanism may require several min-  utes to begin resisting a change in pH, and the renal mechanism  may require one to three days to regulate a changing hydrogen ion  concentration (fig. 21.12).    FIGURE 21.11 [If the concentration of hydrogen ions in body fluids increases, the renal tubules increase their secretion of hydrogen ions into the urine.   buffers may require several minutes to several days to begin resisting a   @ How does respiratory excretion of CO, buffer the pH of  body fluids?    25 How does the respiratory system help regulate acid-base balance?  26 How do the kidneys respond to excess hydrogen ions?    27 How do the rates at which chemical and physiological buffer  systems act differ?    Chemical and physiological buffer systems ordinarily maintain the  hydrogen ion concentration of body fluids within very narrow pH  ranges. Abnormal conditions may disturb the acid-base balance. For  example, the pH of arterial blood is normally 7.35—7.45. A value  below 7.35 produces acidosis. A pH above 7.45 produces alkalosis  (fig. 21.13).   Acidosis results from accumulation of acids or loss of bases,  both of which cause abnormal increases in the hydrogen ion con-    FIGURE 21.13 If the pH of arterial blood drops to 6.8 or rises to 8.0  for more than a few hours, the person usually cannot survive.    centrations of body fluids. Conversely, alkalosis results from a loss  of acids or an accumulation of bases accompanied by a decrease in  hydrogen ion concentrations (fig. 21.14). If the imbalance is due to  a change in respiratory function, it is termed a respiratory distur-  bance. Any other disturbance in acid-base balance is termed meta-  bolic. Such shifts in the pH of body fluids may be life threatening.  A person usually cannot survive if the pH drops to 6.8 or rises to  8.0 for more than a few hours.    The two major types of acidosis are respiratory acidosis and meta-  bolic acidosis. Factors that increase carbon dioxide levels, which  increases the concentration of carbonic acid (the respiratory acid),  cause respiratory acidosis. Metabolic acidosis is due to an abnor-  mal accumulation of any other acids in the body fluids or to a loss  of bases, including bicarbonate ions. Similarly, the two major  types of alkalosis are respiratory alkalosis and metabolic alkalo-  sis. Excessive loss of carbon dioxide and consequent loss of car-  bonic acid cause respiratory alkalosis. Metabolic alkalosis is due  to excessive loss of hydrogen ions or gain of bases.   In respiratory acidosis, carbon dioxide accumulates. Evidence  of respiratory insufficiency, such as labored breathing and cya-  nosis, may be evident. Respiratory insufficiency can result from  factors that hinder alveolar ventilation (fig. 21.15). These factors  include the following:    1. Injury to the respiratory center of the brainstem that decreases  rate and depth of breathing.   2. Obstructions in air passages that interfere with air movement  into and out of the alveoli.   3. Diseases that decrease gas exchange, such as pneumonia or  emphysema.    FIGURE 21.14 Acidosis results from accumulation of acids or  loss of bases. Alkalosis results from loss of acids or accumulation  of bases.    Any of these conditions can increase the level of carbonic acid and  hydrogen ions in body fluids, lowering pH.   Metabolic acidosis is due to either accumulation of nonrespi-  ratory acids or loss of bases (fig. 21.16). Factors that may lead to  this condition include:    1. Kidney disease reduces glomerular filtration and fails to  excrete the acids produced in metabolism (uremic acidosis).   2. Prolonged vomiting loses the alkaline contents of the upper  intestine and acidic stomach contents. (Losing only the stom-  ach contents produces metabolic alkalosis.)   3. Prolonged diarrhea causes loss of alkaline intestinal secretions  (especially in infants).   4. In diabetes mellitus some fatty acids react to produce ketone  bodies, such as acetoacetic acid, beta-hydroxybutyric acid,  and acetone. Normally, these molecules are scarce, and cells  oxidize them as energy sources. However, if fats are used at  an abnormally high rate, as may occur in diabetes mellitus,  ketone bodies may accumulate faster than they can be  oxidized, and as a result spill over into the urine (ketonuria).  In addition, the lungs may release acetone, which is volatile  and imparts a fruity odor to the breath. More seriously, the  accumulation of acetoacetic acid and beta-hydroxybutyric  acid may lower pH (ketonemic acidosis).    FIGURE 21.15 Some of the factors that lead to respiratory acidosis.    FIGURE 21.16 Some of the factors that lead to metabolic acidosis.    Nonrespiratory acids may also combine with bicarbonate  ions in the urine. Too many bicarbonate ions are excreted, inter-  fering with the function of the bicarbonate acid-base buffer sys-  tem. Whatever the cause, metabolic acidosis shifts pH downward.   The symptoms of acidosis result from depression of central  nervous system function. They include drowsiness, disorienta-  tion, stupor, and cyanosis.    The two major types of alkalosis are respiratory alkalosis and met-  abolic alkalosis. Excessive loss of carbon dioxide and consequent  loss of carbonic acid cause respiratory alkalosis. Metabolic alkalo-  sis is due to excessive loss of hydrogen ions or gain of bases.   Respiratory alkalosis develops as a result of hyperventilation,  described in chapter 19 (p. 753). Hyperventilation is accompanied  by too great a loss of carbon dioxide and consequent decreases in  carbonic acid and hydrogen ion concentrations (fig. 21.17).   Hyperventilation may happen during periods of anxiety. It  may also accompany fever or poisoning from salicylates, such  as aspirin. At high altitudes, hyperventilation may be a response  to low oxygen partial pressure. Also, musicians, such as bass  tuba players, who must provide a large volume of air when play-  ing sustained passages, sometimes hyperventilate. In each case,  rapid, deep breathing depletes carbon dioxide, and the pH of  body fluids increases.   Metabolic alkalosis results from a loss of hydrogen ions or  from a gain in bases, both accompanied by a rise in the pH of the  blood (alkalemia) (fig. 21.18). This condition may occur follow-  ing gastric drainage (lavage), prolonged vomiting in which only  the stomach contents are lost, or the use of certain diuretic drugs.  Gastric juice is acidic, so its loss leaves the body fluids with a net  increase of basic substances and a pH shift toward alkaline values.  Metabolic alkalosis may also develop as a result of ingesting too  much antacid, such as sodium bicarbonate, to relieve the symp-  toms of indigestion.   The symptoms of alkalosis include light-headedness, agita-  tion, dizziness, and tingling sensations. In severe cases, impulses  may be triggered spontaneously on motor neurons, and muscles  may respond with tetanic contractions (see chapter 9, p. 304).    FIGURE 21.17 Some of the factors that lead to respiratory alkalosis.    FIGURE 21.18 Some of the factors that lead to metabolic alkalosis.    28 What is the difference between a respiratory acid-base disturbance  and a metabolic disturbance?    29 How do the symptoms of alkalosis compare with those of acidosis?    During an acid-base imbalance, the same mechanisms described  in this chapter, including chemical buffers, respiratory excretion  of CO,, and renal excretion of hydrogen ions, may resist the shift  in pH. This resistance is called compensation. For example, in    The maintenance of water and electrolyte balance requires  that the quantities of these substances entering the body equal  the quantities leaving it. Altering the water balance affects  electrolyte balance.    1. Fluid compartments  a. The intracellular fluid compartment includes the  fluids and electrolytes cell membranes enclose.  b. The extracellular fluid compartment includes all  fluids and electrolytes outside cell membranes.  (1) Interstitial fluid is in tissue spaces.  (2) Plasma is part of the blood.  (3) Lymph is within lymphatic vessels.  (4) Transcellular fluid is in body cavities.  2. Body fluid composition  a. Extracellular fluids have high concentrations of sodium,  chloride, calcium, and bicarbonate ions, with less  potassium, calcium, magnesium, phosphate, and sulfate  ions. Plasma contains more protein than does either  interstitial fluid or lymph.    the case of metabolic alkalosis due to excess administration of  antacids to a patient, all three mechanisms play a role in compen-  sating. Chemical buffers release hydrogen ions to lower the pH.  Also, respiratory control mechanisms inhibit ventilation, thereby  retaining CO, to help lower the pH toward normal. Finally, the  kidneys decrease tubular secretion of hydrogen ions, causing the  urine to become more alkaline, reflecting excretion of the excess base.   Another example of compensation is metabolic acidosis caused  by uncontrolled diabetes mellitus and the resultant accumulation of  acidic ketones in the blood. As blood pH drops, respiratory control  mechanisms increase breathing rate and depth, thereby lowering  carbon dioxide levels, raising blood pH toward normal. Also, the  kidneys begin to excrete the excess hydrogen ions in the urine.   If the disturbance is due to a problem with one of the organ  systems that normally compensates, however, the response is  limited to the remaining mechanisms. If the problem is respira-  tory acidosis due to pulmonary disease, the respiratory system is  not able to take part in the compensation. In this case, compensa-  tory response depends on chemical buffering and on increased  excretion of hydrogen ions by the kidneys. Similarly, in the case  of metabolic acidosis caused by kidney disease, compensation  depends on chemical buffering and on increased CO, excretion  by the respiratory system.    b. Intracellular fluid contains relatively high  concentrations of potassium, magnesium, and  phosphate ions; it also contains a greater concentration  of sulfate ions and lesser concentrations of sodium,  chloride, calcium, and bicarbonate ions than does  extracellular fluid.   (1) Fluid leaves plasma because of hydrostatic  pressure and returns to plasma because of colloid  osmotic pressure.   (3) Osmotic pressure regulates fluid movement in and  out of cells.   b. Sodium ion concentrations are especially important in  fluid movement regulation.    1. Water intake  a. The volume of water taken in varies from person to  person.  b. Most water comes from consuming liquid or moist foods.  c. Oxidative metabolism produces some water.    Acids are electrolytes that release hydrogen ions. Bases  combine with hydrogen ions.    a. The thirst mechanism is the primary regulator of water  intake.  b. Drinking and the resulting stomach distension inhibit  the thirst mechanism.  3. Water output a.  a. Water is lost in a variety of ways.    1. Sources of hydrogen ions.  Aerobic respiration of glucose produces carbon  dioxide, which reacts with water to form carbonic acid.    (1) Itis excreted in the urine, feces, and sweat.  (2) Insensible loss occurs through evaporation from  the skin and lungs.    c. Incomplete oxidation of fatty acids releases acidic  ketone bodies.  d. Oxidation of amino acids containing sulfur produces  sulfuric acid.  e. Hydrolysis of phosphoproteins and nucleic acids  gives rise to phosphoric acid.  2. Strengths of acids and bases    b. Urine is the primary means of water output.  4. Regulation of water output  a. The renal distal convoluted tubules and collecting ducts  regulate water output.   (1) ADH from the hypothalamus and posterior  pituitary gland stimulates water reabsorption in  these segments.   (2) ADH can reduce normal output of 1,500 milliliters  to 500 milliliters per day.    a. Acids vary in the extent to which they ionize.  (1) Strong acids, such as hydrochloric acid, ionize  more completely.  (2) Weak acids, such as carbonic acid, ionize less  completely.  b. Bases vary in strength also.  (1) Strong bases, such as hydroxide ions, combine  readily with hydrogen ions.  (2) Weak bases, such as bicarbonate ions, combine  with hydrogen ions less readily.  3. Regulation of hydrogen ion concentration    1. Electrolyte intake  a. The most important electrolytes in the body fluids are  those that release ions of sodium, potassium, calcium,  magnesium, chloride, sulfate, phosphate, and bicarbonate.  b. These ions are obtained in foods and beverages or as  by-products of metabolic processes.  2. Regulation of electrolyte intake   (1) Chemical buffer systems are composed of sets  of two or more chemicals.   (2) They convert strong acids into weaker acids or  strong bases into weaker bases.   (3) They include the bicarbonate buffer system,  phosphate buffer system, and protein buffer  system.    a. Hunger and thirst usually drive consumption of  sufficient electrolytes.  b. Severe electrolyte deficiency may induce a salt craving.  3. Electrolyte output  a. Electrolytes are lost through perspiration, feces, and    urine.  b. Quantities lost vary with temperature and physical b. The respiratory system excretes carbon dioxide.  exercise. (1) The respiratory center is in the brainstem.  c. The greatest electrolyte loss occurs as a result of kidney (2) Ithelps regulate pH by controlling the rate and  functions. depth of breathing.  4. Regulation of electrolyte output (3) Increasing carbon dioxide and hydrogen ion    concentrations stimulates chemoreceptors  associated with the respiratory center; breathing  rate and depth increase, and carbon dioxide  concentration decreases.    a. Concentrations of sodium, potassium, and calcium ions  in the body fluids are particularly important.   b. The regulation of sodium ions involves the secretion of  aldosterone from the adrenal glands.    inhibits breathing.  c. The kidneys excrete hydrogen ions.  (1) Nephrons secrete hydrogen ions to regulate pH.  (2) Ammonia produced by renal cells helps transport  hydrogen ions to outside the body.  d. Chemical buffers act rapidly; physiological buffers act  more slowly.    aldosterone.  d. Parathyroid hormone regulates calcium ion  concentration in body fluids.  e. The mechanisms that control positively charged ions  secondarily regulate negatively charged ions.  (1) Chloride ions are passively reabsorbed in renal  tubules as sodium ions are actively reabsorbed.  (2) Some negatively charged ions, such as phosphate  ions, are reabsorbed partially by limited-capacity  active transport mechanisms.    1. Acidosis  a. Respiratory acidosis results from increased levels of  carbon dioxide and carbonic acid.  b. Metabolic acidosis results from accumulation of other  acids or loss of bases.  2. Alkalosis  a. Respiratory alkalosis results from loss of carbon  dioxide and carbonic acid.  b. Metabolic alkalosis results from loss of other acids or  gain of bases.    Explain how water balance and electrolyte balance are  interdependent. (p. 804)    The water and electrolytes enclosed by cell membranes  constitute the . (p. 804)   Explain how the fluids in the compartments differ in  composition. (p. 805)   Describe how fluid movements between the compartments  are controlled. (p. 805)    Prepare a list of sources of normal water gain and loss to  illustrate how the input of water equals the output of water.  (pp. 806-807)   Explain how water intake is regulated. (pp. 806-807)  Explain how the kidneys regulate water output. (p. 808)   List the routes by which electrolytes leave the body.  (p. 809)   Explain how the adrenal cortex functions to regulate  electrolyte balance. (p. 809)    1. Ifan acid-base imbalance occurs, chemical buffering,  respiratory mechanisms, and renal mechanisms return  pH to normal. This resistance to pH change is called  compensation.  2. Ifan acid-base imbalance is due to dysfunction of one of  the compensatory mechanisms, another takes over.  a. In arespiratory disturbance, compensation depends on  chemical buffering and renal mechanisms.  b. Inarenal disturbance, compensation depends on  chemical buffering and the respiratory mechanism.    Describe the role of the parathyroid glands in regulating  electrolyte balance. (p. 810)   Describe the mechanisms by which the renal tubules regulate  electrolyte balance. (p. 812)   List five sources of hydrogen ions in the body fluids, and   name an acid that originates from each source. (pp. 812-813)  dissociate to release hydrogen ions more   completely. An example is hydrochloric acid. (p. 813)  dissociate to release fewer hydroxide ions.    ra INTEGRATIVE ASSESSMENTS/CRITICAL THINKING  Outcomes 14.3, 19.5, 19.6, 21.5, 21.6 Outcomes 17.5, 17.8, 17.9, 19.4, 21.5, 21.6    4. Describe what might happen to the plasma pH of a patient,  before compensation occurs, as a result of    1. An elderly, semiconscious patient is tentatively diagnosed as having  acidosis. What components of the arterial blood will be most    valuable in determining if the acidosis is of respiratory origin? a. prolonged diarrhea.  b. suction of the gastric contents.    Outcomes 15.2, 15.4, 16.2, 21.2 ae  d. hypoventilation.  2. If the right ventricle of a patient's heart is failing, increasing the  systemic venous pressure, what changes might occur in the Outcomes 19.4, 21.5, 21.6, 21.7  patient's extracellular fluid compartments? De he ee  5. Astudent hyperventilates and is disoriented just before an  exam. Is this student likely to be experiencing acidosis or  Outcomes 17.2, 17.5, 17.8, 17.9, 21.4, alkalosis? How will the body compensate in an effort to maintain  21.5, 21.6 homeostasis?    3. Radiation therapy may damage the mucosa of the stomach  and intestines. What effect might this have on the patient's  electrolyte balance?    Connect Interactive Questions Reinforce your knowledge using  assigned interactive questions covering fluid compartments and  the regulation of water, electrolyte, and acid-base balance.    Connect Integrated Activity Can you predict the effects of  different types of fluid and electrolyte imbalances?    Several sperm approach an egg, the winners of a race that several hundred  million sperm began (1,500x). Only one sperm cell can fertilize the egg.    The male and female reproductive systems are each connected  sets of organs and glands. Some of the reproductive organs and  glands secrete hormones vital to the development and main-  tenance of secondary sex characteristics and the regulation of  reproductive functions. Reproductive organs produce and nur-  ture sex cells (gametes) and transport them to sites of fertilization.    After you have studied this chapter, you should be able to:    Outline the process of meiosis, and explain how it mixes  up parental genes. (p. 824)    Describe the structure and function(s) of each part of  the male reproductive system. (pp. 826-835)    Explain how the tissues of the penis produce an erection.  (p. 835)  Hormonal Control of Male Reproductive Functions    Explain how hormones control the activities of the male  reproductive organs and the development of male  secondary sex characteristics. (pp. 837-839)    Describe the the structure and function(s) of each part of  the female reproductive system. (pp. 840-848)    Explain how hormones control the activities of the female  reproductive organs and the development of female  secondary sex characteristics. (p. 849)    Describe the major events during a female reproductive  cycle. (pp. 850-852)    Birth Control  Describe several methods of birth control, including the  relative effectiveness of each method. (pp. 854-858)    List the general symptoms of diseases associated with  sexually transmitted infections. (p. 859)   crur-, lower part: crura—diverging parts  at the base of the penis by which it  attaches to the pelvic arch.   fimb-, fringe: fimbriae—irregular extensions  on the margin of the infundibulum of the  uterine tube.   gubern-, to steer, to guide: gubernaculum—  fibrous cord that guides the descent of  a testis.   labi-, lip: labia minora—flattened, longitudi-  nal folds that extend along the margins  of the female vestibule.   prim-, first: primordial follicle—ovarian fol-  licle composed of an oocyte surrounded  by a single layer of cells.    Male sex cells are sperm. Female sex cells are eggs, or oocytes  (o’o-sitz), which in Latin means “egg cells.” Sex cells have one set  of genetic instructions carried on 23 chromosomes, compared to  two sets on 46 chromosomes in other body cells. When sex cells  join at fertilization, the amount of genetic information held in  46 chromosomes is restored. Sperm and oocytes are produced by a  special type of cell division called meiosis.   A normal fertilized human egg contains two copies of each  gene, one from the sperm and one from the egg. The different  possible combinations of variants of these genes explain why  siblings are not exactly alike.    Meiosis (mi-o’sis) includes two successive divisions, called the  first and second meiotic divisions. At the beginning of the process  each diploid cell has two sets of chromosomes (46 chromosomes)  that are in the form of 23 homologous chromosome pairs. In the first  meiotic division (meiosis I) members of each homologous pair are  separated from each other. Homologous pairs are the same, gene for  gene. They may not be identical, however, because a gene may have  variants, and the chromosome that comes from the person’s mother  may carry a different variant for the corresponding gene from the  father’s homologous chromosome. Before meiosis I, each chromo-  some is replicated, so it consists of two DNA molecules called  chromatids. Each chromatid has the complete genetic information  associated with that chromosome. The chromatids of a replicated  chromosome attach at regions called centromeres.   Each of the cells emerges from meiosis I with one member of  each homologous pair, a condition termed haploid. That is, a hap-  loid cell has one set of chromosomes (23 chromosomes, one from  each homologous pair). The second meiotic division (meiosis IT)  separates the chromatids, producing cells that are still haploid, but  whose chromosomes are no longer in the replicated form. After  meiosis II, each of the chromatids is an independent chromosome.    The steps of meiosis are clearer when considered in a time  sequence (fig. 22.1). However, keep in mind that meiosis, like mito-  sis, is a continuous process. Considering it in steps simply makes it  easier to follow.    Prophase I. Individual chromosomes appear as thin threads in  the nucleus that then shorten and thicken. Nucleoli disappear, the  nuclear membrane temporarily disassembles, and microtubules  begin to build the spindle that will separate the chromosomes.  The DNA of the chromosomes has already been replicated.   As prophase I continues, homologous chromosomes pair up  side by side and tightly intertwine. During this pairing, called syn-  apsis, the chromatids of the homologous chromosomes touch at  various points along their lengths. Often, the chromatids break in  one or more places and exchange parts, forming chromatids with  new combinations of genetic information (fig. 22.2). One chromo-  some of a homologous pair is maternal and the other is paternal.  Therefore, an exchange, or crossover, between homologous chro-  mosomes produces chromatids that contain genetic information  from both parents.    Metaphase I. During the first metaphase, chromosome pairs line  up about midway between the poles of the developing spindle, and  they are held under great tension, like two groups of people playing  tug-of-war. Each chromosome pair consists of two chromosomes,  which equals four chromatids. Each chromosome attaches to spin-  dle fibers from one pole. The chromosome alignment is random  with respect to maternal and paternal origin of the chromosomes.  Each of the 23 chromosomes contributed from the mother may be  on the left or the right, and the same is true for the paternal chromo-  somes—t is similar to the number of ways that 23 pairs of children  could line up, while maintaining the pairs. Chromosomes can line  up with respect to each other in many combinations.    Anaphase I. Homologous chromosome pairs separate, and each  replicated member moves to one end of the spindle. Each new, or  daughter, cell receives only one replicated member of a homologous  pair of chromosomes, overall halving the chromosome number.    FIGURE 22.1 (AP|R} Sex cells are formed by a special type of cell division, meiosis. This illustration follows two representative pairs of    Telophase I. The original cell divides in two. Nuclear mem-  branes form around the chromosomes, nucleoli reappear, and the  spindle fibers disassemble into their constituent microtubules.    After telophase I, the second meiotic division begins. Meiosis II  is similar to a mitotic division (see fig. 22.1). During prophase II,  chromosomes condense and reappear, still replicated. They move  into positions midway between the poles of the developing spin-  dle. In metaphase IT, the replicated chromosomes attach to spindle  fibers. In anaphase IT, centromeres separate, freeing the chroma-  tids to move to opposite poles of the spindles. The former chroma-  tids are now considered to be chromosomes. In telophase IT, each  of the two cells resulting from meiosis I divides to form two cells.  Therefore, each cell undergoing meiosis has the potential to pro-  duce four gametes. In males, the gametes mature into four sperm  cells. In females, three of the products of meiosis are “cast aside”  as polar bodies, and one cell becomes the egg.   Meiosis generates astounding genetic variety. Any one of a per-  son’s more than 8 million possible combinations of 23 chromosomes  can combine with any one of the more than 8 million combinations  of his or her mate, raising the potential variability to more than  70 trillion genetically unique individuals! Crossing over contributes  even more genetic variability. Figure 22.3 illustrates in a simplified  manner how maternal and paternal traits reassort during meiosis.    A couple chooses a certified nurse-midwife (CNM) to deliver  their third child because they prefer a home birth. Their first  two children had been delivered in a hospital. The children  are healthy and the births were uncomplicated.   The nurse-midwife meets with the couple throughout  the pregnancy, for at least an hour each time, and is present  for the entire labor and birth. She uses soothing words and  gentle massage to ease the baby into the world. The nurse-  midwife places the newborn on the mother’s chest while she  completes the initial examination.   A CNM provides pregnancy care, but can also provide  primary care, gynecologic care, family planning, treatment  for sexually transmitted infections, and newborn care for the  first month of life. She or he can do physical exams, prescribe  medications, and order and interpret medical tests to provide  a diagnosis.   A nurse-midwife is a registered nurse who has a graduate  degree in midwifery from an accredited program and has  passed a certification or licensing exam. Many nurse-midwives  deliver babies in patients’ homes, but some are affiliated with  hospitals. Nurse-midwives work with physicians who can help  in case of emergency.   (a) Homologous chromosome pair, (b) chromatids cross over, (c) crossing  over recombines genes. The different colors indicate that one of the  homologous chromosomes comes from the individual’s father and one  from the mother.    Organs of the male reproductive system are specialized to pro-  duce and maintain the male sex cells, or sperm cells; transport  these cells and supporting fluids to the outside; and secrete male  sex hormones.   The primary sex organs (gonads) of this system are the two  testes in which the sperm cells (spermatozoa) and the male sex  hormones are formed. The other structures of the male repro-  ductive system are termed accessory sex organs (secondary sex  organs). They include the internal reproductive organs and the  external reproductive organs (fig. 22.4; reference plates 3 and 4,  pp. 40-41).    The testes (tes’téz; sing., testis) are ovoid structures about 5 cen-  timeters in length and 3 centimeters in diameter. Both testes, each  suspended by a spermatic cord, are within the cavity of the saclike  scrotum (fig. 22.4 and reference plate 12, p. 48).    In a male fetus, the testes originate from masses of tissue posterior  to the parietal peritoneum, near the developing kidneys. Usually a  month or two before birth, the testes descend to the lower abdomi-  nal cavity and pass through the abdominal wall into the scrotum.  The male sex hormone testosterone, which the developing tes-  tes secrete, stimulates the testes to descend. A fibrous cord called  the gubernaculum (goo”ber’-nak’u-lum) is attached to each devel-  oping testis and extends into the inguinal region of the abdominal  cavity. The gubernaculum passes through the abdominal wall and  is fastened to the skin of the scrotum. As the body grows the testis   in sex cells varies from cell to cell. Colors represent parent of origin.  Although only one eye color gene pair is illustrated, eye color is polygenic  (involving more than one gene pair).    remains anchored to the gubernaculum, and guided by the guber-  naculum, the testis descends through the inguinal canal (ing’ gwi-  nal kah-nal’) of the abdominal wall and enters the scrotum, where  it remains. Each testis carries a developing ductus (vas) deferens,  blood vessels, and nerves. These structures later in development  form parts of the spermatic cord that suspends the testis in the  scrotum (fig. 22.5).   If the testes do not descend into the scrotum, they cannot  produce sperm cells because the temperature in the abdominal  cavity is too high. If this condition, called cryptorchidism, is left  untreated, the cells that normally produce sperm cells degener-  ate, causing infertility.    4 What are the primary sex organs of the male reproductive system?    As a testis descends, a pouch of peritoneum, called the vaginal  process, moves through the inguinal canal and into the scro-  tum. In about 25% of males, this pouch stays open, providing  a potential passageway through which a loop of intestine may    be forced by great abdominal pressure, producing an indirect  inguinal hernia. If the protruding intestinal loop is so tightly  constricted within the inguinal canal that its blood supply stops,  the condition is called a strangulated hernia. Without prompt  treatment, the blood-deprived tissues may die.    FIGURE 22.4 fAP|R} Male reproductive organs. (a) Sagittal view and (b) posterior view. The paired testes are the primary sex organs, and the other  reproductive structures, both internal and external, are accessory sex organs.    Abdominal —__ 1]  wall  Testis  Lower  abdominal ee  cavity Gubernaculum  Developing Pubic  penis symphysis  (a)  Peritoneum  Testis  Vaginal Inguinal canal  process  (cavity) Gubernaculum  (b)    FIGURE 22.5 During fetal development, each testis develops near  a kidney and then descends through an inguinal canal and enters the  scrotum, completing the journey by the eighth gestational month (a—c).    A tough, white, fibrous capsule called the tunica albuginea  encloses each testis. Along the capsule’s posterior border, the con-  nective tissue thickens and extends into the organ, forming a mass  called the mediastinum testis. From this structure, thin layers of  connective tissue, called septa, pass into the testis and subdivide it  into about 250 lobules.   A lobule contains one to four highly coiled, convoluted semi-  niferous tubules (sem” i-nif’er-us tu’bilz), each approximately 70  centimeters long when uncoiled. These tubules course posteriorly  and unite to form a complex network of channels called the rete  testis (re’te tes’tis). The rete testis is in the mediastinum testis and  gives rise to several ducts that join a tube called the epididymis.  The epididymis, in turn, is coiled on the outer surface of the testis  and continues to become the ductus deferens (figs. 22.6).    The seminiferous tubules are lined with a specialized strati-  fied epithelium, which includes the spermatogenic cells that give  rise to the sperm cells. Other specialized cells, called interstitial  (in’ter-stish’al) cells (cells of Leydig), lie between the seminifer-  ous tubules (fig. 22.6 and fig. 22.7). Interstitial cells produce and  secrete male sex hormones.    The epithelial cells of the seminiferous tubules can give rise  to testicular cancer, a common cancer in young men. In most  cases, the first sign is a painless testis enlargement or a small  lump or area of hardness on the testis. If a biopsy (tissue sam-  ple) reveals cancer cells, surgery is performed to remove the  affected testis (orchiectomy). Radiation and/or chemotherapy  in many cases prevents the cancer from recurring.    The epithelium of the seminiferous tubules consists of supporting  cells called sustentacular cells (Sertoli cells) and spermatogenic  cells (fig. 22.7). The sustentacular cells are columnar and extend  the full thickness of the epithelium, from its base to the lumen of  the seminiferous tubule. The sustentacular cells support, nourish,  and regulate the spermatogenic cells, which give rise to sperm  cells (spermatozoa).   In the male embryo, undifferentiated spermatogenic cells  are called spermatogonia (fig. 22.7). Each spermatogonium has  46 chromosomes (23 pairs) in its nucleus, the number for most  human body (somatic) cells. Hormones stimulate the spermato-  gonia to become active. Some of the cells undergo mitosis (see  chapter 3, pp. 108-110). Mitotic cell division gives rise to two  new cells, with each of these new cells containing 46 chromo-  somes. One cell (type A) maintains the supply of undifferentiated  cells, the other cell (type B) differentiates to become a primary  spermatocyte. Sperm production arrests at this stage.   At puberty, mitosis resumes, and new spermatogonia form.  Testosterone secretion increases, and the primary spermatocytes  divide by meiosis, each forming two secondary spermatocytes.  Each of these cells divides to form two spermatids, which mature  into sperm cells. Meiosis halves the number of chromosomes  in each cell (fig. 22.8). Spermiogenesis is the further develop-  ment of spermatids into sperm (see fig. 22.10). The combined  processes of meiosis and spermiogenesis constitute spermato-  genesis (sper”mah-to-jen’é-sis), taking about 65 to 75 days from  start to finish.   The spermatogonia are located within the seminiferous  tubules, adjacent to the inside surface of the surrounding basement  membrane. As spermatogenesis proceeds, cells in more advanced  stages are pushed along the sides of sustentacular cells toward the  lumen of the seminiferous tubule (fig. 22.9).    section of a testis. (b) Cross section of a seminiferous tubule. (b)    Near the base of the epithelium, tight junctions fuse the  membranous processes of adjacent sustentacular cells (fig. 22.9).  These tightly packed cells and their attachments form the blood-  testis barrier, which prevents some substances from reaching the  developing sperm. The blood-testis barrier helps maintain a favor-  able environment by isolating developing sperm from the male’s  immune system, which might otherwise react to the sperm as  abnormal, nonself cells.    Anton van Leeuwenhoek was the first to view human sperm  under a microscope in 1678, concluding that they were para-  sites in semen. By 1685, he had modified his view, writing that  sperm contain a preformed human being and are seeds requiring    nurturing in a female to start a new life. Although his interpre-  tation was incorrect, he did identify sperm as playing a role in  human reproduction.    Spermatogenesis happens continually in a male, starting at  puberty. The resulting sperm cells collect in the lumen of each  seminiferous tubule, then pass through the rete testis to the epi-  didymis, where they accumulate and mature.   A mature sperm cell is a tiny, tadpole-shaped structure about  0.06 millimeter long. It consists of a flattened head, a cylindrical  midpiece (body), and an elongated tail (flagellum).   The oval head of a sperm cell is primarily composed of a  nucleus and contains highly compacted chromatin consisting of 23  chromosomes. A small caplike covering over the head, called the  acrosome, contains enzymes that aid the sperm cell in penetrating  the layers surrounding the oocyte during fertilization (fig. 22.10). An  enzyme on the sperm cell membrane also contributes to this process.   The midpiece of a sperm has a central, filamentous core and  many mitochondria organized in a spiral. The tail consists of sev-  eral microtubules enclosed in an extension of the cell membrane.  The mitochondria provide ATP for the lashing movement of the  tail that propels the sperm cell. The micrograph in figure 22.11  shows a few mature sperm cells.    Many toxic chemicals that affect sperm hamper the tail’s abil-  ity to propel them, preventing the sperm from reaching an  egg and exposing it to the chemical. An exception is cocaine,  which attaches to thousands of binding sites on a human sperm    cell, without apparently harming the cell or impeding its abil-  ity to ferry cocaine to an egg. However, it is not known what  harm, if any, the drug causes. We do know that fetuses exposed  to cocaine in the uterus may suffer a stroke, or, as infants, be  unable to react normally to their surroundings.    FIGURE 22.8 During spermatogenesis four sperm cells result from meiosis of a primary spermatocyte.    © Why is it important that a sperm possess only 23 chromosomes?    9 Explain the function of the sustentacular cells in the  seminiferous tubules.    The internal accessory organs of the male reproductive system are  specialized to nurture and transport sperm cells. These structures  include the two epididymides, two ductus deferentia, two ejacula-  tory ducts, the urethra, as well as the two seminal vesicles, prostate  gland, and two bulbourethral glands.   The epididymides (ep”i-di-dy’mides; sing., epididymis) are tightly  coiled, threadlike tubes about 6 meters long (see fig. 22.4 and refer-  ence plate 12, p. 48). Each epididymis is connected to ducts in a tes-  tis. It emerges from the top of the testis, descends along its posterior  surface, and then courses upward to become the ductus deferens.    The inner lining of the epididymis is composed of pseu-  dostratified columnar cells that bear nonmotile cilia (fig. 22.12).  These cells secrete glycogen and other substances that support  stored sperm cells and promote their maturation.   When immature sperm cells reach the epididymis, they are  nonmotile. However, as they travel through the epididymis as a  result of rhythmic peristaltic contractions, they mature. Following  this aging process, the sperm cells can move independently and  fertilize egg cells. However, they usually do not move indepen-  dently until after ejaculation.   The ductus deferentia (duk’tus def’er-en’sha; sing., ductus def-  erens), also called vasa deferentia, are muscular tubes about  45 centimeters long lined with pseudostratified columnar epithe-  lium (fig. 22.13). Each ductus deferens originates at the lower end  of the epididymis and passes upward along the medial side of a  testis to become part of the spermatic cord. The ductus deferens  passes through the inguinal canal, enters the abdominal cavity  outside the parietal peritoneum, and courses over the pelvic brim.  From there, it extends backward and medially into the pelvic cavity,  where it ends behind the urinary bladder.    FIGURE 22.9 (AP|R) Mitosis in spermatogonia results in type A spermatogonia that continue the germ cell line and type B spermatogonia that give  rise to primary spermatocytes. The primary spermatocytes, in turn, give rise to sperm cells by meiosis. Changes in chromosome number and structure are  represented by a single pair of chromosomes. Note that as the cells approach the lumen they mature.    FIGURE 22.10 Spermiogenesis—sperm cell maturation. (a) The head of  the sperm develops largely from the nucleus of the formative cell. (b) Parts of    cross section of the ductus deferens (40x). (b) Light micrograph of the wall  of the ductus deferens (400x).    Near its termination, the ductus deferens dilates into a portion  called the ampulla. Just outside the prostate gland, the tube becomes  slender again and unites with the duct of a seminal vesicle. The  fusion of these two ducts forms an ejaculatory duct, which passes  through the prostate gland and empties into the urethra through a slit-  like opening (see fig. 22.4).    The seminal vesicles (or seminal glands) are convoluted, saclike  structures about 5 centimeters long, each attached to the ductus  deferens on the posterior surface and near the base of the urinary  bladder (see fig. 22.4). The glandular tissue lining the inner wall  of the seminal vesicle secretes a slightly alkaline fluid. This fluid  helps regulate the pH of the tubular contents as sperm cells travel  to the outside. Additionally, seminal vesicle fluid neutralizes the  acidic secretions of the vagina, helping to sustain the sperm cells  that enter the female reproductive tract. Seminal vesicle secretions  also include fructose, a monosaccharide that provides energy to  the sperm cells, and prostaglandins, which stimulate muscular  contractions of the female reproductive organs, aiding the move-  ment of sperm cells toward the egg cell.   As sperm move through the ductus deferens into the ejacu-  latory duct, the contents of the seminal vesicles empty into the  ejaculatory ducts. This greatly increases the volume of the fluid  discharged from the ductus deferens.    The prostate (pros’tat) gland (see figs. 22.4 and 22.14) is a  chestnut-shaped structure about 4 centimeters across and 3 cen-  timeters thick that surrounds the proximal portion of the ure-  thra, just inferior to the urinary bladder. It is composed of many  branched tubular glands enclosed in connective tissue. Septa of  connective tissue and smooth muscle extend inward from the cap-  sule, separating the tubular glands. The ducts of these glands open  into the urethra. The prostate gland releases its secretions into the  urethra as smooth muscle contracts in its capsular wall. As this  release occurs, the contents of the ductus deferens and the seminal  vesicles enter the urethra, which increases the volume of the fluid.   The prostate gland secretes a thin, milky fluid. This slightly  acidic secretion also contains citrate, a nutrient for sperm, and  prostate-specific antigen (PSA), an enzyme which helps liquefy  semen following ejaculation. Clinical Application 22.1 discusses  prostate cancer.    The bulbourethral (bul”bo-u-re’thral) glands (Cowper’s glands)  are two small structures, each about a centimeter in diameter.  They are inferior to the prostate gland lateral to the intermediate  part of the urethra and are enclosed by muscle fibers of the uro-  genital diaphragm (see fig. 22.4).   The bulbourethral glands are composed of many tubes whose  epithelial linings secrete a mucuslike fluid. This fluid is released in  response to sexual stimulation and lubricates the end of the penis  in preparation for sexual intercourse (coitus). However, females  secrete most of the lubricating fluid for intercourse.    FIGURE 22.14 Light micrograph of a cross section through the  prostate gland (10x).    Each year in the United States about 240,000 men are diagnosed  with prostate cancer, and about 30,000 die of the disease. How-  ever, many prostate tumors grow so slowly that they are not likely  to affect survival and do not require treatment.   The diagnostic process typically begins with a digital rectal  exam, in which a physician inserts a finger into the patient's rec-  tum to feel for an enlargement of the prostate gland. This exam is  typically coupled with a blood test to detect elevated levels of a  biomarker called prostate-specific antigen (PSA). Normally, secre-  tory epithelium in the prostate gland releases PSA, which liquefies  the ejaculate. When cancer cells accumulate, more PSA is pro-  duced, and it enters capillaries in the prostate.   Health-care organizations’ recommendations for PSA screen-  ing change often, and range from screening all men to screening  none, although any man with symptoms of an enlarged prostate  (frequent and slowed urination) should be tested. The contro-  versy is that the value of saving lives following screening must be  balanced against the risk that high levels of PSA in the absence of  cancer can lead to unnecessary biopsies.   If the physician feels an enlargement of the patient's prostate,  or if the PSA level remains high or rises on tests repeated a few  months later, the next step is a biopsy procedure to sample cells    The fluid the urethra conveys to the outside during ejaculation is  called semen (se’men). It consists of sperm cells from the testes  and secretions of the seminal vesicles, prostate gland, and bulbo-  urethral glands. Semen is slightly alkaline (pH about 7.5), and it  includes prostaglandins and nutrients.   The volume of semen released at one time varies from 2 to 5  milliliters. The average number of sperm cells in the fluid is about  120 million per milliliter.   Sperm cells remain nonmotile while they are in the ducts of the  testis and epididymis, but begin to swim as they mix with the secre-  tions of accessory glands. However, sperm cells cannot fertilize an  egg cell until they enter the female reproductive tract, because here  they undergo capacitation, which weakens the acrosomal mem-  branes. When sperm cells are placed with egg cells in a laboratory  dish to achieve fertilization—a technique called in vitro fertilization,  discussed in From Science to Technology 23.1 (pp. 870—871)—  chemicals are added to simulate capacitation.   Although sperm cells can live for many weeks in the ducts of the  male reproductive tract, they usually survive only up to six days after  being expelled to the outside, even when they are maintained at body  temperature. The ability of a sperm cell to fertilize an oocyte gener-  ally lasts only twenty-four to forty-eight hours after the sperm enter  the female reproductive tract. On the other hand, sperm cells can be  stored and kept viable for years if they are frozen at a temperature  below —100°C. Clinical Application 22.2 describes some causes of  male infertility.    from several sites in the gland. A cancer detected with a biopsy is  assigned a two-digit number, called a Gleason score, which indi-  cates how specialized the cancer cells are. The less specialized  the cells, the more aggressive the disease. Imaging technologies  can then assess whether the cancer has spread beyond the pros-  tate capsule.   Treatment of prostate cancer may be necessary if the tumor  has a high Gleason score or fits the genetic profile of being likely  to spread. Treatments include surgery to remove the prostate  gland, radiation, and hormones. Adverse effects of treatment  include urinary incontinence and erectile dysfunction, which may  improve with time. Fortunately, for many men “active surveil-  lance” to regularly monitor the disease is sufficient. This means  PSA tests twice a year and a biopsy every one to two years, with  treatment only if the condition worsens.   New tests measure the expression of specific genes that  change activity dramatically when the disease spreads. In one large  study that evaluated a gene expression test, doctors switched  37% of men being treated to active surveillance and 23% on active  surveillance to treatment based on test results. It will take a few  years to determine how well gene expression profiling improves  selection of patients for treatment.    14 Where is the prostate gland located?  15 What is the function of the bulbourethral glands?    The male external reproductive organs are the scrotum, which encloses  two testes, and the penis. The urethra passes through the penis.    The scrotum is a pouch of skin and subcutaneous tissue that hangs  from the lower abdominal region posterior to the penis. The sub-  cutaneous tissue of the scrotal wall lacks fat but contains a layer of  smooth muscle fibers that constitute the dartos muscle. Exposure  to cold stimulates these muscle fibers to contract, the scrotal  skin to wrinkle, and the testes to move closer to the body, where  they can absorb heat. In warmer temperatures, the dartos muscle  relaxes and the scrotum hangs loosely. The testes move away from  the body into an environment 3°C (about 5°F) below body tem-  perature, more conducive to sperm production and survival.   A medial septum divides the scrotum into two chambers,  each of which encloses a testis. Each chamber also contains a  serous membrane, which covers the front and sides of the testis  and the epididymis, helping to ensure that the testis and epididy-  mis move smoothly within the scrotum (see fig. 22.4).   The penis is a cylindrical organ that conveys urine and semen through  the urethra to the outside. It is also specialized to enlarge and stiffen,  which enables it to enter the vagina during sexual intercourse.   The body, or shaft, of the penis is composed of three columns  of erectile tissue, which include a pair of dorsally located corpora  cavernosa and a single, ventral corpus spongiosum. A tough cap-  sule of white dense connective tissue called a tunica albuginea  (too’ni-kah al”bu-jin’e-ah) surrounds each column. Skin, a thin  layer of subcutaneous tissue, and a layer of connective tissue  enclose the penis (fig. 22.15).   The corpus spongiosum, surrounding the urethra, enlarges at  its distal end to form a sensitive, cone-shaped glans penis. The  glans covers the ends of the corpora cavernosa and bears the ure-  thral opening—the external urethral orifice. The skin of the glans  is very thin, hairless, and contains sensory receptors for sexual  stimulation. A loose fold of skin called the prepuce (foreskin)  originates just posterior to the glans and extends anteriorly to  cover the glans as a sheath. The prepuce can be removed by a sur-  gical procedure called circumcision.   At the root of the penis, the columns of erectile tissue sepa-  rate. The corpora cavernosa diverge laterally in the perineum and  are firmly attached to the inferior surface of the pubic arch by con-  nective tissue. These diverging parts form the crura (sing., crus) of  the penis. The single corpus spongiosum is enlarged between the  crura as the bulb of the penis, which is attached to membranes of  the perineum (see fig. 22.4D).   During sexual stimulation, parasympathetic impulses from the  sacral portion of the spinal cord release the vasodilator nitric  oxide, which dilates the arteries leading into the penis, increasing    blood flow into erectile tissues. At the same time, the increas-  ing pressure of arterial blood entering the vascular spaces of the  erectile tissue compresses the veins of the penis, reducing flow  of venous blood away from the penis. Consequently, blood accu-  mulates in the erectile tissues, and the penis swells and elongates,  producing an erection (fig. 22.16).    In erectile dysfunction (impotence), the penis cannot become  erect or sustain an erection. Causes of erectile dysfunction  include underlying disease such as diabetes mellitus; paraly-  sis; treatments such as prostate surgery or certain drugs;  smoking cigarettes; and drinking alcohol. Development of  drugs to treat erectile dysfunction grew out of understand-  ing the physiology of erection. The first drug, Viagra (silde-  nafil), blocks the enzyme that breaks down cyclic guanosine  monophosphate in the erectile tissues, which is necessary for  an erection to persist.    The culmination of sexual stimulation is orgasm (or’gazm),  a pleasurable feeling of physiological and psychological release.  Orgasm in the male is accompanied by emission and ejaculation.   Emission (e-mish’un) is the movement of sperm cells from  the testes and secretions from the prostate gland and seminal ves-  icles into the urethra, where they mix to form semen. Emission is  a response to sympathetic impulses from the spinal cord, which  stimulate peristaltic contractions in smooth muscle in the walls of  the testicular ducts, epididymides, ductus deferentia, and ejacula-  tory ducts. Other sympathetic impulses stimulate rhythmic con-  tractions of the seminal vesicles and prostate gland.   As the urethra fills with semen, sensory impulses are stimu-  lated and pass into the sacral part of the spinal cord. In response,  motor impulses are conducted from the spinal cord to certain  skeletal muscles at the base of the erectile columns of the penis,  rhythmically contracting them. This movement increases the pres-  sure in the erectile tissues and aids in forcing the semen through    of the penis. (a) Interior and (b) cross  (b) section of the penis.    Male infertility—the inability of sperm cells to fertilize an egg  cell—has several causes. If, during fetal development, the tes-  tes do not descend into the scrotum, the higher temperature of  the abdominal cavity or inguinal canal impedes development of  sperm cells in the seminiferous tubules. Certain diseases, such as  mumps, may inflame the testes (orchitis), impairing fertility.   The quality and quantity of sperm cells are essential factors in  the ability of a man to father a child. If a sperm head is misshapen,  if the acrosome is too tough to burst and release enzymes, or if  too few sperm cells reach the well-protected egg, fertilization may  not happen. The structure of the sperm tail is particularly impor-  tant. Male infertility can result from sperm tails that are irregularly  shaped, coiled, bent, shortened, or absent.   Computer-aided sperm analysis (CASA) is a technique used  to evaluate a man’s fertility. It can analyze the pathways of up to  200 moving sperm in a few seconds. CASA assesses the number  of cells per milliliter of seminal fluid (density), sperm motility, and  the size and shape of sperm cell parts (morphology).   In a sperm analysis, a man abstains from intercourse for two to  three days, then provides a sperm sample. This may be done either  in a clinical setting or at home using a kit ordered from the Internet,  with the sample mailed to a lab. The man provides information  about his reproductive history and possible exposure to toxins. The  CASA system captures images with a digital camera and analyzes  and integrates information on sperm density, motility, and morphol-  ogy (fig. 22A). A computer may also be used to track sperm prog-  ress, ina woman's body, toward fertilizing an egg cell (fig. 22B).   Devices are being developed that will enable a man to esti-  mate his sperm count at home. They indicate whether a man’s  sperm count is above or below the World Health Organization's  designation of 20 million sperm per milliliter of ejaculate as the  lower criterion for normal fertility. If several tests performed days  apart fall below this level, the man should consult a fertility spe-  cialist for further testing. Table 22A indicates characteristics of a    _ Parasympathetic  neurons release  nitric oxide, causing  dilation of small flow away from  arteries to penis penis    Blood accumulates in the vascular  spaces within erectile tissues of penis    man’s sperm output that are the lowest for which he is still likely to  be fertile. It is clear that the male body manufactures many more  sperm than are necessary to fertilize an egg.    Computer analysis | path  improves the  consistency Average  and accuracy of path  describing sperm  density, motility,  and morphology,  each important    the urethra to the outside—a process called ejaculation (e-jak”u-  la’shun). During ejaculation, the posterior pituitary gland releases  a burst of oxytocin, which stimulates contractions of the epididy-  mides, seminiferous tubules, and prostate gland, aiding the move-  ment of sperm.   The sequence of events during emission and ejaculation is coor-  dinated so that the fluid from the bulbourethral glands is expelled  first. This is followed by the release of fluid from the prostate gland,  the passage of the sperm cells, and finally, the ejection of fluid  from the seminal vesicles into the urethra. Ejaculation forcefully  expels the semen from the body (fig. 22.17).   