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The November 2013 release of new guidelines for the management of overweight and obese patients by the American College of Cardiology, the American Heart Associates, and the Obesity Society is a significant step forward in fighting America's obesity epidemic. The recommendations not only give primary care physicians, many who may not be trained in obesity diagnosis and treatment, a "roadmap" for helping their patients, but the joint effort also marks the first time a nonsurgical society has included bariatric surgery consultation in the disease management model for obesity. The guidelines urge primary health providers to measure patients' body mass index (BMI) at least annually and identify those who may be at high risk of heart attack, stroke, or other diseases because of their excess weight. Physicians are encouraged to develop individual weight loss plans for patients who are overweight (with a BMI of 25 or more) or obese (BMI of 30 or higher). Individual weight loss plans may include lifestyle and behavioral programs that feature a reduced calorie diet, exercise, and counseling. For morbidly obese patients (BMI over 40 or BMI of 35 with comorbidity), the offer to refer the individual to an experienced bariatric surgeon for consultation and evaluation is suggested as an adjunct to the comprehensive lifestyle intervention. This recommendation may help dispel misconceptions some physicians have long held about the merit and safety of bariatric surgery. The new guidelines note that bariatric surgery "leads to improvements in both weight-related outcomes and many obesity-related comorbid conditions. The benefit-to-risk ratio may be favorable in appropriately selected patients at high risk for obesity-related morbidity and mortality." While the new guidelines are an important step in giving primary care physicians a tool to help patients win the war on obesity, there is still much room for improvement. Attitudes towards obesity are still slow to change. More education is needed to help the public, and even physicians, recognize that obesity is a chronic condition that requires lifetime treatment. It may ultimately be up to patients to arm themselves with information, such as these new guidelines, and demand that their healthcare provider better partner with them in managing their weight and their long-term health. Mark A. Colquitt, MD, FACS, FASMBS, is Director of Metabolic and Bariatric Surgery at Blount Memorial Hospital in Maryville, Tennessee, and is a bariatric surgeon with Foothills Weight Loss Specialists, a division of Premier Surgical Associates. Colquitt is board certified by the American Board of Surgery. He is a fellow of the American College of Surgeons and of the American Society of Metabolic and Bariatric Surgery and is a member of the Society of American Gastrointestinal and Endoscopic Surgeons. For more information, visit www.foothillsweightloss.com.
FDA labeling changes target Rx misuse August 31, 2016 by Chain Drug Review Stronger warnings required for certain opioid, CNS drugs SILVER SPRING, Md. — Citing dangers from combined use, the Food and Drug Administration is requiring classwide changes to labeling for opioid analgesics, prescription opioid cough products and benzodiazepines, a group of central nervous system depressant drugs. The FDA said Wednesday that the changes mandate boxed warnings — the agency's strongest warning — and patient medication guides for nearly 400 products overall. The information is intended to better inform health care providers and patients about the serious risks of using these medications at the same time. Risks include extreme sleepiness, respiratory depression, coma and death. The agency, too, has issued a Drug Safety Communication about the risks of combined use of these medicines. An extensive review of scientific data by the FDA revealed that doctors have been increasingly prescribing opioid painkillers and benzodiazepines together, which has correlated with adverse outcomes. The agency said it found that from 2004 to 2011, the rate of emergency room visits involving nonmedical use of both drug classes surged, with overdose deaths — from taking prescribed or greater than prescribed doses — nearly tripling during that period. Also, the number of patients prescribed both an opioid analgesic and benzodiazepine climbed 41% between 2002 and 2014, an increase of more than 2.5 million opioid analgesic patients receiving benzodiazepines. Robert Califf "It is nothing short of a public health crisis when you see a substantial increase of avoidable overdose and death related to two widely used drug classes being taken together," FDA Commissioner Robert Califf said in a statement. "We implore health care professionals to heed these new warnings and more carefully and thoroughly evaluate, on a patient-by-patient basis, whether the benefits of using opioids and benzodiazepines — or CNS depressants more generally — together outweigh these serious risks." Opioid analgesics are powerful pain-reducing medications that include prescription oxycodone, hydrocodone and morphine, among other drugs, under brand and generic names. Other opioid drugs are also approved to treat cough. The FDA noted that opioid analgesic misuse and abuse have soared in the United States over the past two decades and are major public health concerns because of the risk of coma and fatal respiratory depression from overdosing. Benzodiazepines are prescribed for neurological and/or psychological conditions, including anxiety, insomnia and seizure disorders. Both classes of drugs depress the central nervous system, yet each has unique pharmacology, safety risks and labeling information related to its use, according to the FDA. As a result, the agency said it's requiring opioid analgesics, prescription opioid cough products and benzodiazepines to have slightly different labeling. The FDA also is assessing evidence on the use of benzodiazepines and opioids as part of medication-assisted therapy treatment (MAT) for opioid addiction and dependence. The FDA said the labeling actions come as part of its Opioids Action Plan, which focuses on policies to reverse the prescription opioid abuse epidemic without impeding chronic pain patients' access to pain medications. This past February, the FDA received a citizen petition from local and state public health officials and other stakeholders asking the agency to make certain changes to the current labeling for benzodiazepines and opioid analgesics. The FDA said it had already initiated a review of data on combined use of these two drug classes when it received the petition. The agency added that its labeling actions are in line with clinical guidelines from the Centers for Disease Control and Prevention (CDC) and existing labeling warnings regarding combined use caution prescribers about co-prescribing opioids and benzodiazepines to avoid potential serious health outcomes.
Periodontal treatment is necessary when various conditions affect the health of your gums and the regions of your jawbone that hold your teeth in place. Retaining your teeth is directly dependent on proper periodontal care and maintenance. Healthy gums enhance the appearance of your teeth. When your gums become unhealthy, they can either recede or become swollen and red. In later stages, the supporting bone is destroyed and your teeth will shift, loosen, or fall out. These changes affect your ability to chew and speak. Periodontal disease is dangerous in that it is often painless and symptomless. It is important to maintain proper home oral care and regular dentist visits to reduce the risk of obtaining this disease.
We have heard the saying "you are what you eat" – all of our body's tissues – organs, skin, muscles, fascia, etc. – and our body's chemical messengers – hormones and neurotransmitters – are composites of what we put in our mouths. The more quality foods we allow in, the healthier our tissues. Yet in the United States, about three-fourths of the population consumes less than the recommended vegetables, fruits, dairy and oils; greater than half meet or exceed total protein and grain recommendations but do not meet the recommendations for the subgroups (meats, poultry, eggs vs. seafood vs. nuts, seeds, soy; refined grains vs. whole grains); and the majority of Americans eat well above the recommended added sugars, saturated fats and sodium. This is not exactly the best ratio for forming happy tissues and is something to truly consider while pregnant. The discrepancy between what is recommended and what we eat is influenced by a number of factors outside of cost and access, including conflicting information about food and nutrition. In this blog, we will take a look at some of the more current information that is out there regarding nutrition during pregnancy. The body's energy requirements increase during pregnancy to support maternal and fetal metabolism and growth. Generally, the energy requirements during the first trimester are similar to non-pregnant women and then increase in the second and third trimesters. Maintenance of weight to mild weight loss during the first trimester is normal. On average, energy requirements increase 340 kcal/day during the second trimester and 452 kcal per day during the third trimester for "normal weight" women. This translates to approximately one pound of weight gain per week. Below is a chart reflecting recommended total and rates of weight gain based on pre-pregnancy body mass index for an uncomplicated, singleton pregnancy. Energy requirements would increase if carrying multiples. Eating too little, too much or not enough nutrient-dense foods during pregnancy could lead to a number of health problems. These may include preterm birth, gestational diabetes, hypertension and preeclampsia. Balancing both macronutrients and micronutrients are essential to sustaining a healthy pregnancy. Macronutrients include your proteins, total fats and carbohydrates. They should comprise of 10-35%, 20-35% and 45-65% of your daily calories, respectively. Proteins are important in maintaining maternal muscle and body tissue as well as fetal growth and development. A variety of proteins (lean meats, poultry, fish, eggs, dairy, legumes, lentils nuts, soy) are advised to ensure the mother is getting all the essential amino acids. Animal protein appears to be of higher quality compared to vegetable protein, however, mixing different types of vegetables can increase the quality of plant protein. Supplementing vegetarian diets that allow for egg and dairy consumption with micronutrients – vitamin D, folic acid, iodine, iron, vitamin B12, zinc and DHA – can allow for a good nutritional status during pregnancy. Fats, especially your essential fatty acids (DHA and EPA), should be included in the diet during pregnancy as they are not naturally supplied by the body. Essential fatty acids are crucial for fetal brain development and function. The majority of fat intake should come from unsaturated sources such as fish, vegetable oils and nuts. Carbohydrates are the main source of energy for the body and should account for the majority of your daily calories. Many fruits, vegetables, grains and dairy products contain carbohydrates. Whole grains are a good source of dietary fiber (28 grams/day) and enriched refined grains offer the added benefit of two important micronutrients; iron and folic acid. Folic acid during pregnancy is necessary to support rapid cell growth, replication, division and nucleotide synthesis for fetal and placental development. It is recommended that women take folic acid with supplementation or from fortified foods (enriched bread, cereals, pastas, etc.) in addition to consuming a diet rich in food sources of folate. These include citrus fruits, dark-green leafy vegetables, legumes, nuts and liver. Iron needs nearly double during pregnancy as pregnant women have an increased amount of blood in their bodies. Iron is important in immunity and metabolism as well as preventing cardiovascular crisis in mother and offspring. Iron-rich foods include read meat, pork, fish and eggs but can also be drawn from enriched grains, green-leafy vegetables, beans, nuts and dried fruits. It is important to note that the body does not absorb iron as well from those found in plants but eating foods that are high in Vitamin C can help with absorption. The main source of calcium are milk/milk products, cereals and vegetables. Vitamin D is primarily found in fortified milk or juice, eggs and fish. Unpasteurized milk should not be consumed during pregnancy as it may contain Campylobacter, E. coli, Listeria, Salmonella or Tuberculosis and lead to foodborne illness (more on this to come). Vitamin D is also manufactured by the skin when exposed to sunlight. Up to ten minutes of sun exposure can supply a day's worth of Vitamin D but this can vary based on the geographical location and skin tone of the individual. These micronutrients are responsible for bone mineralization and growth. Cell differentiation and proliferation as well as the development of the spine, heart, eyes and ears is dependent on Vitamin A. Excessive Vitamin A has been linked to birth defects but this is tied to the retinol form of Vitamin A, not the carotenoid version found in food sources such as green-leafy vegetables, orange and yellow vegetables, tomato products, fruits and some vegetable oils. Omega-3 fatty acids are critical for fetal brain development and cardiovascular health later in life. Fish that are high in omega-3 but low in mercury include salmon, sardines and anchovies. High mercury fish should be avoided as higher mercury levels in children have been associated with deficits in memory, learning and behavior. Fish that should absolutely be avoided include shark, swordfish, tilefish and king mackerel. Interestingly, the available data does not suggest fish-oil supplements have the same health benefits as the consumption of actual fish. *Check out the safe minimum cooking temperatures here. According to Walsh and McAuliffe, one may want to consider a low glycemic index diet during pregnancy. The glycemic index measures how a carbohydrate-containing food increases blood glucose. A food that has a high glycemic index raises blood glucose more than one with a medium or low glycemic index. Examples of low glycemic index foods include 100% stone-ground whole wheat bread, oatmeal, oat bran, muesli, pasta, converted rick, barley, bulgar, sweet potato, corn yam, lima beans, peas, legumes, lentils, most fruits, non-starchy vegetables and carrots. In their 2015 study, Walsh and McAuliffe assessed the impact of a low glycemic index diet on maternal and foetal health. Eight hundred women were included in the randomized control trial. Those in the control group received routine antenatal care that did not include any formal dietary advice. Those in the intervention group attended one dietary education session for two hours in small groups with a research dietitian. In the session, women were advised on general healthy eating guidelines for pregnancy and then educated on the glycemic index. Intervention participants were encouraged to choose low glycemic index foods and exchange high glycemic index foods for low. The women also received written resources about low glycemic foods after the education session. Follow ups were performed with the research dietitian at 28 and 34 weeks of gestation for reinforcement of the low glycemic diet. At each visit, participants' weight, height and fasting blood glucose were measured. To track compliance with the low glycemic index diet, all participants completed three, three-day food diaries – one prior to the intervention and one in the second and third trimesters. Participants were also given a questionnaire to rate their compliance with the low glycemic index diet (one being "I followed the recommended diet all of the time' and five being "I followed the recommended diet none of the time"). Following intervention, researchers reported that pregnant women who followed a low glycemic index diet helped limit excessive weight gain during pregnancy and improved glucose tolerance. They also revealed that pregnant women are open to education and nutritional and lifestyle interventions and that these interventions have the potential to extend beyond pregnancy. These are important findings as other studies have found that women who gain weight in the appropriate range from their BMI during pregnancy have fewer adverse perinatal outcomes. There are many things to consider in regards to diet while pregnant that may seem overwhelming. However, there are tons of government and professional association supported resources available online. If you are ever in doubt that a food is safe, consult with your healthcare provider or a registered dietitian. If your diet seems on track but you happen to be experiencing any common pelvic floor dysfunctions (i.e. pelvic girdle pain, stress urinary incontinence, etc.) during pregnancy or postpartum check out how pelvic floor physical therapy can help.
Medical analysis is the process of determining which disease or circumstance explains someone's signs and symptoms and signs. Laboratory exams may additionally perceive organisms immediately (e.G., visually, the use of a microscope growing the organism in tradition) or indirectly (e.G., figuring out antibodies to the organism). General sorts of checks encompass microscopy, tradition and immunologic assessments (agglutination exams which include latex agglutination, enzyme immunoassays, western blot, precipitation exams and complement fixation tests) and nucleic acid/ non-nucleic acid-based totally identification techniques. Subtypes of diagnoses include medical, laboratory, radiology, important and admitting diagnosis. Advanced strategies had been applied to diagnose the contamination in any a part of the body. Examples include biomarkers/ Elisa check/ chest x-ray/ skin biopsy/ tympanometry and tympanocentesis.
Abstract—Abstract—Due to the restriction of the number of probes that a patient can tolerate and the inaccurate information provided by the invasive temperature measurements, which provide information only at discrete points, a mathematical model simulation is more effective to help physicians in planning their thermal treatment doses. This simulation will maximize therapeutic effects while minimizing side effects. Prior to the treatment, it will provide a precise idea of the predicted reaction depending on selected doses; so new treatment strategies can be proposed and evaluated. To simulate cerebral circulation , we divide the fluid and matter constituents within the human head into several interacting subunits, so called compartments. Four main characteristics of the analyses of the brain model are fluid dynamics analysis, mechanical analysis, laser beam and heat transfer. The objective of this study is to simulate the Laser Interstitial Thermal Therapy in Treatment (LITT) of brain tumors including all four characteristics described above. The thermal effect of the laser during coagulation lasts around one second and its temperature is between 50 0C and 90 0C. LITT has the following results; the desiccation and retraction of the tissue to destroy tumor phenomena. Index Terms—Index Terms—Laser interstitial thermal therapy, thermal damage, brain cancer, bioheat transfer simulation. Mhamed Nour is with Université du Québec en Outaouais, Québec, Canada (e-mail: [email protected]). Mohammed Bougataya and Ahmed Lakhssassi were with Université du Québec en Outaouais, Québec, Canada (e-mail: [email protected], [email protected],). Cite:Mhamed Nour, Mohammed Bougataya, and Ahmed Lakhssassi, "Modeling the Laser Thermal Therapy in Treatment of Brain Tumors," International Journal of Computer Theory and Engineering vol. 9, no. 4, pp. 313-317, 2017.
Pharmacological prevention of sevoflurane- and desflurane-related emergence agitation in children: a meta-analysis of published studies I. Constant, Y. Nivoche, B. Bruneau, S. Dahmani, C. Lejeune, I. Murat, C. Brasher, I. Stany, C. Wood BRITISH JOURNAL OF ANAESTHESIA SCI(E) SCOPUS Volume 119, Issue suppl_1 Volume 117 Suppl 2 Volume 117, Issue suppl 3 Volume 107 Suppl 1, Issue 1 Volume 69, Issue 7 Suppl 1 Volume 60, Issue suppl_1 216p ~ 239p ISSN 0007-0912 E-ISSN 1471-6771 Oxford University Press in 2010 Oxford MEDLINE®/PubMed® British Library Crossref 10.1093/bja/aep376 서울대학교 서강대학교 상명대학교(서울) settings Medicine > Anesthesiology and Pain Medicine , Medicine > Health anaesthetics i.v., propofol, anaesthetic techniques, regional, caudal, anaesthetics i.v., fentanyl, emergence agitation, anaesthetics i.v., clonidine, Akathisia, Drug-Induced, etiology, prevention & control, Analgesia, Anesthesia Recovery Period, Anesthetics, Inhalation, adverse effects, Anesthetics, Intravenous, therapeutic use, Child, Fentanyl, Humans, Isoflurane, analogs & derivatives, Ketamine, Methyl Ethers, Postoperative Complications, Propofol, Receptors, Adrenergic, alpha-2 Cited Articles open button Background Emergence agitation (EA) in children is increased after sevoflurane anaesthesia. The efficacy of prophylactic treatment is controversial. The aim of this study was to provide a meta-analysis of the studies of the pharmacological prevention of EA in children. Methods A comprehensive literature search was conducted to identify clinical trials that focused on the prevention of EA in children anaesthetized with sevoflurane, desflurane, or both. The data from each trial were combined using the Mantel–Haenszel model to calculate the pooled odds ratio (OR) and 95% confidence interval. I 2 statistics were used to assess statistics heterogeneity and the funnel plot and the Begg–Mazumdar test to assess bias. Results Thirty-seven articles were found which included a total of 1695 patients in the intervention groups and 1477 in the control ones. Midazolam and 5HT3 inhibitors were not found to have a protective effect against EA [OR=0.88 (0.44, 1.76); OR=0.39 (0.12, 1.31), respectively], whereas propofol [OR=0.21 (0.16, 0.28)], ketamine [OR=0.28 (0.13, 0.60)], α2-adrenoceptors [OR=0.23 (0.17, 0.33)], fentanyl [OR=0.31 (0.18, 0.56)], and peroperative analgesia [OR=0.15 (0.07, 0.34)] were all found to have a preventive effect. Subgroup analysis according to the peroperative analgesia given does not affect the results. Conclusions This meta-analysis found that propofol, ketamine, fentanyl, and preoperative analgesia had a prophylactic effect in preventing EA. The analgesic properties of these drugs do not seem to have a role in this effect. No relevant information is available If you register references through the customer center, the reference information will be registered as soon as possible. Articles referencing this article
Citation: ULICNA, S. ... et al., 2019. Deposition and application of a Mo–N back contact diffusion barrier yielding a 12.0% efficiency solution-processed CIGS solar cell using an amine–thiol solvent system. Journal of Materials Chemistry A, 7, pp. 7042-7052. Abstract: The use of a Mo–N barrier for solution-processed CIGS results in reduced MoSe2 formation. This enabled longer selenization time, enhanced grain growth and performance.
Education\| October 2018 Association between Performance in a Maintenance of Certification Program and Disciplinary Actions against the Medical Licenses of Anesthesiologists Yan Zhou, Ph.D.; Yan Zhou, Ph.D. From the American Board of Anesthesiology, Raleigh, North Carolina (Y.Z., H.S., A.M., M.T.K., A.J.P., T.W., A.E.H., D.O.W.); Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California (A.M.); Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota (M.T.K., D.O.W.); Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska (A.J.P.); Department of Anesthesia and Critical Care, The University of Chicago, Chicago, Illinois (M.M.M.). Huaping Sun, Ph.D.; Huaping Sun, Ph.D. Address correspondence to Dr. Sun: The American Board of Anesthesiology, 4208 Six Forks Road, Suite 1500, Raleigh, North Carolina 27609. [email protected]. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology's articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue. Alex Macario, M.D., M.B.A.; Alex Macario, M.D., M.B.A. Mark T. Keegan, M.B., B.Ch.; Mark T. Keegan, M.B., B.Ch. Andrew J. Patterson, M.D., Ph.D.; Andrew J. Patterson, M.D., Ph.D. Mohammed M. Minhaj, M.D., M.B.A.; Mohammed M. Minhaj, M.D., M.B.A. Ting Wang, Ph.D.; Ting Wang, Ph.D. Ann E. Harman, Ph.D.; Ann E. Harman, Ph.D. David O. Warner, M.D. Corresponding article on page 631. Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal's Web site (www.anesthesiology.org). Submitted for publication November 14, 2017. Accepted for publication May 10, 2018. Anesthesiology October 2018, Vol. 129, 812–820. https://doi.org/10.1097/ALN.0000000000002326 Commentary: Maintenance of Certification: Has MOC Gone Amok? Yan Zhou, Huaping Sun, Alex Macario, Mark T. Keegan, Andrew J. Patterson, Mohammed M. Minhaj, Ting Wang, Ann E. Harman, David O. Warner; Association between Performance in a Maintenance of Certification Program and Disciplinary Actions against the Medical Licenses of Anesthesiologists. Anesthesiology 2018; 129:812–820 doi: https://doi.org/10.1097/ALN.0000000000002326 Editor's Perspective What We Already Know about This Topic Anesthesiology board certification is now time-limited, requiring participation in a program to maintain certification It is unknown how physician performance is associated with participation and performance in this program What This Article Tells Us That Is New The introduction in 2000 of certificates that require participation in a program to maintain certification was not associated with a significant change in the incidence of disciplinary license actions Completing maintenance of certification program requirements in a timely fashion was associated with a lower incidence of license actions In 2000, the American Board of Anesthesiology (Raleigh, North Carolina) began issuing time-limited certificates requiring renewal every 10 yr through a maintenance of certification program. This study investigated the association between performance in this program and disciplinary actions against medical licenses. The incidence of postcertification prejudicial license actions was compared (1) between anesthesiologists certified between 1994 and 1999 (non–time-limited certificates not requiring maintenance of certification) and those certified between 2000 and 2005 (time-limited certificates requiring maintenance of certification); (2) within the non–time-limited cohort, between those who did and did not voluntarily participate in maintenance of certification; and (3) within the time-limited cohort, between those who did and did not complete maintenance of certification requirements within 10 yr. The cumulative incidence of license actions was 3.8% (587 of 15,486). The incidence did not significantly differ after time-limited certificates were introduced (hazard ratio = 1.15; 95% CI, 0.95 to 1.39; for non–time-limited cohort compared with time-limited cohort). In the non–time-limited cohort, 10% (n = 953) voluntarily participated in maintenance of certification. Maintenance of certification participation was associated with a lower incidence of license actions (hazard ratio = 0.60; 95% CI, 0.38 to 0.94). In the time-limited cohort, 90% (n = 5,329) completed maintenance of certification requirements within 10 yr of certificate issuance. Not completing maintenance of certification requirements (n = 588) was associated with a higher incidence of license actions (hazard ratio = 4.61; 95% CI, 3.27 to 6.51). These findings suggest that meeting maintenance of certification requirements is associated with a lower likelihood of being disciplined by a state licensing agency. The introduction of time-limited certificates in 2000 was not associated with a significant change in the rate of license actions. licensure, maintenance of certification THE 24 member boards of the American Board of Medical Specialties (Chicago, Illinois) issue certificates to physicians who successfully complete board certification requirements. These certificates are now all time-limited, requiring periodic renewal through a maintenance of certification program. In 2000, the American Board of Anesthesiology (Raleigh, North Carolina) began issuing time-limited certificates that require renewal every 10 yr. American Board of Medical Specialties standards mandate a four-part framework for maintenance of certification: professionalism and professional standing (part I); lifelong learning and self-assessment (part II); assessment of knowledge, judgment, and skills (part III); and improvement in medical practice (part IV). Although previous literature supports the association of achieving primary certification and subsequent measures of physician performance,1–6 there is little direct evidence of how participation in maintenance of certification, or performance in various elements of maintenance of certification, may be associated with physician performance. This lack of evidence has contributed to controversy surrounding the value of maintenance of certification. Assessing this value is challenging as it requires assessing the performance of large populations of physicians. Some studies examining the association between primary certification and physician performance have employed various quality measures related to patient care as outcomes.1,3–5,7,8 Other studies focus on actions by state medical and osteopathic boards against physician medical licenses, which reflect pronounced performance deficiencies.2,6,9,10 In general, primary board certification is associated with a reduced risk of license actions regardless of specialty, supporting the utility of this outcome. Regarding maintenance of certification, lower performance on a cognitive written examination used to fulfill the part III requirement is associated with a higher rate of license actions in diplomates of the American Board of Internal Medicine11 (Philadelphia, Pennsylvania) and the American Board of Anesthesiology.12 However, it is not known whether the inability to pass a cognitive written examination (requirement of part III) indicates an increased likelihood of license actions. The overall goal of this study was to explore the association between participation and performance in the Maintenance of Certification in Anesthesiology program and postcertification physician performance as measured by license actions. We tested three hypotheses: (1) the incidence of license actions was lower in physicians with time-limited certificates (i.e., certified in 2000 or later) than in physicians with non–time-limited certificates (i.e., certified before 2000); (2) among physicians with non–time-limited certificates, participating in maintenance of certification voluntarily is associated with a lower incidence of license actions; and (3) among physicians with time-limited certificates, the incidence of license actions was higher among those who did not complete their maintenance of certification requirements within 10 yr of certification than among those who did. This study was deemed exempt from review by the Mayo Clinic Institutional Review Board (Rochester, Minnesota). A previous report details our method to ascertain license actions.6 To summarize, the Federation of State Medical Boards (Euless, Texas) gathers information from all U.S. state medical and osteopathic boards on license actions and disseminates this information to the American Board of Medical Specialties member boards via the Disciplinary Action Notification Service. License actions are classified as prejudicial (e.g., loss or restriction of license) or nonprejudicial (e.g., lifting of probation conditions). In this study, a license action incident case was defined as receiving at least one prejudicial action; nonprejudicial actions were not included. For a physician receiving multiple prejudicial actions, only the first one was considered an incident case. Two sets of analyses were conducted to address the hypotheses. Participation in Maintenance of Certification and License Actions. The first set of analyses included all anesthesiologists whose primary certificates were awarded in calendar years 1994 to 1999 (n = 9,529) and 2000 to 2005 (n = 6,060). The periods were chosen to bracket the introduction of time-limited certificates in 2000 and to provide sufficient follow-up time to ascertain license actions. Although each cohort included all those awarded a certificate over a 6-yr period, the more recent cohort (i.e., time-limited certificate holders) had fewer physicians due to reductions in residency enrollment.13 Incidences of license actions were compared between the 1994 to 1999 cohort (who were issued non–time-limited certificates and thus not required to participate in maintenance of certification) and the 2000 to 2005 cohort (who were issued time-limited certificates and thus required to participate in maintenance of certification). In an additional analysis, the 1994 to 1999 cohort was split into two subgroups—those who had and those who had not chosen to voluntarily participate in maintenance of certification—and incidences of license actions for each subgroup were compared to that of the 2000 to 2005 cohort. This additional analysis excluded 69 (0.7%) American Board of Anesthesiology volunteers (e.g., standardized oral examination examiners, question authors, and examination committee members) in the 1994 to 1999 cohort who are required to participate in maintenance of certification as a condition of their service. Meeting Maintenance of Certification Requirements and License Actions. The second set of analyses included all physicians receiving time-limited certificates between 2000 and 2005 who were continuously enrolled in maintenance of certification within their 10-yr maintenance of certification cycles and did not fail maintenance of certification requirements because of reasons directly related to license actions (e.g., substance use disorder). Incidences of license actions were compared between those who met maintenance of certification requirements within 10 yr of issuance and those who did not. Additionally, to fully explore whether passing the anesthesiology maintenance of certification examination (necessary to meet the part III requirement) predicted license actions, incidences of license actions were compared for various subgroups within those who did not meet maintenance of certification requirements: (1) physicians who passed the anesthesiology maintenance of certification examination but did not meet at least one other maintenance of certification requirement, (2) physicians who either did not take or did not pass the anesthesiology maintenance of certification examination, (3) physicians who took but did not pass the anesthesiology maintenance of certification examination, and (4) physicians who failed to complete maintenance of certification requirements solely because they failed the anesthesiology maintenance of certification examination. The anesthesiology maintenance of certification examination could be taken beginning in year 7 of the 10-yr maintenance of certification cycle, and those who did not achieve a passing score were allowed to retake the examination until the final year of their cycle. Passing the examination was required to meet the part III requirement. From the 6,060 physicians certified between 2000 and 2005, these analyses excluded those who died (n = 45), retired (n = 11), or had their certificates revoked by the American Board of Anesthesiology before the end of their first 10-yr maintenance of certification cycle (and thus dropped out of maintenance of certification; n = 10), and those who had a shorter than 10-yr maintenance of certification cycle (due to a history of disciplinary issues such as substance use disorder for whom certificate issuance was delayed from the date they passed the certifying examination; n = 25). Also excluded were those who voluntarily withdrew from maintenance of certification because they only wanted to maintain a subspecialty certificate (e.g., pain medicine; n = 9), those who were living in a foreign country and did not maintain a U.S. medical license (n = 5), those who left practice due to health reasons (n = 4), those who were planning to retire and opted not to complete maintenance of certification (n = 3), and those who could not complete maintenance of certification requirements (but were continuously enrolled in maintenance of certification) because of reasons directly related to license actions (e.g., substance use disorder; n = 10). The final study population for these analyses included 5,938 physicians. Demographic characteristics were compared for the 1994 to 1999 and the 2000 to 2005 cohorts with a two-sample Student's t test for continuous variables (age at certification) or a chi-square test for categorical variables (sex and medical school country). The incidence of license actions was analyzed with survival analysis, with the time to event defined as the time elapsed from the date of certification to the time of first prejudicial license action. Incident license action cases occurring before the date of primary certification were excluded from analysis. For the non-license action cases, a physician was censored from the analysis on the date of death if deceased, the date of retirement if retired, or the end of follow-up (i.e., December 31, 2016) if alive and not retired. If the date of death or the date of retirement was unknown, December 31, 2016, was used as the censoring date. For each set of analyses, the cumulative incidence of license actions was visualized for each of the groups being compared with Kaplan–Meier curves, with the x-axis representing number of years since primary certification and the y-axis representing cumulative proportion of individuals who have not had a license action. Group differences in the incidence of license actions were tested with Cox proportional hazards models. Sex and medical school country (American medical graduates vs. international medical graduates) were considered a priori as covariates in multivariable Cox models on the basis of a previous study that demonstrated their association with license actions under some circumstances.6 This study is based on population data, and sample size was not designed with a priori statistical power calculation. A P value less than 0.05 was considered to indicate statistical significance in all the analyses. All statistical analyses were performed in R version 3.3.1 (R Foundation for Statistical Computing, Vienna, Austria; available at https://www.r-project.org/; accessed September 14, 2016). Participation in Maintenance of Certification and License Actions In the overall population of 15,589 physicians for the first set of analyses, 690 (4.4%) incident license action cases were identified. Of these, 103 cases occurring before the date of primary certification were excluded. In the remaining 15,486 physicians, among the 9,463 in the 1994 to 1999 cohort (non–time-limited certificates) there were 420 cases (4.4%), and among the 6,023 in the 2000 to 2005 cohort (time-limited certificates) there were 167 cases (2.8%; table 1; Supplemental Digital Content, http://links.lww.com/ALN/B739). Compared to the 1994 to 1999 cohort, the 2000 to 2005 cohort was older at certification and had a greater proportion of both women and international medical graduates (table 2). By the end of follow-up, 195 physicians were known to have died (nine had an unknown date of death) and 42 were known to have retired (one had an unknown date of retirement). License Action Cases Analyzed for Each Certification Year from 1994 to 2005 Demographic Characteristics for 1994 to 1999 and 2000 to 2005 Cohorts In univariate analysis, the incidence of license actions was not significantly different between the two cohorts (table 3; hazard ratio = 1.18; 95% CI, 0.98 to 1.42; for non–time- limited certificate holders, 1994 to 1999 cohort, compared with time-limited certificate holders, 2000 to 2005 cohort). Results were similar in multivariable analysis, which included sex and medical school country (table 3, multivariable model 1). In this analysis, the incidence of license actions was significantly higher in men than in women but not significantly different between American medical graduates and international medical graduates. Factors Associated with the Incidence of License Actions, Including Cohort Membership and Voluntary Participation in Maintenance of Certification, Among Physicians with Non–time-limited Certificates Within the 1994 to 1999 cohort (excluding 69 American Board of Anesthesiology volunteers), 953 physicians voluntarily participated in maintenance of certification and 8,441 physicians did not. The proportion of women was higher in those who participated than those who did not (table 2). Compared to the 2000 to 2005 cohort, the incidence of license actions was significantly lower in those voluntarily participating in maintenance of certification (hazard ratio = 0.60; 95% CI, 0.38 to 0.94) and significantly higher in those not participating (hazard ratio = 1.22; 95% CI, 1.01 to 1.48), after adjusting for the effects of sex and medical school country (table 3, multivariable model 2; fig. 1). Cumulative proportion of individuals who have not had a license action since receiving primary certification for physicians in the 1994 to 1999 cohort who did not voluntarily participate in maintenance of certification (MOC; n = 8,441, red line), those in the 1994 to 1999 cohort who voluntarily participated in MOC (n = 953, blue line), and those in the 2000 to 2005 cohort who were required to participate in MOC (n = 6,023, black line), as estimated with the Kaplan–Meier method. Shown below the abscissa are the numbers of physicians at risk for each category. Meeting Maintenance of Certification Requirements and License Actions Of the 5,938 physicians who received time-limited certificates between 2000 and 2005 and were considered for the second set of analyses, 168 incident license action cases were identified. Of these, 21 cases occurring before the date of certification were excluded. In the remaining 5,917 physicians, 5,329 (90.1%) completed maintenance of certification requirements by the end of their 10-yr cycle and 588 (9.9%) did not. There were 99 (1.9%) and 48 (8.2%) cases, respectively, among those who did and did not complete maintenance of certification requirements on time. By the end of follow-up, 12 were known to have died and 12 retired. In univariate analysis, the incidence of license actions was significantly higher in physicians who did not complete their maintenance of certification requirements within 10 yr (hazard ratio = 4.63; 95% CI, 3.28 to 6.54; table 4). Results were similar in multivariable analysis, which included sex and medical school country (table 4). In the multivariable analysis, the incidence of license actions was significantly higher in men than in women but not significantly different between American medical graduates and international medical graduates. According to Kaplan–Meier analysis, the estimated cumulative incidence at 15 yr after certification was 2.0% (95% CI, 1.6 to 2.4%) for those who completed maintenance of certification requirements and 8.5% (95% CI, 6.2 to 11.2%) for those who did not (fig. 2). Factors Associated with the Incidence of License Actions, Including Completing Maintenance of Certification on Time, Among Physicians with Time-limited Certificates (2000 to 2005 Cohort, N = 5,917) Cumulative proportion of individuals who have not had a license action since receiving primary certification for physicians in the 2000 to 2005 cohort (i.e., with time-limited certificates) who did (n = 5,329, blue line) and did not (n = 588, red line) complete maintenance of certification (MOC) requirements within the 10-yr period as required, as estimated with Kaplan–Meier method. Shown below the abscissa are the numbers of physicians at risk for each category. Among the 588 physicians who did not complete maintenance of certification requirements on time, 414 (70%) did not meet the part II requirement for lifelong learning and self-assessment, 521 (89%) did not meet the part III requirement for passing the anesthesiology maintenance of certification examination, and 391 (66%) did not meet the part IV requirement for improvement in medical practice. Most physicians not meeting requirements had deficits in more than one element of maintenance of certification (456 physicians, 78%). Sixty-seven physicians (11.4% of those not completing maintenance of certification requirements) passed the anesthesiology maintenance of certification examination (i.e., met part III requirement) but did not meet at least one other maintenance of certification requirement. There were 6 (9.0%) license action cases in these physicians, compared with 42 (8.1%) cases in the 521 physicians who either did not take or did not pass the anesthesiology maintenance of certification examination (hazard ratio = 1.17; 95% CI, 0.50 to 2.75; P = 0.72, univariate). Of those who took but did not pass the anesthesiology maintenance of certification examination (n = 134), there were 6 (4.5%) cases (hazard ratio = 0.43; 95% CI, 0.14 to 1.35; P = 0.15, univariate, compared with the 67 physicians who passed the examination but did not meet at least one other requirement). Finally, there were 48 physicians (0.8% of the 5,917 physicians issued time-limited certificates) who failed to complete maintenance of certification solely because they failed the anesthesiology maintenance of certification examination (i.e., they met all other requirements). There was 1 (2.1%) case among these 48 physicians (hazard ratio = 0.19; 95% CI, 0.02 to 1.60; P = 0.13, univariate, compared with the 67 physicians who passed the examination but did not meet at least one other requirement). The major findings of this study were that (1) the introduction of time-limited certificates in 2000 was not associated with a difference in the postcertification incidence of license actions between physicians certified before and after 2000, (2) voluntary participation in maintenance of certification was associated with a lower incidence of license actions, and (3) not completing maintenance of certification requirements in a timely fashion was associated with a higher incidence of license actions. Initial board certification after residency training (i.e., primary certification) is associated with better physician performance, assessed with patient outcomes,1,3–5,7,8 quality measures,7,8 and license actions.2,6,9,10 Unlike primary certification, little is known regarding how physician participation and performance in maintenance of certification is associated with physician performance. Three studies found an association between scores on the American Board of Internal Medicine maintenance of certification examination and various measures of care quality.14–16 However, none attempted to determine whether quality measures differed between physicians who passed and failed the examination, providing little information to patients since examination scores are not known to the public. In a previous analysis,12 we found that a history of license actions was associated with lower scores on the anesthesiology maintenance of certification examination; comparisons were not made between those who passed and failed the examination. To our knowledge, there are no published studies regarding how performance on the other elements of maintenance of certification, such as lifelong learning and self-assessment (part II) or improvement in medical practice (part IV) may be related to physician performance. One approach to evaluate the impact of maintenance of certification is to compare the performance of physicians certified before and after the introduction of time-limited certificates. Previous work from the American Board of Internal Medicine found that the introduction of their maintenance of certification process was not associated with a change in ambulatory care–sensitive hospitalizations, but was associated with a small reduction in the growth rate of annual healthcare costs.17 We found little effect of the introduction of time-limited certificates in 2000 on the incidence of license actions among anesthesiologists. Although this finding could be interpreted as indicating that maintenance of certification did not improve this measure of physician performance, several factors need to be considered. First, the four-part requirements for maintenance of certification in anesthesiology evolved over time, not reaching relative stability until 2009, which provided a short follow-up time to gauge its effectiveness in improving performance. Second, those certified between 1994 and 1999 had the option to voluntarily participate in maintenance of certification. Approximately 1 in 10 physicians did, and they were significantly less likely to receive license actions. This could have occurred because participation improved performance or because participation was a marker for those physicians who already were at a lower risk for license actions. For example, those who participated may already be better performers or may be more likely to consistently comply with rules of any kind. Indeed, excluding physicians with non–time-limited certificates who voluntarily participated in maintenance of certification from consideration, the introduction of the time-limited certificates (with the attendant requirement to participate in maintenance of certification) was associated with a small but significantly lower risk of license actions (see table 3, multivariable model 2). Again, this may represent participation bias. Third, although we adjusted for the effects of sex and medical school country, it is possible that the two cohorts may have differed in other characteristics or abilities, further confounding any cause-and-effect (or lack thereof) interpretation for maintenance of certification introduction. For example, the proportion of candidates who passed both part I and part II examinations on their first attempts were 67.6% and 64.7% for the 1994 to 1999 cohort and the 2000 to 2005 cohort, respectively (chi-square test, P = 0.0002). Although the certification examinations have evolved over time and pass rates in different years may not be directly comparable, success in passing the anesthesiology certification examinations on the first attempt is associated with a reduced risk of license actions.6 Thus, the higher rate of passing in the earlier cohort could bias against finding a lower incidence of license actions after the introduction of maintenance of certification. We also found that timely completion of maintenance of certification requirements was associated with a lower incidence of license actions; this result, to our knowledge, represents the first demonstration in any specialty of an association between meeting maintenance of certification requirements and a measure of physician performance. This finding was based on physicians who continuously enrolled in maintenance of certification (i.e., did not have their license or certificate revoked during the 10-yr maintenance of certification cycle). The majority of those not completing requirements were deficient in multiple elements of maintenance of certification. This finding could reflect physicians who simply decided not to participate, so did not complete reporting of their maintenance of certification requirements. We were particularly interested in the effectiveness of the anesthesiology maintenance of certification examination in predicting physician performance. Although this exploratory analysis was limited due to the relatively small number of physicians who did not pass the examination, we found little evidence of an association between passing the anesthesiology maintenance of certification examination and license actions. Indeed, among those physicians who did not complete maintenance of certification requirements solely because they failed the anesthesiology maintenance of certification examination, only one license action case was reported. This finding may reflect a relatively high pass rate for the anesthesiology maintenance of certification examination, averaging 94% for first-time takers over the period of study. Nonetheless, it suggests that achieving a passing score on the examination alone has little value in predicting the pronounced practice deficiencies implied by license actions. The anesthesiology maintenance of certification examination was replaced in 2016 by the Maintenance of Certification in Anesthesiology Minute pilot program, a longitudinal assessment of knowledge that applies principles of adult learning theory in an effort to retain and enhance knowledge of the participants that provides 120 questions online each year.18 Future research will investigate whether participation and performance in this program are better predictors of license actions than the anesthesiology maintenance of certification examination. We have previously reported a detailed analysis of incident license actions in anesthesiologists who entered training in U.S. programs from 1971 to 2011, showing that achieving primary certification was associated with a markedly lower risk of actions.6 The risk of license actions was higher in men than women and lower in international medical graduates than in American medical graduates. The current analysis (which included only physicians who achieved primary certification over a more limited date range) confirms the finding of lower risk among women but does not find a significant difference according to medical school country. In this previous analysis, incidence rates for license actions were largely stable over time at approximately 2 to 3 new cases per 1,000 person-years,6 such that approximately 1 in every 20 board-certified anesthesiologists were estimated to experience a license action over the course of a 30-yr career. Accordingly, in the current study 587 individuals (3.8% of the 15,486 anesthesiologists who had not experienced license actions before primary certification) experienced at least one prejudicial license action after primary certification. To put this cumulative incidence in context, a previous report concerning California physicians10 found that the incidence rate of license actions for all California physicians (2.4 new cases per 1,000 person-years) is comparable to what we had previously observed for U.S. anesthesiologists.6 In a case-control analysis of California physicians, anesthesiologists had a similar risk compared with surgeons and internal medicine specialists.9 Further work would be necessary to evaluate hypotheses related to any differential risk of license actions across medical specialties. This analysis has several limitations. Although a major advantage of using license actions is the ability to ascertain this outcome in all licensed physicians, license actions only capture the lower bound of physician performance and do not reflect variations in physician performance above this threshold. The relatively low rates of license actions also may have affected our statistical power to detect a true difference between the 1994 to 1999 cohort and the 2000 to 2005 cohort. Another limitation of using license actions is variability among state boards regarding the criteria for license actions. Unmeasured variables may have confounded the results, especially in the direct comparison of the two cohorts before and after the introduction of maintenance of certification. Due to the relatively high pass rate for those taking the anesthesiology maintenance of certification examination for the first time, we did not account for the number of attempts to pass this examination in the primary analysis (only 3.2% of those passing the examination required more than one attempt to do so). Nevertheless, there was little evidence that the incidence of license actions differed between those who did and did not require multiple attempts to pass the examination (hazard ratio = 1.09; 95% CI, 0.35 to 3.44; P = 0.88, univariate). In summary, although the introduction of time-limited certificates and the maintenance of certification requirement in 2000 was not associated with a difference in the incidence of license actions among board-certified anesthesiologists, both voluntary participation in maintenance of certification and completion of maintenance of certification requirements in a timely fashion were associated with a lower incidence of such actions. These findings suggest that timely completion of maintenance of certification requirements serves as an indication to the public that a physician is less likely to be disciplined by a state licensing agency. These observational data cannot determine whether the association arises because maintenance of certification participation actually improves physician performance or simply serves as a marker for other physician characteristics that reduce the risk of license actions. Support was provided solely from institutional and/or departmental sources. Drs. Harman, Sun, Wang, and Zhou are staff members of the American Board of Anesthesiology, Raleigh, North Carolina. Drs. Keegan, Macario, Patterson, and Warner are American Board of Anesthesiology Directors and receive a stipend for their participation in American Board of Anesthesiology activities. Dr. Minhaj is a nondirector member of the American Board of Anesthesiology Research Committee. Rathore Krumholz Physician board certification and the care and outcomes of elderly patients with acute myocardial infarction. J Gen Intern Med Lipner Chaudhry Duhigg Papadakis Specialty certification status, performance ratings, and disciplinary actions of internal medicine residents. Acad Med Norcini Certifying examination performance and patient outcomes following acute myocardial infarction. Med Educ Prystowsky Bordage Feinglass Patient outcomes for segmental colon resection according to surgeon's training, certification, and experience. discussion 670–2 Even-Shoshan Showan Longnecker Anesthesiologist board certification and patient outcomes. Culley Effectiveness of written and oral specialty certification examinations to predict actions against the medical licenses of anesthesiologists. Orav The relationship between physicians' qualifications and experience and the adequacy of prenatal care and low birthweight. Am J Public Health 8 Pt 1 Ujiki The importance of surgeon volume and training in outcomes for vascular surgical procedures. J Vasc Surg Kohatsu Characteristics associated with physician discipline: A case-control study. Arch Intern Med Wickersham Physicians disciplined by a state medical board. Holmboe Performance during internal medicine residency training and subsequent disciplinary action by state licensing boards. Ann Intern Med Predictors of performance on the Maintenance of Certification in Anesthesiology Program® (MOCA®) examination. J Clin Anesth Substance use disorder among anesthesiology residents, 1975-2009. Setting a fair performance standard for physicians' quality of patient care. The association between physicians' cognitive skills and quality of diabetes care. Meehan Association between maintenance of certification examination scores and quality of care for Medicare beneficiaries. Vandergrift Reschovsky Association between imposition of a Maintenance of Certification requirement and ambulatory care-sensitive hospitalizations and health care costs. Association between participation in an intensive longitudinal assessment program and performance on a cognitive examination in the Maintenance of Certification in Anesthesiology Program®. Copyright © 2018, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Effectiveness of Written and Oral Specialty Certification Examinations to Predict Actions against the Medical Licenses of Anesthesiologists Anesthesiology (June 2017) Maintenance of Certification: Reply Anesthesiologist Board Certification and Patient Outcomes Association between Participation in an Intensive Longitudinal Assessment Program and Performance on a Cognitive Examination in the Maintenance of Certification in Anesthesiology Program ® Anesthesiology (November 2016) Predicting Success on the Certification Examinations of the American Board of Anesthesiology Anesthesiology (January 2010)