Immediately after ejaculation, sympathetic impulses constrict  the arteries that supply the erectile tissue, reducing the inflow of  blood. Smooth muscle in the walls of the vascular spaces partially  contracts, and the veins of the penis carry excess blood out of these  spaces. The penis gradually returns to its flaccid state, and usually    FIGURE 22B Acomputer tracks  sperm cell movements. In semen,  sperm cells swim in a straight line  (a), but as they are activated by  biochemicals in the woman's body,  their trajectories widen (b). The  sperm cells in (c) are in the mucus  of a woman's cervix, and the sperm  cells in (d) are attempting to digest  through the structures surrounding  an egg cell.    TABLE 22A Ranges of Semen and Sperm Characteristics in Healthy Men    Number of sperm 20-150 million/mL  Concentration of sperm 12-16 million/mL  Sperm vitality 55-63%    Hormones secreted by the hypothalamus, the anterior pituitary  Spontaneous emission and ejaculation are common in sleeping gland, and the testes control male reproductive functions. These  adolescent males. Changes in hormonal concentrations that hormones initiate and maintain sperm cell production and oversee  accompany adolescent development and sexual maturation the development and maintenance of male sex characteristics.    => The male body before ten years of age is reproductively imma-  R r] PRACTICE ture with undifferentiated spermatogenic cells in the testes. Then  a series of changes leads to development of a reproductively func-  tional adult. The hypothalamus controls many of these changes.  Recall from chapter 13 (pp. 498-499) that the hypothala-  mus secretes gonadotropin-releasing hormone (GnRH), which    19 What controls blood flow into penile erectile tissues?  20 Distinguish among orgasm, emission, and ejaculation.  21 Review the events associated with emission and ejaculation.    Peristaltic Rhythmic Rhythmic  contractions contractions contractions  in testicular ducts, in erectile in bulbourethral  epididymides, columns of glands, prostate  ductus deferentia, penis gland, and  and ejaculatory seminal vesicles  ducts    enters the blood vessels leading to the anterior pituitary gland. In  response, the anterior pituitary gland secretes the gonadotropins  (go-nad”o-tr6p’inz) called luteinizing hormone (LH) and follicle-  stimulating hormone (FSH). LH, which in males has been referred  to as interstitial cell-stimulating hormone (ICSH), promotes devel-  opment of the interstitial cells of the testes. The interstitial cells  secrete male sex hormones, mainly testosterone. FSH stimulates  the sustentacular cells of the seminiferous tubules to proliferate,  grow, mature, and respond to the effects of the male sex hormone  testosterone. Then, in the presence of FSH and testosterone, sus-  tentacular cells stimulate the spermatogenic cells to undergo  spermatogenesis, giving rise to sperm cells (fig. 22.18). The sus-  tentacular cells also secrete a hormone called inhibin, which inhib-  its the anterior pituitary gland by negative feedback. This action  prevents oversecretion of FSH.    Male sex hormones are termed androgens (an’dro-jenz). Interstitial  cells of the testes produce most male sex hormones, but the adrenal  cortex also synthesizes small amounts (see chapter 13, p. 512).   The hormone testosterone (tes-tos’té-r6n) is the most important  androgen. It is secreted by the testes and transported in the blood,  loosely attached to plasma proteins. Like other steroid hormones,  testosterone binds receptor molecules, which are usually in the  nuclei of its target cells (see chapter 13, p. 490). However, in many  target cells, such as those in the prostate gland, seminal vesicles,  and male external accessory organs, testosterone is first converted to  another androgen called dihydrotestosterone (di-hi”dro-tes-tos’té-  ron), which stimulates the cells of these organs. Most androgen  molecules that do not reach receptors in target cells are changed by  the liver into forms that can be excreted in bile or urine.   Testosterone secretion begins during fetal development and  continues for several weeks following birth; then it nearly ceases    Epididymis Promotes sperm cell maturation; stores  sperm cells; conveys sperm cells to  ductus deferens    Seminal vesicle Secretes an alkaline fluid containing  nutrients and prostaglandins that helps    Secretes a slightly acidic fluid that  contains citrate, a nutrient for sperm    body; inserted into the vagina during  sexual intercourse; the glans penis   is richly supplied with sensory nerve  endings associated with feelings of  pleasure during sexual stimulation    during childhood. Between the ages of thirteen and fifteen, a  young man’s androgen production usually increases rapidly. This  phase in development, when an individual becomes reproductively  functional, is puberty (pu’ber-te). After puberty, testosterone  secretion continues throughout the life of a male.    In a group of disorders called male pseudohermaphroditism, tes-  tes are present but a block in testosterone synthesis prevents the  genetically male fetus from developing male structures. The child  appears to be a female, but at puberty, the adrenal glands begin  to produce testosterone (as they normally do in both sexes) and  masculinization ensues. The voice deepens as muscles build up  into a masculine physique. Breasts do not develop, nor does  menstruation occur. The clitoris may enlarge so greatly under the  adrenal testosterone surge that it looks like a penis.    Cells of the embryonic testes first produce testosterone after about  eight weeks of development. This hormone stimulates the forma-  tion of the male reproductive organs, including the penis, scrotum,  prostate gland, seminal vesicles, and ducts. Later in development,  testosterone causes the testes to descend into the scrotum.   During puberty, testosterone stimulates enlargement of the tes-  tes (the primary male sex characteristic) and accessory organs of the    FIGURE 22.18 The hypothalamus  controls maturation of sperm cells and GnRH  development of male secondary sex ®  characteristics. Negative feedback  among the hypothalamus, the anterior  lobe of the pituitary gland, and the  testes controls the concentration of  testosterone in the male body.    FSH stimulates meiosis  in primary spermatocytes  to form immature sperm  cells; FSH stimulates  secretion of inhibin by  supporting cells    reproductive system, as well as development of male secondary sex  characteristics, which are special features associated with the adult  male body. Secondary sex characteristics in the male include:    1. increased growth of body hair, particularly on the face, chest,  axillary region, and pubic region; growth of hair on the scalp  may slow   2. enlargement of the larynx and thickening of the vocal folds,   4. increased muscular growth, broadening of the shoulders, and  narrowing of the waist    Testosterone also increases the rate of cellular metabolism  and red blood cell production. For this reason, the average num-  ber of red blood cells in a microliter of blood is usually greater in  males than in females. Testosterone stimulates sexual activity by  affecting certain parts of the brain.    The extent to which male secondary sex characteristics develop  is directly related to the amount of testosterone that the intersti-  tial cells secrete. The hypothalamus regulates testosterone output  through negative feedback (fig. 22.18).   As the concentration of testosterone in the blood increases,  the hypothalamus becomes inhibited, decreasing its stimulation of  the anterior pituitary gland by GnRH. As the pituitary’s secretion  of LH falls in response, the amount of testosterone the interstitial  cells release decreases.    Increased growth of  body hair on face, chest, of the vocal folds  axillary and pubic regions    As the blood testosterone concentration drops, the hypothalamus  becomes less inhibited, and it once again stimulates the anterior pitu-  itary gland to release LH. The increasing secretion of LH causes the  interstitial cells to release more testosterone, and blood testosterone  concentration increases. Testosterone level decreases somewhat dur-  ing and after the male climacteric, which is a decline in sexual function  that accompanies aging. At any given age, the testosterone concentra-  tion in the male body is regulated to remain relatively constant.    24 Explain how the secretion of male sex hormones is regulated.    The organs of the female reproductive system are specialized  to produce and maintain the female sex cells, the egg cells (or  oocytes); transport these cells to the site of fertilization; provide  a favorable environment for a developing offspring; move the off-  spring to the outside; and produce female sex hormones.   The primary sex organs (gonads) of this system are the two  ovaries, which produce the female sex cells and sex hormones.  The accessory sex organs (secondary sex organs) of the female  reproductive system are the internal and external reproductive  organs (fig. 22.19; reference plates 5 and 6, pp. 42-43).    FIGURE 22.19 (AP|R} The paired ovaries are the primary female sex organs, and the other structures, both internal and external, are accessory  sex organs. (a) Sagittal view. (b) Transverse section of the female pelvic cavity. (m. stands for muscle.)   The two ovaries are solid, ovoid structures measuring about 3.5  centimeters in length, 2 centimeters in width, and | centimeter in  thickness. The ovaries lie in shallow depressions (ovarian fossae)  on each side in the lateral wall of the pelvic cavity (fig. 22.20).    Several structures help hold each ovary in position. A fold of  peritoneum containing ovarian blood vessels and nerves attaches  each ovary to the largest of these, called the broad ligament.    The broad ligament is also attached to the uterine tubes and  the uterus.   A small fold of peritoneum, called the suspensory ligament,  holds the ovary at its upper end. This ligament also surrounds ovar-  ian blood vessels and nerves. At its lower end, the ovary is attached  to the uterus by a rounded, cordlike thickening of the broad ligament  called the ovarian ligament (fig. 22.20).    The ovaries in a female fetus, like the testes in a male fetus, orig-  inate from masses of tissue posterior to the parietal peritoneum,    near the developing kidneys. During development, these structures  descend to locations just inferior to the pelvic brim, where they  remain attached to the lateral pelvic wall.    Ovary Structure  The tissues of an ovary can be subdivided into two rather indis-  tinct regions, an inner medulla and an outer cortex. The ovarian  medulla is mostly composed of loose connective tissue and con-  tains relatively larger blood vessels, lymphatic vessels, and nerve  fibers. The ovarian cortex consists of more compact tissue and has  a granular appearance due to tiny masses of cells called ovarian  follicles, within which egg cells develop.   A layer of cuboidal epithelial cells covers the free surface of  the ovary. Just beneath this epithelium is a layer of dense connec-  tive tissue called the tunica albuginea.    25 What are the primary sex organs of the female?  26 Describe the attachments of the ovary.    Primordial Follicles  During prenatal (before birth) development of a female, oogonia  divide by mitosis, producing more oogonia. The oogonia develop  into primary oocytes. Each primary oocyte is closely surrounded  by a layer of flattened epithelial cells called follicular cells, form-  ing a primordial follicle.   Early in development, the primary oocytes begin to undergo  meiosis, but the process soon halts and does not continue until the  individual reaches puberty. Once the primordial follicles appear,    Round ligament  of uterus Uterus  FIGURE 22.20 fAP|R) The ovaries are located on each side against  the lateral walls of the pelvic cavity. The right uterine tube is retracted to  reveal the ovarian ligament.    no new ones form. Of the 250,000 to 500,000 primordial follicles  present at birth, 90% will be lost to apoptosis during infancy and  early adulthood. Fewer than 400 or 500 will be released from the  ovary during the female’s reproductive life, with less than ten  going on to form a new individual.    a  Children of older mothers are at risk of having abnormal num-  bers of chromosomes because when meiosis resumes in primary  oocytes after decades, spindle fibers can misalign, leading to  oocytes with extra or missing chromosomes. Exposure to radia-  tion, viruses, and toxins may contribute to the risk.   Oogenesis (0’0-jen’é-sis) is the process of egg cell formation.  Beginning at puberty, some primary oocytes are stimulated to con-  tinue meiosis. The resulting cells, as in the case of sperm cells,  have one-half as many chromosomes (23) in their nuclei as their  parent cells.   Unlike a primary spermatocyte, when a primary oocyte  divides, the cytoplasm is distributed unequally. One of the result-  ing cells, called a secondary oocyte, is large, and the other, called  the first polar body, is small (fig. 22.21).   The large secondary oocyte represents a future egg cell  (ovum) that can unite with a sperm cell, becoming fertilized. If  this happens, the oocyte divides unequally, producing a tiny second  polar body and a large fertilized egg cell, or zygote (zi’ got). The  polar bodies have no further function, and they begin to degenerate  fifteen hours post fertilization.   Formation of polar bodies may appear wasteful, but it has  an important biological function. It allows for production of an  egg cell that has the massive amounts of cytoplasm and abundant  organelles required to carry a zygote through the first few cell  divisions, yet the haploid number of chromosomes.    Follicle Maturation  At puberty, the anterior pituitary gland secretes increased amounts  of FSH, and the ovaries enlarge in response. Primordial folli-  cles begin to mature into primary follicles (pri’ma-re fol’i-k1z).  Figure 22.22 traces the maturation of a primordial follicle in an  ovary. During early follicle maturation, the primary oocyte within  the follicle enlarges, and surrounding follicular cells proliferate by  mitosis, giving rise to stratified epithelium composed of granulosa  cells. A layer of glycoprotein, called the zona pellucida (zo’nah  pel-u’ci-dah), gradually separates the primary oocyte from the  granulosa cells.   Meanwhile, the ovarian cells outside the follicle organize  into layers. The inner vascular layer (theca interna) is largely  composed of steroid-secreting cells, plus some loose connective    FIGURE 22.21 During oogenesis, (a) a  single egg cell (secondary oocyte) results from  meiosis of a primary oocyte. If the egg cell is  fertilized, it generates a second polar body and  becomes a zygote. (Note: The second meiotic  division does not occur in the egg cell if it is not  fertilized.) (b) Light micrograph of a secondary  oocyte and a polar body (arrow) (700x).    tissue and blood vessels. The outer fibrous layer (theca externa)  consists of tightly packed connective tissue cells (fig. 22.23).  The follicular cells continue to proliferate, and when they  form six to twelve layers of cells, irregular, fluid-filled spaces  appear among them. It may take 150 days or more for the primor-  dial follicle to reach the large pre-antral stage of development. The  spaces within the follicle soon join to form a single fluid-filled    cavity (antrum), and the primary oocyte is pressed to one side of  the follicle. At this stage, which may take another sixty-five or  more days to complete, the follicle is called an antral follicle.   After about fifteen days, the mature antral follicle (preovu-  latory, or Graafian, follicle) is about 20 millimeters in diameter,  and its fluid-filled cavity bulges outward on the surface of the  ovary, like a blister. The secondary oocyte within the mature fol-  licle is a large, spherical cell, surrounded by a thick zona pel-  lucida, attached to a mantle of follicular cells called the corona  radiata (ko-ro’nah ra-di-a’ta). Processes from these follicular  cells extend through the zona pellucida and supply nutrients to  the oocyte (fig. 22.23).   Although many primary follicles may begin maturing at any  given time, one follicle usually outgrows the others. Typically,  only the dominant follicle fully develops, and the other follicles    @) At puberty, in response to hormonal stimulation, primordial @ The antral follicle will grow quite rapidly and mature in about  follicles (0.02 mm) begin maturing into primary follicles (0.1 mm). 15 days prior to ovulation (20 mm).   @ It takes two to three months for the primary follicles to reach © Following ovulation, the remants of the antral follicle become  the pre-antral stage. It takes another 70 additional days for a the corpus luteum.    pre-antral follicle to reach a size of 0.2 mm.  @ It fertilization of the ovulated secondary oocyte does not occur,    ©) In another 65 to 70 days the pre-antral follicle will have become the corpus luteum degenerates to become the corpus albicans.  an antral follicle.   (a) Ovary, containing primordial  follicles awaiting development,  with it’s associated portion of  the uterine tube. (b) Stages in  development of a follicle.    simultaneously throughout the  cortex (250x). (c) Oocyte Maturing antral follicle Pre-antral follicle Primordial follicle    (a)  FIGURE 22.23 Ovarian follicle. (a) Structure of a mature antral (Graafian) follicle. (b) Light micrograph of a mature antral follicle (250x).    @ Which structure is formed by follicular cells attached to and surrounding the secondary oocyte?    degenerate. This entire process from a primordial follicle to a the secondary oocyte is released from the ovary it will contact the  dominant, fully developed mature antral follicle takes almost branched extensions (fimbriae) of the associated uterine tube. If  300 days. The process is ongoing in the ovaries, such that a new the secondary oocyte is not fertilized within hours, it degenerates.    dominant mature antral follicle becomes ready for ovulation  approximately every 28 days.    30 Describe changes that occur in a follicle and its oocyte during  maturation.  Certain drugs used to treat female infertility may cause a woman 31    than one secondary oocyte is ovulated. If all of the ovulated  secondary oocytes are fertilized, multiple births may result.   As a follicle matures, its primary oocyte undergoes meiosis I, giv-  ing rise to a secondary oocyte and a first polar body. A process  called ovulation (o’vu-la’shun) releases the secondary oocyte and  first polar body from the mature antral follicle (fig. 22.24).   Release of LH from the anterior pituitary gland plays a role in  triggering ovulation, during which the mature antral follicle swells  and its wall weakens. Eventually the wall ruptures, and the follicu-  lar fluid, accompanied by the secondary oocyte, is released from  the ovary’s surface (fig. 22.24).   After ovulation, the secondary oocyte and one or two lay-  ers of follicular cells surrounding it are normally propelled to the  opening of a nearby uterine tube. Compared to the overall size of  the ovary, the mature antral follicle is so large that no matter where FIGURE 22.24 Light micrograph of a follicle during ovulation (72x).    The internal accessory organs of the female reproductive system  include a pair of uterine tubes, a uterus, and a vagina.    The uterine tubes (Fallopian tubes, or oviducts) are suspended  by portions of the broad ligament and open near the ovaries. Each  tube, about 10 centimeters long and 0.7 centimeters in diameter,  passes medially to the uterus, penetrates its wall, and opens into  the uterine cavity. This allows for the movement of the egg from  the ovary to the uterus.   Near each ovary, a uterine tube expands to form a funnel-  shaped infundibulum (in’fun-dib’u-lum), which partially encir-  cles the ovary. On its margin, the infundibulum bears a number  of irregular, branched extensions called fimbriae (fim’bre) (see  figs. 22.19a and 22.20, fig. 22.25). Although the infundibulum  generally does not touch the ovary, one of the larger extensions  (ovarian fimbria) connects directly to the ovary. This is why some  cases of ovarian cancer actually begin in cells of the fimbriae.   The wall of a uterine tube consists of an inner mucosal layer,  a middle muscular layer of smooth muscle, and an outer covering  of peritoneum. The mucosal layer is drawn into many longitudinal  folds and is lined with simple columnar epithelial cells, some cili-  ated (fig. 22.26). The epithelium secretes mucus, and the cilia beat  toward the uterus. These actions help draw the secondary oocyte  and expelled follicular fluid into the infundibulum following ovu-  lation. Ciliary action and peristaltic contractions of the tube’s  muscular layer aid transport of the egg down the uterine tube.  Fertilization occurs in the uterine tube.   The uterus receives the embryo that develops from an egg cell fer-  tilized in the uterine tube and sustains development of the fetus.  The uterus is hollow, muscular, and shaped like an inverted pear.   The broad ligament, which also attaches to the ovaries and  uterine tubes, extends from the lateral walls of the uterus to the  pelvic walls and floor, creating a drape across the top of the pelvic  cavity (see fig. 22.25). A flattened band of tissue within the broad  ligament, called the round ligament, connects the upper end of the  uterus to the anterior pelvic wall (see figs. 22.20 and 22.25). The  cardinal ligaments attach the lower portion of the uterus to the lat-  eral walls of the pelvis, and the uterosacral ligaments attach the  uterus to the sacrum posteriorly.   The size of the uterus changes greatly during pregnancy. In its  nonpregnant, adult state, it is about 7 centimeters long, 5 centime-  ters wide (at its broadest point), and 2.5 centimeters in diameter.  The uterus is located medially in the anterior part of the pelvic  cavity, superior to the vagina, and usually bends forward over the  urinary bladder.   The upper two-thirds, or body, of the uterus has a dome-shaped  top, called the fundus, and is joined by the uterine tubes, which  enter its wall at its broadest part. The lower one-third, or neck, of  the uterus is called the cervix. This tubular part extends downward  into the upper part of the vagina. The cervix surrounds the opening  called the cervical orifice (ostium uteri), through which the uterus  opens to the vagina.   The uterine wall is thick and composed of three layers  (fig. 22.27). The endometrium (en”do-me’tre-um), the inner muco-  sal layer, is covered with columnar epithelium and contains abun-  dant tubular glands. The myometrium (mi”o-me’tre-um), a thick,  middle, muscular layer, consists largely of bundles of smooth    FIGURE 22.25 (AP|R) The funnel-shaped infundibulum  of the uterine tube partially encircles the ovary (posterior  view). The enlargement shows the oocyte and associated  structures released into the uterine tube during ovulation.    FIGURE 22.26 fAP|R) Uterine tube. (a) Light micrograph of a uterine tube (800x). (b) Falsely colored scanning electron micrograph showing  nonciliated (pink) cells and ciliated (green) cells that line the uterine tube (1,200x).    muscle fibers in longitudinal, circular, and spiral patterns and is  interlaced with connective tissues. During the monthly female  reproductive cycles and during pregnancy, the endometrium and  myometrium extensively change. The perimetrium (per”-i-  me’tre-um) consists of an outer serosal layer, which covers the body  of the uterus and part of the cervix.    A "pap (Papanicolaou) smear test” identifies changes in cells  sampled from the cervix that indicate a localized precancerous  condition called carcinoma in situ. The U.S. Preventive Services  Task Force advises that women aged 21 to 30 years have a Pap  smear every three years, no matter when they became sexu-  ally active, and after age 30 every five years. A second test per-    formed with a Pap smear detects variants of human papilloma  virus (HPV) that cause cervical cancer. Coupling HPV testing to  Pap smears avoids performing more invasive procedures on  women who receive false positive results on the Pap smear.  Many young people are being vaccinated against the cancer-  causing variants of HPV.   The vagina is a fibromuscular tube, about 9 centimeters long,  extending from the uterus to the outside of the body (see fig.  22.19a). It conveys uterine secretions, receives the erect penis dur-  ing sexual intercourse, and provides an open channel for the off-  spring during birth.   The vagina extends upward and back into the pelvic cavity. It is  posterior to the urinary bladder and urethra, anterior to the rectum,  and attached to these structures by connective tissues. The upper  one-fourth of the vagina is separated from the rectum by a pouch  (rectouterine pouch). The tubular vagina also surrounds the end of  the cervix, and the recesses between the vaginal wall and the cervix  are termed fornices (sing., fornix). The fornices are clinically impor-  tant because they are thin-walled and allow the physician to palpate  the internal abdominopelvic organs during a physical examination.  Also, the posterior fornix, which is somewhat longer than the others,  provides surgical access to the peritoneal cavity through the vagina.   The vaginal orifice is partially closed by a thin membrane of  connective tissue and stratified squamous epithelium called the    hymen. A central opening of varying size allows uterine and vagi-  nal secretions to pass to the outside of the body.   The vaginal wall has three layers. The inner mucosal layer is  stratified squamous epithelium and is drawn into many longitudi-  nal and transverse ridges (vaginal rugae). This layer lacks mucous  glands; the mucus in the lumen of the vagina comes from the glands  of the cervix and the vestibular glands at the mouth of the vagina.   The middle muscular layer of the vagina mainly consists of  smooth muscle fibers in longitudinal and circular patterns. At the  lower end of the vagina is a thin band of striated muscle. This band  helps close the vaginal opening; however, another voluntary muscle  (bulbospongiosus) is primarily responsible for closing this orifice.   The outer fibrous layer consists of dense connective tissue inter-  laced with elastic fibers. It attaches the vagina to surrounding organs.    Four young women born with a rare condition that causes under-  development of the uterus and vagina who received tissue-  engineered vaginas are doing well with their new organs a  decade later. The anatomy and physiology of the replacement  parts appear to be normal, and the patients report normal sex-  ual functioning.   To build the vaginas, the tissue engineers began with epi-  thelium and muscle from each patient’s external genitalia. The  cells were expanded in a culture system and then seeded onto  a biodegradable scaffold in the shape of a vagina, designed to  fit each patient. Surgeons then fashioned a canal in the correct    anatomical location and sutured the replacement vagina into  place. The cells divided as blood vessels and nerves infiltrated  the implant. The body eventually absorbed the synthetic scaf-  folding material as the three layers of the new vagina took shape.   Years later, the new vaginas fit perfectly into the young wom-  en's reproductive tracts. Tissue-engineered vaginas can also be  used in patients who have cancer or injuries of the vagina.    33 How does a secondary oocyte move into the infundibulum  following ovulation?    34 How is a secondary oocyte moved along a uterine tube?  35 Describe the structure of the uterus.    The external accessory organs of the female reproductive system  include the labia majora, the labia minora, the clitoris, and the vestib-  ular glands (fig. 22.28). These structures that surround the openings  of the urethra and vagina compose the vulva.   The labia majora (sing., Jabium majus) enclose and protect the  other external reproductive organs. They are homologous struc-  tures, similar in origin and function, to the scrotum of the male and  are composed of rounded folds of adipose tissue and a thin layer of    FIGURE 22.28 fAP|R) Female external reproductive organs and  associated structures. The perineum includes the diamond-shaped area  of the combined urogenital and anal regions extending from the pubic  symphysis to the sacrum.    smooth muscle, covered by skin. On the outside, this skin includes  hairs, sweat glands, and sebaceous glands, whereas on the inside,  it is thinner and hairless.   The labia majora lie close together and are separated longitu-  dinally by a cleft (pudendal cleft), which includes the urethral and  vaginal openings. The labia merge at their anterior ends to form a  medial, rounded elevation of adipose tissue called the mons pubis,  which overlies the pubic symphysis. The labia taper at their poste-  rior ends and merge near the anus.   The labia minora (sing., /abium minus) are flattened longitudinal  folds between the labia majora. They are composed of connective tis-  sue richly supplied with blood vessels, which impart a pinkish appear-  ance. Stratified squamous epithelium covers this tissue. Posteriorly,  the labia minora merge with the labia majora. Anteriorly, they con-  verge to form a hoodlike covering around the clitoris.    The clitoris (kli’to-ris) is visible as a small projection at the ante-  rior end of the vulva between the labia minora. In most women  it is about 2 centimeters long and 0.5 centimeter in diameter,  most of which is embedded in surrounding tissues. The clitoris  is homologous to the penis and has a similar structure. It is com-  posed of two columns of erectile tissue called corpora cavernosa.  A septum separates these columns, which are covered with dense  connective tissue.   At the root of the clitoris, the corpora cavernosa diverge to  form crura, which, in turn, attach to the sides of the pubic arch.  At the anterior end of the clitoris, a small mass of erectile tissue  forms a glans, which is richly supplied with sensory nerve fibers.    The labia minora enclose the space called the vestibule. The vagina  opens into the posterior portion of the vestibule, and the urethra  opens in the midline, just anterior to the vagina and about 2.5 centi-  meters posterior to the glans of the clitoris.   A pair of vestibular glands (Bartholin’s glands), homologous  to the bulbourethral glands in the male, lie on either side of the  vaginal opening. Their ducts open into the vestibule near the lat-  eral margins of the vaginal orifice.   Beneath the mucosa of the vestibule on either side is a mass  of vascular erectile tissue homologous to the corpus spongiosum  in the male. These structures are called the vestibular bulbs. The  vagina and the urethra separate the vestibular bulbs, which extend  forward from the level of the vaginal opening to the clitoris.    37 What is the male counterpart of the labia majora? Of the clitoris?  38 Which structures are within the vestibule?   Erectile tissues in the clitoris and around the vaginal entrance  respond to sexual stimulation. Following such stimulation, para-  sympathetic impulses from the sacral portion of the spinal cord  release the vasodilator nitric oxide, dilating the arteries associated  with the erectile tissues. As a result, blood inflow increases, tissues  swell, and the vagina expands and elongates.   If sexual stimulation is sufficiently intense, parasympathetic  impulses stimulate the vestibular glands to secrete mucus into the  vestibule. This secretion moistens and lubricates the tissues sur-  rounding the vestibule and the lower end of the vagina, facilitating  insertion of the penis into the vagina. Mucus secretion continuing  during sexual intercourse helps prevent irritation of tissues that  might occur if the vagina remained dry.   The clitoris has abundant sensory nerve fibers, which are  especially sensitive to local stimulation. The culmination of such  stimulation is orgasm, the pleasurable sensation of physiological  and psychological release.   Just prior to orgasm, the tissues of the outer third of the vagina  engorge with blood and swell. This increases the friction on the  penis during intercourse. Orgasm initiates a series of reflexes    FIGURE 22.29  Mechanism of erection,  lubrication, and orgasm  in the female.    involving the sacral and lumbar portions of the spinal cord. In  response to these reflexes, the muscles of the perineum and the walls  of the uterus and uterine tubes contract rhythmically (fig. 22.29).  These contractions help transport sperm cells through the female  reproductive tract toward the upper ends of the uterine tubes.   Following orgasm, the flow of blood into the erectile tissues  decreases, and the muscles of the perineum and reproductive tract  relax. Consequently, the organs return to a state similar to that  prior to sexual stimulation. Table 22.2 summarizes the functions  of the female reproductive organs.    40 What changes occur in the vagina just prior to and during  female orgasm?    41 How do the uterus and the uterine tubes respond to orgasm?    Conveys secondary oocyte toward uterus; site of  fertilization; conveys developing embryo to uterus    Vagina Conveys uterine secretions to outside of body; receives  erect penis during sexual intercourse; provides open  channel for offspring during birth process    Clitoris Produces feelings of pleasure during sexual stimulation  due to abundant sensory nerve endings in glans   Vestibule Space between labia minora that contains vaginal  and urethral openings    Orgasm—rhythmic contraction of muscles  of the perineum; muscular walls of  uterus and uterine tubes contract    The hypothalamus, the anterior pituitary gland, and the ovaries  secrete hormones that control maturation of female sex cells, devel-  opment and maintenance of female secondary sex characteristics,  and changes that occur during the monthly reproductive cycle.    A female body is reproductively immature until about ten years of  age. Then, the hypothalamus begins to secrete increasing amounts  of GnRH, which, in turn, stimulate the anterior pituitary gland to  release the gonadotropins FSH and LH. These hormones play pri-  mary roles in controlling female sex cell maturation and in pro-  ducing female sex hormones.   Several tissues, including the ovaries, the adrenal cortices,  and the placenta (during pregnancy), secrete female sex hormones.  These hormones include the group of estrogens (es’tro-jenz) and  progesterone (pro-jes’te-r6n). Estradiol is the most abundant of  the estrogens, which also include estrone and estriol.   The primary source of estrogens in a nonpregnant female is  the ovaries, although adipose tissue also synthesizes some estro-  gens from adrenal androgens. At puberty, under the influence of  the anterior pituitary gland, the ovaries secrete increasing amounts  of estrogens. Estrogens stimulate enlargement of reproductive  organs, including the vagina, uterus, uterine tubes, and ovaries,  as well as the external structures; stimulate the endometrium  to thicken; and are also responsible for the development and    maintenance of female secondary sex characteristics. These are  listed in figure 22.30 and include the following:    1. development of the breasts and the ductile system of the  mammary glands in the breasts   2. increased deposition of adipose tissue in the subcutaneous layer  generally and in the breasts, thighs, and buttocks particularly    The ovaries are also the primary source of progesterone in a non-  pregnant female. This hormone promotes changes in the uterus during  the female reproductive cycle, affects the mammary glands, and helps  regulate secretion of gonadotropins from the anterior pituitary gland.   Certain other changes in females at puberty are related to andro-  gen (male sex hormone) concentrations. For example, increased  growth of hair in the pubic and axillary regions is due to androgen  secreted by the adrenal cortices. Conversely, development of the  female skeletal configuration, which includes narrow shoulders and  broad hips, is a response to a low concentration of androgen.    Female athletes who train for endurance events, such as a mara-  thon, typically maintain about 6% body fat. Male endurance  athletes usually have about 4% body fat. This difference in pro-  portion of body fat reflects the actions of sex hormones in males  and females. Testosterone promotes deposition of protein  throughout the body and especially in skeletal muscles, whereas  estrogens promote deposition of adipose tissue in the breasts,  thighs, buttocks, and the subcutaneous layer of the skin.    LH participates in  the release of an  egg (ovulation); the  remaining follicle  becomes the  hormone-secreting  corpus luteum    FIGURE 22.30 Control of female secondary  sex characteristics development. Estrogens  inhibit LH and FSH during most of the  reproductive cycle except during ovulation.    42 What stimulates sexual maturation in a female?  43 Name the major female sex hormones.  44 What are the functions of estrogens?    The female reproductive cycle is characterized by regular, recur-  ring changes in the endometrium, which culminate in menstrual  bleeding (menses). Such cycles usually begin near the thirteenth  year of life and continue into the early fifties, then cease.   A female’s first reproductive cycle, called menarche (mé-  nar’ke), occurs after the ovaries and other organs of the female  reproductive system mature and begin responding to certain hor-  mones. Then, the hypothalamic secretion of GnRH stimulates the  anterior pituitary gland to release threshold levels of FSH and LH.  As its name implies, FSH stimulates maturation of ovarian folli-  cles. The granulosa cells of the maturing follicles produce increas-  ing amounts of estrogens and some progesterone. LH stimulates  certain ovarian cells (theca interna) to secrete precursor molecules  (such as testosterone), that are also used to produce estrogens.   In a young female, estrogens stimulate development of various  secondary sex characteristics. Estrogens secreted during subsequent  reproductive cycles continue development of these traits and main-  tain them. Table 22.3 summarizes the hormonal control of female  secondary sex characteristics.   Increasing concentration of estrogens during the first week or  so of a reproductive cycle changes the uterine lining, thickening  the glandular endometrium (proliferative phase). Meanwhile, a  dominant developing antral follicle fully matures, and by around  the fourteenth day of the cycle, the mature antral follicle appears  on the surface of the ovary as a blisterlike bulge. Within the folli-  cle, the granulosa cells, which surround the secondary oocyte and  connect it to the inner wall, loosen. Follicular fluid accumulates.   While the follicle matures, it secretes estrogens that inhibit  the release of LH from the anterior pituitary gland but allow LH to    1. The hypothalamus releases GnRH, which stimulates the  anterior pituitary gland.    3. FSH stimulates the maturation of a follicle; granulosa cells of  the follicle produce and secrete estrogens.    4. LH stimulates certain ovarian cells to secrete estrogen  precursor molecules.    5. Estrogens are responsible for the development and  maintenance of most of the female secondary sex  characteristics.    6. Concentrations of androgen affect other secondary sex  characteristics, including skeletal growth and growth of hair.    7. Progesterone, secreted by the ovaries, affects cyclical  changes in the uterus and mammary glands.    be stored in the gland. Estrogens also make the anterior pituitary  cells more sensitive to the action of GnRH, which is released from  the hypothalamus in rhythmic pulses about ninety minutes apart.   Near the fourteenth day of follicular development, the ante-  rior pituitary cells finally respond to the pulses of GnRH and  release stored LH. The resulting surge in LH concentration lasts  about thirty-six hours. In response to the LH, the primary oocyte  within the antral follicle completes meiosis I, giving rise to a sec-  ondary oocyte and a polar body. The LH also interacts synergis-  tically with FSH for the induction of complex interactions with  prostaglandins, progesterone, plasmin, and proteolytic enzymes,  leading to the weakening and rupturing of the bulging follicular  wall. This event sends the secondary oocyte and follicular fluid out  of the ovary (ovulation).   Following ovulation, the space that contained the follicular  fluid fills with blood, which soon clots. Under the influence of  LH, the remnants of the follicle within the ovary form a temporary  glandular structure in the ovary called a corpus luteum (kor’pus  loot’e-um) (“yellow body”) (see fig. 22.22).   Follicular cells secrete some progesterone during the first part  of the reproductive cycle. However, corpus luteum cells secrete  abundant progesterone and estrogens during the second half of the  cycle. Consequently, as a corpus luteum is established, the blood  concentration of progesterone sharply increases.   Progesterone makes the endometrium more vascular and  glandular. It also stimulates the uterine glands to secrete more  glycogen and lipids (secretory phase). The endometrial tissues fill  with fluids containing nutrients and electrolytes, which provide a  favorable environment for embryo development.   High levels of estrogens and progesterone inhibit the release  of LH and FSH from the anterior pituitary gland. Consequently,  no other follicles are stimulated to complete development when  the corpus luteum is active. However, if the secondary oocyte  released at ovulation is not fertilized, the corpus luteum begins to  degenerate (regress) on about the twenty-fourth day of the cycle.  Eventually, connective tissue replaces it. The remnant of such a  corpus luteum is called a corpus albicans (see fig. 22.22).   When the corpus luteum ceases to function, concentrations of  estrogens and progesterone rapidly decline, and in response, blood  vessels in the endometrium constrict. This reduces the supply of  oxygen and nutrients to the thickened endometrium (stratum func-  tionalis and stratum basalis), and these lining tissues (decidua)  soon disintegrate and slough off. At the same time, blood leaves  damaged capillaries, creating a flow of blood and cellular debris,  that passes through the vagina as the menstrual flow (menses).  This flow usually begins about the twenty-eighth day of the cycle  and continues for three to five days, while the concentrations of  estrogens are relatively low.   The beginning of the menstrual flow marks the end of a repro-  ductive cycle and the beginning of a new cycle as a new dominant  developing antral follicle becomes available. This cycle is summa-  rized in table 22.4 and diagrammed in figure 22.31.   Low blood concentrations of estrogens and progesterone  at the beginning of the reproductive cycle mean that the hypo-  thalamus and anterior pituitary gland are no longer inhibited.  Consequently, the concentrations of FSH and LH soon increase,  and a new antral follicle is stimulated to mature. As this follicle    FIGURE 22.31 (AP|R) Major events in the female reproductive cycle. (a) Plasma hormonal concentrations of FSH and LH affect follicle maturation in  and ovulation from the ovaries. (b) Plasma hormonal concentrations of estrogen and progesterone influence changes in the endometrium. (c) Micrographs  of the endometrium during (left panel) the menstrual phase (3x), (center panel) the proliferative phase (40x), and (right panel) the secretory phase (14x).    secretes estrogens, the uterine lining undergoes repair, and the  endometrium begins to thicken again. Clinical Application 22.3  addresses some causes of infertility in the female.    Elite female athletes and professional dancers may have dis-  turbed reproductive cycles, ranging from diminished menstrual  flow (oligomenorrhea) to complete stoppage (amenorrhea). The  more active an athlete or dancer, the more likely it is that she will  have menstrual irregularities, and this may impair her ability to  conceive. Trim elite athletes and dancers have little fat, leading  to decreased secretion of the hormone leptin. Decreased leptin |  secretion is associated with lowered secretion of gonadotropin-  releasing hormone from the hypothalamus, which in turn lowers |  the blood estrogen levels. Adipose tissue itself also produces  some estrogen. Adequate estrogen is necessary for fertility.  These girls and women are at high risk of developing low bone  density and cardiovascular impairments.    After puberty, reproductive cycles continue at regular intervals  into the late forties or early fifties, when the ovaries start to pro-  duce less estrogen and progesterone. This results in the reproduc-  tive cycles becoming less predictable. Then within a few months  or years, the cycles cease. This period in life is called menopause  (men’o-pawz), or female climacteric.   Reduced concentrations of estrogens and lack of progesterone  may change the female secondary sex characteristics. The breasts,  vagina, uterus, and uterine tubes may shrink, and the pubic and axil-  lary hair may thin. The epithelial linings associated with urinary and  reproductive organs may thin. There may be increased loss of bone  matrix (osteoporosis) and thinning of the skin. Because the pituitary  secretions of FSH and LH are no longer inhibited, these hormones  may be continuously released for some time.   About 50% of women reach menopause by age fifty, and  85% reach it by age fifty-two. Of these 85%, about 20% have no  unusual health effects—they simply stop menstruating. However,  about 50% of women experience unpleasant vasomotor signs dur-  ing menopause, including sensations of heat in the face, neck, and  upper body called “hot flashes.” A hot flash may last up to five  minutes and may be accompanied by chills and sweating. Women  may also experience migraine headache, backache, and fatigue  during menopause. These vasomotor symptoms may result from  changes in the rhythmic secretion of GnRH by the hypothalamus  in response to declining concentrations of sex hormones.    To minimize menopause symptoms, some women take hor-  mone replacement therapy (HRT) which consists of estrogen  plus progestin. A woman whose uterus has been removed  may take estrogen alone, called estrogen replacement therapy  (ERT). A doctor prescribes the therapy in any of several forms,  including rings, patches, pills, creams, and gels. The lowest  effective dose is taken for the shortest possible time. HRT is not  advised for women who have a history of or high risk of abnor-  mal blood clotting, heart disease, stroke, breast cancer, or gall-  bladder disease.   3. Granulosa cells of the follicle produce and secrete estrogens.  a. Estrogens maintain secondary sex traits.  b. Estrogens cause the endometrium to thicken.    4. The anterior pituitary gland releases a surge of LH, which  interacts with FSH, progesterone, prostaglandins, plasmin,  and proteolytic enzymes leading to ovulation.    5. Following ovulation, follicular and thecal cells become corpus  luteum cells, which secrete estrogens and progesterone.    b. Progesterone stimulates the endometrium to become more  glandular and vascular.    c. Estrogens and progesterone inhibit secretion of FSH and LH  from the anterior pituitary gland. |    6. If the secondary oocyte is not fertilized, the corpus luteum  degenerates and no longer secretes estrogens and progesterone.    7. As the concentrations of hormones from the corpus luteum  decline, blood vessels in the endometrium constrict.    8. The uterine lining disintegrates and sloughs off, producing  a menstrual flow.    9. The anterior pituitary gland is no longer inhibited and again  secretes FSH and LH.    The mammary glands are accessory organs of the female repro-  ductive system specialized to secrete milk following pregnancy.    The mammary glands are located in the subcutaneous tissue of the  anterior thorax within the hemispherical elevations called breasts. The  breasts overlie the pectoralis major muscles and extend from the sec-  ond to the sixth ribs and from the sternum to the axillae (fig. 22.32a).   A nipple is located near the tip of each breast at about the  level of the fourth intercostal space. It is surrounded by a circular  area of pigmented skin called the areola (fig. 22.32b).    A mammary gland is composed of fifteen to twenty irregularly  shaped lobes. Each lobe contains glands (alveolar glands), drained    For one out of six couples, trying for parenthood is a time of  increasing concern. Infertility is the inability to conceive after a  year of trying. A physical cause is found in 90% of cases, and 60%  of the time, the abnormality lies in the female's reproductive sys-  tem. Some medical specialists (reproductive endocrinologists) use  the term subfertility to distinguish individuals and couples who can  conceive unaided, but for whom this may take longer than usual.   One of the more common causes of female infertility is hypo-  secretion of gonadotropic hormones from the anterior pituitary  gland, followed by inability to ovulate (anovulation). Testing  the woman’s urine for pregnanediol, a product of progesterone  metabolism, can detect an anovulatory cycle, because the con-  centration of progesterone normally rises following ovulation. If  pregnanediol level in the urine during the latter part of the repro-  ductive cycle does not rise, the woman may not have ovulated.   Fertility specialists can treat absence of ovulation due to too  little secretion of gonadotropic hormones by administering hCG  (obtained from human placentas) or another ovulation-stimulating  biochemical, human menopausal gonadotropin (hMG), which  contains LH and FSH and is obtained from the urine of women  past menopause. However, either hCG or hMG may overstimu-  late the ovaries and cause many follicles to release egg cells  simultaneously, resulting in multiple births if fertilization occurs.   Another cause of female infertility is endometriosis, in which  tissue resembling the inner lining of the uterus (endometrium)  grows in the abdominal cavity. This may happen if small pieces  of the endometrium move up through the uterine tubes dur-  ing menses and implant in the abdominal cavity. Here the tissue  changes as it would in the uterine lining during the reproductive  cycle. However, when the tissue begins to break down at the end  of the cycle, it cannot be expelled to the outside. Instead, mate-  rial remains in the abdominal cavity where it may irritate the peri-  toneum and cause considerable pain. These breakdown products  also stimulate formation of fibrous tissue (fibrosis), which may  encase the ovary and prevent ovulation or obstruct the uterine  tubes. Conception becomes impossible.    by alveolar ducts, which drain into a lactiferous duct that leads to  the nipple and opens to the outside. Adipose and irregular dense  connective tissues separate the lobes and support the glands,  attaching them to the fascia of the underlying pectoral muscles.  Other connective tissue, which forms dense strands called suspen-  sory ligaments, extends inward from the dermis of the breast to the  fascia, helping support the breast. Clinical Application 22.4 dis-  cusses diagnosis, treatment, and prevention of breast cancer.    The mammary glands of males and females are similar. As chil-  dren reach puberty, the mammary glands in males do not develop,    Some women become infertile as a result of infections, such  as gonorrhea. Infections can inflame and obstruct the uterine  tubes or stimulate production of viscous mucus that can plug the  cervix and prevent entry of sperm.   The first step in finding the right treatment for a particular patient  is to determine the cause of the infertility. Table 22B describes diag-  nostic tests that a woman having difficulty conceiving may undergo.   Women become infertile if their ovaries are removed, possibly  as treatment for persistent masses on the ovaries, or are damaged  by cancer treatment. To make future pregnancies possible, these  women can have strips of ovarian tissue removed before their  cancer treatment begins. The strips are frozen and stored, then  thawed and implanted under the skin of the forearm or abdomen  or in the pelvic cavity near the ovaries. Secondary oocytes are col-  lected and fertilized in vitro.    Cervix examined soon after unprotected  intercourse to see if mucus is thin  enough to allow sperm through    Small piece of uterine lining sampled and  viewed under microscope to see if it can  support an embryo    Hysterosalpingogram Dye injected into uterine tube and  followed with scanner shows if tube is    whereas estrogens stimulate development of the mammary glands  in females. The alveolar glands and ducts enlarge, and fat is depos-  ited so that each breast contains adipose tissue, except for in the  region of the areola. Chapter 23 (pp. 891-893) describes the hor-  monal mechanism that stimulates mammary glands to produce  and secrete milk.    FIGURE 22.32 fAP|R) Structure of the female breast and mammary glands. (a) Sagittal section. (b) Anterior view. (m. stands for muscle.)    Birth control is the voluntary regulation of the number of offspring  produced and the time they are conceived. This control requires a  method of contraception (kon”trah-sep’shun) designed to avoid  fertilization of an egg cell following sexual intercourse (coitus)  or to prevent implantation of a blastocyst. The several methods of  contraception have varying degrees of effectiveness.    Coitus interruptus (also called the withdrawal method) is the  practice of withdrawing the penis from the vagina before ejac-  ulation, preventing entry of sperm cells into the female repro-  ductive tract. This method can still result in pregnancy because  a male may find it difficult to withdraw just prior to ejaculation.  Also, some semen containing sperm cells may reach the vagina  before ejaculation occurs.    The rhythm method (also called timed coitus or natural family  planning) requires abstinence from sexual intercourse two days  before and one day after ovulation. The rhythm method results  in a relatively high rate of pregnancy because accurately iden-  tifying infertile (“safe”) times to have intercourse is difficult.  Another disadvantage of the rhythm method is that it requires  adherence to a particular pattern of behavior and restricts sponta-  neity in sexual activity.    A woman can increase the effectiveness of the rhythm method  by measuring and recording her body temperature when she  awakens each morning for several months. Body temperature  typically rises only about 0.6°F immediately following ovula-    tion, so she has to use a special, extra-sensitive thermometer.  However, this technique does not work for all women. More pre-  cise may be an “ovulation predictor kit” that detects the surge in  LH preceding ovulation.    51. Why is coitus interruptus unreliable?  52 Describe the idea behind the rhythm method of contraception.    Mechanical barrier contraceptives prevent sperm cells from enter-  ing the female reproductive tract during sexual intercourse. The  male condom is a thin latex or natural membrane sheath placed over  the erect penis before intercourse to prevent semen from entering  the vagina upon ejaculation. A female condom resembles a small  plastic bag (fig. 22.33a). A woman inserts it into her vagina prior  to intercourse. The device blocks sperm from reaching the cervix.  Some men feel that a condom decreases the sensitivity of the penis  during intercourse, and condom use may interrupt spontaneity.    FIGURE 22.33 Devices and  substances used for birth control  include (a) male and female condoms,  (b) a diaphragm, (c) spermicide in film,  sponge, suppositories, gel (d) oral  contraceptive, and (e) an IUD.    © Which of these methods of  birth control are statistically  most effective?    However, condoms are inexpensive and may also protect the user  from contracting or spreading sexually transmitted infections.   Another mechanical barrier is the diaphragm. It is a cup-shaped  structure with a flexible ring forming the rim. The diaphragm is  inserted into the vagina so that it covers the cervix, preventing  sperm cells from entering the uterus (fig. 22.33). To be effective, a  diaphragm must be fitted for size by a physician, inserted properly,  and used in conjunction with a spermicide applied to the diaphragm  surface adjacent to the cervix and to the rim of the diaphragm. The  device must be left in position for several hours following sexual  intercourse, and can be inserted into the vagina up to six hours  before sexual contact.   Similar to but smaller than the diaphragm is the cervical cap,  which must also be fitted by a physician. A woman inserts it with  her fingers before intercourse. Cervical caps have been used for  centuries in different cultures and have been made of such varied  substances as beeswax, lemon halves, paper, and opium poppy  fibers. The cervical shield, which does not need fitting, has a one-  way valve that creates suction against the cervix.    Chemical barrier contraceptives include creams, foams, and  jellies that have spermicidal properties. These chemicals create  an environment in the vagina that is unfavorable for sperm cells  (fig. 22.33c).    Chemical barrier contraceptives are easy to use but have a  high failure rate when used alone. They are more effective when  used with a condom or diaphragm. The contraceptive sponge con-  tains a spermicide and blocks the entry of sperm into the uterus.    Combined hormone contraceptives deliver estrogen and proges-  tin. Various methods are used to administer the hormones, but all  of them work on the same principle with about the same efficacy,  although the amounts of the hormones may vary. One device is a  small flexible plastic ring that is impregnated with the hormones  and is inserted deep into the vagina once a month, remaining in  place three out of four weeks. A plastic patch containing the hor-  mones may be applied to the skin on the buttocks, stomach, arm,  or upper torso once a week for three out of four weeks. The most  commonly used method to deliver the hormones is orally, in pill  form (fig. 22.33d).   Combined hormone contraceptives contain synthetic estrogen-  like and progesterone-like chemicals. These drugs disrupt the nor-  mal pattern of gonadotropin (FSH and LH) secretion, preventing  follicle maturation and the LH surge that contributes to ovulation.  They also thicken cervical mucus to prevent the sperm from join-  ing an egg. Most combined hormone contraceptives cause light  monthly bleeding. A newer type of pill causes only four bleeding  periods a year.    The lifetime risk of developing breast cancer, for a woman, is 1 in  8 (table 22C). About 1% of breast cancer cases are in men. There  are several varieties of breast cancer, distinguished by the types of  cells affected and by certain mutations that increase susceptibil-  ity to the condition. As research reveals the cellular and molecular  characteristics that distinguish types of the disease, treatments are  being increasingly tailored to individuals. This approach may delay  disease progression and increase survival rate, while enabling  patients to avoid drugs that will not work.   Changes that could signal breast cancer include a small area of  thickened tissue; a dimple; a change in contour; or a nipple that is  flattened, points in an unusual direction, or produces a discharge.  A woman can note these changes by performing a monthly “breast  "in which she lies flat on her back with an arm raised  behind her head and feels all parts of each breast. But sometimes  breast cancer gives no warning—fatigue and feeling ill may not  occur until the disease has spread beyond the breast.    30 1 in 2,525 65 1in 17  SD 1 in 622 70 1 in 14  40 1 in 217 75 Tin 11  45 1 in 93 80 1 in 10  50 1 in 50 85 1in9    If used correctly, combined hormone contraceptives are very  effective at preventing pregnancy. However, they may cause nau-  sea, retention of body fluids, increased skin pigmentation, and  breast tenderness. Some women, particularly those over thirty-five  years of age who smoke, may develop intravascular blood clots,  liver disorders, or high blood pressure when using certain types of  these contraceptives. The patch, for example, has a higher amount  of estrogen than other products and bears a warning label about  the association with blood clots.   Similar to, but different from the combined hormone con-  traceptives is the “minipill,’ which contains only progestin. The  progestin thickens the cervical mucus so the sperm have difficulty  reaching the egg. The minipill must be taken every day at approxi-  mately the same time for maximum effectiveness. It is slightly less  effective than combined hormone contraceptives.    After finding a lump, the next step is a physical exam. A health-  care provider palpates the breast and does a mammogram, which  is an X-ray scan that can pinpoint the location and approximate  extent of abnormal tissue (fig. 22C). Women whose breasts have a  high percentage of connective tissue and glandular tissue (“dense  breasts”) are at higher risk of developing cancer than women of  the same age whose breasts have more adipose tissue. The dense  areas appear white on a mammogram. An ultrasound scan can dis-    FIGURE 22C fAP|R) Mammogram of a breast with a tumor (arrow).    An intramuscular injection of medroxyprogesterone acetate  protects against pregnancy for three months by preventing fol-  licle maturation and release of a secondary oocyte. It also makes  the uterine lining less hospitable for a developing embryo. This    A large dose of estrogen in combination with progestin (a syn-  thetic progesterone) can prevent ovulation and may also pre-  vent implantation of a developing embryo in the uterus. Such    a “morning-after pill,” taken shortly after unprotected inter-  course, may prevent pregnancy. However, if the embryo has  already implanted, this treatment will not disrupt the pregnancy.    tinguish between a cyst (a fluid-filled sac of glandular tissue) and a  tumor (a solid mass). If an area is suspicious, a thin needle is used  to take a biopsy (sample) of the tissue, whose cells are scrutinized  under a microscope for the telltale characteristics of cancer.   Further tests can identify estrogen and progesterone recep-  tors on the cancer cells, providing information used to guide treat-  ment choices. A very aggressive form of breast cancer is called triple  negative, because affected cells do not have the receptors (for  estrogen, progesterone, and epidermal growth factor) that many  chemotherapies target. Triple negative breast cancer tends to start  earlier, spread faster, and recur more often than other types.   If the breast cells sampled in a biopsy are cancerous, treat-  ment usually begins with surgery. A lumpectomy removes a  small tumor and some surrounding tissue; a simple mastectomy  removes a breast; and a modified radical mastectomy removes  the breast and usually one or two lymph nodes but preserves the  pectoral muscles. If cancer cells are detected in lymph nodes, fur-  ther surgery is performed.   After surgery, many breast cancers are treated with radiation  and combinations of chemotherapeutic drugs, plus sometimes  newer drugs that are targeted to certain types of breast cancer.  Standard chemotherapies kill all rapidly dividing cells, and those  used for breast cancer include fluorouracil, doxorubicin, cyclo-  phosphamide, methotrexate, and paclitaxol. Protocols that pro-  vide more frequent, lower doses can temper some of the side  effects of these powerful drugs.   Newer treatments are easier to tolerate and can be extremely  effective. Three types of drugs keep signals (estrogen and growth  factors) from stimulating cancer cells to divide:    1. Selective estrogen receptor modulators (SERMs), such as  tamoxifen and raloxifene, block estrogen receptors. About  half of people with breast cancer have receptors for estrogen  on their cancer cells and can benefit from these drugs.    drug is long-acting; it takes ten to eighteen months after the last  injection for the effects to wear off. Use of medroxyprogesterone  acetate requires a doctor’s care, because of potential side effects  and risks.   An implantable rod containing progestin may be inserted  under the skin of the arm. The hormone insert prevents follicle  maturation and ovulation for up to three years.    55 How do combined hormone contraceptives, including oral  contraceptives, and injectable contraceptives prevent pregnancy?    2. Aromatase inhibitors block an enzyme required for tissues  other than those of the ovaries to synthesize estrogens.  These drugs are used in women who are past menopause,  whose ovaries no longer synthesize estrogen. They are  prescribed after a five-year course of a SERM.   3. Herceptin (trastuzumab) can help people whose cancer cells  bear too many receptors that bind epidermal growth factor.  It is a monoclonal antibody, based on an immune system  protein. Herceptin blocks the growth factor from signaling  cell division. This drug treats a particularly aggressive form of  the disease that strikes younger women.   Public health agencies and physicians are debating the exact age  at which women should begin having mammograms, and how  frequently they should have them thereafter. For this reason, it is  important for women to discuss personal mammogram schedules  with health-care providers who are familiar with their family histo-  ries. Although a mammogram can detect a tumor up to two years  before it can be felt, it can also miss some tumors. Thus, breast  self-exam is also important in early detection.   Genetic tests can identify women who have inherited certain vari-  ants of genes—such as BRCA1, BRCA2, p53, and HER-2/neu—that  place them at high risk for developing breast cancer. Some of these  women elect to have their breasts removed to prevent the disease.   Gene expression profiling is beginning to be used to identify  which drugs are most likely to help particular patients with other  cancers, such as leukemia, as described in Clinical Application  14.2 (p. 540). Gene expression profiling of breast cancer cells may  help identify drugs for breast cancer patients, as well as predict  risk of recurrence after surgery. This type of information may help  in deciding on follow-up treatment   Only 5% to 10% of all breast cancers arise from an inherited  tendency. Much research seeks to identify the environmental trig-  gers that contribute to causing the majority of cases.    An intrauterine device, or IUD, is a small, solid object that a phy-  sician places in the uterine cavity. A copper-containing IUD inter-  feres with fertilization and implantation of a blastocyst, perhaps  by inflaming the uterine tissues, for up to ten years (fig. 22.33e). A  levonorgestrel-releasing IUD, combining hormone contraception  with an IUD, is effective in preventing pregnancy for up to five years.  An IUD may be spontaneously expelled from the uterus or  produce abdominal pain or excessive menstrual bleeding. It may  also harm the uterus or produce other serious health problems.    Sterilization methods of contraception include surgical proce-  dures that may be performed on the male or female. In the male,    a physician removes a small section of each ductus (vas) defer-  ens near the epididymis and ties the cut ends of the ducts (fig.  22.34a). This is a vasectomy. It has few side effects, but may  cause some pain for a week or two. After a vasectomy, sperm cells  cannot leave the epididymis, and therefore are not in the semen.  However, sperm cells may already be present in the ducts distal to  the cuts. For this reason, the sperm count may not reach zero for  several weeks.   The corresponding procedure in the female is called tubal  ligation (fig. 22.34b). The uterine tubes are cut and tied so that  sperm cells cannot reach an egg cell. In a nonsurgical method of  sterilization in the female, a physician inserts a tube through the  vagina and uterus into the uterine tubes that delivers a tiny spring-    like device. Within three months, scar tissue blocks the uterine  tubes so sperm cannot reach the egg to fertilize it.   Sterilization methods do not change hormonal concentrations  or sex drives. These procedures provide the most reliable forms of  contraception. Reversing them requires microsurgery. Table 22.5  describes several contraceptive approaches and devices and indi-  cates their effectiveness.    57 Describe the surgical methods of contraception for a male and  for a female.   a  Spermicidal film,  sponge, suppository,  foam, or gel  Combination estrogen  and progestin (pill,    Worn over penis or within vagina,  keeps sperm out of vagina or  from entering cervix   Worn over penis or within vagina,  keeps sperm out of vagina, and  kills sperm that escape    Pregnancies  per Year per  Advantages Disadvantages 100 Women*  85  Protection against sexually Disrupts spontaneity, can 2-12  transmitted infections break, reduces sensation  (latex only) in male  Protection against sexually Disrupts spontaneity, can 2-5  transmitted infections break, reduces sensation  (latex only) in male  Inexpensive Disrupts spontaneity, 6-18  messy, needs to be fitted  by doctor  Inexpensive, can be left in May slip out of place, 6-18  24 hours messy, needs to be fitted  by doctor  Inexpensive, easy to use and Messy, irritates 25% of 3-21  carry users (both male and  female)  Does not interrupt spontaneity, Raises risk of 3  lowers risk of some cancers, cardiovascular disease  decreases menstrual flow in some women, causes  (one type of pill eliminates weight gain and breast  menstruation) tenderness  Does not interrupt spontaneity Menstrual changes 5  Easy to use Menstrual changes, 0.3  weight gain  No cost Difficult to do, hard to 20  predict timing  No cost Difficult to do 4-18  Permanent, does not interrupt Requires surgery 0.15  spontaneity  Permanent, does not interrupt Requires surgery, entails 0.4  spontaneity some risk of infection  Does not interrupt spontaneity Severe menstrual 3    ‘The lower figures apply when the contraceptive device is used correctly. The higher figures reflect human error in using birth control.    Sexually transmitted infection (STI) is replacing the term sexu-  ally transmitted disease (STD) because a person can be infected  with a pathogen and transmit the pathogen to others, but not  develop symptoms of the disease. By the time symptoms appear,  it is often too late to prevent complications or the spread of the  infection to sexual partners. Many diseases associated with STIs  have similar symptoms, and some of the symptoms are also seen  in diseases or allergies not sexually related, so it is wise to consult  a physician if one or a combination of these symptoms appears:   sores, blisters, bumps, or a rash anywhere on the body, particu-  larly the mouth or genitals    Table 22.6 describes some prevalent diseases associated with  sexually transmitted infections. One possible complication of    the associated diseases gonorrhea or chlamydia is pelvic inflam-  matory disease, in which bacteria enter the vagina and spread  throughout the reproductive organs. The disease begins with inter-  mittent cramps, followed by sudden fever, chills, weakness, and  severe cramps. Intravenous antibiotics can stop the infection. The  uterus and uterine tubes are often scarred, resulting in infertil-  ity and increased risk of ectopic pregnancy, in which the embryo  develops in a uterine tube.   Acquired immune deficiency syndrome (AIDS) is a steady  deterioration of the body’s immune defenses in which the body  becomes overrun by infection and possibly cancer. The human  immunodeficiency virus (HIV) that causes AIDS is transmitted in  body fluids such as semen, blood, and milk. It is most frequently  passed during unprotected intercourse or by using a needle con-  taining contaminated blood. Clinical Application 16.1 (pp. 641—  642) explores HIV infection.    58 Why is the term sexually transmitted infection replacing the  term sexually transmitted disease?    60 What are some common symptoms of diseases associated with  sexually transmitted infections? Hl    Initial chancre usually on  genitals or mouth; rash 6  months later; several years  with no symptoms as infection  spreads; finally damage to  heart, liver, nerves, brain    *2012 CDC statistics, Centers for Disease Control and Prevention (U.S.), for all associated diseases except AIDS (2011)    FIGURE 22.34 Surgical methods of birth control. (a) In a vasectomy, each ductus (vas) deferens is cut and ligated (tied). (b) In a tubal ligation, each    1. Sex cells are produced by meiosis consisting of two  divisions, each progressing through prophase, metaphase,  anaphase, and telophase.   a. In the first meiotic division, homologous, replicated  chromosomes (each consisting of two chromatids held  together by a centromere) separate, and their number  is halved.   b. In the second meiotic division, the chromatids part,  producing four haploid cells.   c. Meiosis leads to genetic variability because of the  random alignment of maternally and paternally derived  chromosomes in metaphase I and crossing over.    The primary male sex organs are the two testes, which produce  sperm cells and male sex hormones. Accessory sex organs are  internal and external.  1. Testes  a. Descent of the testes   (1) Testes originate posterior to the parietal peritoneum  near the level of the developing kidneys.   (2) The gubernaculum guides the descent of the testes  into the lower abdominal cavity and through the  inguinal canal.   (3) Undescended testes cannot produce sperm cells  because of the high abdominal temperature.   (1) The testes are separated by connective tissue and  filled with seminiferous tubules.   (2) The seminiferous tubules unite to form the rete  testis that joins the epididymis.    (3) The seminiferous tubules contain spermatogenic  cells that give rise to sperm cells.   (4) The interstitial cells that produce male sex  hormones are between the seminiferous tubules.    (1) The epithelium lining the seminiferous tubules  includes sustentacular cells and spermatogenic cells.  (a) The sustentacular cells support and nourish the   (2) Spermatogenesis produces sperm cells from  spermatogonia that have differentiated to become  primary spermatocytes.   (b) Meiosis halves the number of chromosomes in  sperm cells (46 to 23).   (3) Membranous processes of adjacent sustentacular  cells form a barrier in the epithelium.    (1) Each epididymis is a tightly coiled tube on the  outside of the testis that leads into the ductus  deferens.   (2) They store and nourish immature sperm cells and  promote their maturation.    Gamete production, fertilization, embryonic  and fetal development, and childbirth are  essential for survival of the species.    during lactation.  Skeletal, cardiac,  and smooth muscles  La all play a role in  reproductive  ( processes and  iF | sexual activity.  Nervous System  The nervous system  plays a major  role in sexual  activity and    Hormones control  the production of  eggs in the female  and sperm in the    Blood pressure is  necessary for the  normal function  of erectile tissue  in the male and  female.   oxygen that assists  in the production of  ATP needed for egg   (1) Each ductus deferens is a muscular tube that forms  part of the spermatic cord.   (2) They pass through the inguinal canal, enter the  abdominal cavity, course medially into the pelvic  cavity, and end behind the urinary bladder.   (3) They fuse with the ducts from the seminal vesicles  to form the ejaculatory ducts.    1. Hypothalamic and pituitary hormones  The male body remains reproductively immature until  the hypothalamus releases GnRH, which stimulates the  anterior pituitary gland to release gonadotropins.  a. FSH stimulates spermatogenesis.  b. LH (ICSH) stimulates the interstitial cells to produce    (1) Each seminal vesicle is a saclike structure attached  to the ductus deferens.   (2) They secrete an alkaline fluid that contains  nutrients, such as fructose, and prostaglandins.   (3) This secretion is added to sperm cells entering the  ejaculatory ducts.   (1) The prostate gland surrounds the urethra just  inferior to the urinary bladder.   (2) It secretes a thin, milky fluid containing citrate and  prostate-specific antigen.   (1) These glands are two small structures inferior to  the prostate gland.   (2) They secrete a fluid that lubricates the penis in  preparation for sexual intercourse.   (1) Semen consists of sperm cells and secretions of the  seminal vesicles, prostate gland, and bulbourethral  glands.   (2) This fluid is slightly alkaline and contains nutrients  and prostaglandins.   (3) Sperm cells in semen swim, but cannot  fertilize egg cells until they enter the female  reproductive tract.    Male sex hormones are called androgens.  Testosterone is the most important androgen.  Testosterone is converted into dihydrotestosterone in  some organs.   Androgens that fail to become fixed in tissues are  metabolized in the liver and excreted.    Testosterone stimulates the development of the male  reproductive organs and causes the testes to descend.  It is responsible for the development and maintenance  of male secondary sex characteristics.   (1) As the concentration of testosterone rises, the  hypothalamus is inhibited, and the anterior pituitary  gland secretion of gonadotropins is reduced.   (2) As the concentration of testosterone falls, the  hypothalamus signals the anterior pituitary gland  to secrete gonadotropins.    a. Scrotum  (1) The scrotum is a pouch of skin and subcutaneous 22.4 Organs of the Female Reprod uctive  tissue that encloses the testes.  (2) Contraction of the dartos muscle in the scrotal wall System (page 839)  causes the scrotal skin to wrinkle and the testes to The primary female sex organs are the two ovaries, which  move closer to the pelvic cavity or with relaxation produce female sex cells and sex hormones. Accessory sex  of the muscle fibers the scrotum hangs loosely, organs are internal and external.  regulating the environmental temperature of the 1. Ovaries  testes, important for sperm production and survival. a. Ovary attachments  b. Penis (1) Several ligaments hold the ovaries in position.   (2) It becomes erect for insertion into the vagina  during sexual intercourse.   (3) Its body is composed of three columns of erectile  tissue surrounded by connective tissue.   (4) The root of the penis is attached to the pelvic arch  and membranes of the perineum.   (1) During erection, vascular spaces in the erectile  tissue become engorged with blood as arteries  dilate and veins are compressed.   (2) Orgasm is the culmination of sexual stimulation  and is accompanied by emission and ejaculation.   (3) Semen moves along the reproductive tract as  smooth muscle in the walls of the tubular structures  contracts by reflex.   (1) The ovaries descend from posterior to the parietal  peritoneum near the developing kidneys.   (2) They attach to the pelvic wall just inferior to the  pelvic brim.   (1) The ovaries are subdivided into a medulla and a  cortex.   (2) The medulla is composed of connective tissue,  blood vessels, lymphatic vessels, and nerves.   (3) The cortex contains ovarian follicles and is covered  by cuboidal epithelium.   (1) During prenatal development, oogonia divide by  mitosis to produce more oogonia that develop into  primary oocytes.    (2) Each primordial follicle contains a primary oocyte  and a layer of flattened epithelial cells.   (3) The primary oocyte begins to undergo meiosis,  but the process soon halts and does not resume  until puberty.   (4) The number of oocytes steadily declines  throughout the life of a female.   (1) Beginning at puberty, some primary oocytes are  stimulated to continue meiosis.   (2) When a primary oocyte undergoes oogenesis, it  gives rise to a secondary oocyte in which the original  chromosome number is halved (from 46 to 23).   (3) A secondary oocyte may be fertilized to produce  a zygote.   (2) During maturation of the follicle, the primary  oocyte enlarges, the follicular cells proliferate,  and a fluid-filled cavity (atrum) appears.   (4) A mature antral follicle contains a secondary oocyte  surrounded by a zona pellucida and corona radiata.   (1) Ovulation is the release of a secondary oocyte and  first polar body from an ovary.   (3) After ovulation, the secondary oocyte is drawn into  the opening of the uterine tube.   (2) The end of each uterine tube is expanded, and its  margin bears irregular extensions.   (3) Ciliated cells that line the tube and peristaltic  contractions in the wall of the tube move an egg  cell into the tube’s opening.   (1) The uterus receives the embryo and sustains it  during development.   (2) It receives the erect penis, conveys uterine  secretions to the outside, and provides an open  channel for the fetus during birth.   (3) A thin membrane, the hymen, partially closes the  vaginal orifice.   (4) The vaginal wall consists of a mucosal layer,  muscular layer, and outer fibrous layer.   (1) The labia majora are rounded folds of adipose  tissue and skin that enclose and protect the other  external reproductive parts.   (2) The anterior ends form a rounded elevation over  the pubic symphysis.   (1) The labia minora are flattened, longitudinal folds  between the labia majora.   (1) The clitoris is a small projection at the anterior end  of the vulva; it is homologous to the male penis.   (3) Its root is attached to the sides of the pubic arch.   (1) The vestibule is the space between the labia minora  that encloses the vaginal and urethral openings.   (2) The vestibular glands secrete mucus into the  vestibule during sexual stimulation.   (1) During periods of sexual stimulation, the erectile  tissues of the clitoris and vestibular bulbs become  engorged with blood and swollen.   (2) The vestibular glands secrete mucus into the  vestibule and vagina.   (3) During orgasm, the muscles of the perineum,  uterine wall, and uterine tubes contract  rhythmically.    Hormones from the hypothalamus, anterior pituitary gland,  and ovaries play important roles in the control of sex cell  maturation, the development and maintenance of female  secondary sex characteristics, and changes that occur during  the monthly reproductive cycle.    A female body remains reproductively immature until  about ten years of age, when gonadotropin secretion  increases.  The most important female sex hormones are estrogens  and progesterone.  (1) Estrogens are responsible for the development  and maintenance of most female secondary sex  characteristics.  (2) Progesterone prepares the uterus for pregnancy.    The reproductive cycle is characterized by regularly  recurring changes in the uterine lining culminating in  menstrual flow.   In response to the LH surge, just prior to ovulation, the   (1) The corpus luteum secretes estrogens and  progesterone, which cause the uterine lining to  become more vascular and glandular.    luteum begins to degenerate. shields.  (3) As the concentrations of estrogens and progesterone 4. Chemical barriers  decline, the uterine lining disintegrates, causing a. Spermicidal film, sponges, suppositories, foams, and  menstrual flow. gels are chemical barriers to conception.  h. During this cycle, estrogens and progesterone inhibit b. These provide an unfavorable environment in the  the release of LH and FSH (except for the large increase vagina for sperm survival.  at mid-cycle). As the concentrations of estrogens and 5. Combined hormone contraceptives  progesterone decline, the anterior pituitary gland secretes a. A flexible ring inserted deep into the vagina, a plastic  FSH and LH again, stimulating a new reproductive cycle. patch, or a pill can deliver estrogen and progestin to  3. Menopause prevent pregnancy.  a. Menopause is cessation of the female reproductive b. They disrupt the normal pattern of gonadotropin  cycles. Less estrogens and progesterone are produced. secretion which prevents follicle maturation and  b. The female reproductive organs decrease in size. ovulation, and they thicken cervical mucus to prevent  the sperm from joining the egg.  22.6 M ammary Glands (page 852) c. When used correctly, combined hormone    contraceptives are almost 100% effective.  d. Some women develop undesirable side effects.  e. A minipill contains only progestin and must be taken at  the same time daily.  . Other hormone contraceptives    1. Location of the glands  a. The mammary glands are located in the subcutaneous  tissue of the anterior thorax within the breasts.  b. The breasts extend between the second and sixth ribs 6  and from sternum to axillae.  2. Structure of the glands  a. The mammary glands are composed of lobes that  contain tubular glands.  b. Dense connective and adipose tissues separate the lobes.    c. Ducts connect the mammary glands to the nipple.  3. Development of the breasts a. AnJUD isa solid object inserted in the uterine cavity.    b. It prevents pregnancy by interfering with fertilization  and implantation of a blastocyst.    a. Intramuscular injection with medroxyprogesterone  acetate every three months prevents pregnancy.  b. An implantable rod containing progestin may prevent  pregnancy for up to three years.  7. Intrauterine devices    (1) Alveolar glands and ducts enlarge. c. A hormone-releasing IUD can effectively prevent  (2) Fat is deposited in the breasts. pregnancy for up to five years.  d. It may be expelled spontaneously or produce  ° undesirable side effects.  22.7 Birth Control oo 8. Sterilization methods   Birth control is the voluntary regulation of the number of a. These are surgical procedures.   children produced and the time they are conceived. This usually (1) Vasectomy is performed in males.   involves some method of contraception. (2) Tubal ligation is performed in females.   1. Coitus interruptus b. A nonsurgical method inserts a tiny coil into each  a. Coitus interruptus is withdrawal of the penis from the uterine tube, causing scarring that blocks fertilization.   vagina before ejaculation. c. Sterilization methods are the most reliable contraception.    b. Some semen may be expelled from the penis before  ejaculation. 22.8 Sexually Transmitted Infections (page 859)  2. Rhythm method  a. Abstinence from sexual intercourse two days before and  one day after ovulation is the rhythm method.  b. Itis difficult to predict the time of ovulation.  3. Mechanical barriers    1. Sexually transmitted infections are passed during sexual  contact and may go undetected for years.   2. Many of the diseases associated with sexually transmitted  infections share symptoms.    Male sex cells are called , and female sex cells are  called . (p. 824)   Construct a table of the steps in meiosis including the major  event(s). (pp. 824-825)    Distinguish between the primary and accessory male  reproductive organs, then explain how each organ’s  structure affects the organ’s function. (pp. 826-836)  Describe the descent of the testes. (p. 826)   Explain the function of the sustentacular cells in the testis.  (p. 828)   Trace the path of the ductus deferens from the epididymis to  the ejaculatory duct. (pp. 830 and 833)   On a diagram, locate the seminal vesicles, prostate gland,  and bulbourethral glands, and describe the composition of  their secretions. (p. 833)   Explain the mechanism that produces an erection of the  penis. (p. 835)   Distinguish between emission and ejaculation. (pp. 835-836)  Explain the mechanism of ejaculation. (pp. 835-836)    Describe the role of GnRH in the control of male  reproductive functions. (p. 838)   Distinguish between androgen and testosterone. (p. 838)  Define puberty. (p. 838)   List several male secondary sex characteristics. (p. 839)  Explain the regulation of testosterone secretion. (p. 839)    Distinguish between the primary and accessory female  reproductive organs, then explain how each organ’s  structure affects the organ’s function. (pp. 840-848)  Describe how the ovaries are held in position. (p. 840)  Describe the descent of the ovaries. (pp. 840-841)  Define primordial follicle. (p. 841)    Describe how a follicle matures. (pp. 841-844)  Distinguish between a pre-antral and an antral follicle.  (pp. 841-842)   Describe the process of an erection in the female  reproductive organs. (p. 848)    Describe the role of GnRH in regulating female reproductive  functions. (p. 849)   List several female secondary sex characteristics. (p. 849)  Explain how a reproductive cycle is initiated. (p. 850)  Summarize the major events in a reproductive cycle.   Describe the structure of a mammary gland. (pp. 852-853)  Birth Control    (pp. 854-858)  (1) withdrawal A. kills sperm  (2) rhythm method B. keeps sperm out of vagina or  (3) condom from entering cervix  (4) spermicide C. prevents implantation of  (5) estrogen/ a blastocyst  progesterone D. no intercourse during fertile  (6) |UD times  (7) vasectomy E. penis removed from vagina    Common symptoms of diseases associated with sexually  transmitted infections include . (p. 859)   If left untreated, a complication of the diseases gonorrhea  and chlamydia is . (p. 859)    1. What changes, if any, might occur in the secondary sex  characteristics of an adult male following removal of one testis?  Following removal of both testes? Following removal of the  prostate gland?    2. Understanding the causes of infertility can be valuable  in developing new birth control methods. Cite a type of    (a) failure to ovulate due to a hormonal imbalance; (b) a large  fibroid tumor that disturbs the uterine lining;   (c) endometrial tissue blocking uterine tubes; (d) low sperm  count (too few sperm per ejaculate).    3. What effect would removal of an ovary have on a woman’s  reproductive cycles? What effect would removal of both  ovaries have?    4. Does a tubal ligation cause a woman to enter menopause  prematurely? Why or why not?    5. As amale reaches adulthood, what will be the consequences if  his testes have remained undescended since birth? Why?    6. Some men are unable to become fathers because their spermatids  do not mature into sperm. Injection of their spermatids into their  partner's secondary oocytes sometimes results in conception. Men  have fathered healthy babies this way. Why would this procedure  work with spermatids but not with primary spermatocytes?    7. Sometimes a sperm cell fertilizes a polar body rather than  a secondary oocyte. An embryo does not develop, and the  fertilized polar body degenerates. Why is the polar body unable  to support development of an embryo?    Connect Interactive Questions Reinforce your knowledge  using assigned interactive questions covering the anatomy of  the reproductive systems and the hormonal control of male and  female reproductive functions.    Connect Integrated Activity Can you differentiate the  physiological events that occur in spermatogenesis from those  that occur in oogenesis?    Anatomy & Physiology Revealed Go more in depth into the  human body exploring the structures of the reproductive organs  in a cadaver or viewing animations on spermatogenesis and the  female reproductive system.    After you have studied this chapter, you should be able to:    23.1  1  2  23.2  3  4  >  “Higher multiples” such as quadruplets face health risks, but twins usually 6  do very well.  7  8  THE W PICTURE 9  A sperm cell and an egg cell (secondary oocyte) unite, forming a  ; : : : 10  zygote, and the journey of pregnancy begins. Following thirty-  eight weeks of cell division, growth, and specialization into dis- 11  tinctive tissues and organs, a new human being enters the world.  Humans grow, develop, and age. Growth is an increase in 23.3  size. As a human grows, cell numbers increase as a result of mito- iv  sis, followed by enlargement of the newly formed cells and of  the body. The diverse parts of our bodies—the many specialized  cells that form tissues, organs, and organ systems—originated 13  from just one cell. That initial cell began with a unique combina-  tion of genes from the gametes of both parents. 23.4  Development, which includes growth, is the continuous 14  process by which an individual changes from one life phase to 15  another. These life phases include a prenatal period, which  begins with the fertilization of an egg cell and ends at birth, and  a postnatal period, which begins at birth and ends with death.  i s|Rev  aprevealed.com ~ aN.  <* cS  Module 14: Reproductive System Sj 2  %s s    Fertilization  Trace the movement of sperm toward an egg. (p. 868)  Describe, in detail, fertilization. (p. 869)    List and provide details of the major events of cleavage.  (pp. 870-871)   Describe the extraembryonic membranes. (pp. 873-876)  Describe the formation and function of the placenta.  (pp. 873-876)   Explain how the primary germ layers originate, and list  the structures each layer produces. (pp. 876-878)    Define fetus, and describe the major events of the fetal  stage of development. (pp. 881-882)   Trace the path of blood through the fetal cardiovascular  system. (pp. 883-887)   Discuss the hormonal and other changes in the maternal  body during pregnancy. ((pp. 887-889)    Explain the role of hormones in the birth process and  milk production. (pp. 890-892)  Postnatal Period    Name the postnatal stages of development of a human,  and indicate the general characteristics of each stage.  (pp. 894-897)    Describe the major cardiovascular and physiological  adjustments in the newborn. (pp. 894-895)   Distinguish between passive and active aging. (p. 899)  Contrast life span and life expectancy. (p. 899)    allant-, sausage: allantois—tubelike  structure extending from the yolk  sac into the connecting stalk of  an embryo.   umbil-, navel: umbilical cord—structure at-  tached to the fetal navel (umbilicus) that  connects the fetus to the placenta.    The union of a secondary oocyte and a sperm cell is called fertil-  ization (fer’ti-li-za’shun), or conception. This usually takes place  in the infundibulum of a uterine tube.    Before fertilization can occur, a secondary oocyte must be ovu-  lated and enter a uterine tube. During sexual intercourse, the  male deposits semen containing sperm cells in the vagina near  the cervix. To reach the secondary oocyte, the sperm cells must  then move upward through the uterus and uterine tube (fig. 23.1).  Prostaglandins in the semen stimulate lashing of sperm tails, and  muscular contractions within the walls of the uterus and uterine  tube aid the sperm cells’ journey. Also, under the influence of high  concentrations of estrogens during the first part of the reproductive  cycle, the uterus and cervix contain a thin, watery secretion that    promotes sperm transport and survival. Conversely, during the lat-  ter part of the cycle, when the progesterone concentration is high,  the female reproductive tract secretes a viscous fluid that hampers  sperm transport and survival.   Sperm movement is inefficient. Even though as many as  200 million to 600 million sperm cells may be deposited in the  vagina by a single ejaculation, only a few hundred ever reach a sec-  ondary oocyte. The journey to and through a uterine tube takes less  than an hour following sexual intercourse. Many sperm cells may  reach a secondary oocyte, but usually only one sperm cell fertilizes it  (fig. 23.2). If a second sperm were to enter, the fertilized ovum would  have three sets of chromosomes and be very unlikely to develop.   A secondary oocyte may survive for only twelve to twenty-  four hours following ovulation. In contrast, sperm cells may survive  for up to six days after ejaculation into the woman’s body, but they  are best able to fertilize an oocyte within twenty-four to forty-eight  hours after entering the female reproductive tract. Consequently,    sexual intercourse that takes place between forty-eight hours before  ovulation and twenty-four hours after ovulation is more likely to  result in fertilization.    Sperm cells first invade the corona radiata, which is a layer that  consists of follicular cells that adhere to the secondary oocyte’s sur-  face. An enzyme associated with the sperm cell membrane (hyal-  uronidase) aids this initial penetration (fig. 23.3). The sperm next  bind a specific class of proteins on the zona pellucida, which is a  membrane rich in glycoproteins that is the layer closest to the sec-  ondary oocyte’s cell membrane. With this contact, the acrosome  releases enzymes by exocytosis that digest the material of the zona  pellucida. The sperm now have direct access to the oocyte.   Hundreds of sperm take part in removing the layers that sur-  round the oocyte, but only one sperm will actually fertilize the  oocyte. That sperm cell binds to and then fuses with the oocyte  membrane. Then the sperm head enters the secondary oocyte, leav-  ing the mitochondria-rich middle section and tail outside. Sperm  entry triggers lysosome-like vesicles just beneath the oocyte cell  membrane to release enzymes that harden the zona pellucida. This  reduces the chance that other sperm cells will penetrate.    The exact moment of sperm-oocyte contact is an interaction  between a protein on the sperm head and a receptor that  extends from the oocyte’s cell membrane. Researchers identi-  fied the sperm protein, naming it Izumo1 after a Japanese mar-  riage shrine, in 2005, and the receptor on the oocyte, naming it  Juno for the Roman goddess of fertility, in 2014. So far the two  proteins that orchestrate conception have been found in several  mammalian species. The genes that encode the proteins are in  the human genome, so the search is on to observe Izumo1 and  Juno as human gametes meet.    The sperm nucleus enters the secondary oocyte’s cytoplasm  and swells. The secondary oocyte then divides unequally to form a  large cell, whose nucleus contains one copy of the female’s genetic  contribution, and a tiny second polar body, which is later expelled  (see fig. 22.21, p. 842). Meiosis is completed. The approaching  nuclei from the two sex cells are called pronuclei, until they join.  When the pronuclei unite, their nuclear membranes disassemble,  and their chromosomes mingle, finishing the process of fertilization.   Each sex cell has 23 chromosomes, so the product of fertiliza-  tion is a cell with 46 chromosomes—the usual number in a human  body cell (somatic cell). This cell, called a zygote (zi’git), is the  first cell of the future offspring. From Science to Technology 23.1  describes assisted routes to conception.    1 Where in the female reproductive system does fertilization  take place?    2 What factors aid the movements of the secondary oocyte  and sperm cells through the female reproductive tract?    FIGURE 23.2 Scanning electron micrograph of sperm cells on the  surface of a secondary oocyte (650x). Only one sperm cell actually  fertilizes a secondary oocyte.    The 52-year-old man had spent many summers working as  a landscaper, and now he is at his internist’s office, where  a physician’s assistant (PA) is examining several patches of  scaly light-colored skin on the man’s arms. One area looks  as if it could be cancerous, so the PA removes the skin and  prepares a biopsy slide to send to a laboratory for analysis.  Then he teaches the patient how to care for the wound.   Three days a week the PA examines patients at the  office, ordering tests, diagnosing conditions, prescribing  medications, and providing counseling and treatments. On  the other two days the PA visits patients at assisted living  facilities, doing routine checkups and diagnosing and treating  uncomplicated problems such as infections and minor injuries.   A PA practices medicine under the supervision of a  physician, and has national certification and state licensure.  Training takes three years. Applicants must have completed  the same prerequisites as medical school requirements,  including courses in anatomy and physiology, chemistry,  microbiology, and biology. Three years of health-care  experience is required by most programs.   Training includes the prerequisite subjects in greater  depth, and adds pathophysiology, biochemistry, psychology,  pharmacology, physical diagnosis, clinical laboratory science,  and bioethics. A minimum of 2,000 hours of clinical rotations  provides experience in pediatrics, family medicine, internal  medicine, obstetrics and gynecology, emergency medicine,  general surgery, and psychiatry. Continuing medical  education is required to maintain skills and licensure.   Medical practices that employ PAs can see more patients.  In underserved areas, a PA may communicate with the  supervising physician online or by phone. Several factors—  including an aging population, a physician shortage, and an  increase in prevalence of chronic diseases—make the job  market for PAs very promising.    Conception requires the meeting and merging of sperm cell and  egg cell, which naturally occurs in the woman’s uterine tube. Abnor-  mal production of gametes or blockages that impede this meeting  of cells can result in infertility (see Clinical Applications 22.2 and  22.3, pp. 836-837, 853). Assisted reproductive technologies (ART)  can help couples conceive. The procedures usually involve a labora-  tory technique and sometimes participation of a third person. Many  of these techniques are costly and may take several attempts to  work. In the United States about 1% of the 4 million or so births each  year result from an ART. Here is a look at some of the procedures.    In intrauterine (“artificial”) insemination (IUI), a doctor places  donated sperm in a woman’s reproductive tract. A woman might  seek IUI if her partner is infertile or carries a gene for an inherited  illness that could affect a child’s health, or if she desires to be a  single parent or raise a child with a female partner.   Millions of babies have been born worldwide as a result of  IUI. The first human IUls by donor were done in the 1890s. For  many years, donating sperm was a way for male medical students  to earn a few extra dollars. By 1953, sperm could be frozen and  stored. Today, sperm banks provide the cells to physicians who  perform the procedure. Since 1983 sperm banks have asked  donors if they wish to be contacted by their children years later.  The first such meetings occurred in 2002, and thousands of oth-  ers have followed. Today several websites offer DNA tests that  help people find their sperm donor fathers.   A woman or couple choosing IUI can select sperm from a cat-  alog that lists characteristics of the donors, including blood type;    A couple expecting a child can estimate the approximate time  of fertilization (conception) by adding 14 days to the date of the  onset of the last menstrual period. They can predict the time  of birth by adding 266 days (38 weeks) to the fertilization date.  Most babies are born within 10 to 15 days of this calculated time.   Tracking a pregnancy’s progress can be confusing, because  some health-care providers measure 40 weeks from the last  menstrual period, rather than the more accurate 38 weeks from  fertilization. Obstetricians can, however, estimate the date of  conception by scanning the embryo with ultrasound and com-  paring the crown-to-rump length to known values that are the  average for each day of gestation. This approach is inaccurate if  an embryo is smaller or larger than usual.    Pregnancy (preg’nan-se) is the presence of a developing offspring  in the uterus. Pregnancy consists of three periods called trimesters,  each about three months long.    hair, skin, and eye color; build; and even educational level and  interests. Not all of these traits are inherited. On rare occasion |UI  has led to dilemmas (table 23A).    In in vitro fertilization (IVF), which means “fertilization in glass,” a  sperm cell fertilizes an egg cell outside of the woman's body. The  fertilized egg cell divides two or three times, producing a four- or  eight-celled embryo, and is then introduced into the egg donor's    1. Aphysician in California used his own sperm for intrauterine  insemination of fifteen patients and told them that he had  used sperm from anonymous donors.    2. Cases of sperm donors fathering more than 150 children each  led to sperm donation limits.    3. Aman who donated sperm when he was healthy later  developed a genetic disease. Each of the eighteen children  conceived using his sperm faces a 1 in 2 chance of having  inherited spinocerebellar ataxia.    4. Aplane crash killed the wealthy parents of two early embryos  frozen in a hospital in Melbourne, Australia. Adult children of  the couple were asked to share their estate with the embryos.    5. Two Rhode Island couples sued a fertility clinic for misplacing  embryos.    6. Aman sued his ex-wife for possession of their frozen embryos  as part of the divorce settlement.    The prenatal period (prena’tal pe’re-od) of development of  the offspring usually lasts for thirty-eight weeks from conception.  It can be divided into an embryonic stage and a fetal stage.    The embryonic stage extends from fertilization through the  eighth week of prenatal development. During this time the pla-  centa forms, the main internal organs develop, and the external  body structures appear.    The fertilization sequence of events is completed when the pro-  nuclei of a sperm cell and a secondary oocyte join, forming a  zygote. Thirty hours later, the zygote undergoes mitosis, giving  rise to two new cells. These cells in turn divide to form four cells,  which then divide into eight cells, and so forth. The divisions are  rapid, with little time for the cells to grow, so the resulting cells  of these initial divisions are increasingly smaller (fig. 23.4). This  rapid cell division and distribution of the zygote’s cytoplasm  into progressively smaller cells is called cleavage (klév’ij),  and the resulting cells are called blastomeres. The ball of cells   A woman might undergo IVF if her ovaries and uterus function  but her uterine tubes are blocked. To begin, she takes a hormone that  hastens maturity of several secondary oocytes. Using a laparoscope  to view the ovaries and uterine tubes, a physician removes a few of  the largest egg cells and transfers them to a dish, then adds chemicals  similar to those in the female reproductive tract, and sperm cells.   If a sperm cell cannot penetrate the secondary oocyte in vitro,  it may be sucked up into a tiny syringe and injected into the sec-  ondary oocyte using a tiny needle (fig. 23A). This variant of IVF,  called intracytoplasmic sperm injection (ICSI), has a 68% fer-  tilization rate. It can help men with very low sperm counts, high  numbers of abnormal sperm, or injuries or illnesses that prevent  ejaculation. However, if ICSI is done to help a man become a  father who has an inherited form of infertility, he may be passing  the problem on to a son. In ICSI, minor surgery removes testicu-  lar tissue, from which viable sperm are isolated and injected into  eggs. A day or so later, a physician transfers some of the resulting  balls of eight or sixteen cells to the woman’s uterus. The birth rate  following IVF for a woman implanted with her own egg is about  26%, compared with 31% for natural conceptions.    One reason that IVF rarely works is the artificial fertilization environ-  ment. A procedure called GIFT (gamete intrafallopian transfer) moves  fertilization to the woman's body. A woman takes a superovulation  drug for a week and then has several of her largest eggs removed.   The tiny mass of cells moves through the uterine tube to the  uterine cavity, aided by the beating of cilia on the surface of the  epithelium lining the tube and by weak peristaltic contractions of  smooth muscles in the tubular wall. Secretions from the epithelial  lining bring nutrients to the developing organism.   The trip to the uterus takes about three days. By then the  structure consists of a solid ball, called a morula (mor’u-lah),  of about sixteen cells (fig. 23.4). The morula remains unattached  within the uterine cavity for about three days. Cell division con-  tinues, and the solid ball of cells gradually hollows out. During  this stage, the zona pellucida of the original secondary oocyte  degenerates. The now-hollow structure, called a blastocyst  (blas’to-sist), adheres to the endometrium. Figure 23.5 diagrams  this process.   By the end of the first week of development, the blastocyst  superficially implants in the endometrium (fig. 23.6a). Up until  this point, the cells that will become developing offspring are plu-  ripotent stem cells, which means they can give rise to several spe-  cialized types of cells, as well as yield additional stem cells.    A man donates a sperm sample, and a physician separates the most  active cells. The collected eggs and sperm are deposited together  in the woman's uterine tube, at a site past any obstruction so that  implantation can occur. GIFT is 22% successful. In another variation  called zygote intrafallopian transfer (ZIFT), a physician places an  in vitro fertilized secondary oocyte in a woman’s uterine tube.    FIGURE 23A intracytoplasmic sperm injection (ICSI) is injection  of a single sperm cell into the cytoplasm of an egg.    Within the blastocyst, cells in one region group to form an  inner cell mass (or embryoblast) that eventually gives rise to the  embryo proper (em’bre-o prop’er)—the body of the develop-  ing offspring. The cells that form the wall of the blastocyst make  up the trophoblast, which develops into structures that assist the  development of the embryo proper.    If two ovarian follicles release secondary oocytes simultane-  ously, and both are fertilized, the resulting zygotes develop  into fraternal (dizygotic) twins, which are no more alike geneti-  cally than any nontwin siblings. Twins may develop from  a single fertilized oocyte (monozygotic twins) if two inner  cell masses form within a blastocyst and each produces an  embryo. Twins of this type usually share a single placenta, and  they are genetically identical. They are always of the same sex  and similar in appearance.    The blastocyst attaches to the uterine lining, aided by its secre-  tion of proteolytic enzymes that digest part of the endometrium    FIGURE 23.3 Steps in fertilization: (1) The sperm cell reaches the corona radiata surrounding the secondary oocyte. (2) An enzyme on the sperm surface  digests a path through the corona radiata. (3) The sperm binds to proteins in the zona pellucida, triggering the release of digestive enzymes from the acrosome by  exocytosis. (4) Once the sperm is through the zona pellucida, the sperm head fuses with the oocyte membrane, and the sperm nucleus enters the oocyte.  Although only a single sperm can actually fertilize the egg, hundreds of sperm are necessary to break down these barriers encountered along the way.    (Q) How many chromosomes are contained in the secondary oocyte prior to fertilization?    (fig. 23.6b,c). Cells of the trophoblast begin to produce tiny,  fingerlike extensions (microvilli) that grow into the endome-  trium. At the same time, growth of the endometrium envelopes  the blastocyst until it is completely embedded in the uterine wall.  This nestling of the blastocyst into the uterine lining is called  implantation (im’-plan-ta’shun). It begins toward the end of the  first week and completes during the second week of development  (fig. 23.7).   The trophoblast secretes the hormone human chorionic  gonadotropin (hCG), which maintains the corpus luteum during  the early stages of pregnancy and keeps the immune system from  rejecting the blastocyst. This hormone also stimulates synthesis  of other hormones from the developing placenta. The placenta  (plah-sen’tah) is a vascular structure, formed by the cells sur-  rounding the embryo and cells of the endometrium, that anchors  the embryo to the uterine wall and exchanges nutrients, gases,  and wastes between the maternal blood and the embryo’s blood.    