Unlocking the potential of engineered C-C bond forming enzymes for biocatalysis Lead Research Organisation: University of Bristol Department Name: Biochemistry The future success of the global pharmaceutical and chemical industries is dependent on the successful development of efficient, selective and sustainable ways of making new organic molecules with useful properties. Historically, such methods have centered on the use of synthetic organic chemistry to fuse and tailor simple chemical building blocks into a vast array of complex molecular architectures, which may in-turn be used as the basis for amongst other things new drugs, crop protection agents, or materials. Despite the undoubted success of synthetic chemistry, problems exist, including the over-reliance on certain types of reactions that have led to an excessive representation of molecules with predominantly flat, 2D architectures, which are of limited value as drugs. In contrast to chemical catalysts, biological catalysts, termed enzymes, are able to perform challenging chemical reactions that can rapidly build complex 3D chemical structures with multiple bonds under precise stereochemical control. In addition, enzymes can perform such reactions under ambient conditions and without any requirement for environmentally damaging reagents. For these reasons there is significant interest in developing biocatalytic routes to current and future pharmaceuticals and similarly important molecules. A carbon-carbon bond forming reaction known as the Diels-Alder reaction is an effective means of building complex 3D molecules in a single step. However, a limitation of this reaction is that to achieve high yields, stereoselectivity and regioselectivity, the electronic properties of the reactants need to be complementary and often harsh reaction conditions are required. This research project builds on our exciting recent discovery of a naturally evolved co-factor independent enzyme that catalyzes the Diels-Alder reaction at room temperature and on substrates which cannot be transformed using conventional synthetic organic chemistry. This discovery opens up the possibility of using this enzyme to generate a whole new series of complex molecules that could form the basis of new drugs or similarly important chemical compounds. During this project we will establish the practical and theoretical limits of the reactions that this and other related Diels-Alderases can catalyze, we will also rationally re-engineer these enzyme to purposefully change their function to allow access to an even greater variety of products. We will partner these engineered biocatalysts with auxiliary enzymes which catalyze further ring forming reactions to develop routes to industrially useful molecules. This project is a strategically important partnership between the University of Bristol and the pharmaceutical company AstraZeneca, and we will work together to develop natural and engineered enzymes and deploy them to generate a vast array of new 3D molecules that can be used as the basis for new drugs to treat a diverse array of human diseases. The Diels-Alder reaction, a [4+2] cycloaddition of a conjugated diene to a dienophile, is widely recognised as one of the cornerstone synthetic organic reactions of the 20th century. It is commonly employed in the synthesis of bioactive natural products and in the rapid construction of sp3 rich cyclic and polycyclic compounds. This reaction opened the way to the synthesis of numerous important pharmaceuticals including the anti-viral agents Tamiflu and Peramivir, the anti-fungal Tolciclate, and opiates including Morphine and the smoking cessation aid Varenicline. It has also been widely used in the preparation of vitamins, steroid hormones, agrochemicals (Isopyrazam, Bixafen, Cycocel), and numerous fragrance and flavour compounds. Despite its unquestionable usefulness, the versatility of this reaction is limited by its distinctive steric and electronic requirements, along with the harsh reaction conditions which often must be employed. By contrast, the development of protein catalysts for this reaction remains a major goal, as access to enzymes capable of catalyzing Diels-Alder reactions under ambient conditions and in the absence of co-factors, would enable new, green routes to a wide variety of valuable chemical building blocks, natural products and lead scaffolds. In this academic-industrial LINK project, which builds on substantive collaborative research undertaken by the academic PI and Co-Is in the identification and characterisation of natural Diels-Alderases and associated ring forming enzymes, the researchers will:(i) Answer pressing, unresolved fundamental questions, regarding the enzymology of naturally evolved Diels-Alderases, (ii) undertake structure and simulation-guided reengineering and directed evolution of these enzymes; and (iii) deploy this portfolio of biocatalysts, in combination with auxiliary enzymes, to enable the preparation of chemical building blocks, pharmaceutical lead scaffolds and bioactive natural products. This project will deliver (i) detailed molecular insight into a poorly understood and hitherto unexploited group of naturally evolved biocatalysts, (ii) a suite of engineered variants of these enzymes with modified substrate selectivities and catalytic properties, and (iii) a portfolio of new bioactive molecules and lead compounds for further investigation and exploitation. As such we consider this research to have potential broad ranging intellectual, economic and potential clinical impact. The outlined research programme will contribute substantially to the UK's global leadership in the areas of biocatalysts and drug discovery, and aligns well with current BBSRC strategic priorities and cross-council initiatives. The applicants are committed to ensuring that the outputs from this research impact upon policy-makers, funding bodies, academic institutions, and industry by providing clear evidence of the value of strategically aligned fundamental and applied interdisciplinary research. This is a collaborative LINK project with the multi-national pharmaceutical company AstraZeneca (AZ), with whom we will work in partnership to realise the impacts of this research. This will be through the generation of IP and licensing agreements centered on the enzymes and small molecules that will be generated. The project will establish a strategically important partnership between UK academia and a multi-national pharmaceutical company in an application area that is of major economic significance to the UK. The outcomes of this project are of direct strategic relevance to AZ's future research strategy and will deliver significant industrial and commercial impact. Should any of the new compounds isolated during the course of this study prove to be useful drug leads we will work with AZ to deliver the potentially significant resulting medical and industrial impact. A key output of this work will also be the establishment of general methods to advance our fundamental understanding of enzyme catalysis and our ability to manipulate naturally evolved enzymes to produce new chemical compounds. These discoveries will impinge on the emerging field of synthetic biology, and have the potential to transform industrial processes and practices specifically in the areas of biotechnology and pharmaceutical development. We will maintain an open dialogue with key industrial stakeholders and policy makers during the lifetime of the project, such that they are informed and in a position of readiness to act appropriately as outputs emerge. The outlined programme will offer those involved (PDRAs, students, etc.) experience and training at the chemistry-biology interface, providing them with a range of technical and intellectual skills required to succeed in careers in academia, industry or the third sector. The research outputs from this program will be reported to the wider scientific community through publication in leading peer-reviewed journals, presentation at national and international conferences and at meetings with industrial and academic collaborators. Training will be given to those involved in the preparation of papers, posters and oral presentations to ensure that, alongside their scientific knowledge and skills, they are developing a portfolio of widely transferable skills. Further, significant opportunities exist for the presentation of research findings by all those involved to a more general audience through public engagement activities organised by the University of Bristol and AZ (school talks, science festivals, etc.). Such activities will ensure that as broad an audience as is feasible will be informed of our ongoing research. BB/T001968/1 Paul Raymond Race Biomolecules & biochemistry Biological & Medicinal Chem. Catalysis & enzymology Novel industrial products University of Bristol, United Kingdom (Lead Research Organisation) AstraZeneca PLC, United Kingdom (Project Partner) Paul Raymond Race (Principal Investigator) Marc Willem Van Der Kamp (Co-Investigator) http://orcid.org/0000-0002-8060-3359 Chris Willis (Co-Investigator) http://orcid.org/0000-0002-3919-3642 Bunnak W (2020) SAXS reveals highly flexible interdomain linkers of tandem acyl carrier protein-thioesterase domains from a fungal nonreducing polyketide synthase. in FEBS letters Marucci L (2020) Computer-Aided Whole-Cell Design: Taking a Holistic Approach by Integrating Synthetic With Systems Biology. in Frontiers in bioengineering and biotechnology Maddock RMA (2020) Enzyme-catalysed polymer cross-linking: Biocatalytic tools for chemical biology, materials science and beyond. in Biopolymers Williams SE (2020) The Bristol Sponge Microbiome Collection: A Unique Repository of Deep-Sea Microorganisms and Associated Natural Products. in Antibiotics (Basel, Switzerland)
My name is Jörg-Uwe Pott, and I am a staff member in the Galaxies and Cosmology department at the Max Planck Insitute for Astronomy. We mostly observe active galactic nuclei (short: AGN) at highest angular resolution to reveal their basic physical properties, typically on linear scales between 10 mpc and 10 pc. Focus lies on high-angular resolution instrumentation and related observing strategies. This means in particular using modern infrared interferometers, like the VLTI, the LBT, and Keck-IF, typically in combination with adaptive optics technology. Vibration sensing and development of related control strategies to improve the sensitivity of our cameras is a currently hot topic for us. We are directly involved in major instrumentation initiatives (LBT/LINC-NIRVANA, E-ELT/MICADO, VLTI/MATISSE), which will typically deliver a 10x higher resolution (sharpness of the image) than todays ground- or space-based instruments. Funded graduate or post-graduate job openings will be posted in AAS, when available. Additionally, individual stipends and fellowships to support your graduate and postgraduate research project are available from DFG, Humbold-Gesellschaft, and the Marie-Curie Fellowships of the European Union. Bachelor- and Masterprojects both in astronomy and related engineering disciplines are possible, in collaboration with your university and within the above research scope of my group. If you are interested, please contact me, with a brief CV, and description of your research ideas.
CHETRE Centre for Health Equity Training, Research & Evaluation Our Streams Locational Disadvantage – evidence in practice Students & Interns CHETRE secures international and local grants for COVID-19 rapid research response The health equity research projects will look at the longer-term social dimensions of the pandemic. Two COVID-19 Rapid Research Grants through the Canadian Institute of Health Research (CIHR) The Centre for Health Equity Training, Research and Evaluation (CHETRE) has been successful, with Canadian colleagues, in securing two COVID-19 Rapid Research grants through the Canadian Institute of Health Research (CIHR). "Although the disease itself is ravaging the health of individuals and populations, the emerging patterns for effects on populations over time are even more disturbing," says Professor Evelyne de Leeuw from CHETRE and UNSW Medicine. "Some groups seem more affected by the disease and therefore by health flow-on effects than others. But the longer-term socio-economic effects of the pandemic – such as economic downturn, reduction in livelihoods, travel, contact, etc. – make things even worse." Role of Chief Medical Officers in COVID-19 response One CIHR project will look at the role of Chief Medical Officers (CMOs), or their equivalents, across states, provinces and territories in Britain, New Zealand, Canada and Australia in taking up scientific advice, framing policies and interventions, and communicating them. The researchers will also roll out population surveys to take stock of popular perceptions of the CMO roles. This project will be undertaken with Professor Patrick Fafard of the Global Strategy Lab at York University and the University of Ottawa. COVID-19 economic strain and effects on health and liveability The second project will look at the effects of financial hardship on health and liveability and how we can better know who is affected. It will also frame whole-of-government responses to the resulting inequities of COVID-19-related economic strain. It will be jointly run in Canada and Australia by Professor Candace Nykiforuk (University of Alberta) and Professor de Leeuw. Two local grants Urban planning and respiratory pandemics Dr Patrick Harris, senior research fellow and acting deputy director at CHETRE, will lead two new projects that have secured funding in Australia. The Healthy Urban Environments (HUE) Collaboratory, at Sydney Partnership for Health, Education, Research and Enterprise (SPHERE), will fund a project that aims to inform the prevention of respiratory pandemics through urban planning and design practices, guidelines, policies, governance and institutional frameworks. "COVID-19 requires a multi-level urban planning and design response encompassing policy measures, governance, infrastructure provision, and design features," says Dr Harris. "Those most vulnerable to infection must be considered primarily, as must unanticipated consequences for the whole population including risk of disadvantage. Fortunately, pandemics over history can inform the response." Health and related risks associated with informal and unregulated accommodation Dr Harris is also chief investigator on a project funded by Australian Housing and Urban Research Institute (AHURI) which will investigate health and related risks associated with informal and unregulated accommodation, using unique data sets on informal and short-term rental housing markets in major Australian cities. It will also canvass policy options for expanding housing system capacity during health and other emergencies, serving vulnerable populations or essential workers. Author CHETREPosted on 29 June 2020 29 June 2020 Categories COVID-19, NewsTags Chief Medical Officers, coronavirus pandemic, covid19, grants, housing, news, social determinants of health, urban planning Further challenges for new migrants and humanitarian entrants in COVID-19 By Andrew Reid There is a concern that COVID-19 may exacerbate inequality towards vulnerable groups, including migrants and refugees. Here, I highlight a few from past experiences between 2006 – 2011 as a Non-Government Organisation (NGO) project and casework officer. My role included assisting and supporting Australian permanent residents within the first five years of arrival. This group included humanitarian entrants, family stream migrants with low English proficiency; and other selected visa subclasses. This group was located in Outer and Inner Western Sydney, under the Settlement Grants Program (SPG), now known as Settlement Engagement and Transition Support (SETS), funded by the Federal Department of Home Affairs. Information and service access issues SETS workers from 78 providers across Australia, funded under SETS – Client Services for the period 1 January 2019 to 30 June 2022, during this COVID-19 period, will necessarily be delivering services 'from home.' As a consequence, the SETS target group, including 20,102 humanitarian entrants that are settled in all states/territories between 1 January 2019 to 31 December 2019 (see figure 1 below), are likely to receive less face-to-face casework, interaction, and access to services at a time of even greater need to address their current settlement issues and concerns. Figure 1: Permanent Settlers (All Streams) in all States/Territories with a Date of Settlement* between 01 January 2019 and 31 December 2019 There are a number of translation and interpreting services in Australia, such as the Federal Government Translating and Interpreting Service (TIS) operating 24/7 and the NSW Multicultural Health Communication Service, that cover a very large number of languages. The Federal Government on 11/3/2020 announced a $30 million public information campaign. However, with increased demand many new migrants and refugees may find it more difficult than usual to get the necessary information, assistance, and support when needed. There are more than 21% of the population who speak languages other than English at home, and 6% that either speak little English or none at all. It is likely that there will be longer wait times from increasing demand in this COVID-19 period for such essential services. A significant number of new migrants and humanitarian entrants that have resettled in Australia, particularly in the past 5 years, struggle with accessing information and services on their own. COVID-19 has forced a large number of Australians to 'self-isolate' or 'stay at home.' This has made it much harder for this population group. One contributing factor to this is the considerably diverse educational backgrounds of recently arrived humanitarian migrants. Some have relatively few years of education. Research, in 2017, found that 15% had no formal education and a further 18% had six or fewer years of schooling). Another contributing factor is digital exclusion. Research in 2019 has shown recently-arrived Culturally and Linguistically Diverse (CALD) migrants who had arrived under the humanitarian immigration program recorded a lower level of digital inclusion than the national average, primarily due to very low levels of affordability. Older people in this population group are particularly at risk of not understanding and adhering to the required course of action needed to keep people safe and reduce the spread of COVID-19. As Associate Professor Robyn Woodward-Kron, at Melbourne University, explains, "some of the older migrants in Australia have had very little schooling, so they need reliable information that they can understand." It is particularly important that there is a 'coordinated and creative' approach involving a diverse range of stakeholders including community leaders, different multicultural organisations and community groups to develop the required information and disseminate it in appropriate and effective ways. Increased Survivor's Guilt Research in 2019 found humanitarian migrant populations remain at high risk for mental illness over the first 3 years of resettlement in Australia. One contributing factor to this is survivor's guilt. This is a sense of deep guilt a person may experience because they have survived a life-threatening situation (i.e., wars, natural disasters, and other traumas), when others have not. COVID-19 may be likely to increase survivor's guilt among newly arrived migrants and refugees to Australia. This could be exacerbated by numerous domestic and overseas news reports of the alarming speed and spread of COVID-19 across the globe as well as fears of the unknown and for the welfare of friends and family left behind in home countries and refugee camps. Survivor's guilt is a symptom of Post-Traumatic Stress Disorder (PTSD). Thus COVID-19 could potentially raise the positive screening of PTSD above the 52.4%, shown in a 2019 study, among the humanitarian migrant populations in Australia. Further stigma Stigma is already identified as one of the critical barriers to help-seeking for mental health or other health advice, particularly amongst refugee men in Australia. History and international experiences suggest COVID-19, like other pandemics (i.e., Spanish Flu and Ebola), could very well increase this stigma in the recently-arrived CALD migrant population who entered the country under the humanitarian program. This could mean less COVID-19 testing, social rejection, denial of services, and reduced treatment opportunities for Australian new migrants and refugees. Moreover, it can also lead to elevated depressive symptoms, stress, and substance use within this population group. Therefore, COVID-19 can effectively cause further stigma, which can result in mental and physical harm. This could include increasing the present prevalence estimates for depression and anxiety above the current 20% for migrants and 40% for refugees. A final note, although COVID-19 is having significant impacts on the Australian community, newly arrived migrants and humanitarian entrants are at risk of experiencing increasing challenges as a result of this pandemic. Author Andrew ReidPosted on 17 April 2020 24 September 2020 Categories Blog post, COVID-19, Locational disadvantageTags coronavirus, covid19, health equity, migrant health, pandemic The social gradient of COVID-19 by Andrew Reid and Siggi Zapart While COVID-19 does not discriminate, the impacts of the virus will not be equitably distributed. Vulnerable populations living in low socioeconomic disadvantaged communities will feel its health and educational impacts far more strongly than those living in more affluent areas. Reduced access to essential healthcare Some health experts suggest the COVID-19 pandemic could infect up to 70% of Australians. Based on estimates of current infection, more than 45,000 Australians will have COVID-19 by 10 April, 2020. At least 2,254 people would require ICU beds, (more than the current Australian capacity of 2,229). People in lower socioeconomic disadvantaged communities generally have poorer health and higher rates of heart and respiratory disease, and chronic illnesses. This means they could make up a large proportion of people likely to need ICU beds, and/or find it a lot harder to receive critical healthcare for their other illnesses in their local hospitals. Furthermore, the Australian Government's plan to implement a 'whole-of-population telehealth' approach will disadvantage vulnerable populations who do not have access to smartphones or computer technology due to lower income or education levels. The 'whole-of-population telehealth' includes phone and video mental health, allied health, and primary health consultations. Moreover, even those with internet access will be disadvantaged due to inferior NBN service types(see graph below). Research conducted in 2016 showed only 29% the most disadvantaged areas across Australia (SEIFA decile of 1) had fibre-to-the-premise (FTTP) – considered the best broadband technology solution available – or fibre-to-the-node (FTTN) connections. In the least disadvantaged(SEIFA decile of 10), 93 % had FTTP or FTTN. This is clear evidence that optimal NBN service increases as the SEIFA decile increases. Hence, even though telehealth is covered by Medicare, people living in disadvantaged suburbs are likely to miss out on the much needed essential services. Impact on mental health The continuing upward trend in the number of confirmed COVID-19 cases across Australia is causing increased anxiety and stress among disadvantaged communities. This is due to multiple and simultaneously occurring factors including, risk and uncertainty associated with the virus; feeling of powerlessness in the current situation; inconsistent messaging and confusion about social distancing measures; separation from loved ones due to quarantine or self-isolation; loss of freedom, and increased boredom; low income reducing to no income; and the type and condition of housing many people in these areas reside in. Most residents in these communities live in low-cost private rentals, social housing, and for some (many with disability, health or mental health issues, victims of domestic violence, people recently released from prison etc.) and social housing bedsits. The pandemic can potentially raise the Australian adult rates of poor mental health(currently 20%) and high or very high psychological distress (13%). Educational impact Across Australia, some states have closed schools, commencing school holidays early. Others like NSW have kept them open but encouraged parents to keep children at home. All schools are preparing for online learning, though at this stage, options for school attendance will be available for those that need it in some states. However, given the low attendance rates (20-30% last week), it seems many parents think it safer to keep their children at home. For students in vulnerable communities, online learning could lead to increased barriers to education. Not all will have access to computers, the internet, or quality technology, such as wireless networks at home or quality NBN service. Many students might have mobile phones, but these may not be enough to engage with the curriculum or complete required tasks. Shools could send home lessons and resources for parents to use, but many parents in these communities would struggle, or not feel confident to teach their children at home. In addition, the Federal Government's closure of public libraries and community centres will hurt the educational outcomes of children in disadvantaged communities as these facilities provide a safe environment to facilitate lifelong learning. Public libraries offer free or affordable access to the internet, computers, printers, photocopiers, and a wide range of educational resources. Several community centres host Learning Clubs, i.e., after school programs designed to provide extra assistance to primary and secondary students in developing academic skills, such as homework, numeracy, and literacy. Not having access to these facilities and programs will prevent a large number of children in these disadvantaged communities from participating in learning, completing online school assignments, and having the right to a high-quality education experience. So, a final note, although COVID-19 is impacting the entire population, those doing it tough already are and will continue to experience even more severe consequences as a result of the pandemic. Author Andrew ReidPosted on 31 March 2020 24 September 2020 Categories Blog post, COVID-19, Locational disadvantageTags coronavirus pandemic, covid-19, health equity, inequality, Locational disadvantage, mental health, social determinants of health CHETRE Proudly powered by WordPress
Mar 7, 2012. Anything lower is acidic, and anything higher is basic (or alkaline). Dropping by 1 on the pH scale means the acidity is 10 times higher, so even small decreases in pH can mean big increases in acidity. A normal stomach pH is between 1 and 4. It's already acidic. "The stomach's pH is low because it. The esophageal pH test is performed to measure the amount of acid that flows into the esophagus from the stomach. WebMD explains the procedure. This causes metabolic alkalosis, and the resulting excess of bicarbonate in the stomach and blood alters the PH balance of the body.The bacterium H.pylori ( Helicobacter Pylori) thrives in this medium of lowered stomach acid, and may cause ulcers and stomach ulcers, as the body can't kill it off without that acidic medium. Gastrin release is also stimulated by the stretch of the stomach walls during a meal, the presence of certain foods (particularly proteins) within the stomach cavity and an increase in the pH levels of the stomach (i.e. the stomach becoming less acidic). The production and release of gastrin is slowed by the hormone. Pantoloc For Acid Reflux Aug 14, 2017. If you experience symptoms of acid reflux or heartburn, your doctor may prescribe Prilosec (omeprazole) or Protonix (pantoprazole) to decrease the amount of acid produced in your stomach. Both drugs belong to a group of medications called proton pump inhibitors. Prilosec is also available without a. Pantoloc: Pantoprazole belongs to the family of medications called proton pump inhibitors (PPIs). Proton pump inhibitors are used to treat conditions such as stomach. If you have heartburn, acid reflux, gastroesophageal reflux disease (GERD), peptic ulcer disease or any acid-related condition, chances are very high that you've been. Jun 29, 2012. A list of Acid / Alkaline Forming Foods: Your body pH affects everything. Balancing the pH is a major step toward well-being and greater health. Oct 7, 2016. You are causing a reaction with the alkalinity of the bicarb with the acidity in your stomach. Optimal burp time 1-2mins; If you burp before 1 mins your stomach acid is too high and we need to calm digestive fire; If you burp between 2-3mins you have slightly low levels of stomach acid; If you burp between 3-5. Reflux of stomach acids into the esophagus. Loss of GPX7 led to the accumulation of high levels of ROS and oxidative DNA damage in esophageal cells. The findings suggest that GPX7 protects esophageal cells from acid-induced. This condition may cause Delayed, or Marked-delayed, emptying time of the stomach's contents. In many cases, Patients with Delayed and Marked-delayed emptying, will retain food in their stomachs for 6 to 24 hours, or much longer in many cases. A Patient that has Fasted may have stomach acid level of pH 1.0 or. The idea that we need to balance our inner pH with a special diet is a trendy one, but is there any evidence behind it? The pH level (the balance of acid and alkaline) in your body is important, and can affect multiple body functions, but balancing pH is more complicated than simply changing your diet. It is true that a majority. Tomato Acidity Tomatoes are generally considered a high acid food item with a pH below 4.6. Unfortunately, a lot of misinformation has been printed. Gastrin is a gastrointestinal hormone which stimulates the secretion of gastric acid, which helps the stomach digest food. The kidneys are responsible. Restoring pH Balance in the Body: Video demonstration of how to use pH test strips and an explaination of how to balance the body's pH using diet and nutritional supplementation. A pH. the stomach. We are talking about the pH of the body's fluids and tissues which is an entirely different matter unrelated to stomach acid. Dear Pharmacist: In a previous column on apple cider vinegar (ACV), you stated that "heartburn and reflux can sometimes be related to insufficient levels. is pH sensitive and in a healthy person, it stays shut because of the natural. What is alkaline water and can it really help with heartburn? – Among those perks is the belief that alkaline H2O—which, by definition, has a higher pH (and lower acidity) than what comes out of the tap—can help neutralize stomach acid and relieve. All foods and beverages have a pH level. This. Cimetidine was a miracle drug, but there were concerns that reducing acid in the stomach would be adversely affect digestion and would also allow bacteria to enter the body – bacteria that would have normally been killed by the natural. When H. pylori makes its way into the stomach to begin colonization, it has to survive the acidic pH of the stomach lumen, or cavity. It moves through it, While H. pylori can avoid being wiped out by gastric acid, low levels of gastric acid make it quite easy for the bacteria to enter and infect the stomach. Even if your levels of. Gastric acid, gastric juice or stomach. but the acid is diluted in the stomach lumen to a pH between. gastrin levels, leading to excess gastric acid. Acid-Stopping Omeprazole The Food and Drug Administration approved omeprazole—sold commercially as GastroGard for horses—for equine use in 1999 as a way to increase the stomach's pH levels, thereby reducing acid production. Nov 13, 2009. All without scientific merit. Even if you manage to raise the pH of your stomach significantly (say, with antacids), eventually the stomach acids will restore the stomach pH to its regular levels. Nothing you eat or drink will have a significant effect on the pH of food once it reaches your intestine to be absorbed. Dear Suzy: In a column on apple cider vinegar, you stated that "heartburn and reflux can sometimes be related to insufficient levels. sphincter is pH sensitive, and in a healthy person, it stays shut because of the natural stomach. Patients with persistent symptoms on acid suppressive. the pH sensors were calibrated using buffered pH solution of pH 4.0 and 7.0 as specified by the manufacturer. The probe was then inserted transnasally through the esophagus into. A pH of 7 is neutral, meaning water. In a resting state, the stomach's pH is around 4. When food enters the stomach, it triggers the release of hydrochloric acid to digest the food. The stomach's pH can quickly drop to approximately 1. When the pH of the stomach gets too low, somatostatin secretion is stimulated. Somatostatin inhibits acid secretion by direct effects on parietal cells, and also by inhibiting release of the positive regulators histamine and gastrin. The balance of activity of the different regulators changes as food is consumed and passes. When a dog or cat swallows a commercial pet food (high carbohydrate, high plant protein, low meat protein diet), acid-secreting cells in the stomach are not stimulated to produce as much hydrochloric acid, thus the pH does not drop as low. The acidic chyme (food mixed with gastric juices) leaving the stomach is the trigger. These drugs reduce acid by blocking the action of tiny "pumps" within the acid-secreting cells of the stomach. Patients underwent an intraesophageal/intragastric 24-hour pH study on day five. When assessing acid control, clinicians. Mar 6, 2012. The acidic environment destroys pathogenic organisms that may be ingested in both food and water. Altering this acid environment leaves you wide open to intestinal infections. At least half of everyone over 60 suffers from some level of low stomach acid. This condition can be compounded by the. Restoring pH Balance in the Body: Video demonstration of how to use pH test strips and an explaination of how to balance the body's pH using diet and nutritional. Normal pH levels for the human stomach range between 1 and 5, according to About.com. These numbers indicate high acidity, which is because the stomach produces. Aug 28, 2013. The pH scale is like this: every point on the scale represents ten times more (or fewer, depending on which way you're going) hydrogen ions. Slightly counter- intuitively. You could get some hydrochloric acid (the stuff in your stomach) and dilute it, and its pH would actually go up. Really. If you drop a bit of. A peptone meal adjusted to pH 5-5 produced gastric acid similar to the maximal response to hista- mine. A graded decrease of pH of the peptone meal to 1-0 resulted in the progressive inhibition of the gastric acid secretion and the concomitant suppression of the serum gastrin level. Exogenous secretin given in graded. Enamel can start to wear away at the pH level of 5.5. Stomach acid has a pH of 2.0 which is very acidic and can cause a lot of harm to your teeth. Some foods that can cause acid reflux are spicy foods, acidic foods and beverages, fatty. eating acidic food and a loose esophageal sphincter allowing stomach acid to splash around in the throat. The acidic food lowers the pH levels of the stomach, making sufferers more vulnerable to acidic splash-back. A loose esophageal.
Genetic engineering could open possibilities for patients with Parkinson's disease By Angela Betsaida B. Laguipo, BSNSep 11 2019 People with Parkinson's disease experience loss of dopamine-producing brain cells, leading to tremors, rigidity, bradykinesia, and postural instability, the primary symptoms of the disease. The loss of dopamine-producing neurons is a pathologic hallmark of Parkinson's disease. However, the exact mechanisms remain unclear. A team of researchers at the Sechenov University and University of Pittsburgh unveiled the most promising strategies in applying genetic engineering in a study and treatment of Parkinson's disease. The noble method can help study the role of cellular processes in the disease progression, develop new treatment methods and drugs, and estimate their effectiveness using animal disease models. Parkinson's disease (PD) is a neurodegenerative disorder that affects one's motor skills, including balance and coordination. Across the globe, about 6.5 million people have Parkinson's disease in 2016, compared to 2.5 million in 1990. In Australia, the prevalence of people with PD was higher than many cancers in 2014, and an estimated one in every 308 people lives with Parkinson's. Brain mechanisms trigger disease progression The neurodegenerative disorder has many motor and cognitive impairments and is usually seen among older adults, who are more than 55 years old. The disease progresses slowly and gradually, as it worsens over time. In severe cases, the patient may experience difficulty in controlling their motor skills and movements, talking, and independent actions, such as taking care of themselves. A noble treatment is important to help improve the quality of life of those inflicted with the disease. Published in the journal Free Radical Biology and Medicine, the study highlights how mechanisms in the brain trigger the development and progression of PD. Possible mechanisms of development of Parkinson's disease and the most promising ways of applying CRISPR/Cas9 for its studying and treating. Image Credit: Alena Manuzina They found many mechanisms that seem to trigger and hasten the development of Parkinson's disease. They discovered that 10 percent of all cases of PD are genetically predetermined. In most cases, the conditions stem from both genetic and environmental risk factors. While the aberrant redox metabolism is linked to iron dysregulation and accumulation of impaired mitochondria and is considered as one of the major drivers for neurodegeneration and death of dopaminergic cells, the specific mechanisms and anomalies are still unclear. The researchers focused on probable causes of the disease, which are associated with the oxidation-reduction (redox) reactions in cells, and the mechanisms of cell death, dubbed as apoptosis and ferroptosis. CRISPR, a genetic engineering technology, is a promising method to find new and effective drugs and treatments for neurodegenerative disease. There are many ways CRISPR can help address Parkinson's disease. Mitochondria and Parkinson's disease pathology Some genetic sequencing misses out large parts of the genome Hobbyist DNA services may be vulnerable to genetic hacking The first group of mechanisms connects the role of mitochondria with Parkinson's disease pathology. The mitochondria, or powerhouses of the cells, form reactive oxygen species (ROS) that are important in homeostasis regulation and signaling. When there is a damage in the mitochondria, ROS would accumulate and cause damage to cell structures. Since mitochondria damage can lead to progressive error in the cell, it's important that aged and damaged mitochondria should be eliminated immediately, in a turnover called mitophagy. When there is excess or inefficient mitophagy, it can lead to neurodegeneration. People with a mutation in the genes for PINK1 and Parkin, which are proteins important for mitochondrial functioning, had muscle degeneration, mitochondrial dysfunction, and loss of dopaminergic brain cells, which is typical to Parkinson's disease. In this scenario, CRISPR can help search for unknown genes and their protein products, which are drivers for disease development and progression. These proteins can be targets for the discovery of noble drugs and therapies, in the aims of treating people with PD. 3d illustration of CRISPR-Cas9 technology - Image Credit: Meletios Verras / Shutterstock Iron homeostasis in cell functioning Homeostasis is the internal balance of body processes. The second group of cellular processes is associated with iron homeostasis or balance. Iron and ROS are important for the proper functioning of the cells, and if there is any alteration, it could lead to disruptions in vital cellular processes. If there is an imbalance in iron, it can accumulate in the brain tissues of older adults. Usually, they can deposit in areas of the brain that controls motor and cognitive functions. In previous studies, high level of iron in the substantia nigra is accompanied by dopaminergic brain cell death. CRISPR technology can help develop drugs that can normalize iron balance in the affected areas of the body, in this case, the brain. Apoptosis and ferroptosis The last group of processes is cell death programs, called apoptosis and ferroptosis. The cells' proteins and DNA are broken down with enzymes during apoptosis until it disintegrates. After which, ferroptosis occurs, wherein the iron-dependent oxidation of lipid classes. Oxidation byproducts accumulate in the cell, which leads to poisoning. These cell death programs may contribute to the development of neurodegenerative diseases, since they speed up the death of cells, including the dopaminergic neurons. CRISPR can help in this case by providing detailed studies of cell death pathways, leading to a better understanding of their roles in the development of Parkinson's disease and other brain diseases. "This is one important step of many toward bringing the promise of this new technology to patients with serious diseases like neurodegenerative disorders. It has already been used in human trials (in China, Germany, the USA) to treat patients with cancer at a late stage and beta-thalassemia," Margarita Artyukhova, study author, said. "Such studies allow us to see the vast potential of genome editing as a therapeutic strategy. It's hard not to be thrilled and excited when you understand that progress of genome editing technologies can completely change our understanding of the treatment of Parkinson's disease and other neurodegenerative disorders," she added. Artyukhova, M., Tyurina, Y., Chu, C., Zharikova, M., Bayir, H., Kagan, V., and Timashev, P. (2019). Interrogating Parkinson's disease associated redox targets: Potential application of CRISPR editing. Free Radical Biology and Medicine. https://www.sciencedirect.com/science/article/pii/S0891584919302515?via%3Dihub Posted in: Medical Research News \| Medical Condition News Tags: Apoptosis, Beta-Thalassemia, Bradykinesia, Brain, Brain Cell, Cancer, Cas9, Cell, Cell Death, CRISPR, DNA, Dopamine, Dopaminergic, Drugs, Ferroptosis, Genes, Genetic, Genetic Engineering, Genome, Genome Editing, Medicine, Metabolism, Mitochondria, Muscle, Mutation, Neurodegeneration, Neurodegenerative Disease, Neurodegenerative Diseases, Neurodegenerative Disorder, Neurons, oxygen, Parkinson's Disease, Pathology, Poisoning, Protein, Thalassemia Angela Betsaida B. Laguipo Angela is a nurse by profession and a writer by heart. She graduated with honors (Cum Laude) for her Bachelor of Nursing degree at the University of Baguio, Philippines. She recently completed a Master's Degree where she specialized in Maternal and Child Nursing and is now working as a clinical instructor and educator in the School of Nursing at the University of Baguio. Laguipo, Angela. (2019, September 11). Genetic engineering could open possibilities for patients with Parkinson's disease. News-Medical. Retrieved on January 20, 2020 from https://www.news-medical.net/news/20190911/Genetic-engineering-could-open-possibilities-for-patients-with-Parkinsone28099s-disease.aspx. Laguipo, Angela. "Genetic engineering could open possibilities for patients with Parkinson's disease". News-Medical. 20 January 2020. <https://www.news-medical.net/news/20190911/Genetic-engineering-could-open-possibilities-for-patients-with-Parkinsone28099s-disease.aspx>. Laguipo, Angela. "Genetic engineering could open possibilities for patients with Parkinson's disease". News-Medical. https://www.news-medical.net/news/20190911/Genetic-engineering-could-open-possibilities-for-patients-with-Parkinsone28099s-disease.aspx. (accessed January 20, 2020). Laguipo, Angela. 2019. Genetic engineering could open possibilities for patients with Parkinson's disease. News-Medical, viewed 20 January 2020, https://www.news-medical.net/news/20190911/Genetic-engineering-could-open-possibilities-for-patients-with-Parkinsone28099s-disease.aspx. New molecular mechanism can reverse genetic defect responsible for Friedreich's ataxia First patient recruited for UK-wide Parkinson's disease trial VA researchers find new evidence on the underlying biological causes of anxiety CHOP-led study reveals how genetic variations can influence variety of common diseases Study provides new insights into small acidic protein linked to Parkinson's disease Researchers uncover genetic anomaly linked with poor response to common asthma treatment Genetic signature helps distinguish latent autoimmune diabetes in adults from pediatric-onset T1D Major genetic study provides most comprehensive map of breast cancer risk variants to date Post-mortem genetic testing used to find underlying cause of sudden deaths in Amish families
Dr. Chaney - Do Antioxidants Really Matter? You've seen the headlines. Several studies of high dose, single antioxidant supplements have failed to show a protective effect against heart disease. Perhaps we shouldn't be surprised. In nature there are thousands of antioxidants in our food supply, and they interact synergistically. Until now no one has investigated how the total antioxidant capacity of the diet is associated with the incidence of heart disease. This study (Rautiainen et al, American Journal of Medicine, 125: 974-980, 2012) did just that. The scientist in charge of this study evaluated data collected in the Swedish Mammography Cohort study. They randomly selected 32,561 women aged 49 to 83 who had no evidence of cardiovascular disease at the start of the study and followed them for an average of 9.9 years. They did a comprehensive diet analysis at the start of the study and, based on the known antioxidant potential of the individual foods, they calculated the total antioxidant capacity of the diet. The women were divided into five groups based on the total antioxidant capacity of their diet. The scientists directing the study were able to determine the total number of fatal and nonfatal heart attacks in each group of women because Sweden keeps a comprehensive health record of everybody in the country. In analyzing these data the frequency of heart attacks in each group was adjusted according to weight, smoking, alcohol consumption, physical activity, hormone replacement therapy use, hypercholesterolemia, family history of heart disease, and food supplement use. The results were clear cut. The women with the highest antioxidant intake were 20% less likely to have a heart attack during the 9.9 year follow-up than women with the lowest antioxidant intake. The bottom line is pretty simple and non-controversial. It really is a pretty good idea to consume a healthy diet rich in antioxidants from a variety of sources. The women in this study with the highest antioxidant intake were getting 44% of their antioxidants from 6 to 7 servings of fruits and vegetables per day, 18% of their antioxidants from 3 to 4 servings of whole grains per day, 14% of their antioxidants from consuming 3 to 4 servings of coffee a day, and 4% of their antioxidants from consuming less than one serving of chocolate per week. And, just consuming one kind of food just won't do. While this study showed a highly significant correlation between total antioxidant intake and heart disease, the correlations became non-significant when the investigators looked at any single food category such as fruits and vegetables, whole grains, or coffee. Of course, since the data were normalized for supplement use, this study doesn't really speak to whether antioxidants supplements might provide any benefit. It's pretty clear that high-dose, single antioxidant supplements provide little protection against heart disease. But what about antioxidant supplements that provide a full-spectrum of naturally occurring antioxidants? Is there any evidence that they might provide benefit? In fact there is such a study. The Landmark Study (Block et al, Nutrition Journal 2007, 6:30doi:10.1186/1475-2891-6-30) looked at people who were consuming a complete spectrum of antioxidants from supplements along with a multivitamin, B vitamins and omega-3 fatty acids (something I call a holistic approach to supplementation) for 20 years* and compared the prevalence of heart disease in that group to matched groups - one who consumed just a multivitamin for 20 years and the other who consumed no supplements whatsoever. The participants in this study who were pursuing a holistic approach to supplementation had a three-fold lower prevalence of heart attacks, angina, and congestive heart failure than the other two groups. Don't rely on a single food or food category to get your antioxidant nutrients; consume a wide variety of antioxidant rich foods. Based on this clinical study you might want to aim for 6 to 7 servings of fresh fruits and vegetables and 3 to 4 servings of whole grains on a daily basis. Coffee or tea can add your total antioxidant intake, and even an occasional piece of chocolate is okay. This group used supplements from Shaklee Corporation for 20 years or more. *Vitalizer is a convenient source of the nutrients that Dr. Chaney suggests. Really antioxidant has huge benefits for human body. I love this post very much. So much informative and useful too. Thanks for sharing with us.