If an embryo implants in tissues outside the uterus, such as those  of a uterine tube, an ovary, the cervix, or an organ in the abdomi-  nal cavity, the result is an ectopic pregnancy. A fertilized egg  implanted in the uterine tube is a tubal pregnancy. The tube usu-  ally ruptures as the embryo enlarges, resulting in severe pain and    heavy vaginal bleeding. Treatment is prompt surgical removal of  the embryo and repair or removal of the damaged uterine tube.    4 What is cleavage?  5 How does a blastocyst attach to the endometrium?  6 How does the endometrium respond to the activities of the    FIGURE 23.4 Light micrographs of (a) a human secondary oocyte  surrounded by follicular cells and sperm cells (250x), (b) the two-cell stage  (600x), and (c) a morula (500x).    As the embryo implants in the uterus, proteolytic enzymes from  the trophoblast break down endometrial tissue, providing nutri-  ents for the developing embryo. A second layer of cells begins to  line the trophoblast, and together these two layers form a structure  called the chorion (ko’re-on), the outermost extraembryonic mem-  brane. Soon slender projections grow out from the trophoblast,  including the new cell layer, eroding their way into the surround-  ing endometrium by continuing to secrete proteolytic enzymes.  These projections become increasingly complex and form the  highly branched chorionic villi, which are well established by the  end of the fourth week (fig. 23.8). Figure 24.13 (p. 919) depicts  prenatal genetic tests performed on chorionic villi.   Continued secretion of proteolytic enzymes forms irregular  spaces called lacunae in the endometrium around and between the  chorionic villi. These spaces fill with maternal blood from endo-  metrial blood vessels eroded by enzyme action. At the same time,  embryonic blood vessels carrying blood to and from the embryo  extend through the connecting stalk, which attaches the embryo to  the developing placenta. Capillary networks from the embryo form  in the developing chorionic villi. These embryonic vessels allow  nutrient exchange with blood in the lacunae, meeting the increased  nutrient demands of the growing embryo.   While the placenta is forming from the chorion, a second mem-  brane, called the amnion (am’ne-on), develops around the embryo  proper. It appears during the second week. Its margin is attached  around the edge of the flattened inner cell mass or embryonic  disc. Fluid, called amniotic fluid, fills the space (amniotic cavity)  between the amnion and the embryonic disc. The amniotic fluid pro-  vides a watery environment in which the embryo can grow freely  without being compressed by surrounding tissues. The amniotic  fluid also protects the embryo from being jarred by the movements  of the woman’s body, and maintains a stable temperature for embry-  onic and fetal development. Figure 24.13 (p. 919) illustrates amnio-  centesis, which examines chromosomes in fetal cells shed into the  amniotic fluid.    If a pregnant woman repeatedly ingests an addictive substance  that crosses the placenta, her newborn may suffer from with-  drawal symptoms when amounts of the chemical the fetus was    accustomed to receiving suddenly plummet after birth. Newborn  addiction occurs with certain drugs of abuse, such as heroin, and  with certain prescription drugs used to treat anxiety.    The margins of the amnion fold, enclosing the embryo in the  amnion and amniotic fluid. The amnion envelopes the tissues on the  underside of the embryo, particularly the connecting stalk, by which  it is attached to the chorion and the developing placenta. In this  manner, the umbilical cord (um-bil’i-kal kord) forms (figs. 23.9  and 23.10). The fully developed umbilical cord is about | centimeter  in diameter and about 55 centimeters in length. It originates at the    Y Stem cells  i} ah |  N  ; y  iL)  0  Day 1 Day 2 Day 3 Day 4  Day 0 Zygote First cleavage division 2-cell stage 4-cell stage Early morula Late morula    Fertilization  occurs about  12-24 hours  Day 6-7  after ovulation Blastocyst  implantation    FIGURE 23.6 At about the sixth day of development, the blastocyst  (a) adheres to the uterine wall and (b) begins to implant. The trophoblast,  which will help form the placenta, secretes hCG, a hormone that maintains  the pregnancy. (c) Light micrograph of a blastocyst from a monkey in    Six-year-old Molly would probably have died within a year or two  of Fanconi anemia, had she not received a very special gift from  her baby brother Adam—his umbilical cord stem cells. Not only  was Adam free of the mutation that causes the anemia, but his cell  surfaces matched those of his sister, making a transplant likely to  succeed. But the parents didn’t have to wait until Adam’s birth in  August 2000 to know that his cells could save Molly—they knew  when he was a mere eight-celled cleavage embryo (fig. 23B).   When a compatible bone marrow donor for Molly could not  be found, her parents turned to preimplantation genetic diagnosis  (PGD). Following in vitro fertilization, described in From Science to  Technology 23.1, a single cell was removed from each of several  eight-celled cleavage embryos. The cells were probed to detect  those free of the disease-causing mutation. They were also scruti-  nized for the HLA genes, which control rejection of a transplanted  organ, and the ball of cells that would become Adam was chosen.  The cleavage embryo divided in the laboratory until it was about  120 cells, and then it was implanted into Lisa’s uterus. A month  after Adam was born, physicians infused the umbilical cord stem  cells into his sister. Today Molly is healthy.   PGD works because up until a certain point in early develop-  ment of an embryo, a cell or two can be removed, yet the remain-  der of the embryo can continue to develop normally in a uterus.  PGD, implemented in 1989, at first helped a few families avoid  devastating inherited illnesses in their sons. Then in 1992, a baby  was born free of the cystic fibrosis that made her brother very ill,  thanks to PGD. In 1994 came another milestone, when a girl was  conceived and selected to provide umbilical cord stem cells that  cured her teenage sister's leukemia. This case became the basis of  a popular novel.   Thousands of children have been born following PGD, free of  the disorders that run in their families. PGD also enables couples  who repeatedly lose early embryos due to chromosome abnor-  malities to select chromosomally normal embryos. PGD is becom-  ing routine with IVF, because it ensures that only embryos with  normal-appearing chromosomes or lacking a family’s mutation are  implanted. PGD is often confused with genetic modification (engi-  neering), which it is not. It is selection of an embryo.    umbilicus of the embryo and inserts into the center of the placenta.  The umbilical cord suspends the embryo in the amniotic cavity. The  cord contains three blood vessels—two umbilical arteries and one  umbilical vein—that transport blood between the embryo and the  placenta (fig. 23.11).   Eventually the amniotic cavity becomes so enlarged that the  membrane of the amnion contacts the thicker chorion around it. The  two membranes fuse into an amniochorionic membrane. In addition  to the chorion and amnion, two other extraembryonic membranes  form during development. They are the yolk sac and the allantois.   The yolk sac forms during the second week, and it is attached  to the underside of the embryonic disc (see figs. 23.9 and 23.10).  This structure forms blood cells in the early stages of development  and gives rise to the cells that later become sex cells. The yolk sac  also produces stem cells of the bone marrow, which are precur-    FIGURE 23B Preimplantation  genetic diagnosis probes  disease-causing genes in an  eight-celled cleavage embryo.    If genetically healthy, the  embryo is allowed to continue  development, introduced into  the woman and results in a  baby (the remaining 7 cells  can complete normal  development).    If the gene for the  disease is present,  the embryo is not  introduced into the  woman.    sors to many cell types, but predominantly to blood cells. Parts of  the yolk sac form the embryonic digestive tube as well. Part of the  membrane derived from the yolk sac becomes incorporated into the  umbilical cord, and the remainder lies in the cavity between the cho-  rion and the amnion near the placenta. The allantois (ah-lan to-is)  forms during the third week as a tube extending from the early yolk  sac into the connecting stalk (see figs. 23.9 and 23.10). It, too, forms  blood cells and gives rise to the umbilical blood vessels.   The disc-shaped area where the chorion still contacts the  uterine wall develops into the placenta. The embryonic portion  of the placenta is composed of parts of the chorion and its villi;  the maternal portion is composed of the area of the uterine wall  (decidua basalis) where the villi attach (fig. 23.11). The fully  formed placenta is a reddish-brown disc about 20 centimeters long  and 2.5 centimeters thick, weighing about 0.5 kilogram.    FIGURE 23.7 Light micrograph of a human blastocyst (arrow)  implanting in the endometrium (18x).    A thin placental membrane separates embryonic blood  in the capillary of a chorionic villus from maternal blood in a  lacuna. This membrane is composed of the epithelium of the cho-  rionic villus and the endothelium of the capillary inside the villus  (fig. 23.12). Through this membrane, substances are exchanged  between the maternal blood and the embryo’s blood. Oxygen and  nutrients diffuse from the maternal blood into the embryo’s blood,  and carbon dioxide and other wastes diffuse from the embryo’s  blood into the maternal blood. Active transport and pinocytosis  also move substances through the placental membrane.   The placenta synthesizes progesterone from cholesterol in  the maternal blood. Cells associated with the developing adrenal  glands use the placental progesterone to synthesize estrogens. The    estrogens, in turn, promote changes in the maternal uterus and  breasts and influence maternal metabolism and the development of  organs in the embryo.    7 Describe the structure of a chorionic villus.  8 What is the function of amniotic fluid?    9 What types of cells and other structures are derived from the  yolk sac?    Gastrulation and Organogenesis  Gastrulation is the movement of cells within the embryonic disc  to form multiple layers. By the end of the second week the embry-  onic disc consists of two distinct layers: an outer ectoderm and an  inner endoderm. A short time later, through a process called gas-  trulation, a third layer of cells, the mesoderm, forms between the  ectoderm and endoderm. These three layers of cells are called the  primary germ layers (pri’ma-re jerm la’erz) of the primordial  embryo (see fig. 23.8). They are the primitive tissues from which  all organs form in a process called organogenesis. At this point  the embryo is termed a gastrula (gas’troo-lah). Table 23.1 sum-  marizes the stages of early human prenatal development.  Gastrulation is an important process in prenatal develop-  ment because a cell’s fate is determined by which layer it is in.  The cells of the ectoderm and endoderm are epithelia. The meso-  derm is loosely organized connective tissue. Ectodermal cells give  rise to the nervous system, parts of special sensory organs, the  epidermis, hair, nails, glands of the skin, and linings of the mouth  and anal canal. Mesodermal cells form all types of muscle tissue,  bone tissue, bone marrow, blood, blood vessels, lymphatic vessels,  internal reproductive organs, kidneys, and the epithelial linings of  the body cavities. Endodermal cells produce the epithelial linings  of the digestive tract, respiratory tract, urinary bladder, and urethra    FIGURE 23.9 The primary germ layers collectively serve as primitive tissues from which all organs form.    (see fig. 23.9). The primary germ layers retain stem cells, a few of  which persist in the adult, enabling tissues to grow and repair damage.   During the fourth week of development, the flat embryonic  disc becomes cylindrical, and the precursor of the central nervous  system, called the neural tube, forms. By the end of week four,  the head and jaws appear, the heart beats and forces blood through  blood vessels, and tiny buds form that will give rise to the upper  and lower limbs (fig. 23.13).   During the fifth through the seventh weeks, as figure 23.14a—e  shows, the head grows rapidly and becomes rounded and erect. The    FIGURE 23.10 As Chorion Umbilical  the amnion develops, it cord  surrounds the embryo, and Amnion   the umbilical cord begins to  form from structures in the  connecting stalk.    face develops eyes, nose, and mouth. The upper and lower limbs  elongate, and fingers and toes form. By the end of the seventh  week, all the main internal organs are established, and as these  structures enlarge and elaborate, the body takes on a humanlike  appearance (fig. 23.14f g and fig. 23.15). By the beginning of  the eighth week, the embryo typically is 30 millimeters long and  weighs less than 5 grams.   Until about the end of the eighth week, the chorionic villi  cover the entire surface of the former trophoblast. However, as  the embryo and the surrounding chorion enlarge, only villi that    Cleavage 30 hours to third day — Mitosis increases cell number  Morula Third to fourth day Solid ball of cells  Blastocyst Fifth day through Hollow ball consisting of the sag Maternal  second week trophoblast (outside), which Lacuna blood  implants and helps form the filled with Section of villus |  placenta, and inner cell mass, maternal  which flattens to form the blood  embryonic disc , C  Gastrula End of second week _— Primary germ layers form Se  Embryonic a  ‘ illari  contact the endometrium endure. The others degenerate, and the ca is |  areas of the chorion where they were attached become smooth. j  The region of the chorion still in contact with the uterine wall is Wall of villus Placental  restricted to the placenta. membrane  The embryonic stage concludes at the end of the eighth week. Chorionic villi Connective tissue  It is the most critical period of development, because during it, the  embryo implants in the uterine wall and all the essential external FIGURE 23.12 The placental membrane consists of the endothelium    of an embryonic capillary and the epithelial wall of a chorionic villus, as    the embryonic stage can cause major malformations or malfunc-  tions. This is why early prenatal care is important.    FIGURE 23.13 Embryo. (a) A human embryo at three weeks, posterior view; (b) at three and one-half weeks, lateral view; (c) at about four weeks,  lateral view. (Figures are not to scale.)    FIGURE 23.14 Changes  occurring during the fifth  (a-c), sixth (a), seventh (e),  and eighth (f-g) weeks of  development (sizes are  measured from crown to  rump). Figures are not drawn  to scale. The enlarged photo  corresponds to forty-nine  days of development.    FIGURE 23.15 By the beginning of the eighth week of development,  the embryonic body is recognizable as a human.    Factors that cause congenital malformations by affecting an  embryo during its period of rapid growth and development or the  specialization of structures during fetal development are called  teratogens. Such agents include drugs, viruses, radiation, and  even large amounts of otherwise healthful substances, such as fat-  soluble vitamins. Each prenatal structure has a time in develop-  ment, called its critical period, when it is sensitive to teratogens  (fig. 23.16).   A critical period may extend over many months or just a day  or two. Neural tube defects, for example, are traced to day twenty-  eight in development, when a sheet of ectoderm folds to form  the neural tube. When this process is disrupted, an opening may  remain in the spine (spina bifida). In contrast, the critical period for  the developing brain begins when the anterior neural tube begins  to swell into a brain, and continues throughout gestation. This is  why so many teratogens affect the brain. Clinical Application 23.1  discusses some teratogens and their effects.    12 Which tissues and structures develop from ectoderm? from  mesoderm? from endoderm?    The fetal stage begins at the end of the eighth week of prenatal  development and lasts until birth. During this period, growth is  rapid, and body proportions change considerably. At the beginning  of the fetal stage, the head is disproportionately large, and the lower  limbs are relatively short. Gradually, proportions come to more  closely resemble those of a child (fig. 23.17).    | | 1 | | | | | |  2 3 4 5 6 7 8 9    FIGURE 23.16 Critical periods. (a) Structures in the developing  embryo and fetus (b) are sensitive to specific teratogens at different  times in gestation.    During the third month, body lengthening accelerates, but  head growth slows. The upper limbs of the fetus (fe’tus) achieve  the relative length they will maintain throughout development, and  ossification centers appear in most bones. By the twelfth week, the  external reproductive organs are distinguishable as male or female.  Figure 23.18 illustrates how these external reproductive organs of  the male and female differentiate from precursor structures.   In the fourth month, the body grows rapidly and reaches a  length of up to 20 centimeters and weighs about 170 grams. The  lower limbs lengthen considerably, and the skeleton continues to  ossify. The fetus has hair, nipples, and nails, and may even scratch  itself. A four-month-old fetus will startle and turn away from a  bright light flashed on a pregnant woman’s belly, and may also  react to sudden loud noises.   In the fifth month, growth slows. The lower limbs achieve  their final relative proportions. Skeletal muscles contract, and the  pregnant woman may feel fetal movements. Some hair grows on  the fetal head, and fine, downy hair called lanugo covers the skin.  A cheesy mixture of sebum from the sebaceous glands and dead  epidermal cells (vernix caseosa) also coats the skin. The fetus,  about 30 centimeters long and weighing about 450 grams, curls  into the fetal position.   During the sixth month, the fetus gains substantial weight.  Eyebrows and eyelashes appear. The skin is wrinkled and translu-  cent. Blood vessels in the skin cause a reddish appearance.   In the seventh month, the skin becomes smoother as fat is  deposited in the subcutaneous tissues. The eyelids, which fused  during the third month, reopen. At the end of this month, the fetus  is about 40 centimeters long.    The idea that the placenta protects the embryo and fetus from  harmful substances was tragically disproven between 1957 and  1961, when 10,000 children in Europe, Africa, and Canada were  born with malformed limbs. Doctors soon identified a mild tranquil-  izer, thalidomide, that all of the mothers of the deformed infants had  taken early in pregnancy during the time of limb formation, as the  cause. Although some women in the United States did use thalido-  mide in a clinical trial and had affected children, the United States  was spared a thalidomide disaster because an astute government  physician noted adverse effects of the drug on monkeys in experi-  ments, and she blocked marketing of the drug. However, thalido-  mide is used today to treat leprosy and certain blood disorders.    The virus that causes rubella (German measles) is a powerful  teratogen. Australian physicians first noted its effects in 1941, and  a rubella epidemic in the United States in the early 1960s caused  20,000 birth defects and 30,000 stillbirths. Exposure in the first tri-  mester leads to cataracts, deafness, and heart defects, and later  exposure causes learning disabilities, speech and hearing problems,  and type 1 diabetes mellitus. Successful vaccination programs that  provide maternal immunity to the virus have greatly lowered the  incidence of “congenital rubella syndrome” in many countries.    A pregnant woman who has just one or two alcoholic drinks a  day, or perhaps many drinks at a crucial time in prenatal devel-    In the final trimester, fetal brain cells rapidly form networks,  as organs specialize and grow. A layer of fat is laid down beneath  the skin. The testes of males descend from regions near the devel-  oping kidneys, through the inguinal canal, and into the scrotum  (see chapter 22, p. 826). The digestive and respiratory systems  mature last, which is why premature infants may have difficulty  digesting milk and breathing.    Each year in the U.S., 1 in 8 babies are born preterm, defined as  delivery before 37 weeks of gestation. Such premature infants’   | survival chances increase directly with age and weight, and par-  allel increasing maturity of the lungs. A baby born at 23 weeks  has an almost 30% chance of survival; at 24 weeks a 50% to  60% chance; at 25 weeks a 75% chance; and at 27 to 28 weeks,  a greater than 90% chance.    Approximately 266 days after a single sperm fertilized a sec-  ondary oocyte, a baby is ready to be born. It is full-term. It is about  50 centimeters long and weighs 2.7 to 3.6 kilograms. The skin has    opment, risks fetal alcohol syndrome (FAS) or the more preva-  lent fetal alcohol effects in her unborn child. The effects of small  amounts of alcohol at different stages of pregnancy are not yet  well understood, and because each woman metabolizes alcohol  slightly differently, women are advised to avoid drinking alcohol  entirely when pregnant or when trying to become pregnant.   A child with FAS has a small head, misshapen eyes, and a  flat face and nose (fig. 23C). Growth is slow before and after  birth. Intellect is impaired, ranging from minor learning disabili-  ties to severe intellectual disability. Teens and young adults with  FAS are short and have small heads. Many individuals remain at  the early grade-school level of intellectual development. They  often lack social and communication skills, such as understand-  ing the consequences of actions, forming friendships, taking ini-  tiative, and interpreting social cues. People with FAS are more  likely to have seizures.   Problems in children of alcoholic mothers were noted by  Aristotle more than twenty-three centuries ago. Today in the United  States, fetal alcohol syndrome is the third most common cause of  intellectual disability in newborns. Each year in the United States  about 5,000 children are born with FAS, and many more are born  with milder “alcohol-related effects.”   Chemicals in cigarette smoke stress a fetus. Carbon monox-  ide crosses the placenta and binds to fetal hemoglobin in a  way that prevents the hemoglobin from delivering oxygen to  the fetal tissues. Other chemicals in smoke prevent nutrients    lost its downy hair but is still coated with sebum and dead epider-  mal cells. The scalp is usually covered with hair; the fingers and toes  have well-developed nails; and the skull bones are largely ossified.  The fetus is usually positioned upside down (fig. 23.19) with its  head toward the cervix (vertex position).   The birth of a live, healthy baby is against the odds, consid-  ering human development from the beginning. Of every 100 sec-  ondary oocytes exposed to sperm, 84 are fertilized. Of these, 69  implant in the uterus, 42 survive one week or longer, 37 survive  six weeks or longer, and only 31 are born alive. Of those that do  not survive to birth, about half have chromosomal abnormalities  too severe to maintain life. Table 23.2 summarizes the stages of  prenatal development.    14 What major changes happen during the fetal stage of  development?    16 How is a fetus usually positioned in the uterus as birth nears?    from reaching the fetus. Snoke-exposed placentas lack impor-  tant growth factors. The result of these assaults is poor growth  before and after birth. Cigarette smoking during pregnancy is  linked to spontaneous abortion, stillbirth, prematurity, and low  birth weight.    Certain nutrients in large amounts, particularly vitamins, act in  the body as drugs. The acne medication isotretinoin (Accutane) is  a derivative of vitamin A that causes spontaneous abortions and  defects of the fetal heart, nervous system, and face. A psoriasis  drug based on vitamin A, as well as excesses of vitamin A itself,  also cause birth defects because some forms of the vitamin are  stored in body fat for up to three years after ingestion.   Malnutrition during pregnancy causes intrauterine growth  retardation (IUGR). Malnutrition before birth also causes shifts in  metabolism to make the most of calories from food. This protec-  tive action, however, sets the stage for developing obesity and  associated disorders, such as type 2 diabetes mellitus and cardio-  vascular disease, in adulthood.    The workplace can be a source of teratogens. Women who work  with textile dyes, lead, certain photographic chemicals, semicon-  ductor materials, mercury, and cadmium have increased rates of  spontaneous abortion and delivering children with birth defects.  Men whose jobs expose them to sustained heat, such as smelter    _ A fetus can receive medical treatments. Tubes can be inserted  | to remove abnormal fluid accumulations, such as in the blad-  der or in the brain, and tumors removed. Correcting the   neural tube defect spina bifida in a fetus is more successful  | in enabling the child to eventually walk than correcting the  | defect after birth.    Throughout fetal development, the maternal blood supplies oxy-  gen and nutrients and carries away wastes. These substances dif-  fuse between the maternal and fetal blood through the placental  membrane, and the umbilical blood vessels carry them to and  from the fetus (fig. 23.20). The fetal blood and cardiovascular  system are adapted to this intrauterine environment. For exam-  ple, the concentration of oxygen-carrying hemoglobin in the  fetal blood is about 50% greater than in the maternal blood, and  fetal hemoglobin has a greater attraction for oxygen than does  adult hemoglobin. As a result of these adaptations, at the oxygen    FIGURE 23C Fetal alcohol syndrome. Some children whose  mothers drank alcohol during pregnancy have characteristic flat  faces. Women who drink while pregnant have a chance of having  a child affected to some degree by prenatal exposure to alcohol.    workers, glass manufacturers, and bakers, may produce sperm  that can fertilize a secondary oocyte, but possibly lead to sponta-  neous abortion or a birth defect. A virus or a toxic chemical carried  in semen may also cause a birth defect.    partial pressure of the placental capillaries, fetal hemoglobin can  carry 20% to 30% more oxygen than adult hemoglobin. Different  genes encode the protein subunits of hemoglobin in embryos,  fetuses, and individuals after birth. The different subunits have  different affinities for oxygen.   In the fetal cardiovascular system, the umbilical vein trans-  ports blood rich in oxygen and nutrients from the placenta to the  fetal body. This vein enters the body through the umbilical ring  and continues along the anterior abdominal wall to the liver. About  half the blood it carries passes into the liver, and the rest enters  a vessel called the ductus venosus (duk’tus ven-o’sus), which  bypasses the liver.   The ductus venosus extends a short distance and joins the  inferior vena cava. There, oxygen-rich blood from the placenta  mixes with oxygen-poor blood from the lower parts of the fetal  body. This mixture continues through the inferior vena cava to  the right atrium.    “ To Chapter 15, Blood Flow Through the Heart,  pages 562-563.    Embryonic stage First week Cells undergo mitosis, blastocyst forms; inner cell mass appears; blastocyst implants in uterine wall  *Size: 0.25 inch (0.63 centimeter), weight: 1/120 ounce (0.21 gram)    Second through Inner cell mass becomes embryonic disc; primary germ layers form, embryo proper becomes  eighth week cylindrical; main internal organs and external body structures appear; placenta and umbilical cord  form, embryo proper is suspended in amniotic fluid    *Size: 0.75 inch (1.9 centimeters) as measured from crown to rump, weight: 1/30 ounce (0.8 gram)    Fetal stage Ninth through Ossification centers appear in bones; sex organs differentiate; nerves and muscles coordinate so that  twelfth week the fetus can move its limbs    *Size: 2.13 inches (5.41 centimeters) as measured from crown to rump, weight: 1/2 ounce (14 grams)    *Size: 4.57 inches (11.6 centimeters) as measured crown to rump, weight: 3.5 ounces (100 grams)    Seventeenth through Muscle movements are stronger, and woman may be aware of slight flutterings; skin is covered with  twentieth week fine downy hair (lanugo) and coated with sebum mixed with dead epidermal cells (vernix caseosa)    *Size: 6.46 inches (16.4 centimeters) as measured from crown to rump, weight: 10.5 ounces (300 grams)    Twenty-first through Body gains weight, subcutaneous fat deposited; eyebrows and lashes appear; eyelids reopen;  thirty-eighth week testes descend    *Size: 19.6 inches (49.8 centimeters) as measured from crown to heel, weight: 6 to 10 pounds  (2.7 to 4.5 kilograms)    * Measurements pertain to the end of the designated time period.    Labia majora  Anus  (c)  Glans penis Prepuce  Glans clitoris  Urethral orifice  Hymen  Scrotum Vaginal  orifice  Anus  (d) (f)    FIGURE 23.18 Formation of external reproductive organs. (a and b) The genital tubercle, urogenital fold, and labioscrotal folds, which appear during  the fourth week of development, may differentiate into (c and d) male external reproductive organs or (e and f) female external reproductive organs.    Postnatally, the blood from the right atrium enters the right ven-  tricle and is pumped through the pulmonary trunk and pulmonary  arteries to the lungs. In the fetus, however, the lungs are not func-  tioning in gas exchange, and the blood largely bypasses them. As  blood from the inferior vena cava enters the fetal right atrium, much  of it is shunted directly into the left atrium through an opening in the  atrial septum. This opening is called the foramen ovale (fo-ra’men  o-val’e), and the blood passes through it because the blood pressure  in the right atrium is greater than that in the left atrium. Furthermore,  a small valvelike structure (septum primum) on the left side of the  atrial septum overlaps the foramen ovale and helps prevent blood  from moving in the reverse direction.    The rest of the fetal blood entering the right atrium, includ-  ing a large proportion of the oxygen-poor blood entering from the  superior vena cava, passes into the right ventricle and out through  the pulmonary trunk. Only a small volume of blood enters the pul-  monary circuit because the lungs are collapsed and their blood  vessels have a high resistance to blood flow. However, enough  blood reaches the lung tissues to sustain them.   Most of the blood in the pulmonary trunk bypasses the lungs  by entering a fetal vessel called the ductus arteriosus (duk’tus  ar-te”re-o’sus), which connects the pulmonary trunk to the  descending portion of the aortic arch. As a result of this connec-  tion, the blood with a relatively low oxygen concentration, return-    FIGURE 23.19 A full-term  fetus is usually positioned with its  head near the cervix.    FIGURE 23.20 Oxygen and nutrients diffuse into the fetal  blood from the maternal blood. Waste diffuses into the maternal  blood from the fetal blood.    ing to the heart through the superior vena cava, bypasses the lungs  and does not enter the part of the aorta that branches to the heart  and brain. (This might seem odd, but remember that fetal blood  becomes oxygenated in the placenta, not in the fetal lungs.)   The more highly oxygenated blood that enters the left atrium  through the foramen ovale mixes with a small amount of oxygen-  poor blood returning from the pulmonary veins. This mixture    moves into the left ventricle and is pumped into the aorta. Some of  it reaches the myocardium through the coronary arteries, and some  reaches the brain tissues through the carotid arteries.   Blood carried by the descending aorta includes the less-  oxygenated blood from the ductus arteriosus. Some of the blood is  carried into the branches of the aorta that lead to the lower regions  of the body. The rest passes into the umbilical arteries, which   In most newborns the umbilical cord contains two arteries  and one vein. On rare occasion a newborn has only one umbilical 18 What is the function of the ductus venosus?  artery. This condition is often associated with other cardiovascu- 19 How does fetal circulation allow blood to bypass the lungs?  lar, urogenital, or gastrointestinal disorders. The vessels in the  severed cord are routinely counted following a birth to rule out  these conditions.    At the time of birth, important adjustments must occur in the car- During a typical reproductive cycle, the corpus luteum degener-  diovascular system when the placenta ceases to function and the ates about two weeks after ovulation. Consequently, concentra-  newborn begins to breathe. tions of estrogens and progesterone decline rapidly, the uterine    FIGURE 23.21 The general pattern of fetal circulation is shown anatomically. (Position of the right atrium has been shifted slightly to reveal the  foramen ovale.)    FIGURE 23.22 The general pattern of fetal circulation is shown schematically.    lining breaks down, and the endometrium sloughs off as menstrual  flow. If this occurs following implantation, the embryo is lost in a  spontaneous abortion.   The hormone hCG normally helps prevent spontaneous abor-  tion. It functions similarly to LH, and it maintains the corpus  luteum, which continues secreting estrogens and progesterone.  Thus, the uterine wall continues to grow and develop (fig. 23.23).  At the same time, hCG inhibits the anterior pituitary gland’s  release of FSH and LH, halting the normal reproductive cycles.   Secretion of hCG continues at a high level for about two  months, then declines to a low level by the end of four months.  Although the corpus luteum persists throughout pregnancy, its func-  tion as a source of hormones becomes less important after the first  three months (first trimester), when the placenta secretes sufficient  estrogens and progesterone (fig. 23.24).    Detecting hCG in a woman’s urine or blood is used to confirm  pregnancy. The level of hCG in a pregnant woman’s body fluids  peaks at fifty to sixty days of gestation, then falls for the remain-  der of her pregnancy. Later on, measuring hCG has other uses.  If awoman miscarries but her blood still shows hCG, fetal tissue  may remain in her uterus, and this material must be removed.  Between the fifteenth week and twentieth week of pregnancy,  most women have a blood test that measures levels of five  substances produced by the fetus—alpha fetoprotein (AFP),  estradiol (an estrogen), inhibin A, pregnancy-associated plasma  protein (PAPP-A), and hCG. If AFP, estradiol, and PAPP-A are  low and inhibin A and hCG are elevated, the fetus is at risk of  having an extra chromosome 21 (Down syndrome). Further  tests, discussed in Chapter 24 (pp. 919-920), are necessary for  a definitive diagnosis.    Umbilical Carries nutrient-rich, oxygen-rich blood from the  vein placenta to the fetus    Conducts about half the blood from the umbilical vein  directly to the inferior vena cava, bypassing the liver   ovale the right atrium from the inferior vena cava,  through the atrial septum, and into the left atrium,  bypassing the lungs    Conducts some blood from the pulmonary trunk to  the aorta, bypassing the lungs    Carry the blood containing carbon dioxide and wastes  from the internal iliac arteries to the placenta    For the remainder of the pregnancy, placental estrogens and  placental progesterone maintain the uterine wall. The placenta also  secretes a hormone called placental lactogen that, with the aid of pla-  cental estrogens and progesterone, stimulates breast development and  prepares the mammary glands to secrete milk. Placental progesterone  and a polypeptide hormone called relaxin from the corpus luteum and  the placenta inhibit the smooth muscle in the myometrium, suppress-  ing uterine contractions until the birth process begins.   The high concentration of placental estrogens during preg-  nancy enlarges the vagina and the external reproductive organs.  Also, relaxin relaxes the connective tissue of the pubic symphysis  and sacroiliac joints. Relaxin action allows for greater movement at  these joints, aiding passage of the fetus through the birth canal.   Other hormonal changes during pregnancy include increased  secretion of aldosterone from the adrenal cortex and of parathyroid  hormone from the parathyroid glands. Aldosterone promotes renal  reabsorption of sodium, leading to fluid retention. Parathyroid hor-  mone helps to maintain a high concentration of maternal blood cal-  cium, because fetal demand for calcium can cause hypocalcemia,  which promotes cramps. Table 23.4 summarizes the hormonal  changes of pregnancy.    FIGURE 23.23 Mechanism that preserves the uterine lining during  early pregnancy.    0 1 2 3 4 5 6 7 8 9  Months of pregnancy    FIGURE 23.24 Relative concentrations of three hormones in maternal  blood during pregnancy.    »  yf PRACTICE  20 What are the sources of the hormones that sustain the uterine  wall during pregnancy?    1. Following implantation, cells of the trophoblast begin to  secrete hCG.    2. hCG maintains the corpus luteum, which continues to secrete  estrogens and progesterone.    3. As the placenta develops, it secretes abundant estrogens and  progesterone.    4. Placental estrogens and progesterone  a. stimulate the uterine lining to continue development.  b. maintain the uterine lining.    c. inhibit secretion of FSH and LH from the anterior pituitary  gland.    5. Relaxin from the corpus luteum also inhibits uterine contractions  and relaxes the pelvic ligaments.    8. Parathyroid hormone from the parathyroid glands helps maintain  a high concentration of maternal blood calcium.    A woman’s body changes as it responds to the increased  requirements of a growing offspring. The uterus enlarges greatly,  extending upward from its normal location in the pelvic cavity, in  some cases eventually reaching the level of the ribs. The abdomi-  nal organs are displaced upward and compressed against the dia-  phragm. The enlarging uterus also presses on the urinary bladder.  As a result, a pregnant woman may be unable to eat large meals,  may develop heartburn, and may have to urinate frequently.   The growing and developing placenta requires more blood,  and as the offspring enlarges, it needs more oxygen and produces  more waste that must be excreted. The pregnant woman’s blood  volume, cardiac output, breathing rate, and urine production all  increase to accommodate offspring growth.   The pregnant woman must eat more to obtain adequate  nutrition for the offspring and herself, specifically supplying suf-  ficient vitamins, minerals, and proteins. The offspring tissues  have a greater capacity to capture available nutrients than do the  maternal tissues. Consequently, if the pregnant woman’s diet is  inadequate, her body will usually show symptoms of a deficiency  condition before offspring growth is adversely affected.    Maternal nausea and vomiting in pregnancy may shield a fetus  from foods that might contain toxins or pathogens. The con-  dition affects two in three pregnancies and coincides with the  time in gestation when a woman's immune system is at its weak-  est. An analysis of more than 80,000 pregnant women found  that they avoid foods that spoil easily, such as eggs and meats,  as well as coffee and alcohol. Yet many pregnant women eat  more fruits and vegetables than usual. In societies where the  diet is mostly grains with little if any meat, incidence of morn-  ing sickness is much lower than in groups with more varied, and  possibly dangerous, diets. Rates of morning sickness are high-  est in Japan, where raw fish is a dietary staple, and European  countries, where undercooked meat is often eaten.    Pregnancy terminates with the birth process (parturition). It is  complex. Progesterone plays a major role in its start. During  pregnancy, this hormone suppresses uterine contractions. As the  placenta ages, progesterone concentration in the uterus declines,  which stimulates synthesis of a prostaglandin that promotes uter-  ine contractions. At the same time, the cervix begins to thin and  then open. Changes in the cervix may begin a week or two before  other signs of labor.   Stretching of the uterine and vaginal tissues late in preg-  nancy also stimulates the birth process. This action initiates  impulses to the hypothalamus, which in turn signals the poste-  rior pituitary gland to release the hormone oxytocin (see chap-  ter 13, p. 503), which stimulates powerful uterine contractions.  Combined with the greater excitability of the myometrium due  to the decline in progesterone secretion, stimulation by oxytocin  aids labor in its later stages.    During labor, muscular contractions force the fetus through  the birth canal. Waves of rhythmic contractions that begin at the  top of the uterus and continue down its length force the contents of  the uterus toward the cervix.   The fetus is usually positioned head downward, so labor  contractions force the head against the cervix. This action  stretches the cervix, which elicits a reflex that stimulates still  stronger labor contractions. Thus, a positive feedback system  operates in which uterine contractions produce more intense  uterine contractions until effort is maximal (fig. 23.25). At the  same time, dilation of the cervix reflexly stimulates an increased  release of oxytocin from the posterior pituitary gland.   As labor continues, positive feedback stimulates abdominal  wall muscles to contract, helping to propel the fetus through the  birth canal (cervix, vagina, and vulva) to the outside. Table 23.5  summarizes some of the factors promoting labor. Figure 23.26  illustrates the steps of the birth process.   Following birth of the fetus, the placenta, which initially  remains inside the uterus, separates from the uterine wall and  is pushed by uterine contractions through the birth canal. This    FIGURE 23.25 A positive feedback mechanism operates in the  birth process.    1. As the time of birth approaches, secretion of progesterone  declines, and its inhibiting effect on uterine contractions lessens.    2. Decreasing progesterone concentration stimulates synthesis of  prostaglandins, which initiate labor.    3. Stretching uterine tissues stimulates release of oxytocin from the  posterior pituitary gland.    4. Oxytocin stimulates uterine contractions and aids labor in its  later stages.    5. As the fetal head stretches the cervix, a positive feedback  mechanism results in stronger and stronger uterine contractions  and a greater release of oxytocin.    6. Positive feedback stimulates abdominal wall muscles to contract  with greater and greater force.    7. The fetus is forced through the birth canal to the outside.    FIGURE 23.26 Stages in birth. (a) Fetal position before labor, (b) dilation of the cervix, (c) expulsion of the fetus, (d) expulsion of the placenta.    expelled placenta, called the afterbirth, is accompanied by  bleeding, because vascular tissues are damaged in the process.  However, continued contraction of the uterus compresses the  bleeding vessels, minimizing blood loss. Oxytocin stimulates  this contraction. Breastfeeding also contributes to returning the  uterus to its original, prepregnancy size, because suckling by  the newborn stimulates the mother’s posterior pituitary gland to  release oxytocin.    An infant passing through the birth canal can stretch and tear  perineal tissues between the vulva and anus. Before the birth  is complete, a physician may make an incision along the mid-    line (clinical perineum) from the vestibule to within 1.5 centime-  ters of the anus. This procedure, called an episiotomy, ensures  that the perineal tissues are cut cleanly rather than torn, which  aids healing.    For several weeks following childbirth, a process called invo-  lution shrinks the uterus. The endometrium sloughs off and is  discharged through the vagina as a bloody and then yellowish dis-  charge over the course of a few weeks. An epithelial lining charac-  teristic of a nonpregnant female then returns.    22 Describe the role of progesterone in initiating labor.  23 Explain how dilation of the cervix affects labor.    24 Explain how bleeding is naturally controlled after the placenta is  expelled.    During pregnancy, placental estrogens and progesterone stimu-  late further development of the mammary glands. Estrogens cause  the ductile systems to grow and branch, and deposit abundant fat  around them. Progesterone stimulates the development of the alve-  olar glands at the ends of the ducts. Placental lactogen also pro-  motes these changes.   The breasts may double in size during pregnancy because  of hormonal activity. At the same time, glandular tissue replaces  the adipose tissue of the breasts. Beginning about the fifth week  of pregnancy, the anterior pituitary gland releases increas-  ing amounts of prolactin. Prolactin is synthesized from early  pregnancy throughout gestation, peaking at the time of birth.  However, milk secretion does not begin until after birth. This is  because during pregnancy, placental progesterone inhibits milk  production, and placental lactogen blocks the action of prolactin    (see chapter 13, p. 500). Consequently, even though the mammary  glands can secrete milk, none is produced. The micrographs in  figure 23.27 compare the mammary gland tissues of a nonpreg-  nant woman with those of a lactating woman.   Following childbirth and the expulsion of the placenta, mater-  nal blood concentrations of placental hormones rapidly decline.  The action of prolactin is no longer inhibited. Prolactin stimulates  the mammary glands to secrete milk. This hormonal effect does  not occur until two or three days following birth. In the meantime,  the glands secrete a thin, watery fluid called colostrum. It is rich  in proteins, particularly antibodies from the mother’s immune sys-  tem that protect the newborn from certain infections. However, this  “first milk” has lower concentrations of carbohydrates and fats than  the mature milk that will gradually come in a few days.    FIGURE 23.27 Mammary glands. (a) Light micrograph of a mammary  gland in a nonpregnant woman (160x). (b) Light micrograph of an active  (lactating) mammary gland (160x).    Milk does not flow readily through the ductile system of the  mammary gland, but is actively ejected as specialized myoepithelial  cells surrounding the alveolar glands contract (fig. 23.28). A reflex  action controls this process and is elicited when the breast is suckled  or the nipple or areola is otherwise mechanically stimulated. Then,  impulses from sensory receptors in the breasts travel to the hypothala-  mus, which signals the posterior pituitary gland to release oxytocin.  The oxytocin reaches the breasts by means of the blood and stimu-  lates the myoepithelial cells in both breasts to contract (fig. 23.29).  Within about thirty seconds, milk is ejected from the breast into a  suckling infant’s mouth.   Sensory impulses triggered by mechanical stimulation of  the nipples also signal the hypothalamus to continue secreting  prolactin. In this way, prolactin is released as long as breast-    FIGURE 23.29 Myoepithelial cells contract to release milk from an  alveolar gland.    feeding continues. However, if stimulation of the nipple does A woman who is breastfeeding usually does not ovulate for    not occur regularly, the hypothalamus inhibits secretion of pro- several months, because prolactin suppresses release of gonado-  lactin, and within about one week the mammary glands stop tropins from the anterior pituitary gland. When a woman stops  producing milk. breastfeeding, the anterior pituitary gland stops secreting prolac-    tin. Then FSH is released, and the reproductive cycle is activated.  A new mother will be fertile approximately two weeks prior to the  A woman who is breastfeeding feels her milk “let down,” or return of her menstrual period.   flood her breasts, when her infant suckles. If the baby nurses Table 23.6 summarizes the hormonal control of milk produc-  on a regular schedule, the mother may feel the letdown shortly tion, and table 23.7 lists some agents that adversely affect lacta-  before the baby is due to nurse. The connection between mind tion or harm the child. Clinical Application 23.2 explains the  and hormonal control of lactation is so strong that if a nursing benefits of breastfeeding.    To wean a nursing child, it is best to stop breastfeeding gradu- 26 What stimulates the mammary glands to produce milk?  ally, by eliminating one feeding per day each week, for example. If 27 What causes milk ejection?  a woman stops nursing abruptly, her breasts will become painfully 28 What happens to milk production if milk is not regularly    . Estrogens cause the ductile system to grow and branch. . Mechanical stimulation of the breasts releases oxytocin from the    . Oxytocin stimulates release of milk from ducts.  . Placental lactogen promotes development of the breasts. y    . Prolactin is secreted throughout pregnancy, but placental . As long as breastfeeding continues, more prolactin is released; if  progesterone inhibits milk production and placental lactogen the nipple is not stimulated regularly, milk production ceases.  blocks the action of prolactin.    Ethanol (alcohol) (large amounts) Drug of abuse Weak, drowsy; infant decreases in length but gains  weight; decreased milk ejection reflex    The female human body manufactures milk that is a perfect food for  a human newborn in several ways. Human milk is rich in the lipids  required for rapid brain growth, and it is low in protein. Cow's milk is  the reverse, with three times as much protein as human milk. Much  of cow's milk protein is casein, which spurs a calf's rapid muscle  growth but forms hard-to-digest curds in a human baby’s stomach.  The protein in human milk has a balance of essential amino acids  more suited to human growth and development than the protein in  cow’s milk.   Human milk protects a newborn from many infections. For  the first few days after giving birth, the breasts produce colos-  trum, which has less sugar and fat than mature milk but more pro-  tein, and is rich in antibodies. The antibodies protect the baby  from such infections as Salmonella poisoning and polio. When the  milk matures by a week to ten days, it has antibodies, enzymes,  and white blood cells from the mother that continue infection  protection. A milk protein called lactoferrin binds iron, mak-  ing it unavailable to microorganisms that might use it to thrive  in the newborn's digestive tract. Another biochemical in human  milk, bifidus factor, encourages the growth of the bacterium    Following birth, both mother and newborn experience physi-  ological and anatomical changes. The postnatal period of devel-  opment lasts from birth until death. It can be divided into the  neonatal period, infancy, childhood, adolescence, adulthood, and  senescence. Dying is also part of the life cycle.    The neonatal (ne”o-na’tal) period, which extends from birth  to the end of the first four weeks, begins abruptly at birth. At  that moment, physiological adjustments must occur quickly  because the newborn (neonate) must suddenly do for itself  what the mother’s body had been doing for it. The newborn  must respire, obtain and digest nutrients, excrete wastes, and  regulate body temperature. However, a newborn’s most imme-  diate need is to obtain oxygen and excrete carbon dioxide, so  the first breath is critical.   The first breath must be particularly forceful, because the  newborn’s lungs are collapsed and the airways are small, offer-  ing considerable resistance to air movement. Also, surface tension  adheres the moist membranes of the lungs. However, the lungs of  a full-term fetus continuously secrete surfactant (see chapter 19,  p. 745), which reduces surface tension. After the first powerful  breath begins to expand the lungs, breathing eases.   Several factors stimulate a newborn’s first breath: increasing  concentration of carbon dioxide, decreasing pH, low oxygen con-  centration, drop in body temperature, and mechanical stimulation    Lactobacillus bifidus, which manufactures acids in the baby’s  digestive system that kill harmful bacteria.   A breastfed baby typically drinks only until full, which may  explain why breastfed babies are less likely to be obese than bot-  tlefed infants. Babies nurtured on human milk are also less likely  to develop allergies to cow’s milk. A nursing mother must eat  about 500 calories per day more than usual to meet the energy  requirements of milk production. Still, she loses weight faster  than a mother who bottlefeeds, because the fat reserves set aside  during pregnancy are used to manufacture milk.   Breastfeeding is not the best choice for all women. It may  be impossible to be present for each feeding or to provide milk.  Also, drugs a mother takes may enter breast milk and affect the  baby. Another disadvantage of breastfeeding is that the father  cannot do it.   An alternative to breastfeeding is infant formula, which is usu-  ally cow’s milk plus fats, proteins, carbohydrates, vitamins, and  minerals added in proportion to make it as much like human milk  as possible. Although infant formula is nutritionally sound, breast  milk is a more digestible first food.    during and after birth. Also, in response to the stress to the fetus  during birth, blood concentrations of epinephrine and norepineph-  rine rise significantly (see chapter 13, pp. 509-510). These hor-  mones promote normal breathing by increasing the secretion of  surfactant and dilating the airways.   For energy, the fetus primarily uses glucose and fatty acids  in the pregnant woman’s blood. The newborn, on the other hand,  is suddenly without an external source of nutrients. The mother  will not produce mature milk for two to three days, by which time  the infant’s gastrointestinal tract will be able to digest it. The early  milk, colostrum, is an adaptation to the state of the newborn’s  digestive physiology. The newborn has a high metabolic rate, and  its liver, not fully mature, may be unable to supply enough glu-  cose to support metabolism. Instead, the newborn uses stored fat  for energy.   A newborn’s kidneys are usually unable to concentrate  urine, so the baby excretes dilute urine. This may cause dehy-  dration and a water and electrolyte imbalance. Also, certain  homeostatic control mechanisms may not function adequately.  For example, during the first few days of life, body temperature  may respond to slight stimuli by fluctuating above or below the  normal level.   When the placenta ceases to function and breathing begins,  the newborn’s cardiovascular system changes. Following birth, the  umbilical vessels constrict. The umbilical arteries close first, and  if the umbilical cord is not clamped or severed for a minute or so,  blood continues to flow from the placenta to the newborn through  the umbilical vein, adding to the newborn’s blood volume.    The proximal portions of the umbilical arteries persist in the  adult as the superior vesical arteries that supply blood to the uri-  nary bladder. The more distal portions become solid cords (lateral  umbilical ligaments). The umbilical vein becomes the cordlike  ligamentum teres that extends from the umbilicus to the liver in an  adult. The ductus venosus constricts shortly after birth and appears  in the adult as a fibrous cord (ligamentum venosum) superficially  embedded in the wall of the liver.   The foramen ovale closes as a result of changes in blood pres-  sure in the right and left atria. As blood ceases to flow from the  umbilical vein into the inferior vena cava, the blood pressure in the  right atrium falls. Also, as the lungs expand with the first breath-  ing movements, resistance to blood flow through the pulmonary  circuit decreases, more blood enters the left atrium through the  pulmonary veins, and blood pressure in the left atrium increases.   