Botox: In orthodontics Harshal Ashok Patil1, Veerendra V Kerudi1, Prasad Vasudeo Bonde1, Pawankumar Dnyandeo Tekale2 1 Department of Orthodontics, ACPM Dental College, Dhule, Maharashtra, India 2 Department of Orthodontics, Dr. Rajesh Ramdasji Kambe Dental College and Hospital, Akola, Maharashtra, India Date of Web Publication 1-Jul-2016 Pawankumar Dnyandeo Tekale Dnyanita Orthodontic Care, Aurangabad, Maharashtra Botulinum toxin type A (BTX-A) (Botox, Allergan, Irvine, CA, USA) has been studied since the late 1970s for the treatment of several conditions associated with excessive muscle contraction. Smile esthetics has become a major concern among patients and orthodontists. This article describes the efficient, nonsurgical, and less invasive use of BTX-A injection for the correction of a gummy smile in orthodontics. Keywords: Botulinum toxin, gummy smile, orthodontics Patil HA, Kerudi VV, Bonde PV, Tekale PD. Botox: In orthodontics. J Dent Allied Sci 2016;5:21-4 Patil HA, Kerudi VV, Bonde PV, Tekale PD. Botox: In orthodontics. J Dent Allied Sci [serial online] 2016 [cited 2023 Jan 30];5:21-4. Available from: https://www.jdas.in/text.asp?2016/5/1/21/185190 As society becomes more esthetically conscious orthodontists are more challenged to produce not only outstanding occlusions but also outstanding esthetics. Every minute, detail is becoming more important in separating the good from the great orthodontist. Recent studies have indicated that the amount of gingival display on smiling is very important to smile attractiveness.[1] In fact, Van der Geld et al. found that the amount of gingival display was an important characteristic in a person's own satisfaction with their smile.[2] The display of excessive gingival tissue in the maxilla upon smiling, or "gummy smile," is both an oral hygiene and cosmetic issue with no simple remedy. Excessive gum exposure is frequently attributable to over-contraction of the upper lip muscles, particularly the levator labii superioris alaeque nasi. Although several surgical techniques have been reported in the literature for the correction of hyperfunctional upper lip elevator muscles, such as the Rubenstein and Kostianovsky,[3] Miskinyar,[4] and Rees and LaTrenta [5] techniques, they are not routinely used to treat a gummy smile.[6] In general, the most common surgical corrections currently used are the LeFort I maxillary osteotomies with impaction for skeletal vertical maxillary excess, and gingivectomies for delayed passive dental eruption with excessive gingival display.[6],[7] Some patients do not wish to go through the long presurgical orthodontic treatment in preparation for a LeFort I osteotomy. Others wish to avoid the possible complications surrounding surgery such as postoperative pain, swelling and infection, permanent or temporary nerve damage, root damage during osteotomy, surgical or orthodontic relapse, possible need for blood transfusion, and finally a less than optimal occlusal outcome. A nonsurgical alternative for reducing excessive gingival display caused by muscle hyperfunction would be advantageous. Botulinum toxin (BTX) has been under the clinical investigation since the late 1970s for the treatment of several conditions associated with excessive muscle contraction or pain.[8] Furthermore, it is the first-choice treatment for wrinkles located on the upper third of the face, BTX is also widely used in the prevention and correction of changes caused by muscle contraction in the middle and lower thirds of the face and neck, including a gummy smile. BTX, a natural protein, is one of the most potent biological substances known. The toxin inhibits the release of acetylcholine (ACH), a neurotransmitter responsible for the activation of muscle contraction and glandular secretion. Administration of the toxin results in a reduction of tone in the injected muscle. Some nerve terminals are not affected by the toxin, allowing the injected dystonic muscle to contract, but with less force. This weakness allows for improved posture and function of the hypertonic muscle. The degree of weakening depends on the dose, and the duration of weakness is further dependent on the serotype of BTX employed. The seven distinct serotypes, A, B, C, D, E, F, and G, differ in their potency, duration of action, and cellular target sites.[9],[10] BTX-A is marketed worldwide under the name Botox ® (Allergan Inc., Irvine, CA, USA) and in Europe as Dysport ® (Speywood Pharmaceuticals Ltd., Maidenhead, UK). Botox ® has been approved by the US Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm,[11] focal spasms, including hemifacial spasm,[12] cosmetically for the facial glabellar lines,[13] and more recently for the treatment of cervical dystonia [14] and axillary hyperhydrosis. BTX-B has been approved by the FDA for the treatment of cervical dystonia and will be marketed under the name Myobloc ® in the US and Neurobloc ® in Europe (Solstice Neurosciences Inc., South San Francisco, CA, USA). BTX is synthesized as a large single-chain peptide. Activation requires a two-step modification in the tertiary structure of the protein. This process converts the single-chain neurotoxin to a di-chain neurotoxin comprising a 100,000-Da heavy chain (HC) linked by a disulfide bond to a 50,000-Da light chain (LC). BTX acts at the neuromuscular junction where it exerts its effect by inhibiting the release of ACH from the presynaptic nerve terminal. ACH is contained in vesicles, and several proteins (vesicle-associated membrane protein [VAMP], synaptosomal-associated protein 25 kDA {SNAP-25}, and syntaxin) are required to release these vesicles through the axon terminal membrane. BTX binds to the presynaptic terminal via the HC. The toxin is then internalized, and the HC and LC are separated. The LC from BTX-A cleaves SNAP-25, the LCs from serotypes B and F cleave VAMP, and from serotype C cleaves syntaxin.[15] This disrupts ACH release and subsequent neuromuscular transmission resulting in weakness of the injected muscle. The potency of BTX is expressed as mouse units, with 1 mouse unit equivalent to the median lethal dose (LD 50) for mice. Botox ® is dispensed in small vials containing 100 U, while a vial of Dysport ® contains 500 U. The relative potency of Botox ® units to Dysport ® units is approximately 1:4. The lethal dose of Botox ® in humans is not known, although it has been estimated to be about 3000 U. The usual maximum total recommended dose at an injection session in the dental office is about 80-100 U. This means that the injector will have to inject 30 vials before a potentially lethal outcome. There is such a huge disproportion between the clinical dose and the lethal dose that a fatal overdose is almost impossible. The toxin is produced by the gram-negative anaerobic bacterium Clostridium botulinum. It is harvested from a culture medium after fermentation of a toxin-producing strain of C. botulinum, which lyses and liberates the toxin into the culture. The toxin is then extracted, precipitated, purified, and finally crystallized with ammonium sulfate. In this form, BTX-A should be stored in a refrigerator but not frozen. BTX-A should be diluted with preservative-free saline and the preparation used within 4 h of reconstitution. Conditions for the stability of the toxin in solution include pH 4.2-6.8 and temperature <20°C. The large molecule is very fragile and is inactivated easily in solution by shaking. Injection Site for Gummy Smile: Yonsei Point BTX should be injected in small, carefully titrated doses to limit muscular over-contraction of the upper lip, thus reducing exposure of the upper gums when smiling. Hwang et al., at Yonsei University College of Dentistry, Seoul, Korea have proposed an injection point for BTX and named it as Yonsei point.[16] It is basically a point located at the center of the triangle formed by levator labii superioris, levator labii superioris alaeque nasi, and zygomaticus minor. A dose of 3 U is recommended at each injection site. If applied in small, carefully titrated doses, these muscles can be proportionately weakened with Botox, which will reduce exposure of the upper gums when smiling. Contraindication Patients should not be treated or treated with extreme caution who are: Psychologically unstable or who have questionable motives and unrealistic expectations. Dependent on intact facial movements and expressions for their livelihood (e.g. actors, singers, musicians, and other media personalities). Afflicted with a neuromuscular disorder (e.g. myasthenia gravis and Eaton-Lambert syndrome). Allergic to any of the components of BTX-A or BTX-B (i.e., BTX, human albumin, saline, lactose, and sodium succinate). Taking certain medications that can interfere with neuromuscular impulse transmission and potentiate the effects of BTX (e.g. aminoglycosides, penicillamine, quinine, and calcium blockers). Pregnant or lactating (BTXs are classified as pregnancy category C drugs).[17] Local effects of BTX are generally transient. Hypersensitivity reactions have not been described. At present, no long-term complications of Botox therapy have been identified.[18] Some short-term, unwanted side effects are a pain, bruising, weakness of adjacent muscles, ptosis, delayed eyelid closure, decreased blink response, excessive tearing, asymmetry of the face, headache, antibody development, and necrotizing fasciitis.[19] According to Sarver, a slight amount of gingival exposure is acceptable and that contrary to posed smile, an unposed smile is natural in that it expresses authentic human emotion.[20] The best orthodontically treated subjects may not be satisfied by the treatment if soft tissue problem is not corrected. Botox is indicated when the gummy smile is due to hyperfunctional upper lip elevator muscles (muscular capacity to raise the upper lip is higher than average), and Botox is an excellent nonsurgical alternative. Botox is a conservative, safe, minimally invasive treatment modality to achieve enhancing esthetic results. The procedure is to be performed by a dermatologist who is also a Botox certified physician. BTX-A was diluted according to the manufacturer's recommendations to provide 2.5 units per 0.1 ml by adding 4.0 ml normal saline solution to 100 units of vacuum-dried clostridium BTX-A.[21] Training is absolutely necessary for dentists to administer injections, but the learning curve is very short because dentists can already achieve profound anesthesia in the orofacial region, thus making patient more comfortable and at ease. Polo [6] conducted a study on 30 patients received BTX-A injections to reduce excessive gingival display. Patients were followed at 2, 4, 8, 12, 16, 20, and 24 weeks postinjection, with changes documented by photographs and videos. At week 2, the patients rated and evaluated with the effects of BTX-A. The result stated that BTX-A injections for the neuromuscular correction of gummy smiles caused by hyperfunctional upper lip elevator muscles were effective and statistically superior to baseline smiles, although the effect is transitory. Sandler et al.[22] treated a female patient of age 35 with a gummy smile, and the result showed that the BTX-A injections for the neuromuscular correction of gummy smiles caused by hyperfunctional upper lip elevator muscles were effective minimally invasive and temporary treatment outcome. Patel et al.[23] conducted a study on 60 subjects age from 18 to 23 years with excessive gingival display due to hyperfunctional upper lip elevator muscles were treated with BTX-A injections, and the patients were evaluated clinically evaluated after 3 days, 7 days, 14 days, 1.5 months, 2.5 months, 4.5 months, and 6 months. The study concluded that the treatment modality was effective, producing esthetically acceptable smiles in these patients, and the improvements lasted 3-6 months. Amin et al.[7] reported a case in which the patient with excessive gingival display was treated with BTX-A injection, and it was concluded that the use of Botox is conservative treatment in a patient with short upper lip and gummy smile. However, the improvement is temporary and must be repeated every 6 months to 1 year. Hyperfunction of the upper lip elevators muscles (levator labii superioris, alaeque nasi, levator anguli oris, and the zygomaticus muscle) can all play a major etiological role in a gummy smile. Thus, concise evaluation of etiology, diagnosis, and implementation of treatment plan had an important role in treatment outcome. The ability of BTX-A to produce muscle paralysis by chemodenervation has been utilized to treat the patient with hyperactive upper lips. The only disadvantage is that treatment with Botox is not a permanent option, unlike other surgical alternatives. The effect of this treatment is for short-term usually for 6 months, and the patient has to get it redone after that. It is important to note that injection of Botox should not be given prematurely before the effect of earlier treatment has worn off completely as this can result in buildup of antibodies to Botox that will dilute the effect of further treatments. Moreover, the treatment might sometimes produce asymmetrical results due to injection at wrong site or by an inexperienced clinician, and the cost is also high for such a treatment.[24] Injection with BTX-A provides effective, minimally invasive, temporary improvement of gummy smiles for patients with hyperfunctional upper lip elevator muscles. Ker AJ, Chan R, Fields HW, Beck M, Rosenstiel S. Esthetics and smile characteristics from the layperson's perspective: A computer-based survey study. J Am Dent Assoc 2008;139:1318-27. Van der Geld P, Oosterveld P, Van Heck G, Kuijpers-Jagtman AM. Smile attractiveness. Self-perception and influence on personality. Angle Orthod 2007;77:759-65. Rubenstein A, Kostianovsky A. Cosmetic surgery for the malformation of the laugh: Original technique. Prensa Med Argent 1973;60:952. Miskinyar SA. A new method for correcting a gummy smile. Plast Reconstr Surg 1983;72:397-400. Rees T, LaTrenta G. The long face syndrome and rhinoplasty. Perspect Plast Surg 1989;3:116. Polo M. Botulinum toxin type A in the treatment of excessive gingival display. Am J Orthod Dentofacial Orthop 2005;127:214-8. Amin V, Amin V, Swathi, Jabir A, Shetty P. Enhancing the smile with Botox — Case report. Glob J Med Res 2013;13:14-8. Brin MF, Hallett M, Jankovic J, editors. Preface. In: Scientific and Therapeutic Aspects of Botulinum Toxin. Philadelphia: Lippincott Williams and Wilkins; 2002. p. v-vi. Dolly O. Synaptic transmission: Inhibition of neurotransmitter release by botulinum toxins. Headache 2003;43 Suppl 1:S16-24. Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon 2000;38:245-58. Jankovic J, Brin MF. Therapeutic uses of botulinum toxin. N Engl J Med 1991;324:1186-94. Brashear A, Gordon MF, Elovic E, Kassicieh VD, Marciniak C, Do M, et al. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med 2002;347: 395-400. Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM. Botulinum toxin type A (BOTOX) for treatment of migraine headaches: An open-label study. Otolaryngol Head Neck Surg 2000;123:669-76. Brashear A. The botulinum toxins in the treatment of cervical dystonia. Semin Neurol 2001;21:85-90. Blasi J, Chapman ER, Link E, Binz T, Yamasaki S, De Camilli P, et al. Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 1993;365:160-3. Hwang WS, Hur MS, Hu KS, Song WC, Koh KS, Baik HS, et al. Surface anatomy of the lip elevator muscles for the treatment of gummy smile using botulinum toxin. Angle Orthod 2009;79:70-7. Moriarty KC. Botulinum Toxin in Facial Rejuvenation; Revised; 2006 United States Elsevier. Naumann M, Jankovic J. Safety of botulinum toxin type A: A systematic review and meta-analysis. Curr Med Res Opin 2004;20:981-90. Dastoor SF, Misch CE, Wang HL. Botulinum toxin (Botox) to enhance facial macroesthetics: A literature review. J Oral Implantol 2007;33:164-71. Mazzuco R, Hexsel D. Gummy smile and botulinum toxin: A new approach based on the gingival exposure area. J Am Acad Dermatol 2010;63:1042-51. Sarver DM. The importance of incisor positioning in the esthetic smile: The smile arc. Am J Orthod Dentofacial Orthop 2001;120:98-111. Sandler PJ, Alsayer F, Davies SJ. Botox: A possible new treatment for gummy smile. Virtual J Orthod 2007;7:30-4. Patel DP, Mehta F, Thakkar SA, Suthar JR, Verma S. Botulinum toxin type A (Botox) for the neuromuscular correction of excessive gingival display on smiling (gummy smile). Indian J Basic Appl Med Res 2014;3:237-44. Bansal A, Jain M, Joshi M, Agarwal D. Botox in dentistry: The healing side of A poison. J Adv Med Dent Sci 2014;2:95-9. Patil HA Kerudi VV Bonde PV Tekale PD Injection Site f...
To improve accessibility of healthcare and to enhance communication between Healthcare Providers and their Clientele in a secure environment. To provide a means for Healthcare Providers to monetize their consultations when away from the consultation venue. To help healthcare consumers and healthcare providers stay connected online. Smartphones are readily available and affordable to the masses. Internet connectivity is widespread and information about health and diseases is easily accessible online. However, it is difficult to interpret pertinent health information without the expertise of a healthcare professional. Even so, it takes a proper understanding of a patient's individual needs and medical history to correctly diagnose and treat an ailment. Social networks or messaging apps are NOT places to discuss or exchange private health information, hence, the best way to meet the needs of Healthcare Consumers and Healthcare Providers is to enable them to engage and communicate on a secure user-friendly platform. The GoConsult Platform addresses all these needs and more. Follow-ups can be cumbersome & inconvenient. GoConsult provides an efficient solution to conduct follow-up consultations via our cloud based telehealth solution. Variations in health conditions between scheduled appointments can sometimes cause worry. Founded in 2015, GoConsult Sdn Bhd along with our partners Agmo Studio is backed by a team with an abundance of experience in the mobile app development industry. Our vision is to deliver easy to use, innovative technological solutions backed by efficient operations.
Journal of Child Language Email your librarian or administrator to recommend adding this journal to your organisation's collection. URL: /core/journals/journal-of-child-language Who would you like to send this to? * You are leaving Cambridge Core and will be taken to this journal's article submission site. Popular Recent Articles Child Bilinguals FirstView articles To send this article to your account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about sending content to . < Back to all issues Page/Article number: low to high Page/Article number: high to low Title Type Online publication date Early phonological and lexical development and otitis media: a diary study* Mavis L. Donahue This diary study describes early phonological and lexical development in a child with chronic otitis media with effusion. Equipped with the tools of a referential/analytic language-learner, the child solved the problem of reduced and fluctuating auditory input with phonological selection and avoidance strategies that capitalized on prosodie cues. This 'tone-language' approach resulted in a lexical inventory that would be categorized as an extreme expressive style. Having 'boot-strapped' her lexical learning, the child continued to rely on phonological constraints and selection strategies to fuel lexical and syntactic growth, i.e. cross-domain interactions leading to a vocabulary spurt and the onset of two-word utterances. These findings illustrate the need to consider interactions among performance, input and linguistic constraints in order to explain individual variation in language learning. Vowel dominance in overregularizations* Joseph Paul Stemberger When children produce regularizations like comed, not all verbs are equally likely to be regularized. Several variables (e.g. lexical frequency) have been shown to be relevant, but not all the variability between verbs is understood. It is argued here that one predictor is which vowels are present in the base form vs. the past tense form. Using a notion of recessive vs. dominant vowel (where recessive vowels are more likely to be replaced by dominant vowels than vice versa) based on adult phonological processing, it is predicted that regularizations should be likely when the base vowel is dominant and unlikely when the past tense vowel is dominant. Data from 17 children reported in the literature, aged 1;6–5;6, show that this prediction is correct. Implications for the role of phonological variables in the processing of irregular past tense forms are discussed. Early lexical development in Spanish-speaking infants and toddlers* Donna Jackson-Maldonado, Donna Thal, Virginia Marchman, Elizabeth Bates, Vera Gutierrez-Clellen This paper describes the early lexical development of a group of 328 normal Spanish-speaking children aged 0;8 to 2;7. First the development and structure of a new parent report instrument, Inventario del Desarollo de Habilidades Communcativas is described. Then five studies carried out with the instrument are presented. In the first study vocabulary development of Spanish-speaking infants and toddlers is compared to that of English-speaking infants and toddlers. The English data were gathered using a comparable parental report, the MacArthur Communicative Development Inventories. In the second study the general characteristics of Spanish language acquisition, and the effects of various demographic factors on that process, are examined. Study 3 examines the differential effects of three methods of collecting the data (mail-in, personal interview, and clinic waiting room administration). Studies 4 and 5 document the reliability and validity of the instrument. Results show that the trajectories of development are very similar for Spanish-and English-speaking children in this age range, that children from varying social groups develop similarly, and that mail-in and personal interview administration techniques produce comparable results. Inventories administered in a medical clinic waiting room, on the otherhand, produced lower estimates of toddler vocabulary than the other two models. Reanalysing rote-learned phrases: individual differences in the transition to multi-word speech Julian M. Fine, Elena V. M. Lieven The present study investigates the possibility that the previously documented relationship between referential–expressive and nominal–pronominal styles (Nelson, 1975) may be best explained not so much in terms of 'object-orientation' or 'noun-preference', as in terms of the direction from which different children break into structure, with some children tending to construct patterns by combining two or more items from their single-word vocabularies and others tending to develop patterns by gaining productive control over 'slots' in previously unanalysed phrases. In order to do so it makes use of a methodology for distinguishing between productive and unanalysed multi-word speech proposed in Lieven, Pine & Dresner-Barnes (1992) which is applied to observational and maternal-report data from a longitudinal study of seven children between the ages of 0; 11 and 1; 8. The results suggest not only that variation in children's early word combinations can indeed be explained in terms of different routes to multi-word speech, but also that, far from being atypical, a strategy involving the breaking down of originally unanalysed phrases may be used by all children, though to varying degrees. Pronoun reversals: who, when, and why?* Philip S. Dale, Catherine Crain-Thoreson Seventeen of a sample of 30 precocious talkers aged 1;8 produced at least one pronoun reversal (I/you) during unstructured play. This finding led to an examination of the role of cognitive and linguistic individual differences as well as contextual factors and processing complexity as determinants of pronoun reversal. Contrary to predictions derived from previous hypotheses, there were few differences between reversers and non-reversers, other than higher use of second person forms by reversers. Reversals were more likely to occur in certain contexts: semantically reversible predicates with two noun phrases, and in imitations (though the rate of imitation was lower overall in reversers). We propose that pronoun reversals commonly result from a failure to perform a deictic shift, which is especially likely when children's psycholinguistic processing resources are taxed. Children who did not produce any pronoun reversals tended to avoid pronoun use, especially second person forms. Overt reversal may thus reflect a risk-taking approach to language acquisition, which may be particularly characteristic of precocious children. Event knowledge and early language acquisition* Michael Jeffrey Farrar, Margaret J. Friend, James N. Forbes The role of event knowledge in early language acquisition was investigated. Thirteen two-year-olds were observed interacting with their mothers over a five-week period. During weekly observational sessions, dyads interacted in both a familiar-event context and an unfamiliar-event context. Events were represented by complex toys (e.g. airport, marina, etc.). In the familiar-event, dyads interacted with the same event-toy during each observation period. In the unfamiliar-event, these same dyads interacted with a different novel toy during each observation period. The results indicated that children's increasing event knowledge facilitated their language development. Specifically, children's lexical type use, action verb use, and MLU increased in the familiar-event, but remained unchanged in the unfamiliar-event. Event knowledge also facilitated children's lexical token use. Results are discussed in terms of the role of event knowledge in language acquisition. On the origins of denial negation* Peter Hummer, Heinz Wimmer, Gertraud Antes These are the principal questions of this study: are the early fonctions of negation, such as REJECTION, and the later emerging DENIAL no developmentally related? And when do children start to deny? So far, evidence for the questions at hand has been almost exclusively observational. We decided on a simple elicitation procedure instead, asking 48 children (ages between 1;1 and 2;7) easy yes/no-questions. The most likely age range for the appearance of denial no was 1;8–2;1. Its error-free acquisition supports the continuity theory of negation development, which holds that essentials of denial no carry over from the earlier fonctions of no. Finally an attempt is made to account for the beginnings of denial in terms of semantics and the representational theory of child cognition. Uses of past forms in the social pretend play of Italian children* Tullia Musatti, Margherita Orsolini In different languages children have been found to use past verb forms to express the meaning of 'unreality' during social pretend play. In this study, the verb forms used by 14 four-year-old Italian children in their pretend play were investigated. Results show that different Italian past verb forms tend to co-occur with different play activities. The imperfect occurs mainly when children plan and negotiate their pretend activities and marks the transition from a real to a pretend frame of reference. The present perfect occurs mainly when children implement their plans and communicate within a pretend frame that has already been established. Results of this study are discussed in comparison with findings on the pretend language of children speaking other languages. Marking of verb transitivity by Hebrew-speaking children* Ruth A. Berman The study examines children's command of transitivity permutations in Hebrew, where a change in verb-argument syntax entails a change in verb-morphology. 30 children aged two, three and eight were required to produce existing and novel Hebrew verbs differing in transitivity. Younger children showed a good grasp of the syntax and semantics, but not the morphological marking of transitivity, three-year-olds did much better, and eight-year-olds produced mainly adultlike responses. Results were higher on existing verbs than on novel forms. Direction of change had little effect with existing verbs, but with novel verbs success was much higher in changing intransitive to transitive forms than the converse. Some alternations proved easier than others, e.g. intransitive activity verbs in the basic pa'al verb-pattern yielded more causative hif'il forms than intransitive inchoative verbs in the nif'al pattern. Findings throw light on the development of derivational morphology, item-based versus class-based learning, and the impact of lexical productivity and language-particular properties on acquisition. Remembered voices* Richard Ely, Allyssa McCabe The speech children spontaneously quote was examined in two studies. In Study 1, a corpus of personal narratives from 96 children aged 4;0 to 9;0 was analysed; Study 2 investigated reported speech in 25 younger children aged 1;2 to 5;2 interacting with their parents. In both studies, the frequency of reported speech increased with age. Direct quotation was more common than indirect or summarized quotation at all ages. In Study 1, children quoted themselves more frequently than any other speaker, and their mothers more frequently than their fathers. Directives were the most commonly reported speech act from the distant past in both older (Study 1) and younger (Study 2) children. In Study 1, girls used reported speech more frequently than did boys, and their quotations were more direct in form than were those of boys. Phonological devices in poems by English and Italian children* Ann Dowker, Giuliana Pinto Poems were elicited from 133 English children between two and six and 171 Italian children between three and seven, using a similar technique, and the results were compared. Both groups produced large numbers of poems. There were great similarities and some differences. The majority of poems in both samples contained phonological devices (mostly rhyme and alliteration) and the proportion was higher (87%) in the Italian sample than in the English sample (59%). The proportion of poems that contained rhyme was close to 45% in each sample, with no consistent age difference in either sample. About one-third of Italian poems and just over a fifth of English poems contained alliteration. The frequency of alliteration declined with age in the English sample but not in the Italian sample. Possible reasons for the differences between the samples are considered. It is argued that the similarities are more important, and their theoretical implications are discussed. The acquisition of Italian morphology: a reply to Hyams* Elena Pizzuto, Maria Cristina Caselli In Pizzuto & Caselli (1992, hereafter: P&C) we provided an overview of morphological development in Italian, focusing on three aspects of free speech production (verbs, pronouns and articles), in the longitudinal records of three children. We analysed our data using criteria appropriate to allow reliable cross-linguistic comparisons with data from English. By this means we evaluated the plausibility of a nativist, parameter-setting account of language development in Italian and English, as proposed for these two languages by Hyams (1986a b; 1987; 1988). We concluded that our data did not support the strong predictions made within such a parameter-setting account, and that the developmental patterns observed were best explained by a combination of cognitive, perceptual and distributional factors of the sort that are proposed in most other models of language acquisition. Harald Clahsen, Child language and developmental dysphasia. Linguistic studies of the acquisition of German. Amsterdam: John Benjamins, 1991. Pp. ix + 350. (English translation of: Normale und gestörte Kindersprache: linguistische Untersuchungen zum Erwerb von Syntax und Morphologie. Amsterdam: John Benjamins, 1988.) Saskia Stoessel-Deschner M. F. McTear & G. Conti-Ramsden, Pragmatic disability in children. London: Whurr Publishers, 1992. Pp. ix + 235. Leonard Abbeduto L. Frazier & J. De Villiers (eds) Language processing and language acquisition. Dordrecht: Kluwer. 1990. Pp. 400. Rosemary J. Stevenson M. A. Forrester, The development of young children's social-cognitive skills. Hove: Erlbaum, 1992. x + 215 pp. A. J. Wootton Index of Books Received Published online by Cambridge University Press: 26 September 2008, p. 731 JCL volume 20 issue 3 Cover and Front matter Published online by Cambridge University Press: 26 September 2008, pp. f1-f2 JCL volume 20 issue 3 Cover and Back matter Published online by Cambridge University Press: 26 September 2008, pp. b1-b10
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A health outcomes and disease management network (100) and related method is provided for efficiently and effectively monitoring patient status and providing recommendations for patient healthcare. The system and method deploys a plurality of monitoring stations and a computer network. Each of the monitoring stations includes a measuring device. Healthcare managers coordinate with each other to develop patient treatment programs based in part on data received from the monitoring stations. The present application claims benefit under 35 U.S.C. § 119(e) of a U.S. provisional application of Glenn P. Vonk, Ann K. Frantz, David J. Whellan, Christopher M. O'Connor and George Goldman entitled "A Health Outcomes and Disease Management Network and Related Method for Providing Improved Patient Care", Serial No. 60/215,254, filed June 29, 2000 . A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by any one of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever. The present invention relates to a health outcomes and disease management network for providing improved healthcare. More particularly, the present invention relates to a network of healthcare managers and healthcare providers who interactively cooperate with patients to monitor and evaluate patient status to provide the most appropriate treatment for the patients in the most cost-effective manner, thus improving overall healthcare. The health outcomes and disease management network consists of both local networks located within a healthcare provider organization, and a meta-network which links the local networks to a metaservice. Meta-services aggregate data from local networks, process the data to reveal population trends and outcomes, and provide rapid feedback and information on the best medical/economic practices to the local networks. Modem healthcare and disease management is becoming more complex due to the many different options that are becoming available for providing short-term and long-term patient treatment, as well as the many different types of payment and insurance programs in existence. In evaluating all the different options to arrive at the most suitable, the interests of all "stakeholders" involved should be taken into consideration. The various stakeholders involved in healthcare may be broadly classified into three groups: payors, providers (or care teams), and patients. Payors generally address concerns associated with increasing financial pressures of healthcare. Payors tend to be skeptical about new concepts since their profit margins are generally at risk and declining. Payors include traditional fee for service insurance companies, Health Maintenance Organizations (HMOs), Physician Provider Organizations (PPOs), and Integrated Delivery Networks (IDNs). The government is also a payor, and is continually looking for new ways to reduce the cost of care delivery in order to control escalating medical expenditures. Government payors are particularly important since they pay for the most care and set precedents for payment. Providers include hospitals, nurses, case managers, social workers, doctors, and many others in contact with patients. Providers are largely concerned with efficiency and quality of the care delivered, and frequently complain that they have little time for preventive interventions since they have to limit their attention to acute cases. This sub-optimization in care delivery is universally appreciated, but little has been done to bring a more strategic perspective to the providers' world. Additionally, providers are often skeptical that these disease management initiatives might limit their flexibility to manage patients. Often, these initiatives are designed to bring additional cost controls to bear on provider organizations. These controls further reduce revenue for providers and drive the provider to a lower standard of care in order to increase patient volume and maintain income. Providers seeking good clinical outcomes for their patients are often frustrated by these situations. Patients, on the other hand, are concerned with living a long life, having good care and good quality of life at an affordable price. Patients frequently complain of poor service, such as long waits, limited access to important information, and confusing billing, to name a few. Patients therefore often grow weary of endless repeated questions and being treated as a "member of plan A" rather than a person. Patients generally want to be in control of their own care. Few provider organizations inquire about the patient's goals even though the individual outcomes desired may vary considerably. Related to patient is the patient's family. Often, a spouse, other immediate family member or significant other provides substantial support to the patient. These individuals may be granted pre-approval, in consultation with the patient, to access certain elements of the disease management network. For example, a family member may obtain educational information, information on the patient's status, access a chat session, and interact with the healthcare manager to provide effective local support to the patient. Payors, providers, and patients are generally unsatisfied with healthcare services prevalent today. Methods commonly referred to as "disease management" promise to address the diverse needs of the stakeholders, but have not delivered on these promises due to lack of sufficient integration. Present disease management companies may be classified into either service or device suppliers. Service suppliers have demonstrated that intensive patient management does significantly improve clinical outcomes. However, the cost of this intensive intervention by highly trained personnel has been unsustainable. In response, certain of these companies have moved from a relatively high cost of home based or local delivery to a centralized, less intensive approach relying predominately on remote nurses interacting with patients by telephone. Under these circumstances, the care delivered has not been adequate to generate equivalent clinical outcomes. Further, these remote organizations lack credibility among local providers. Service oriented disease management companies have not succeeded broadly for any disease state. Device oriented disease management companies appreciate the fact that remote service suppliers have been unable to effectively monitor patients at remote locations. These businesses seek to provide this monitoring using remote devices and a data network to transfer information about patient status to the providers. Examples of device oriented disease management systems are described in published International Patent Application No. WO 99/04043 of Abbott Laboratories, in published International Patent Application No. WO 99/46718 of Healthware Corporation, and in U.S. Patent No. 5,987,519 . Device oriented disease management companies have not succeeded broadly in the marketplace for several reasons. First, the devices are generally expensive and difficult to use. Second, the receipt of raw patient information presents a liability to the provider. The provider must evaluate this information in real time or risk litigation in the event that this information provided early warning of a significant health event that was not acted upon in time. Both device and service oriented companies have failed to justify their costs to healthcare organizations over time. Frequently, clinical outcomes are presented for small numbers of patients over short time periods to establish program credibility. While clinical outcomes may look attractive, payors and providers are not generally convinced by these studies. Generally, there is minimal description of the necessary expenditures to deliver these results. Further, no information has been provided on the efficacy of any program to a number of health systems. Payors question if it will work in their venue. This incredulity has led to business models which reduce the risk of adoption by healthcare organizations through risk sharing. Disease management companies may go at risk for sub-populations within provider organizations. The first phase of these arrangements allows the supplier to recover the investment needed to install the system. The second phase allows some split of the savings between provider, payor, and supplier. These arrangements sound attractive, but are difficult to administer since the supplier depends on the healthcare organizations to share the economic and clinical data required to administer the split. Also, there are significant cultural barriers for provider organizations to "carve out" populations to external suppliers. These barriers include the tacit admission that the provider organization cannot provide the care for the population and the concern that doctor - patient relationships will suffer. A third difficulty with present disease management suppliers concerns poor definition of the optimal customer. Early disease management suppliers marketed systems to provider organizations. These suppliers succeeded only in very limited venues under extreme cost pressure or capitated reimbursement. Generally, provider organizations risk declining utilization when effective disease management is incorporated into healthcare delivery and are dis-incented to participate. Disease management has also been marketed to payor organizations with similar results. While some payors appreciate the potential of disease management they do not provide care. No matter how good the disease management system is, payors often lack influence to change care paradigms among providers. Neither can payors understand the subtle real and cultural issues which play when disease management is incorporated into the provider system. Certain disease management models rely on patients to self-pay for care. However, most patients are reluctant to incur significant out of pocket expenses for healthcare. Yet another model seeks to market disease management to physicians. These models have limited financial potential and often are a financial liability to individual providers due to increased time requirements and lack of reimbursement for regular disease management consultations. A fourth difficulty with disease management suppliers concerns their inability to encourage healthy behaviors. Most disease management programs use disease-specific population-based practice guidelines to manage high risk patient populations. These guidelines describe well defined patient and provider activities which improve clinical outcomes. Performance tracking against guidelines is often required to achieve accreditation as a center of excellence. However, performance tracking is costly and often not implemented even when the provider organization complies with accepted guidelines. Provider organizations which fail to demonstrate performance against accepted guidelines may risk loss of professional accreditation and erosion of goodwill. Further, provider organizations lack expertise to influence both individual providers and patients to adopt healthy behaviors suggested by the guidelines. What these organizations uniformly lack are tools to change behaviors. Performance benchmarking is one of the more useful tools for encouraging superior behaviors. A fifth problem concerns the progress of medical knowledge, which rapidly obsoletes established practice. Medical practice is justifiably conservative. New therapies are often greeted with "healthy" skepticism until proven to be valuable across a wide diversity of unique patient concerns and comorbidities. However, the development of data driven and evidence based medicine will be greatly accelerated by telecommunications. It is expected that this information will, in turn, accelerate both the rate of change and the complexity of medical best practices. Providers will find it necessary to formulate integrated treatment plans which process personal genomic information, monitoring, assessments, pharmacogenomics, psychosocial evaluations, value, and other specialized information in the light of the patient's own expressed wishes and needs. Guidelines will become customizable to specific patient issues. Effective communication of improved guidelines to providers will be required to achieve the promised benefits. Ultimately, providers will desire tools to assist with the many complexities of customized best practices. Accordingly, a need exists for a health outcomes and disease management network capable of providing optimum patient care in the most efficient and cost-effective manner, and which satisfies patients, providers and payors. Patent number US 5,960,403 discloses a system as defined by the preamble of claim 1. The present invention is defined by the appended claims. An objective of the present invention is to establish a health outcomes and disease management network which is capable of providing optimum patient care in the most efficient and cost-effective manner, and which satisfies patients, providers and payors. Another objective of the present invention is to provide a healthcare management network that enables care managers and care providers to interact with patients to improve patient treatment, as well as overall healthcare for existing and new patients, while also taking issues pertaining to payors into consideration. A further objective of the present invention is to provide a healthcare and disease management network that enables patients to self-monitor their treatment and status and provide information to healthcare managers which, in cooperation with health care providers, establish recommendations for treatment to optimize patient care. Yet another objective of the present invention is to provide effective patient education using both conventional web-based user interfaces and high bandwidth interactive video. Effective patient education can facilitate client self-management improving clinical and economic outcomes. Interactive video can provide these services in an asynchronous mode with substantial cost savings. That is, clients can interact with the same video session many times without taking time from individual providers. If a person to person intervention is required, the individual provider can choose the appropriate time with the assistance of resource management tools provided by the disease management network rather than having to respond immediately to a large number of urgent and disruptive, but low priority queries. These and other objects of the present invention are substantially achieved by providing a health outcomes and disease management network for efficiently and effectively monitoring patient status as well as providing recommendations for improved patient healthcare. The network can be configured, for example, as an Internet-based network which enables information to be efficiently exchanged between healthcare managers, healthcare providers, and patients. The network includes a centralized network comprising, for example, a computer or computer network, and a centralized database for storing information pertaining to the healthcare management network, such as patient information, treatment plan information, recommendations from care providers, recommendations from healthcare managers, and so on. The centralized network communicates via the Internet, for example, to workstations that can be used by care managers, and workstations that can be used by care providers, such as physicians and specialized healthcare providers, so that the managers and providers can readily add and retrieve information to and from the database. The centralized network also communicates via the Internet, for example, to one or more IDNs or other payors. The network further includes terminals, such as interactive televisions or workstations, which can be provided to each patient subscribing to the network, and which communicate with the centralized network via the Internet, for example. The patients also can be provided with health monitoring tools, such as testing equipment and the like, which enable the patients to add and retrieve information to and from the centralized database via the patient workstation. When a patient is selected for participation in the network, information relevant to the patient's healthcare treatment as well as the patient's disease, if any, is collected and entered into the centralized database. A patient periodically updates this information as instructed by a healthcare manager who monitors the information provided by patients to which he or she is assigned. The healthcare manager is any individual provider that serves as the primary contact between a patient and the care team. The healthcare manager may be a staff person, a nurse, a physician assistant, or a medical doctor. Most preferably, the healthcare manager will be part of the local provider organization. The healthcare manager uses this information to coordinate treatment plans for the patient with the healthcare providers, and to provide suggestions and recommendations to the patient for improved overall healthcare. The healthcare manager further uses the information collected from the patients and providers to identify improvements in care that can be provided by adjusting the treatment plans for certain individual patients or groups of patients. The above objects are also substantially achieved by providing a system for monitoring health-related conditions of patients, employing a plurality of remote monitoring stations and a computer network. Each of the remote monitoring stations includes at least one measuring device, adapted to measure a physiological condition of a respective patient, and to provide data representative of the physiological condition for inclusion among patient health-related data pertaining to a respective patient. The health-related data can include, for example, data relating to a patient's heart. The computer network comprises a database containing accumulated health-related data pertaining to health-related conditions and treatment. The computer network is adapted to receive the patient health-related data from the remote monitoring stations via, for example, the Internet, to establish treatments programs for the patients based on their respective patient health-related data and the accumulated health-related data, and to revise the accumulated health-related data based on the patient health-related data. The computer network further includes at least one data access device, adapted to provide a health care provider access to the computer network and the database. The computer network is adapted to generate reports, each including health-related information pertaining to a respective said patient. The computer network is adapted to provide the accumulated health-related data stored in the database to organizations financing at least a portion of the treatment programs, and is adapted to receive financial data pertaining to the treatment programs from the organizations and to store the financial data in the database. Fig. 13 is a flowchart illustrating an example of specific activities performed by a client in the network shown in Fig. 1. A health outcomes and disease management network 100 according to an embodiment of the present invention is shown in Fig. 1. As illustrated, the network 100 includes a centralized computer or computer network 102 including a centralized database 104 for storing information pertaining to patients in the network, as well as healthcare and health outcomes information. The network 100 is preferably an Internet-based network which enables parties participating in the network 100 to access the centralized database 104 via the internet. In this example, the network 100 is used to monitor heath outcomes and manage patients suffering from heart disease. However, the basic principles of the network 100 can be used for any health outcomes and disease management and patient education program. The network 100 further includes one or more care teams 106 that include, for example, primary care teams (PCT), extended care teams (ECT) and an appropriate number of healthcare managers, the responsibilities of each are described in more detail below. For simplicity, only one care team 106 is shown. However, network 100 can include any suitable number of care teams, and each care team can include any suitable number of managers, a primary care team and extended care teams. The members of the care team 106 have access to workstations, such as personal computers, handheld devices, pagers, wireless phones or the like, which can interact with the centralized network 102 via the Internet 108 to access data in the centralized database 104 and to provide data to the centralized database 104 as described in more detail below. The centralized network 102 also communicates via the Internet with networks and databases 110 of one or more IDNs or other payors for purposes discussed in more detail below. As further illustrated in Fig. 1, the network 100 further includes patients or clients 112 which receive treatment by the care team 106, and whose health status and outcomes are monitored by members of the care team 106 as described in more detail below. For simplicity, only one client 112 is shown in Fig. 1. However, as can be appreciated by one skilled in the art, the network can have any suitable number of clients, such as several hundred thousand or even millions, as long as the clients can be properly serviced by the care teams 106. As further illustrated, the clients 112 each have access to a workstation 114, such as an interactive TV computer workstation or the like, which can access the centralized network 102 and centralized database 104 via the Internet 108. The workstation 114 serves the client 112 by providing automated answers to many questions about management of the client's disease state, as described in more detail below. The workstation 114 also enables such information to be communicated from the client 112 to centralized database 104 which provide services to a care team in charge of monitoring the client 112. Patient education may be "prescribed" through the healthcare network by a member of the care team or obtained through patient self-exploration using a home information appliance (interactive television, pager, wireless phone, handheld device). The clients 112 are also each provided with monitoring or diagnostic tools, such as blood pressure measuring devices 116, electronic scales 118, and disease management information charts 120, as well as glucometers, thermometers, spirometers, medication management and various other devices which can be used to obtain diagnostic and assessment information from the clients 112. As described in more detail below, the clients 112 use these tools to enter information about themselves and their condition into the centralized database 104 and then communicate personal information via their workstations 114. The client may manually enter the information into the workstation 114, or this information may be transparently transferred between the devices and the workstation 114 by wireless or cabled means. Members of their care team 106 can review that information and monitor the clients' status as well as provide treatment information and recommendations to the client 112. Specifically, the centralized network 102 interprets the diagnostic and assessment information and presents it to the appropriate care team 106 in a manner that both improves the provider's productivity and limits liability of information overload. As discussed in more detail below, the centralized network 102 stratifies clients 112 into various prioritized risk related groups for action by the care team. An interactive dashboard on the workstation can be used that profiles the client population by selected risk factors which may include time since last contact, assessment and diagnostic information (for example, blood glucose, glycated hemoglobin, weight, blood pressure), abnormal medication usage, significant comorbidities, psychosocial data, and quality measures. Tools are also provided to assist providers as they respond to this patient information including resource management, scheduling, guidelines, protocols, and behavioral tools. The provider team is much more productive since many of the routine diagnostic and assessment functions have been automated. Client information is then archived into a second database for further analysis to benchmark performance and identify opportunities for improvement of care practices. The model uses a blend of devices and services to maximize value for all the stakeholders. Whenever information is transmitted the disease management network will maintain appropriate security and confidentiality of patient information. For example, the Health Insurance Portability and Accountability Act of 1996 (Public Law 104-191), also known as HIPAA, was enacted as part of a broad Congressional attempt at healthcare reform. HIPPA requires the United States Department of Health and Human Services (HHS) to develop standards and requirements for maintenance and transmission of health information that identifies individual patients. HIPPA both standardizes the interchange of electronic patient data for certain administrative or financial transactions, and specifies standards to ensure confidentiality of electronic health information. Home wireless networks must also ensure reliability and confidentiality of personal health information. This may be achieved through unique identification of personal devices and through encryption. Potentially, individual patients and providers, and other items important to patient health may be identified to the disease management network with RF tags. Aggregation of population based information will also require standards to ensure confidentiality through anonymity and contractual means similar to those in place for obtaining the Medicare Provider Analysis and Review (MEDPAR) file of inpatient hospital and Skilled Nursing Facility (SNF) final action stay records from the Health Care Financing Administration. Fig. 2 is a conceptual business model diagram generally illustrating the benefits received by participants in the network 100. The business model functions as follows. Clients 112 receive services which confer significant wellness benefits. These services also confer financial benefits to payors who pay a management fee to local provider organizations. Payors may experience some increased cost due to improved utilization of drug therapies. The providers may pass through some of this fee to the network 100. The network 100 provides disease management protocols, frameworks, and technology to support local providers, including support to participate in clinincal trials. Local providers may charge a per patient per month (PPPM) fee, some of which may be passed on to the network 100 in return for on-going support. The network 100 also provides behavioral tools which assist providers with understanding and motivating patients. Fig. 3 is a flowchart providing a general illustration of activities performed by the network 100 and its participants. As shown in step 1000, the business relationships are defined that are to exist between care team members 106 (including medical doctors, nurse practitioners, nurses, and physical assistants), payors 110 and clients 112. The healthcare managers and their associated responsibilities will also be identified, and publicizing and marketing of the network 100 will be performed. The initial clients 112 are selected in step 1100 and assigned to respective health managers in the care team 106. While the most preferred method of disease management is through a local provider and care team, we anticipate certain patients, their physicians, or their provider networks may independently elect to participate in aspects of the disease management network while administering other aspects independently. For example, the physician may elect to participate in a monitoring service using devices only while providing disease management services in her own practice. Likewise, certain clients may elect to participate in the disease management independently of their payors. These clients would self-pay these expenses. In step 1200, the healthcare managers develop a respective client plan of care (CPOC) and medical plan of care (MPOC) for their respective clients 112 in cooperation with the care providers, such as the primary care physicians, hospitals and specialists. In step 1300, the healthcare managers accordingly care for their respective clients 112 between the primary care team and extended care teams, while also receiving, monitoring and evaluating information provided by the clients 112. During this time, the clients 112 are also responsible for monitoring and managing their conditions, and providing data to the centralized database 104. In step 1400, the healthcare managers review the status of their respective clients 112 and compare their client's progress to expected outcomes. The managers can coordinate with the care providers to revise the CPOCs and MPOCs for their respective clients 112, and report relevant information to the clients, PCTs, ECTs and payors, as necessary. The members of the care team 106 can then analyze the data received from all the clients 112 or a sample of clients, as appropriate, and revise the standards of care for particular health conditions, as deemed necessary. Fig. 4 illustrates a detailed flowchart of an example of activities performed during the general steps shown in Fig. 3, and the tables shown in Figs. 5-9 provide descriptive information pertaining to these activities. For instance, during the preplanning step 1000, the network 100 performs step 1010, which involves publicizing the network 100. In step 1020, healthcare managers are identified. Most preferably, the healthcare manager can be selected from the local provider organization. During the selection step 1100 shown in the flowchart in Fig. 3, several substeps shown in the flowchart of Fig. 4 and as described in the table in Fig. 6 are performed. For example, the health care managers are selected in step 1110 who are to manage certain groups of clients 112. In step 120, potential clients 112 are recognized for participation in the network 100, and in step 1130, the clients 112 are selected for participation in the network 100. The client selection process is an interactive process between the client 112, healthcare manager, care providers and payors. For example, a client 112 wishing to participate in the network may make an inquiry to a healthcare manager regarding the details associated with participating in the network 100. Most preferably, a provider (hospital discharge manager, physician) will recommend a client for participation in the disease management network. A healthcare provider, such as a physician, uses inclusion and exclusion criteria to evaluate the suitability of a client 112 for participation in the program. For example, inclusion criteria for a patient participating in a heart disease monitoring program may have a requirement that the client 112 receive a primary diagnosis of congestive heart failure (CHF), and that the client 112 is at a high risk of future admissions to, for example, a hospital or a long-term healthcare facility. Exclusion criteria may include factors such as whether the potential client 112 is unable to read or speak English, is deaf, is younger than 18 years old, or is unwilling to have a telephone. The disease management network may ultimately incorporate features to overcome these limitations including multilingual capability, speech recognition and synthesis, wireless communications, and so on. When a healthcare provider has analyzed a particular client 112 based on the inclusion and exclusion criteria, the healthcare provider can contact the healthcare manager with a recommendation to either accept or reject the client's participation. The payor can also use the same or similar inclusion or exclusion criteria to evaluate the suitability of a client 112 for participation in the program. Once an evaluation has been made, the payor can contact the healthcare manager with a recommendation to either accept or reject the client's participation in the program. The payor would also coordinate with, for example, a hospital discharge planer which will oversee the release of client 112 from the hospital or long-term care facility. In all cases, the intent will be to maintain control of the client's primary care physician or cardiologist. The disease management network will enhance and extend the reach of the existing medical decision markers. Once the information has been gathered and the recommendations have been made in step 1130, the healthcare manager contacts the client 112 in step 1140, and the client 112 can then agree to participate in the network 100. For example, the client 112 can receive a call or an e-mail from the healthcare manager and agree to participate in the network verbally and through written signed consent, via return e-mail and/or regular mail. The client 112 can then schedule a date for a visit with the healthcare manager. When the client 112 has agreed to participate in the network 100, the healthcare provider, such as a physician, receives notification from the network 100 of the client's agreement to participate. The payor 110 also receives notification of the clients' participation. Furthermore, while the client 112 is in communication with the healthcare manager, the healthcare manager can describe the program to the client 112 and solicit questions from the client 112 to determine if the client 112 actually meets the criteria for participation. If the healthcare manager agrees after receiving this additional information that the client 112 is suited for participation, the healthcare manager coordinates with the client 112 to schedule a date for a visit with the client 112. Also during this process, the information being provided by the client's, healthcare providers, payors and healthcare managers is being collected at the central network 102 and in the central database 104. The central network 102 can then generate lists of clients 112 that are selected as potential clients, as well as groups of clients 112 who have agreed to participate in the program and groups of clients 112 who have not agreed to participate in the program. The members of the care team 106 and payors 110 can readily access this information via the Internet using their workstations. Once the substeps of step 1100 have been performed, the process proceeds to the enrollment phase in step 1200 shown in Fig. 3, and the following substeps are performed as shown in Fig. 4 and as described in the table in Fig. 7. Specifically, in step 1210, the manager collects the initial data from the client 112. For example, the client 112 will provide the manager with information required for initial enrollment. The healthcare manager collects demographic data for the enrollment and enters this initial data into the database 104, which receives and categorizes this data as appropriate. During this step, support can be provided to the healthcare manager concerning system utilization and troubleshooting. In step 1220, the healthcare manager may conduct a visit with the client 112. The client 112 can stay at home while the healthcare manager visits so that the client 112 can share the appropriate information with the healthcare manager in a comfortable environment. Alternately, the interview may be conducted from a remote location using any normal means of telecommunication (for example telephone, e-mail, wireless phone). The healthcare manager also conducts a client interview which includes an evaluation of the client's medical condition as well as the client's physical and psychosocial conditions, and environmental conditions. During the client visit, the healthcare manager can also perform a risk factor assessment. The healthcare manager then can set an emergency treatment plan for the client 112 and provide the client 112 with the necessary instructions to implement such a plan. The healthcare manager also orients the client 112 to the network, and may install any of the devices shown in Fig. 1, such as a blood pressure monitoring kit 116, an electronic scale 118, interactive TV equipment and the like. Alternately, less acute patients may be monitored through clinic visits on an outpatient basis. Support can be provided to the healthcare manager in setting up the client's equipment and for troubleshooting malfunctions in the equipment. The centralized network 102 of the network receives acknowledgement of the client's agreement to participate, the client's medical release and the client's acknowledgment of the client's bill of rights. The database receives the data provided by the client 112, and the centralized network 102 receives the emergency treatment plan. The centralized network 102 can then acknowledge the link via, for example, the internet 102, with the client 112 interactive devices, such as the blood pressure monitoring kit 116, electronic scale 118, and the like. In step 1230, the healthcare manager contacts the healthcare provider, such as the clients' primary care physician. The physician receives a telephone call, for example, from the healthcare manager, and then the healthcare manager and physician share important information pertaining to client 112. The healthcare manager also can contact the extended care physician regarding the client's healthcare and can confer with the physicians concerning the initial assessment data, the results of the data collection from the client 112, and the initial MPOC set by the physician. The healthcare manager can also educate the physician as necessary with regard to the attributes of the network 100. The manager also enters the MPOC, assessment data and data collection results into the centralized network 102 and centralized database 104 of the network 100. The centralized network 102 upon receiving this information places the information in the appropriate format. The extended care team also share the MPOC regarding comorbidities with the healthcare manager. Support can be provided for the health care manager regarding utilization and troubleshooting. The process continues to step 1240 where the healthcare manager confirms and redefines plans of care for the client 112, such as the CPOC and MPOC. The physician receives the MPOC from the healthcare manager and can confirm the MPOC or communicate any discrepancies in the MPOC with the healthcare manager. The healthcare manager forms the primary care team based on the initial assessment data, data collection results and MPOC and comorbidities received in step 1230. In doing so, the healthcare manager creates a clinical and encounter schedule, develops an initial client plan of care, establishes coordination of the care with the extended care team, and confirms the patient formally. The health care manager enters the CPOC into the centralized network 102 and database 104 of the network, and as discussed above, sends the MPOC and CPOC to the physician for information. The centralized network 102 and database 104 receives the MPOC and CPOC from the healthcare manager, and the centralized network 102 confirms the patient's familiarity with the healthcare manager. The centralized network 102 then sends the encounter schedule to the client's workstation 114 via the Internet 108 so that the client 112 can view the encounter schedule at his or her workstation 114, which can be a computer terminal or interactive TV as described above. At all times, support can be provided for the health care manager for system utilization and troubleshooting purposes. Once the processes in the enrollment 1200 have been performed as described above, the process proceeds to the management steps 1300 shown in the flowchart of Fig. 3. The substeps of the manager process 1300 are then performed in the following manner as shown in flowchart of Fig. 4 and as described in the table shown in Fig. 8. For example, steps 1310, 1320 and 1330 can be performed simultaneously by the different parties involved. That is, in step 1310, the healthcare manager coordinates the primary care team and the extended care team. During this time, the healthcare manager coordinates conferences with the primary care team regarding the client's CPOC, tracks changes in the client's MPOC set by the extended care team members, and communicates the changes to the primary care team. The healthcare manager also confirms that changes are address with the client 112 and entered properly into the centralized network 102. Also during this time, the client 112 participates in primary care team conferences as appropriate, while the physician is notified of primary care team conferences and participates in them as appropriate. The physician also can communicate concerns regarding the client's condition or health management to the healthcare manager. The primary care team participates in a regular team conferences about the client's CPOC and MPOC, and provides advice regarding the best CPOC for the client 112. The primary care team can also contact the client 112 as necessary regarding management issues, such as nutrition, medications, physical activity, finances, stress, and the like. The extended care team updates the healthcare manager concerning changes in the client's MPOC concerning comorbidities. The centralized network 102 receives the information recorded during the team conferences, as well as data for updated CPOC and MPOC. The centralized network 102 recognizes primary care team members and receives data specific to their proposed interventions, such as changes in the client's diet, exercise plan, medication interactions or contra indications, and financial planning. During this time, customer service support can be provided to the healthcare manager regarding system utilization and troubleshooting. In step 1320, the healthcare manager conducts the clinical encounters in accordance with the healthcare plan. Specifically, the healthcare manager follows clinical encounters schedules and scripts and assesses client's physical and psychological responses. The client 112, on the other hand, prepares for regular encounters with the healthcare managers and participates in those regularly scheduled encounters. Customer service support can also be provided to the healthcare manager as necessary. In step 1330, the client 112 executes self-management and self-education. That is, the client 112 integrates the MPOC and CPOC into his or her lifestyle consistently, while exploring and following self-education modules and asking questions during the regularly scheduled encounters with the healthcare manager. The healthcare manager tracks client's responses to self-education modules, assesses the responses for consistent integration of CPOC and MPOC into the client's lifestyle, and answers questions during the encounters. If the healthcare manager is unable to answer a question, the healthcare manager can refer the questions to the appropriate team member. The healthcare manager can also respond as necessary to emergency or urgent conditions, or symptoms of concern. During this time, the primary care team can answer client questions that the manager is unable to answer, while responding to the client 112 in a efficient and effective manner. The extended care team can also answer questions as appropriate, and respond in an effective and efficient manner. In this way, the primary team consists of any person concerned with the client's primary diagnosis. The primary care team may include the client, the client's general practitioner, primary care physician, or cardiologist, nurse practitioners, pharmacists, dieticians, social workers and others. The extended care team is concerned with secondary comorbidities. For example, if the primary diagnosis is heart failure, a member of the extended care team might include an endocrinologist treating diabetes, a comorbidity. While these activities are being performed, the centralized network 102 tracks ongoing client utilization of self-education modules, notifies the healthcare manager of client questions, and alerts the healthcare manager of emergency, urgent, or symptoms of concern. Customer service can also be provided during this time as appropriate. In step 1340, the client 112 performs the self-monitoring of his or her condition using the equipment provided such as the blood pressure measurement equipment 116, electronic scale 118, and the like. For instance, the client 112 can enter daily weight and blood pressure measurements, which can be forwarded to the centralized network 102 via the client's workstation 114, and that data can be entered into the centralized database 104. The client 112 can input additional physiological data through the MPOC, such as glucose measurements, ECG, and so on. The client 112 learns which values are normal and which are outside desired limits, and completes data surveys, such as an SF-36, and a food diary, if appropriate. The client 112 provides all this information to the centralized network 102 via the client workstation 114. During this activity, the healthcare manager tracks physiological data from the client 112 and responds to values outside the normal limits. The healthcare manager can contact the physician as appropriate with values outside the normal limits, and tracks the survey data provided by the client 112 in the SF-36, food diary, or a stress audit. The physician can respond the healthcare manager in a efficient and effective manner regarding physiological parameters outside the desire limits, as appropriate. During this time, the centralized network 102 is receiving input of the data and using preset parameters to determine if the data is outside normal limits. The centralized network 102 notifies the healthcare manager of the data that is outside the limits, and receives, stores and tracks the data provided by the client 112. At all times, customer services and support can be provided as necessary. As further shown in Fig. 4, the evaluation process 1400 shown in Fig. 3 includes several sub processes as described in the flowchart in Fig. 9. For example, in step 1410, the healthcare manager evaluates outcomes of the client's progress verses client expectations. Specifically, the healthcare manager reviews the data from the client 112 regularly, evaluates whether the data is consistent with expected outcomes, and communicates with the client 112 regarding inconsistent outcomes. The data is archived and surveyed by the centralized network 102, which can send data messages from the client 112 to the healthcare manager for evaluation. The client 112 also learns of ongoing evaluation and receives personal responses from the healthcare manager, as well as outcomes relating to the MPOC and CPOC. Customer support can be provided during this process as necessary. In step 1420, the healthcare manager communicates with the primary and extended care teams regarding client outcome and can, if necessary, define the treatment plans. For instance, the healthcare manager coordinates a primary care team conference regarding the patient outcomes, and communicates client outcomes to the physician. The physician can collaborate with the healthcare manager on defining the CPOC and MPOC for the client 112, and can communicate with the extended care team regarding pertinent client outcomes. The extended care team receives a contact from the healthcare manager regarding the pertinent client outcomes and can collaborate with the healthcare manager and, if necessary, the primary care team to define the MPOC if necessary. During this time, the centralized network 102 is receiving and documenting all client-related communications, as well as MPOC and CPOC refinements from the healthcare manager. Customer service support can also be provided. At this time, the client 112 also learns of ongoing evaluation of his or her personal responses, and outcomes to his or her MPOC and CPOC. In step 1430, the healthcare manager reports on the client's progress. For example, the healthcare manager can interact with the centralized network 102 to create an outcomes report, and to send the report to the client 112, physician, primary care team and payor, for example. The primary care team, physician and client 112 receive the report from the healthcare manager. The centralized network 102 can remind the healthcare manager when the outcome reports are due. At this time, customer service can be provided to the healthcare manager, as well as administration, marketing, research and development. Updated data can be received on all of the network's clients, and bench marking can be done for clinical and economic outcomes. It is also noted that in step 1440, the healthcare manager can analyze the aggregate, clinical and economic data cross client populations and identify improvements that can be made in client healthcare. For instance, the healthcare manager can evaluate aggregate clinical and economic data with regard to standards of care, encounter protocols, CPOC tools, and so on, and suggest potential improvements that can be made to the network 100 and overall healthcare provided. The primary care team can evaluate the aggregate data, as well as the clinical and economic data and also suggest improvements that can be made. The centralized network 102 provides the data necessary to perform these evaluations to the healthcare manager and the designated primary care team members and provide support for additional data process analysis. At this time, the aggregate report data can be reviewed for improvements. The advisory board can consider the improvement suggestions and provide a recommendation for a pertinent plan of action. If appropriate, the improvements are incorporated into the network as well as into the generic standards of care that have been predeveloped and are shown in the activities box labeled 1450. As indicated, these standards of care are influenced by advances in science shown in the box labeled 1460, which influences the client management approach developed by the extended care team and extended care team activities as indicated in boxes 1470 and 1480. Although Figs. 3 and 4 show the steps in a particular order, certain steps can be performed simultaneously, and the steps can otherwise be performed in any practical order which will achieve the intended outcome. Fig. 10 is a flowchart illustrating activities and operations performed by a healthcare manager. Many of these steps are included in or compliment the steps shown in the flowchart of Fig. 4 described above. That is, as shown in step 1500, the healthcare manger will monitor the status of the clients 112 he or she is managing. In step 1600, the healthcare manager can receive messages from any of a number of sources, such as clients, pager messages, or messages from the PCT or ECT. If appropriate, the healthcare manager performs resource management activities in step 1700, which include personal scheduling of meetings with clients 112, management of resources and client encounters. In step 1800, the healthcare management can use client stratification tools to analyze the status of the clients being managed. In step 1900, the healthcare manager can use client management tools, such as those associated with enrollment, as well as the CPOC, MPOC and monitoring or assessment management tools. In step 2000, the healthcare manager can use client assessment tools to assess the status of the client's condition. For example, the manager can use tools for monitoring the client's blood pressure, weight, glucose measurement and medications, and can use assessment tools which consider the client's medical history and results of various surveys relevant to the client's treatment. In step 2100, the healthcare manager performs evaluation activities, which include evaluation of individual client outcomes, evaluation of the generic healthcare standards used in the network 100 and outcomes of patients and the general population. The healthcare manager can also use an OASIS tool (Outcomes Assessment Information Set) and generate reports. Automated support for other regulatory, reporting, and billing requirements may also be provided including those required by the Joint Commission on Accreditation of Healthcare Organizations (JACHO), the National Committee for Quality Assurance (NCQA) / Health Plan Employer Data and Information Set (HEDIS), the Prospective Payment System (PPS), and Medicare/Medicaid. OASIS evaluation of each patient is required by the HCFA for reimbursement to home care agencies. In step 2200, the healthcare manager can perform education-related activities, and in step 2300, the healthcare manager can perform healthcare sub-portal access activities. This operation will now be described in more detail with respect to Fig. 11. In particular, during the status monitor step 1500, the healthcare manager waits for a status alert which comes, for example, from a client 112 or care provider. When a status alert has been received, the manager can then receive a message in step 1600. As illustrated, the healthcare manager determines in step 1610 whether the message was from a client 112. If so, the healthcare manager takes the appropriate action in step 1620 to handle client messages. If the message was not a client message, the healthcare manager determines if the message was received by his or her pager in step 1630. If so, the healthcare manager responds to the pager message as appropriate in step 1640. In similar manner, the healthcare manager determines in step 1650 if he or she has received an alert from the PCT. If so, the healthcare manager takes the appropriate action in step 1660. The healthcare manager also determines whether the message has been received from the ECT in step 1670. If so, the healthcare manager takes the appropriate action in step 1680. It is noted that when the healthcare manager takes the appropriate action associated with a particular type of message in step 1620, 1640, 1660 and 1680, the healthcare manager can still check for additional types of messages. That is, the healthcare manager can receive client messages, pager messages, PCT alerts and ECT messages pertaining to a particular client, and can take the appropriate action for each message in steps 1620, 1640, 1660 and 1680. Once the healthcare manager has considered all of the messages and has performed the appropriate action, the healthcare manager reports the appropriate information to the centralized network 102 which is then stored in the centralized database 104. In step 1700, the healthcare manager can take the appropriate resource management steps as described briefly above. That is, in step 1710, the healthcare manager determines whether any personal scheduling with, for example, clients, needs to be done. If so, the healthcare manager does the scheduling in step 1720. In step 1730 the healthcare manager determines whether any resources need to be allocated. If so, the healthcare manager performs the appropriate resource managing activities in step 1740. In step 1750, the resource manager determines whether any client encounters need to be performed. If so, the resource manager schedules the client encounters in step 1760. As illustrated, once the healthcare manager has performed the activities in steps 1720, 1740, and 1760, as appropriate, the healthcare manager reports the data as necessary to the centralized network 102 in step 1780, and the centralized network can store that data in a appropriate format in the database 104. The healthcare manager can than use the appropriate client stratification tools in step 1800 to perform the client's stratification operations in step 1810. The healthcare manager then can use the management tools in step 1900 to perform the appropriate managing activities, if necessary. For example, the healthcare manager can determine in step 1910 whether any enrollment operations need to be performed. If so, the healthcare manager can use the appropriate enrollment tools in step 1920. The healthcare manager can determine whether any CPOC has been established and if so, can obtain the CPOC document in step 1940. In step 1950, the healthcare manager can determine whether any MPOC has been established and, if so, can obtain the MPOC document in step 1960. In step 1970, the healthcare manager determines whether any monitoring or assessment management activities need to be performed. If so, such activities are preformed in step 1980. Once the above operations have been performed in steps 1920, 1940, 1960 and 1980, as appropriate, the healthcare manager can provide the appropriate data to the centralized network 102 in step 1990. The centralized network 102 can then store the data in centralized database 104, as necessary, and permit access to the data by the care team and payors. For example, payors can access the data to collect the data from all clients who are the payor's responsibility. The payors can then statistically review the collected data to determine, for example, whether any client's should receive reimbursements, and for outcomes analysis, preapproval of claims, and so on. In step 2000, the healthcare manager uses the appropriate tools for monitoring and assessing the status of the clients 112. For example, if the healthcare manager determines in step 2005 that monitoring steps are to be performed, the manager will determine whether the client's blood pressure needs to be monitored in step 2008. If so, the manager will monitor the client's blood pressure reading in step 2010. The manager will also determine in steps 2012, 2017 and 2022 whether the client's weight, glucose measurement and medication, respectively, need to be monitored and will monitor the weight measurement, glucose measurement and medication in steps 2015, 2020 and 2025 respectively, as necessary. Once the appropriate monitoring activities have been performed, the manager reports the data in step 2027 to the centralized network 102, which can store the data in database 104. The manager then determines in step 2030 whether any client assessment activity needs to be performed. If so, the manager determines in steps 2032, 2037, 2042 and 2047 whether any medical history updates, SF-36 forms, Duke Activity Indexes or DQUIPs, respectively, need to be used. Standard Form-36 (SF-36) available at www.sf36.com is an assessment tool used to determine quality of life and indicates both physical and psychosocial client status. SF-36 does not evaluate sleep adequacy, cognitive functioning, sexual functioning, health distress, family functioning, self-esteem, eating, recreation/hobbies, communication, and symptoms/problems that are specific to one condition. Symptoms and problems that are specific to a particular condition are not included in the SF-36 because the SF-36 is a generic measure. Consequently, SF-36 may be used to indicate quality of life in widely divergent populations and conditions, but is less useful for more targeted evaluations. The Duke Activity Index assesses the client's ability to perform routine physical activities. Other tools are targeted to specific disease states. For example, The Diabetes Quality Improvement Project (DQIP) represents a set of guidelines agreed upon by both the NCQA and the Foundation for Accountability (FACCT) as the standard for quality diabetes care. If any of these tools need to be used to assess the client's status, the manager obtains and uses the appropriate tools in steps 2035, 2040, 2045 and 2050, as necessary, and then continues to step 2052. In steps 2052, 2057, 2062, 2067 and 2072, the manager determines whether any spiritual perspective clinical scales, geriatric depression scales, Minnesota Living with Heart Failure Surveys, nutrition assessment tools or Sheehan patient anxiety scales, respectively, need to be used. If any of these tools need to be used to assess the client's status, the manager obtains and uses the appropriate tools in steps 2055, 2060, 2065, 2070 and 2075, as necessary, and then continues to step 2077. In step 2077, the manager reports the data obtained from the use of all the tools described above to the centralized network 102, which stores the relevant data in the centralized data base 104. The manager's activity then proceeds to the evaluation process 2100. During the evaluation process, the manager determines in steps 2105, 2115 and 2125 whether individual client outcomes, generic standards and population outcomes, respectively, need to be evaluated. If any of these outcomes require evaluation, the manager evaluates the outcomes as appropriate in steps 2110, 2120 and 2130, respectively. The manager then determines in step 2135 whether an OASIS reimbursement process for payors should be performed. If so, the manager performs the OASIS reimbursement process in step 2140. In step 2145, the manager determines whether any reports on the above evaluations or process should be generated. OASIS evaluations constitute a significant portion of the documentation required under the Prospective Payment System (PPS). PPS is the proposed government reimbursement mechanism for home care agencies. If so, the manager generates the reports in step 2150. Once the necessary evaluations and processes have been performed and the appropriate reports, if any, have been generated, the manager reports the data to the centralized network 102 in step 2155, which stores the data in the centralized data base 104 as appropriate. The manager's activity then proceeds to the education process in step 2200. During the evaluation process, the manager determines in steps 2205, 2215, 2225, 2235, 2245 and 2255 whether information relating to the client's treatment program, medication, stress and activity, disease process, symptom management and nutrition, respectively, should be conveyed to the client 112. If any of this information should be conveyed, the manager provides the information to the client 112 in steps 2210, 2220, 2230, 2240, 2250 and 2260, respectively, as appropriate. The manager then determines in step 2265 whether helpful heath tips should be provided to the client 112 in step 2270. The manager then reports the data obtained in the above steps to the centralized network 102, which can store the data in the centralized data base 104 as necessary. The manager's activity then proceeds to the health sub-portal services process in step 2300. Health sub-portals provide links to various other information services including Medscape, WebMD, and Oncolink. If the manager determines that sub-portal services should be accessed, the services are accessed in step 2310. The manager then continues to monitor for additional status alerts in step 1500, and the process repeats as above for each status alert received. Although Figs. 10 and 11 show the steps in a particular order, certain steps can be performed simultaneously, and the steps can otherwise be performed in any practical order which will achieve the intended outcome. Fig. 12 is a flow chart illustrating general activities performed by a client 112 participating in the network 100 viewed from the perspective of the client 112. These steps are included in or complement the steps shown in the flowchart of Fig. 4 as described above. For example, the client 112 monitors for a status alert in step 2400. When the client 112 receives a status alert from the network, the client 112 can perform the appropriate enrollment activity, when applicable, in step 2500. In step 2600, the client 112 monitors for messages that can be received from the network 100. In step 2700, the client 112 provides information to enable the manager to perform the assessment steps described above. Similarly, in step 2800, the client 112 monitors his or her conditions, as appropriate, and provides the results of the monitoring to the network for evaluation by the manager. The client 112 also performs self-evaluation activities in step 2900. In step 3000, the client 112 receives, reviews and uses the educational information provided by the manager, which assists the client 112 with his or her self-management activities in step 3100. Clients may seek educational information independently as well. The client 112 also receives the heart-flash information in step 3200, and performs health sub-portal access activities in step 3300. Further details of the steps shown in Fig. 12 will now be illustrated and described with respect to the flowchart in Fig. 13. As discussed above, the client 112 awaits receipt of a status alert in step 2400. When the network 100 provides a status alert to the client 112 in step 2410, the client 112 determines in step 2500 whether any enrollment activity needs to be performed. If enrollment activities are to be performed, the client 112 performs the enrollment activities described above in step 2510. Also, in step 2520, the client 112 can interact with a commitment screen which is displayed on the client workstation 114 (see Fig. 1), to report data to the centralized network 102 in step 2530. The centralized network 102 can store the data in the appropriate format in data base 104. Once the enrollment activity has either been completed or skipped, as appropriate, the client 112 can determine in step 2600 whether he or she has received any messages. For example, in steps 2610, 2630 and 2650, the client 112 determines whether he or she has received a client message, a page, or a PCT alert, respectively, and takes the appropriate action in steps 2620, 2640 and 2660, respectively. The client 112 then reports the data to the centralized network 102 in step 2670, which can store the data in data base 104 and allow the data to be accessed by the appropriate personnel. Once the messaging activity has been completed or skipped, as appropriate, assessment activities may be performed. If so, the client 112 participates in steps 2702, 2707, 2712 and 2717 to complete any medical history updates, SF-36 forms, Duke Activity Indexes or DQIPs, respectively. Generally, the manager determines the schedule for monitoring and assessments. However, the client may also initiate these processes as desired. If any of these tools need to be used to assess the client's status, the client 112 uses the appropriate tools in steps 2705, 2710, 2715 and 2720, as necessary, and then continues to step 2722. In steps 2722, 2727, 2732 and 2737, any spiritual perspective clinical scales, geriatric depression scales, Minnesota Living with Heart Failure Surveys, or nutrition assessment tools, respectively, may be used. Generally, the manager determines the schedule for monitoring and assessments. However, the client may also initiate these processes as desired. If any of these tools need to be used to assess the client's status, the client 112 uses the appropriate tools in steps 2725, 2730, 2735 and 2740, as necessary, and then continues to step 2742. In step 2742, the client 112 reports the data obtained from the use of all the tools described above to the centralized network 102, which stores the relevant data in the centralized data base 104. The processing then proceeds to step 2800. In step 2800, the client 112 uses the appropriate tools for monitoring and assessing his or her status, if necessary. For example, the client 112 or manager will determine whether the client's blood pressure needs to be monitored in step 2810. If so, the client 112 will take his or her blood pressure reading in step 2020. The client 112 or manager may also determine in steps 2830, 2850 and 2870 whether the client's weight, glucose measurement and medication, respectively, need to be monitored and will take the weight measurement, glucose measurement and medication in steps 2840, 2860 and 2880 respectively, as necessary. Once the appropriate measurements have been taken, the client 112 reports the data in step 2890 to the centralized network 102. The client's activity then proceeds to step 2900, where the client 112 or manager determines whether or not to perform a self-evaluation. If a self evaluation is to be performed, the client 112 uses selected profiles and history information in step 2910, as well as generic standards for CPOC and MPOC, to perform the self evaluation. The client's activity then proceeds to determine in step 3000 whether the education activity should be performed. If so, the client 112 or manager determine in steps 3005, 3015, 3025, 3035, 3045 and 3055 whether information relating to the client's nutrition, symptom management, disease process, stress and activity, medications and treatment program, respectively, should be received from the client's health manager. If any of this information should be received, the client 112 receives and uses the information in steps 3010, 3020, 3030, 3040, 3050 and 3060, respectively, as appropriate. In step 2890, the client 112 then reports any data obtained in the above steps to the centralized network 102, which can store the data in the centralized data base 104 as necessary. The network education tools may assess the client's understanding of the educational material and customize further sessions to optimize learning of important material. These tools may be interactive and delivered over high capacity data networks. The client 112 then determines in step 3100 whether he or she needs to perform self management. If so, the client 112 in step 3110 uses the client management tools provided by the manager, along with the generic standards for CPOC and MPOC in step 3120. The health manager may grant permission to the client to engage in self-management processes contingent on successful completion of education and assessment programs. In step 3130, the client 112 then reports any data obtained in the above steps to the centralized network 102, which can store the data in the centralized data base 104 as necessary. If the manager has sent a health tip to the client 112, the client 112 can receive the health tip in steps 3200 and review the information in step 3210. In step 3300, the client 112 determines whether to access health sub-portal services. If so, the client 112 accesses the services in step 3310. After the above steps have been either performed or skipped, as appropriate, the client 112 awaits receipt of another status alert in step 2400, and the above steps are repeated as necessary. Although Figs. 12 and 13 show the steps in a particular order, certain steps can be performed simultaneously, and the steps can otherwise be performed in any practical order which will achieve the intended outcome. As can be appreciated from the above, the network 100 and corresponding business model shown in Fig. 2 presupposes a minimal set of services and technology required to achieve critical mass for effective client management. Since all stakeholders find value, they are all motivated to participate in the program. Although conventional disease management services provide high intensity clinical support for patients at relatively high cost, information technology can significantly reduce the cost of delivering high intensity services. For instance, Web technology and the Internet permits asynchronous communications between clients 112 and individual providers. Since the provider does not have to be online at the same time as the client 112 (as in a video arrangement), the provider can prioritize interventions based on real importance rather than urgency. Further, this environment provides significant improvements through automation. Traditional disease management enterprises use paper records or require manual entry of assessment data into a database. However, the network 100 uses automated entry of client data into a database where it can be processed and presented to the providers in a format which maximizes their productivity. This automation includes patient stratification and surveillance using provider-defined criteria. In the event of emergency, the network 100 can escalate priority to notify the provider in real time thus limiting liability associated with higher data flux. Also, as discussed above, the payors can access and collect the data for clients who are the payor's responsibility. The payors can then statistically review the collected data to determine, for example, whether any client's should receive reimbursements, and for outcomes analysis, preapproval of claims, and so on. Furthermore, state of the art disease management provides specialized tools for patient education. Clients will find answers to chronic problems on the Web that will help them feel better. Also, as discussed above, inexpensive devices (blood pressure, scale, glucometer, thermometer, therapeutic devices, diagnostic instruments) can be connected to an information appliance (for example an interactive TV) which serves as a conduit for automated transfer of this information over a data network to the provider's server for processing and presentation to the providers. This information can, in turn, be transferred to a second database for outcomes analysis and benchmarking within the health delivery organization. This information can be processed to remove patient identities and analyzed for intersystem benchmarking and outcome comparisons. As discussed in the background section above, there have been few disease management studies that credibly demonstrate attractive clinical and economic outcomes. Clinical outcomes should be based on easily measured results such as hospitalizations or emergency visits. Numerous tools exist to evaluate quality of life including SF-36, the Minnesota Living with Heart Failure survey and others. Economic outcomes require detailed information about interventions and their cost. These studies need to be performed at sufficient scale and duration such that the results are statistically valid. Only when these studies are replicated at a number of diverse healthcare organizations do the results become truly credible. The network 100 described above can establish the necessary credibility. First, credibility is established by bringing together multiple medical centers experienced in large clinical trials. Second, IDNs afford the best location for these studies since they have access to financial information on diverse patient populations in multiple care delivery venues. Certain at-risk IDNs are unique in having both world class reputation and the broad diversity to evaluate clinical and economic outcomes as described above. The network 100 provides a third way to ensure credibility by engaging a well-known independent actuary to establish the credibility of the results. The network 100 further enhances the credibility of the disease management system by gaining access to more information about patient status using remote monitoring and assessment. A high degree of credibility will enable simple business arrangements based on per patient per month charges rather than difficult to administer, less profitable risk sharing agreements. As explained above, the network 100 provides software tools, devices, protocols, computers, and data networks resident at the local provider sites. In addition, local providers are installed, customized, and trained, so that they will, in turn, provide care to local patients. Local providers will have an option for local branding or co-branding with a world class medical center. Since care is delivered locally, credibility with local individual providers and provider organizations is likely to be high versus remote management. Further, the network 100 provides a venue for converting expensive acute care operations to more profitable and sustainable preventive operations. This is especially important given the number of local disease management start-ups that fail due to lack of expertise, resources needed to achieve scale, insufficient value, or inability to demonstrate credible outcomes. The network 100 further provides for an effective use of information technologies to facilitate behavior modification through rapid promulgation of best medical practices, standardization and quality control of medical best practices, customization to individual patient (client 112) needs, and specialized patient education and self-management tools. As explained above, specialized devices can transmit data from remote sites that is extremely useful for rapid assessment of patient status. These assessments are almost invisible to the patient. The resulting early interventions enhance the patient's wellness and motivation to participate in the management process. Patients will also participate in the management process, and they may self-manage their conditions once they achieve proficiency with disease states. For example, a patient may obtain on-line help with insomnia associated with medication schedules. Behavioral assessment tools such as "Rodger's Readiness to Change" can profile a patient's readiness and ability to participate in a management process before funds are committed. Care providers often know what behaviors are desirable, but have difficulty convincing patients to adopt healthy behaviors. On-line help for providers will suggest important motivational techniques to assist with these situations. It can be further appreciated that control of disease management protocols and rapid evaluation facilitated by telecommunications are keys to driving the measurement and evaluation cycle. Patients managed under the network 100 will benefit from the most progressive evidenced-based data driven paradigms. It is well known that rapid responses to client questions are very important to building confidence in a service organization. Telecommunications can provide these services in a unique and cost-effective venue. New developments in medical practice may be rapidly promulgated through these networks. Protocols may be standardized across systems where appropriate. Appropriate latitude can be granted to accommodate both individual patient goals and requirements and the special needs of local populations. Also, the patient's primary care physician will have control over the patient's care. Although only a few exemplary embodiments of this invention have been described in detail above, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention. characterised in that said computer network (100) is further adapted to establish treatment program for said patient based on their respective patient health-related data and said accumulated health-related data, and to revise said accumulated health-related data based on said patient health-related data. said assessment tools allow a health care provider to monitor said patient health-related data relating to integration of a selected one of said treatment programs into the patient's lifestyle and determine readiness of the patient for self-management under the selected treatment program. said remote monitoring stations are adapted to provide said patient health-related data to said computer network over the Internet. said computer network is adapted to generate reports each including health-related information pertaining to a respective said patient. said computer network is adapted to provide said accumulated health-related data stored in said database to organizations financing at least a portion of said treatment programs, and is adapted to receive financial data pertaining to said treatment programs from said organizations and to store said financial data in said database. each said remote monitoring station receives from its respective said patient said health-related data including pertaining to the cardiovascular system of said patient.