As the blood pressure in the left atrium rises and that in the  right atrium falls, the valvelike septum primum on the left side of  the atrial septum closes the foramen ovale. In most individuals this  valve gradually fuses with the tissues along the margin of the fora-  men. In an adult, a depression called the fossa ovalis marks the site  of the past opening.   The ductus arteriosus, like other fetal vessels, constricts after  birth. Once this happens, blood can no longer bypass the lungs by  moving from the pulmonary trunk directly into the aorta. In an  adult, a cord called the ligamentum arteriosum represents the duc-  tus arteriosus.    In patent ductus arteriosus (PDA), the ductus arteriosus does  not close completely. After birth, the metabolic rate and oxygen  consumption in neonatal tissues increase, in large part to main-  tain body temperature. If the ductus arteriosus remains open,    bypassing the pulmonary circuit, the newborn's blood oxygen  concentration may be too low to adequately supply body tis-  sues, including the myocardium. If PDA is not corrected surgi-  cally, the heart may fail, even though the myocardium is normal.    Changes in the newborn’s cardiovascular system are gradual.  Although constriction of the ductus arteriosus may be functionally    Distal portions  of umbilical  arteries constrict  and become  medial umbilical  ligaments    complete within fifteen minutes, the permanent closure of the fora-  men ovale may take up to a year. These cardiovascular changes are  illustrated in figure 23.30 and summarized in table 23.8.   Fetal hemoglobin production falls after birth. By the time an  infant is four months old, most of the circulating hemoglobin is  the adult type.    Closes by valvelike septum primum as blood pressure  in right atrium decreases and blood pressure in left  atrium increases    Becomes ligamentum teres that extends from the umbilicus to the liver    Becomes ligamentum venosum superficially embedded in the wall of  the liver    Valve fuses along margin of foramen ovale and is marked by a  depression called the fossa ovalis  Becomes ligamentum arteriosum that extends from the pulmonary   31 What does a newborn use for energy during its first few days?  32 How do the kidneys of a newborn differ from those of an adult?    33 What is the fate of the foramen ovale? of the ductus arteriosus?    The period of continual development extending from the end of  the first four weeks to one year is called infancy. During this time,  the infant grows rapidly and may triple its birth weight. Teeth  begin to erupt through the gums, and the muscular and nervous  systems mature so that movements become increasingly coordi-  nated. The infant is soon able to visually follow objects, reach for  and grasp objects, and sit, crawl, and stand.   Infancy also brings the beginning of the ability to communicate.  The infant learns to smile, laugh, and respond to some sounds. By the  end of the first year, the infant may be able to say two or three words.   The infant and young child have particular nutritional require-  ments to fuel rapid growth. In addition to an energy source, the  body requires proteins to provide the amino acids necessary to  form new tissues, calcium and vitamin D to promote the devel-  opment and ossification of skeletal structures (see chapter 7,  pp. 207-209), iron to support blood cell formation, and vitamin C  for production of structural tissues such as cartilage and bone.    Childhood begins at the end of the first year and ends at puberty.  During this period, growth continues at a rapid rate. The primary  teeth erupt, and then secondary teeth replace them (see chapter 17,  pp. 655-656). The child develops voluntary muscular control and  learns to walk, run, and climb. Bladder and bowel controls are  established. The child learns to communicate effectively by speak-  ing, and later, learns to read, write, and think. At the same time, the  child is maturing emotionally.    Adolescence is the period of development between puberty and  adulthood when anatomical and physiological changes result in  reproductively functional individuals (see chapter 22, pp. 837-839  and 849). Most of these changes are hormonally controlled, and  they include the appearance of secondary sex characteristics as  well as growth spurts in the muscular and skeletal systems.  Females usually experience the changes of adolescence at  younger ages than males. Early in adolescence, females may be    taller and stronger than their male peers. However, females attain  full growth at earlier ages, and in late adolescence the average  male is taller and stronger than the average female.   The periods of rapid growth in adolescence, which usu-  ally begin between the ages of eleven and thirteen in females  and between thirteen and fifteen in males, increase demands for  certain nutrients. It is not uncommon for a teenager to consume  a huge plate of food, go back for more—and still remain thin. In  addition to energy sources, foods must provide ample amounts of  proteins, vitamins, and minerals to support growth of new tissues.  Adolescence also brings increasingly refined motor skills, intel-  lectual ability, and emotional maturity.    Adulthood (maturity) extends from adolescence to old age. As we  age, we become gradually aware of certain declining functions—  yet other abilities remain adequate. The “Life-Span Changes” sec-  tions in previous chapters have chronicled the effects of aging on  particular organ systems. It is interesting to note the peaks of par-  ticular structures or functions throughout an average human life.   By age eighteen, the human male is producing the most tes-  tosterone he will ever have, and as a result his sex drive is strong.  In the twenties, muscle strength peaks in both sexes. Hair is at its  fullest, each hair its thickest. By the end of the third decade of life,  signs of aging may appear as a loss in the elasticity of facial skin,  producing small wrinkles around the mouth and eyes. Height is  already starting to decrease, but not yet at a detectable level.   The age of thirty is a developmental turning point. After this,  hearing often becomes less acute. Heart muscle begins to thicken.  The elasticity of the ligaments between the small bones in the back  lessens, setting the stage for the slumping posture that becomes  apparent in later years. Researchers estimate that beginning  roughly at age thirty, the human body becomes functionally less  efficient by about 0.8% every year.   During their forties, many people weigh 10 to 20 pounds (4.5 to  9 kilograms) more than they did at the age of twenty, thanks to a slow-  ing of metabolism and decrease in activity level. They may be 1/8 inch  (0.3 centimeter) shorter. Hair may be graying as melanin production  wanes, and some hair may fall out. Vision may become farsighted.  The immune system is less efficient, making the body more prone to  infection and cancer. Skeletal muscles lose strength as connective tis-  sue appears within them; the cardiovascular system is strained as the  lumens of arterioles and arteries narrow with fatty deposits; skin loos-  ens and wrinkles as elastic fibers in the dermis break down.   The early fifties bring further declines. Nail growth slows,  taste buds die, and the skin continues to lose elasticity. For most  people, the ability to see close objects becomes impaired, but  for the nearsighted, vision improves. Women stop menstruating,  although interest in sex continues (see chapter 22, p. 852). Delayed  or reduced insulin release by the pancreas, in response to a glucose  load, may lead to diabetes. By the decade’s end, muscle mass and  weight begin to decrease. A male produces less semen but is still  sexually active. His voice may become higher as his vocal cords  degenerate. A man has half the strength in his upper limb muscles  and half the lung function as he did at age twenty-five. He is about  3/4 inch (2 centimeters) shorter.    The sixty-year-old may experience minor memory losses. A  few million of the person’s billions of brain cells have been lost  over his or her lifetime, but for the most part, intellect remains  sharp. By age seventy, height decreases a full inch (2.5 centi-  meters). Sagging skin and loss of connective tissue, combined  with continued growth of cartilage, make the nose, ears, and eyes  more prominent.    Senescence (se-nes’ens) is the process of growing old. It is a con-  tinuation of the degenerative changes that begin during adulthood.  The body becomes less able to cope with the demands placed on it  by the individual and by the environment.   Senescence is a result of the normal wear and tear of body  parts over many years. For example, the cartilage covering the  ends of bones at joints may wear away, leaving the joints stiff and  painful. Other degenerative changes are caused by disease pro-  cesses that interfere with vital functions, such as gas exchanges  or blood circulation. Metabolic rate and distribution of body fluids  may change. The rate of division of certain cell types declines, and  immune responses weaken. The person becomes less able to repair  damaged tissue and more susceptible to disease.   Decreasing efficiency of the central nervous system accompa-  nies senescence. The person may lose some intellectual functions.  Also, the physiological coordinating capacity of the nervous sys-  tem may decrease, and homeostatic mechanisms may fail to oper-  ate effectively. Sensory functions decline with age also.   Death usually results, not from these degenerative changes,  but from mechanical disturbances in the cardiovascular system,  failure of the immune system, or disease processes that affect  vital organs. Table 23.9 summarizes the major phases of post-  natal life and their characteristics, and table 23.10 lists some  aging-related changes.    From 65% to 80% of all deaths in the United States take place in  hospitals, often with painful and sometimes unwanted interven-  tions to prolong life. The medical community is trying to remedy  shortcomings in the treatment of the dying. Medical training is  increasing emphasis on providing palliative care for the termi-  nally ill. Such care seeks to make a patient comfortable, even if  the treatment does not cure the disease or extend life.    Nearing the end of life is a personal process, influenced by belief  as well as circumstance. However, if the person has been chroni-  cally ill and is receiving comfort (palliative) care, certain signs of  impending death may appear, in many cases in a sequence. A person  may exhibit some or all of these signs.   Health-care professionals view the dying process in two stages—  preactive dying and active dying. Preactive dying may take up to three  months. During this time, some people are aware of what is happen-  ing and begin the psychological process of coming to terms with their  mortality. A month or more before death, the person starts to with-  draw, losing interest in news from the outside world and possibly    | Time  Stage Period Major Events  Neonatal Birth to end Newborn begins to carry on  period of fourth respiration, obtain nutrients, digest  week nutrients, excrete wastes, regulate  body temperature, and make  cardiovascular adjustments  Infancy End of Growth rate is high; teeth  fourth week begin to erupt; muscular and  to one year nervous systems mature so that  coordinated activities are possible;  communication begins  Childhood One year to Growth rate is high; primary teeth  puberty erupt and are replaced by secondary  teeth; high degree of muscular  control is achieved; bladder and  bowel controls are established;  intellectual abilities mature  Adolescence Puberty to Person becomes reproductively  adulthood functional and emotionally more    mature; growth spurts occur in  skeletal and muscular systems; high  levels of motor skills are developed;  intellectual abilities increase    Adulthood Adolescence Person remains relatively  to old age unchanged anatomically and  physiologically; degenerative  changes begin to occur  Senescence Old age to Degenerative changes continue;    death body becomes less able to cope  with demands; death usually results  from mechanical disturbances in  the cardiovascular system or from  diseases that affect vital organs    requesting that visits from friends and relatives cease or shorten. He  or she sleeps more and might not even get out of bed on some days.  Conversation lags. Gradually the loss of interest in everyday activi-  ties extends to eating. This parallels physical changes, such as diffi-  culty swallowing, that make eating increasingly difficult. The person  might first give up eating meats, then fibrous vegetables, until it is  clear that softer foods are preferred. The person might eat and drink  astonishingly little, and the family might feel the need to try to force  eating—which could cause the dying person discomfort. Dry mouth  is common. The caregiver can provide ice chips or popsicles, or fre-  quently wet the mouth with a swab.   Active dying presents a distinct set of signs, which might  appear only on the day before death, or might begin up to two  weeks earlier. During this phase the person sleeps often but can  easily be awakened. Even if sleep is deep, the person can hear,  because this is the last sense to fade. He or she may confuse  time, place, and identities. A nurse might be mistaken for a rel-  ative, or an adult child might not be recognized. An actively  dying person may go back in time, talking to a deceased spouse,  for example. Signs of agitation appear, such as picking lint on  the blanket or thrashing the arms about. Appetite may be nil.   In active dying, the organ systems slowly shut down.  Cardiovascular signs include falling blood pressure (systolic    Degenerative loss of collagen and elastin  fibers in dermis; decreased production of  pigment in hair follicles, hair eventually  turns white; reduced activity of sweat and  sebaceous glands; skin thins, wrinkles,  and becomes drier    Degenerative loss of bone matrix; bones  become thinner, less dense, and more  likely to fracture; stature may shorten due  to compression of intervertebral discs  and vertebrae    Loss of skeletal muscle fibers;  degenerative changes in neuromuscular  junctions; loss of muscular strength    Nervous system Degenerative changes in neurons; loss  of dendrites and synaptic connections;  accumulation of lipofuscin in neurons;  decreases in sensation; decreasing  efficiency in processing and recalling  information; decreasing ability to  communicate; diminished senses of  smell and taste; loss of elasticity of  lenses and consequent loss of ability to  accommodate for close vision    Reduced hormonal secretions; decreased  metabolic rate; reduced ability to cope  with stress; reduced ability to maintain  homeostasis    Cardiovascular system Degenerative changes in cardiac muscle;  decrease in lumen diameters of arteries  and arterioles; decreased cardiac output;  increased resistance to blood flow;    Decrease in efficiency of immune system;  increased incidence of infections and  neoplastic diseases; increased incidence  of autoimmune diseases    Digestive system Decreased motility in gastrointestinal  tract; reduced secretion of digestive    Degenerative loss of elastic tissue in lungs;  fewer alveoli; reduced vital capacity;  increase in dead air space; reduced ability  to clear airways by coughing    Degenerative changes in kidneys; fewer  functional nephrons; reductions in filtration  rate, tubular secretion, and tubular  reabsorption    Male Reduced secretion of sex hormones;  enlargement of prostate gland; decrease  in sexual energy    below 70, diastolic below 50). The pulse may race or slow, or  alternate. Poor circulation, which redirects the blood supply to  the body’s core, ushers in peripheral changes. The limbs feel cool  to the touch, and the person may note numbness. The extremi-  ties become pale, then take on a bluish tinge. Skin areas under  pressure, such as the undersides of the limbs, become mottled (dis-  colored). Sensitivity to touch and pain declines.   The slowing circulation affects muscles. Poor ability to cough  and swallow causes secretions to build up in the lungs. Secretions  may not be suctioned, because this increases their rate of accu-  mulation. The person can be repositioned to provide some relief.  Congestion is intermittent. One day it may be so severe that eat-  ing is impossible; the next day breathing may ease. Cheyne-Stokes  breathing—shallow mouth-breathing interspersed with increas-  ingly long periods of apnea—is common. The normal rate of 16  to 20 breaths per minute may speed to more than 50, slow pre-  cipitously, perhaps pausing for 10 to 30 seconds, and then the  person gasps and breathes rapidly again. As the throat muscles  relax, exhalation over the vocal cords causes a passive moaning  sound—this does not indicate that the person is in pain. A day or  two before death, breathing may become loud and labored.   Control of body temperature is altered, and the person may  have elevated body temperature or feel cold. The skin may be  alternately flushed, then blue with an internal chill. Sweating is  common, and as death nears, the skin takes on a yellowish pallor.   In the day or two before death, the signs intensify, although  a last burst of energy may occur. A bedridden person may sud-  denly wish to be propped up in the living room and see people, or,  after weeks of barely eating, suddenly request an ice cream sun-  dae. Meanwhile, respiration and circulation slow, and decreased  oxygen delivery may cause restlessness and agitation. The pulse  becomes thready. Right before death the person may lose control  of the bladder or bowels. Breathing becomes more irregular, with  longer periods between breaths, and the lung rattling intensifies.  Consciousness fades in and out. The eyes may be unfocused and  appear glassy, or may be only partially open, and may tear fre-  quently. Finally the person can no longer respond. After one, two,  or three long, last breaths, the eyes become fixed and open, the  pupils dilate, the jaw relaxes, and the mouth may slightly open.  The journey of life has ended.    38 How does the body change during adolescence?  39 What changes occur during adulthood?  40 What changes accompany senescence?    The aging process is difficult to analyze because of the intricate  interactions of the body’s organ systems. Breakdown of one struc-  ture ultimately affects the functioning of others. The medical field  of gerontology examines the biological changes of aging at the  molecular, cellular, organismal, and population levels. Aging is  both passive and active.    Aging as a passive process is a breakdown of structures and slow-  ing of functions. At the molecular level, passive aging is seen in  the degeneration of the elastin and collagen proteins of connective  tissues, causing skin to sag and muscle to lose its firmness.   During a long lifetime, biochemical abnormalities accumulate.  Mistakes occur throughout life when DNA replicates in dividing cells.  Usually repair enzymes correct this damage immediately. But over  many years, exposure to chemicals, viruses, and radiation disrupts  DNA repair mechanisms so that the error burden becomes too great  to be fixed. The cell may die as a result of faulty genetic instructions.    | DNA continues to mutate, even in the oldest old. A study of a  woman who died at age 115 in 2005 revealed that at that age,  her white blood cells had 450 mutations, whereas her brain  neurons had no mutations. This finding indicated that muta-  tions were continuing in rapidly dividing cell types—and with no  apparent ill effects. |    Another sign of passive aging at the biochemical level is the  breakdown of lipids. As aging membranes leak during lipid degen-  eration, a fatty, brown pigment called lipofuscin accumulates.  Mitochondria also begin to break down in older cells, decreasing  the supply of chemical energy to power cell functions.   The cellular degradation associated with aging may be set  into action by highly reactive chemicals called free radicals. The  most abundant type of free radical forms from oxygen atoms. A  molecule that is a free radical has an unpaired electron in its out-  ermost valence shell. This causes the molecule to grab electrons  from other molecules, destabilizing them, and a chain reaction of  chemical instability begins that could kill the cell. Free radicals  are a by-product of normal metabolism and also form by exposure  to radiation or toxic chemicals. The bile pigment bilirubin protects  against free radicals. Enzymes that usually inactivate free radi-  cals diminish in number and activity in the later years. One such  enzyme is superoxide dismutase (SOD).   Aging also entails new activities or the appearance of new sub-  stances. Lipofuscin granules, for example, may be considered an  active sign of aging, but they result from the passive breakdown of  lipids. Another example of active aging is autoimmunity, in which  the immune system turns against the body, attacking its cells as if  they were invading organisms.   Active aging begins before birth, as certain cells die as part of  the developmental program encoded in the genes. This process of  programmed cell death, called apoptosis (ap”o-t6’sis), occurs regu-  larly in the embryo, degrading certain structures to pave the way for  new ones. The number of neurons in the fetal brain, for example, is  halved as those that make certain synaptic connections are spared  from death. In the fetal thymus, T cells that do not recognize “self”  cell surfaces die, thereby building the immune system. Throughout  life, apoptosis enables organs to maintain their characteristic shapes.   Mitosis and apoptosis are opposite, but complementary, pro-  cesses. As organs grow, the number of cells in some regions increases,    but in others the number decreases. Cell death is not a phenomenon  only of the aged. It is a normal part of life. Clinical Application 23.3  discusses characteristics shared by people who live past 100.    The human life span—the length of time that a human can theo-  retically live—is 120 years. Although most people succumb to  disease or injury long before that point, in many countries the  fastest-growing age group is those over age eighty. Many of these  “oldest old,” having passed the age when cancer and cardiovascu-  lar disease typically strike, are quite healthy.   Life expectancy is a realistic projection of how long an indi-  vidual will live, based on epidemiological information. In the  United States, life expectancy currently is 76.3 years for men and  81.1 years for women. Yet in some African nations being decimated  by infectious diseases, life expectancy is in the thirties. Some life  expectancy estimates account for future health-care progress. For a  female born today, life expectancy exceeds 87 and for a male, 83.   Medical advances have greatly contributed to improved  life expectancy. Antibiotics have tamed some once-lethal infec-  tions, drugs enable many people with cancer to survive, and such  advances as beta-blocker drugs and coronary bypass surgery have  extended the lives of people with heart disease. However, the rise  of new or renewed infectious diseases, such as AIDS, polio, and  measles, also indicates that we cannot yet conquer all illnesses.  Although we can alter our environment more than other species  can, some forces of nature remain beyond our control. Table 23.11  lists the top 10 causes of death in the United States.    42 How is aging a passive process?  43 How is aging an active process?    TABLE 23.11 The Ten Leading Causes of Death  in the United States, 2013  Percent of    People who live past 100 years are called centenarians, and past  110, supercentenarians. About 70 supercentenarians are alive at any  given time, most of them female. Most centenarians enjoy excellent  health and remain active and engaged in activities, then succumb  rapidly to diseases that typically claim people decades earlier. Some  never get these disorders at all. Researchers hope that learning  which gene variants and environmental factors centenarians share  will lead to a better understanding of the common disorders of later  adulthood—heart disease, cancers, stroke, type 2 diabetes mellitus,  and dementias.   While the environment seems to play an important role in the  deaths of people ages 60 to 85, after that age genes predomi-  nate. Someone who dies at age 65 of lung cancer can probably  blame decades of smoking, but a smoker who dies at age 101 of  the same type of cancer probably had protective gene variants.  Centenarians have higher levels of HDL cholesterol than other  people, which researchers estimate adds 20 years of life. Factors  that vary widely among centenarians include religion, education  level, socioeconomic status, ethnicity, and diet. They share nor-  mal or low weight, not smoking, handling stress well, and not  having dementia. Women who gave birth late in life are overrep-  resented, perhaps because their reproductive systems, and the  rest of their bodies, age slowly.   Children and siblings of centenarians also tend to be long-  lived, suggesting a large inherited component. The saying of the  New England Centenarian Study, one of the longest-running pro-  grams, is “The older you get, the healthier you've been,” rather  than associating extreme old age with sickness.   Centenarians have luckily inherited two general types of gene  variants: those that are directly protective, and normal variants of  genes that, when mutant, cause disease. Specifically, single genes  important in aging affect:    Fertilization occurs with the union of a secondary oocyte  and a sperm cell.    1. Transport of sex cells  a. The secondary oocyte is ovulated and enters a  uterine tube.  b. A-sperm cell moves, by its tail lashing and muscular  contraction in the female reproductive tract, into a  uterine tube.    FIGURE 23D Researchers are discovering clues to good health by  probing the genomes of centenarians.    Several studies are identifying the gene variants and lifestyle  practices that contribute to living long and well. The New England  study is amassing the “healthy standard genome.” Investigators  at the Coriell Institute in New Jersey are probing the genomes of  the oldest old in nursing homes. So far, what these people share  is never having had heart disease and never having smoked.  Several have had cancer, indicating that this disorder is surviv-  able. Researchers at the University of Pittsburgh are pursuing gene  variants that preserve cognition. The National Institute on Aging  is currently seeking families with more than two long-lived mem-  bers living near Boston, New York, or Pittsburgh to participate in  the Long Life Family Study, which will collect and study genetic and  health information for clues to longevity. Perhaps this information  will help the majority of us, who have not inherited longevity gene  variants, discover how to control our environments in ways that  promote long and healthy lives.   a. With the aid of enzymes, a sperm cell penetrates the   b. When a sperm cell fuses with the secondary oocyte’s  membrane, changes in the oocyte cell membrane and  the zona pellucida prevent entry of additional sperm.  Completion of meiosis II forms the second polar body.  d. Fusion of the pronuclei of a sperm and a secondary    Pregnancy is the presence of a developing offspring in the  uterus. The prenatal period of the offspring is divided into  the embryonic stage and the fetal stage.    1. Embryonic stage (fertilization through the eighth week)  a. During cleavage the zygote undergoes mitosis, and the  newly formed cells divide mitotically.   (a) It gives rise to blood cells and cells that later  form sex cells.   (a) The embryonic portion consists of the chorion  and its villi.   (a) Oxygen and nutrients diffuse from the  maternal blood through the placental  membrane and into the fetal blood.    (b) Carbon dioxide and other wastes diffuse  from the fetal blood through the placental  membrane and into the maternal blood.    (1) Gastrulation is the movement of cells within the  embryonic disc to form layers.   (2) The cells of the embryonic disc fold inward,  forming a gastrula that has two and then three  primary germ layers.   (3) The primitive tissues in the germ layers will form  organs in the process of organogenesis.   (a) Ectoderm gives rise to the nervous system,  portions of the skin, the lining of the mouth,  and the lining of the anal canal.   (b) Mesoderm gives rise to muscles, bones, blood  vessels, lymphatic vessels, reproductive  organs, kidneys, and linings of body cavities.   (c) Endoderm gives rise to linings of the digestive  tract, respiratory tract, urinary bladder, and  urethra.   (4) The embryo develops a head, face, upper limbs,  lower limbs, and mouth, and appears more  humanlike.   (5) By the beginning of the eighth week, the embryo is  recognizable as a human.   (6) Teratogens can cause congenital malformations  by affecting an embryo or fetus in periods of  rapid growth, development, or specialization of  body structures.    2. Fetal stage (the end of the eighth week through birth)  a. The body enlarges, upper and lower limbs reach final    relative proportions, the skin is covered with sebum and  dead epidermal cells, the skeleton continues to ossify,  external reproductive organs are distinguishable as  male or female, muscles contract, and fat is deposited  in subcutaneous tissue.    (1) Itis about 50 centimeters long and weighs  2.7-4.5 kilograms.  (2) Itis positioned with its head toward the cervix.   (1) Umbilical vessels carry blood between the placenta  and the fetus.   (2) Fetal blood carries a greater concentration of  oxygen than does maternal blood because the  concentration of oxygen-carrying hemoglobin is  greater in fetal blood, and fetal hemoglobin has  greater affinity for oxygen.   (3) Blood enters the fetus through the umbilical vein  and partially bypasses the liver by means of the  ductus venosus.   (4) Blood enters the right atrium and partially bypasses  the lungs by means of the foramen ovale.   (5) Blood entering the pulmonary trunk partially  bypasses the lungs by means of the ductus  arteriosus.   (6) Blood enters the umbilical arteries from the  internal iliac arteries.   (1) Estrogens and progesterone maintain the uterine wall  and inhibit secretion of FSH and LH.   (4) Relaxin helps relax the connective tissue of the  pelvic joints.   The woman’s blood volume, cardiac output, breathing  rate, and urine production increase.   is inadequate, fetal tissues have priority for use of  available nutrients.   (1) A decreasing concentration of progesterone and  the release of prostaglandins may initiate the birth  process.   (4) Positive feedback causes stronger contractions and  greater release of oxytocin.   (3) Prolactin is released during pregnancy, but  progesterone inhibits milk production.   As long as milk is removed from the breasts, more milk    The postnatal period includes the neonatal period, infancy,  childhood, adolescence, adulthood, and senescence.    The neonatal period extends from birth to the end of  the fourth week.   The newborn must begin to respire, obtain nutrients,  excrete wastes, and regulate its body temperature.  The first breath must be powerful to expand the lungs.  (1) Surfactant reduces surface tension.    d. The liver is immature and unable to supply sufficient  glucose, so the newborn depends primarily on stored fat  for energy.   e. Immature kidneys cannot concentrate urine very well.  (1) The newborn may become dehydrated.   f. Homeostatic mechanisms may function imperfectly, and  body temperature may be unstable.   (3) The foramen ovale is closed by a valve as blood  pressure in the right atrium falls and blood pressure  in the left atrium rises.   a. Infancy extends from the end of the fourth week to one  year of age.   (1) The muscular and nervous systems mature, and  coordinated activities become possible.   c. Rapid growth depends on an adequate intake of proteins,  vitamins, and minerals in addition to energy sources.   a. Childhood extends from the end of the first year to  puberty.   c. Itis a period of rapid growth, development of muscular  control, and establishment of bladder and bowel control.   b. Physiological and anatomical changes result in a  reproductively functional individual.   c. Females may be taller and stronger than males in early  adolescence, but the situation reverses in late adolescence.   d. Adolescents develop high levels of motor skills, their  intellectual abilities increase, and they continue to  mature emotionally.   b. The adult remains relatively unchanged physiologically  and anatomically for many years.   b. Degenerative changes continue, and the body becomes  less able to cope with demands.   c. Changes occur because of prolonged use, effects of  disease, and cellular alterations.   d. An aging person usually loses some intellectual  functions, sensory functions, and physiological  coordinating capacities.   e. Death usually results from mechanical disturbances in  the cardiovascular system or from disease processes  that affect vital organs.    Gradually the organ systems shut down. The skin  becomes mottled as circulation slows and congestion  and loud breathing occur.    Describe how sperm cells move in the female reproductive  tract. (p. 868)   Summarize the events occurring after the sperm cell head  enters the oocyte’s cytoplasm. (p. 869)   Describe the process of cleavage. (pp. 870-871)  Distinguish between a morula and a blastocyst. (p. 871)  Describe the formation of the inner cell mass, and explain  its significance. (p. 871)   Explain what happens when the blastocyst nestles into the  endometrium. (p. 872)   Distinguish between the chorion and amnion. (p. 873)  Explain the function of the amniotic fluid. (p. 873)  Describe the formation of the umbilical cord. (pp. 873  and 875)   Explain how the yolk sac and the allantois are related, and  list the functions of each. (p. 875)   Describe the formation of the placenta, and explain its  functions. (pp. 875-876)   List the structures formed from the primitive tissues of the  ectoderm, mesoderm, and endoderm. (pp. 876-878)  Explain why the embryonic period is so important. (p. 879)  Give the time frame for the fetus, listing the major changes  that occur during fetal development. (pp. 881-882)  Describe a full-term fetus. (p. 882)   Explain how the fetal cardiovascular system is adapted to  intrauterine existence. (pp. 883-887)   Compare the properties of fetal hemoglobin to those of  adult hemoglobin. (p. 883)   Trace the pathway of blood from the placenta to the fetus  and back to the placenta. (pp. 883-887)    d. Lipid breakdown in aging membranes releases  lipofuscin.  e. Free radical damage escalates.  2. Active aging  a. In autoimmunity, the immune system attacks the body.  b. Apoptosis is a form of programmed cell death. It  occurs throughout life, shaping organs.  3. The human life span  a. The theoretical maximum life span is 120 years.  b. Life expectancy, based on real populations, is  76.3 years for men and 81.1 years for women in the  United States, and may be lower in poorer nations and  those ravaged by infectious diseases.  c. Medical technology makes life expectancy more  closely approach life span.    Explain the hormonal changes in the maternal body during  pregnancy. (pp. 887-889)   Describe the nonhormonal changes in the maternal body  during pregnancy. (p. 890)   Describe the role of progesterone in initiating the birth  process. (p. 890)   Explain positive feedback and the role of hormones in  expelling the fetus and the afterbirth. (p. 890)   Detail the roles of prolactin and oxytocin in milk production  and secretion. (pp. 891-893)   List some of the factors that stimulate the first breath. (p. 894)  Explain why newborns tend to develop water and electrolyte  imbalances. (p. 894)   Distinguish between a newborn and an infant. (pp. 894  and 896)   Describe the characteristics of an infant. (p. 896)  Distinguish between a child and an adolescent. (p. 896)  Define adulthood. (p. 896)   List some of the degenerative changes that begin during  adulthood. (pp. 896-897)   List some of the factors that promote senescence. (p. 897)  Contrast preactive dying and active dying. (pp. 897-898)   Discuss the signs of passive and active aging and the  physiological causes of these signs. (p. 899)   is the length of time a human can  theoretically live, whereas is the realistic  projection of how long an individual will live. (p. 899)    *, INTEGRATIVE ASSESSMENTS/CRITICAL THINKING  ye  Outcomes 6.5, 7.12, 8.4, 9.8, 11.8, 12.5, 13.11, Outcomes 16.4, 23.1  1 5.8, 1 6.5, 17.1 0, 1 8.9, 19.7, 20.5, 23.3, 23.4 4. Why can twins resulting from a single fertilized secondary    oocyte exchange blood or receive organ transplants from each  other without rejection, while twins resulting from two fertilized  secondary oocytes in some cases cannot?    1. If an aged relative came to live with you, what special provisions  could you make in your household environment and routines  that would demonstrate your understanding of the changes  brought on by aging?   Outcomes 15.2, 15.5, 23.2, 23.3 5. Why do toxins cause more severe medical problems in a   child if exposure was during the first eight weeks of prenatal    6. What technology would enable a fetus born in the fourth month  to survive in a laboratory setting? (This is not yet possible.)    2. What symptoms may appear in a newborn if its ductus arteriosus  fails to close?    3. Why is it important for a middle-aged adult who has neglected  physical activity for many years to have a physical examination  before beginning an exercise program?    Note the similar profiles of the four generations of this family. Researchers  have discovered the genes that determine the distances between facial  features, molding our appearances.    Genetics is the study of inherited traits, their variation, and how  they are transmitted between generations. Inherited traits range  from obvious physical characteristics, such as red hair and freck-  les, to many aspects of health, including disease. Within the 3  billion bases of the human genome lies the information that cells  use to synthesize proteins, which in turn provide traits. The unit  of genetic information is a gene, which encodes a protein. Genes  interact with each other and environmental influences to help  mold who we are.    and treatment choices. Tens of thousands of people have already  had their genomes sequenced, although all of the information has  yet to be interpreted.    After you have studied this chapter, you should be able to:   Identify the two processes that transfer genetic  information between generations. (p. 906)   Explain how the environment influences how genes are  expressed. (p. 907)   Explain the basis of multiple alleles of a gene. (p. 909)  Distinguish between heterozygous and homozygous;  genotype and phenotype; dominant and recessive. (p. 909)  Distinguish between autosomal recessive and autosomal  dominant inheritance. (p. 910)    Factors That Affect Expression of Single Genes  Explain how and why the same genotype can have  different phenotypes among individuals. (p. 912)    Multifactorial Traits  Describe and give examples of how genes and the  environment determine traits. (pp. 912-913)   Describe how and when sex is determined. (p. 914)  Explain how X-linked inheritance differs from inheritance  of autosomal traits. (pp. 914-915)   Discuss factors that affect how phenotypes may differ  between the sexes. (p. 916)   Contrast the value of whole genome sequencing with  that of single gene tests. (pp. 920)   Explain how understanding gene expression patterns can  improve and personalize health care. (pp. 920-921)    phen-, show, be seen: phenotype—physical  appearance or health condition that re-  sults from the way genes are expressed  in an individual.    Genetics (jé-net’iks) is the study of inheritance of characteris-  tics. Genes are sequences of DNA that encode particular proteins.  They contribute to our physical diversity, including eye, skin,  and hair color; many aspects of health; abilities and talents; and  hard-to-define characteristics such as personality traits. We often  equate the study of genetics with disease, but it is more accu-  rately described as the study of inherited variation. Our genomes  are more than 99.9% alike in DNA sequence; within that less than  0.1% of genetic variation lies our individuality.   The human genome is written in the language of DNA molecules.  Recall from figure 4.20 (p. 135) that DNA consists of sequences of  the nucleotide building blocks A (adenine), G (guanine), C (cytosine),    and T (thymine). In somatic cells, two copies of the human genome of  3.2 billion building blocks each are dispersed among the 46 chromo-  somes (fig. 24.1).   The transfer of genetic information from one generation to the  next occurs through the processes of meiosis and fertilization, when  one copy of the genome from each parent join. The cells that give  rise to eggs and sperm, like all somatic cells, are diploid, with two  copies of each of the 23 chromosomes. Eggs and sperm are haploid,  with one set of chromosomes. The joining of an egg and a sperm  reconstitutes the diploid state.    ~« 4 To Chapter 22, Formation of Sperm Cells, page 828,  and Oogenesis, page 841.    FIGURE 24.1 From DNA to gene to chromosome. Chromosomes in a cell about to divide consist of sister chromatids, each of which is a continuous  DNA double helix and associated proteins. Chromosomes condense just prior to cell division, becoming visible under a microscope. The DNA winds    around proteins, enabling the long molecule to fit inside the cell.    The human genome includes 20,325 protein-encoding genes,  constituting the exome. Different cell types access (through tran-  scription and translation) different subsets of the genome to produce  particular proteins and in this way take on the distinctive charac-  teristics of the hundreds of types of specialized cells in the body.  Messenger RNA molecules can represent parts of different genes,  so that the 20,325 genes actually encode 100,000 to 200,000 differ-  ent proteins. It is a little like creating a great variety of stories from  a set of words. The exome accounts for only a little less than 2%  of the 3.2 billion DNA bases of the human genome. The remaining  sequences control how the exome is used. The first human genomes  were sequenced by the year 2000 and took thousands of researchers  more than a decade, costing $3 billion. Today a human genome  can be sequenced in under a day, for about $1,000. However,  researchers are still analyzing what all of our genes do, how genes  interact, and how we vary genetically.   Genetic information functions at several levels. It is encoded  in DNA and expressed in RNA and protein; affects cells and tis-  sues; affects the individual; and is also passed to the next genera-  tion. Figure 24.2 depicts the inherited disease cystic fibrosis (CF)  viewed at several levels.    “ To Chapter 4, Nucleic Acids and Protein Synthesis,  pages 132-142.    Until recently, the field of medical genetics dealt mostly with  rare disorders that could be traced to the malfunction or absence  of single genes. However, information from the human genome  sequence and about which genes are expressed (transcribed and  translated) under specific circumstances is providing a new view  of physiology as a complex interplay of gene functions.    Discovering how diseases are related at the genetic level is  enabling physicians to “repurpose” existing drugs. This is the  case for progeria, an inherited disease that causes a young child  to show signs of greatly accelerated aging.   Shortly after birth, in a child with progeria, weight gain  slows and hair thins. Teeth never erupt, joints stiffen and bones  weaken, and the skin wrinkles and toughens. Blood vessels  stiffen with premature atherosclerosis, fat pockets shrink, and  connective tissue hardens. The child usually dies during adoles-  cence, from a heart attack or stroke.   Fewer than 250 children worldwide are known to have pro-  geria. When researchers in 2003 identified the mutant gene, they  realized, from the nature of the molecular defect, that several  existing drugs might alleviate certain symptoms. They tested a  failed cancer drug, and several children began to gain weight,  and their arteries grew less stiff as the blockages shrunk. Hearing  improved and bones became stronger. An unanticipated outcome  was that these children, who face a life expectancy of 14 years,  lived at least 1.6 years longer.   Understanding how a mutation causes a disease is an impor-  tant first step in finding a treatment. The drug that helps children  with progeria is now being tested in people who develop athero-  sclerosis as part of aging.    Genes are important, but they do not determine who we are,  nor do they act alone. The environment influences how genes are  expressed—under which circumstances they are transcribed into  mRNA and those mRNA molecules translated into protein. The envi-  ronment includes the chemical, physical, social and biological factors  surrounding an individual, and also the conditions to which a cell is  exposed. A common medical condition may result from inheriting  risk factors and exposure to environmental influences. For example,  development of cardiovascular disease may reflect not only inheri-  tance of specific gene variants that control blood pressure, blood clot-  ting, and cholesterol metabolism, but also lifestyle influences such  as stress, smoking, poor diet, and lack of physical exercise that may  affect the expression of those genes in negative ways. The inaccurate  idea that “we are our genes” is called “genetic determinism.”    1. What is the chemical composition of the genetic material?  2 Define gene, genome, and exome.    3 Explain how the human genome encodes more proteins than it  has genes.    The pregnant patient is anxious after receiving a phone call  reporting the test result that she is a carrier for cystic fibrosis.  She soon meets with a genetic counselor, who explains how  the disease is inherited and describes testing options. The  next step is to test the father-to-be, and when he is found not  to have a cystic fibrosis mutation, the couple relaxes. Had he  also carried a mutation, the counselor explained, each child  would have had a 25% chance of inheriting the disease, which  could have been detected with further testing.   A genetic counselor is a health-care professional trained  in genetics, psychology, statistics, and counseling techniques  to provide guidance to patients taking genetic tests or  with inherited diseases in their families. A certified genetic  counselor has a master’s degree in the field, but nurses, social  workers, physicians, and PhD geneticists also provide genetic  counseling. The counselor explains inheritance patterns,  assesses risks for specific individuals in a family, recommends  tests, and interprets the results of tests.   Genetic counselors work in medical centers, in  physicians’ offices, in research laboratories, and at  companies that provide genetic tests. They may specialize  in prenatal care or work in clinics for patients with specific  diseases, such as familial cancers, hereditary forms of  blindness, or inherited blood disorders. Genetic counselors  are hired to help in the ongoing effort to identify the  functions of all of the genes in the human genome, a  process called annotation. This entails searching disease  and mutation databases and reading the scientific and  medical literature to connect reports and information to  DNA sequences. Genetic counselors are at the forefront of  making practical sense of the human genome sequences.    FIGURE 24.2 From gene to protein to person. (a) The gene encoding the CFTR protein, and causing cystic fibrosis when mutant, is on the seventh  largest chromosome. CFTR protein folds into a channel that regulates the flow of chloride ions into and out of cells lining the respiratory tract, pancreas,  intestines, and elsewhere. (b) In most cases of cystic fibrosis, the CFTR protein is missing an amino acid, which alters its folding and results in very thick  mucus and other secretions in the places highlighted in the illustration. The sticky secretions impair breathing and increase the risk of certain respiratory  infections. Source: Data from M. C. lannuzi and F. S. Collins, “Reverse Genetics and Cystic Fibrosis,” in American Journal of Respiratory Cellular and    Genetics has the power of prediction. Knowing how genes are dis-  tributed in meiosis and the combinations in which they can join  at fertilization makes it possible to calculate the probability that  a certain trait will appear in the offspring of two particular indi-  viduals. The patterns in which genes are transmitted in families  are termed modes of inheritance. An educator, monk, and gardener  named Gregor Mendel deciphered the modes of inheritance in the  1860s by breeding pea plants and following easily visible traits  over several generations. The laws he derived apply to humans  because our cells are diploid, like those of peas and most other  multicellular organisms.    The basis of making genetic predictions is the way in which genes  are carried as parts of chromosomes. Charts called karyotypes  display the 23 chromosome pairs in size order (fig. 24.3). Pairs 1  through 22 are autosomes (aw’to-somz), which do not carry genes  that determine sex. The other two chromosomes, the X and the Y,  include genes that determine sex and are called sex chromosomes.  A female is XX and a male is XY. (See the section of this chapter  entitled “Matters of Sex.’”)   Each chromosome includes hundreds or thousands of genes. A  human somatic cell has two copies of each chromosome, and there-  fore two copies of each gene. The two members of a gene pair are    FIGURE 24.3 A normal human karyotype has 22 pairs of autosomes  aligned in size order, plus the sex chromosomes. This karyotype is from a  female; note the two X chromosomes.    (Q) How would a karyotype for a male look different from  this one?    located at the same position on homologous chromosomes. Because  a gene consists of hundreds of nucleotide building blocks, it can  exist in variant forms, called alleles (ah-lélz’), that differ in DNA  sequence. A person who has two identical alleles of a particular  gene is homozygous (ho”mo-zi’gus) for that gene. A person with  two different alleles for a gene is heterozygous (het”er-o-zi’ gus) for  it. A gene may have multiple alleles, but an individual person can  normally have a maximum of two alleles for a particular gene.    The allele that causes most cases of cystic fibrosis was discov-  ered in 1989, and a test was developed to detect it. However,  other alleles were soon discovered. Today, more than 1,600  mutations (changes) in the cystic fibrosis gene are known.  Different allele combinations produce different combinations  and severities of symptoms.    The combination of gene variants (alleles) in a person’s  genome constitutes the genotype (je’no-tip). That is, all humans  have the same types of genes, but differ in the specific variants.  The appearance or health condition of the individual that develops  as a result of the ways the genes are expressed is the phenotype  (fe’no-tip). An allele is wild type if its associated phenotype is  either normal function or the most common expression in a pat-  ticular population. Wild type is indicated with a + sign. An allele    that is a change from wild type, perhaps producing an uncommon  phenotype, is mutant. Disease-causing alleles are mutant, but not  all mutations cause disease. Some mutations, such as the one that  prevents HIV from entering cells, can be advantageous.    For many genes, in heterozygotes, one allele determines the phe-  notype. Such an allele whose action masks that of another allele  is termed dominant. The allele whose expression is masked is  recessive. For genes with only two alleles, the dominant ones are  usually indicated with a capital letter.   An allele that causes a disease can be recessive or dominant.  It may also be autosomal (carried on a nonsex chromosome) or  X-linked (carried on the X chromosome) or Y-linked (carried on  the Y chromosome). The mode of inheritance refers to whether  a trait is dominant or recessive, autosomal or carried on a sex  chromosome. This designation has important consequences in  predicting the chance that offspring will inherit an illness or trait.  The following rules emerge:    1. An autosomal condition is equally likely to affect either  sex. X-linked characteristics affect many more males  than females.   2. A person most likely inherits a recessive condition from two  parents who are heterozygotes (carriers). The parents are  usually healthy. For this reason, recessive conditions can  “skip” generations.   3. A person who inherits a dominant condition has at least one  affected parent. Therefore, dominant conditions do not skip  generations. If, by chance, a dominant trait does not appear  in a generation in a particular family, it does not reappear  in subsequent generations, as a recessive trait might. (An  exception is if the dominant allele arises as a new mutation  in the sperm or egg.)    Cystic fibrosis (CF) is an example of an autosomal recessive  disorder. The wild type allele for the CFTR gene, which is domi-  nant over the disease-causing allele, specifies formation of chlo-  ride channels in the cell membranes of cells lining the structures  depicted in figure 24.2. Certain recessive mutant alleles disrupt the  structure and/or function of the chloride channels.   An individual who inherits two identical mutant alleles has  CF and is homozygous recessive. A person inheriting one reces-  sive mutant allele plus a dominant wild type allele is a carrier  and transmits the disease-causing allele in half of the gametes.  A person who has two wild type alleles is homozygous domi-  nant and does not have or carry CF. The three possible geno-  types are associated with only two phenotypes, because carriers  and homozygous dominant individuals do not have the illness.  A person who has two different mutant alleles is called a com-  pound heterozygote, and may or may not have symptoms,  depending upon the effects of the allele combination on the  chloride channels.   Using logic, understanding how chromosomes and genes are  distributed among gametes in meiosis, and knowing that mutant  alleles that cause CF are autosomal recessive, we can predict  genotypes and phenotypes in the next generation. Figure 24.4  illustrates two carriers of CF. Half of the man’s sperm contain a    specific mutant allele, as do half of the woman’s eggs. Sperm and  eggs combine at random, so each offspring has a    ¢ 25% chance of inheriting two wild type alleles (homozygous  dominant, healthy, and not a carrier)   e 50% chance of inheriting a mutant allele from either parent  (heterozygous and a carrier, but healthy)   ¢ 25% chance of inheriting a mutant allele from each parent  (homozygous recessive, has CF)    Genetic counselors use two tools to explain inheritance to  families: Punnett squares and pedigrees. A Punnett square is a  table that symbolizes the logic used to deduce the probabilities of  genotypes in offspring. The mother’s alleles (for a specific gene)  are listed atop the four boxes comprising the square, and the  father’s alleles are listed along the left side. Each box records an  allele combination at fertilization. (When more than one gene is  considered, the Punnett square has more boxes.)   A pedigree is a diagram that depicts family relationships and  known genotypes and phenotypes. Circles are females and squares  are males; shaded-in symbols represent people who have a trait or  condition; half-shaded symbols denote carriers. Roman numerals  indicate generations. Figure 24.4 and figure 24.5 show Punnett  squares and pedigrees.   