2016 polls! We're heading into election season here in the United States, which reminds us that we haven't run any polls recently at Practical Fragments. How has the community changed in the past few years? To find out, please answer the three questions in the poll on the right-hand side of the page, under "Editors." Also, please note that you need to hit "vote" for each question separately. The first question asks whether you are in academia or industry and whether you practice FBLD. The second question asks what methods you use to find fragments. For purposes of this poll please choose all that apply, whether primary or secondary screens. You can read about these methods in the following links. Functional screening (high concentration biochemical, FRET, etc.) Thermal shift assay (or DSF) Other – please specify in comments The third question asks what metrics (listed below) you use. Again, you can choose multiple answers. Antibacterial efficiency BEI (binding efficiency index) Enthalpic efficiency FQ (fit quality) Fsp3 GE (group efficiency) LE (ligand efficiency) LELP (ligand-efficiency-dependent lipophilicity) LLE or LipE (ligand lipophilic efficiency) LLEAT %LE PEI (percentage efficiency index) SEI (surface-binding efficiency index) SILE (size-independent ligand efficiency) Finally, are there other topics you'd like to see polled? Please let us know in the comments. Labels: academia, fragment finding, industry, metrics, Poll Crystallographic screening of a nuclear receptor Crystallography as a primary screen seems to be gaining traction. As the old cliché goes, a picture is worth a thousand words. And as Andrey Grishin recently commented on an earlier post, the increasing speed and capacity at synchrotrons lowers the barrier for data collection. A new paper in ChemMedChem by Yafeng Xue and colleagues at AstraZeneca provides yet more support for starting with crystallography. The researchers were interested in the retinoic-acid related orphan receptor γt (RORγt), a potential target for autoimmune diseases. The protein is a nuclear hormone receptor, and like many members of this family, ligands tend to be lipophilic with poor physical properties. Also, work by other companies around this target had created a thicket of intellectual property claims. To find new and attractive chemical matter, the researchers turned to fragments. The ligand binding domain of RORγt was crystallized and soaked against a library of 384 fragments chosen on the basis of maximum diversity and previous success in crystallography. Fragments were screened at 75 mM concentration in pools of four, with members chosen to have different shapes. This process did require "extensive optimization", and even then about 15% of the datasets were not usable. But the effort paid off, resulting in 21 hits from 18 pools. Hits were then tested by SPR, revealing that the best had an affinity of just 0.2 mM (though with an impressive LE of 0.42 kcal mol-1 per heavy atom), while some were > 5 mM. As expected, many of the fragments bound in the large and lipophilic ligand binding pocket, accessing various binding modes previously seen with other ligands. This is a nice confirmation that fragments are able to sample chemical space very efficiently, as shown five years ago for HSP90. Indeed, for one particularly productive pool, three of the fragments bound simultaneously at different subsites within the ligand binding pocket! Of course, proteins are often highly dynamic in solution, and one concern with crystallographic screening is that the protein crystals may not allow much movement. In this case the researchers did observe several cases of induced fit, with one side chain residue shifting more than 3 Å to accommodate a fragment. This revealed a type of interaction that was not predicted using a computational approach: a victory – for now – for the power of empiricism. As discussed earlier this year, secondary ligand binding sites appear to be common, and indeed five fragments bound outside the ligand binding pocket. Three of these bind at what seems to be a protein-protein interface for other receptors, which could lead to highly selective molecules. It's a long way from a 0.2 mM fragment to a useful lead series, but having a structure (or 21) dramatically improves the odds – as demonstrated here and here. The paper ends by suggesting that such a series has indeed been identified, and it will be fun to watch as the story unfolds. Labels: crystallography, fragment finding Dynamic combinatorial chemistry and fragment linking Dynamic combinatorial chemistry (DCC) sounds incredibly cool. The idea is that libraries spontaneously form and reform. Add a protein and Le Châtelier's principle favors the formation of the best binders. In other words, not only does cream rise to the top, more cream is actually created. The applications of DCC for fragment linking are obvious, and indeed early reports date back nearly twenty years to the dawn of practical FBDD. The latest results are described in a new paper in Angew. Chem. Int. Ed. by Anna Hirsch and collaborators mostly at the University of Groningen. The researchers were interested in the aspartic protease endothiapepsin, which is a model protein for more disease-relevant targets. This is a dream protein: it is easy to make in large amounts, crystallizes readily, and is stable for weeks at room temperature. Readers will recall that this protein has also been the subject of multiple screening methods. Previous efforts using DCC had generated low micromolar inhibitors such as 1 and 2. These acylhydrazones form reversibly from hydrazides and aldehydes. Crystallography had also previously revealed that compound 1 binds in the so-called S1 and S2 subsites of endothiapesin while compound 2 binds in the S1 and S2' subsites. In the current paper, the researchers enlisted DCC to try to combine the best of the binding elements. To do this, the researchers chose isophthalaldehyde, which contains two aldehyde moieties, and nine hydrazides, which could give a total of 78 different bis-acylhydrazones. They incubated 50 µM of isophthalaldehyde with either four or five of the hydrazides (each at 100 µM), with or without 50 µM protein, and in the presence of 10 mM aniline to accelerate the exchange. Reactions were allowed to incubate at room temperature at pH 4.6 for 20 hours, after which the protein was denatured and the samples were analyzed by HPLC to see whether some products were enriched in the presence of protein. Biologists may want to consider whether their favorite proteins would remain folded and functional under these conditions, and chemists may also balk at molecules containing an acylhydrazone moiety – let alone two. Leaving aside these concerns, though, what were the results? As one would hope, some molecules were enriched over others when protein was present, though only by a modest two or three-fold. Two of the enriched molecules – both homodimers – were resynthesized and tested. Compound 13 was quite potent, and crystallography revealed that it binds in a similar fashion to compound 1, though electron density is missing for part of the molecule. Compound 16, on the other hand, is only marginally more potent than the starting molecules. Unfortunately the researchers do not discuss the activities of molecules that had not been enriched at all. The paper ends by stating rather hopefully that DCC "holds great promise for accelerating drug development for this challenging class of proteases, and it could afford useful new lead compounds. This approach could be also extended to a large number of other protein targets." I'm not so sure. This is an interesting study; the work was carefully done and thoroughly documented—but I'm less sanguine about whether DCC will actually ever be practical for lead generation. Indeed, the very fact that the experiments were done well yet are incapable of distinguishing a strong binder from a weaker one argues that the technique is inherently limited. I would love to see DCC work, but it seems to me that, even after two decades of effort, DCC has not been able to move beyond proof of concept studies. Does anyone have a good counterexample? Labels: DCC, dynamic combinatorial chemistry, fragment linking Metallophilic fragments revisited Way back in 2010 we highlighted work out of Seth Cohen's lab at UC San Diego on "metallophilic fragments", which are specifically designed to bind to metal ions. As long as one avoids PAINS, the approach could be useful for targeting metal-dependent enzymes. Indeed, multiple drugs derive much of their affinity by binding to metals; these include HDAC inhibitors (for cancer) and integrase inhibitors (for HIV). In a recent paper in J. Med. Chem., Cohen and colleagues describe work against an influenza target. The researchers were interested in the so-called "PA subunit" of RNA-dependent RNA polymerase, which is both essential and highly conserved among influenza strains. The endonuclease in the PA subunit requires two metal ions, either Mn2+ or Mg2+, and in fact previous publications had demonstrated that metal chelators could inhibit the enzyme. In the current paper, the team screened about 300 fragments at 200 µM in an activity assay; those that inhibited >80% were retested to produce dose-response curves. Compound 1 came in as reasonably potent and impressively ligand-efficient, as is often the case with metal-binding fragments. Docking studies suggested that it could bind to both of the metal ions in the active site. Initial SAR around compound 1 led to compound 10, with a significant improvement in potency that the researchers attribute to increased basicity and thus stronger interactions with the metals. Taking pieces from previously published molecules led to another increase in potency (compound 63). Separate fragment growing efforts off compound 1 led to sub-micromolar inhibitors such as compound 35. Combining both series led to compound 71, which is the best of the bunch with low nM activity, though it fell short of the hoped-for additivity of binding energies. Compound 71 was also tested in cellular assays. Happily, it was able to protect cells from a lethal dose of influenza virus with an EC50 in the low micromolar range, about 100-fold below the cytotoxic dose observed in the same cell line. Of course, there is still a long way to go: no pharmacokinetic data are provided, and selectivity against other metalloproteins may be a challenge. Still, it will be interesting to watch future developments, both with this series and with the approach in general. Labels: FBDD, fragment growing, fragment merging, library design Lead Generation: Methods, Strategies, and Case Studies Lead generation refers to that point in drug discovery when initial screening hits against a target are wrought into compelling chemical matter. This chemical matter is often plagued with deficiencies in terms of potency, pharmacokinetics, or novelty, yet it provides a starting point for further optimization. This is the subject of a massive (800+ pages!) new two-volume work edited by Jörg Holenz (GlaxoSmithKline, formerly AstraZeneca) as part of Wiley's Methods and Principles in Medicinal Chemistry series. Readers of this blog will not be surprised to find that fragments play a major role; indeed, the molecule on the cover of the book came out of FBLD. I won't attempt to summarize all 25 chapters here, but will simply highlight those most relevant to FBLD. Mike Hann (GlaxoSmithKline) sets the stage in chapter 1 by briefly describing the characteristics of successful leads. He emphasizes the importance of physicochemical properties and avoiding molecular obesity, and how judicious use of metrics can help navigate away from perilous chemical space. He also summarizes internal programs that again demonstrate that fragment-derived leads tend to be smaller and less lipophilic than those from other lead discovery techniques. In chapter 3, Udo Bauer (AstraZeneca) and Alex Breeze (University of Leeds) discuss the concept of ligandability – the ability of a target to bind to a small molecule with high affinity. Fragments are ideally suited for assessing ligandability, and the researchers briefly describe fragment-based experimental and computational approaches to do so. They also include a nice 11-point summary of factors to consider when starting lead generation on a new target, ranging from the presence of small-molecule binding sites to the number of patent applications. Chapter 6, by Ivan Efremov (Pfizer) and me, is entirely about fragment-based lead generation. I'm undoubtedly biased, but I think it provides a self-contained and fairly detailed guide to FBLD, including topics such as screening methods, hit validation, metrics, hit optimization, fragment growing vs fragment linking, and case studies on vemurafenib, BACE, MMP-2, LDHA, venetoclax, MCL-1, and GPCRs. Helmut Buschmann and colleagues at RD&C Research, Development, and Consulting, focus in chapter 9 on optimizing side effects of known molecules to develop new drugs, but they also discuss some interesting older work reporting that 418 of 1386 drugs contain other drugs as internal fragments. Chapter 12, by Dean Brown (AstraZeneca), is devoted to the hit-to-lead stage, and much of his advice is applicable to FBLD. Dean also includes a fantastic metaphor to illustrate the size of chemical space: "if a typical corporate screening collection were to fit on a postcard, the rest of the earth is the amount of available drug-like space." This assumes a million-compound library and a conservative estimate of 1023 drug-sized molecules, so if anything it is an understatement. Molecular recognition is critical for both FBLD and lead generation in general, and this is the topic Thorsten Nowak (C4X Discovery Holdings) tackles in chapter 13. He covers key areas such as thermodynamics, emphasizing the importance of enthalpy while acknowledging the difficulty of prospectively using thermodynamic data. The role of water and halogen bonds are covered, along with some freakishly high ligand efficiency values. There are a couple errors: one paper is categorized as using dynamic combinatorial chemistry when in fact it actually used static libraries, and Tethering is confused with Chemotype Evolution, but overall there's lots of good stuff here. Biophysical methods are covered in chapter 14, by Stefan Geschwindner (AstraZeneca). These include NMR, SPR, ITC, thermal shift assays, native mass spectrometry, microscale thermophoresis, and more. Chapter 16, by Ken Page and colleagues at AstraZeneca, discusses "lead quality." This often entails various metrics, from simple ones such as ligand efficiency and LLE to more complicated attempts to predict clinical dosages. Although it is easy to poke fun at metrics, most thoughtful scientists find them useful for making sense of the reams of data generated in lead optimization campaigns. Chapter 17, by Steven Wesolowski and Dean Brown (both AstraZeneca), is arguably the most entertaining. Entitled "The strategies and politics of successful design, make, test, and analyze (DMTA) cycles in lead generation," it is replete with pithy quotes and even an original (and highly geeky) cartoon. Along with multiple examples, the chapter formulates plenty of questions to consider during lead optimization, and ends with a particularly relevant quote by Billings Learned Hand: "Life is made up of a series of judgments on insufficient data, and if we waited to run down all our doubts, it would flow past us." In chapter 23, Sven Ruf and colleagues at Sanofi-Aventis Deutschland describe a success story generating leads against cathepsin A, a target for cardiovascular disease. HTS yielded three different chemical series with sub-micromolar activities, each with different liabilities. Crystallography revealed their binding modes, and this allowed the team to mix and match fragments across the different series to generate a molecule that ultimately went into the clinic. Although this may not be classic FBLD, it does seem to be a good case of using concepts from the field, or fragment-assisted drug discovery. A similar, if less directed, approach is the subject of chapter 25, the last in the book. Pravin Iyer and Manoranjan Panda (both AstraZeneca) describe "fragmentation enumeration," in which known drugs or clinical candidates are fragmented into component fragments and recombined. On some level the fragments themselves are likely to be privileged; the researchers cite the famous quote by Sir James Black that "the most fruitful basis of the discovery of a new drug is to start with an old drug." Most of the work is computational, although one molecule derived from the approach has encouraging cellular activity against Mycobacterium tuberculosis. There's far more to this book than could be listed even in this relatively long post, including multiple case studies, so for those of you who are interested in lead generation definitely check it out! Labels: fragment finding, lead discovery, lead optimization, ligandability, metrics Lead Generation: Methods, Strategies, and Case Stu...
Nature Biotechnology publication: New immunotherapy for cancer based on the mechanism of transplant rejection The new treatment makes the patient's immune cells "believe" that cancer is a transplanted organ that should be rejected. The results were published in Nature Biotechnology, one of the world's most prestigious cross-disciplinary scientific journals, on 6 December 2021. A team of scientists at the University of Oslo, Oslo University Hospital (OUH) Radiumhospitalet and Karolinska Institutet, led by Professor Johanna Olweus, has developed a new type of immunotherapy for cancer. The new treatment makes the patient's immune cells "believe" that cancer is a transplanted organ that should be rejected. The immune cells then attack and fight the cancer cells, thereby curing the cancer. This is made possible thanks to a new technology, developed by the research group, and genetic modification of the immune cells. The scientists have demonstrated the efficacy of the new treatment on patient leukemia cells in cell cultures and in mouse models, and are planning a clinical trial in patients with acute leukemia. – Our results indicate that the new therapy would be efficacious and safe in treatment of acute lymphoblastic leukemia, the most common cancer in children and young adults. This therapy could mean new hope for children and adults with an otherwise deadly disease when standard therapies fail, and thus potentially give a new future for young people who should have their whole life in front of them, Olweus comments. The immune system "rejected" the cancer developed in transplanted organs Johanna Olweus (photo:Kristin Ellefsen, UiO) Professor Olweus got the idea behind the technology while she worked as a medical doctor with transplantation immunology at OUH Rikshospitalet. When an organ is transplanted from a donor to a patient, the patient must receive life-long immunosuppressive medication to avoid rejection of the organ. If medication is stopped, the patient's immune cells, so-called T cells, will reject the transplanted organ in a short time. Cancer can occasionally develop in the transplanted organ. Professor Olweus took notice of the fact that stopping immunosuppression in such cases usually suffices to "reject" also the cancer, even if it has metastasized outside of the organ. – The same mechanism that is responsible for transplant rejection, thus also seemed capable of curing cancer, she says. If T cells could be "instructed" to attack only one type of cell instead of a whole organ containing a large number of different cell types, this might provide a basis for development of a new type of immunotherapy. The research group embarked on the task. After many years, the scientists succeeded in identifying killer T cells that efficiently recognize one single target in a cell. Genetic modification gave immune cells "eyes" to detect cancer cells – Another challenge was to identify targets in cancer cells that separate them from other, normal, cells, Professor Olweus explains. The T cells needed to know which cells to reject. Molecules called T cell receptors (TCR) function as "eyes" for the T cells, enabling them to "see" potential targets inside the cancer cells. This opened up for new possibilities. – Many, many more candidate targets are available in the cell interior, as compared with the cell membrane. If we choose the right target inside the cancer cell and find a TCR capable of recognizing it, we can use this TCR to give patient T cells new "eyes" that allow them to detect cancer cells, says Dr. Muhammad Ali, first author on the study. By exploiting the technology that he took part in developing in the group, he was able to identify TCRs recognizing an enzyme that is present at high levels in the nucleus of leukemia cancer cells. – We genetically modified the T cells in the laboratory to equip them with the therapeutic TCR, and then infused the cells back into the blood stream of the mice. This allowed the T cells to find the leukemia cells spread in different organs of the mice, and eliminate them, explains scientist Eirini Giannakopoulou, who is shared first author with Ali on the study. From left: Muhammad Ali, Eirini Giannakopoulou (shared first authors) and Johannna Olweus (senior author). Photo: Fridtjof Lund-Johansen. Crucial contributions from Karolinska Institutet The present study was conducted in an international collaboration, and Olweus emphasises instrumental contributions from Assistant Professor Petter S. Woll and Professor Sten Eirik Jacobsen and their teams at the Department of Medicine, Huddinge, Karolinska Institutet, in particular doctoral students Madeleine Lehander and Stina Virding Culleton. They tested efficacy of the treatment in mice transplanted with leukemia cells from patients, and safety in a mouse model with normal human blood cell formation. – In addition to the dramatic efficacy, we also saw no negative effect on healthy B and T cells or on the development of new blood cells, which suggests that the treatment can be safe, Petter S. Woll adds. The researchers in Oslo and at Karolinska Institutet are now planning to conduct laboratory and animal studies to test the method on more cancer types. KI co-authors. From left: Stina Virding Culleton, Petter Woll, Sten Eirik Jacobsen and Madeleine Lehander. Photo: Karin Belander-Strålin Will test the treatment in patients with leukemia – Together with clinicians at the Department of Pediatrics and Oncology and the Department of Hematology at OUH we are currently planning for a clinical trial to test the treatment in patients with acute leukemia. The patient T cells will be genetically modified in the recently established Center for Advanced Cell and Gene therapy (ACT Center) at OUH. The trial will include patients for whom there is currently no curative therapy, says Professor Olweus. In addition, the research group will use the same technology to develop therapeutic TCRs also for other cancer types. The Nature Biotechnology article, published 06 December 2021: T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes Muhammad Ali, Eirini Giannakopoulou, Yingqian Li, Madeleine Lehander, Stina Virding Culleton, Weiwen Yang, Cathrine Knetter, Mete Can Odabasi, Ravi Chand Bollineni, Xinbo Yang, Zsofia Foldvari, Maxi-Lu Böschen, Eli Taraldsrud, Erlend Strønen, Mireille Toebes, Amy Hillen, Stefania Mazzi, Arnoud H. de Ru, George M. C. Janssen, Arne Kolstad, Geir Erland Tjønnfjord, Benedicte A. Lie, Marieke Griffioen, Sören Lehmann, Liv Toril Osnes, Jochen Buechner, K. Christopher Garcia, Ton N. Schumacher, Peter A. van Veelen, Matthias Leisegang, Sten Eirik W. Jacobsen, Petter Woll & Johanna Olweus Show fewer authors Online 6 december, 2021, doi: 10.1038/s41587-021-01089-x News articles from various outlets: From the Norwegian Broadcasting Corporation (NRK): Mulig kur mot akutt leukemi: – Jeg begynte å hoppe av glede da jeg så resultatene From forskning.no: Forskere har funnet en mulig kur mot akutt leukemi. Nå skal den testes ut på mennesker From uio.no: Ny immunterapi for kreft basert på mekanismen for transplantasjonsavvisning From ki.se (in Swedish): Ny sorts immunterapi mot leukemi upptäckt \| Karolinska Institutet Nyheter Home page of Johanna Olweus Experimental Immunotherapy Group Department of Cancer Immunology
December 2014 - Volume 35 - Issue 10 Thought you might appreciate this item(s) I saw at Otology & Neurotology. Middle Ear and Mastoid Disease Cholesteatoma Recidivism: Comparison of Three Different Surgical Techniques Neudert, Marcus; Lailach, Susen; Lasurashvili, Nikoloz; Kemper, Max; Beleites, Thomas; Zahnert, Thomas Department of Otorhinolaryngology, Head and Neck Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Saxony, Germany Address correspondence and reprint requests to Marcus Neudert, M.D., Department of Otorhinolaryngology, Head and Neck Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscher Strasse 74, 01307 Dresden, Saxony, Germany; E-mail: [email protected] The work was done in the aforementioned institute. M.N. and S.L. contributed equally to this work and should therefore be considered first authors of this article. This work was presented in part at the 82nd annual meeting of the "Deutsche Gesellschaft für HNO-Heilkunde, Kopf- und Hals-Chirurgie," June 5, 2011, Freiburg, Germany The authors disclose no conflicts of interest. Otology & Neurotology: December 2014 - Volume 35 - Issue 10 - p 1801–1808 doi: 10.1097/MAO.0000000000000484 To compare cholesteatoma recidivism rates after exclusive transcanal technique (ETC), combined transcanal and mastoidal technique (TCM, both subsets of intact canal wall technique, ICW), and canal wall down surgery (CWD). Retrospective case review and clinical case study Tertiary referral center. 406 cholesteatoma surgeries (2007–2009), 116 ears in clinical re-examination at least 1 year postoperatively. Sequential cholesteatoma surgery with ETC, TCM, or CWD. Main Outcome Measures Cholesteatoma recidivism, residual and recurrent disease, localization of recidivism, validity of clinical findings. Out of 406 patients, ETC was performed in 227 (56%), TCM in 122 (30%), and CWD in 57 (14%) cases. Recidivism rates after ICW (15%) and CWD (16%) were almost similar. Recidivism was more frequent after ETC (11%) than after TCM (25%). Residuals were observed in 2% after ETC, 6.5% after TCM, and 7% after CWD. Incidence of recurrent disease was 9% for ETC, 18% for TCM, and 9% for CWD. Preferred localization of recidivism was the tympanic cavity after ETC (92%) and CWD (56%) and the mastoid cavity after TCM (53%). The clinical re-examination showed no further recidivistic disease. Sequential surgery is an effective and successful strategy in cholesteatoma eradication, providing a similar recidivism rate compared to following cholesteatoma retrograde and resection of the posterior canal wall. Lower recidivism after ETC was observed as a consequence of limited disease and the postoperative middle ear status determined the higher rate of recurrence after TCM. Therefore, the restricted visualization of the middle ear during ICW surgery does not increase the rate of recidivism, compared with CWD, as described in other studies. Cholesteatoma recidivism is mainly attributed to the surgeon's experience that outweighs the chosen strategy. Copyright © 2014 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company Otology & Neurotology35(10):1801-1808, December 2014. Canal wall down, Cholesteatoma, Recidivism, Recurrent disease, Surgical technique, Transcanal technique Articles in PubMed by Marcus Neudert Articles in Google Scholar by Marcus Neudert Other articles in this journal by Marcus Neudert Ménière's Syndrome or Disease: Time Trends in Management and Quality of Evidence Over the Last Two Decades Decisive Criteria Between Stapedotomy and Cochlear Implantation in Patients with Far Advanced Otosclerosis Tympanoplasty for Chronic Tympanic Membrane Perforation in Children: Systematic Review and Meta-analysis Surgical Findings and Long-Term Hearing Results in 3,050 Stapedotomies for Primary Otosclerosis: A Prospective Study with the Otology-Neurotology Database Long-Term Follow-up Results of Canal Wall Down Tympanoplasty With Mastoid Obliteration Using the Bone Pate Plate for Canal Wall Reconstruction in Cholesteatoma Surgery Otology & Neurotology, Inc.
Cases of extensive epithelioma (left) and rodent ulcer (right), historical medical illustration. Epithelioma is an abnormal growth of the epithelium, a layer of tissue that covers the surfaces of organs and other parts of the body. It may be benign or malignant. A rodent ulcer (basal cell carcinoma) is a common form of skin cancer, and is most often caused by over-exposure to sunlight. From Atlas of Venereal and Skin Diseases by Prince Albert Morrow, published in 1889.
Department of Zoology, Immunopharmacology and Molecular Cell Biology Laboratory, University of Gour Banga, Malda - 732103, West Bengal, India. ABSTRACT: Phytochemicals are bioactive compounds produced by plant through primary and secondary metabolism. Phytochemicals are found to be more effective than conventional synthetic chemicals. Rice is considered as the staple food for most of the people residing in this part of world, i.e., the eastern part of India. There are many varieties of rice cultivated in West Bengal, India and among which Gobindobhog and black rice are common. In the present study, qualitative and quantitative analyses of phytochemicals like flavonoids, alkaloids, steroids, riboflavin, ascorbic acid, thiamine, etc. of Gobindobhog and black rice were performed. All the methods followed are standard biochemical and spectrophotometric procedures for detection and quantification of phytochemicals. Qualitative screening of phytochemicals indicated the presence of glycoside, steroid, phenol, protein and carbohydrate in both of the rice varieties, whereas tannin, phlobatannin, terpenoid, alkaloid and flavonoid were identified only in black rice. Quantitative analysis indicated the presence of ascorbic acid, riboflavin and lipid in significant amount in both of these rice varieties. Therefore, it can be concluded that both Gobindobhog and black rice possess medicinal properties apart from their food value. Therefore, isolation and identification of active principles from these rice varieties should be prioritized and it will advance the existing knowledge in relation to human health. INTRODUCTION: Rice (Oryza sativa L.) is used as a staple food by a large part of world's population. The major nutrients in rice are carbohydrates, proteins, fatty acids, vitamins and some minerals. Being easily available and digestible, rice has been used for curing various neuromascular, digestive and respiratory diseases as mentioned in the ayurvedic literatures 1. Traditional coloured rice varieties are rich in dietary fibres, starch, flavonoids, phenols, etc. and therefore, consumption of these pigmented rice varieties are reported to play a major role in attenuating the incidence of non - communicable disease like cardiovascular disease, diabetes, cancer and stroke 2, 3. Phytochemicals are the bioactive compounds which possess antioxidant activity and play a major role in protecting body from diseases. Antioxidants delay or inhibit cellular damage through different properties 4. Medicinal plants have great antioxidant potential which is due to their contents of variable phytoconstituents. Though a large number of experiments have been carried out concerning the antioxidant activity of several medicinal plants, scanty works have been done on the phytochemical profiling in rice varieties. Phytochemicals like anthocyanins and oligomeric procyanidins were found to be present in the black and red varieties of rice grown in the Camargue region of France 5. According to some Ayurvedic studies, medicinal rice like Njavara contains high minerals and carbohydrate. It is used in the treatment of arthritis, cervical spondylitis, muscle wasting, skin disease and certain neurological disorders 6, 7. However, till date, no scientific data are available on the nutritional and medicinal properties of Gobindobhog and black rice, the two most popular rice varieties in West Bengal, India. Gobindobhog is an indigenous, small-grained aromatic rice variety, having white grain, whereas black rice, as the name suggested, have black coloured grain but without aroma. Therefore, the aim of the present study was to investigate the presence of different phytochemicals both qualitatively and quantitatively in Gobindobhog and black rice. The whole grain was examined qualitatively for the presence of different phytochemicals such as tannins, phlobatannins, terpenoids, glycosides, steroids, cholesterol, alkaloids, phenols, flavonoids, anthraquinones and also for carbohydrate and protein. The quantitative estimation of alkaloids, flavonoids, tannins, riboflavin, thiamine, ascorbic acid, total phenol, protein, lipid, sugar, moisture and ash content were also determined by standard method for both of the rice varieties. Sample Collection: Gobindobhog rice was collected from the local market of different areas of Burdwan, West Bengal, India, whereas the black rice was collected from the local farmers of Raiganj, West Bengal, India. Sample Preparation: Small sand particles and other impurities were separated carefully from the sample. The sample was then grinded to powder. The powder was passed through a 0.5 mm metallic mesh. The resultant crude fine powder was used for phytochemical investigation according to previously described standard chemical tests 8, 9, 10, 11. Qualitative Phytochemical Analysis: 10 g of crude dried sample was taken in 250 ml conical flask and 100 ml of double distilled water was added to it. The solution was mixed on magnetic stirrer for 10 h. The mixture was filtered through Whatman filter paper no. 1 and the filtrate was used for the following phytochemical tests. Tannin: 10 ml of aqueous extract was mixed with few drops of 0.1% FeCl3 solution. Blue-black precipitation formation upon addition of ferric chloride solution indicates the presence of tannin. Phlobatannin: 10 ml of aqueous extract was taken in a test tube and 2 ml of concentrated HCl was added to it. The mixture was boiled for 1 min. Caution was taken so that the hot solution does not bump out of the test tube. Deposition of red precipitate indicated the presence of phlobatannins. Carbohydrate: 2 ml of aqueous extract was mixed with 2 ml of Molish's reagent (5% α-napthol in absolute ethanol) and shaken vigorously to mix properly. 2 ml of concentrated H2SO4 was added carefully by means of pipette along the wall of the test tube. Formation of reddish - violet ring at the junction of two liquids indicated the presence of carbohydrates. Protein: 2 ml of aqueous extract was taken in a test tube and 1 ml of 40% NaOH solution was added to it. The solution was mixed properly and 1 - 2 drops of CuSO4 solution was added to it. Change in the colour to violet indicated the presence peptide linkage in the solution which in turn was an indication of the presence of proteins. 10 g of crude dried sample was taken in 250 ml conical flask and 100 ml of 70% methanol was added to it. The solution was mixed on magnetic stirrer for 10 h. The mixture was filtered through Whatman filter paper no. 1 and the filtrate was used for the following phytochemical tests. Terpenoid: 5 ml of methanol extract was mixed with 2 ml of chloroform. 3 ml of concentrated H2SO4 was added to the solution slowly along the wall of the test tube. Care was taken not to stir the solution in the test tube. Reddish-brown coloration formed at the junction of two liquid phases indicated the presence of terpenoids. Glycoside: 5 ml of methanol extract was taken in a separate test tube and 2 ml of glacial acetic acid containing 2% FeCl3 solution was added to it. One ml of concentrated H2SO4 was added slowly along the wall of the test tube. Formation of Brown ring at the interphase of two liquid indicated the presence of glycoside. Steroid: 5 ml of methanol extract was taken in a test tube and treated with 0.5 ml of anhydrous acetic acid and was cooled on an ice bath for 15 min. Then 0.5 ml of chloroform was added to the solution. 1 ml of concentrated H2SO4 was added along the wall of the test tube carefully by means of pipette. At the separation of two liquid phases, a reddish- brown ring was formed, as an indication of presence of steroids. Cholesterol: 2 ml of ethanol extract was mixed with 2 ml of chloroform. 10 - 12 drops of acetic acid anhydride was added to the tube and shaken. 2 drops of concentrated H2SO4 was added to it. Change of reddish- brown coloration to blue - green on addition of H2SO4 indicated the presence of cholesterols. Alkaloid: 2 ml of methanol extract was taken in a test tube and 2 ml of 2N HCl was added to it. The solution was shaken vigorously to mix and kept aside for five minutes. Aqueous phase was separated from two liquid phases and few drops of Mayer's reagent (HgCl2 + KI in water) was added to it and shaken to observe the formation of creamy coloured precipitate. The presence of the creamy precipitate indicated the presence of alkaloids. Phenol: 10 ml of ethanol extract was treated with 4-5 drops of 2% FeCl3 solution. Change of coloration of the solution indicated the presence of phenolic compounds. Flavonoid: 2 g of crude sample was heated with 10 ml of ethyl acetate over a water stream bath for 5 min. The solution was filtered through Whatman paper no. 1. 4 ml of the filtrate was mixed with dilute ammonia solution (10%) and shaken vigorously. Yellow coloration of the solution indicated the presence of flavonoids. Anthraquinone: 0.5 g of crude sample was taken in a 100 ml conical flask and 20 ml benzene was added to it. The solution was mixed on magnetic stirrer for 4 h. 10 ml of filtrate was mixed with 0.5 ml ammonia solution (10%) and mixed properly. Presence of violet colour at the layer phase indicated presence of anthroquinone. Saponin: 0.5 g crude sample was boiled with 15 ml of double distilled water in a boiling water bath. Formation of intensive froth is the indication of presence of saponin. Alkaloid Determination: The assay was performed according to the standard method 11, 12. 5 g of crude sample was taken in a 250 ml conical flask and 250 ml of 20% CH3COOH in ethanol was added to it. The solution was mixed on magnetic stirrer for 10 h at room temperature. The solution was filtered through Whatman paper no. 1 and the resultant was placed on hot water bath (60 °C) until the extract volume turns ¼ of its initial volume. Concentrated NH4OH was added to it drop-wise which forms thick precipitate. NH4OH was added until the precipitate formation was complete. The whole solution was allowed to settle down. The precipitate was collected by filtration, dried in an oven and weighed. Flavonoid Determination: A standard procedure was followed with slight modifications to quantify the total flavonoid content 13. 10 g of crude dried sample was taken in 250 ml conical flask and 100 ml of 70% methanol was added to it. The solution was mixed on magnetic stirrer for 3 h. The mixture was filtered through Whatman paper no. 1. The remaining powdered material was re-extracted once again with 70% methanol and filtered. Both the filtrates were mixed and transferred into a crucible and evaporated to dryness over a water bath of 60°C and weighed. Tannin Determination: The assay was performed according to the standard method 14. 1 g of crude powder sample was taken in 100 ml flask and 50 ml of double distilled water was added to it and shaken on magnetic stirrer for 10 h at room temperature. It was then filtered into a 50 ml volumetric flask and made up to the mark using distilled water. 5 ml of solution was pipetted out in a test tube and 0.008 M K4[Fe(CN)6] and 0.1 M FeCl3 in 0.1N of HCl was added to it. The absorbance was measured in spectrophotometer at 120 nm wavelength within 10 min. A suitable blank was prepared and read at same wavelength. A standard was prepared using tannic acid and measured. Determination of Riboflavin: The test was performed according to the standard method with slight modification 15. 10g of crude dried sample was taken in 250 ml conical flask and 100 ml of 50% ethanol was added to it and stirred on magnetic stirrer for 10 h at room temperature. The solution was filtered and 25 ml of 5% KMnO4 solution was added to it. The mixture was stirred using a glass rod continuously while 25 ml of 30% H2O2 was added to it. This was placed on an 80 °C water bath for 30 min. 5 ml of 40% Na2SO4 was added to it and the absorbance was measured at 510 nm using spectrophotometer. A suitable blank was prepared and read at same wavelength. The riboflavin content was calculated from riboflavin standard curve. Determination of Thiamine: A previously described standard method was followed with slightly modifications to quantify the thiamine content 16. 5 g of crude powder was mixed with 50 ml of 20% ethanolic NaOH and stirred on a magnetic stirrer for 3 h at room temperature. The resultant was filtered in 100 ml conical flask. 10 ml of filtrate was separated out and 10 ml of 2% K2Cr2O7 solution was added to it. As a result colour was developed which was read against 360 nm against a suitable blank. The blank contents all the chemicals except the plant material. The thiamine content was calculated from thiamine standard curve. Determination of Ascorbic Acid: The test was performed according to a previously described method with slight modifications 17. 5 g crude plant powder was mixed with 100 ml of extraction mixture (TCA: EDTA at 2:1) and stirred on a magnetic stirrer for 3 h at room temperature. This was transferred into a centrifuge tube and centrifuge at 2000 rpm for 30 min. After centrifugation the supernatant liquid was filtered. 2-3 drops of 1% starch solution was added to it and titrated against 20% CuSO4 solution until a dark end point was reached. Determination of Total Phenol: To estimate the total phenol content, test sample was prepared to be fat free. To do that, 5 g of crude powder was mixed with 100 ml of n-hexane and defatted using a Sohxlet apparatus for 2 h. The resultant was used for determination of total phenols according to a previously described method 17. For the extraction of the total phenolic content, the fat free sample was boiled with a 50 ml of ether for 15 min. The resultant was filtered and 5 ml of the filtrate was pipetted into a 50 ml flask. 10 ml of double distilled water was added to it. 2 ml of NH4OH solution and 5 ml of concentrated amyl alcohol was added to the solution with constant stirring. The flask was incubated at room temperature for 30 min for colour development. The absorbance of the solution was read using spectrophotometer at 550 nm against a suitable blank. The phenolic content was evaluated from a gallic acid standard curve. Estimation of Total Protein: Total protein was estimated according to the standard method with slight modifications 10. Known concentrations of bovine serum albumin was taken as standard and the OD was read at 595 nm using a suitable blank. Estimation of Total Lipid: The assay was performed according to a standard method with slight modifications 17. 1 g of dried sample was macerated with 10 ml distilled water. To this, 30 ml of chloroform - methanol (2:1 v/v) was mixed thoroughly and the mixture was left overnight at room temperature. 20 ml of chloroform and equal volume of distilled water were added and centrifuged at 1000 rpm for 10 min. After centrifugation three layers were formed, out of which the lower layer was collected which contained chloroform containing lipid. The mixture was kept in an oven for one hour at 50 °C which resulted in the evaporation of chloroform. Weight of the remaining was measured. Total Sugar Estimation: The total sugar content was determined according to standard method with slight modifications 17. 50 g of the powdered test sample was macerated in a pestle and mortar with 20 ml of ethanol and kept for incubation at 30 °C for 10 h. The mixture was centrifuged at 1500 rpm for 20 min and the supernatant was collected separately. One ml of this alcoholic extract was taken and 1 ml of 5% phenol solution was added in it. 5 ml of concentrated H2SO4 was added rapidly with constant stirring. This was allowed to stand for 30 min at room temperature. The solution colour changed in to yellow orange and the OD was measured at 490 nm against a blank. The blank standard curve was prepared using known concentrations of glucose. The quantity of the sugar was expressed as mg/g fresh weight of the sample. Statistical Analysis: All the experiments were performed three times and the data were reported as the mean ± SD of three measurements. Statistical analysis was performed using KyPlot version 2.0 beta 15 (32 bit). RESULTS: Results of the qualitative and quantitative phytochemical analysis indicated the presence of steroids, phenolics, flavonoids, tannins, glycosides, terpenoids and other phytochemicals in Gobindobhog and black rice. These phytochemicals were also estimated quantitatively. The results are listed in the Table 1 and Table 2. From the present study, it is observed that the lipid content in Gobindobhog (125.66 ± 4.04 mg/g) was higher than that of black rice (38.33 ± 1.52 mg/g). Similarly, the total sugar content in black rice (0.15 ± 0.03 mg/g) was found to be nearly half of the total sugar content in Gobindobhog rice (0.29 ± 0.04 mg/g) whereas, the thiamine content in black rice (39.45 ± 0.65 mg / 100 g) was found to be double than that of Gobindobhog rice (17.03 ± 0.15 mg / 100 g). DISCUSSION: Gobindobhog is one of the most popular aromatic rice varieties of India especially among the people of West Bengal, whereas the demand and popularity of the black rice is getting increasing day by day throughout the world for its nutritional and medicinal properties. The grain of Gobindobhog rice is white in colour, having a beautiful aroma whereas for the black rice, as the name suggested, the grain is black in color. Both of the rice varieties are consumed in various forms as food in different parts throughout the state of West Bengal, India, where the present study has been conducted. In the present study, phytochemical analysis of Gobindobhog and black rice was done using biochemical and spectrophotometric methods. Qualitative screening of phytochemicals identified the presence of glycoside, steroid, phenol, protein and carbohydrate in both of the rice varieties, whereas tannin, phlobatannin, terpenoid, alkaloid and flavonoid were identified only in black rice. These phytochemicals are the essential constituents of herbal medicine and also commonly detected in root, leaf, stem and fruits in most of the angiosperms. Alkaloids are naturally occurring nitrogenous compound. Many of them are used in medical purposes such as, atropine as anticholinergic and morphine as analgesic. In the present study, a small amount of alkaloids is present in black rice while it is completely absent in Gobindobhog rice. Phenolic compounds are considered as the alternative to conventional anti-inflammatory therapeutics in case of chronic inflammatory diseases; whereas, flavonoids are bioactive compounds which influence cellular mechanisms related to carcinogenesis, regulate cell cycle and apoptosis 18. It is evident that flavonoid, especially quercetin may reduce the risk of lung cancer 19. Present study indicated the absence of flavonoid in Gobindobhog rice, whereas flavonoid content in the black rice is found to be significant. In both of the rice varieties, moderate quantity of phenolic compounds has been estimated. Both these classes of compounds have good antioxidant potential and their effects on human nutrition and health are considerable. The mechanism of action of flavonoids is through scavenging or chelation 20. Phenolic compounds are also very important plant constituents because their hydroxyl groups confer scavenging ability 21. Tannin plays a major role in protection from predation. Tannin possesses remarkable toxic activity against bacteria 22. Results indicated the presence of significant amount of tannin in black rice, whereas, in case of Gobindobhog rice, tannin is absent. Therefore, black rice may play a useful role against the toxicity of pathogens. Riboflavin or vitamin B2 in rice is used as a dietary supplement. UV light activates riboflavin, produce active oxygen that damages cell membrane and prevents replication of the harmful pathogens found in the human blood 23. Results of the present study indicated that Gobindobhog rice contains significant amount of riboflavin that is higher than that of black rice, therefore, Gobindobhog rice may possess antipathogenic activity by activating molecular oxygen. Thiamine or vitamin B1 plays an important role in energy metabolism. It is important in the breakdown of carbohydrate from rice to produce energy. Significant amount of thiamine was found in both of the rice varieties. It is found that thiamine content in black rice is higher than that of Gobindobhog rice. Therefore, it can be assumed that black rice is a better source of energy than Gobindobhog rice which justifies the increasing popularity and demand of black rice over other conventional varieties. Ascorbic acid, commonly known as vitamin C, is a water soluble vitamin used as a dietary supplement. It helps in biosynthesis of collagen and certain neurotransmitters require ascorbic acid for better functioning 24. Ascorbic acid is a potent antioxidant, stops the chain radical reaction and scavenges free radicals. In both of the rice varieties, the amount of ascorbic acid is significant, thereby indicating their bioactive potential. Moreover, rice is used mainly as a high energy source to pursue our daily work and, protein and carbohydrate play an important role in this regard. Both Gobindobhog and black rice contain high calorific value due to the presence of high amount of proteins and carbohydrates. CONCLUSION: Present study indicated the presence of some medicinally important phyto-chemicals like alkaloids, glycosides, flavonoids, phenolic compounds and other secondary metabolites in two common rice varieties, and thereby indicating that apart from their food value, both black rice as well as Gobindobhog rice may be used to treat various kinds of diseases. This preliminary phytochemical investigation will provide valuable information which may help future investigators towards isolation and identification of active principles from these rice varieties and it will advance the existing knowledge in relation to human health. ACNOWLEDGEMENT: Authors would like to thank Mr. Prabir Mandal for his help towards the collection of indigenous black rice from the authentic vendors. Deepa G, Singh V and Naidu KA: A comparative study on starch digestibility, glycemic index and resistant starch of pigmented ('Njavara' and 'Jyothi') and non-pigmented ('IR 64') rice varieties. Journal of Food Science and Technology 2010; 47: 644-649. Hanhineva K, Törrönen R, Bondia-Pons I, Pekkinen J, Kolehmainen M, Mykkänen H and Poutanen K: Impact of dietary polyphenols on carbohydrate metabolism. International Journal of Molecular Sciences 2010; 11: 1365-1402. Zhang H, Shao Y, Bao J and Beta T: Phenolic compounds and antioxidant properties of breeding lines between the white and black rice. Food chemistry 2015; 172: 630-639. Ashraf A, Sarfraz RA, Rasid MA and Shahid M: Antioxidant, antimicrobial, antitumor, and cytotoxic activities of an important medicinal plant (Euphorbia royleana) from Pakistan. Journal of Food and Drug Analysis 2015; 23: 109-115. Pereira-Caro G, Cros G, Yokota T and Crozier A: Phytochemical profiles of black, red, brown, and white rice from the Camargue region of France. Journal of Agricultural and Food Chemistry 2013; 61: 7976-7986. Umadevi M, Pushpa R, Sampathkumar KP and Bhoumik D: Rice - traditional medical plant in India. Journal of Pharmacognosy and Phytochemistry 2012; 1: 6-12. Deepa G, Singh V and Naidu KA: Nutrient composition and physicochemical properties of Indian medicinal rice - Njavara. Food Chemistry 2008; 106: 165-171. Durai MV, Balamuniappan G, Anandalakshmi R, Geetha S and Kumar NS: Qualitative and quantitative analysis of phytochemicals in crude extract of big - leaf mahogany (Swietenia macrophylla King). International Journal of Herbal Medicine 2016; 4: 88-91. Santhi K and Sengottuvel R: Qualitative and Quantitative Phytochemical analysis of Moringa concanensis International Journal of Current Microbiology and Applied Sciences 2016; 5: 633-640. Prabhavathi RM, Prasad MP and Jayaramu M: Studies on qualitative and quantitative phytochemical analysis of Cissus quadrangularis. Advances in Applied Science Research 2016; 7: 11-17. Harborne JB: Phytochemical methods. Chapman and Hall, Third edition 1983. Danlami U, Cecilia OE and Ifeanyi OM: Evaluation of the phytochemicals and antimicrobial activities of the ethanolic, hexane and ethyl acetate extracts of Spigelia anthelmia International Journal of Pharmacy and Chemistry 2017; 3: 29-32. Agostini-Costa TS, Teodoro AP, Neves Alves RB, Braga LR, Ribeiro IF, Silva JP, Quintana LG and Burle ML: Total phenolics, flavonoids, tannins and antioxidant activity of lima beans conserved in a Brazilian Genebank. Journal of Food Science and Tech. 2015; 45: 335-341. Xie L, Wehling RL, Ciftci O and Zhang Y: Formation of complexes between tannic acid with bovine serum albumin, egg ovalbumin and bovine beta-lactoglobulin. Food Research International 2017; 102: 195-202. Nandagoapalan V, Doss A and Marimuthu C: Phyto-chemical Analysis of Some Traditional Medicinal Plants. Bioscience Discovery 2016; 7: 17-20. Poornima GN and Rai VR: Evaluation of phytonutrients and vitamin contents in a wild yam, Dioscorea belophylla (Prain) Haines. African Journal of Biotechnology 2009; 8: 971-973. Dey P, Roy S and Chaudhuri TK: A quantitative assessment of bioactive phytochemicals of Nerium indicum: An ethnopharmacological herb. International Journal of Research in Pharmaceutical Sciences 2012; 3: 579-587. Xingkang H and Sun L: Dietary intake of flavonoid subclasses and risk of colorectal cancer: evidence from population studies. Onco target 2016; 7: 26617-26627. Khan F, Niaz K, Maqbool F, Hassan FI, Abdollahi M, Venkata KCN, Nabavi SM and Bishayee A: Molecular targets underlying the anticancer effects of quercetin: An update. Nutrients 2016; 8: 529-548. Ivey KL, Hodgson JM, Croft KD, Lewis JR and Prince RL: Flavonoid intake and all-cause mortality. The American Journal of Clinical Nutrition 2015; 101: 1012-1020. Diplock AT: Will the good fairies please prove to us that vitamin E lessens human degenerative disease? Free Radical Research 1997; 27: 511-532. Rodrigues CG, Ferreir PRB, Mendes CSO, Ronaldo RJ, Valerio HM, Brandi IV and Oliveira DA: Antibacterial activity of tannins from Psidium guineense (Myrtaceae). Journal of Medical Plants Research 2014; 8: 1095-1100. Zeddies S, Cuyper IMD, Meer PF, Daal BB, Korte D, Gutiérrez L and Thijssen-Timmer DC: Pathogen reduction treatment using riboflavin and ultraviolet light impairs platelet reactivity toward specific agonists in vitro 2014; 54: 2292-2300. Carr AC and Frei B: Towards a new recommended dietary allowance for vitamin C based on antioxidant and health effect in humans. The American Journal of Clinical Nutrition 1999; 69: 1089-1107. Bhattacharyya S and Roy S: Qualitative and quantitative assessment of bioactive phytochemicals in Gobindobhog and black rice, cultivated in West Bengal, India. Int J Pharm Sci & Res 2018; 9(9): 3845-51. doi: 10.13040/IJPSR.0975-8232.9(9).3845-51.
Mar 27, 2018 at 3:57 p.m. A previously-developed groundwater model of the Suwannee River Basin was modified and calibrated to represent transient conditions. A simulation of recent conditions was developed for the 372-month period 1970-2000, and was compared with a simulation of future conditions for a similar-length period 2039-2069, which uses downscaled GCM (Global Climate Model) data. The MODFLOW groundwater-simulation code was used in both of these simulations, and two different MODFLOW boundary condition "packages" (River and Streamflow Routing Packages) were used to represent interactions between surface-water and groundwater features. The parameters for the simulation of future conditions were developed from dynamically downscaled precipitation and evapotranspiration data generated by the Community Climate System Model.
Seeing gray whiskers in the mirror? You're getting old. You have lots of wrinkles because you worry all the time. And nothing worries guys more than Prostate Cancer. The prostate has the simple job of secreting about 30% of liquid ejaculate. It is the size of a chestnut, which makes it slightly larger than the male brain. As you age, the spongy gland undergoes hardening and swelling that gradually obstructs the flow of urine, a simple condition that is easily treated with a set of barbaric instruments that would have been the delight of any torturer from the middle ages. But if cancer develops and spreads slowly to bone, you could suffer years of agonizing pain and eventual fatality. One out of six men are diagnosed with prostate cancer during their lifetime, and with a 18% average chance of death, it would seem a no-brainer (even for "Chestnut Brains") to have the prostate removed. However, surgery can cause loss of sexual function and the inability to control your urine. Therapy can include radiation, removal of the testicles, and drugs with nasty side effects that nobody wants to discuss at the dinner table. And those treatments are often limited in effectiveness. Prostate-Specific Antigen (PSA) is a blood test that can detect prostate cancer -- a seemingly perfect justification for biopsy. So why are some limiting use of the test? Consider this: a dozen needles are poked rectally into this sensitive area to get tissue samples. About 75% of the time the biopsy will be negative, but since the cancer may be small, you are likely to face another biopsy next year if the PSA continues to be high. If cancer is diagnosed, you face even worse choices. Many nervous patients choose aggressive treatment even though progression of prostate cancer is often indolent. The truth is that most men will end up dying of something else, and statistics show that sweating over annual PSA tests does not statistically reduce the likelihood of death. Should you be tested for PSA? In the context of a strong genetic history and judicious interpretation by a trusted urologist, PSA can be a life saver. But remember -- a little knowledge is a dangerous thing. Particularly if your brain is the size of a chestnut.
Home » Table of Contents » Functional & Reconstructive Rhinoplasty » Saddle Nose Deformity: Selection of Augmentation Materials and Management Saddle Nose Deformity: Selection of Augmentation Materials and Management by Fred Fedok, MD, FACS, Jacob Sedgh, MD and Eelam A. Adil, MD, MBA on 08/12/2011 Fred Fedok, MD, FACS Division of Otolaryngology-Head and Neck Surgery [email protected] Jacob Sedgh, MD [email protected] Eelam A. Adil, MD, MBA [email protected] https://oto.hms.harvard.edu/people/eelam-adil A saddle nose deformity is characterized by a markedly depressed bony dorsum and an accompanying collapse of the middle nasal vault in relation to the tip and dorsum1. This deformity is the result of a complex interplay of factors leading to the loss of structural support of the nasal septum and upper lateral cartilages, collectively known as the middle vault, and their junction with the bony dorsum and cartilaginous tip Saddle nose deformity can present as one of the more dreaded complications of nasal surgery. Regardless of its cause, management poses one of the more daunting challenges for the reconstructive surgeon. The etiologies of saddle nose deformity can be quite variable. They include congenital diseases such as Binder syndrome, which is characterized by nasomaxillary hypoplasia with abnormal and deficient nasal bones,systemic diseases such as relapsing polychondritis, Wegener's granulomatosis, sarcoid, and Crohn's disease2,3. Infectious processes such as septal abscess, leprosy and syphilis tend to affect the middle vault. Cocaine abuse, trauma and prior surgical procedures constitute some of the other factors that cause damage to the mucoperichondrial layer of the nasal septum and resultant cartilage dissolution and saddling1. Post-operative saddle nose deformity can be caused by a variety of factors including the overzealous use of flat osteotomies, the overuse of rasps, or the overuse of saws. Saddling may occur during or after rhinoplasty when there has been weakening of the dorsal support of the nose. Patients with short nasal bones are at higher risk for this complication. Overresection of the dorsum at the level of rhinion, which has the thinnest soft tissue envelope during dorsal hump reduction, may predispose to disconjugation of the balance between the upper and middle vaults of the nose, thus creating a saddled appearance without an actual weakening of support4. The understanding of the local anatomy and dynamic structural relations of the bony and cartilaginous vaults of the nose is imperative in both the avoidance of producing a saddle nose deformity during nasal surgery and in planning a repair. The nose is commonly assessed and regarded by surgeons as being divided into three components: the upper bony vault, the middle cartilaginous vault, and the lower cartilaginous vault. The bony vault is composed of the paired nasal bones, articulating laterally with the frontal process of maxilla, and superiorly with the nasal process of the frontal bone. In the midline, these paired bones approximate each other and the perpendicular plate of ethmoid bone, which is a component of the nasal septum. At the inferior end of the upper bony vault, the paired nasal bones will meet the upper lateral cartilages of the nasal sidewall. The point in the midline where the paired nasal bones and upper lateral cartilages meet is called the rhinion. The lower two components of the nose correspond to the areas supported by the upper and lower lateral cartilages respectively. The upper lateral cartilages invariably underlay and are attached to the underside of the nasal bones for a variable distance of 3 to 10 mm. Disruption of this relationship either traumatically or iatrogenically plays a role in middle vault collapse and potential compromise of the airway4. The dimensions and patency of the middle vault will have to be reconstructed in many cases of saddle nose deformity through the application of grafting techniques such as spreader grafts and battons. The paired upper lateral cartilages are fused with the quadrangular septal cartilage in the midline. The quadrangular cartilage articulates with the perpendicular plate of ethmoid bone superiorly and the vomer inferiorly via a system of fibrous attachments. The cartilaginous septum is attached to the upper lateral cartilages dorsally and proceeds caudally to form the anterior septal angle where it intercalates with the alar cartilages, and inferiorly ends in its attachment to the nasal spine of maxilla at the posterior septal angle. The dorsum of the nose derives most of its strength from the midline continuation of the bony and cartilaginous septum4. During septorhinoplasty, this dorsal support is preserved by the maintenance of adequate caudal and dorsal "struts." The lower cartilaginous vault, is shaped by the intricate forms of the lower lateral cartilages, the fibrofatty lateral ala, the caudal septum and the junctions that this compartment makes with the upper lateral cartilages cephalically, the upper lip caudally, and the cheeks laterally. The three main mechanisms of tip support include: the intrinsic strength and resilience of lower lateral cartilages, the attachments of lower lateral cartilages to upper lateral cartilages, and the attachment of the medial crura of the lower lateral cartilages to the caudal septum. Many surgical maneuvers during rhinoplasty will disrupt several of these support mechanisms and they must be reconstituted or mimicked if nasal tip position is to be preserved5. Given a particular osseocartilaginous skeleton, innumerable permutations of external appearance are possible, dictated by the characteristics of the soft tissue envelope. Of course, such variations need to be accounted for by the rhinoplasty surgeon while designing reductive contouring of the dorsal septum to avoid creating a saddle nose deformity. Figure 1. Lateral drawing depicting the relationships between the upper, middle, and lower nasal vaults. (1) nasal bone (2) nasion (3) internasal suture (4) nasomaxillary suture (5) ascending process of maxilla (6) rhinion (7) upper lateral cartilage (8) lateral edge of upper lateral cartilage (9) anterior septal angle (10) lateral crus of lower lateral cartilage (11) medial crural footplate (12) intermediate crus (13) sesamoid cartilage (14) pyriform aperture Aesthetic analysis and preoperative evaluation The face and nose are ascertained by their recognizable patterns of light and shadows, subtle convexities, and concavities that are imparted by the form inherent in the combination of the soft tissue cover and influenced by the underlying skeleton. As described below, there are a number of accepted dimensions and relationships that characterize the aesthetic nose. The nose projects antero-inferiorly from the nasion that corresponds to the suture line between the frontal and paired nasal bones. Clinically this area marks the junction between the forehead and the nasal dorsum and is the origin of the nasofrontal angle. This angle is formed by the relationship between the forehead at the glabella and the nasal dorsum. Figure 2. Lateral drawing showing external soft tissue landmarks and angles. (1) glabella (2) nasofrontal angle (3) rhinion (4) supratip (5) tip-defining point (6) infratip lobule (7) columella (8) nasolabial angle (9) alar facial groove The angle normally ranges between 115 to 130 degrees, with females tending to have an angle that falls in the more obtuse limits of that range and with males possessing an angle in the more acute limit6. There are no well-established parameters to determine the correct depth of this angle, however, the dorsum should be of sufficient height to create a distinct anatomical separation of the eyes and give a third dimension to the upper portion of the face6. With the eyes in forward gaze, the nasofrontal angle should intersect a horizontal line originating between the superior lash line and the supratarsal crease. On profile, the nasal dorsum proceeds anterio-inferiorly from nasion towards the tip in a straight or slightly convex fashion4. Ideally the transition from the nasal dorsum to the tip should include a distinct change in the contour of the dorsum, known as supratip break. In examining the patient in frontal view, the nasal dorsum should be outlined by two slightly curved divergent lines that extend from the medial supracilliary ridges to the tip defining points. This line is known as the brow-nasal aesthetic line. In patients with saddle nose deformity, they tend to have a "washed-out" central facial appearance with a lack of dimension and detail. The nose appears to be in two compartments, with the dorsum appearing flat and dimensionless, and the tip appearing to rise independently from the shallow midface. Frequently, the depressed central face takes the form of an inverted "V" in the frontal view. The surgeon should also assess dorsal and tip support by both anterior rhinoscopy and digital palpation, including Q-tip examination of internal nasal valves, and tip recoil. The state of integrity of structural supports will greatly influence the methods utilized in the correction of "saddling"7. The Surgical Techniques for the Repair of Saddle Nose Deformity The particular approach for the repair of a saddle nose deformity that one employs is influenced by the characteristics of the deformity to be addressed. For the correction of minimal deformities, a closed approach with septal and auricular might be employed. As the extent and severity of the deformity increases, the surgeon should progress along the path of more aggressive techniques including an open approach, and the use of larger volumes of material for augmentation. Commonly used approaches include the endonasal approach, the cartilage delivery approach, and the open approach. It is the degree of complexity of the problem and surgeon's comfort and skill level with each technique that will determine the chosen strategy. In the senior author's opinion, if the amount of recontouring and augmentation is expected to be minimal, the closed approach is recommended. A closed approach allows the avoidance of some of the potential problems encountered in an open approach such as the disruption of the original structural support of the nose and tip, the external scar, and the increased operative time and postoperative tip edema. However, the open approach will provide more visible exposure if the corrective surgery requires the placement of a large graft or grafts, there is considerable asymmetry, or other challenging anatomic features. Grafting and Augmentation Materials Autografts It is the opinion of the authors that the surgeon should use, when possible, autogenous materials. Autogenous materials have several advantages that include a low extrusion and infection rate and the ability to withstand transient bacterial contamination once revascularized. Autogenous materials also have the unique availability from the patient. The disadvantages are the obviously potential donor site morbidity and limitedness of the donor supply9. Septal Cartilage It is a common belief among many surgeons that the septum provides the optimal material for the fabrication of small to moderate sized grafts. It has favorable elastic characteristics that allow precise carving to correct subtle contour deficiencies; on the other hand, it can be used in several layers to correct more severe deficiencies. There are a variety of tools available to change the physical properties of these grafts, including morsilizers and crushers, to make changes in the cartilage for concealing subtle irregularities10. In addition to providing volume for the correction of dorsal deficiencies, septal cartilage is frequently used in a variety of other applications. The septum, if available in adequate amounts, is generally considered the optimal choice for such applications as spreader grafts, columellar struts, and septal extension grafts. One major limiting feature of its use, particularly in a patient who has previously undergone septal surgery or has saddling due to loss of the dorsal cartilaginous septum is its relatively limited supply. Auricular Cartilage These grafts are harvested from the anatomical locations of the concha cavum and concha symba and may have several advantages compared to septal cartilage. First, they are more abundant and generally available in patients with a history of previous septoplasty or non-iatrogenic causes of saddle deformity. Secondly, in a selective fashion the surgeon can employ the natural curvature and suppleness of conchal cartilage. As far as disadvantages, these cartilages are not as easily carved or morsalized as septal cartilage, and have a tendency to reveal their edges on the dorsum particularly in patients with thin skin and soft tissue envelope, unless they are meticulously tapered to the local contours11. Costal cartilage harvested from the transverse portions of the 6th through 8th ribs provides an abundance of grafting material that can be utilized to correct a sizable dorsal deficiency in cases of insufficient septal or auricular cartilage. An obvious advantage of the use of rib cartilage for augmentation grafting is the sheer abundance of the material that is available, so that it can be carved into a variety of shapes and used to fill huge voids. Disadvantages include the potential donor site morbidity, including pneumothorax, hemothorax, and chest wall deformity. Patients usually have significant chest wall pain after the procedure. Another important disadvantage is the potential for "warping" or bending of the cartilage, which is a well-known complication, fairly unique to rib cartilage. The risk of this complication is thought to be minimized by "balanced carving", and proper site selection12. Diced Cartilage Grafts Some authors have advocated the application of diced cartilage grafts, which can be placed as the primary graft, or also in combination with soft tissue graft (i.e. covered or wrapped in fascia). One obvious concern with this technique is resorption; however there are recent reports in literature with long term follow up showing success with this approach13. Split Calvarial Bone Graft There are some situations when bone grafts are preferable to cartilage grafts. It is the opinion of the authors that when a bone graft is desirable, the use of split calvarial has several advantages compared to other bony donor sites. It is readily accessible during nasal surgery, and is associated with minimal donor site morbidity and pain in comparison with some other bone graft donor sites such as the iliac crest. The posterior parietal area of the skull is our usual donor site as that area has a sufficiently thick diploic space and there is an ample area to obtain at sufficiently long specimen. Another advantage of these grafts is that they can be cantilevered at the nasion so that dorsal nasal support can be created in situations when there is a total loss of midline nasal support. As far as disadvantages, bone grafts are rigid and non-resilient, with a higher risk of fracture following future traumas. This is, therefore, prone to be problematic in the younger athletically active patient. Soft Tissue – Perichondrium and Temporalis Fascia The use of rigid or semi rigid augmentation material in rhinoplasty can occasionally lead to visible irregularities along the nasal dorsum, even with meticulous contouring techniques. This is particularly an issue with patients with thin skin. If this is anticipated in these situations, the soft tissue cover can be "thickened", at least temporarily, while scar contraction is taking place with the use of soft tissue camouflaging grafts. The advantages of using perichondrium and temporalis fascia in these situations includes the absence of an immunologic response or infectious complication,as it is a concern with alloplasts, while the disadvantages include increased operative time and additional donor site morbidity. Homografts There continues to be use of homograft material in rhinoplasty. Irradiated cartilage has been safely used for structural grafting over the last several decades. There have been numerous articles describing its use and arguable persistence in the nose. There appears to be some persistence of augmentation, which is probably either due to the slow replacement of the implanted material by native fibrous tissue, or in some cases by the persistence of the material as a non-viable implant. It should be understood, however, that no viable chondrocytes are present in the grafted material and hence there is no revascularization of the graft, growth, or true integration with the native tissues. The use of homograft cartilage in the authors' opinion should be limited to circumstances in which there are compelling reasons not to use native materials16,17. On the other hand, another homograft tissue, processed dermis has been used in rhinoplasty. This material frequently serves well as a temporary soft tissue cushion that may help prevent scar contracture of the native skin over an irregular dorsum. The material appears to have considerable application as a single or double layer to serve to thicken the soft tissue envelope. The authors, however, would not recommend its use as a "filler" of defects, and again to be considered as a secondary choice to the native tissue, such as perichondrium or temporalis fascia. The long-term results of acellular dermal grafts have shown a high resorption rate and the need for overcorrection when the graft is used for augmentation18,19. Alloplasts Porous polyethylene, polytetrafluoroethylene, and silicone-based implants have been among the most widely used alloplastic materials in primary and revision rhinoplasty. In the authors' opinion, in general, the use of alloplasts should be employed in situations when the use of autogenous tissues has been precluded. The nose frequently sustains minor and major trauma that leads to variably sized tears of the nasal lining causing at least a transient bacterial contamination. The mobile nature of the distal nose may further allow a breach of the lining or prevent effective vascular cover of semirigid alloplastic augmentation material. This may contribute to the higher risk of infection and extrusion associated with these materials. Nevertheless, there are some situations where it becomes necessary to use alloplasts, and when encountered, some authors suggest the avoidance of the use of rigid and semirigid alloplasts in the mobile aspects of the nose14,15. Graft Fixation Grafts for augmentation can be placed in an "on-lay" fashion; usually describing the simple placement of well-contoured tapered grafts. For larger midline dorsal grafts, the authors frequently use a variety of methods to "fix" or suture the grafts in place using absorbable suture. When grafts are placed during a smaller revision procedure, precise pockets can be dissected over the region in question allowing a form-fitting pocket to be developed to hold a graft in place. Finally, some surgeons use a variety of bioadhesives to hold the grafts in place. Postoperative Analysis and Follow-up For improvement of patient care and for the development of the surgeon in the craft of rhinoplasty, it is essential that patients be followed over time to assess the patient's personal progress and to assess the effectiveness of the surgeon's technique. We typically follow patients at 1 week, 2 weeks, 1 month, 4 months, and one year after the surgery date. Thereafter, the patient is followed at yearly intervals. Photodocumentation is the same as for preoperative analysis. It is through this longitudinal study that that surgeon can hone his craft and correct any deficiencies that are noticed over time. These intervals are shortened if there is any undesirable occurrence as recovery, healing, and scar contracture is taking place. Illustrative Cases The following clinical situations illustrate a spectrum of problems that may be encountered and the variety of techniques that may be employed in the approach to the patient with a saddle nose deformity. The patient depicted in figure 3 presented with posttraumatic bilateral middle vault collapse, severe septal deflection and a foreshortened septum. This was addressed via an open approach. The middle vault was managed with bilateral spreader grafts, followed by placement of auricular cartilage as a dorsal onlay graft and a blanket of auricular perichondrium as a camouflaging graft placed over dorsum and sidewall to minimize potential postop irregularities. The patient also had a septoplasty, lateral osteotomies, the placement of a columellar strut and a tip graft. Figure 3. Frontal, lateral, and base views of a patient with posttraumatic bilateral middle vault collapse, severe septal deflection and a foreshortened septum. (A-C) Pre-operative imaging depicting saddle nose deformity. (D-F) The same patient following open rhinoplasty with bilateral spreader grafts, dorsal onlay graft, and auricular perichondrium as a camouflaging graft. The patient depicted in figure 4 had a nasal dermoid cyst that was removed as a child and left her with dorsal insufficiency and arrest of normal dorsal growth. She was initially treated with a polytetraflouroethylene onlay implant to reduce her deformity until she was old enough to undergo definitive repair through autologous cartilage grafting. At age 17, she presented with displacement of her polytetraflouroethylene implant following a trauma and as such she underwent revision surgery via open approach and replacement of the implant using a double layered auricular cartilage graft as dorsal onlay to address her dorsal insufficiency. She also underwent bilateral auricular composite grafts to address her alar retraction, and placement of a columellar strut graft. Figure 4. Patient with saddle nose deformity following dermoid cyst excision. (A) Lateral pre-operative view depicting saddle nose deformity. (B) Intraoperative view showing the template for the polytetraflouroethylene (PTFE) dorsal onlay graft. (C) Lateral post-operative view with correction of saddle nose deformity. (D) Lateral view of the same patient 12 years later after replacement of the PTFE graft with a costal cartilage dorsal onlay graft. The PTFE graft had been displaced following a nasal trauma. The patient in figure 5 is a patient who presented ten years years after a severe playground accident. Examination revealed saddling of the bony and cartilaginous dorsum with a foreshortened nose, contraction of the soft tissue envelope, severe septal deviation and left middle vault collapse.. Repair was performed via an open approach, with septoplasty, application of bilateral extended spreader grafts and an L-strut graft constructed from a costal cartilage donor site. She also underwent medial and lateral osteotomies, a septal extension graft. Figure 5. Frontal and lateral pre and post-operative photographs in a patient with saddle nose deformity following trauma. Note the bony vault deficiency, moderate dorsal saddling, and foreshortened nose. Post-operative photographs performed prior to secondary procedure to take down small dorsal convexity and further augment the columella. The management of the patient with a saddle nose necessitates the surgeon to call upon his or her understanding of aesthetic principles and technical abilities. When presented with the situation, the surgeon has the privilege of intervening in a problem that may be of significant dissatisfaction for the patient. As illustrated above saddle nose deformity can present in a wide spectrum of severity and involving multiple structural components of the nose. In the patient with adequate midline nasal and tip support and presenting with only deficiencies of dorsal height and abnormal contour, relatively simple techniques might be employed. Such techniques may even involve a closed approach and an onlay graft over the nasal dorsum constructed using septal or auricular cartilage. As the problem becomes more complex with collapse of the middle vault due to weakness or deficiency of upper lateral cartilages or dorsal septum, then application of spreader grafts are of paramount importance in reconstituting both function and aesthetics in such noses. The more complex saddle noses, particularly in case of posttraumatic etiologies, present with a variety of other abnormalities including deflection or other deficiencies of septum, bony vault abnormalities, and the need for tip maneuvers in conjunction with middle vault issues. The goal of this chapter was to give a practical overview and treatment strategy of saddle nose deformity, as one the more challenging problems faced by rhinoplastic surgeons. When successful in this endeavor, they have the gift of transforming the situation to one of great satisfaction and joy for the patient. So one continue to learn and teach; examine and study our results, so that one may rise to the occasion of performing our craft to the best of our abilities. Pribitkin EA, Ezzat WH.Classification and Treatment of the Saddle Nose Deformity. Otolaryngol Clin North Am. 2009;42(3):437-461. Munro IR, Sinclair WJ, Rudd NL. Maxillonasal dysplasia (Binder's syndrome). Plast Recontr Surg1979;63:657–663. Merkonidis C, Verma S, Salam MA. Saddle nose deformity in a patient with Crohn's disease. J Laryngol Otol. 2005;119(7):573-576. Fedok FG, Preston TW. Managing the overresected dorsum. In: Becker DG, Park SS, editors. Revision rhinoplasty,.New York: Thieme; 2008:96-111. Tardy ME, Rhinoplasty tip ptosis: etiology and prevention. Laryngoscope 1973;83:923-929. Boahene DO, Orten SS, Hilger PA. Facial analysis of rhinoplasty patient, In Papel ID. (Ed). Facial Plastics and Reconstructive Surgery, 3rd ed. New York, Thieme. 2008:477-488. Kim DW, Toriumi DM. Nasal analysis for secondary rhinoplasty. Facial Plastic Surg Clin North Am 2003;11:399-419. Adamson PA, Doud Galli SK. Rhinoplasty approaches: current state of the art. Arch Facial Plast Surg. 2005;7(1):32-37. Adamson PA. Grafts in rhinoplasty, autogenous grafts are superior to alloplastics , Arch Otolaryngol Head Neck Surg. 2000;126: 561-562. Calmak O, Buyuklu F. Crushed cartilage grafts for concealing irregularities in rhinoplasty. Arch Facial Plast Surg 2007;9(5):352-357. Becker DG, Becker SS, Saad AA. Auricular cartilage in revision rhinoplasty, Facial Plastic Surg 2003;19(1):41-52. Sherris DA, Kern EB. The versatile autogenous rib graft in septorhinoplasty. Am J Rhinology 1998;12(3):221-227. Daniel RK. Diced cartilage grafts in rhinoplasty surgery: current techniques and applications Plast Reconstr Surg. 2008;122(6):1883-1891. Maas CS, Monhian N, Shah SB. Implants in Rhinoplasty, Facial Plast Surg. 1997;13(4):279-290. Romo T, Sonne J, Choe KS, Sclafani AP. Revision rhinoplasty. Facial Plast Surg. 2003;19(4) 299-307. Clark JM, Cook TA, Immediate reconstruction of extruded alloplastic nasal implants with irradiated homograft costal cartilage. Laryngoscope. 2002; 112(6): 968-974. Kridel RW, Ashoori F, Liu ES, Hart CG. Long-term use and follow-up of irradiated homologous costal cartilage grafts in the nose. Arch Facial Plast Surg. 2009;11(6):378-394. Tarhan E, Cakmak O, Ozdemir BH, Akdogan V, Suren D. Comparison of alloderm, fat, fascia, cartilage, and dermal grafts in rabbits. Arch Facial Plast Surg 2008;10(3):187-193. Sclafani AP, Romo T, Jacono AA, et al. Evaluation of acellular dermal graft (alloderm) sheet for soft tissue augmentation: a1-year follow-up of clinical observations and histological findings. Arch Facial Plast Surg. 2001;3(2):101-103. Filed Under: Functional & Reconstructive Rhinoplasty Tagged With: Nasal, Rhinoplasty, Saddle Nose Deformity, USA
Locating the thapsigargin-binding site on Ca(2+)-ATPase by cryoelectron microscopy. Young HS., Xu C., Zhang P., Stokes DL. Thapsigargin (TG) is a potent inhibitor of Ca(2+)-ATPase from sarcoplasmic and endoplasmic reticula. Previous enzymatic studies have concluded that Ca(2+)-ATPase is locked in a dead-end complex upon binding TG with an affinity of <1 nM and that this complex closely resembles the E(2) enzymatic state. We have studied the structural effects of TG binding by cryoelectron microscopy of tubular crystals, which have previously been shown to comprise Ca(2+)-ATPase molecules in the E(2) conformation. In particular, we have compared 3D reconstructions of Ca(2+)-ATPase in the absence and presence of either TG or its dansylated derivative. The overall molecular shape of Ca(2+)-ATPase in the reconstructions is very similar, demonstrating that the TG/Ca(2+)-ATPase complex does indeed physically resemble the E(2) conformation, in contrast to massive domain movements that appear to be induced by Ca(2+) binding. Difference maps reveal a consistent difference on the lumenal side of the membrane, which we conclude corresponds to the thapsigargin-binding site. Modeling the atomic structure for Ca(2+)-ATPase into our density maps reveals that this binding site is composed of the loops between transmembrane segments M3/M4 and M7/M8. Indirect effects are proposed to explain the effects of the S3 stalk segment on thapsigargin affinity as well as thapsigargin-induced changes in ATP affinity. Indeed, a second difference density was observed at the decavanadate-binding site within the three cytoplasmic domains, which we believe reflects an altered affinity as a result of the long-range conformational coupling that drives the reaction cycle of this family of ATP-dependent ion pumps. 10.1006/jmbi.2001.4558 J Mol Biol Adenosine Triphosphate, Animals, Binding Sites, Calcium-Transporting ATPases, Cryoelectron Microscopy, Crystallization, Dansyl Compounds, Fourier Analysis, Image Processing, Computer-Assisted, Models, Molecular, Protein Conformation, Rats, Sarcoplasmic Reticulum, Thapsigargin
Newborn discharge timing and readmissions: California, 1992-1995. CPQCC Publication Title Newborn discharge timing and readmissions: California, 1992-1995. Authors Danielsen B, Castles AG, Damberg CL, Gould JB Journal Pediatrics Issue 1 Pt 1 Pagination 31-9 Date Published 2000 Jul Keywords California, Dehydration, Ethnic Groups, Female, Humans, Infant, Newborn, Infections, Jaundice, Neonatal, Length of Stay, Male, Mothers, Patient Discharge, Patient Readmission, Prenatal Care, Prevalence, Risk, Socioeconomic Factors, Time Factors CONTEXT: Hospital stays for newborns and their mothers after uncomplicated vaginal delivery have decreased from an average of 4 days in 1970 to 1.1 days in 1995. Despite the lack of population-based research on the quality-of-care implications of this trend, federal legislation passed in 1996 mandated coverage for 48-hour hospital stays after uncomplicated vaginal delivery. OBJECTIVE: To assess the impact of very early discharge (defined as discharge on the day of birth) on the risk of infant readmission during the neonatal period in a California healthy newborn population. DESIGN: Retrospective cohort study, based on a linked dataset consisting of the birth certificate, newborn, and maternal hospitalization record, and linked infant readmission records for all healthy, vaginally delivered, and routinely discharged California newborns from 1992 to 1995. OUTCOME MEASURES: Very early discharge and infant readmission during the first 28 days of life. RESULTS: The percentage of infants discharged very early or early (after a 1-night stay) increased from 71% in 1992 to 85% in 1995. The percentage of infants discharged very early increased from 5.0% in 1992 to 5.7% in 1993 and 7.0% in 1994, then decreased to 6.7% in 1995. Characteristics that have been previously associated with suboptimal pregnancy outcomes were found to decrease the likelihood of very early discharge, eg, maternal complications, primiparity, and Hispanic, African American, South East Asian, or other Asian race/ethnicity. The rate of readmission in the neonatal period initially decreased from 27.6 infants per 1000 in 1992 to 25.67 infants per 1000 in 1994, then increased to 30.2 infants per 1000 in 1995. For infants discharged early, no statistically significant increase in the risk of readmission was observed, compared with infants discharged after a 2+-night stay. The adjusted odds ratio (OR) for readmission was statistically significantly higher for infants who were discharged very early, compared with infants discharged early (OR: 1.27), first order births (OR: 1.21), infants born to mothers who experienced complications (OR: 1.11), infants with Medicaid insurance (OR: 1.23), and infants born to mothers who received adequate plus prenatal care (OR: 1.15). The risk was statistically significantly lower for female infants (OR: 0.75). The proportion of infants rehospitalized for dehydration and low-risk infections over the 4 study years combined was statistically significantly higher in infants discharged very early (4.37 per thousand and 10.30 per thousand, respectively), compared with infants discharged early (3.59 per thousand and 8.16 per thousand, respectively) or after a 2+-night stay (2.91 per thousand and 7.95 per thousand, respectively). The proportion of infants rehospitalized for dehydration increased statistically significantly from 2.89 per thousand in 1992 to 4.52 per thousand in 1995. CONCLUSIONS: One-night stays with adequate antenatal and postnatal care outside the hospital do not increase the risk of readmission for healthy, vaginally delivered infants born in California. However, the decision to discharge infants on the day of birth should be applied conservatively because of the increased risk of infant readmission associated with very early discharge. DOI 10.1542/peds.106.1.31 Alternate Journal Pediatrics
Hutchison's Clinical Methods, 23/e /shop/product/hutchison-s-clinical-methods-23-e-3853 ₨ 1075.00 ₨ 1721.61 1721.61250359 NPR ₨ 1075.00 Author: Glynn Edition: 23/e Hutchion's Clinical Methods, first published over a century ago, is the classic textbook on clinical examination. It provides an outstanding source of learning and reference for undergraduate medical students and postgraduate doctors. Hutchison's Clinical Methods An Integrated Approach to Clinical Practice Hutchison's Clinical Methods, first published over a century ago, is classic textbook on clinical examination. It provides an outstanding source of learning and reference for undergraduate medical students and postgraduate doctors. It teaches an integrated approach to taking a history, examining a patient and formulating a differential diagnosis. In this latest edition new methods and investigations are incorporated with established patterns of clinical practice, rather than added on as something extra. The text is organized so the both system-related and problem-oriented chapters are included. Particular emphasis is placed on the importance of the doctor-patient relationship, as well as the essential skills needed for clinical examination and for planning the appropriate choice of investigations in diagnosis and management. The book begins with a group of chapters that describe the general clinical assessment and the overall approach to a patient, including ethical considerations. A new section of six chapters groups together the clinical methods relevant to particular patient groups such as the elderly, the young, and those in pair or in emergency situations. five chapters cover the assessment of the core body systems – respiratory, cardiovascular, gastrointestinal, locomotor and neurological. A final section groups together the key clinical specialties including skin, endocrine, diabetes and ENT. This 23rd edition of Hutchison's clinical methods is an invaluable resource for all those learning and training in medical and is an essential adjunct to a standard textbook of medicine, surgery or other specialty. [email protected] Bazaar International Copyright © Bazaar International - Terms of Use - Privacy Policy - Legal Info Copyright © Bazaar International. All rights reserved.