A person who has an autosomal recessive illness has par-  ents who are carriers—they do not have the illness. Or, if the  phenotype is mild, a parent might be homozygous recessive  and affected. A person who has an autosomal dominant condi-  tion typically has an affected parent, and need inherit only one  copy of the mutant allele to have the associated phenotype. In  contrast, expression of an autosomal recessive condition requires  inheriting two mutant alleles.    Certain recessive alleles that cause illness remain in a popula-  tion because they protect carriers from another condition, such  as an infectious disease. For example, in carriers of sickle cell  disease (see fig. 4.26, p. 143), not enough red blood cells are  deformed to block circulation under normal atmospheric condi-  tions, but enough are sickle shaped to prevent malaria parasites  from infecting many red blood cells. Carriers for sickle cell dis-  ease and certain other inherited anemias do not easily contract  malaria. If they do contract malaria, the symptoms are mild.    An example of an autosomal dominant condition is Huntington  disease (HD). Symptoms usually begin in the late thirties or early  forties and include loss of coordination, uncontrollable dancelike  movements, behavioral changes, and cognitive decline. Figure 24.5  shows the inheritance pattern for HD. If one parent has the mutant  allele, half of his or her gametes will have it. Assuming the other par-  ent does not have a mutant allele, each child conceived has a | in 2  chance of inheriting the disease allele and, eventually, developing  the condition.   Most of the 3,000 or so known human inherited disorders are  autosomal recessive. These conditions tend to produce symptoms  in childhood. Autosomal dominant conditions often begin to cause    FIGURE 24.4 Cystic fibrosis is autosomal recessive. (a) Each child of  carrier parents has a 25% chance of being unaffected and not a carrier, a 50%  chance of being an unaffected carrier, and a 25% chance of being affected.  Sexes are affected with equal frequency. A Punnett square (b) and a pedigree  (c) also display this information. Symbols in the pedigree with both black and  white indicate unaffected carriers (heterozygotes). The pedigree illustrates  the makeup of one possible family.    © If a mother is homozygous wild type for the CFTR gene,    symptoms in adulthood, and they remain in populations because  people have children before knowing they could pass on the ill-  ness. For some autosomal dominant disorders, genetic tests can  reveal that a disease-causing genotype has been inherited, even  before symptoms begin.    FIGURE 24.5 Huntington disease is autosomal dominant. (a) A  person with one HD allele develops the disease. A Punnett square (b) and  pedigree (c) depict the inheritance of HD. The pedigree symbols for HD  are completely filled in to indicate that the person is affected. Autosomal  dominant conditions affect both sexes.    People of all ages take genetic tests. A couple contemplating  parenthood may take blood tests that detect carriers of nearly  500 single-gene diseases. Newborns are routinely screened  for 50 or more genetic diseases. Children with unusual sets of    symptoms have their exomes sequenced to identify mutations.  Genetic tests can indicate which drugs are most likely to be  effective in particular patients. Genetic tests are also used to  evaluate forensic evidence and to trace ancestry.    Most genes exhibit complete dominance or recessiveness.  Interesting exceptions are incomplete dominance and codominance.   In incomplete dominance, the heterozygous phenotype is  intermediate between that of either homozygote. For example, in  familial hypercholesterolemia (FH), a person with two disease-  causing alleles completely lacks LDL (low-density lipoprotein)  receptors on liver cells that take up cholesterol from the blood-  stream (fig. 24.6). A person with one disease-causing allele (a het-  erozygote) has half the normal number of cholesterol receptors.  Someone with two wild type alleles has the normal number of  receptors. The associated phenotypes parallel the number of recep-  tors—those with two mutant alleles develop severe disease as chil-  dren, individuals with one mutant allele may become ill in young  or middle adulthood, and people with two wild type alleles do not  develop this type of hereditary heart disease.   Different alleles that are both expressed in a heterozygote are  codominant. For example, two of the three alleles of the / gene,  which determines ABO blood type, are codominant (see fig. 14.21,  p. 550). The J gene encodes the enzymes that place the A and B anti-  gens on red blood cell surfaces. The three alleles are [, /°, and i.  People with type A blood may be either genotype //‘ or /“i; type  B corresponds to /°/* or [°i; type AB to 7°; and type O to ii. The 4  and /* alleles are codominant.    FIGURE 24.6 Incomplete dominance is seen in the plasma  cholesterol levels of heterozygotes and homozygotes for familial  hypercholesterolemia (FH). This condition increases serum cholesterol  level in the blood, raising the risk of developing cardiovascular disease.  The photograph shows cholesterol deposits near the eyes of a person  who is a homozygote for the disease-causing allele.    Distinguish between autosomes and sex chromosomes.  Distinguish between genotype and phenotype.    How do the modes of transmission of autosomal recessive and  autosomal dominant inheritance differ?    The expression of most genotypes varies from person to person,  due to the effects of the environment and other genes. Even identi-  cal twins may not exhibit a phenotype in the exact same way. The  terms penetrance, expressivity, and pleiotropy are used to describe  some of these distinctions of genotype expression.    Penetrance refers to the all-or-none expression of a genotype in  an individual, whereas expressivity refers to degrees of a pheno-  type. Some disease-causing allele combinations are completely  penetrant, which means that everyone who inherits a particu-  lar genotype expresses the associated phenotype. A genotype is  incompletely penetrant if some individuals do not express the  associated phenotype. Polydactyly, having extra fingers or toes, is  incompletely penetrant (see fig. 7.47, p. 239). Some people who  inherit the autosomal dominant allele have more than five digits on  a hand or foot, yet others known to have the allele (because they  have an affected parent and child) have ten fingers and ten toes.  Most traits are incompletely penetrant.   The penetrance of a gene is described numerically. If 80 of  100 people who have inherited the dominant polydactyly allele  have extra digits, the allele is 80% penetrant. Penetrance may  reflect environmental effects. For example, a person who inherits  a genotype that increases the risk of lung cancer many not develop  the cancer if the lungs remain free of smoke and pollution.   A phenotype is variably expressive if the manifestation  varies in intensity in different people—which is nearly always  the case. One person with polydactyly might have an extra digit  on both hands and a foot; another might have two extra digits  on both hands and both feet; a third person might have just one  extra fingertip. Polydactyly is both incompletely penetrant and  variably expressive.    A single gene that effects several phenotypic traits exhibits pleiot-  ropy (ple’ot-ro-pe). Family members who have different sets of  symptoms can appear to have different illnesses, when they actu-  ally have the same pleiotropic disorder.    Pleiotropy is seen in genetic diseases that affect a single  protein found in different parts of the body. This is the case for  Marfan syndrome, an autosomal dominant defect in an elastic con-  nective tissue protein called fibrillin. The protein’s abundance in  the lens of the eye; in the bones of the limbs, fingers, and ribs; and  in the aorta explains the symptoms of lens dislocation, long limbs,  spindly fingers, and a caved-in chest. The most serious symptom  is weakening in the aorta wall, which can burst the vessel. If the  weakening is detected early, a synthetic graft can be used to patch  that part of the vessel wall, saving the person’s life.    The same phenotype resulting from the actions of different genes  is called genetic heterogeneity (jé-net’ik het”er-o-je-ne’i-te). For  example, the nearly 200 forms of hereditary deafness are each due  to impaired actions of a different gene. Different genes affect dif-  ferent aspects of hearing.   Genetic heterogeneity occurs when genes encode different  enzymes that catalyze the same biochemical pathway, or encode  different proteins that are part of the pathway. For example, eleven  biochemical reactions lead to blood clot formation. Clotting disor-  ders may result from mutations in the genes that specify any of the  enzymes that catalyze these reactions, leading to several types of  bleeding disorders.    A couple was arrested on suspicion of child abuse because  their toddler suffered repeated broken bones. Tests for the  gene known to cause osteogenesis imperfecta, “brittle bone  disease,” which can break bones even in a fetus (see fig. 7.6b,  p. 204), revealed that the parents did not have the disease-  causing allele. They were found guilty. However, discovery of  a second gene that causes osteogenesis imperfecta enabled  them to be tested again, for mutations in this gene, and their  conviction was overturned. Mutations in at least eight genes  cause the brittle bones of osteogenesis imperfecta.    9 Distinguish between penetrance and expressivity.  10 What is pleiotropy?  11. What is genetic heterogeneity?    Most, if not all, characteristics and disorders considered “‘inher-  ited” reflect input from the environment as well as genes.  Characteristics molded by one or more genes plus the environ-  ment are termed multifactorial traits. They are also called  “complex traits,” but this is a less precise definition.   A trait determined by more than one gene is termed poly-  genic. Most polygenic traits are also influenced by the environment.    Usually, several genes each contribute to differing degrees toward  molding an overall phenotype. A polygenic trait, with many  degrees of expression because of the input of several genes, is said  to be continuously varying. Height, skin color, and eye color are  polygenic traits (figs. 24.7, 24.8, and 24.9).   Although the expression of a polygenic trait is continuous,  we can categorize individuals into classes and calculate the  frequencies of the classes. When we do this and plot the fre-  quency for each phenotype class, a bell-shaped curve results.  This curve indicating continuous variation of a polygenic trait  is strikingly similar for different characteristics, such as finger-  print patterns, height, eye color, and skin color. Even when dif-  ferent numbers of genes contribute to the phenotype, the curve  is the same shape.   Eye color illustrates how interacting genes can mold a single  trait. The colored part of the eye, the iris, darkens as melanocytes  produce the pigment melanin. Unlike melanin in skin melano-  cytes, the pigment in the eye tends to stay in the cell that produces  it. Blue eyes have just enough melanin to make the color opaque,  and dark blue or green, brown or black eyes have increasingly  more melanin in the iris.    Because the genes that determine eye color are present in all  cells, forensic scientists can determine the eye color of a corpse    Two genes (OCA2 and HERC2) control melanin synthesis and  deposition. The alleles of the two genes interact additively, produc-  ing distinct eye colors. Figure 24.9 depicts how this might happen  to account for five colors—light blue, deep blue or green, light  brown, medium brown, and dark brown/black. If each dominant  allele contributes a certain amount of pigment, then the greater the  number of such alleles, the darker the eye color. The bell curve arises  because there are more ways to inherit light brown eyes, with any  two dominant alleles, than there are ways to inherit the other colors.   Other genes modify the expression of the two genes that con-  trol melanin synthesis. Two genes add greenish hues. Overlying  the colors and tones are specks and flecks, streaks and rings, and  regions of dark versus light that arise from the way pigment is laid  down onto the distinctive peaks and valleys at the back of the iris.   Height and skin color are multifactorial as well as polygenic,  because environmental factors influence them: good nutrition  enables a person to reach the height dictated by genes, and sun  exposure affects skin color. Most of the more common illnesses,  including heart disease, diabetes mellitus, hypertension, and can-  cers, are multifactorial.    FIGURE 24.7 Height is a polygenic trait. These students in a genetics class lined up by height to illustrate the continuously varying nature of the trait.    FIGURE 24.8 Variations in skin color. A model of three genes, with two alleles each, can explain some of the hues of human skin. In actuality, this trait  likely involves many more than three genes. The mid-range colors are more common.    FIGURE 24.9 Variations in eye color. A model of two genes, with two alleles each, can explain five human eye colors. If eye color is controlled by two  genes A and B, each of which comes in two allelic forms A and a and B and b, then the lightest color would be genotype aabb; the darkest, AABB.    Human somatic (body or nonsex) cells include an X and a Y chro-  mosome in males and two X chromosomes in females. All eggs  carry a single X chromosome, and sperm carry either an X or a  Y chromosome. Sex is determined at conception: a Y-bearing  sperm fertilizing an egg conceives a male, and an X-bearing sperm  conceives a female (fig. 24.10). The female is termed the homo-  gametic sex because she has two of the same type of sex chromo-  some, and the human male is called the heterogametic sex because  his two sex chromosomes are different.    Maleness derives from a Y chromosome gene called SRY, which  stands for sex-determining region of the Y. The SRY gene encodes  a type of protein called a transcription factor, which switches  on other genes. SRY activates transcription of genes that direct  development of male structures in the embryo, while suppressing    formation of female structures. Figure 24.11 shows the sex chro-  mosomes. A female develops in the absence of the SRY transcrip-  tion factor, and if a gene called Wnf4 is expressed.    Genes that are part of the X and Y chromosomes are inherited in  different patterns than are genes on the autosomes because of the  different sex chromosome constitutions of males and females.  Traits transmitted on the X chromosome are X-linked, and those  transmitted on the Y chromosome are Y-linked. The two sex  chromosomes are dramatically different in size. The X chromo-  some has more than 1,500 genes; the Y chromosome has only 231  protein-encoding genes.   Y-linked genes are considered in three groups, based on their  similarity to X-linked genes. One group consists of genes at the  tips of the Y chromosome that have counterparts on the X chro-  mosome. These genes encode a variety of proteins that function  in both sexes, participating in or controlling such activities as    FIGURE 24.10 Sex determination. An egg contributes an X  chromosome, and a sperm, either an X or a Y. If an X-bearing sperm  fertilizes an egg, the zygote is female (XX). If a Y-bearing sperm fertilizes an  egg, the zygote is male (XY).    FIGURE 24.11 The X and Y chromosomes. The SRY gene, at one end  of the short arm of the Y chromosome, starts the cascade of gene activity  that directs development of a male (31,000x).    bone growth, the synthesis of hormones and receptors, and energy  metabolism. The members of the second functional group of Y  chromosome genes are similar in DNA sequence to certain genes  on the X chromosome, but they are not identical. These genes  are expressed in nearly all tissues, including those found only in  males. The third group of genes includes those unique to the Y  chromosome. Many of them control male fertility, such as the SRY    gene. Some cases of male infertility arise from tiny deletions of  these male-specific parts of the Y chromosome. Other genes in this  group encode proteins that participate in cell cycle control; pro-  teins that regulate gene expression; enzymes; and protein recep-  tors for immune system biochemicals.   Y-linked genes are transmitted only from fathers to sons,  because only males have Y chromosomes. The differences in  inheritance patterns of X-linked genes between females and  males result from the fact that any gene on the X chromosome  of a male is expressed in his phenotype, because he has no sec-  ond allele on a second X chromosome to mask its expression.  The human male is hemizygous for X-linked traits because he  has only one copy of each X chromosome gene. Red-green color-  blindness is a recessive X-linked trait.   A male always inherits his Y chromosome from his father and  his X chromosome from his mother. A female inherits one X chro-  mosome from each parent. If a mother is heterozygous for a par-  ticular X-linked gene, then her son has a 50% chance of inheriting  either allele from her. X-linked genes are therefore passed from  mother to son.   The transmission pattern of hemophilia A illustrates X-linked  recessive inheritance. This clotting disorder is passed from carrier  mother to affected son with a risk of 50%, because he can inherit  either her normal allele or the mutant one. A daughter has a 50%  chance of inheriting the hemophilia allele and being a carrier like  her mother and a 50% chance of not inheriting the allele.    The contribution of the X chromosome is equal in males and  females, even though males have one X and females have two,  because one X is silenced in every somatic cell of a female. She is  a mosaic, with genes from her father’s X chromosome expressed  in some cells, and genes from her mother’s X chromosome  expressed in others.    A woman would not know that she is a carrier of an X-linked  recessive trait unless she has an affected son, or if there is a bio-  chemical test that reveals that her cells have half the normal  amount of the gene’s protein product. For a daughter to inherit an  X-linked recessive disorder or trait, her father must be affected  and her mother must be a carrier or affected. The daughter would  need to inherit one affected X chromosome from each parent.   For X-linked recessive traits that seriously impair health,  affected males may not feel well enough to have children.  Therefore, X-linked recessive conditions that are nearly as com-  mon among females as males tend to have mild phenotypes.  Colorblindness is a mild X-linked trait—men who are colorblind  are as likely to have children as men with full color vision.   Dominant disease-causing alleles on the X chromosome are  rare. Males are usually much more severely affected than females,  who have a second X that provides protection. In a condition  called incontinentia pigmenti, for example, a female has swirls of  pigment in the skin where melanin in the epidermis extends into  the dermis, and may have abnormal teeth, sparse hair, visual prob-  lems, and seizures. Males are so severely affected that they do not  survive to be born.    Certain autosomal traits are expressed differently in males and  females, due to differences between the sexes. A sex-limited  trait affects a structure or function present in only males or  only females. Such a gene may be X-linked or autosomal. Beard  growth and breast size are sex-limited traits. A woman cannot  grow a beard because she does not manufacture sufficient hor-  mones required for facial hair growth, but she can pass to her sons  the genes that specify heavy beard growth.   In sex-influenced inheritance, an allele is dominant in one  sex but recessive in the other. Again, such a gene may be X-linked  or autosomal. This difference in expression reflects hormonal dif-  ferences between the sexes. For example, a gene for hair growth  pattern has two alleles, one that produces hair all over the head and  another that causes pattern baldness. The baldness allele is domi-  nant in males but recessive in females, which is why more men  than women are bald. A heterozygous male is bald, but a heterozy-  gous female is not. A bald woman would have two mutant alleles.   About 1% of human genes exhibit genomic imprinting, in  which the expression of a disorder differs depending upon which  parent transmits the disease-causing gene or chromosome. The  phenotype may differ in degree of severity, in age of onset, or  even in the nature of the symptoms. The physical basis of genomic  imprinting is that methyl (—CH,) groups cover the gene inherited  from one parent, blocking it from being transcribed and translated.    15 Which chromosomes and genes determine sex?  16 What are the three functional classes of genes on the Y chromosome?    17 Why do X-linked recessive conditions appear most commonly in  males?    Deviations from the normal human chromosome number of 46  produce syndromes because of the excess or deficit of genes.  Rearrangement of chromosomes, such as an inversion of a sec-  tion of a chromosome, or two nonhomologous chromosomes  exchanging parts, may also cause symptoms. This may hap-  pen if the rearrangement disrupts a vital gene or if it results in  “unbalanced” gametes that contain too little or too much genetic  material. Chromosome number abnormalities may involve single  chromosomes or entire sets of chromosomes.   The most extreme upset in chromosome number is having an  entire extra set or sets, which is called polyploidy (pol’e-ploi’de).  This results from formation of a diploid, rather than a normal hap-  loid, gamete. For example, if a haploid sperm fertilizes a diploid  egg, the fertilized egg is triploid, with three copies of each chro-  mosome. Most human polyploids cease developing as embryos or  fetuses, but occasionally an infant survives for a few days, with  many abnormalities.    Some organs normally have a few polyploid cells, with no  adverse effects on health. Skeletal muscle cells, for example,  have multiple nuclei, and therefore more than the usual number  of each chromosome.    Aneuploidy  A normal chromosome number is termed euploid (u’ploid). Cells  missing a chromosome or having an extra one are aneuploid (an’u-  ploid). Aneuploidy results from an error in meiosis called nondis-  junction (non’dis-jungk’shun) (fig. 24.12). In normal meiosis, pairs  of homologous chromosomes separate, and each of the resulting  gametes contains only one member of each pair. In nondisjunction,  a chromosome pair does not separate, either at the first or at the sec-  ond meiotic division, producing a sperm or egg that has two copies  of a chromosome or none, rather than the normal one copy. When  such a gamete fuses with its partner at fertilization, the resulting  zygote has either 47 or 45 chromosomes, instead of the normal 46.  The symptoms that result from aneuploidy depend upon  which chromosome is missing or extra, and which genes are part  of the chromosome. Autosomal aneuploidy often results in intel-  lectual disability; because many genes affect brain function the  absence of or extra copies of any autosome is likely to affect such  a gene. Extra genetic material is less dangerous than missing  material. This is why most children born with the wrong number  of chromosomes have an extra one, called a trisomy (tri’so-me),  rather than a missing one, called a monosomy (mon’o-so-me).  Aneuploid conditions have historically been named for the  researchers or clinicians who identified them, but chromosome des-  ignations are more precise and for this reason are more clinically  useful. Down syndrome, for example, refers to a distinct set of symp-  toms usually caused by trisomy 21. It is the most common autosomal  aneuploid. However, the syndrome may also arise from one copy of  chromosome 21 exchanging parts with a different chromosome in  a gamete and the fertilized ovum receiving excess chromosome 21  material. This exchange of genetic material is a type of chromosomal  aberration called a translocation. Knowing whether an individual has  trisomy 21 or translocation Down syndrome is important, because  the probability of trisomy 21 recurring in a sibling is about | in 100,  but the chance of translocation Down syndrome recurring is much  greater. Clinical Application 24.1 takes a closer look at trisomy 21.  Trisomies 13 and 18 are the next most common autosomal  aneuploids and usually result in miscarriage. An infant with tri-  somy 13 has an underdeveloped face, extra and fused fingers and  toes, heart defects, small adrenal glands, and a cleft lip or palate.  An infant with trisomy 18 suffers many of the problems seen in  trisomy 13, plus a peculiar positioning of the fingers and flaps of  extra abdominal skin. Table 24.1 indicates the rarity of trisomies    | Type of Incidence at Percent of Conceptions That |  _ Trisomy Birth Survive 1 Year After Birth  13 (Patau) 1/12,500-1/21,700 <5%  18 (Edward) 1/6,000-1/10,000 <5% |  21 (Down) 1/800-1/826 85% |    The most common autosomal aneuploid is trisomy 21, which is an  extra chromosome 21. The characteristic slanted eyes and flat face  prompted Sir John Langdon Haydon Down to coin the term mon-  golism when he described the syndrome in 1886. As the medical  superintendent of a facility for the profoundly intellectually dis-  abled, Down noted that about 10% of his patients resembled peo-  ple of the Mongolian race. The resemblance is coincidental. Males  and females of all races can have the syndrome.   A person with Down syndrome (either trisomy or translo-  cation) is short and has straight, sparse hair and a tongue pro-  truding through thick lips. The eyes slant and have upward  “epicanthal” skin folds in the inner corners. Ears are abnormally  shaped. The hands have an unusual pattern of creases, the joints  are loose, and reflexes and muscle tone are poor. Developmental  milestones (such as sitting, standing, and walking) are slow, and  toilet training may take several years. Intelligence varies greatly,  from profound intellectual disability to being able to follow sim-  ple directions, read, and use a computer. Some colleges special-  ize in educating people with Down syndrome (fig. 24A).   Down syndrome is associated with many physical problems,  including heart and kidney defects, susceptibility to infections,  and blockages in the digestive system. An affected child is fifteen  times more likely to develop leukemia than a healthy child, but  this is still a low figure. People with Down syndrome have a risk  of developing Alzheimer disease of 25%, compared to 6% for the  general population.    FIGURE 24A Many people with Down syndrome can learn, go to  school, and hold jobs. This young lady is learning from a chef.    The likelihood of giving birth to a child with trisomy 21 Down  syndrome increases dramatically with the age of the mother  (table 24A). However, 80% of children with trisomy 21 are born to  women under age thirty-five, because younger women are more  likely to become pregnant and until recently less likely to have  prenatal testing. About 95% of cases of trisomy 21 can be traced  to nondisjunction in the egg.   The age factor in Down syndrome may be because meiosis in  the female is completed after conception. The older a woman is,  the longer her oocytes have been arrested on the brink of com-  pleting meiosis. During this time, the oocytes may have been  exposed to chromosome-damaging chemicals or radiation.   In 1910, life expectancy for people with Down syndrome  was only to age nine. Many of the medical problems that  people with Down syndrome suffer are treatable, raising life  expectancy to sixty years. New treatments or drugs repurposed  to treat trisomy 21 Down syndrome may become available  because researchers now have a way to study the condition in  cells growing in laboratory glassware. Researchers use the gene  that normally turns off one X chromosome in females (see the  blue box on page 915) to turn off the third copy of chromo-  some 21 in stem cells made from skin fibroblasts of people with  Down syndrome. This approach, called genome editing, may  reveal how the abnormalities associated with trisomy 21 Down  syndrome begin.    Risk for Any  Maternal Age Trisomy 21 Risk § Aneuploidy  20 1/1,667 1/526  24 1/1,250 1/476  | 28 1/1,053 1/435  30 1/952 1/385  BZ 1/769 1/322  35 1/378 WAG  36 1/289 1/156  37 1/224 1/127  38 1/173 1/102 |  40 1/106 1/66 |  45 1/30 1/21  48 1/14 1/10    FIGURE 24.12 Extra or missing chromosomes constitute aneuploidy. Unequal division of chromosome pairs into sperm and egg cells can occur at  either the first or the second meiotic division. (a) A single pair of chromosomes is unevenly partitioned into the two cells arising from the first division of  meiosis in a male. The result: two sperm cells that have two copies of the chromosome and two sperm cells that have no copies of that chromosome.  When a sperm cell with two copies of the chromosome fertilizes a normal egg cell, the zygote produced is trisomic for that chromosome; when a sperm  cell lacking the chromosome fertilizes a normal egg cell, the zygote is monosomic for that chromosome. Symptoms depend upon which chromosome is  involved. (b) This nondisjunction occurs at the second meiotic division, leaving two of the mature sperm normal, and two aneuploid. Egg cells can undergo  nondisjunction as well, leading to zygotes with extra or missing chromosomes when they are fertilized by normal sperm cells.    13, 18, and 21 and that it is rarer still for an affected newborn to  survive infancy. However, a few individuals with trisomy 18 have  survived into their twenties. Trisomies of autosomes other than 13,  18, and 21 do not develop beyond the embryonic period.   Sex chromosome aneuploids are less severely affected than  are autosomal aneuploids. XO syndrome (Turner syndrome)  affects 1 in 2,000 newborn girls, but these represent only 1% of  XO conceptions. The other 99% presumably do not complete  prenatal development. Often the only symptom is delayed sexual  development. With hormone supplements, life can be fairly nor-  mal, except for infertility.    About | in every 1,000 to 2,000 females has an extra X chro-  mosome in each cell, which is called triplo-X. Often the only  associated characteristics of triplo-X are great height and men-  strual irregularities. Males with an extra X chromosome have  XXY syndrome (Klinefelter syndrome). Like XO females, XXY  males may not realize they have an unusual number of chromo-  somes until they have fertility problems and their chromosomes are  checked. Associated characteristics are sexual underdevelopment  (rudimentary testes and prostate glands and no pubic or facial  hair), growth of breast tissue, long limbs, and large hands and  feet. XXY syndrome affects 1 in every 500 to 2,000 male births.    One male in 1,000 has an extra Y chromosome, called XYY syn-  drome, or Jacobs syndrome. A fertilized ovum that has one Y chromo-  some and no X chromosome has never been observed. Presumably,  when a zygote lacks an X chromosome, so much genetic material is  missing that only a few, if any, cell divisions are possible.    Several types of tests performed on pregnant women can identify  anatomical or physiological features of fetuses that are often found  with a specific chromosomal problem or detect the abnormal chro-  mosomes (fig. 24.13). An ultrasound scan, for example, can reveal  the fusion of the eyes, cleft lip and/or palate, malformed nose, and  extra fingers and toes that indicate trisomy 13 (fig. 24.14). A blood  test performed on the woman during the fifteenth week of preg-  nancy detects levels of certain biochemicals in serum. Levels of  these maternal serum markers, which include alpha fetoprotein, an  estrogen, pregnancy-associated plasma protein A, and human cho-  rionic gonadotropin, can indicate an underdeveloped liver, which is  associated with trisomies 13, 18, and 21.   Detecting abnormal maternal serum marker levels is indirect  and imprecise, and so it is considered to be a screening rather than a  diagnostic test. Maternal serum marker screening is gradually being  replaced with analysis of cell-free fetal DNA. Pieces of fetal DNA  are normally in a pregnant woman’s bloodstream, and because these  pieces are smaller than maternal DNA, they can be separated. If the    FIGURE 24.14 In an ultrasound exam, sound waves are bounced  off the embryo or fetus, and the pattern of deflected sound waves is  converted into an image. Ultrasound reveals the face of this healthy  13-week fetus.    ratio of number of pieces from one chromosome type is 50% greater  than the number of pieces from the other chromosomes, then a tri-  somy is indicated. A fetus with trisomy 21, for example, would have  50% more DNA pieces in the maternal bloodstream from chromo-  some 21 compared to the number of pieces from the other chromo-  somes, representing the extra chromosome.    FIGURE 24.13 Three ways to check a fetus’s chromosomes. (a) Chorionic villus sampling removes cells that would otherwise develop into the placenta.  Because these cells descended from the fertilized ovum, they should have the same chromosomes as the fetus. (b) Amniocentesis draws out amniotic fluid.  Fetal cells shed into the fluid are collected and their chromosomes examined. (c) Analysis of small pieces of cell-free fetal DNA in a pregnant woman's  circulation allows comparison to detect extra or absent chromosomes. Fetal DNA is tested anytime after the tenth week of gestation, and may replace the    After maternal serum marker screening and/or ultrasound  indicates increased risk, the patient is offered either of two  invasive tests, to provide a definitive diagnosis. In chorionic  villus sampling (CVS), a physician collects chorionic villus cells  through the cervix as early as 10 weeks. The basis of the test is  that, theoretically, these cells are genetically identical to fetal cells  because they too descend from the fertilized ovum. However, a  mutation can occur in a villus cell only, or a fetal cell only, creating  a false positive or false negative test result, respectively.   In amniocentesis, a needle inserted into the amniotic sac with-  draws about 5 milliliters of fluid. Fetal fibroblasts in the sample  are cultured and a karyotype constructed, which reveals extra,  missing, or translocated chromosomes or smaller abnormalities.  However, additional tests on amniotic fluid or fibroblast DNA are  necessary to detect mutations in individual genes.   Cell-free fetal DNA testing may replace CVS and amnio-  centesis. It is also called non-invasive prenatal testing, or NIPT,  but this designation also includes ultrasound scans. Researchers  have sequenced genomes from fetuses using cell-free fetal DNA.  Table 24.2 and figure 24.13 summarize the tests used to visualize  fetal chromosomes as a window to health status.    19 Why do deviations from the normal chromosome number of 46  affect health?    People may have their entire genomes sequenced, but they might  not know what to do with the information. The situation is simi-  lar to owning a car. A warning light on the dashboard flashes,  telling the driver to check the brakes, steering, or oil. Perhaps the  motorist already knows there is a problem, from an odd sound or  different handling of the car. Would it be helpful for the driver to  be able to name every car part, down to the tiniest screw? Probably  not. Similarly, single-gene tests or symptoms may be more useful  than knowing the sequence of all 3.2 billion DNA bases that con-  stitute a human genome, at least for now.   The number of human genomes sequenced will soon exceed  a million, and their analysis will provide information on the func-  tions of our 20,325 genes and their variants. Health-care pro-  fessionals are learning how and under what circumstances to  incorporate genetic and genomic information into medical practice.  One impending challenge is that exome and genome sequences  provide “actionable” information—that is, evidence of treat-  able conditions—as well as unexpected disease risks, often called  “incidental” or “unsolicited” findings. The potential consequences  of clinical exome and genome sequencing are a little like taking a  car to a mechanic to fix one problem and finding another. However,  exome and genome sequencing are already solving diagnostic mys-  teries, as Clinical Application 24.2 explains.    To test the practicality of whole genome sequencing, a forty-  year-old biomedical engineer reported on his personal genome  sequence in a medical journal. He sought sequencing because  a young cousin had died of sudden cardiac arrest, and although  the engineer’s heart and blood vessels were healthy, he wanted to  know if he shared any gene variants with his unfortunate cousin  that might elevate his disease risk. The man’s genome revealed  that he indeed had inherited a tendency for atherosclerosis and  inappropriate blood clotting that could cause a thrombus or  embolism. His genome also revealed that cholesterol-lowering  drugs would work and not have side effects, and that one anti-  platelet drug would be effective but another would not be.  This “personalized medicine” approach will likely enable the  engineer to avoid his cousin’s fate. But like the car analogy, he  could have learned the risks from standard blood tests for lipid  levels and blood clotting combined with clues from a detailed  family history.   Considering patterns of gene expression is a different type of  genetic information than a sequence of DNA bases. Gene expres-  sion means identifying which genes are active in particular cell  types under particular conditions. This approach monitors the  proteins that a cell produces, providing snapshots of physiology  in action at the cellular level.   Changes in gene expression accompany all diseases, not just  the rare ones caused by mutations in single genes. Gene expres-  sion profiles provide valuable information about individuals as  well as populations. Within a person, changing gene expression  reflects health. Among populations, changing patterns of gene  expression reveal basic information about diseases. For example,  white blood cells in a person produce different types of pro-  teins when the body is fighting an infection than when it is not.  Comparing people, a muscle cell from someone with diabetes  mellitus expresses different genes than a muscle cell from a person  whose blood glucose level is controlled.    The exome is the part of the genome that encodes protein. It is  less than 2% of the genome—45 million of the 3.2 billion DNA  bases—but includes 85% of the mutations known to affect health.   Knowing the exome sequence of a patient with an unusual  set of symptoms can help a physician make a diagnosis by reveal-  ing what is abnormal at the molecular level. Consider the follow-  ing examples.   By the time he was four years old, the boy had already had 100  surgeries, including removal of his colon. His gastrointestinal tract  had been riddled with holes, starting at age two with an abscess in  his rectum. Feces leaked from his intestines. He was fed by tube,  and weighed less than 20 pounds. Doctors thought he was suffer-  ing from inflammatory bowel disease, but his symptoms seemed  much too severe.   Researchers at the medical center where the boy was being  treated had received funding to perform one of the very first  exome-sequencing experiments, planned for 2014. When the  boy’s doctors implored the researchers to help, the date was  moved up to 2009, and the boy became the first person to  receive a diagnosis based on the results of exome sequencing.   The procedure uncovered more than 16,000 variations in  gene sequences, and narrowed those down to 32 “candidate  genes.” The boy’s symptoms were explained by a mutation in  only one of those genes—a gene that normally prevents cells of  the gastrointestinal tract from dying during infection. The disease  corresponding to the mutation was known, but as an immune  system disorder, not a digestive one. It was treatable with a    Analyzing gene expression for the whole exome (the protein-  encoding part of the genome) can suggest new ways to treat dis-  eases by identifying biochemical changes that traditional tests  do not reveal. Such a discovery sometimes leads to a new use for  an existing drug. For example, statin drugs used to lower serum  cholesterol level are being tested on people with or at high risk of  developing Alzheimer disease, because people with heart disease  due to high serum cholesterol share gene expression patterns with  people who have Alzheimer disease.   Physicians are increasingly using tests of gene expression to  select or track responses to treatment. In an approach called phar-  macogenetics, tests based on gene expression profiling predict  which drugs will be most effective and least likely to cause adverse  effects in a particular patient. Physicians may use this approach to  select anticoagulants, antidepressants, cancer medications, and  cholesterol-lowering drugs. This is a more personalized approach to  medicine than trying one drug at a time, based on the fact that each  drug helps some people.    cord-blood stem cell transplant, but until the exome sequenc-  ing, nobody knew that this condition was what the boy had. He  received stem cells from an anonymous donor, rapidly gained  weight, and today is much improved.   Each of the twelve children in a study conducted at a large medi-  cal center had developmental delay or intellectual disability, plus  birth defects. None had a known inherited disease, or had been  exposed to trauma or a toxin that might have caused the prob-  lems. Exome sequencing identified causative mutations for seven  of the children. The information is practical. For example, one  child’s symptoms were due to a mutation in a gene that encodes a  sodium channel protein, and the child would have reacted severely  to certain drugs. The parents now know to avoid these drugs.   A larger study sequenced and analyzed hundreds of exomes  from patients whom doctors had been unable to diagnose, and  found answers for a fourth of them. The researchers had to narrow  down 400 to 700 gene variants per patient! A two-year-old boy who  had severe feeding difficulties and poor weight gain had a mutation  known to cause Marfan syndrome, although his symptoms were  atypical. One symptom of Marfan syndrome is an enlarged aorta,  the largest artery. An ultrasound revealed that the boy indeed had  a bulge in the wall of the aorta near the heart, which could have  caused sudden death. He was successfully treated.   As the cost of exome sequencing falls, it may become a  standard part of diagnostic medicine. Studies are under way to  sequence exomes to better understand the physiology behind  many diseases.    Overall, examining our genes and what they do provides a  new type of window into the functioning, and malfunctioning, of  the human body. In the coming years, as more individual genomes  are sequenced and compared, detailed portraits of the living chem-  istry within our cells, and the chemical crosstalk among cells, will  enhance our view of anatomy and physiology.    “ To Chapter 4, Nucleic Acids and Protein Synthesis,  pages 132-142.    Genetics is the study of inheritance of characteristics and  human variation.    Genetic information is passed from generation to  generation through meiosis and fertilization, when the  haploid genomes of the parents join.   The protein-encoding portion of the genome is small and  called the exome.   The human genome assembles many more proteins than  there are genes by combining gene parts.   Genetic information functions at the biochemical, cell,  tissue, individual, family, and population levels.   Genes influence each other and their expression responds  to environmental influences.   b. Chromosomes | through 22, numbered in decreasing  size order, are autosomes. They do not have genes that  determine sex.   c. The X and Y chromosomes are sex chromosomes.  They have genes that determine sex.   d. An allele is an alternate form (variant) of a gene. A  person can have a maximum of two different alleles for  a gene, but the gene can have many alleles, because a  gene consists of many building blocks, any of which  may be altered.   e. A person with a pair of identical alleles for a particular  gene is homozygous; if the alleles are different, the  individual is heterozygous.   f. The combination of gene variants in an individual’s  cells constitutes the genotype; the appearance or traits  of the individual is the phenotype.   g. A wild type allele provides normal function or the most  common expression. A mutant allele causes disease or an  unusual trait; it is a change from the wild type condition.   a. Ina heterozygote, an allele expressed when the other  is not expressed is dominant. The masked allele is  recessive.   b. Recessive and dominant genes may be autosomal or  X-linked or Y-linked.   c. An autosomal recessive condition affects both sexes  and may skip generations. The homozygous dominant  and heterozygous individuals have normal phenotypes.  An affected individual inherits one mutant allele from  each parent. The mutant alleles may be different.   d. An autosomal dominant condition affects both sexes  and does not skip generations. A person inherits it from  one affected parent.   a. In incomplete dominance, a heterozygote has a phenotype  intermediate between those of both homozygotes.   a. A genotype is incompletely penetrant if not all  individuals inheriting it express the phenotype.   b. A genotype is variably expressive if it is expressed to  different degrees in different individuals.   a. In pleiotropy, a disorder has several symptoms,  different subsets of which may affect individuals.   b. Pleiotropy results from a gene product that is part of  more than one biochemical reaction or is in several  organs or structures.   a. Genetic heterogeneity refers to a phenotype resulting  from mutation in more than one gene.   b. The same symptoms may result from mutations  in genes whose products are enzymes in the same  biochemical pathway.    A trait caused by the action of one or more genes and the  environment is multifactorial.   A trait caused by the action of a single gene is monogenic,  and by the action of more than one gene, polygenic.  Height, skin color, eye color, and many common illnesses  are multifactorial traits.   A frequency distribution for a polygenic trait forms a bell curve.    A female has two X chromosomes; a male has one X and one  Y chromosome. The X chromosome has many more genes  than the Y.   a. A male zygote forms when a Y-bearing sperm fertilizes  an egg. A female zygote forms when an X-bearing  sperm fertilizes an egg.   b. A gene on the Y chromosome, SRY, switches on genes  in the embryo that promote development of male  characteristics.   c. Lack of SRY and activation of Wnf4 direct development  as female.   a. Genes on the sex chromosomes follow different  inheritance patterns than those on autosomes.   b. Y-linked genes are in three functional groups: those  with counterparts on the X; those similar to genes on  the X; and genes unique to the Y, many of which affect  male fertility. Y-linked genes pass from fathers to sons.   c. Males are hemizygous for X-linked traits; they can  have only one copy of an X-linked gene, because they  have only one X chromosome.   d. Females can be heterozygous or homozygous for genes on  the X chromosome, because they have two copies of it.   e. A male inherits an X-linked trait from a carrier mother.  These traits are more common in males than in females.   f. A female inherits an X-linked mutant gene from her  carrier mother and/or from her father if he is well  enough to have children.   g. Dominant X-linked traits are typically lethal to males  before birth.   a. Sex-limited traits affect structures or functions seen in  only one sex and may be autosomal.   b. Sex-influenced traits are dominant in one sex and  recessive in the other.   c. In genomic imprinting, the severity, age of onset, or  nature of symptoms varies according to which parent  transmits a mutation.    Extra, missing, or rearranged chromosomes or parts of them  can cause syndromes, because they alter the balance of genetic  material or disrupt a vital gene.    1. Polyploidy  a. Polyploidy is an extra chromosome set.  b. Polyploidy results from fertilization with or by a  diploid gamete.  c. Polyploids do not survive long.  2. Aneuploidy  a. Cells with the normal chromosome number are  euploid. Cells with an extra or missing chromosome  are aneuploid.  b. Aneuploidy results from nondisjunction, in which  a chromosome pair does not separate, in meiosis I  or meiosis II, producing a gamete with a missing or  extra chromosome. At fertilization, a monosomy or  trisomy results.    Which choice places the structures in order of increasing  size? (pp. 906-907)   d. population, family, individual, organ, tissue, cell, DNA  Discuss the origin of the 23 chromosome pairs in a diploid  human cell. (p. 906)   Explain how a certain number of genes hold enough  information to encode a greater number of proteins. (p. 907)  Explain how genes can respond to environmental factors.  (p. 907)    Explain the two factors considered in determining mode of  inheritance. (p. 908)   f. incomplete dominance and codominance. (pp. 908-911)  Explain how a gene might have hundreds of alleles. (pp. 909)    c. Acell with an extra chromosome is trisomic. A cell  with a missing chromosome is monosomic. Individuals  with trisomies are more likely to survive to be born than  those with monosomies.   b. Maternal serum marker tests indirectly detect a small  fetal liver, which can indicate a trisomy.   c. Chorionic villus sampling obtains and examines  chorionic villus cells, which descend from the fertilized  egg and therefore are presumed to be genetically  identical to fetal cells.   d. Amniocentesis samples and examines fetal  chromosomes from fetal cells in amniotic fluid.   e. Cell-free fetal DNA testing detects aneuploids from  fetal DNA in the maternal circulation.    1. People can now have their entire genomes sequenced, but  focusing on specific genes may be more useful.   2. Exome and genome sequencing reveal actionable as well  as unsolicited findings.   3. Comparing profiles of gene expression reveals aspects  of physiology and makes possible more personalized  treatments for disease.   14 Explain why the frequency distributions of different  multifactorial traits give very similar bell curves. (p. 913)   15 Give an example of how the environment can influence a  multifactorial trait. (p. 913)   17 Explain why Y-linked traits are passed only from fathers to  sons. (p. 915)   18 Explain why the inheritance pattern of X-linked traits differs  in males and females. (p. 915)   19 Distinguish between a sex-limited and a sex-influenced trait.  (p. 916)    24.6 Chromosome Disorders  21 State whether trisomy 21 Down syndrome is euploid,  aneuploid, or polyploid. (p. 916)  22 In nondisjunction . (p. 916)  a. multiple sets of chromosomes are inherited  b. gametes receive only even-numbered chromosomes or  only odd-numbered chromosomes  a chromosome pair does not separate during meiosis  d. two eggs fertilize each other    1. Bob and Joan know from a blood test that they are each  heterozygous (carriers) for the autosomal recessive gene that  causes sickle cell disease. If their first three children are healthy,  what is the probability that their fourth child will have the disease?    2. Why are medium-brown skin colors more common than very fair  or very dark skin?    3. A balding man undergoes a treatment that transfers some of the  hair from the sides of his head, where it is still plentiful, to the  top. Is he altering his phenotype or his genotype?    4. A young couple is devastated when their second child is  diagnosed with CF. Their older child is healthy, and no one else  in the family has CF. How is this possible?    5. CFis an autosomal recessive disorder that varies widely in  phenotype, from great difficulty in breathing and digesting, to  frequent bouts of sinusitis, bronchitis, and/or pneumonia. In  the Maxwell family, the mother, Matilda, has a mild case—she  often suffers from respiratory infections. Her husband Jake is  a heterozygote, and testing reveals that he carries an allele  associated with severe disease. Of the four Maxwell children,    24 Discuss the benefits and limitations of whole genome  sequencing. (p. 920)   25 Distinguish the types of information provided in an exome or  genome sequence and in a gene expression profile. (p. 920)    Katie and Jim have fairly severe disease, although Jim has to be  hospitalized more frequently than Katie. The other two children,  Emily and Rose, do not have CF.    a. Explain how Katie and Jim can have severe cases of CF when  one parent does not have the disease and the other has a  mild case.   b. Explain how Katie and Jim have different severities of the illness.   c. What is the probability that Emily or Rose is a carrier, like  their father?    6. Describe a genetic test or technology that can predict whether a  person who smokes is likely to develop lung cancer.    7. In Hunter syndrome, lack of an enzyme leads to build up  of sticky carbohydrates in the liver, spleen, and heart. The  individual is also deaf and has unusual facial features. Hunter  syndrome is inherited as an X-linked recessive condition.  Intellect is usually unimpaired, and life span can be normal.  A man who has mild Hunter syndrome has a child with a  woman who is a carrier (heterozygote).    a. What is the probability that a son inherits the syndrome?  b. What is the chance that a daughter inherits it?  c. What is the chance that a girl would be a carrier?    8. Would you have your own genome sequenced? Cite a reason for  your answer.    Connect Integrated Activity Can you assist a genetic counselor  in explaining the inheritance of various inherited disorders?    Our knowledge of how the human body works is based on centuries of  careful observation and experimentation. A way of thinking and orga-  nizing information, called the scientific method, guides the acquisi-  tion and interpretation of new information about the human body. The  scientific method is used to either support or challenge a scientific  theory, which is a systematically organized body of knowledge that  applies to a variety of situations. It is a key part of a general process  known as scientific inquiry, which includes other ways of investigat-  ing the natural world. The scientific method is a framework in which  to consider ideas and evidence that involves use of familiar skills of  observing, questioning, reasoning, predicting, testing, interpreting,  and concluding.   The scientific method provides a sequence of logical steps  that address a specific question. A proposed answer to the question  is stated as a hypothesis, or “educated guess.” More than a hunch, a  hypothesis is based on existing knowledge and is often phrased in  the form “if this is true, then that must follow.” It is specific and test-  able, and should examine only one changeable factor, or variable.  Even though the hypothesis may seem attractive and may make sense,  it is not accepted until sufficient experimental evidence supports it.  Indeed, it may be proven wrong. Experimental findings that go against  the hypothesis are just as important as those that support it.   The process of drug development illustrates the use of the scien-  tific method in anatomy and physiology. Consider a hypothesis to test  a new cancer treatment:    If a drug blocks the receptor proteins to which a growth factor  binds on cancer cells, then the cells may stop dividing and halt  progression of the cancer.    