Update on the epidemiology and management of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, in patients with cystic fibrosis Anne Stone, Lisa Saiman PURPOSE OF REVIEW: Staphylococcus aureus is one of the first and most common pathogens to be isolated from the respiratory tract of patients with cystic fibrosis. The prevalence of respiratory tract colonization/infection with both methicillin-susceptible and methicillin-resistant S. aureus has increased over the past decade. The clinical significance of colonization/infection with these pathogens is variable, leading to numerous therapeutic strategies: primary prophylaxis, eradication, treatment of cystic fiboris pulmonary exacerbations, and treatment of methicillin-resistant S. aureus. RECENT FINDINGS: Studies have demonstrated increased prevalence of S. aureus in clinical laboratories that use selective media. Additionally, small colony variant S. aureus has been associated with persistent infection, co-infection with Pseudomonas aeruginosa, and frequent courses of antibiotics, but this phenotype may be difficult to identify in clinical laboratories. Increased prevalence of methicillin-resistant S. aureus has led to use of oral and inhaled antibiotics in attempts to eradicate this pathogen; these studies have yielded variable results. SUMMARY: The epidemiology of S. aureus in cystic fibrosis has changed. Studies are needed to assess the clinical significance of the increased prevalence of both methicillin-susceptible and methicillin-resistant S. aureus, and whether primary prophylaxis or new treatment/eradication protocols are effective. Current opinion in pulmonary medicine https://doi.org/10.1097/MCP.0b013e3282efbbac Methicillin Coinfection Small colony variant Stone, A., & Saiman, L. (2007). Update on the epidemiology and management of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, in patients with cystic fibrosis. Current opinion in pulmonary medicine, 13(6), 515-521. https://doi.org/10.1097/MCP.0b013e3282efbbac Update on the epidemiology and management of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, in patients with cystic fibrosis. / Stone, Anne; Saiman, Lisa. In: Current opinion in pulmonary medicine, Vol. 13, No. 6, 01.11.2007, p. 515-521. Stone, A & Saiman, L 2007, 'Update on the epidemiology and management of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, in patients with cystic fibrosis', Current opinion in pulmonary medicine, vol. 13, no. 6, pp. 515-521. https://doi.org/10.1097/MCP.0b013e3282efbbac Stone A, Saiman L. Update on the epidemiology and management of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, in patients with cystic fibrosis. Current opinion in pulmonary medicine. 2007 Nov 1;13(6):515-521. https://doi.org/10.1097/MCP.0b013e3282efbbac Stone, Anne ; Saiman, Lisa. / Update on the epidemiology and management of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, in patients with cystic fibrosis. In: Current opinion in pulmonary medicine. 2007 ; Vol. 13, No. 6. pp. 515-521. @article{15358efd93314e0da088361a14b0b091, title = "Update on the epidemiology and management of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, in patients with cystic fibrosis", abstract = "PURPOSE OF REVIEW: Staphylococcus aureus is one of the first and most common pathogens to be isolated from the respiratory tract of patients with cystic fibrosis. The prevalence of respiratory tract colonization/infection with both methicillin-susceptible and methicillin-resistant S. aureus has increased over the past decade. The clinical significance of colonization/infection with these pathogens is variable, leading to numerous therapeutic strategies: primary prophylaxis, eradication, treatment of cystic fiboris pulmonary exacerbations, and treatment of methicillin-resistant S. aureus. RECENT FINDINGS: Studies have demonstrated increased prevalence of S. aureus in clinical laboratories that use selective media. Additionally, small colony variant S. aureus has been associated with persistent infection, co-infection with Pseudomonas aeruginosa, and frequent courses of antibiotics, but this phenotype may be difficult to identify in clinical laboratories. Increased prevalence of methicillin-resistant S. aureus has led to use of oral and inhaled antibiotics in attempts to eradicate this pathogen; these studies have yielded variable results. SUMMARY: The epidemiology of S. aureus in cystic fibrosis has changed. Studies are needed to assess the clinical significance of the increased prevalence of both methicillin-susceptible and methicillin-resistant S. aureus, and whether primary prophylaxis or new treatment/eradication protocols are effective.", keywords = "Epidemiology, Eradication, Methicillin-resistant, Small colony variant, Staphylococcus aureus, Virulence", author = "Anne Stone and Lisa Saiman", doi = "10.1097/MCP.0b013e3282efbbac", journal = "Current Opinion in Pulmonary Medicine", T1 - Update on the epidemiology and management of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus, in patients with cystic fibrosis AU - Stone, Anne AU - Saiman, Lisa N2 - PURPOSE OF REVIEW: Staphylococcus aureus is one of the first and most common pathogens to be isolated from the respiratory tract of patients with cystic fibrosis. The prevalence of respiratory tract colonization/infection with both methicillin-susceptible and methicillin-resistant S. aureus has increased over the past decade. The clinical significance of colonization/infection with these pathogens is variable, leading to numerous therapeutic strategies: primary prophylaxis, eradication, treatment of cystic fiboris pulmonary exacerbations, and treatment of methicillin-resistant S. aureus. RECENT FINDINGS: Studies have demonstrated increased prevalence of S. aureus in clinical laboratories that use selective media. Additionally, small colony variant S. aureus has been associated with persistent infection, co-infection with Pseudomonas aeruginosa, and frequent courses of antibiotics, but this phenotype may be difficult to identify in clinical laboratories. Increased prevalence of methicillin-resistant S. aureus has led to use of oral and inhaled antibiotics in attempts to eradicate this pathogen; these studies have yielded variable results. SUMMARY: The epidemiology of S. aureus in cystic fibrosis has changed. Studies are needed to assess the clinical significance of the increased prevalence of both methicillin-susceptible and methicillin-resistant S. aureus, and whether primary prophylaxis or new treatment/eradication protocols are effective. AB - PURPOSE OF REVIEW: Staphylococcus aureus is one of the first and most common pathogens to be isolated from the respiratory tract of patients with cystic fibrosis. The prevalence of respiratory tract colonization/infection with both methicillin-susceptible and methicillin-resistant S. aureus has increased over the past decade. The clinical significance of colonization/infection with these pathogens is variable, leading to numerous therapeutic strategies: primary prophylaxis, eradication, treatment of cystic fiboris pulmonary exacerbations, and treatment of methicillin-resistant S. aureus. RECENT FINDINGS: Studies have demonstrated increased prevalence of S. aureus in clinical laboratories that use selective media. Additionally, small colony variant S. aureus has been associated with persistent infection, co-infection with Pseudomonas aeruginosa, and frequent courses of antibiotics, but this phenotype may be difficult to identify in clinical laboratories. Increased prevalence of methicillin-resistant S. aureus has led to use of oral and inhaled antibiotics in attempts to eradicate this pathogen; these studies have yielded variable results. SUMMARY: The epidemiology of S. aureus in cystic fibrosis has changed. Studies are needed to assess the clinical significance of the increased prevalence of both methicillin-susceptible and methicillin-resistant S. aureus, and whether primary prophylaxis or new treatment/eradication protocols are effective. KW - Epidemiology KW - Eradication KW - Methicillin-resistant KW - Small colony variant KW - Staphylococcus aureus KW - Virulence U2 - 10.1097/MCP.0b013e3282efbbac DO - 10.1097/MCP.0b013e3282efbbac JO - Current Opinion in Pulmonary Medicine JF - Current Opinion in Pulmonary Medicine 10.1097/MCP.0b013e3282efbbac
There's no better place for Breast Imaging than SVMC. Not only are we recognized as a Breast Imaging Center of Excellence, we offer all-encompassing breast care through our comprehensive Breast Care Program. Ours is a fully integrated system that ensures every patient* receives the highest level of care and attention. Note: Although breast disease most commonly affects women, it can affect men as well. Our program offers the best care available for each patient, regardless of gender. Although some patients begin their relationship with the Breast Care Program with education or an evaluation of family history, most patients begin in our Women's Imaging Department. There we offer routine breast mammograms, follow up mammograms, breast ultrasound and breast MRIs. SVMC Imaging is accredited in breast mammography and ultrasound by the American College of Radiology (ACR). Abnormalities in breast tissue are very common. Whether you notice a breast abnormality at home, during a clinical breast exam or during a regularly scheduled mammogram, we will work with you to ensure that you are getting the best care. After the detection of an abnormality, patients usually receive advanced imaging. From there a board-certified Radiologist will interpret your results. If recommended, we will guide you through a biopsy. Our imaging department offers ultrasound guided breast biopsy, stereotactic core breast biopsy and, when indicated, MRI guided breast biopsy. We do it so well that we are ACR accredited for both ultrasound and stereotactic biopsies. Most often—in nearly 75 percent of cases—biopsies reveal no need to worry. Only five in 1,000 women is diagnosed with breast cancer. Our pathologists are board certified with special certifications in breast pathology. They work with your care team to get you results in a timely manner. If you are diagnosed with breast cancer, we offer lots of support. A Breast Health Navigator, a registered nurse, will guide you through the diagnostic process—reviewing test results with you, answering questions, providing resources, facilitating communication between you and your doctor(s), and doing all that can be done to support you and your family. Your navigator will stay with you through imaging and if needed, surgery, oncology and into survivorship. Should you need a surgical consult for management of benign breast disease or management of high risk lesions, or if you choose surgery as part of your breast cancer treatment, it can be accomplished right here with the board-certified surgeons at SVMC General Surgery. In addition, your physician can connect you with plastic and reconstructive surgeries if you choose. The clinicians at Southwestern Vermont Regional Cancer Center are here for you. Through clinical trials, tumor boards, and genetic counseling, they have direct access to all of the research and physicians at Dartmouth-Hitchcock, one of only three NCI-designated comprehensive cancer centers in New England. American Cancer Society resources, including Reiki and massage, nutritional counseling, psychological support, lymphedema and other symptom management and transportation. The Cancer Center Patient Resources Fund is for patients who need help with financial strain related to treatment.
Most U.S. residents are unaware there are shortages in the availability of cancer drugs, such as those for multiple myeloma, a type of cancer that starts in the bone marrow. In a recent survey led by researchers at Dana-Farber Cancer Institute and Brigham Women's Hospital, only 16 percent of respondents said they knew about the cancer drug shortage. In addition, even though non-cancer patients were unaware of the shortage, most said they would want to know if a substitute therapy had to be used in their care during a shortage. In fact, a significant percentage of respondents would prefer to transfer care to avoid a substitution if the alternate therapy had major differences from the preferred therapy. The findings from this survey were published under the title "Cancer Drug Shortages: Awareness and Perspectives From a Representative Sample of the US Population" in CANCER, the peer-reviewed journal of the American Cancer Society (ACS). Drug shortages could impact patient care, raise costs and hamper clinical trials. However, little research has been done about how patients might approach such an event. To investigate, a 13-item survey was given to 420 respondents representative of the U.S. population with respect to age, gender, race and ethnicity, geography, education, and income. Understandably, respondents with a personal history of cancer were more likely to be aware of the latest events (31% versus 14%). To avoid a substitution with major differences from the preferred cancer therapy, most people also said they would prefer to transfer care — 72% would transfer care for major differences in effectiveness and 61% would do so for major differences in side effects. However, African-American respondents, uninsured patients, unemployed people, those with lower incomes and those with less education all were less likely to report that they would transfer care to avoid differences in effectiveness. Findings from this study raise the concern that disclosure regarding cancer drug shortages actually could exacerbate care disparities, specifically because of what this group reported. In addition, black, uninsured and unemployed individuals said they were less likely to use publicly reported shortage data in deciding where to seek treatment. Awareness of cancer drug shortages, however, potentially could increase pressure to solve the system-wide problems that lead to shortages, Frosch emphasized. "It's important that everyone — clinicians, patients, and the public — have a seat at the table as these strategies are developed," he said. In conclusion, this study suggests that most U.S. citizens are unaware of national cancer drug shortages and, when faced with even minor consequences from drug substitutions, they would want to know about the change. In addition, when the differences between the preferred and substitute cancer therapies are great, many reported they would transfer their care to continue receiving the preferred regimen. In alignment with other studies, traditionally vulnerable populations were found to be less likely to report they would transfer their care to avoid the negative impact of substitutions, suggesting that care shortages may represent a new source of health-related disparities in the near future. Tagged African-Americans, cancer awareness, cancer therapies, drug shortage, survey, U.S. population, vulnerable population.
Dr. Wakefield Sues Brian Deer and BMJ's Fiona Godlee That's My Boy! The Inflammation Highway: aka Autism By Lisa Goes "The one thing about my husband and I...we laugh...A lot. We find a way. We really do. Poop filled sleepless nights, injuries, missed appointments, clutter everywhere, missing paperwork...sometimes all you can do is laugh. But today, looking at the dark circles we've seen so many times under our children's eyes, seeing the suffering, the real genuine human suffering that we have worked for three years to alleviate...to see it reach these depths...there is no laughing today. There is sadness. Even the fight is gone. I should be sleeping, but I have to read up on one of our new remedies. Maybe this will be the one that touches his immune damage and regulates him? Maybe. Maybe, it will work for him like it has for THOUSANDS of other children. Maybe. I can't sleep when this could be it and I could be calling the next doctor tomorrow and we could have one less day of this. Plus, I already have an appointment to see a doctor tomorrow and I will need him to know that I know what I'm talking about. If there is one thing you learn as an autism parent it is that YOU MUST KNOW WHAT YOU ARE TALKING ABOUT WITH DOCTORS. You must learn to speak their language. If you don't you will get dismissed. Must read, now. But, before I go, just need to let everyone know the women who work for us are angels from God. They were hurt today. Two of them. In their sweetest voices they kept repeating, "nice hands." And "time to get down monkey" when he climbed on the counter for the 27th time on their shift. He is 50 lbs now. Very fast and very strong. They get him. They see the real Noah in there, fighting like hell. He is mad. In fact, that's what he said in therapy today, "I'm MAD!" His therapists were thrilled. They were so excited to see him emote appropriately. I agree with them, it's encouraging. It's just that, he's mad he's sick. He's mad his head hurts all the time. He's mad his three year old brother can use the toliet and he cannot. He's mad that his body is rebelling against him and everything hurts. He's mad that in addition to not getting to go where everyone else goes and doing all the fun things other 5 year olds do, he also cannot EAT anything they do. It seems cruel doesn't it? It is. Autism is the cruelest most malicious, devious, conniving, heinous disease. If you fear the chicken pox or diarrhea more you are in big, big trouble. Because I guarantee with the new schedule autism will come a knocking at your door. And it will get in. It finds a way. Sometimes it looks like OCD, sometimes it looks like ADHD, even arthritis. "That's nuts!", you say. Not really. It should all just be called autism. Because any time pharma causes inflammation they don't want you to find out about, they just make up a word for it. Autism. Asthma. ADD. Just made up words for inflammation. Off to read ABOUT AUTISM . It's a good one, you might want to check it out yourself... Much hope for all our beautiful children. xo lj " Lisa Goes is Contributing Editor to Age of Autism. Posted by Age of Autism on January 07, 2012 at 05:45 AM in LJ Goes \| Permalink \| Comments (573) The RAS system is involved in all sorts of development including ovarian and placental. It is also involved in retinal issues. I think I remember you saying your husband had some sort of eye condition. Am I remembering correctly? It is starting to look like the RAS may be a substantial part of the picture. The Aldosterone component is implicated too so I would include it as well. RAAS = renin-angiotensin-aldosterone system. Posted by: Visitor \| December 17, 2015 at 03:42 PM My uncle had a blocked blood vessel to his heart and so he grew another one all on his own. Sounds like the same thing going on here too. Posted by: Benedetta \| December 17, 2015 at 01:07 AM The continued angiogenesis mentioned two posts back seems to indicate that it is persistent though no reasons for this condition are stated. If Olmesartan down blocks AT1 receptors it may reduce angiogenesis and it may also increase activation of angiotensin AT2 and AT4 receptors that "trigger brain anti-ischemic mechanisms by favouring cerebral blood flow (angiogenesis and recruitment of pre-existing collateral circulation, specifically in the ischemic brain where AT2 receptors are overexpressed) or by directly increasing neuronal resistance to anoxia." Angiotensin AT1-receptor blockers and cerebrovascular protection: do they actually have a cutting edge over angiotensin-converting enzyme inhibitors? "First, an update of the vascular systemic and tissue renin-angiotensin-aldosterone system is provided to explain how it is regulated at the systemic and tissue levels, and how many angiotensin peptides and receptors can be modulated by the various antihypertensive drugs. Second, experimental data is presented to support the hypothesis that antihypertensive drugs that increase angiotensin II formation, such as diuretics, AT1-receptor blockers and dihydropyridines, may have greater brain anti-ischemic effects than antihypertensive drugs that decrease angiotensin II formation, such as beta-blockers and angiotensin-converting enzyme inhibitors, because they increase activation of angiotensin AT2 and AT4 receptors. Indeed, these trigger brain anti-ischemic mechanisms by favouring cerebral blood flow (angiogenesis and recruitment of pre-existing collateral circulation, specifically in the ischemic brain where AT2 receptors are overexpressed) or by directly increasing neuronal resistance to anoxia." Reduced angiogenesis and delay in wound healing in angiotensin II type 1a receptor-deficient mice "Angiotensin II (Ang II) is a bioactive peptide that plays important roles in blood pressure regulation and salt–water homeostasis. Recently, Ang II was reported to function in the promotion of angiogenesis. Since the wound healing process is highly dependent upon angiogenesis, we employed Ang II receptor knockout mice (AT1a−/−) to investigate whether or not Ang II facilitates angiogenesis and wound healing via AT1a receptor signaling. In comparison to wild-type (WT) mice, wound healing and wound-induced angiogenesis were significantly suppressed in AT1a−/− mice, and these mice exhibited reduced expression of CD31 in wound granulation tissues. In comparison to vehicle-treated mice, wound healing was delayed significantly in mice treated with an AT1-R antagonist and this delay was accompanied by the reduced expression of vascular endothelial growth factor in wound granulation tissues. These findings suggest that Ang II–AT1a signaling plays a crucial role in wound healing and wound-induced angiogenesis." http://www.em-consulte.com/en/article/230197 There are some disconnects in how reducing angiogenesis may be therapeutic at the same time reducing wound healing, but this remains to be understood. I o9mmitted a link when I said this: Please read beyond the abstact and click on "look inside" in the top blue bar" It is here. Regulation of Angiogenesis by Angiotensin II http://link.springer.com/chapter/10.1007%2F978-3-642-18495-6_4 If you have followed this thread you will have seen how I have emphasized the Angiotensin system. The relation of hypoxic. inflammatory, and ischemic events effecting the brain and its vasculature is beginning to be grasped as it relates to Autism and it appears Schizophrenia. Vaccines upregulating or causing these effects, particularly in what seems to be increasing amounts of infants with preexisting or hypersensitive inflammatory profiles would point to greater amounts of vaccine effects in these pathologies of the vasculature. This is a report I for which I have been hoping. Olmesartan...? Please read beyond the abstact and click on "look inside" in the top blue bar. Neovascularization is a mechanism of wound response and attempt at healing, increasing blood supply, and oxygen supply. B6 levels increase after surgical wounds and b6 levels are often related to Autism. Wounded children. Scientists find new vessel for detecting autism "Evidence of autism may be found in the composition and malfunction of the brain's blood vessels, a team of scientists has found. Their research sheds new light on the causes of autism, which previously had pointed to neurological make-up rather than to the vascular system, and identifies a new target for potential therapeutic intervention. "Our findings show that those afflicted with autism have unstable blood vessels, disrupting proper delivery of blood to the brain," explains Efrain Azmitia, a professor in NYU's Department of Biology and the study's senior author. The study, "Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum," appears in the Journal of Autism and Developmental Disorders. Its other co-authors were: Zachary Saccomano, an NYU graduate student; Mohammed Alzoobaee, an NYU undergraduate at the time of the study; Maura Boldrini, a research scientist in the Department of Psychiatry at Columbia University; and Patricia Whitaker-Azmitia, a professor in the Department of Psychology and director of the Graduate Program in Integrative Neurosciences at Stony Brook University. "In a typical brain, blood vessels are stable, thereby ensuring a stable distribution of blood," adds Azmitia, also an adjunct professor at NYU School of Medicine's Department of Psychiatry. "Whereas in the autism brain, the cellular structure of blood vessels continually fluctuates, which results in circulation that is fluctuating and, ultimately, neurologically limiting." In their study, the researchers examined human postmortem brain tissue—some from normal brains and others from those with an autism diagnosis. In the microscopic analysis, the scientists were blind to the nature of the tissue, not knowing if it came from an autistic brain or a typical one. Their cellular studies uncovered angiogenesis—the creation of new blood vessels—in the autistic brain tissue, but not in that of typical brains. The distinction is a significant one—evidence of angiogenesis indicates that these vessels are repeatedly being formed and in constant flux, underscoring an instability in the blood's delivery mechanism. Specifically, in autistic brains, they found increased levels of the proteins nestin and CD34—molecular markers of angiogenesis—compared to typical brains. "We found that angiogenesis is correlated with more neurogenesis in other brain diseases, therefore there is the possibility that a change in brain vasculature in autism means a change in cell proliferation or maturation, or survival, and brain plasticity in general. These changes could potentially affect brain networks," Boldrini noted. "It's clear that there are changes in brain vascularization in autistic individuals from two to 20 years that are not seen in normally developing individuals past the age of two years," observes Azmitia. "Now that we know this, we have new ways of looking at this disorder and, hopefully with this new knowledge, novel and more effective ways to address it." http://medicalxpress.com/news/2015-12-scientists-vessel-autism.html Angiotensin converting enzyme activity is positively associated with IL-17a levels in patients with schizophrenia. "Previous studies of our group showed increased plasmatic Angiotensin-I Converting Enzyme (ACE) activity in schizophrenia (SCZ) patients compared to healthy controls, which was also associated to poor cognitive functioning. The ACE main product angiotensin II (Ang-II) has pro-inflammatory properties. Activated immune-inflammatory responses in SCZ and their association with disease progression and cognitive impairments are also well-described. Therefore, we examined here the association of plasma ACE activity and inflammatory mediators in 33 SCZ patients and 92 healthy controls. Non-parametric correlations were used to investigate the association of the enzyme activity and the peripheral levels of immune inflammatory markers as interleukins, tumor necrosis factor (TNF-α), and interferon (IFN-γ). Although no significant correlations could be observed for ACE activity and measured cytokines levels in healthy controls, a significant positive correlation for ACE enzymatic activity and IL-17a levels was observed in SCZ patients. Correcting for gender did not change these results. Moreover, a significant association for ACE activity and IFN-γ levels was also observed. To our knowledge, this is the first study to show a significant association between higher ACE activity and the levels of cytokines, namely IL-17a and IFN-γ, in patients with SCZ." Increased serum Osteopontin levels in autistic children: Relation to the disease severity. "Autoimmunity to brain may play an etiopathogenic role in autism. Osteopontin is a pro-inflammatory cytokine that has been shown to play an important role in various autoimmune neuroinflammatory diseases. Osteopontin induces IL-17 production by T-helper 17 lymphocytes, the key players in the pathogenesis of autoimmune disorders. Anti-osteopontin treatment reduces the clinical severity of some autoimmune neuroinflammatory diseases by reducing IL-17 production. We are the first to measure serum osteopontin levels, by ELISA, in 42 autistic children in comparison to 42 healthy-matched children. The relationship between serum osteopontin levels and the severity of autism, which was assessed by using the Childhood Autism Rating Scale (CARS), was also studied. Autistic children had significantly higher serum osteopontin levels than healthy controls." Osteopontin - Wiki "Stimulation of OPN expression also occurs upon exposure of cells to pro-inflammatory cytokines,[31] classical mediators of acute inflammation (e.g. tumour necrosis factor α [TNFα], infterleukin-1β [IL-1β]), angiotensin II, transforming growth factor β (TGFβ) and parathyroid hormone (PTH),[32][33] although a detailed mechanistic understanding of these regulatory pathways are not yet known. Hyperglycemia and hypoxia are also known to increase OPN expression." https://en.wikipedia.org/wiki/Osteopontin As an addition to the last post here is another related article addressing causes of Ovarian issues including Polycystic Ovarian Disease. I had posted in this thread in 2012. It adds a larger perspective that the you tube in the last post. Environmental toxicants causing ovarian disease across generations "WSU reproductive biologist Michael Skinner and his laboratory colleagues, including Eric Nilsson and Carlos Guerrero-Bosagna, looked at how fungicide, pesticide, plastic, dioxin and hydrocarbon mixtures affected a gestating rat's progeny for multiple generations. They saw subsequent generations inherit ovarian disease by "epigenetic transgenerational inheritance." Epigenetics regulates how genes are turned on and off in tissues and cells. Three generations were affected, showing fewer ovarian follicles -- the source of eggs -- and increased polycystic ovarian disease. The findings suggest ancestral environmental exposures and epigenetics may be a significant added factor in the development of ovarian disease, Skinner said. "What your great grandmother was exposed to when she was pregnant may promote ovarian disease in you, and you're going to pass it on to your grandchildren," he said. "Ovarian disease has been increasing over the past few decades to affect more than 10 percent of the human female population, and environmental epigenetics may provide a reason for this increase.... The new study, Skinner said, provides a proof of concept that ancestral environmental exposures and environmental epigenetics promote ovarian disease and can be used to further diagnose exposure to toxicants and their subsequent health impacts. It also opens the door to using epigenetic molecular markers to diagnose ovarian disease before it occurs so new therapies could be developed. In a broader sense, the study shows how epigenetics can have a significant role in disease development and life itself." All the increased risks for autism from modern inventions, but no real increase in autism? Glyphosate makes the list. The 3 Causes of Polycystic Ovarian Syndrome (PCOS) and High Androgens https://www.youtube.com/watch?v=qz4V_oNoclY A New Autism Risk Factor: Moms with Polycystic Ovaries http://www.scientificamerican.com/article/a-new-autism-risk-factor-moms-with-polycystic-ovaries/ A couple of weeks back I posted this: "There is a lot unknown about the mitochondrial relation with NLRP3. I theorize a relation between NLRP3, NEk7,and microtubule formation and that this bears on neuronal plasticity and function. I have not gotten very far yet." Today I found what is supposed to be a new finding about Nek7 and its relation to NLRP3. I had already believed this was the case, but I can't test what I find. I am encouraged and will pursue a relationship to microtubules. Enzyme involved in cell division also plays a role in inflammation "DALLAS - Dec. 7, 2015 - UT Southwestern Medical Center and California researchers today provide the first report that an enzyme previously known solely for its role in cell division also acts as an on-off switch in the innate immune system -- the body's first defense against infection. The identification of the NEK7 enzyme's switch-like activity in immunity could lead to new treatments for a variety of medical conditions linked to inflammation via the NRLP3 inflammasome pathway, including certain metabolic disorders, influenza A, gout, atherosclerosis, and possibly some forms of cancer. The current study investigated mouse models of inflammatory bowel disease and multiple sclerosis. "NRLP3 is one of several inflammasomes - multiprotein structures in disease-fighting white blood cells - the first of which was identified less than 15 years ago. The NRLP3 complex responds to microbes and other danger signals by activating molecules called cytokines, such as interleukin-1 beta, which trigger inflammation to fight infection," said Nobel Laureate Dr. Bruce Beutler, Director of the Center for the Genetics of Host Defense at UT Southwestern and senior author of the study published online in Nature Immunology"... The researchers genetically screened thousands of mice and conducted exhaustive interdisciplinary experiments: identifying a defect in inflammasome function, ascribing that defect to a mutation in the gene for the NEK7 enzyme, and fully characterizing NEK7 function in innate immunity. The enzyme was previously known only for its involvement in cell division, or mitosis, a process that involves the creation of two daughter cells from one parental cell. Specifically, mitosis is the phase of cell division in which the nucleus, which holds all of the cell's genetic material, divides to form two new cells, each with a full complement of genes. "Our work has shown that the inflammasome cannot become activated during mitosis. This is possibly a protective mechanism that prevents damage to DNA during this part of the cell cycle," said Dr. Beutler, who shared the 2011 Nobel Prize in Physiology or Medicine for his groundbreaking work on innate immunity. Dr. Beutler, a Texas Regental Professor, also holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr." http://www.sciencecodex.com/enzyme_involved_in_cell_division_also_plays_a_role_in_inflammation-171255 My odds and ends posts might be delayed. Today I found what is supposed to be news about Nek7 and NLRP3. I am encouraged and will see if the there is a relationship to microtubules. A few old odds and ends with this post and a couple of the next to follow. A credentialed source by the way. IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia. "Schizophrenia is a complex brain disorder that may be accompanied by idiopathic inflammation. Classic central nervous system (CNS) inflammatory disorders such as viral encephalitis or multiple sclerosis can be characterized by incongruent serum and cerebrospinal fluid (CSF) IgG due in part to localized intrathecal synthesis of antibodies. The dietary antigens, wheat gluten and bovine milk casein, can induce a humoral immune response in susceptible individuals with schizophrenia, but the correlation between the food-derived serological and intrathecal IgG response is not known. Here, we measured IgG to wheat gluten and bovine milk casein in matched serum and CSF samples from 105 individuals with first-episode schizophrenia (n=75 antipsychotic-naïve), and 61 controls. We found striking correlations in the levels of IgG response to dietary proteins between serum and CSF of schizophrenia patients, but not controls (schizophrenia, R(2)=0.34-0.55, p⩽0.0001; controls R(2)=0.05-0.06, p>0.33). A gauge of blood-CSF barrier permeability and CSF flow rate, the CSF-to-serum albumin ratio, was significantly elevated in cases compared to controls (p⩽0.001-0.003). Indicators of intrathecal IgG production, the CSF IgG index and the specific Antibody Index, were not significantly altered in schizophrenia compared to controls. Thus, the selective diffusion of bovine milk casein and wheat gluten antibodies between serum and CSF in schizophrenia may be the function of a low-level anatomical barrier dysfunction or altered CSF flow rate, which may be transient in nature." Copyright © 2014 Elsevier Inc. All rights reserved. KEYWORDS: Arachnoid membrane; Autism; Bipolar disorder; Blood–brain barrier; Choroid plexus; Endothelial; Epithelial; Gastrointestinal; Psychoses What you said makes sense and some things we are encountering with good intent are a problem for many. The same way ramping up the immune system in little ones can change the microbiota in the gut and then further effect the immune system and gut/brain axis, though it is hard to know this is the sequence or if it is reciprocal process all along with the gut immunity and the immune system peripheral to it being disturbed together. It seems in the regressive Autism the effect of the vaccine, whnen involved, acts fairly quickly and tends to support the idea that the immune stimulation/inflammatory response leads to the gut microbiota changes being made. It also seems some increased products from certain bacteria like propionic acid, while causing other problems, are the attempt to prevent even worse colonization and even keep fungal numbers in check. So while dysbiosis creates problems it seems even this represent some helpful elements. Hi Visitor: was looking back at some of your recent posts - I can see you mentioned folic acid early in November. I do think the synthetic version folic acid is not a good thing, that brains would need folate in the natural plant form and that the synthetic version might displace what little there is of the real stuff in a pregnant mum and I don't think manmade vitamins can ever do exactly the same thing that human development evolved with over the course of history. There is a group called Vitamin Angels, a non profit pushing vitamins over in undeveloped countries to "help" them. I sent them information several months ago re: the potential issue with folic acid, since most of their "partners" use folic acid in their vitamins, hoping to get their attention. No response. Those poor people in those countries who think they are recipients of only good charity are destined to be victims of the same tragedy American children and pregnant women have gone through, a combination of synthetic folic acid and forced vaccines. So sad. Posted by: Jenny \| December 03, 2015 at 06:34 PM About three post back I mentioned microtubule formation, as in stability. The following link speaks about a theory, concerning microtubules, I have followed for a long time and thought it had merit. This is a jump ahead, maybe in a primary way, in terms of process about what I have posted, but for those who wonder about the biomedical disruptions in the "soft machine" relating to consciousness this may be intriguing, and for now is a bit of a frontier marker for me. Discovery of quantum vibrations in 'microtubules' inside brain neurons supports controversial theory of consciousness "A review and update of a controversial 20-year-old theory of consciousness published in Physics of Life Reviews claims that consciousness derives from deeper level, finer scale activities inside brain neurons. The recent discovery of quantum vibrations in "microtubules" inside brain neurons corroborates this theory, according to review authors Stuart Hameroff and Sir Roger Penrose. They suggest that EEG rhythms (brain waves) also derive from deeper level microtubule vibrations, and that from a practical standpoint, treating brain microtubule vibrations could benefit a host of mental, neurological, and cognitive conditions. The theory, called "orchestrated objective reduction" ('Orch OR'), was first put forward in the mid-1990s by eminent mathematical physicist Sir Roger Penrose, FRS, Mathematical Institute and Wadham College, University of Oxford, and prominent anesthesiologist Stuart Hameroff, MD, Anesthesiology, Psychology and Center for Consciousness Studies, The University of Arizona, Tucson. They suggested that quantum vibrational computations in microtubules were "orchestrated" ("Orch") by synaptic inputs and memory stored in microtubules, and terminated by Penrose "objective reduction" ('OR'), hence "Orch OR." Microtubules are major components of the cell structural skeleton. Orch OR was harshly criticized from its inception, as the brain was considered too "warm, wet, and noisy" for seemingly delicate quantum processes.. However, evidence has now shown warm quantum coherence in plant photosynthesis, bird brain navigation, our sense of smell, and brain microtubules. The recent discovery of warm temperature quantum vibrations in microtubules inside brain neurons by the research group led by Anirban Bandyopadhyay, PhD, at the National Institute of Material Sciences in Tsukuba, Japan (and now at MIT), corroborates the pair's theory and suggests that EEG rhythms also derive from deeper level microtubule vibrations. In addition, work from the laboratory of Roderick G. Eckenhoff, MD, at the University of Pennsylvania, suggests that anesthesia, which selectively erases consciousness while sparing non-conscious brain activities, acts via microtubules in brain neurons. "The origin of consciousness reflects our place in the universe, the nature of our existence. Did consciousness evolve from complex computations among brain neurons, as most scientists assert? Or has consciousness, in some sense, been here all along, as spiritual approaches maintain?" ask Hameroff and Penrose in the current review. "This opens a potential Pandora's Box, but our theory accommodates both these views, suggesting consciousness derives from quantum vibrations in microtubules, protein polymers inside brain neurons, which both govern neuronal and synaptic function, and connect brain processes to self-organizing processes in the fine scale, 'proto-conscious' quantum structure of reality." After 20 years of skeptical criticism, "the evidence now clearly supports Orch OR," continue Hameroff and Penrose. "Our new paper updates the evidence, clarifies Orch OR quantum bits, or "qubits," as helical pathways in microtubule lattices, rebuts critics, and reviews 20 testable predictions of Orch OR published in 1998 -- of these, six are confirmed and none refuted..." Posted by: Visitor \| December 03, 2015 at 08:46 AM The first report does not mention effects on other neurons, but you have to think... Aluminum Activates PERK-EIF2α Signaling and Inflammatory Proteins in Human Neuroblastoma SH-SY5Y Cells. "Aluminum is the third most abundant element present in the earth's crust and human exposure to it is possible due to industrialization, utensils, medicines, antiperspirants, etc. Evidences suggest involvement of aluminum in a variety of neurodegenerative disorders including Alzheimer's disease. Endoplasmic reticulum (ER) stress has been implicated in various neurological disorders. ER stress may be a result of impaired calcium homeostasis due to perturbed redox balance and is known to elicit inflammation through the activation of unfolded protein response (UPR). In the present study, we aimed to investigate the role of aluminum in ER stress-mediated activation of inflammatory responses in neuroblastoma cells. Lactate dehydrogenase (LDH) release assay revealed that aluminum compromised the membrane integrity of neuroblastoma cells, probably due to membrane damage, as indicated by enhanced levels of lipid peroxidation (LPO). Besides this, our results clearly demonstrated elevated reactive oxygen species (ROS) levels and a weakened antioxidant defence system manifested by decrease in catalase (CAT) activity and cellular glutathione (GSH). Moreover, we studied the expression of key apoptosis-related proteins, ER stress-mediated activation of UPR, and its downstream inflammatory pathway. It was observed that aluminum potentially enhanced protein levels of PERK, EIF2α, caspase 9, caspase 3, and inflammatory markers like NF-κB, NLRP3, HMGB1, and nitric oxide (NO). Furthermore, aluminum altered TNFα, IL1β, IL6, and IL10 mRNA levels as well. The overall findings indicated that aluminum mediates UPR activation through ER stress, which results in induction of inflammatory pathway and apoptotic proteins in neuronal cells." HMGB1 levels may be already be higher in those susceptible to vaccine injury and this would tie increased autoimmune and inflammatory conditions in the population to the increase in Autism as reports have found HMGB1 levels elevated in those with Autism. HMGB1 acts as an adjuvant itself and the trigger of the vaccine{esp. aluminum} may moderately to precipitously raise inflammation and include effects on neuronal migration and plasticity involving NLRP3 as previously addressed. Severe reactions could kill and show as a child with a severely inflamed body and brain. Mothers and grandmothers may be having increased epigenetic and immune effects that are predisposing their offspring. Hep B below http://www.rescuepost.com/.a/6a00d8357f3f2969e20111683a026e970c-pi Microglia Control Synapse Number in Multiple Disease States http://www.alzforum.org/news/conference-coverage/microglia-control-synapse-number-multiple-disease-states HMGB1 and Cord Blood: Its Role as Immuno-Adjuvant Factor in Innate Immunity Posted by: Visitor \| November 29, 2015 at 10:08 PM Likely part of Dr. Bradstreet's venue and related to NLRP3. NLRP3 inflammasome and its inhibitors: a review "Cannabinoid receptor 2 (CB2R) is an already demonstrated therapeutic target in inflammation-related diseases (Smoum et al., 2015). Work from our own laboratory (Shao et al., 2014) has shown that autophagy induction may help explain why activation of the anti-inflammatory CB2R leads to inhibition of NLRP3 inflammasome priming and activation in mouse BV2 microglia stimulated with LPS and ATP as well as in a mouse model of EAE. Such CB2R activation reduces the severity of EAE in mice. Thus CB2R agonists similar to the HU-308 used in our work may become an effective therapy for treating NLRP3 inflammasome-related diseases by inducing autophagy." http://journal.frontiersin.org/article/10.3389/fphar.2015.00262/full There is a lot of interrelated function with NLRP3 and various autoimmune and auotinflammatory conditions. "Nothing happens in a vacuum in life: every action has a series of consequences, and sometimes it takes a long time to fully understand the consequences of our actions." The Adaptor MAVS Promotes NLRP3 Mitochondrial Localization and Inflammasome Activation http://cureautism.com/2013/06/30/the-adaptor-mavs-promotes-nlrp3-mitochondrial-localization-and-inflammasome-activation/ NLRP3 is involved in inflammatory conditions highlighted in RA studies and effect. The mitochondrial issues in Autism likely relate to this function and immune stimulation due to various causes including vaccines. Still not sure if TNFAIP3 expression in some with inflammatory conditions related to Autism bears on the increase of NF-kappa B found in groups with Autism. Vaccine Adjuvants - Review Good To Read Mechanisms of adjuvants "Adjuvants may exert their effects through different mechanisms. Some adjuvants, such as alum and emulsions (e.g. MF59®), function as delivery systems by generating depots that trap antigens at the injection site, providing slow release in order to continue the stimulation of the immune system. These adjuvants enhance the antigen persistence at the injection site and increase recruitment and activation of antigen presenting cells (APCs). Particulate adjuvants (e.g. alum) have the capability to bind antigens to form multi-molecular aggregates which will encourage uptake by APCs [1]. Some adjuvants are also capable of directing antigen presentation by the major histocompatibility complexes (MHC) [1]. Other adjuvants, essentially ligands for pattern recognition receptors (PRR), act by inducing the innate immunity, predominantly targeting the APCs and consequently influencing the adaptative immune response. Members of nearly all of the PRR families are potential targets for adjuvants. These include Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs) and C-type lectin receptors (CLRs). They signal through pathways that involve distinct adaptor molecules leading to the activation of different transcription factors. These transcription factors (NF-κB, IRF3) induce the production of cytokines and chemokines that play a key role in the priming, expansion and polarization of the immune responses. Activation of some members of the NLR family, such as NLRP3 and NLRC4, triggers the formation of a protein complex, called inflammasome, implicated in the induction of the pro-inflammatory cytokines IL-1β [2] and IL-18. The NLRP3 and NLRC4 inflammasomes have been involved in the innate immunity induced by certain adjuvants but their mechanism of action remains unclear. Alum & emulsions Alum is the most commonly used adjuvant in human vaccination. It is found in numerous vaccines, including diphtheria-tetanus-pertussis, human papillomavirus and hepatitis vaccines [3]. Alum provokes a strong Th2 response, but is rather ineffective against pathogens that require Th1–cell-mediated immunity. Alum induces the immune response by a depot effect and activation of APCs. Recently, the NLRP3 inflammasome has been linked to the immunostimulatory properties of alum [2] although its role in adjuvant-induced antibody responses remains controversial." http://www.invivogen.com/review-vaccine-adjuvants There is a lot unknown about the mitochondrial relation with NLRP3. I theorize a relation between NLRP3, NEk7,and microtubule formation and that this bears on neuronal plasticity and function. I have not gotten very far yet. TNFAIP3 - Wiki "This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded by this gene is a zinc finger protein, and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. Knockout studies of a similar gene in mice suggested that this gene is critical for limiting inflammation by terminating TNF-induced NF-kappa B responses.[2]" https://en.wikipedia.org/wiki/TNFAIP3 Measurement in saliva from neurotypical adults of biomarkers pertinent to autism spectrum disorders http://www.future-science.com/doi/10.4155/fso.15.70 To be clear, after the pathology in the gut than nutrient and vitamin status would change and supplementation of some vitamins would then become therapeutic. Definitely two reports, after the Wiki blurb, that are extremely woth reading below. It seems that while an immune stressor or trigger like vaccines may start or elevate a condition, the table has often been set in the womb as autism occurs without vaccine being implicated and maybe more so as the years go by. If autism was exceedingly rare before 194o then it would appear that a lack of vitamin supplementation was not a reason for autism. It may be that the increase in processed foods had a bearing on a mother and, by extension, child's neurodevelopment, but the total picture does not lend credence to the idea that lack of vitamin's was a big factor in the increase in autism. The increased ingestion of some vitamins along with all the environmental factors{negative contributors, toxins, chemicals, metals, v etc...