This hypothesis is based on past experiments that identified the  specific receptors and growth factors that fuel a particular type of  cancer and described how they interact, and observations that the  cells of certain cancers have excess growth factor receptors com-  pared to healthy cells. Using that knowledge and the hypothesis,  researchers design an experiment (clinical trial), which is a test that  yields information:    One group of patients receives the experimental treatment  (new drug) and a second group (the control) receives an  existing treatment.    Experiments are carefully planned to make the results as mean-  ingful as possible. In drug development, the control group provides a  point of comparison for the new treatment, because the participants    are selected to be as alike as possible. In this way, differences due  to the drug can stand out. Studies should also be “double blinded”  whenever possible, which means that neither participants nor  researchers know which patients receive which treatment until the  end of the study. Outcomes are specific. At the end of six months,  if significantly more of the patients taking the experimental drug  show measurable signs of improvement compared to the control  group, then further study is warranted. Repeating scientific findings  is essential to confirming experimental results. Before a new drug  is prescribed for patients, it is tested on thousands of individuals in  multiple clinical trials.   The scientific method is not a linear process, but a cycle, because  results and conclusions often suggest new questions to explore.  Something about the new cancer drug, for example, may suggest how it  could be “repurposed” to treat a different condition. Testing begins anew.   In scientific investigations, so-called “negative” results are just  as important as results that support the hypothesis. If the drug being  tested doesn’t work, researchers can either modify the hypothesis  (perhaps the drug only works on certain subtypes of the disease) or  develop more effective versions of the drug. Medical journals provide  diverse examples of how the scientific method lies behind the drugs  and procedures that have vastly improved the lives of many of us.    Length 1 kilometer (km) 1,000 (107) m 1 km = 0.62 mile 1 mile = 1.61 km  1 meter (m) 100 (107) cm 1 m=1.1 yards 1 yard = 0.9m  1,000 (107) mm = 3.3 feet 1 foot = 0.3 m  = 39.4 inches  1 decimeter (dm) 0.1 107) m 1 dm = 3.94 inches 1 inch = 0.25 dm    1 centimeter (cm) 0.01 (107) m 1 cm = 0.4 inches 1 foot = 30.5 cm  1 inch = 2.54 cm  1 millimeter (mm) 0.001 (10-3) m 1 mm = 0.04 inches  0.1 (107) cm  1 micrometer (um) 0.000001 (10-°) m  0.001 (10°) mm    1 kilogram (kg) 1,000 (10%) g 1 kg = 2.2 pounds 1 pound = 0.45 kg    Volume (liquids 1 liter (L) 1,000 (10°) mL 1 L= 1.06 quarts 1 gallon = 3.78 L  and gases) 1 quart = 0.95 L    1 milliliter (mL) 0.001 (10-3) L 1 mL = 0.03 fluid ounce 1 quart = 946 mL  1 cubic centimeter 1 mL = 1/5 teaspoon 1 fluid ounce = 29.6 mL  (cc or cm*) 1 mL = 15-16 drops 1 teaspoon = 5 mL    Men: 14-18 g/100 mL  Women: 12-16 g/100 mL  Children: 11.2-16.5 g/100 mL  (varies with age)    Values increase in multiple myeloma and decrease with proteinuria and as a result of  severe burns.    Ratio of albumin to globulin is lowered in kidney diseases and malnutrition.  Values increase in severe liver disease, pneumonia, shock, and congestive heart failure.    Values increase in acute pancreatitis, intestinal obstructions, and mumps. They  decrease in chronic pancreatitis, cirrhosis of the liver, and toxemia of pregnancy.    Values increase in conditions causing red blood cell destruction or biliary obstruction.    Values increase in various kidney disorders and decrease in liver failure and during  pregnancy.    Values increase in hyperparathyroidism, hypervitaminosis D, and respiratory conditions  that cause a rise in CO, concentration. They decrease in hypoparathyroidism,  malnutrition, and severe diarrhea.    Values increase in respiratory diseases, intestinal obstruction, and vomiting. They  decrease in acidosis, nephritis, and diarrhea.    Values increase in nephritis, Cushing syndrome, dehydration, and hyperventilation. They  decrease in metabolic acidosis, Addison disease, diarrhea, and following severe burns.    Values increase in diabetes mellitus and hypothyroidism. They decrease in pernicious  anemia, hyperthyroidism, and acute infections.    Values increase in liver disease. Decreased values are associated with an increased risk  of atherosclerosis.    Values increase in muscular dystrophy, nephritis, severe damage to muscle tissue, and  during pregnancy.    Values correlate with total body iron store. They decrease with iron deficiency.    Values increase in diabetes mellitus, liver diseases, nephritis, hyperthyroidism, and  pregnancy. They decrease in hyperinsulinism, hypothyroidism, and Addison disease.    Values increase in polycythemia due to dehydration or shock. They decrease in anemia  and following severe hemorrhage.    Values increase in polycythemia, obstructive pulmonary diseases, congestive heart  failure, and at high altitudes. They decrease in anemia, pregnancy, and as a result of  severe hemorrhage or excessive fluid intake.    Values increase in various anemias and liver disease. They decrease in iron-deficiency anemia.    *These values may vary with hospital, physician, and type of equipment used to make measurements.    0.6-1.8 mEq/L  70-200 U/L  450-850 mg/100 mL  1.3-2.1 mEq/L  26-32 pg/RBC  86-98 pp mm?/RBC  275-295 mOsm/kg  Arterial: 96-100%  Venous: 60-85%    Values increase in iron-deficiency anemia and pregnancy. They decrease in  pernicious anemia, liver disease, and chronic infections.    Values increase with muscular activity and in congestive heart failure, severe  hemorrhage, and shock.    Values increase in pernicious anemia, myocardial infarction, liver disease, acute  leukemia, and widespread carcinoma.    Values increase in hypothyroidism, diabetes mellitus, and nephritis. They decrease  in hyperthyroidism.    Values increase in renal failure, hypothyroidism, and Addison disease. They  decrease in renal disease, liver disease, and pancreatitis.    Values increase in liver disease and pernicious anemia. They decrease in iron-  deficiency anemia.    Values increase in dehydration, hypercalcemia, and diabetes mellitus. They  decrease in hyponatremia, Addison disease, and water intoxication.    Values increase in polycythemia and decrease in anemia and obstructive pulmonary  diseases.    Values increase in respiratory diseases, intestinal obstruction, and vomiting. They  decrease in acidosis, nephritis, and diarrhea.    Values increase due to mild vomiting, Cushing syndrome, and hyperventilation.  They decrease as a result of hypoventilation, severe diarrhea, Addison disease, and  diabetic acidosis.    Values increase in polycythemia. They decrease in anemia and obstructive  pulmonary diseases.    Values increase in cancer of the prostate gland, hyperparathyroidism, certain liver  diseases, myocardial infarction, and pulmonary embolism.    Values increase in hyperparathyroidism (and in other conditions that promote  resorption of bone), liver diseases, and pregnancy.    Values increase in kidney diseases, hypoparathyroidism, acromegaly, and  hypervitaminosis D. They decrease in hyperparathyroidism.    Values increase in polycythemia and certain anemias. They decrease in acute  leukemia and aplastic anemia.    Values increase in Addison disease, hypoventilation, and conditions that cause  severe cellular destruction. They decrease in diarrhea, vomiting, diabetic acidosis,  and chronic kidney disease.    Values increase in severe dehydration and shock. They decrease in severe  malnutrition and hemorrhage.    Values increase in certain hemorrhagic diseases, liver disease, vitamin K deficiency,  and following the use of various drugs.    Values increase as a result of severe dehydration or diarrhea, and decrease in  anemia, leukemia, and following severe hemorrhage.    Values increase in infectious diseases, menstruation, pregnancy, and as a result of  severe tissue damage.    *These values may vary with hospital, physician, and type of equipment used to make measurements.    Values increase in nephritis and severe dehydration. They decrease in Addison  disease, myxedema, kidney disease, and diarrhea.    Values increase in deficiencies of blood factors VIII, IX, and X.    Values increase in hypothyroidism and decrease in hyperthyroidism.  Values increase in hyperthyroidism and pregnancy. They decrease in hypothyroidism.  Values increase in myocardial infarction, liver disease, and diseases of skeletal muscles.    Values increase in liver disease, nephrotic syndrome, hypothyroidism, and  pancreatitis. They decrease in malnutrition and hyperthyroidism.    Values increase in gout, leukemia, pneumonia, toxemia of pregnancy, and as a result  of severe tissue damage.    Neutrophils increase in bacterial diseases; lymphocytes and monocytes increase  in viral diseases; eosinophils increase in collagen diseases, allergies, and in the  presence of intestinal parasites.    Values increase in acute infections, acute leukemia, and following menstruation.  They decrease in aplastic anemia and as a result of drug toxicity.    *These values may vary with hospital, physician, and type of equipment used to make measurements.    Values increase in infections, and decrease in muscular atrophy, anemia, leukemia,  and kidney diseases.    Values increase in renal diseases.  Values increase in diabetes mellitus and various pituitary gland disorders.    Blood may occur in urine as a result of extensive burns, crushing injuries, hemolytic  anemia, or blood transfusion reactions.    Values increase in hepatic cirrhosis, congestive heart failure, and Addison disease.  They decrease in hypokalemia, hypercalcemia, and diabetes insipidus.    Values increase in urinary tract infections and chronic renal failure. They decrease in  diabetes mellitus, emphysema, and starvation.    Values increase in diabetes mellitus, nephrosis, and dehydration. They decrease in  diabetes insipidus, glomerulonephritis, and severe renal injury.    Values increase as a result of excessive protein breakdown. They decrease as a result  of impaired renal function.    Values increase in liver diseases and hemolytic anemia. They decrease in complete  biliary obstruction and severe diarrhea.    *These values may vary with hospital, physician, and type of equipment used to make measurements.    The 1-18 group designation has been recommended by the International Union of Pure and Applied Chemistry (IUPAC) but is not yet in wide use.    Elements up to 122 have been reported. Of these, some of the higher-numbered elements have only been observed under laboratory  conditions, and have not been confirmed.   Figure E.1 illustrates the chemical reactions of glycolysis. In the  early steps of this metabolic pathway, the original glucose molecule  is altered by the addition of phosphate groups (phosphorylation)  and by the rearrangement of its atoms. ATP supplies the phos-  phate groups and the energy to drive these reactions. The result is  a molecule of fructose bound to two phosphate groups (fructose-  1,6-bisphosphate). This molecule is split through two separate reac-  tions into two 3-carbon molecules (glyceraldehyde-3-phosphate).  Since each of these is converted to pyruvic acid, the following reac-  tions, | through 5, must be counted twice to account for breakdown  of a single glucose molecule.    1. An inorganic phosphate group is added to glyceraldehyde-  3-phosphate to form 1,3-bisphosphoglyceric acid, releasing two  hydrogen atoms, to be used in ATP synthesis, described later.    2. 1,3-bisphosphoglyceric acid is changed to 3-phosphoglyceric  acid. As this occurs, some energy in the form of a high-energy  phosphate is transferred from the 1,3-bisphosphoglyceric acid  to an ADP molecule, phosphorylating the ADP to ATP.    4. A change in 2-phosphoglyceric acid converts it into  phosphoenolpyruvic acid.    5. Finally, a high-energy phosphate is transferred from the  phosphoenolpyruvic acid to an ADP molecule, phosphorylating  it to ATP. A molecule of pyruvic acid remains.    Overall, one molecule of glucose is ultimately broken down to  two molecules of pyruvic acid. Also, a total of four hydrogen atoms  are released (step | above), and four ATP molecules form (two in  step 2 and two in step 5, above). However, because two molecules of  ATP are used early in glycolysis, there is a net gain of only two ATP  molecules during this phase of cellular respiration.   In the presence of oxygen, each pyruvic acid molecule is oxi-  dized to an acetyl group, which then combines with a molecule of  coenzyme A (obtained from the vitamin pantothenic acid) to form  acetyl coenzyme A. As this occurs, two more hydrogen atoms and  one carbon dioxide molecule are released for each molecule of  acetyl coenzyme A formed. The acetyl coenzyme A is then broken  down by means of the citric acid cycle, which figure E.2 illustrates.   Because obtaining energy for cellular metabolism is vital, disrup-  tions in glycolysis or the reactions that follow it can devastate health.    An acetyl coenzyme A molecule enters the citric acid cycle by com-  bining with a molecule of oxaloacetic acid to form citric acid. As  citric acid is produced, coenzyme A is released and thus can be used    again to form acetyl coenzyme A from pyruvic acid. The citric acid is  then changed by a series of reactions back into oxaloacetic acid, and  the cycle may repeat.   Steps in the citric acid cycle release carbon dioxide and hydro-  gen atoms. More specifically, for each glucose molecule metabolized  in the presence of oxygen, each of the two molecules of acetyl coen-  zyme A enters a citric acid cycle. The two cycles release a total of four  carbon dioxide molecules and sixteen hydrogen atoms. At the same  time, two more molecules of ATP form.   The released carbon dioxide dissolves in the cytoplasm and  leaves the cell, eventually entering the bloodstream. Most of the  hydrogen atoms released from the citric acid cycle, and those released  during glycolysis and during the formation of acetyl coenzyme A,  supply electrons used to produce ATP.    Note that in figures E.1 and E.2 various metabolic reactions release  hydrogen atoms. The electrons of these hydrogen atoms contain  much of the energy associated with the chemical bonds of the origi-  nal glucose molecule. To keep this energy in a usable form, these  hydrogen atoms, with their high energy electrons, are passed in pairs  to hydrogen carriers. One of these carriers is NAD* (nicotinamide  adenine dinucleotide). When NAD* accepts a pair of hydrogen  atoms, the two electrons and one hydrogen nucleus bind to NAD* to  form NADH, and the remaining hydrogen nucleus (a hydrogen ion)  is released as follows:    NAD* is a coenzyme obtained from a vitamin (niacin), and  when it combines with the energized electrons it is said to be  reduced. Reduction results from the addition of electrons, often as  part of hydrogen atoms. Another electron acceptor, FAD (flavine  adenine dinucleotide), acts in a similar manner, combining with  two electrons and two hydrogen nuclei to form FADH, (fig. E.2).  In their reduced states, the hydrogen carriers NADH and FADH,  now hold most of the energy once held in the bonds of the original  glucose molecule.   Figure 4.13 (p. 131) shows that NADH can release the elec-  trons and hydrogen nucleus. Since this reaction removes electrons,  the resulting NAD* is said to be oxidized. Oxidation results from  the removal of electrons, often as part of hydrogen atoms; it is the  opposite of reduction. The two electrons this reaction releases pass  to a series of electron carriers. The regenerated NAD* can once again  accept electrons, and is recycled.   The molecules that act as electron carriers comprise an elec-  tron transport chain, described in chapter 4 (pp. 129-131). As  electrons are passed from one carrier to another, the carriers are  alternately reduced and oxidized as they accept or release electrons.  The transported electrons gradually lose energy as they proceed  down the chain.    FIGURE E.1 Chemical reactions of glycolysis. There is a net production of 2 ATP molecules from each glucose molecule. The four hydrogen  atoms released provide high-energy electrons that may be used to generate ATP in the electron transport chain, described later.    Among the members of the electron transport chain are several  proteins, including a set of iron-containing molecules called cyto-  chromes. The chain is located in the inner membranes of the mito-  chondria (fig. E.3; also see chapter 3, p. 92). The folds of the inner  mitochondrial membrane provide surface area on which the energy  reactions take place. In a muscle cell, the inner mitochondrial mem-  brane, if stretched out, may be as much as forty-five times as long as  the cell membrane!   Note in figure E.3, that as electrons pass through the electron  transport chain, hydrogen ions are forced into the space between the    inner and outer mitochondrial membranes. This sets up a concentra-  tion gradient for the hydrogen ions to diffuse back into the mitochon-  drial matrix via the enzyme complex ATP synthase. Much of their  energy is used by the synthase to synthesize ATP.   The final cytochrome of the electron transport chain (cytochrome  oxidase) gives up a pair of electrons and causes two hydrogen ions  (formed at the beginning of the sequence) to combine with an atom of  oxygen. This process produces a water molecule:    FIGURE E.2 Chemical reactions of the citric acid cycle. NADH and FADH, molecules carrying hydrogens are highlighted.    Thus, oxygen is the final electron acceptor. In the absence of  oxygen, electrons cannot pass through the electron transport chain,  NAD* cannot be regenerated, and aerobic respiration halts.   As electrons pass through the electron transport chain, energy  is released. Some of this energy is used by a mechanism involving  the ATP synthase to combine phosphate and ADP by a high-energy  bond (phosphorylation), forming ATP.   Note in figures E.1 and E.2 that twelve pairs of hydrogen atoms  are released during the complete breakdown of one glucose molecule—  two pairs from glycolysis, two pairs from the conversion of pyruvic  acid to acetyl coenzyme A (one pair from each of two pyruvic acid    molecules), and eight pairs from the citric acid cycle (four pairs for  each of two acetyl coenzyme A molecules).   High-energy electrons from ten pairs of these hydrogen atoms  produce thirty ATP molecules in the electron transport chain. Two  pairs enter the chain differently and form four ATP molecules.  Because this process of forming ATP involves both the oxidation of  hydrogen atoms and the bonding of phosphate to ADP, it is called oxi-  dative phosphorylation. Also, there is a net gain of two ATP molecules  during glycolysis, and two ATP molecules form by direct enzyme  action in two turns of the citric acid cycle. Thus, a maximum of thirty-  eight ATP molecules form for each glucose molecule metabolized.    FIGURE E.3 High-energy electrons moving down the electron transport chain force hydrogen ions into the space between the mitochondrial  membranes. This sets up a gradient for hydrogen ions to diffuse back into the matrix by way of ATP synthase, which converts much of their  energy into ATP.    FIGURE F.1 The nucleotides of a double-stranded DNA molecule pair so that an adenine (A) of one strand hydrogen bonds to a thymine (T) of  the other strand, and a guanine (G) of one strand hydrogen bonds to a cytosine (C) of the other. The dotted lines represent hydrogen bonds.    Figure 1.7: The heat would come on until the  temperature reached the new set point.   Figure 1.21: The hand is more lateral than the hip  (remember that anatomical position is the reference).    Figure 2.8: The number of protons equals the number  of electrons.   Figure 2.10: The solution at pH 6.4 has 100 times the  hydrogen ion concentration of a solution at pH 8.4.    Figure 3.3: Nucleus (nuclear envelope) mitochondria,  lysosomes, vesicles, endoplasmic reticulum, cell  membrane, golgi apparatus    Figure 4.10: Glycolysis occurs in the cytosol and  cellular respiration occurs in the mitochondria.  Figure 4.24: They are all informational molecules,  but differ in their structures.    Figure 9.8: Diffusion  Figure 9.10: The length does not change, only the  degree to which they overlap.    Figure 11.15: In the gray matter and in the dorsal root  ganglion   Figure 11.23: In both directions—sensory impulses  travel toward the CNS and motor impulses travel away  from the CNS.    Figure 13.2: They are equally specific because only  cells with receptors, either for the neurotransmitter or  the hormone, will respond.   Figure 13.36: As blood glucose drops several hours  after a meal, insulin levels will decrease in response,  but glucagon levels will rise in response.   Figure 15.28: Plasma proteins including the albumins  Figure 15.46: Radial and ulnar arteries    Figure 17.2: 19.7 inches (based on the measurements  in the figure)   Figure 17.47: The major secretion of the large  intestinal wall is mucus to lubricate and protect against  the abrasiveness of material moving through the   tube, to bind fecal matter and control pH of the large  intestinal contents. Other cells in the small intestinal  wall secrete digestive enzymes and hormones, in  addition to those cells secreting mucus.    Figure 18.8: BMI will vary from individual to  individual. Suggestions for adjusting diet to achieve/  maintain healthy weight include: lower than healthy  weight-increase calorie intake, especially proteins;    healthy weight-continue with your current diet unless  your activity level changes; overweight-decrease your  calorie intake and increase your activity level; obese-  see your physician for advice on diet (lowering calorie  intake, particularly carbohydrates and lipids) and  exercise (you may have medical conditions that limit  your physical activity or require you to slowly build up  your activity level).   Figure 18.12: Bone deformities result from insufficient  calcium deposition in the bones. Vitamin D is important  for the absorption of calcium in the small intestine.    Figure 19.14: Pulmonary arterioles carry oxygen-poor  blood from the heart to the lungs.  Figure 19.27: The pen would move upward.    Figure 20.15: Vasoconstriction of the afferent arteriole  Figure 20.19: Tubular reabsorption   Figure 21.12: Because of the bicarbonate-buffer  reaction (CO, + H,O o H,CO, o HCO, +H*),  CO, and hydrogen ions are in balance with each  other. Exhaling more CO, will lower the hydrogen  ion concentration in the plasma (raising the pH)  and exhaling less CO, will raise the hydrogen   ion concentration (lowering the pH). Respiratory  adjustments help to keep the pH of the internal  environment in the range 7.35—7.45.    Figure 22.8: It is important for the sperm and egg to  each possess 23 chromosomes, so that upon fertilization  of the egg by the sperm, the developing zygote will have  the full complement of 46 chromosomes (no more, no  less) found in human body cells.   Figure 23.21: Umbilical vein, ductus venosus,  foramen ovale, ductus arteriosus, umbilical arteries    Figure 24.3: The male karyotype would have one  X chromosome and one Y chromosome.  Figure 24.4: Zero chance of having the disease    Each word in this glossary is followed by a pho-  netic guide to pronunciation. In this guide, any  unmarked vowel that ends a syllable or stands  alone as a syllable has the long sound. Thus, play  would be spelled pla. Any unmarked vowel that  is followed by a consonant has the short sound.  Tough, for instance, is spelled tuf: If a long vowel  appears in the middle of a syllable (followed by  a consonant), it is marked with the macron ,  the sign for a long vowel. Thus, the word plate  would be phonetically spelled plat. Similarly, if a  vowel stands alone or ends a syllable, but has the  short sound, it is marked with a breve .    abdominal (ab-dom’i-nal) Pertaining to  the portion of the body between the  diaphragm and the pelvis.   abdominal cavity (ab-dom’i-nal kav’i-te)  Space between the diaphragm and the  pelvic inlet that contains the abdominal  viscera.   acetylcholine (as”é-til-ko’lén) Type of  neurotransmitter, which is a biochemical  secreted into the synaptic clefts at the  axon ends of neurons; ACh.    actin (ak’tin) Protein in a muscle fiber  that forms the thin filaments that  slide between filaments of the protein  myosin, shortening the muscle fibers.   active transport (ak’tiv trans’port) Process  that requires energy and a carrier  molecule to move a substance across a  cell membrane against the concentration  gradient.   adenylate cyclase (ah-den’i-lat  si‘klas) Enzyme activated when  certain hormones bind receptors  on cell membranes. It catalyzes the  circularization of ATP to cyclic AMP.   afterload (af’ter-l6d) The force required to  open the semilunar valves to eject blood  from the ventricles; determined largely  by arterial pressure.   agglutination (ah-gloo’ti-na’shun) Clumping  of blood cells in response to a reaction  between an antibody and an antigen.   albumin (al-bu’min) Plasma protein that  contributes to the colloid osmotic  pressure of plasma.   aldosterone (al-dos’ter-6n) Adrenal cortical  hormone that regulates sodium and  potassium ion concentrations and fluid  volume.   allantois (ah-lan’to-is) Structure in the  embryo from which the umbilical cord  blood vessels develop.   allele (ah-lél) One of two or more different  forms of a gene.   all-or-none response (al’or-nun’ re-spons’)  A response that occurs completely or  not at all, such as a neuron generating  an action potential in response to a  stimulus of threshold strength.   alveolar duct (al-ve’o-lar dukt) Fine tube that  conducts air to and from an alveolar sac of  the lungs.   alveolar pore (al-ve’o-lar por) Small opening  in the walls between alveoli that permits  air to pass from one alveolus to another.    alveolar process (al-ve’o-lar pros’es)  Projection on the border of the jaw that  holds the bony sockets of the teeth.   alveolar sac (al-ve’o-lar sak) A space at the  center of a cluster of alveoli.   alveolus (al-ve’o-lus) Any of the 300  million microscopic air sacs of the lungs  (pl., alveoli).   amine (am’in) Type of nitrogen-containing  organic compound, including hormones  from the adrenal medulla.   amino acid (ah-me’no as’id) Organic  compound that includes an amino group  (—NH,) and a carboxyl group (-COOH);  the structural unit of a protein molecule.   amniocentesis (am”ne-o-sen-te’ sis)  Removal of a sample of amniotic  fluid through the abdominal wall of a  pregnant woman. Fetal cells in it are  cultured and checked for chromosome  complement.   amnion (am’ne-on) Extraembryonic  membrane that encircles a fetus and  amniotic fluid.   ampulla (am-pul’ah) Expansion at the end  of each semicircular canal that houses a  crista ampullaris.   anal canal (a’nal kah-nal’) The most distal  two or three inches of the large intestine  that open to the outside at the anus.   anaphase (an’ah-faz) Stage in mitosis  when sister chromatids separate and  move as chromosomes to opposite  poles of the cell.   anatomy (ah-nat’o-me) Branch of science  dealing with the form and organization  of body parts.   aneuploid (an’u-ploid) Cell with one or  more extra or missing chromosomes.   anion (an’i-on) Atom or molecule carrying  a net negative charge due to one or more  extra electrons.   antibody (an’ti-bod”e) Protein that B cells of  the immune system produce in response  to anonself antigen that then reacts with  the antigen; immunoglobulin.   antigen-presenting cell (an’ti-jen-pre-sen’ting  cel) The cell that displays an antigen  to the cells of the immune system so  they can defend the body against that  particular antigen.   antithrombin (an’ti-throm’bin) Plasma  protein that inhibits the action of  thrombin, and thus inhibits blood clotting.   aorta (a-or’tah) Systemic artery that  receives blood directly from the left  ventricle.   aortic valve (a-or’tik valv) Flaplike  structures in the wall of the aorta near  its origin that prevent aortic blood from  returning to the left ventricle of the heart.   aponeurosis (ap”o-nu-ro’sis) Sheet of  connective tissue that attaches muscles  to bone and other muscles.   arachnoid granulation (ah-rak’noid gran”u-  la’shun) Any of several fingerlike  structures that projects from the  subarachnoid space of the meninges into  blood-filled dural sinuses and reabsorbs  cerebrospinal fluid.   areola (ah-re’o-lah) Pigmented region  surrounding the nipple of the mammary  gland or breast.   arteriole (ar-te’re-61) Small branch of  an artery that communicates with a  capillary network.   arteriosclerosis (ar-te”re-o-sklé-ro’ sis)  Condition in which the walls of  arteries thicken and lose their elasticity,  hardening of the arteries.   articular cartilage (ar-tik’u-lar kar’ti-lij)  Hyaline cartilage that covers the ends of  bones in synovial joints.   ascending colon (ah-send’ing ko’lon)  Portion of the large intestine that  passes upward on the right side of the  abdomen from the cecum to the lower  edge of the liver.   ascending tract (ah-send’ing trakt) Group  of axons in the spinal cord that conducts  sensory impulses upward to the brain.   astigmatism (ah-stig’mah-tizm) Visual  defect due to errors in refraction caused  by abnormal, assymetric curvatures in  the surface of the cornea or lens.   astrocyte (as’tro-sit) Type of neuroglia  that connects neurons to blood vessels  in the CNS.   atom (at’om) Smallest particle of an  element that has the properties of that  element.   atomic weight (ah-tom’ik wat) Number of  protons plus the number of neutrons in  an atom of an element.   ATPase Enzyme that transfers the energy  stored in terminal phosphate bonds of  ATP molecules.   atrioventricular bundle (a’tre-o-ven-trik’  u-lar bun’dl) Group of specialized  muscle fibers that conducts impulses  from the atrioventricular node to the  Purkinje fibers in the ventricular muscle  of the heart, AV bundle, bundle of His.   atrioventricular node (a”tre-o-ven-trik’u-  lar nod) Specialized mass of cardiac  muscle fibers in the interatrial septum of  the heart that conducts cardiac impulses  from the sinoatrial node to the AV  bundle; AV node.   atrioventricular orifice (a’tre-o-ven-trik’u-  lar or’i-fis) Opening between the  atrium and the ventricle on each side of  the heart.   atrioventricular sulcus (a”tre-o-ven-trik’u-lar  sul’kus) Groove on the surface of the  heart that marks the division between an  atrium and a ventricle.   atrioventricular valve (a”tre-o-ven-trik’u-lar  valv) Cardiac valve between an atrium  and a ventricle.   atrium (a’tre-um) Either of the two upper  chambers of the heart (pl., atria).   auricle (aw’ri-kl) Flaplike structure on the  anterior wall of the atrium.   autoregulation (aw”to-reg”u-la’shun)  Ability of an organ or tissue to  maintain a local process despite  changing local conditions, as in  autoregulation of glomerular filtration  rate in the kidney.   axial skeleton (ak’se-al skel’é-ton) The  part of the skeleton that supports and  protects the organs of the head, neck,  and trunk.    ball-and-socket joint (bawl-and-sok’et joint)  A bone with a spherical head on one end  joined with a bone that has a cup-shaped  cavity; spheroidal joint.   base (bas) Substance that ionizes in water,  releasing hydroxide ions (OH_) or other  ions that combine with hydrogen ions.   beta oxidation (ba’tah ok” si-da’shun)  Chemical process that breaks fatty acids  down to form acetyl coenzyme A, which  can enter the citric acid cycle.   bicarbonate buffer system (bi-kar’bo-nat  buf’er sis‘tem) System in which  carbonic acid acts as a weak acid and  bicarbonate ion acts as a weak base that  weakens a strong base and a strong acid,  respectively; resists a change in pH.   bile (bil) Fluid secreted by the liver and  stored in the gallbladder.   bile duct (bil dukt) Tube that transports  bile from the cystic duct and common  hepatic duct to the duodenum.   biotin (bi’o-tin) A water-soluble vitamin;  member of the vitamin B complex.   blastocyst (blas’to-sist) Early stage of  prenatal development when the embryo is  a hollow ball of cells.   blood (blud) A connective tissue,  consisting of cells in a liquid matrix  called plasma, that circulates through  the heart and vessels carrying  substances throughout the body.   B lymphocyte (B lim’fo-sit) Lymphocyte  that produces and secretes antibodies  that bind and destroy nonself molecules;  B cell.   A measure of relative weight  (underweight, normal weight,  overweight, obesity) calculated as  weight in kilograms divided by the  square of height in meters; BMI.   bone (bon) Any of the 206 individual  parts of the skeleton composed of cells  and inorganic, mineral matrix; also a  connective tissue and a type of cell.   brainstem (bran’stem) Portion of the brain  that includes the midbrain, pons, and  medulla oblongata.   Broca’s area (bro’kahz a’re-ah) Region  of the frontal lobe that coordinates  complex muscular actions of the mouth,  tongue, and larynx, making speech  possible.   bronchial tree (brong’ke-al tré) The  bronchi and their branches that carry air  between the trachea and the alveoli of  the lungs.   bronchus (brong’kus) Branch of the  trachea that leads to a lung (pl.,  bronchi).   buccal (buk’al) Pertaining to the mouth and  inner lining of the cheeks.   buffer (buf’er) Substance that can react  with a strong acid or base to form a  weaker acid or base, and thus resist a  change in pH.   bulbourethral gland (bul”bo-u-re’thral  gland) Gland that secretes a viscous  fluid into the male urethra during sexual  excitement; Cowper’s gland.   bursa (bur’sah) Saclike, fluid-filled  cushioning structure, lined with synovial  membrane, near a joint (pl., bursae).   calorimeter (kal’o-rim’é-ter) Device that  measures the heat energy content of  foods, bomb calorimeter.   canaliculus (kan’ah-lik’u-lus) Microscopic  canal that connects lacunae of bone  tissue (pl., canaliculi).   capacitation (kah-pas”i-ta’shun) Activation  of a sperm cell to fertilize an egg cell.   capillary (kap’i-ler”€) Small blood vessel  that connects an arteriole and a venule  and allows diffusional exchange of  nutrients and wastes.   carbohydrate (kar”bo-hi’drat) Organic  compound consisting of carbon,  hydrogen, and oxygen, in a 1:2:1 ratio.   carbonic anhydrase (kar-bon’ik an-hi’dras)  Enzyme that catalyzes the reaction  between carbon dioxide and water to  form carbonic acid.   cardiac output (kar’de-ak owt’poot) The  volume of blood per minute that the  heart pumps (stroke volume in milliliters  multiplied by the heart rate in beats per  minute).   cardiac vein (kar’de-ak van) Any of the  blood vessels that returns blood from  the venules of the myocardium to the  coronary sinus.   carina (kah-ri’nah) Cartilaginous ridge  between the openings of the right and  left bronchi.   carotene (kar’o-tén) Yellow, orange,  or reddish pigment in plants and a  precursor of vitamin A.   carotid bodies (kah-rot’id bod’éz) Masses  of chemoreceptors in the wall of the  carotid artery near the carotid sinus.   carpal (kar’pal) Pertaining to the wrist or  any of the individual wrist bones.   cartilage (kar’ti-lij) Type of connective tissue  in which cells are in lacunae separated by  a semisolid extracellular matrix.   catalyst (kat’ah-list) Chemical that increases  the rate of a chemical reaction, but is not  permanently altered by the reaction.   cation (kat’i-on) Atom or molecule  carrying a net positive charge due to a  deficiency of electrons.   cecum (se’kum) Pouchlike part of the large  intestine attached to the small intestine.   cell body (sel bod’e) Part of a nerve cell  that includes a cytoplasmic mass and  a nucleus, and from which processes  extend.   cell cycle (sel si-kl) Life cycle of a  cell consisting of G, (growth), S  (DNA synthesis), G, (growth), mitosis  (nuclear division), and cytokinesis  (cytoplasmic division).   cementum (se-men’tum) Bonelike material  that surrounds the root of a tooth.   central canal (sen’tral kah-nal’) Tiny  channel in bone tissue that contains a  blood vessel; Haversian canal. Also  a tube in the spinal cord continuous  with brain ventricles that contains  cerebrospinal fluid.   centromere (sen’tro-mér) Region of a  chromosome where spindle fibers attach  during mitosis; region where chromatids  are attached.   cerebrospinal fluid (ser”é-bro-spi’nal  floo’id) Fluid in the ventricles of the  brain, the subarachnoid space of the  meninges, and the central canal of the  spinal cord; CSF.   cerebrum (ser’é-brum) Part of the brain in  the upper part of the cranial cavity that  provides higher mental functions.   chemical buffer system (kem-i-kal buf’er  sis’‘tem) Pair of chemicals, one a weak  acid, the other a weak base, that resists  pH changes.   chief cell (chéf sel) Cell type in a gastric  gland that secretes digestive enzymes.   chloride shift (klo’rid shift) Movement of  chloride ions from the blood plasma  into red blood cells as bicarbonate ions  diffuse out of the red blood cells into the  plasma.   cholecystokinin (ko”le-sis”to-ki’nin)  Hormone the small intestine secretes  that stimulates release of pancreatic  juice from the pancreas and bile from  the gallbladder.   cholesterol (ko-les’ter-ol) A lipid produced  in the body and acquired from food that  cells use to synthesize steroid hormones.   chordae tendineae (kor’de ten’di-ne)  Fibrous strings attached to the cusps of  the tricuspid and mitral valves in the  heart.   chorion (ko’re-on) Extraembryonic  membrane that forms the outermost  covering around a fetus and contributes  to formation of the placenta.    chorionic villus (ko”re-on‘ik vil’us)  Projection that extends from the outer  surface of the chorion and helps attach  an embryo to the uterine wall.   chyme (kim) Semifiuid mass of partially  digested food that passes from the  stomach to the small intestine.   ciliary body (sil’e-er”e bod’e) Structure  associated with the choroid layer of the  eye that secretes aqueous humor and  contains the ciliary muscle.   circular muscles (ser’ku-lar mus’1z)  Muscles whose fibers are organized  in circular patterns, typically around  an opening or in the wall of a tube;  sphincter muscles.   circumduction (ser”kum-duk’ shun)  Movement of a body part, such as a  limb, so that the end follows a circular  path.   cisterna (sis-ter’nah) Enlarged portion of  the sarcoplasmic reticulum near the  actin and myosin filaments of a muscle  fiber.   cleavage (klév’ij) Early successive  divisions of the zygote into a ball of  progressively smaller cells.   clitoris (kli’to-ris) Small erectile organ  in the anterior vulva of the female,  corresponding to the penis in the male.    clone (kl6n) Group of cells that descend  from a single cell and are therefore  genetically identical to it.   codon (ko’don) Set of three contiguous  nucleotides of a messenger RNA  molecule that specifies a particular  amino acid.   coenzyme (ko-en’zim) Small, nonprotein  organic molecule required for the  activity of a particular enzyme.   coenzyme A (ko-en’zim) A molecule that  reacts with a 2-carbon acetyl group,  forming acetyl coenzyme A, which  enters the citric acid cycle.   collagen (kol’ah-jen) Protein in the white  fibers of connective tissues and in bone  matrix.   collecting duct (ko-lek’ting dukt) In the  lymphatic system, ducts into which  lymphatic trunks drain; in the kidney,  tubule that receives fluid from several  nephrons.   compact bone (kom’pakt bin) Dense bone  tissue in which cells are organized in  osteons without apparent spaces.   complementary base pair (kom”plé-men’ ta-  re bas par) Hydrogen bonded adenine  and thymine (A-T) or guanine and  cytosine (G—C) in DNA. Adenine bonds  to uracil (A-U) in RNA.   complete protein (kom-plét pro’tén)  Protein that contains adequate amounts  of the essential amino acids to maintain  body tissues and to promote normal  growth and development.   condom (kon’dum) Latex sheath used  to cover the penis or line the vagina,  preventing sperm from entering the  uterus during sexual intercourse. Also  used to minimize the risk of transmitting  infection.   conduction (kon-duk’shun) Movement of  body heat into the molecules of cooler  objects in contact with the body surface.   cone (kon) Photoreceptor in the retina of  the eye that can detect color.   conformation (kon-for-ma’shun) Three-  dimensional structure of a protein,  determined by its amino acid sequence  and attractions and repulsions between  amino acids in different parts of the  molecule.   conjunctiva (kon”junk-ti’vah) Mucous  membrane covering the inside of the  eyelid and much of the anterior surface  of the eye.   connective tissue (k6-nek’tiv tish’u) Basic  tissue type that consists of cells within  an extracellular matrix, including  bone, cartilage, blood, loose and dense  connective tissues.   contractility (kon trak-til’i-te) A measure  of the force generated by contraction of  the heart muscle with a given volume of  blood in the ventricles.   convection (kon-vek’shun) Transmission of  heat from one substance to another through  the circulation of heated air particles.   convergence (kon-ver’jens) Two or more  neurons forming synapses with the  same neuron.   cornea (kor’ne-ah) Transparent anterior  portion of the outer layer of the eye wall.   corona radiata (ko-ro’nah ra-di-a’ta)  Follicular cells surrounding the zona  pellucida of an ovum.   corpus luteum (kor’pus lu’te-um)  that forms from the tissues of a  ruptured ovarian follicle and secretes  progesterone and estrogens.   cortex (kor’teks) Outer portion of an organ  such as the adrenal gland, cerebrum, or  kidney.   cortical nephron (kor’ti-kl nef’ron)  Nephron with a corpuscle in the renal  cortex near the surface.   cranial (kra’ne-al) Pertaining to the  cranium. The part of the skull that does  not include the face.   cranial nerve (kra’ne-al nerv) Any of  the nerves that arise from the brain or  brainstem.   cranium (kra’ne-um) Structure that  encloses and protects the brain, formed  by eight of the skull bones; brain case.   crista ampullaris (kris’tah am-pul-lah’ris)  Sensory organ in a semicircular canal  that functions in the sense of dynamic  equilibrium.   cystic duct (sis’tik dukt) Tube that connects  the gallbladder to the bile duct.    cytokine (si’to-kin) Type of polypeptide  secreted by a T lymphocyte that  enhances cellular responses to antigens.  cytokinesis (si-to-kin-e’sis) Division of the  cytoplasm during the cell cycle.  cytoplasm (si’to-plazm) The contents of  a cell including the gel-like cytosol  and organelles, excluding the nucleus,  enclosed by the cell membrane.  cytoskeleton (si’to-skel”e-ton) System  of protein tubules and filaments that  reinforces a cell’s three-dimensional  form and provides scaffolding and  transport pathways for organelles.  cytosol (si’to-sol) Fluid portion of the  cytoplasm.   dental caries (den’tal kar’éz) Destruction  of the enamel and dentin of teeth; tooth  decay.   deoxyribonucleic acid (dé-ok’si-ri”bd-nu-  klé”ik as’id) The genetic material; a  double-stranded polymer of nucleotides,  each containing a phosphate group, a  nitrogenous base (adenine, thymine,  guanine, or cytosine), and the sugar  deoxyribose; DNA.   depolarization (de-po”lar-i-za’shun) The  membrane of a neuron becoming less  negative (more positive) than the resting  potential.   dermatome (der’mah-tom) Area of the  body supplied by sensory nerve fibers  associated with a particular dorsal root  of a spinal nerve.    descending colon (de-send’ing ko’lon)  Part of the large intestine that passes  downward along the left side of the  abdominal cavity to the brim of the  pelvis.   descending tract (de-send’ing trakt) Group  of axons that conducts impulses  downward from the brain through the  spinal cord to motor neurons controlling  muscles and glands.   detrusor muscle (de-triz’or mus’l) Muscular  layer of the wall of the urinary bladder.   diabetes mellitus (di”ah-be’téz mel-li’tus)  Elevated glucose in the urine and blood  due to a deficiency of insulin or a poor  response to it.   diaphragm (di’ah-fram) A sheetlike  structure largely composed of skeletal  muscle and connective tissue that  separates the thoracic and abdominal  cavities; also a contraceptive device  inserted in the vagina.   diastole (di-as’to-le) Phase of the cardiac  cycle when a heart chamber wall relaxes.   diencephalon (di”’en-sef’ah-lon) Part of  the brain in the region of the third  ventricle that includes the thalamus and  hypothalamus.   diffusion (di-fu’zhun) Random movement  of molecules from a region of higher  concentration toward one of lower  concentration.   digestion (di-jest’yun) Breaking down  of large nutrient molecules into  molecules small enough to be absorbed;  hydrolysis.   dihydrotestosterone (di-hi’dro-tes-tos’ter-6n)  Hormone produced from testosterone  that stimulates certain cells of the male  reproductive system.   diploid (diploid) Body cell with a full,  paired, set of chromosomes (half from  each parent); in humans 46 chromosomes  (2 x 23).   DNA repair Reactions that enable a cell to  correct certain types of mutations that  occur during replication.   dorsal root (dor’sal root) Structure  containing axons of sensory neurons  that emerges from the spinal cord to  form part of each spinal nerve.   dorsum (dor’sum) Pertaining to the back  surface of the body or a body part.   ductus deferens (duk’tus def’er-ens) Tube  that leads from the epididymis to the  urethra of the male reproductive tract  (pl., ductus deferentia); vas deferens.   ductus venosus (duk’tus ven-o’sus) Blood  vessel that connects the umbilical vein  and the inferior vena cava in a fetus.   duodenum (du”o-de’num) _ First portion of  the small intestine that leads from the  stomach to the jejunum.    eccentric contraction (ek-sen’trik kon-  trak’shun) A lengthening contraction,  in which the force in a muscle is less  than an opposing force.   ejaculatory duct (e-jak’u-lah-to”re dukt)  Tube, formed by the joining of the  ductus deferens and the tube from the  seminal vesicle, that carries sperm to the  urethra.   elastic fiber (e-las’tik fiber) Stretchy,  yellow connective tissue fiber consisting  of the protein elastin.   electrocardiogram (e-lek”tro-kar’de-o-  gram”) Recording of the electrical  activity associated with the cardiac  cycle; ECG or EKG.   electron (e-lek’tron) A small, negatively  charged particle that encircles the  nucleus of an atom.   electron shell (e-lek’tron shel) The space  occupied by an electron or several  electrons encircling the nucleus of an  atom at a particular energy level.   electron transport chain (e-lek’tron  trans’pohrt) Series of oxidation-  reduction reactions that takes high-  energy electrons from glycolysis and the  citric acid cycle to form water and ATP.   embolus (em’bo-lus) Blood clot, gas  bubble, or other object carried in  circulation that may obstruct a blood  vessel.   embryo (em’bre-o) A prenatal stage of  development from fertilization through  the eighth week of development, when  the rudiments of all organs are present.   emission (e-mish’un) Movement of sperm  cells and prostate and seminal vesicle  secretions into the urethra.   emulsification (e-mul’si-fi’ka’shun)  Breaking up of fat globules into smaller  droplets by the action of bile salts.   enamel (e-nam’el) Hard covering on the  exposed surface of a tooth.    end-diastolic volume (end-di-a-stol’ik  vol’tm) Blood volume remaining in  the ventricles at the end of ventricular  diastole.   endocrine gland (en’do-krin gland) Gland  that secretes hormones directly into the  blood; hormone secreting gland.   endolymph (en’do-limf) Fluid in the  membranous labyrinth of the inner ear.   endomysium (en”do-mis’e-um) Layer of  connective tissue surrounding each  skeletal muscle fiber.   endoneurium (en”do-nu’re-um) Layer of  loose connective tissue that surrounds  individual nerve fibers.   endoplasmic reticulum (en-do-plaz’mic  ré-tik’u-lum) Organelle composed of  a network of connected membranous  tubules and vesicles.   endosteum (en-dos’té-um) _ Tissue lining the  medullary cavity in a bone.   end-systolic volume (end-sis-tol’ik vol’tm)  Blood volume remaining in the ventricles  at the end of ventricular systole.   enkephalin (en-kef’ah-lin) Any group of  neuropeptides in the brain and spinal  cord that inhibits pain impulses.    epicardium (ep”i-kar’de-um) Visceral part  of the pericardium on the surface of the  heart.   epididymis (ep”i-did’i-mis) Highly coiled  tubule that leads from the seminiferous  tubules of the testis to the ductus  deferens (pl., epididymides).    i-du’ral spas) Space  between the dural sheath of the spinal  cord and the bone of the vertebral canal.   epiglottis (ep”i-glot’is) Flaplike,  cartilaginous structure attached at the  back of the tongue near the entrance to  the trachea.   epiphyseal plates (ep”i-fiz’e-al platz)  Cartilaginous layers between the  epiphyses and diaphysis of a long bone  that grow, lengthening the bone.   erythroblastosis fetalis (€-rith”ro-blas-to’sis  fe-tal’is) Life-threatening massive  agglutination in the fetus or neonate  due to the mother’s anti-Rh antibodies  reacting with the baby’s Rh-positive red  blood cells.   estrogens (es‘tro-jenz) Group of hormones  (including estradiol, estrone, and estriol)  that stimulates the development of female  secondary sex characteristics and produces  an environment suitable for fertilization,  implantation, and growth of an embryo.   eversion (e-ver’zhun) Turning the plantar  surface of the foot outward, away from  midline.   exocrine gland (ek’so-krin gland) Gland  that secretes its products into a duct or  onto an outside body surface.    facilitated diffusion (fah-sil’i-tat’id di-  fu’zhun) Diffusion in which a protein  channel or a carrier molecule transports  a substance across a cell membrane  from a region of higher concentration to  a region of lower concentration.    facilitation (fah-sil”i-ta’shun) Subthreshold  stimulation of a neuron that increases  the likelihood that it will reach threshold  with further stimulation.   fascia (fash’e-ah) Sheet of dense connective  tissue that encloses a muscle.   fat (fat) An organic molecule that includes  glycerol and fatty acids; adipose tissue.   fever (fe’ver) Elevation of body  temperature due to an elevated set point.   fibrin (fi’brin) Insoluble, fibrous protein  formed from fibrinogen during blood  coagulation.   fibrocartilage (fi”bro-kar’ti-lij) Strongest  and most durable cartilage; made up of  cartilage cells and many collagen fibers.   fimbria (fim’bre-ah) Fringelike process at  the distal end of the infundibulum of a  uterine tube.   flagellum (flah-jel’um) Relatively long,  motile process that extends from the  surface of a sperm cell.   follicle-stimulating hormone (fol’i-kl stim’u-  la’ting hor’m6n) Hormone secreted by  the anterior pituitary gland to stimulate  development of an ovarian follicle in a  female or production of sperm cells in a  male; FSH.   foramen magnum (fo-ra’men mag’num)  Larger opening in the occipital bone of  the skull through which the spinal cord  passes.   foramen ovale (fo-ra’men o-val’e) Opening  in the interatrial septum of the fetal  heart.   forebrain (for’bran) Anteriormost part of  the developing brain; gives rise to the  cerebrum and basal nuclei.   fovea centralis (fo’ve-ah sen-tral’is)  Depressed region of the retina,  consisting of densely packed cones, that  provides the greatest visual acuity.   Frank-Starling law of the heart (frank  star’ling law of thé hart) The relatively  longer the cardiac muscle fibers are  stretched by filling, the greater the force  of contraction.   ganglion (gang’gle-on) Mass of neuron  cell bodies located outside the central  nervous system (pl., ganglia).   gastric juice (gas’trik joo-s) Secretion  of the gastric glands in the stomach  containing mucus, digestive enzymes,  and hydrochloric acid.    gastrula (gas’troo-lah) Embryonic stage  after the blastula; cells differentiate and  aggregate into endoderm, mesoderm,  and ectoderm.   gene (jén) Part of a DNA molecule that  encodes the information to synthesize a  protein; the unit of inheritance.   genetic code (jé-net’ik k6d) Information for  synthesizing proteins, encoded in the  nucleotide sequence of DNA molecules.   genomics (je-nom’iks) Study of all of the  genetic information in an individual  organism.   glans penis (glanz pe’nis) Enlarged mass  of corpus spongiosum at the end of the  penis; may be covered by the foreskin.   glomerulus (glo-mer’u-lus) Capillary tuft  partially enclosed by the glomerular  capsule of a nephron.   glottis (glot’is) The true vocal cords and the  slitlike opening between them.   glucocorticoid (gloo”ko-kor’ti-koid) Any of  several hormones that the adrenal cortex  secretes that affects carbohydrate, fat,  and protein metabolism.   glucose (gloo’kos) Monosaccharide in  blood that is the primary source of  cellular energy.   glycolysis (gli-kol’i-sis) The energy-  releasing breakdown of glucose to  produce 2 pyruvic acid molecules and a  net of 2 ATP.   gomphosis (gom-fo’sis) Type of joint in  which a cone-shaped process is fastened  in a bony socket.   G protein (g pro’tén) Organic compound  which activates an enzyme bound to  the inner surface of the cell membrane,  eliciting a signal.   gray matter (gra mat’er) Regions of the  central nervous system that contain cell  bodies and unmyelinated axons, and  thus appears gray.   growth hormone (groth hor’mdn) Hormone  released by the anterior lobe of the  pituitary gland that promotes growth of  the organism; GH.   gubernaculum (goo”ber’nak’u-lum) A cord  that connects two structures; guides the  descent of the testes during development  in the male.    hair cell (har sel) Mechanoreceptor in the  inner ear that triggers action potentials in  fibers of the auditory nerve in response to  sound vibrations.   hematocrit (he-mat’o-krit) The percentage by  volume of red blood cells in a sample of  whole blood; packed cell volume (PCV).   hematopoiesis (hem”ah-to-poi-e’sis)  Production of blood cells from dividing  stem and progenitor cells; hemopoiesis.   hemizygous (hem”i-zi’gus) The genotype  of having only one copy of a particular  gene, such as certain genes on the X  chromosome in males.   hilum (hi/lum) Depression where vessels,  nerves, and other structures (bronchus,  ureter, etc.) enter an organ.   hindbrain (hind’bran) Posteriormost part of  the developing brain that gives rise to the  cerebellum, pons, and medulla oblongata.   hinge joint (hinj joint) Two bones joined  where the convex end of one bone fits  into the complementary concave end  of another.   homeostatic mechanism (ho”me-o-stat’ik  mek’ah-nizm) Any of the control  systems that help maintain a normal  internal environment in the body.   hormone (hor’moén) Substance secreted by  an endocrine gland and transported in the  blood, which has actions on its target cells.   hydrogen bond (hi’ dro-jen bond) Weak  bond between a hydrogen atom and an  atom of oxygen or nitrogen.   hypertonic (hi’per-ton’ik) Solution with  a greater osmotic pressure than the  solution (usually body fluids) to which it  is compared.    hypothalamus (hi’po-thal’ah-mus) Part of  the brain located below the thalamus and  forming the floor of the third ventricle.   hypotonic (hi’po-ton’ik) Solution with a  lower osmotic pressure than the solution  (usually body fluids) to which it is  compared.   ileum (il’e-um) Part of the small intestine  between the jejunum and the cecum.   immunosuppressive drugs (im”u-no-  si-pres’iv drugz) Substances that  suppress the immune response against  transplanted tissue.   infancy (in’fan-se) Period of life from the  fifth week after birth through the end of  the first year.   inferior (in-fér’e-or) Situated below  something else; pertaining to the lower  surface of a part.   inflammation (in’flah-ma’shun) Tissue  response to stress that includes pain,  warmth, redness, and swelling.    infundibulum (in”’fun-dib’u-lum) Stalk  attaching the pituitary gland to the base  of the brain; also, the funnel-shaped end  of a uterine tube.   inguinal canal (ing’gwi-nal kah-nal’) Passage  in the lower abdominal wall through  which a testis descends into the scrotum.   inhibin (in’hib’in) Hormone secreted  by cells of the testes and ovaries that  inhibits the secretion of FSH from the  anterior pituitary gland.   insulin (in’su-lin) Hormone the pancreatic  islets secrete that stimulates cells to take  up glucose.   interphase (in’ter-faz) Period between cell  divisions when a cell metabolizes and  prepares to divide.   intestinal gland (in-tes’ti-nal gland)  Tubular gland at the base of a villus in  the intestinal wall.   intrauterine device (in’trah-u’ter-in de-vis)  Object placed in the uterine cavity to  prevent implantation of a fertilized  ovum; IUD.   ionic bond (i-on’ik bond) Chemical bond  that results between two ions formed by  transfer of electrons; electrovalent bond.   iris (iris) Colored, muscular part of the eye  around the pupil that regulates its size.   isotonic (i”so-ton’ik) Solution with the  same Osmotic pressure as the solution  (usually body fluids) to which it is  compared.   isotope (i’so-top) Atom that has the same  number of protons in its nucleus as other  atoms of that element but has a different  number of neutrons.    jejunum (jé-joo’num) _ Part of the small  intestine between the duodenum and  the ileum.   joint capsule (joint kap’sul) An envelope,  attached to the end of each bone at  the joint, enclosing the cavity of a  synovial joint.    juxtaglomerular apparatus (juks”tah-glo-  mer’u-lar ap”ah-ra’tus) A structure in  the nephron including cells in the wall  of the afferent arteriole Guxtaglomerular  cells) and cells in the ascending limb of  the nephron loop (macula densa) that  helps control renin secretion.    karyotype (kar’é-o-tip) A chart of the  chromosomes arranged in size-  ordered homologous pairs. The human  karyotype has 23 chromosome pairs.   ketone body (ke’t6n bod’e) Compound  produced during fat catabolism,  including acetone, acetoacetic acid, and  betahydroxybutyric acid.   kwashiorkor (kwash”e-or’kor) Starvation  caused by switching from breast milk to  food low in protein.   labyrinth (lab’i-rinth) System of  connecting tubes in the inner ear,  including the cochlea, vestibule, and  semicircular canals.   lactase (lak’tas) Enzyme that catalyzes  breakdown of lactose into glucose and  galactose.   lacteal (lak’te-al) Lymphatic capillary  associated with a villus of the small  intestine.   lamella (lah-mel’ah) Layer of matrix  surrounding the central canal of an osteon.   lamellated corpuscle (lah-mel’a-ted kor’pusl)  Sensory receptor deep in the dermis  providing perception of pressure;  Pacinian corpuscle.   large intestine (lahrj in-tes’tin) Part of the  gastrointestinal tract from the ileum to  the anus, divided into the cecum, colon,  rectum, and anal canal.    laryngopharynx (lah-ring” go-far’ingks)  Lower part of the pharynx, posterior to  the larynx, that leads to the esophagus.   latent period (la’tent pe’re-od) Time between  the application of a stimulus and the  beginning of a response in a muscle fiber.   leptin (lep’tin) Hormone, produced by  fat cells, that binds receptors in the  hypothalamus, suppressing hunger.   lever (lev’er) Simple mechanical device  consisting of a rod, fulcrum, weight, and  a force that is applied to some point on  the rod.   linea alba (lin’e-ah al’bah) Narrow band  of tendinous connective tissue in the  midline of the anterior abdominal wall.   lingual frenulum (ling’gwal fren’ u-lum)  Fold of tissue that anchors the tongue to  the floor of the mouth.   lipid (lip’id) Group of organic compounds  that includes fats (triglycerides),  phospholipids, and steroids.   liver (liv’er) Large, dark red organ in the  upper right quadrant of the abdomen that  detoxifies blood, stores glycogen and fat-  soluble vitamins and synthesizes proteins,  including clotting factors and enzymes.   long-term synaptic potentiation (long-term  si-nap’tik po-ten’she-a-shun) Theory  that frequent, repeated stimulation of  the same neurons in the hippocampus  strengthens their synaptic connections.   lower esophageal sphincter (loh’er &-sof”ah-  je’al sfingk’ter) Ring of smooth muscle,  at the distal end of the esophagus where  it joins the stomach, that prevents food  from re-entering the esophagus when the  stomach contracts; cardiac sphincter.   luteinizing hormone (lu’te-in-iz”ing hor’mon)  A hormone that the anterior pituitary  gland secretes that controls formation  of the corpus luteum in females and  stimulates sex hormone secretion in  both sexes.   lymph (limf) Fluid, derived from  interstitial fluid, that the lymphatic  vessels carry.   lymph node (limf nod) Mass of lymphoid  tissue located along the course of a  lymphatic vessel.    macromolecule (mak’ro-mol’é-kil) Very  large molecule, such as a protein, starch,  or nucleic acid.   macronutrient (mak’ro-nu’tre-ent) Nutrient  (carbohydrate, lipid, and protein)  required in a large amount.   major mineral (ma’jor min”er-al) Inorganic  substance necessary for metabolism  that is part of a group that accounts  for 75% of the mineral elements in the  body; macromineral.   mast cell (mast sel) Cell to which antibodies  formed in reponse to allergens attach,  causing the cell to release allergy  mediators which cause symptoms.   mechanoreceptor (mek”ah-no-re-sep’tor)  Sensory receptor sensitive to mechanical  stimulation, such as changes in pressure  or tension.   meiosis (mi-o’sis) Cell division that halves  the chromosome number, producing egg  and sperm cells (gametes).   membrane potential (mem’bran po-ten’shal)  Stored electrical energy across a cell  membrane due to the unequal distribution  of ions on the two sides of the membrane.   memory cell (mem’o-re sel) B lympho-  cyte or T lymphocyte produced in a  primary immune response that can be  activated rapidly if the same antigen is  encountered again.   memory consolidation (mem’o-re kon-sol’i-  da’shun) Conversion of short-term  memories to long-term memories.   meninx (me’-ninks) Any of the three layers  of membrane that covers the brain and  spinal cord (pl., meninges).   meniscus (men-is’kus) Fibrocartilage that  separates the articulating surfaces of  bones in the knee (pl., menisci).    menses (men’séz) Shedding of blood and  tissue from the uterine lining at the end  of a female reproductive cycle.   mesentery (mes’en-ter”e) Fold of peritoneal  membrane that attaches abdominal  organs to the posterior abdominal wall.   messenger RNA (mes’in-jer RNA) RNA that  carries information for a protein’s amino  acid sequence from the nucleus of a cell  to the cytoplasm; mRNA.   metaphase (met’ah-faz) Stage in mitosis  when chromosomes align in the middle  of the cell   microglia (mi-krog’le-a) Neuroglia of  the CNS that support neurons and  phagocytize bacteria and cellular debris.   midbrain (mid’bran) Small region of the  brainstem between the diencephalon and  the pons.    mitral valve (mi’tral valv) Heart valve  between the left atrium and the left  ventricle; bicuspid valve.   mixed nerve (mikst nerv) Nerve that  includes both sensory and motor nerve  fibers.   monocyte (mon’o-sit) Type of white blood  cell that can leave the bloodstream and  become a macrophage.   motor end plate (mo’tor end plat)  Specialized part of a muscle fiber  membrane at a neuromuscular junction.   motor nerve (mo’tor nerv) Nerve that  consists of axons of motor neurons.   motor neuron (mo’tor nu’ron) Neuron  that conducts impulses from the central  nervous system to an effector.   myosin (mi’o-sin) Protein that, with actin,  forms the filaments that interact to  contract muscle fibers.    nail (nal) Protective plate at the distal end  of a finger or toe.   nasal concha (na’zal kong’kah) Any of the  six shelflike bones or bony processes that  extend from the wall of the nasal cavity;  a turbinate bone.   nasal septum (na’zal sep’tum) Wall of bone  and cartilage that separates the nasal  cavity into two parts.   nephron (nef’ron) Any of the one million  functional units of a kidney, consisting  of a renal corpuscle and a renal tubule.   neurofibril (nu’ro-fi’bril) Fine cytoplasmic  thread that extends from the cell body  into the axon of a neuron.    neuroglia (nu-ro’gle-ah) Specialized cells of  the nervous system that produce myelin,  maintain the ionic environment, provide  growth factors that support neurons,  provide structural support, and play a role  in cell-to-cell communication.   neuromuscular junction (nu”ro-mus’ku-lar  jungk’shun) Synapse between a motor  neuron and a skeletal muscle fiber;  myoneural junction.   neuronal pool (nu’ro-nal pool) A group of  nerve cells in the central nervous system  that synapse with each other.   neuropeptide (nu”ro-pep’tid) Peptide  in the brain that functions as a  neurotransmitter or neuromodulator.   neurosecretory cell (nu”ro-se-kre’to-re sel)  Cell in the hypothalamus that conducts  impulses like a neuron but secretes into  the bloodstream.   neurotransmitter (nu”ro-trans-mit’er)  Chemical that an axon secretes, into  a synapse, that stimulates or inhibits  an effector (muscle or gland) or other  neuron.   node of Ranvier (nod of Ron’vee-ay)  Any of the many gaps in the myelin  sheath along axons of neurons of the  peripheral nervous system.   norepinephrine (nor’ep-i-nef rin)  Neurotransmitter released from the axons  of some nerve fibers; a hormone from the  adrenal medulla; noradrenaline.   normal range (nor’mal ranj) Range of  values for a particular measurement  obtained from a sample of the healthy  population.   nuclear envelope (nu’kle-ar en’vé-lop)  Double bilayer membrane surrounding  the cell nucleus and separating it from  the cytoplasm.   nucleolus (nu-kle’o-lus) Small structure in  the cell nucleus that contains RNA and  proteins and is the site of ribosome  production (pl., nucleoli).   nucleotide (nu’kle-o-tid”) Building block  of a nucleic acid molecule, consisting  of a sugar, nitrogenous base, and  phosphate group.   nucleus (nu’kle-us) The dense core of an  atom that is composed of protons and  neutrons; cellular structure enclosed by  a double bilayer nuclear envelope and  containing DNA; masses of interneuron  cell bodies in the CNS (pl., nuclei).   nutrition (nu-trish’un) Study of the sources,  actions, and interactions of nutrients.    obesity (0-bés’i-te) Excess adipose tissue;  a body mass index greater than 30.   occipital (ok-sip’i-tal) Pertaining to the  lower, back portion of the head.   oncogene (ong’ko-jén) Gene that normally  controls cell division but when  overexpressed leads to cancer.   optic chiasma (op’tik ki-az’mah) X-shaped  structure on the underside of the brain  formed by optic nerve fibers that cross  over.   optic disc (op’tik disk) Region in the retina  of the eye where sensory fibers exit,  becoming part of the optic nerve.   organ (organ) Structure consisting of  two or more tissues with a specialized  function.   orgasm (or’gaz-em) An intense sensation that  is the culmination of sexual stimulation.   origin (or’i-jin) End of a muscle that  attaches to a relatively immovable part.   osmoreceptor (0z”mo-re-sep’tor) Receptor  that senses changes in the osmotic  pressure of body fluids.   osmosis (0z-mo’sis) Movement of water  through a selectively permeable  membrane toward a greater  concentration of impermeant solute.   osteon (os’te-on) Cylinder-shaped unit  containing bone cells and matrix  lamellae that surround a central canal;  Haversian system.   osteoporosis (os”te-o-po-ro’sis) Condition in  which bones break easily because bone  matrix is lost faster than it is replaced.   otolith (o’to-lith) A small particle of  calcium carbonate associated with the  receptors of static equilibrium.   oxygen debt (ok’si-jen det) Amount of  oxygen muscle cells require after  physical exercise to restore levels of  glucose, ATP, and creatine phosphate.    pacemaker (pas’mak-er) Mass of  specialized cardiac muscle tissue that  controls the rhythm of the heartbeat; the  sinoatrial node.   pancreas (pan’kre-as) Glandular organ  in the abdominal cavity that secretes  hormones and digestive enzymes.   papillary muscles (pap’i-ler”e mus’elz)  Muscles that extend inward from the  ventricular walls of the heart and to  which the chordae tendineae attach.   paradoxical sleep (par”ah-dok’se-kal slép)  Sleep in which some areas of the brain  are active, producing dreams and rapid  eye movements.   paranasal sinus (par’ah-na’zal si-nus)  Air-filled cavity in a cranial or facial  bone, lined with mucous membrane  and connected to the nasal cavity.   parasympathetic division (par”ah-sim” pah-  thet’ik di-vizh’un) Part of the  autonomic nervous system that arises  from the brain and sacral region of the  spinal cord.   parathyroid gland (par’ah-thi’roid gland)  One of four small endocrine glands  embedded in the posterior part of the  thyroid gland.   parathyroid hormone (par’ah-thi’roid  hor’mdn) Hormone secreted by  the parathyroid glands that helps  regulate the level of blood calcium and  phosphate ions; PTH.   parietal cell (pah-ri’é-tal sel) Cell of a  gastric gland that secretes hydrochloric  acid and intrinsic factor.   parotid glands (pah-rot’id glandz) Large  salivary glands deep to the sides of the  face just in front and below the ears.   pedigree (ped’i-gre) Chart that displays  relationships among family members  and their inherited traits and disorders.   peptide bond (pep’tid bond) Bond between  the carboxyl group of one amino acid  and the amino group of another.   perforin (per’fo-rin) Protein that natural  killer cells release that forms pores in  the cell membrane of infected cell.   perichondrium (per’i-kon’dre-um) Layer  of dense connective tissue that encloses  cartilaginous structures.   perilymph (per-i-limf) Fluid in the space  between the membranous and osseous  labyrinths of the inner ear.   perimysium (per”’i-mis’e-um) Sheath of  connective tissue that encloses a bundle  of skeletal muscle fibers or a fascicle.   perineal (per’i-ne’al) Pertaining to the  perineum, the diamond-shaped area  extending from the coccyx to the pubic  symphysis.    perineurium (per’i-nu-re-um) Layer of  connective tissue that encloses a bundle  of nerve fibers in a nerve.   periodontal ligament (per”e-o-don’tal lig’ah-  ment) Dense connective tissue that  surrounds a tooth and attaches it to the  jawbone.   periosteum (per”e-os’te-um) Dense  connective tissue covering the surface  of a bone.   peripheral protein (pé-rif’er-al pro’tén)  Globular protein associated with the  outer surface of the cell membrane.   peripheral resistance (pé-rif’er-al re-zis’tans)  Resistance to blood flow due to friction  between blood and blood vessel walls.   peritoneum (per”i-to-ne’um) Serous  membrane that lines the abdominal cavity  and encloses the abdominal viscera.   peroxisome (pé-roks’i-som) _Membranous  cytoplasmic vesicle that contains enzymes  that catalyze reactions that produce and  decompose hydrogen peroxide.   pharynx (far’ingks) Portion of the digestive  tube posterior to the nasal and oral  cavities, as well as the larynx.   phenotype (fe’no-tip) A trait or health  condition caused by the expression of a  gene or genes.   phosphate buffer system (fos’fat buf’er  sis‘tem) A mixture in which sodium  monohydrogen phosphate acts as a  weak base and sodium dihydrogen  phosphate acts as a weak acid; resists  changes in pH.   phospholipid (fos”fo-lip’id) Molecule  consisting of two fatty acids and a  phosphate group bound to a glycerol  molecule.   PH scale (pH skal) Shorthand notation for  the hydrogen ion concentration used to  indicate the acidic or alkaline condition  of a solution; values range from 0 to 14.   pia mater (pi’ah ma’ter) Inner layer of  meninges that encloses the brain and  spinal cord.   pineal gland (pin’e-al gland) Small  structure in the central part of the brain  that secretes the hormone melatonin,    pinocytosis (pin’o-si-to’sis) Process by  which a cell engulfs droplets of fluid  from its surroundings.   pituitary gland (pi-tu’i-tar”e gland)  Endocrine gland attached to the base of  the brain that consists of anterior and  posterior lobes; the hypophysis.   pivot joint (piv’ut joint) End of a bone  moving within a ring formed by another  bone and connective tissue.   placenta (plah-sen’tah) Structure that  attaches the fetus to the uterine wall,  delivering nutrients to and removing  wastes from the fetus.   plasmin (plaz’min) Protein-splitting enzyme  that can digest fibrin in a blood clot.   pluripotent (ploo-rip’o-tent) Cell able to  differentiate to yield several specialized  cell types.   polarization (po”lar-i-za’shun) Electrical  charge difference across a cell membrane  surface due to an unequal distribution of  positive and negative ions on either side.   polygenic (pol”é-jén’ik) An inherited trait  that results from the actions of more  than one gene.   pons (ponz) Part of the brainstem above  the medulla oblongata and below the  midbrain.   postsynaptic potential (post”si-nap’tik  po-ten’shal) Membrane polarization  is decreased (excitatory) or increased  (inhibitory) in the postsynaptic neuron  with repeated stimulation over an  excitatory or inhibitory pathway so that  the neuron will either fire or not respond.   pregnancy (preg’nan-se) Condition in  which a female has a developing  offspring in her uterus.   preload (pre’l6d) The volume of blood  filling the relaxed ventricles prior to  their contraction.   primary germ layers (pri’ma-re jerm  la’erz) Three layers of cells in the  embryo that divide and differentiate into  specific tissues and organs; endoderm,  mesoderm, and ectoderm.   progenitor cell (pro-jen’i-tor sel) Daughter  cell of a stem cell whose own daughter  cells are restricted to follow specific  lineages.   progesterone (pro-jes’té-ron) Female  hormone secreted by the corpus luteum  of the ovary and by the placenta.   projection (pro-jek’shun) Process by which  the brain causes a sensation to seem to  come from the region of the body being  stimulated.   prolactin (pro-lak’tin) Hormone secreted  by the anterior pituitary gland that  stimulates the production of milk in the  mammary glands; PRL.   prophase (pro’faz) Stage of mitosis when  chromosomes become distinguishable  when stained and viewed under a  microscope.   prostate gland (pros’tat gland) Gland  surrounding the male urethra below the  urinary bladder that secretes fluid into  semen prior to ejaculation.   puberty (pu’ber-te) Stage of development  in which the reproductive organs  become functional.   pulmonary valve (pul’mo-ner’e valv)  Valve leading from the right ventricle  to the pulmonary trunk; pulmonary  semilunar valve.   pulse (puls) Surge of blood pressure felt  through the walls of arteries due to the  contraction of the heart ventricles.   pupil (pu’pil) Opening in the iris through  which light enters the eye.   purine (pu rén) Type of nitrogen-  containing base that is part of DNA and  RNA and has two organic rings; adenine  and guanine.   pyloric sphincter (pi-lor’ik sfingk’ter) Ring  of smooth muscle in the stomach wall  where it joins the duodenum; controls  food entry into the duodenum.   pyrimidine (pe-ri’mi-dén) Type of  nitrogen-containing base that is part of  DNA and RNA and has two organic  rings; thymine, cytosine, and uracil.    radiation (ra”de-a’shun) Form of energy  that includes visible light, ultraviolet  light, and X rays; the means by which  body heat is lost as infrared rays.    rate-limiting enzyme (rat lim’i-ting en’zim)  Enzyme, usually present in small amounts,  that controls the rate of a metabolic  pathway by regulating one of its steps.   receptor (re’sep’tor) Specialized cell or  structure that provides information  about the environment; also, cell surface  molecule that binds other molecules,  called ligands, thereby conveying a  signal to inside the cell.   rectum (rek’tum) Terminal end of the  digestive tube between the sigmoid  colon and the anus.   red blood cell (red blud sel) Disc-shaped  cell, lacking a nucleus, that is packed  with the oxygen-carrying molecule  hemoglobin; erythrocyte.   referred pain (re-ferd’ pan) Pain that feels  as if it is originating from a part other  than the site being stimulated.   reflex arc (re’fleks ark) Components of a  reflex, consisting of a sensory receptor,  sensory neuron, interneuron (usually),  motor neuron, and effector.   relaxin (re-lak’sin) Hormone from the  corpus luteum that causes relaxation of  the joints of the pelvic girdle.   renal corpuscle (re’nal kor’pusl) Part of  a nephron that consists of a glomerulus  and a glomerular capsule (Bowman’s   renal tubule (re’nal tu’bul) = Tubular part of  a nephron that extends from the renal  corpuscle to the collecting duct.   renin (re’nin) Enzyme that kidneys release  that helps maintain blood pressure,  plasma sodium, and blood volume.   renin-angiotensin system (re’nin-an’’je-o-  ten’sin sis’tem) A series of reactions  involving an enzyme, renin, that  ultimately forms angiotension II, a  vasoconstrictor and stimulator of  aldosterone and antidiuretic hormone  secretion.   repair enzyme (re-par’ en’zim) Protein that  removes mismatched nucleotides from a  section of DNA and replaces them with  complementary nucleotides.   residual volume (re-zid’u-al vol’tm)  Volume of air remaining in the lungs  after the most complete expiration.  resorption (re-sorp’shun) Decomposition of  a structure and return of the components  to the bloodstream.    reticulocyte (ré-tik’u-lo-sit) Immature red  blood cell that has a network of fibrils in  its cytoplasm.   rhodopsin (ro-dop’sin) Light-sensitive  pigment in the rods of the retina; visual  purple.   ribonucleic acid (ri”bo-nu-kle’ik as’id)  Single stranded polymer of nucleotides,  in which each nucleotide includes a  phosphate group, a nitrogen-containing  base (adenine, uracil, cytosine, or  guanine), and the sugar ribose; RNA.   ribosomal RNA (ri-bo-som’al) Type of RNA  that forms part of the ribosome; rRNA.   ribosome (ri’bo-som) Organelle composed of  RNA and protein that provides structural  support and enzymes for protein synthesis.   rod (rod) Type of light receptor that  provides colorless (black and white)  vision.    saccule (sak’il) Saclike cavity that makes  up part of the membranous labyrinth of  the inner ear.   sacral (sa’kral) Pertaining to the five fused  (pelvic) vertebrae at the inferior end of  the spinal column.   saddle joint (sad’l joint) Two bones joined,  each with a convex and concave surface  that are complementary.   sagittal (saj’i-tal) Plane or section that divides  a structure into right and left portions.   salivary gland (sal’i-ver-e gland) Any of  the glands, associated with the mouth,  that secrete saliva.   salt (sawlt) Compound produced by a  reaction between an acid and a base.   saltatory conduction (sal’tah-tor-e kon-  duk’shun) Impulse conduction along  an axon that seems to jump from one  node to the next.   sarcoplasmic reticulum (sar”ko-plaz’mik  ré-tik’u-lum) _Membranous network  of channels and tubules in a muscle  fiber, corresponding to the endoplasmic  reticulum of other cells.   saturated fat (sat’u-rat”ed fat) Fat molecule  that contains only fatty acid molecules  with as many hydrogen atoms as  possible, and therefore no double-  bonded carbon atoms.   Schwann cell (shwahn sel) Type of  neuroglia that surrounds an axon  of a peripheral neuron, forming the  neurilemma and myelin.   secretin (se-kre’tin) Hormone from the  small intestine that stimulates the  pancreas to release pancreatic juice rich  in bicarbonate ion.   semen (se’men) Fluid containing sperm  cells and secretions discharged from the  male reproductive tract at ejaculation.   semicircular canal (sem”i-ser’ku-lar kah-  nal’) Tubular structure in the inner ear  that contains the receptors providing the  sense of dynamic equilibrium.   sensory neuron (sen’so-re nu’ron) Neuron  that conducts an impulse from a receptor  to the central nervous system.   serous cell (se’rus sel) Glandular cell  that secretes a watery lubricating fluid  (serous fluid).   set point (set point) Target value of a  physiological measure maintained  automatically in the body.   sex chromosome (seks kro’mo-sdm)  Either of two chromosomes that carries  genes responsible for the development  of characteristics associated with  maleness or femaleness; an X or  Y chromosome.   sigmoid colon (sig’moid ko’lon) S-shaped  part of the large intestine between the  descending colon and the rectum.   signal transduction (sig’nahl trans-duk’shun)  Series of biochemical reactions that  allows cells to receive and respond to  messages reaching the cell membrane.    single nucleotide polymorphism (sing’el  nu’kle-o-tid pol”e-mor’fiz-em)  A variant base at a particular place in  the genome that occurs in at least 1% of  a population.   sinoatrial node (si’no-a’tre-al nod)  Specialized tissue in the wall of the right  atrium that initiates cardiac cycles; the  pacemaker; SA node.   sliding filament model (sli’ding fil’eh-ment  ma’dul) Muscles shorten when the  thin (actin) and thick (myosin) filaments  slide past each other, pulling on the  muscle ends.   small intestine (smaw] in-tes’tin) Part of  the digestive tract extending from the  stomach to the cecum; consisting of the  duodenum, jejunum, and ileum.   sodium/potassium pump (so’de-um-  po-tas’e-um pump) Active transport  mechanism that concentrates sodium  ions outside and potassium ions inside a  cell membrane.   somatostatin (so-mat’o-sta’tin) Hormone  secreted by the pancreatic islets that  inhibits the release of glucagon and  insulin.   special sense (spesh’al sens) Sense that  stems from receptors associated with  specialized sensory organs, such as the  eyes and ears.   species resistance (spe’séz re-zis’tans) Natural  ability of one type of organism to resist  infection by pathogens that cause disease  in another type of organism.   spermatic cord (sper-mat’ik kord) Structure  consisting of blood vessels, nerves,  the ductus deferens, and other vessels  extending from the abdominal inguinal  ring to the testis.   spinal cord (spi’nal kord) Part of the  central nervous system extending from  the brainstem through the vertebral  canal.   spinal nerve (spi’nal nerv) Nerve that  arises from the spinal cord.   spiral organ (spi rul or’gan) Organ in the  cochlear duct containing the receptors  for hearing. It consists of hair cells and  supporting cells.   spleen (splén) Large organ in the upper  left quadrant of the abdomen that  processes old red blood cells.   spongy bone (spunj’e bon) Bone that  consists of bars and plates separated by  irregular spaces; cancellous bone.   stem cell (stem sel) Undifferentiated  cell that can divide to yield two  daughter stem cells or a stem cell and a  progenitor cell.   stereoscopic vision (ster”e-o-skop’ik vizh’un)  The ability, using two eyes, to perceive  objects as three-dimensional; depth  perception.   stomach (stum’ak) Digestive organ  between the esophagus and the small  intestine.   stratum basale (stra’tum ba’sal) Deepest  layer of the epidermis, where cells  divide; stratum germinativum.   stretch receptor (strech re-sep’ter) Sensory  receptor that responds to a change in  length or volume.   subarachnoid space (sub”ah-rak’noid spas)  Space in the meninges between the  arachnoid mater and the pia mater.   sulcus (sul’kus) Shallow groove, such as  that between gyri on the brain surface  (pl., sulci).   summation (sum-ma’shun) Increased force  of contraction by a skeletal muscle  fiber when a twitch occurs before the  previous twitch relaxes.   sweat gland (swet gland) Exocrine gland  in skin that secretes a mixture of water,  salt, and wastes such as urea.   sympathetic nervous system (sim”pah-thet’ik  ner’vus sis’tem) That part of the  autonomic nervous system that arises  from the thoracic and lumbar regions of  the spinal cord.   synapse (sin’aps) Functional connection  between the axon of one neuron and the  dendrite or cell body of another neuron  or the membrane of another cell type.   synaptic knob (si-nap’tik nob) Tiny  enlargement at the end of an axon that  secretes a neurotransmitter.   synovial membrane (si-no’ve-al mem’bran)  Membrane that forms the inner lining of  the capsule of a freely movable joint.   systemic circuit (sis-tem’ik ser’kit) Vessels  that transport blood between the heart  and all body tissues except the lungs.  systole (sis’to-le) Phase of the cardiac cycle  when a heart chamber wall contracts.  systolic pressure (sis-tol’ik presh’ur)  Arterial blood pressure reached during  the systolic phase of the cardiac cycle.   tactile corpuscle (tak’til kor’pus-l) Sensory  receptor close to the surface of the  skin that is sensitive to light touch;  Meissner’s corpuscle.   taste bud (tast bud) Organ containing  receptors associated with the sense of  taste.   tendon (ten’don) Cordlike or bandlike mass  of dense connective tissue that connects  a muscle to a bone.   teratogen (ter’ah-to-jen) Chemical or other  environmental agent that causes a birth  defect.   testis (tes’tis) Primary male reproductive  organ; sperm cell-producing organ (pl.,  testes).   testosterone (tes-tos’té-ron) Male sex  hormone secreted by the interstitial cells  of the testes.   thalamus (thal’ah-mus) Mass of mostly  gray matter at the base of the cerebrum,  bulging from the wall on either side of  the third ventricle.   threshold stimulus (thresh’old stim’u-lus)  Stimulation level that must be reached  to elicit an action potential in a neuron  or a muscle fiber.   thrombin (throm’bin) Blood-clotting  enzyme that catalyzes formation of  fibrin from fibrinogen.   thymosins (thi’mo-sins) Group of peptides  the thymus gland secretes that increases  production of certain types of white  blood cells.   thyroid gland (thi’roid gland) Endocrine  gland just below the larynx and in front  of the trachea that secretes thyroid  hormones.   thyroid-stimulating hormone (thi’roid-  stim”u-lat’eng hor’mdn) Hormone  secreted from the anterior pituitary  gland that controls secretion from the  thyroid gland; TSH.   tidal volume (tid’al vol’tm) Volume of  air entering and leaving the lungs in a  respiratory cycle.   T lymphocyte (T lim’fo-sit) Type of white  blood cell that interacts with antigen-  bearing cells and particles and secretes  cytokines, contributing to the cellular  immune response; T cell.   totipotent (to-tip’o-tent) Ability of a cell to  differentiate into any type of cell. Only a  fertilized ovum is totipotent.   transcytosis (trans”si-to’sis) Combination  of receptor-mediated endocytosis and  exocytosis that moves particles through  a cell layer.   transfer RNA (trans’fer RNA) RNA  molecule that carries a specific amino  acid to a ribosome in protein synthesis;  tRNA.   translation (trans-la’ shun) Assembly  of an amino acid chain according to  the sequence of base triplets in an  mRNA molecule.   transverse (trans-vers’) Plane that divides  a structure into superior and inferior  portions.   transverse colon (trans-vers’ ko’lon) Part  of the large intestine that extends across  the abdominal cavity from right to left  below the stomach.   tricuspid valve (tri-kus’pid valv) Heart  valve between the right atrium and the  right ventricle.   triglyceride (tri-glis’er-id) Lipid com-  posed of three fatty acids and a glycerol  molecule; fat.   trisomy (tri’so-me) Condition in which  a cell has three copies of a particular  chromosome instead of two.   trophoblast (trof’o-blast) Outer cells  of a blastocyst that give rise to cells  that become part of the placenta and  extraembryonic membranes.   troponin (tro’po-nin) Protein that regulates  muscle contraction by altering the  position of tropomyosin.   tubular reabsorption (too’bu-lar re”ab-  sorp’shun) Transport of substances out  of the renal tubule into the interstitial  fluid from which the substances diffuse  into peritubular capillaries.   tubular secretion (too’bu-lar se-kre’shun)  Movement of substances out of the  peritubular capillaries into the renal  tubule for excretion in the urine.   twitch (twich) Single contraction of a  muscle fiber followed by relaxation.   tympanic membrane (tim-pan’ik mem’bran)  Thin membrane that covers the auditory  canal and separates the outer ear from  the middle ear; the eardrum.    ultratrace element (ul’trah-tras el’é-ment)  Basic chemical substance needed in  very small quantity.  umbilical (um-bil’i-kal)  navel.  umbilical cord (um-bil’i-kal kord) Cordlike  structure that connects the fetus to the  placenta.  umbilical region (um-bil’i-kal re’jun)  Central portion of the abdomen.  umbilicus (um-bil’i-kus) Region to which the  umbilical cord was attached; the navel.  unipolar neuron (un”i-po’lar nu’ron)  Neuron that has a single process  associated with its cell body.  unsaturated fat (un-sat’u-rat”ed fat) Fat  molecule that includes one or more  unsaturated fatty acids, each with one  or more double bonds.  upper limb (uh’per lim) Superior  appendage consisting of the arm,  forearm, and hand.   ureter (u-re’ter) Muscular tube that carries  urine from the kidney to the urinary  bladder.   urethra (u-re’thrah) Tube leading from the  urinary bladder to the outside of the body.   urine (u’rin) Wastes and excess water  removed from the blood and excreted  by the kidneys into the ureters to the  urinary bladder and out of the body  through the urethra.   uterine tube (u’ter-in tib) Tube that  extends from the uterus on each side  toward an ovary; fallopian tube or  oviduct.   utricle (u’tri-kl) Chamber in the inner ear  associated with static equilibrium.   uvula (u’vu-lah) Fleshy portion of the soft  palate that hangs down above the root of  the tongue.    vaccine (vak’sén) Preparation that includes  antigens that stimulate an immune  response to prevent an infectious disease.   vagina (vah-ji‘nah) Tubular organ that  leads from the uterus to the vestibule of  the female reproductive tract.   varicose veins (var’i-kos vanz) Abnormally  swollen and enlarged veins, especially  in the legs.   vasa recta (va’sah rek’tah) Branch of the  peritubular capillary that parallels the  structure of the nephron loop.   vena cava (vén’ah kav’ah) One of two large  veins that conveys oxygen-poor blood to  the right atrium of the heart.   ventral root (ven’tral roo-t) Structure  containing axons of motor neurons that  emerges from the spinal cord to form part  of each spinal nerve.    ventricles (ven’tri-klz) Cavities, such as brain  ventricles filled with cerebrospinal fluid;  also heart ventricles that contain blood.   vestibule (ves’ti-bil) Bony chamber in the  inner ear; also, space into which the  vagina and urethra open in the female.   villus (vil’us) Tiny, fingerlike projection  that extends from the inner lining of the  small intestine into the lumen (pl., villi).   viscosity (vis-kos’i-te) Tendency for a  fluid to resist flowing due to the internal  friction of its molecules.   vital capacity (vi’tal kah-pas’i-te) The  maximum volume of air a person can  exhale after taking the deepest breath  possible.    needed for normal metabolism that the  body cannot synthesize in adequate  amounts and must therefore be obtained  in the diet.   vitreous body (vit’re-us bod’e) Collagen  fibers and fluid in the posterior cavity of  the eye.    water balance (wot’er bal’ans) When the  volume of water entering and produced by  the body is equal to the volume leaving it.   Wernicke’s area (ver’ni-kez air’i-ah)  Region in the temporal lobe, usually  in the left hemisphere, important in  understanding and formulating written  and spoken language.   wild type (wild tip) Phenotype or allele  that is the most common for a certain  gene in a population.    X-linked trait (eks-linkt’trat) Trait  determined by a gene on an  X chromosome.   X ray (eks ray) Used as a noun: a  photograph produced by X radiation;  radiogram. May also be used as an  adjective: X-ray image.   yolk sac (yok sak) Membranous sac  connected to the embryo that contains  stem cell precursors to many cell types.   zygote (zi’got) Cell produced by the fusion  of an egg and sperm; a fertilized egg  cell; fertilized ovum.    Page vi: Courtesy of Fran Simon; p. vi:  Courtesy of Michael’s Photography; p. vi:  Courtesy of Dr. Wendy Josephs; p. v (top):  Courtesy of Leslie Day; p. v (bottom): Courtesy  of Gary Pilcher; p. xvii (left): Courtesy of  Leslie Day; p. xvii (right): Courtesy of Gary  Pilcher; p. xix (preview): © Comstock Images/  Jupiterimages RF; p. xix (1): © Brand X  Pictures/PunchStock RF; p. xix (2): © Dr. Tim  Evans/SPL/Science Source; p. xix (3): © K.R.  Porter/Science Source; p. xix (4): © Biophoto  Associates/SPL/Science Source; p. xx (5, 6):  © Science Photo Library/Getty Images RF;   p. Xx (7): © McGraw-Hill Education/Dennis  Strete, photographer; p. xx (8): © Keith  Brofsky/Getty Images RF; p. xx (9): © CNRI/  SPL/Science Source; p. xxi (10): © Nancy  Kedersha/UCLA/SPL/Science Source; p. xxi  (11): © Secchi-Lecaque/Roussel-UCLAF/  CNRA/SPL/Science Source; p. xxi (12):   Photo Library/Getty Images RF; p. xxii (18):  © Digital Vision/Getty Images RF; p. xxii (19):  © Susumu Nishinaga/SPL/Science Source; p.  xxii (20): © Prof. P. Motta/Dept. of Anatomy/  University “La Sapienza” Rome/SPL/Science  Source; p. xxiii (21): © Prof. PM. Motta & M.  Castellucci/SPL/Science Source; p. xxiii (22):  © Brand X Pictures/Corbis RF; p. xxiii (23):  © Big Cheese Photo/Jupiterimages RF; p. xxiii  (24): © Barros & Barros/Getty Images.    Opener: © Brand X Pictures/PunchStock RF;  1.1: © Classic Image/Alamy; 1A: © Keith  Brofsky/Getty Images RF; 1B: © Jim Wehtje/  Getty Images RF; 1C: © SPL/Science Source;  1.4: © McGraw-Hill Education/Carol D.  Jacobson, Ph.D., Dept. of Veterinary Anatomy,  Iowa State University; 1.21 (left, right):    photographer; 1.22 (top left, right): © McGraw-  Hill Education/Karl Rubin; 1.22 (bottom left):  © Living Art Enterprises/Science Source;   © Southern Illinois University School of  Medicine; 2.7, 2.23a—e: Courtesy of John W.  Hole, Jr.; 2.23f: Courtesy Hyland Optical  Technologies Corp.; 2Da: © SPL/Science  Source; 2Db: © CNRI/SPL/Science Source; 2E:  © WDCN/Univ. College London/Science Source.   I. Walker/Science Source; 3.5b: © Biophoto  Associates/Science Source; 3.5c: © Susumu  Nishinaga/Science Source; 3.9a: © Don W.  Fawcett/Science Source; 3.10a: © Biophoto  Associates/Science Source; 3.12: © Bill  Longcore/Science Source; 3.13: © Dr. Gopal  Murti/Science Source; 3.14a: © Don W.  Fawcett/Science Source; 3.15a: © Oliver  Meckes/Science Source; 3.16: © Juergen  Berger/Science Source; 3.17: © Dr. Alexey  Khodjakov/Science Source; 3.18b, 3.19b:   © Dr. Gopal Murti/Science Source; 3.25a-c:  © David M. Phillips/Science Source; 3.36a-—e:  © Ed Reschke; 3.37a—c: © Steve Gschmeissner/  Science Source; 3.38: © Tony Brain/Science  Source; 3.42: © Peter Skinner/Science Source.    Opener: © Science Photo Library/Getty Images  RF; 5.2a: © McGraw-Hill Education/A] Telser,  photographer; 5.2b: © Victor P. Eroschenko;  5.3b-c: © McGraw-Hill Education/A] Telser,  photographer; 5.4b, 5.5b: © Victor P. Eroschenko;  5.6: © Fawcett, Hirokawa, Heuser/Science  Source; 5.7b: © McGraw-Hill Education/   5.14: © McGraw-Hill Education/A] Telser,  photographer; 5.15: © Juergen Berger/Science  Source; 5.16: © Biology Pics/Science Source;  5.17: © Steve Gschmeissner/Science Source;  5.18: © Prof. P. Motta/Univ. “La Sapienza’’/  Science Source; 5.19b—5.21b: © McGraw-Hill  Education/A] Telser, photographer; 5.22b:   © McGraw-Hill Education/Dennis Strete,  photographer; 5.23b—5.25b: © McGraw-Hill  Education/Al Telser, photographer; 5.26b:   © Victor P. Eroschenko; 5.27b: © McGraw-Hill  Education/Dennis Strete, photographer; 5.27c:  © Prof. P. Motta/Univ. “La Sapienza’’/Science  Source; 5.28b: © McGraw-Hill Education/  Dennis Strete, photographer; 5.29b-5.32b &  p. 176: © McGraw-Hill Education/Al Telser,  photographer.    Opener: © Science Photo Library/Getty Images  RF; 6.1—-6.3b: © McGraw-Hill Education/Al  Telser, photographer; 6.4a: © Don W. Fawcett/  Science Source; 6Aa: ©Science Photo Library/  Getty Images RF; 6Ab: © Science Photo  Library/Alamy RF; 6Ac: © McGraw-Hill  Education; 6.5: © Medical-on-Line/Alamy;  6.7b: © McGraw-Hill Education/A] Telser,  photographer; 6B: © Anthony Saint James/  Getty Images RF; 6.8: OCNRI/SPL/Science  Source; 6.9: © McGraw-Hill Education/   © McGraw-Hill Education; 6.14: © Mauro  Fermariello/Science Source; 6.16: © Ingram  Publishing RF.    Opener: © McGraw-Hill Education/Dennis  Strete, photographer; 7.3a: © Ed Reschke/  Getty Images; 7.3b-c: Courtesy of John   W. Hole, Jr.; 7.5: © Andrew Syred/Science  Source; 7.6a: © Biophoto Associates/Science  Source; 7.6b: Photo courtesy of T.D. Gelehrter  and FS. Collins; 7.7: © Secchi, Lecaque,  Roussel, Uclaf, CNRA/SPL/Science Source;  7.10b: © McGraw-Hill Education/A] Telser,  photographer; 7.11: © Biophoto Associates/  Science Source; 7.12: © Ed Reschke/Peter  Arnold/Getty Images; 7.13: Courtesy of John  W. Hole, Jr.; 7C: © Michael Klein/Getty  Images; 7.31: © Thinkstock/Jupiterimages  RF; 7.36: © Stockbyte/PunchStock RF;    7.39b: © Thinkstock/Jupiterimages RF; 7.41b,  7.43d, 7.46c: Courtesy, Dale Butler; 7.47:   © Dr. Charles Eaton/e-hand Electronic Textbook  of Hand Surgery (www.e-hand.com); 7.48b:   © Image Source/Getty Images RF; 7.5 1a,  7.54a, 7.55b: Courtesy, Dale Butler; 7.56 (left,  right): Courtesy of Pat Hesse; Plates 26-54:  Courtesy of John W. Hole, Jr.    Opener: © Keith Brofsky/Getty Images RF;  8.3a—b: Courtesy of John W. Hole, Jr.; 8.10-8.12  (all): © J & J Photography; 8.13b, 8.15b: © Dr.  Ronald Bergman; 8.17a—b: Courtesy of John W.  Hole, Jr.; 8.18b, 8.20b: © Dr. Ronald Bergman;  8.22: © Alexander Tsiaras/Science Source;  8.23a—b: © Chris Priest/Science Source.   © Ed Reschke/Getty Images; 9.5a: © H.E.  Huxley; 9.8b: © McGraw-Hill Education/Carol  D. Jacobson Ph.D., Dept. Veterinary Anatomy,  Iowa State University; 9.10b: © H.E. Huxley;  9.19: © Dr. Paul Heidger, University of lowa  College of Medicine; 9.20a: © Oscar Moncho/  agefotostock RF; 9.20b: © Sheila Terry/Science  Source; 9.20c: © View Stock/Getty Images RF;  p. 345 (left, right) : © Corbis RF; Plates 55-65:  © Dr. Kent M. Van De Graaff; Plates 66-75:    Opener: © Secchi-Lecaque/Roussel-UCLAF/  CNRA/SPL/Science Source; 11A: © Paul  Jasienski/Getty Images; 11Ca—b: © Dr. Kent M.  Van De Graaff; 11.6b: © Martin Rotker/Science  Source; 11.8: © McGraw-Hill Education/  Rebecca Gray, photographer/Don Kincaid,  dissections; 11D: © AFP/Getty Images; 1 1E:  Courtesy National Human Genome Research  Institute/Kondi Wong, Armed Forces Institute  of Pathology; 11.19b: © McGraw-Hill Education/  Photo and dissection by Christine Eckel;  11.15b: © Carolina Biological Supply  Company/Phototake; 11.24: © Manfred Kage/  Science Source.    Opener: © SPL/Science Source; 12.1b: © Ed  Reschke; 12.1c: © Ed Reschke/Getty Images;   © Pallava Bagla/Corbis; 12C: © K.S. Matz;  12.6: © Dwight Kuhn; 12.8: © Victor B. Eichler,  Ph.D.; 12.9b: © J & J Photography; 12D:   © Gene J. Puskar/AP Photo; 12.14a: © Biophoto  Associates/Science Source; 12.14b: © Dr. Fred  Hossler; 12.19: Courtesy of Dean E. Hillman;  12.27: © SPL/Science Source; 12.33: © Ed  Reschke/Peter Arnold/Getty Images; 12.34b:    Opener: © Prof. P. Motta/Dept. of Anatomy/  University of “La Sapienza’ Rome/SPL/Science  Source; 13.14: © Michael Ross/Science Source;  13.19: © Dr. Fred Hossler; 13.21: © Medical-on-  Line/Alamy; 13.22: © imagingbody.com; 13.23:  © Lester V. Bergman/Corbis; 13.25: © Victor P.  Eroschenko; 13.29: © Ed Reschke/Getty Images;  13.35: © Victor P. Eroschenko; 13B: Wellcome  Library, London. Creative Commons License  http://creativecommons.org/licenses/by/4.0; 13C:  © Imagezoo/PunchStock RF.   © Keith Brofsky/Getty Images RF; 14.1  (middle): © Comstock/PunchStock RF; 14.1  (right): © Keith Brofsky/Getty Images RF;  14A: © Photodisc Collection/Getty Images RF;  14.4b: © McGraw-Hill Education/A] Telser,  photographer; 14.5b: © Bill Longcore/Science  Source; 14.7a: © McGraw-Hill Education;  14.7b: © Cultura Science/Michael J. Klein,  M.D./Oxford Scientific/Getty Images; 14.10—  14.14: © Ed Reschke; 14Ba: © McGraw-Hill  Education/Al Telser, photographer; 14Bb:   © McGraw-Hill Education; 15.8a: © McGraw-  Hill Education/Karl Rubin, photographer;  15.12: © David Bassett/Science Source; 15A:  © F. Schussler/PhotoLink/Getty Images RF;  15.23c: © McGraw-Hill Education/A] Telser,  photographer; 15.26b-—c: © Don W. Fawcett/  Science Source; 15.27: © Thomas Deerinck,  NCMIR/Science Source; 15.31: © Johner/  SuperStock RF; 15Fa: © Ed Reschke/Peter  Arnold/Getty Images; 15Fb: © Image Source/  Getty Images; 15Fc: © Alfred Pasieka/Getty  Images; 15.42b: © Dr. Kent M. Van De Graaff;  15.46: © PDSN/Phototake.    Opener: © Dr. Kari Lounatmaa/SPL/Science  Source; 16.3: © McGraw-Hill Education/  Dennis Strete, photographer; 16.5: © Ed  Reschke/Getty Images; 16.9: © Dr. Kent   M. Van De Graaff; 16.10b: © McGraw-Hill  Education/Al Telser, photographer; 16.12b:   © McGraw-Hill Education/Dennis Strete,  photographer; 16.14b: © McGraw-Hill  Education/Al Telser, photographer; 16.16:   © Science Photo Library/Getty Images RF;  16.18b: © Manfred Kage/Science Source;  16A: Merck Archives. Merck, Sharp & Dohme  Corp., 2013/Photo by Phillip A. Harrington;  16.22b: © Steve Gschmeissner/Science Source;  16B: © Zeva Oelbaum.    Opener: © Science Photo Library/Getty  Images RF; 17.8: © McGraw-Hill Education/  Rebecca Gray, photographer; 17.9b: © Nick  Koudis/Getty Images RF; 17A: © SPL/  Science Source; 17.12a: © McGraw-Hill  Education/Al Telser, photographer; 17.12b:   © Biophoto Associates/Science Source;  17.12c: © McGraw-Hill Education/Al] Telser,  photographer; 17.16: © Ed Reschke/Getty  Images; 17.18: © Dr. Kent M. Van De Graaff;  17.19b: © McGraw-Hill Education/A] Telser,  photographer; 17.27c: © Victor P. Eroschenko;  17.29: © Southern Illinois University/Science  Source; 17.32: © tbradord/Getty Images;  17.36, 17.37b: © McGraw-Hill Education/Al  Telser, photographer; 17.44: © Jim Wehtje/  Getty Images RF; 17.46: © Ed Reschke/Getty  Images; 17.47: © Ed Reschke.    Opener: © Digital Vision/Getty Images RF;  18.9a: © McGraw-Hill Education/Lars A.  Niki, photographer; 18.9b: © PhotoLink/  Getty Images RF; 18.12: © Jeff Rotman/  Alamy; 18.18: © BioPhoto/Science Source;  18.20b: © McGraw-Hill Education/Al  Telser, photographer; 18.20c: © Biophoto  Associates/Science Source; 18A: © Charles  D. Winters/Science Source; 18.21: USDA.  USDA does not endorse any products,  services, or organizations; 18.22a: © AFP/  Getty Images; 18.22b: © Copyright 1997 IMS  Communications Ltd./Capstone Design. All  Rights Reserved; 18.23: © Brand X Pictures/  PunchStock RF.    Opener: © Susumu Nishinaga/SPL/Science  Source; 19.3b: © Biophoto Associates/Science  Source; 19.4a—b: © Anthony Bradshaw/Getty  Images; 19A (left): © St. Bartholomew’s  Hospital/Science Source; 19A (right):    Source; 19.7c: © CNRI/Science Source; 19.10:  © Biophoto Associates/Science Source; 19.13:  © Medical-on-Line/Alamy; 19.15: © McGraw-  Hill Education/A] Telser, photographer; 19.16:  © Motta & Macchiarelli/Anatomy Dept./Univ.  “La Sapienza”, Rome/Science Source; 19.18:  Courtesy of the American Lung Association;  19C: R.N. Clark, R.O. Green, G.A. Swayze,   G. Meeker, S. Sutley, T.M. Hoefen, K.E. Livo,  G. Plumlee, B. Pavri, C. Sarture, S. Wilson,   J. Boardman, I. Brownfield, C. Gent, L.C.  Morath, J. Taggart, P.M. Theodorakos, and   M. Adams, 2001, Environmental Studies of the  World Trade Center area after the September  11, 2001 attack. U.S. Geological Survey, Open  File Report OFR-01-0429; 19.26: © Edward  Lettau/Science Source; 19Da—b: © Victor B.  Eichler, Ph.D.; 19.32: Courtesy of the American  Lung Association; 19.34: © imagingbody.com;  19E (left): © AFIP/Science Source; 19E (right):  © Biophoto Associates/Science Source.   © Susumu Nishinaga/Science Source; 20.7b:  Courtesy of R.B. Wilson M.D., Department  of Pathology and Microbiology, University of  Nebraska Medical Center; 20.9b: © Thomas  Deerinck, NCMIR/Science Source; 20.1 la:    © Biophoto Associates/Science Source;  20.11b: © McGraw-Hill Education/A] Telser,  photographer; 20.25: © Biophoto Associates/  Science Source; 20A: © Stephen J. Krasemann/  Science Source; 20.28: © McGraw-Hill  Education/Al Telser, photographer; 20.29:   22.7: © McGraw-Hill Education/A] Telser,  photographer; 22.11: © Pascal Goetgheluck/  Science Source; 22.12: © Image Source RF;  22.13a—b: © McGraw-Hill Education/AI] Telser,  photographer; 22.14: © Kage Mikrofotografie/  Phototake; 22.21b: © Prof. P.M. Motta/Univ.  “La Sapienza”, Rome/Science Source; 22.22c:  © Biophoto Associates/Science Source;   22.23b: © McGraw-Hill Education/A] Telser,  photographer; 22.24: © P.M. Motta & J. Van  Blerkom/Science Source; 22.26a: © McGraw-  Hill Education/Al Telser, photographer; 22.26b:  © Science Photo Library/Getty Images RF;  22.27: © McGraw-Hill Education/Carol D.  Jacobson, Ph.D., Department of Veterinary  Anatomy, Iowa State University; 22.31c (left-  right): © Alvin Telser, Ph.D.; 22.33a—b:    photographer; 22.33c: © PhotoLink/Getty  Images RF; 22.33d: © Don Farrall/Getty  Images RF; 22.33e: © McGraw-Hill Education/  Jill Braaten, photographer; 22C: © Southern  Illinois University School of Medicine.    Opener: © Big Cheese Photo/Jupiterimages  RF; 23.2: © Eye of Science/Science Source;  23A: © Science Photo Library/Getty Images  RF; 23.4a: © A. Tsiara/Science Source; 23.4b:  © Omikron/Science Source; 23.4c: © Petit  Format/Nestle/Science Source; 23.6c, 23.7:  Courtesy of Ronan O’Rahilly; 23.13a: Human  Developmental Anatomy Center, National  Museum of Health and Medicine, Silver Spring,  MD 20910; 23.13b: © Omikron/Science  Source; 23.13c: © Petit Format/Nestle/Science  Source; 23.14e: © ISM/Phototake; 23.15:    Opener: © Barros & Barros/Getty Images; 24.3:  Courtesy Genzyme Corporation; 24.6: © Medical-  on-Line/Alamy; 24.7: © McGraw-Hill Education/  Photo by David Hyde and Wayne Falda; 24.11:  © Biophoto Associates/Science Source; 24A:    This text contains a substantial number of  supporting graphics. To ease index use, regular  page numbers indicate both discussion and  figure on the same page; page numbers with f  indicate additional figures on a different page;  t indicates a table; bold refer to illustrations  (reference plates).    A bands, 295  Abdomen, 51-52  Abdominal aorta, 47, 592, 594, 595f  Abdominal cavity, 18, 19f, 47, 50-52, 622  female torso, 42, 43, 44  male torso, 40, 41  Abdominal reflexes, 414  Abdominal region, 30, 31f, 32f  Abdominal viscera, 55—56, 588, 603, 604f  female torso, 42, 43, 44  male torso, 40, 41  Abdominal wall, 320f, 325, 328t, 329f, 598,  603, 604f, 746  Abdominopelvic cavity, 19f  Abdominopelvic membranes, 20, 21f  Abducens nerves, 422, 424t  Abduction, 274, 275f  Abductor brevis muscle, 43  Abductor muscles, 43, 318-19, 327f  Abductor pollicis longus muscle, 328f  ABO blood groups, 548-51, 911  Absolute refractory period, 378  Absorption, 650  large intestine, 685-86  organ systems, 23-24  small intestine, 681-82  Accelerator nerves, 572  Accessory nerves, 424  Accessory structures  digestive system, accessory organs of, 652f  external accessory organs, 847  of joints, 270-71  sex organs, 839  of skin, 184—88, 195  visual accessory organs, 468-70  Accidents, and spinal cord injuries, 419  Accommodation, of eye, 472-73, 474f  ACE inhibitors, 512  Acetabul- (prefix), 200  Acetabulum, 200, 240f, 241t, 281  Acetaminophen, 450  Acetic acid, 129  Acetoacetic acid, 818  Acetone, 697, 818  Acetyl coenzyme A (acetyl CoA), 128f, 129,  709    Acetylcholine (ACh), 297, 380, 381t, 436,  437, 512  Acetylcholinesterase, 300, 381, 437  Achilles tendon. See Calcaneal tendon  Acid, 66-68, 812  Acid indigestion, 667  Acid-base balance, 812-19  Acid-base buffer systems, 814-15  Acidic ketone bodies, 813  Acidosis, 67-68, 804, 813, 817-18  Acini, 668  Acne, 186, 188  Acquired immune deficiency syndrome  (AIDS), 286, 539t, 641, 757, 859  Acromegaly, 210, 501  Acromial region, 30, 32f  Acromioclavicular joint, 278t  Acromion process, 233, 234f, 348  Acrosome, 829, 872f  ACTH. See Adrenocorticotropic hormone  Actin, 97f, 293  Action potentials, 297, 361, 375-77  Activation energy, 123  Active aging, 899  Active dying, 897  Active sites, 123  Active transport, 99, 102-3, 107t, 787f  Acute cardiac tamponade, 590  Acute cholecystitis, 675  Acute glomerulonephritis (AGN), 778  Acute lymphoblastic leukemia (ALL), 540  Acute pain fibers (A-delta fibers), 449  Acute pancreatitis, 668  Acute respiratory distress syndrome (ARDS),  757  Adaptive (specific) defenses, 625, 627-40  Addiction, drug, 89  Addison disease, 513, 813  Adduction, 275f, 276  Adductor brevis muscle, 331f, 333, 334t  Adductor longus muscle, 41-42, 331f, 333,  334t, 356  Adductor magnus muscle, 331f, 333, 333f, 334t  Adductor muscles, of thigh, 331f, 333  A-delta fibers, 449  Adenoids, 654  Adenosine diphosphate (ADP), 126, 303  Adenosine triphosphate (ATP)  aerobic reactions, 129  cellular metabolism, 125-27  cellular respiration, 92, 127  chemical energy release, 126-27  dietary supplements, 719  muscle contraction, 299f, 300-302, 303  Adenylate cyclase, 492, 493f  ADH. See Antidiuretic hormone; Antidiuretic  hormone    Adip- (prefix), 149  Adiponectin, 704  Adipose (fat) tissue, 149, 163, 169t, 189  Adolescence, 896, 897t. See also Children  ADP. See Adenosine diphosphate  Adrenal Androgens, 514t  Adrenal cortex, 488, 491t, 508  Adrenal cortex disorders, 513  Adrenal cortex hormones, 510-12, 513, 514t  Adrenal gland, 43, 431, 436, 508-14, 520, 522,  773  Adrenal medulla, 488, 491t, 496, 508-10  Adrenergic receptors, 433, 436-37  Adrenocorticotropic hormone (ACTH), 488,  491t, 500, 504t, 512, 518  Adrenoleukodystrophy (ALD), 94  Adulthood, 896-97  Aer- (prefix), 121  Aerobic, 302  Aerobic exercise, 308, 340  Aerobic reactions, 127, 129-32  Aerobic respiration, 128f, 812-13  Af- (prefix), 769  Afferent arterioles, 769, 772  Afferent fibers, 420  Afferent lymphatic vessels, 622  Africa, and famines, 722  Afterbirth, 891  Afterload, and blood pressure, 587  Age and aging. See also Elderly; Infants;  Life-span changes  allergic reactions, 638  changes in organ systems, 519-20, 522, 898t  chromosome defects in children of older  mothers, 841, 920  heatstroke, 808  prescription of drugs, 798  process of, 27, 896-97, 898-99  skin, 192-93, 195  testosterone concentration in males, 839  “Age spots,” 193  Age-related macular degeneration, 482, 577  Ageusia, 456t  Agglutin- (prefix), 528  Agglutination, 528, 548, 550f, 634, 635t  Agglutinins, 548  Agglutinogens, 548  Agonist, 312, 384  Agranulocytes, 536, 541t  Agriculture, “organic” in, 68  AIDS, 286, 539t, 641, 757, 859  Air pollution, 743  Air pressure, 741, 744  Alanine, 141t, 699t  Alb- (prefix), 178  Albinism, 178, 183, 185, 478  Albumin, 75, 541, 542t, 709    Alcohol and pregnancy, 882-83  Alcoholism, 708  “Alcohol-related effects,” 882  Aldosterone, 490, 491t, 510-11, 512f, 514t,  589, 714, 809, 889  Ali, Muhammed, 404  Aliment- (prefix), 650  Alimentary canal, 650-52, 653f  Alkaline tide, 665  Alkaloids, 455  Alkalosis, 67, 817, 818  Alkaptonuria, 797  Allant- (prefix), 868  Allantois, 868, 874  Alleles, 909  Allergen, 617, 636, 637f  Allergies and allergic reactions, 160, 539t,  636-38, 639t  Allograft, 192, 639  All-or-none response, 305, 377  Alopecia areata, 186  Alpha cells, 514  Alpha fetoprotein (AFP), 919  Alpha globulin, 541, 542t  Alpha radiation, 60, 62  Alpha receptors, 436-37  Alpha waves, 410  Alpha-synuclein, 404  Alpha-tocopherol, 707  Alternative pathway, of complement, 626  Altitude sickness, 756  Alveol- (prefix), 731  Alveolar arch, 221, 259  Alveolar capillaries, 590  Alveolar dead space, 748  Alveolar ducts, 738f, 739, 853  Alveolar gas exchanges, 753-57, 758f  Alveolar glands, 156, 852  Alveolar macrophages, 754  Alveolar pores, 754, 755f  Alveolar process, 221, 222  Alveolar sacs, 739  Alveolar ventilation, 749  Alveolar wall, 593f  Alveolus (alveoli), 593f, 731, 738f, 739, 740,  TAIf, 754, 762  Alzheimer disease, 27, 75, 150, 899t  Amacrine cells, 474  Ameboid motion, 538  Amenorrhea, 852  American Dietetic Association, 720  American Heart Association, 591, 698  Amine hormones, 489, 491t, 492f  Amino acids, 73, 380. See also Protein  acid-base balance, 813-14  dehydration synthesis, 121-22  digestion of, 682t  structure of, 73-74  Amino group, amino acid, 73  Ammonia, 686  Ammonium ions, 816  Amniocentesis, 919f, 920  Amniochorionic membrane, 874  Amnion, 873-74, 878f  Amniotic cavity, 874 
holes-human-anatomy-physiology-pdfdrive Hole’s Human Anatomy & Physiology ( PDFDrive )_djvu.txt