} could have made the need for other vitamins greater and a cycle of supplementation of some vitamins at certain states, esp. in pregnancy became more crucial. For example the rise of spina bifida causing more folic acid to curb. Anyway, the altered gene expression in those with autism and other conditions may be a reaction to the taxing of some nutrients and the excess of others. Morning sickness may be in part result of these imbalances and for the disturbance in the methyl groups sulfation and other systems needed catecholamine cycles and processing xenobiotics and detoxification. It may be why only certain vitamins are found helpful for some autism as well as the imbalance creates greater need. Wiki - Vitamin "Until the mid-1930s, when the first commercial yeast-extract vitamin B complex and semi-synthetic vitamin C supplement tablets were sold, vitamins were obtained solely through food intake, and changes in diet (which, for example, could occur during a particular growing season) usually greatly altered the types and amounts of vitamins ingested. However, vitamins have been produced as commodity chemicals and made widely available as inexpensive semisynthetic and synthetic-source multivitamin dietary and food supplements and additives, since the middle of the 20th century." https://en.wikipedia.org/wiki/Vitamin Microarray Analysis Reveals Higher Gestational Folic Acid Alters Expression of Genes in the Cerebellum of Mice Offspring—A Pilot Study "Folate is a water-soluble vitamin that is critical for nucleotide synthesis and can modulate methylation of DNA by altering one-carbon metabolism. Previous studies have shown that folate status during pregnancy is associated with various congenital defects including the risk of aberrant neural tube closure. Maternal exposure to a methyl supplemented diet also can alter DNA methylation and gene expression, which may influence the phenotype of offspring. We investigated if higher gestational folic acid (FA) in the diet dysregulates the expression of genes in the cerebellum of offspring in C57BL/6 J mice. One week before gestation and throughout the pregnancy, groups of dams were supplemented with FA either at 2 mg/kg or 20 mg/kg of diet. Microarray analysis was used to investigate the genome wide gene expression profile in the cerebellum from day old pups. Our results revealed that exposure to the higher dose FA diet during gestation dysregulated expression of several genes in the cerebellum of both male and female pups. Several transcription factors, imprinted genes, neuro-developmental genes and genes associated with autism spectrum disorder exhibited altered expression levels. These findings suggest that higher gestational FA potentially dysregulates gene expression in the offspring brain and such changes may adversely alter fetal programming and overall brain development." Early Infant Exposure to Excess Multivitamin: A Risk Factor for Autism? "Autism, a neurodevelopmental disorder that affects boys more than girls, is often associated with altered levels of monoamines (serotonin and catecholamines), especially elevated serotonin levels. The monoamines act as both neurotransmitters and signaling molecules in the gastrointestinal and immune systems. The evidence related to monoamine metabolism may be summarized as follows: (i) monoamine neurotransmitters are enzymatically degraded/inactivated by three mechanisms: oxidative deamination, methylation, and sulfation. The latter two are limited by the supply of methyl groups and sulfate, respectively. (ii) A decrease in methylation- and sulfation-mediated monoamine inactivation can be compensated by an increase in the oxidative deamination catalyzed by monoamine oxidase, an X-linked enzyme exhibiting higher activity in females than in males. (iii) Vitamins can, on one hand, facilitate the synthesis of monoamine neurotransmitters and, on the other hand, inhibit their inactivation by competing for methylation and sulfation. Therefore, we postulate that excess multivitamin feeding in early infancy, which has become very popular over the past few decades, may be a potential risk factor for disturbed monoamine metabolism. In this paper, we will focus on the relationship between excess multivitamin exposure and the inactivation/degradation of monoamine neurotransmitters and its possible role in the development of autism...." "It has been known for over a century that the dose-response curve for many micronutrients is nonmonotonic, having an initial stage of increasing benefits with increased intake, followed by increasing costs as excesses become toxic [39]. Both vitamin deficiency and vitamin excess are known to cause toxicity, including neurotoxicity [15, 40]. A meta-analysis of randomized trials of antioxidant supplements for primary and secondary prevention suggests that supplementation of vitamin A and E may increase mortality [41]. Supplemental folic acid (the synthetic form of folate) was also found to be associated with increased mortality [42, 43]. Davis and colleagues [44] found an association between high serum thiamine levels and sudden infant death syndrome (SIDS, a sudden and unexplained infant death most likely to occur between 2 and 4 months of age), and they further demonstrated that high doses of thiamine could cause death in rabbits and mice due to respiratory failure." http://www.hindawi.com/journals/aurt/2013/963697/ Posted by: Visitor \| November 09, 2015 at 11:59 AM Speaking of Dr. Wakefield, he, with others released a report a number of years back about theses matters related to the second article in last post. It is linked below. The report mentions esophageal reflux, gastritis, and constipation related to autism and the gut matters discussed. I had noted and dealt with these in my wife in 96' forward and found it very confirming that these conditions{with others} originally present in that overall assessment were later associated as conditions found in much higher amounts in many with autism. Review article: The concept of enterocolonic encephalopathy, autism and opioid recepter ligands http://www.researchgate.net/publication/238203532_Review_article_The_concept_of_enterocolonic_encephalopathy_autism_and_opioid_recepter_ligands In some, maybe a large part, the vaccines may disturb the gut, and brain neuroplasticity along with the glial effects. Then the gut function being altered makes this an ongoing pathology with neuroinflammation and mild or more encephalopathy. Perinatal brain damage in children: neuroplasticity, early intervention, and molecular mechanisms of recovery. "During the perinatal period, the nervous system is very vulnerable to insult. At this time, the brain undergoes fast and complex maturational processes such as synaptogenesis, arborization, and apoptosis, and the response to the insult is highly dependent on its exact timing. There is evidence that some of the neuroplastic mechanisms adopted by the young brain after damage are unavailable at a later stage of maturation. This applies, for example, to the reorganization of language, the sensorimotor system, or the visual system. Expanding our knowledge on these mechanisms could help the development of early therapeutic interventions aimed at supporting and enhancing functional reorganization at a time of greatest potential brain plasticity." The elements of immune response to HBV and related synaptic plasticity mentioned in the last post overlaps with those elements of inflammatory microglial activation associated with intestinal and peripheral inflammation. The nest report details a number related things such as colitis that covers and may include the similar gut issue defined by Dr. Wakefield. The whole article should be read to see the full idea. It also makes a reassessment of minocycline in some with autism seem desirable. Microglia-Dependent Alteration of Glutamatergic Synaptic Transmission and Plasticity in the Hippocampus during Peripheral Inflammation "Peripheral inflammatory diseases are often associated with behavioral comorbidities including anxiety, depression, and cognitive dysfunction, but the mechanism for these is not well understood. Changes in the neuronal and synaptic functions associated with neuroinflammation may underlie these behavioral abnormalities. We have used a model of colonic inflammation induced by 2,4,6-trinitrobenzenesulfonic acid in Sprague Dawley rats to identify inflammation-induced changes in hippocampal synaptic transmission. Hippocampal slices obtained 4 d after the induction of inflammation revealed enhanced Schaffer collateral-induced excitatory field potentials in CA1 stratum radiatum. This was associated with larger-amplitude mEPSCs, but unchanged mEPSC frequencies and paired-pulse ratios, suggesting altered postsynaptic effects. Both AMPA- and NMDA-mediated synaptic currents were enhanced, and analysis of AMPA-mediated currents revealed increased contributions of GluR2-lacking receptors. In keeping with this, both transcripts and protein levels of the GluR2 subunit were reduced in hippocampus. Both long-term potentiation (LTP) and depression (LTD) were significantly reduced in hippocampal slices taken from inflamed animals. Chronic administration of the microglial/macrophage activation inhibitor minocycline to the inflamed animals both lowered the level of the cytokine tumor necrosis factor α in the hippocampus and completely abolished the effect of peripheral inflammation on the field potentials and synaptic plasticity (LTP and LTD). Our results reveal profound synaptic changes caused by a mirror microglia-mediated inflammatory response in hippocampus during peripheral organ inflammation. These synaptic changes may underlie the behavioral comorbidities seen in patients. Peripheral inflammation is a feature of many diseases, including inflammatory bowel disease (Häuser et al., 2011), rheumatoid arthritis (Maini et al., 2004; Mayoux-Benhamou, 2006), and inflammatory liver disease (Gralnek et al., 2000; Butterworth, 2013; D'Mello and Swain, 2014), and is often associated with marked behavioral changes, including mood disorders, fatigue, cognitive and memory dysfunction, and sleep disturbances. Moreover, the inflammation is capable of aggravating other neurological and neuropsychiatric conditions, including seizure disorders (Vezzani et al., 2013), major depression (Raison et al., 2006), Alzheimer's disease (Ferrari and Tarelli, 2011), multiple sclerosis (Benson and Kerr, 2014), Parkinson's disease (Collins et al., 2012), and stroke (Ferrari and Tarelli, 2011). These comorbid effects can have considerable impact on both health and the quality of life of the patients. The behavioral manifestations associated with peripheral inflammation clearly indicate CNS involvement; thus, a number of mechanisms have been suggested to underlie the communication between these peripheral inflammatory conditions and the brain (Walker et al., 2014). Peripheral tissue inflammation results in the production of proinflammatory cytokines that signal to the brain via cytokine receptors at the blood–brain barrier, within circumventricular organs or on sensory afferents. There is now compelling evidence that the cytokines generated during peripheral inflammation activate a secondary, mirror inflammatory response in the brain that is characterized by activation of microglia and production of proinflammatory cytokines, most importantly, tumor necrosis factor α (TNFα), interleukin (IL)-1β, and IL-6 (Quan et al., 1998; D'Mello et al., 2013; Thomson et al., 2014). These cytokines have profound effects on synaptic transmission and synaptic plasticity (for review, see Pickering and O'Connor, 2007), effects that most likely underlie the cognitive dysfunction, altered behavior, and other interactions with preexisting pathologies seen in peripheral inflammatory disease (Raison et al., 2006; Galic et al., 2012; Santello and Volterra, 2012; Nisticò et al., 2013; Camara et al., 2015). There is accumulating evidence that alterations in glutamatergic transmission underlie some of these behaviors (for review, see Walker et al., 2014). In a rat model of inflammatory colitis, we previously reported reduced thresholds to chemically induced seizures in vivo and increased excitability of the hippocampus in vitro (Riazi et al., 2008). The increased excitability is mediated by activated microglia and production of TNFα in the hippocampus. However, the neuronal and synaptic changes that correlate with such increased excitability are unknown. Previous work indicates that TNFα alters expression of glutamate (Stellwagen and Malenka, 2006) and GABA (Pribiag and Stellwagen, 2013) receptors in vitro. In addition, direct application of proinflammatory cytokines to hippocampal slices in vitro alters the ability of excitatory synapses to display long-term potentiation (LTP; Pickering and O'Connor, 2007), a type of plasticity associated with learning and memory. Following up on our previous studies revealing an elevation of inflammatory cytokines in the brain (Riazi et al., 2008), we hypothesize that glutamatergic synaptic transmission and plasticity are altered during inflammatory colitis due to microglial activation. In a rat model of inflammatory colitis, we now report changes in hippocampal synaptic transmission associated with a profound reduction in synaptic plasticity." http://www.jneurosci.org/content/35/12/4942.full Autistic enterocolitis: Fact or fiction? "Autism spectrum disorder refers to syndromes of varying severity, typified by impaired social interactions, communicative delays and restricted, repetitive behaviours and interests. The prevalence of autism spectrum disorders has been on the rise, while the etiology remains unclear and most likely multifactorial. There have been several reports of a link between autism and chronic gastrointestinal symptoms. Endoscopy trials have demonstrated a higher prevalence of nonspecific colitis, lymphoid hyperplasia and focally enhanced gastritis compared with controls. Postulated mechanisms include aberrant immune responses to some dietary proteins, abnormal intestinal permeability and unfavourable gut microflora. Two autism spectrum disorder patients with chronic intestinal symptoms and abnormal endoscopic findings are described, followed by a review of this controversial topic."... There have been several reports, mainly anecdotal, of a link between ASD and chronic gastrointestinal (GI) symptoms; however, scientific data are scarce and often criticized. Frequent complaints have included chronic diarrhea, bloating, abdominal pain, distension and abnormal stool consistency. In a recent cross-sectional study, comparing autistic children with matched neurotypical controls as well as children with other developmental disabilities (ODD), 70% of children with ASD reported a history of GI complaints, compared with 28% of neurotypical controls (P<0.001) and 42% with ODD (P=0.03) (5). GI problems have more commonly been linked to a 'regressive' form of autism, characterized by loss of previously acquired skills and late onset of behavioural anomalies, not observed in the first year of life. One of the earliest studies investigating GI anomalies in autistic children was reported by Wakefield et al (6) in 1998. In this study, 12 children with regressive developmental disorders (nine of whom were autistic) were all reported to have abnormal colonoscopies. The most consistent finding was lymphoid nodular hyperplasia (LNH), present in nine of the 12 children. Eight had mucosal abnormalities including granularity, loss of vascular pattern, patchy erythema, aphthoid ulcerations and 'red halo' signs in the cecal base. Histologically, the lamina propria was infiltrated by mononuclear cells in a focal or diffuse pattern, in the absence of intraepithelial lymphocytes, granulomata or crypt abscesses (6). This mild to moderate colitis was deemed nonspecific on the basis of not fulfilling criteria for either Crohn's disease or ulcerative colitis. Criticism regarding the 'normalcy' of LNH in children prompted Wakefield et al (7) to perform ileocolonoscopy in 60 children with regressive developmental disorders and compare them with 37 developmentally normal controls. In this trial, ileal LNH was present in 93% of affected children versus 14.3% of controls (P<0.001), with chronic colitis in 88% of affected children versus 4.5% of controls (7). With respect to the upper GI tract, Horvath et al (8) investigated 36 autistic children complaining of abdominal pain, bloating or chronic diarrhea by gastroscopy. The most common histological finding was reflux esophagitis (69.4%), while 41.7% had chronic gastritis and 66.7% had chronic duodenitis in the absence of H pylori infection...." ASD patients and their caregivers often report improvement on elimination diets, not only in the GI symptoms, but also in behavioural and cognitive problems such as hyper-activity, communication skills and attentiveness. Interestingly, 36% of children with ASD have a history of cow's milk and/or soy protein intolerance in infancy (8). Also, while studies have not proven an increased incidence of celiac disease in these individuals, parents have often reported an improvement in their child's behavioural disturbances on a gluten-free diet. These benefits have not consistently been seen in randomized trials (10), however a Cochrane review (11) did report a significant reduction in autistic traits on a gluten-free casein-free diet. One hypothesis is that ASD may be accompanied by aberrant innate immune responses to dietary proteins, leading to GI inflammation and aggravation of behavioural problems. One study (12) measuring proinflammatory cytokines in response to common dietary proteins showed a greater than two SD excess in tumour necrosis factor-alpha and interferon-gamma production in response to gluten and cow's milk protein among ASD children compared with controls. A subsequent study confirmed a higher prevalence of elevated tumour necrosis factor-alpha and interleukin-12 production with beta-lactoglobin and alpha-lactoglobin, but not casein, in autistic children as well as children with nonallergic food hypersensitivity, compared with normal controls (13). Another theory suggests that abnormal intestinal permeability in children with ASD causes them to absorb fragments of incompletely broken-down peptides such as gluten or casein, which cross the blood-brain barrier and act as endogenous opioids. D'Eufemia et al (14) demonstrated a higher mean lactulose recovery in 43% of autistic subjects versus none of the controls. The gut microflora has also been targeted as a potential player. There have been anecdotal reports of the onset of autism following broad-spectrum antibiotics, suggesting that disruption of the indigenous flora may lead to colonization by neurotoxin-producing bacteria. Autistic children have been shown to have higher counts and more species of clostridia than age- and sex-matched controls (15–17). A small prospective trial (18) demonstrated a significant but transient improvement in autistic features following a course of vancomycin therapy, with relapses presumed to occur because of persistent spores that proliferate on antibiotic discontinuation." The last two posts were quite speculative, but even so I mentioned possible effects of neurogenesis in the pre-frontal cortex and apparently those neurons numbers are static at birth except in those born pre-mature so a vaccine would seem not to be causing neurogenesis there. The reports are speaking of neurogenesis in the hippocampus though synaptic effects might be more broad. This report by the same authors answers whether there could be conflicting effects from other vaccines. I should have read a bit further in the kinks on the original page. They say Hepatitis B vaccine gives an opposite effect. Neonatal vaccination with bacillus Calmette-Guérin and hepatitis B vaccines modulates hippocampal synaptic plasticity in rats. "Immune activation can exert multiple effects on synaptic transmission. Our study demonstrates the influence of neonatal vaccination on hippocampal synaptic plasticity in rats under normal physiological conditions. The results revealed that neonatal BCG vaccination enhanced synaptic plasticity. In contrast, HBV hampered it. Furthermore, we found that the cytokine balance shifted in favour of the T helper type 1/T helper type 2 immune response in BCG/HBV-vaccinated rats in the periphery. The peripheral IFN-γ:IL-4 ratio was positively correlated with BDNF and IGF-1 in the hippocampus. BCG raised IFN-γ, IL-4, BDNF and IGF-1 and reduced IL-1β, IL-6, and TNF-α in the hippocampus, whereas, HBV triggered the opposite effects." I put the wrong title for the abstract in the last post it is: Neonatal BCG Vaccination of Mice Improves Neurogenesis and Behavior in Early Life. This is more of an anecdotal report, but it is funny how they so easily tie the BCG vaccine to neurogenesis and report what appears to be a positive effect inducing ostensibly neuroprotection in mice. For kicks, and giving the theory and results some credence, think of the notion of the proposition that a somewhat common vaccine can effect the brain. Also, if this one does would other vaccines quite possibly, or even likely have effects in the brain as well? If this theory is translated to humans then tampering with microglial activation in an infant who does not need intervention for brain conditions is rolling the dice and you have to ask what is the unintended consequence of increasing neurogenesis in subject. Given that many with autism have increased neuronal synapses and an excess of neurons in the pre-frontal cortex it makes you wonder in vaccines are triggering these outcomes. Not to mention possible compound effects from multiple vaccines and/or conflicting effects on microglia from various vaccines. The opening line of the abstract says; "Bacillus Calmette-Guérin (BCG) is administered to neonates worldwide, but it is still unknown whether this neonatal vaccination affects brain development during early postnatal life, despite the close association of the immune system with the brain." This implies that it is reasonable to wonder what immune system stimulation/alteration might do in the brain and I would add the gut and maybe additional organs. Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. "Bacillus Calmette-Guérin (BCG) is administered to neonates worldwide, but it is still unknown whether this neonatal vaccination affects brain development during early postnatal life, despite the close association of the immune system with the brain. Newborn C57BL/6 mice were injected subcutaneously with BCG or phosphate-buffered saline (PBS) and their mood status and spatial cognition were observed at four and eight weeks (w) old. The mice were also subjected to tests at 2 and 6 w to examine BCG's effects on neurogenesis, the hippocampal microglia phenotype and number, and the expression of hippocampal neuroimmune molecules and peripheral cytokines. The BCG-injected mice showed better behavioral performances at 4 w. We observed elevated neurogenesis, M2 microglial activation and a neurotrophic profile of neuroimmune molecules [more interferon (IFN)-γ, interleukin (IL)-4, transforming growth factor (TGF)-β, brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF)-1 and less tumor necrosis factor (TNF)-α and IL-1β] in the hippocampus of the 2-w-old BCG-mice. In the periphery, BCG induced a T helper (Th)-1 serum response. At the individual level, there were positive correlations between the serum IFN-γ/IL-4 ratio and the levels of neurotrophins and neurogenesis in the hippocampus. These findings suggest that neonatal BCG vaccination improved neurogenesis and mouse behavior in early life by affecting the neuroimmune milieu in the brain, which may be associated with a systemic Th1 bias." The development of brain trajectory in autism suggests the growth and microglial status is later skewed negatively and boosting or skewing in infancy would be a good idea to consider for later maladaptive function. More inflammation, yet this report suggests less able to fight off infection in autism. Study confirms mitochondrial deficits in children with autism "Children with autism experience deficits in a type of immune cell that protects the body from infection. Called granulocytes, the cells exhibit one-third the capacity to fight infection and protect the body from invasion compared with the same cells in children who are developing normally. The cells, which circulate in the bloodstream, are less able to deliver crucial infection-fighting oxidative responses to combat invading pathogens because of dysfunction in their tiny energy-generating organelles, the mitochondria.... In an earlier study the research team found decreased mitochondrial fortitude in another type of immune cell, the lymphocytes. Together, the findings suggest that deficiencies in the cells' ability to fuel brain neurons might lead to some of the cognitive impairments associated with autism. Higher levels of free radicals also might contribute to autism severity. "The response found among granulocytes mirrors earlier results obtained with lymphocytes from children with severe autism, underscoring the cross-talk between energy metabolism and response to oxidative damage," said Cecilia Giulivi, professor in the Department of Molecular Biosciences in the UC Davis School of Veterinary Medicine and the study's senior author. "It also suggests that the immune response seems to be modulated by a nuclear factor named NRF2," that controls antioxidant response to environmental factors and may hold clues to the gene-environment interaction in autism, Giulivi said." http://www.ucdmc.ucdavis.edu/publish/news/newsroom/8932 Posted by: Visitor \| October 30, 2015 at 09:34 PM Increased plasma levels of the high mobility group box 1 protein (HMGB1) are associated with a higher score of gastrointestinal dysfunction in individuals with autism. "Autism is a disorder of neural development characterized by impairments in communication, social interaction, restricted interests and repetitive behavior. The etiology of autism is poorly understood, the evidence indicates that inflammation may play a key role. In autism a high prevalence of gastrointestinal disturbances is reported, that are linked to a low-grade chronic inflammation of the intestinal mucosa. High mobility group box 1 protein (HMGB1) is an intranuclear protein that can be passively released from necrotic cells or actively secreted under inflammatory conditions as alarmin or late proinflammatory cytokine. The objective of this study was to measure plasma levels of HMGB1 in individuals with autism and to analyze their association with gastrointestinal symptoms. The study involved 31 subjects with low-functioning autistic disorder aged 2-22 years and 16 healthy controls. Plasma HMGB1 levels were significantly higher in individuals with autism than in controls (13.8+/-11.7 ng/ml vs. 7.90+/-4.0 ng/ml, p<0.02). In subjects with plasma HMGB1 levels higher than 11 ng/ml severe forms of GI disorders were more prevalent (83.3 %) than in subjects with lower levels (38.9 %, p<0.04). Results of the study support the involvement of the systemic low-grade inflammation in the pathomechanisms of autism and its possible association with GI symptoms." Increased serum levels of high mobility group box 1 protein in patients with autistic disorder. "High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein that functions as an activator for inducing the immune response and can be released from neurons after glutamate excitotoxicity. The objective of the present study was to measure serum levels of HMGB1 in patients with autistic disorder and to study their relationship with clinical characteristics. We enrolled 22 adult patients with autistic disorder (mean age: 28.1+/-7.7 years) and 28 age- and gender-matched healthy controls (mean age: 28.7+/-8.1 years). Serum levels of HMGB1 were measured by enzyme-linked immunosorbent assay (ELISA). Compared with healthy subjects, serum levels of HMGB1 were significantly higher in patients with autistic disorder (10.8+/-2.6 ng/mL versus 5.6+/-2.5 ng/mL, respectively, P<0.001). After adjustment for potential confounders, serum HMGB1 levels were independently associated with their domain A scores in the Autism Diagnostic Interview-Revised, which reflects their impairments in social interaction. These results suggest that HMGB1 levels may be affected in autistic disorder. Increased HMGB1 may be a biological correlate of the impaired reciprocal social interactions in this neurodevelopmental disorder." Thanks, Visitor Posted by: Jenny \| October 27, 2015 at 12:53 PM Serotonin, tryptophan metabolism and the brain-gut-microbiome axis "Tryptophan and its metabolite serotonin have an expansive physiological repertoire, making them fundamental to health and there are numerous associations between alterations in this system and disease [1], [2] and [3]. A growing body of data is also pointing to the influence of this system far beyond the traditional focus on its signalling pathways in the central nervous system (CNS) (see Reviews in this Special Issue). Moreover, emerging data implicates the gut microbiome in the regulation of brain and behaviour in general with a specific emphasis on its impact on tryptophan metabolism and the serotonergic system. Research in this area builds on the principles of the brain-gut axis concept (see Fig. 1), a bidirectional communication network between the brain and the gut with serotonin functioning as a key signalling molecule in both the enteric nervous system (ENS) and the CNS [4], [5] and [6]. Recently, it has become clear that the gut microbiome is a critical component of this axis and one which exerts control at multiple levels, not just locally in the gastrointestinal tract [7], [8], [9] and [10]. Using a variety of preclinical strategies, it has been established that manipulating the composition of the gut microbiota across the lifespan or altering the trajectory of microbial colonisation of the gastrointestinal tract early in life influences the availability of tryptophan. In tandem and possibly related to this capacity, this research has also illuminated a role for the gut microbiota in serotonergic signalling at the level of the CNS. There is also a substantial overlap between many of the behaviours underpinned by serotonergic signalling and those which are influenced by alterations in the composition, diversity or stability of the microbiota. Taken together, it seems plausible that the gut microbiota can either directly or indirectly recruit tryptophan metabolism and serotonergic signalling within the framework of the brain-gut axis to modulate host behaviour." Posted by: Visitor \| October 27, 2015 at 11:15 AM There is more delved into than just depression in the article. Here is a snippet. Could Depression Be Caused By An Infection? "Dr. Roger McIntyre, a professor of psychiatry and pharmacology at the University of Toronto, tells Shots that he believes an upset in the "immune-inflammatory system" is at the core of mental illness and that psychiatric disorders might be an unfortunate cost of our powerful immune defenses. "Throughout evolution our enemy up until vaccines and antibiotics were developed was infection," he says. "Our immune system evolved to fight infections so we could survive and pass our genes to the next generation. However, our immune-inflammatory system doesn't distinguish between what's provoking it." McIntyre explains how stressors of any kind — physical or sexual abuse, sleep deprivation, grief — can activate our immune alarms. "For reasons other than fighting infection, our immune-inflammatory response can stay activated for weeks, months or years and result in collateral damage," he says." http://www.npr.org/sections/health-shots/2015/10/25/451169292/could-depression-be-caused-by-an-infection Stress sounds the alarmin: The role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming. As inositol is made in the body it is often thought that you need not supplement it. I don't think it is in most multi vitamins, but as you know, it can be purchased. Benedetta may have more thoughts on it as she said she used it for one of her children and seemed to think lithium actually facilitated it's availability though I have found literature still stating that lithium interferes with its metabolism. There are those who say it helps with mood, ocd, and anxiety, but I have found little about how much it might be of use in Autism. While we never used it in additional amounts wo what was in the Vitamin complex we used it seems reasonable that in some cases it would be helpful with some symptoms. http://evolutionarypsychiatry.blogspot.com/2011/05/inositol-nervous-systems-pony-express.html http://www.curezone.org/forums/fm.asp?i=49840 http://wrongplanet.net/forums/viewtopic.php?t=139560 http://www.autismweb.com/forum/viewtopic.php?t=22412 http://www.walkwithben.com/blog/?tag=inositol Very interesting about thiamin, and leptin, too. Info on leptin and grehlin is very interesting to me right now, in regard to their effect on mood. I'm interested, too, in the mention of inositol 1,4,5 in relation to relevant neurological pathways, though I don't see mention of tics on the chart, though anxiety and OCD are there and I think of tics being in that same behavior class. Would supplementing with inositol alone be worthwhile? Isn't it a b vitamin? I'm not sure it's included in regular B vitamin complexes or not, though. It's necessary for the growth of yeast, I read, so I could see how one might think twice about using it, yet other b vitamins are critical, it appears, so why not b8? Posted by: Jenny \| October 26, 2015 at 11:36 AM Some of the inflammatory mediators have been connected to Autism others have not, though they seem to all be involved in my wife's case. {NLRP3 = NALP3} The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: a role for the NLRP3 inflammasome. "The alarmin high mobility group box-1 (HMGB1) has been implicated as a key factor mediating neuroinflammatory processes. Recent findings suggest that the redox state of HMGB1 is a critical molecular feature of HMGB1 such that the reduced form (fr-HMGB1) is chemotactic, while the disulfide form (ds-HMGB1) is pro-inflammatory. The present study examined the neuroinflammatory effects of these molecular forms as well as the ability of these forms to prime the neuroinflammatory and microglial response to an immune challenge. To examine the neuroinflammatory effects of these molecular forms in vivo, animals were administered intra-cisterna magna (ICM) a single dose of fr-HMGB1 (10 μg), ds-HMGB1 (10 μg) or vehicle and basal pro-inflammatory effects were measured 2 and 24h post-injection in hippocampus. Results of this initial experiment demonstrated that ds-HMGB1 increased hippocampal pro-inflammatory mediators at 2h (NF-κBIα mRNA, NLRP3 mRNA and IL-1β protein) and 24h (NF-κBIα mRNA, TNFα mRNA, and NLRP3 protein) after injection. fr-HMGB1 had no effect on these mediators. These neuroinflammatory effects of ds-HMGB1 suggested that ds-HMGB1 may function to prime the neuroinflammatory response to a subsequent immune challenge. To assess the neuroinflammatory priming effects of these molecular forms, animals were administered ICM a single dose of fr-HMGB1 (10 μg), ds-HMGB1 (10 μg) or vehicle and 24h after injection, animals were challenged with LPS (10 μg/kg IP) or vehicle. Neuroinflammatory mediators and the sickness response (3, 8 and 24h after injection) were measured 2h after immune challenge. We found that ds-HMGB1 potentiated the neuroinflammatory (NF-κBIα mRNA, TNFα mRNA, IL-1β mRNA, IL-6 mRNA, NLRP3 mRNA and IL-1β protein) and sickness response (reduced social exploration) to LPS challenge. fr-HMGB1 failed to potentiate the neuroinflammatory response to LPS. To examine whether these molecular forms of HMGB1 directly induce neuroinflammatory effects in isolated microglia, whole brain microglia were isolated and treated with fr-HMGB1 (0, 1, 10, 100, or 1000 ng/ml) or ds-HMGB1 (0, 1, 10, 100, or 1000 ng/ml) for 4h and pro-inflammatory mediators measured. To assess the effects of these molecular forms on microglia priming, whole brain microglia were pre-exposed to these forms of HMGB1 (0, 1, 10, 100, or 1000 ng/ml) and subsequently challenged with LPS (10 ng/ml). We found that ds-HMGB1 increased expression of NF-κBIα mRNA and NLRP3 mRNA in isolated microglia, and potentiated the microglial pro-inflammatory response (TNFα mRNA, IL-1β mRNA and IL-1β protein) to LPS. fr-HMGB1 failed to potentiate the microglial pro-inflammatory response to LPS. Consistent with prior reports, the present findings demonstrate that the disulfide form of HMGB1 not only potentiates the neuroinflammatory response to a subsequent immune challenge in vivo, but also potentiates the sickness response to that challenge. Moreover, the present findings demonstrate for the first time that ds-HMGB1 directly potentiates the microglia pro-inflammatory response to an immune challenge, a finding that parallels the effects of ds-HMGB1 in vivo. In addition, ds-HMGB1 induced expression of NLRP3 and NF-κBIα in vivo and in vitro suggesting that the NLRP3 inflammasome may play role in the priming effects of ds-HMGB1. Taken together, the present results suggest that the redox state of HMGB1 is a critical determinant of the priming properties of HMGB1 such that the disulfide form of HMGB1 induces a primed immunophenotype in the CNS, which may result in an exacerbated neuroinflammatory response upon exposure to a subsequent pro-inflammatory stimulus." Innate Immunity and Neuroinflammation http://www.hindawi.com/journals/mi/2013/342931/ The relation between things like Fibro and Chronic Fatigue show a relation to microglia as has been known. They are related to Autism and lately to Schizophrenia it appears. While not quoted below the article mentions Naltrexone and Curcumin related to calming neuroinflammation. This article ties Leptin to CFS as seems true and addressed in the following. Solving the mysteries of fibromyalgia could help patients break free "Younger, an associate professor recruited to the UAB College of Arts and Sciences Department of Psychology in 2014, became interested in fibromyalgia and chronic fatigue syndrome as a postdoctoral fellow at Stanford University's medical school. He had been studying pain more broadly when he realized how poorly understood these disorders were. "Patients are wholly affected," Younger says. "Some used to be athletes, some used to be business owners, and then their lives are taken over." Often, he points out, patients visit doctor after doctor, only to be told repeatedly that they're healthy—and that the pain or fatigue is all in their heads. Younger, along with many other researchers and clinicians, believed otherwise. "I made it my mission to figure out what is wrong with these patients and how to treat them," he says. As a Stanford postdoctoral fellow and faculty member, Younger spearheaded studies that surveyed immune molecules in the blood. He homed in on one particular protein called leptin, released by fat tissue, which appears in greater amounts in the blood of chronic fatigue patients. In fact, Younger could even gauge the day-to-day severity of a patient's symptoms just by tracking his or her leptin levels. These initial findings spurred him to continue investigating inflammatory immune molecules—and to start looking at the brain's role in the diseases. Leptin has the ability to cross the blood-brain barrier and affect neural cells, causing pain and fatigue. But exactly how that happens remains a mystery. Younger thinks it has something to do with microglia, a type of immune cell found in the brain that normally helps to protect neurons. "Microglia defend our brain against everything," Younger explains. "When we get the flu, for instance, microglia are activated. These cells make us want to crawl into bed and do nothing—so our body can devote its resources to fighting off the flu." In both fibromyalgia and chronic fatigue patients, Younger hypothesizes, the microglia are turned on when they're not supposed to be, causing fatigue or pain, a depressed mood, and cognitive dysfunction. At UAB, he is planning follow-up studies to help find evidence supporting this idea. He faces a crucial challenge, however: Currently, no methods are available to look directly at the activation or inflammation of microglia in living humans. But Younger and his colleagues are working on solutions, including specialized brain scans that measure the temperature of the brain or the presence of certain chemicals. "It's only very recently that people are starting to explore what sensitizes microglia," Younger says. "The cells can be in a quiet, helpful state, or an active, warlike state." His findings, he hopes, will help reveal the difference." http://medicalxpress.com/news/2015-10-mysteries-fibromyalgia-patients-free.html The next report emphasizes maternal infection and immune response as effecting neurodevelopment, but the immune response is goes beyond what may happen in the womb for most and may happen in the individual post utero in most imo. Both pre and post utero or a combination of effect may be the case from person to person. Infections and Brain Development. "Several different bodies of evidence support a link between infection and altered brain development. Maternal infections, such as influenza and human immunodeficiency virus, have been linked to the development of autism spectrum disorders, differences in cognitive test scores, and bipolar disorder; an association that has been shown in both epidemiologic and retrospective studies. Several viral, bacterial, and parasitic illnesses are associated with alterations in fetal brain structural anomalies including brain calcifications and hydrocephalus. The process of infection can activate inflammatory pathways causing the release of various proinflammatory biomarkers and histological changes consistent with an infectious intrauterine environment (chorioamnionitis) or umbilical cord (funisitis). Elevations in inflammatory cytokines are correlated with cerebral palsy, schizophrenias, and autism. Animal studies indicate that the balance of proinflammatory and anti-inflammatory cytokines is critical to the effect prenatal inflammation plays in neurodevelopment. Finally, chorioamnionitis is associated with cerebral palsy and other abnormal neurodevelopmental outcomes. In conclusion, a plethora of evidence supports, albeit with various degrees of certainty, the theory that maternal infection and inflammation that occur during critical periods of fetal development could theoretically alter brain structure and function in a time-sensitive manner." I read and post all studies and articles posted with the notion others will follow the overall understanding of the complete picture by comprehending the information in it's full by reading and seeing the full picture and by following up by researching elements contained within. For Benedetta I add this link. Activation of ligand-responsive sigma-1 receptor by agonists is likely to have beneficial effects in the cells. Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication Accumulating evidence suggests that sigma-1 receptor regulates a variety of cellular functions, such as inositol 1,4,5-triphosphate (IP3) receptor-mediated Ca2+ signaling, ion channel firing, protein kinase location/activation, cellular redox, neurotransmitter release, inflammation, cellular differentiation, neuronal survival and synaptogenesis (3), (4) and (5). Furthermore, sigma-1 receptor plays an important role in neuronal plasticity, a process implicated in the pathophysiology of neuropsychiatric diseases (5), (6), (7), (8) and (9). http://www.sciencedirect.com/science/article/pii/S1347861314000176?np=y I have stalled and taken a good break on the recent area of study in the last several posts and hope to re-engage the subjects, but the theme of microglia, Angiotensin, and inflammatory aspects are something I like to note. The gut immune relation, and the bacterial toxins figure as agents priming the inflammation as many like ,myself hold. Gene expression is theorized to be effected in this scenario of dysfunction. Chronic Brain Inflammation: The Neurochemical Basis for Drugs to Reduce Inflammation. "It is now recognized that the brain and the peripheral immune system have bidirectional communication in both health and neuronal diseases. Brain inflammation results after both acute injury and also with the appearance of mutated proteins or endogenous neurotoxic metabolites associated with slow neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and some psychiatric disorders. Microglia play a key role in brain inflammation by the release of pro-inflammatory cytokines and with ageing, microglia exhibit 'priming' leading to increased basal release of the pro-inflammatory cytokines. Neurochemical targets to reduce or slow chronic brain inflammation include cyclooxygenase enzymes, Nrf2 transcription factor, angiotensin AT1 receptors and sigma-1 receptors. Development of more selective drugs to act at these targets is occurring but large scale clinical trials to validate the drugs will take significant time." This is a quote I meant to place from this report: Rats fed a thiamin-deficient diet had higher concentra- tions of P450, cytochrome b5, and NADPH:cytochrome c reductase activity in liver microsomes than those fed a diet sufficient in thiamin. The deficient rats also had increased rates in the metabolism of acetaminophen, NDMA, amino- pyrine, ethylmorphine, zoxazolamine, heptachlor, aniline, N-methylaniline, acetanilide, and BP, but not in the metabo- lism of hexobarbital (8). Recent studies from our laboratory indicated that thiamin deficiency increased the hepatic micro-somal P450 2E1 level (two- to fivefold) but not the P450 2Cll level (44). This observation provides an enzymatic basis for the enhanced rate of in vivo metabolism of aniline, NDMA, and acetaminophen, all of which are substrates for P450 2El. Thiamin deficiency was shown to increase cytosolic glutathi-one S-transferase activity moderately but not steroid isomer-ase activity (44). The mechanisms of these effects on drug-metabolizing enzymes remain to be elucidated. www.fasebj.org/content/6/2/737.full.pdf Posted by: Visitor \| July 02, 2015 at 11:17 PM edit last post..I meant: "How this relates to pregnancy issues like morning sickness and p450 function" Posted by: Visitor \| July 01, 2015 at 10:18 AM Thiamine relation to autism is not obscure as many have reported on, and discussed the matter as it pertains to autism and possible PON 1 function and other areas. This report discusses a lot of factors that those of us finding diet and yeast being involved in ASD. It discusses thiamine deficiency and totally syncs with many accounts I have read of others dealing with such factors. It also briefly mentions vaccination. How this relates to pregnancy issues like morning sickness and p400 function is what I am looking at related to some heavy metals and toxins like glyphosate. The their is apparently something going on in pregnancy that is perturbed in these areas and morning sickness and some areas of detoxification in the mother may be because of nutrient metabolism or deficiency or even some levels of nutrient levels like thiamine may be lowered in early pregnancy to balance certain detox function. Still studying. The whole report is very good and I suggest you read it. I am just posting a small snippet. Dysautonomia in Autism Spectrum Disorder: Case Reports of a Family with Review of the Literature "Pregnancy toxemia has been linked to thiamine deficiency..." Not much of a credential with this, but I thought I would post it for thought. "As all these hormonal changes are occurring there are also some symptoms the mother experiences, such as morning sickness. Pregnancy sickness is an adaptation or solution to the problem of teratogen ingestion during fetal organogenesis. Teratogens are drugs and other agents that can cause fetal malformation. During pregnancy sickness the mother experiences nausea, with or without vomiting, during the first trimester. It has been shown that women that experience morning sickness are less likely to miscarry during the first trimester than are asymptomatic women. https://scholarblogs.emory.edu/evmed/2013/05/01/pregnancy/ Effects of thiamine deficiency on hepatic cytochromes P450 and drug-metabolizing enzyme activities. Dietary effects on cytochromes P450, xenobiotic metabolism, and toxicity. "The levels and activities of cytochrome P450 enzymes are influenced by a variety of factors, including the diet. In this article, the effects of selected non-nutritive dietary chemicals, macronutrients, micronutrients, and ethanol on cytochromes P450 and xenobiotic metabolism are reviewed in the light of our current understanding of the multiplicity and substrate specificity of cytochrome P450 enzymes. Although the mechanisms of action of several dietary chemicals on specific cytochrome P450 isozymes have been established, those for macro- and micronutrients are largely unknown. It is known, however, that specific nutrients may have varied effects on different cytochrome P450 forms and thus may affect the metabolism of various drugs differently. Nutritional deficiencies generally cause lowered rates of xenobiotic metabolism. In certain cases, such as thiamin deficiency and mild riboflavin deficiency, however, enhanced rates of metabolism of xenobiotics were observed. The effects of dietary modulation of xenobiotic metabolism on chemical toxicity and carcinogenicity are discussed...." "During fasting, microsomal aminopyrine N-demethylase and hexobarbital hydroxylase activities were decreased, but aniline p-hydroxylase and p-nitroanisole O-demethylase ac- tivities were increased in male rats (32). The induction of P450 2E1 by fasting (17) can account for the increased ani- line hydroxylase and NDMA demethylase activities. Fasting for 2 or 3 days caused a 50% decrease in the level of the male-specific P450 2C11 (33), and this may account for the previously observed decrease in aminopyrine demethylase activity. During fasting, the mRNA for P450 2E1 was sig- nificantly elevated, a situation similar to diabetes (34), but such elevation was not observed during the induction of P450 2E1 by acetone pretreatment (19). The results Suggest that there are differences in the mechanisms of P450 2E1 in- duction under these conditions." Sex steroid hormones regulate constitutive expression of Cyp2e1 in female mouse liver. "CYP2E1 is of paramount toxicological significance because it metabolically activates a large number of low-molecular-weight toxicants and carcinogens. In this context, factors that interfere with Cyp2e1 regulation may critically affect xenobiotic toxicity and carcinogenicity. The aim of this study was to investigate the role of female steroid hormones in the regulation of CYP2E1, as estrogens and progesterone are the bases of contraceptives and hormonal replacement therapy in menopausal women. Interestingly, a fluctuation in the hepatic expression pattern of Cyp2e1 was revealed in the different phases of the estrous cycle of female mice, with higher Cyp2e1 expression at estrus (E) and lower at methestrus (ME), highly correlated with that in plasma gonadal hormone levels. Depletion of sex steroids by ovariectomy repressed Cyp2e1 expression to levels similar to those detected in males and cyclic females at ME. Hormonal supplementation brought Cyp2e1 expression back to levels detected at E. The role of progesterone appeared to be more prominent than that of 17β-estradiol. Progesterone-induced Cyp2e1 upregulation could be attributed to inactivation of the insulin/PI3K/Akt/FOXO1 signaling pathway. Tamoxifen, an anti-estrogen, repressed Cyp2e1 expression potentially via activation of the PI3K/Akt/FOXO1 and GH/STAT5b-linked pathways. The sex steroid hormone-related changes in hepatic Cyp2e1 expression were highly correlated with those observed in Hnf-1α, β-catenin, and Srebp-1c. In conclusion, female steroid hormones are clearly involved in the regulation of CYP2E1, thus affecting the metabolism of a plethora of toxicants and carcinogenic agents, conditions that may trigger several pathologies or exacerbate the outcomes of various pathophysiological states." Hypoxia-inducible factor 1 transactivates the human leptin gene promoter. "Increased placental leptin has been demonstrated in preeclampsia, a pregnancy disorder associated with placental hypoxia. This suggests that leptin gene expression is enhanced in response to oxygen deficiency in this organ. In support of this hypothesis, we have previously shown that hypoxia activates the leptin promoter in trophoblast-derived BeWo cells. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric HIF-1alpha/HIF-1beta complex that regulates the transcription of hypoxia-responsive genes. To test whether this factor is involved in hypoxia-induced leptin promoter activation, BeWo cells were transiently transfected with a HIF-1alpha expression vector. Exogenous HIF-1alpha markedly increased luciferase reporter activity driven by the leptin promoter when HIF-1beta was co-expressed in the same cells. This effect was similar to that elicited by CoCl2, an agent known to stabilize endogenous HIF-1alpha. These data suggest that HIF-1alpha/HIF-1beta dimers are involved in the effect of CoCl2 to activate the leptin promoter. To confirm the implication of HIF-1, the cells were transfected with a dominant negative form of HIF-1alpha producing transcriptionally inactive HIF-1beta/HIF-1alpha dimers. This mutant HIF-1alpha protein abolished CoCl2 activation of the leptin promoter, providing direct evidence that the effect of CoCl2 is mediated by endogenous HIF-1alpha. Deletion analysis and site-specific mutagenesis demonstrated that a HIF-1 consensus binding site (HRE) spanning -120 to -116 bp relative to the start site was required for CoCl2 and exogenous HIF-1alpha induction of leptin promoter activity. Electrophoretic mobility shift assays performed with in vitro-translated HIF-1alpha and HIF-1beta proteins demonstrated binding to this HRE and not to mutated sequences only when both subunits were used together. These data demonstrate that leptin is a new hypoxia-inducible gene, which is stimulated in a placental cell line through HIF-1 interaction with a consensus HRE site located at -116 in the proximal promoter." Hypoxia-ischemia and thiamine deficiency. "In order to test the hypothesis that Wernicke's encephalopathy is of topographic rather than of pathogenetic specificity we examined the brains of 49 patients without any evidence of chronic alcoholism. They had died at least four days after an event of severe hypoxia-ischemia. They all showed extensive lesions in the cortex, in the thalamus and in other regions. In 19 of them there was additional necrosis in the mamillary bodies which apparently was of the same age as the associated cortical and thalamic lesions and which could not be distinguished from Wernicke's encephalopathy. In three of the 19 cases there was a total necrosis within the mamillary bodies. By re-examining the mamillary bodies of 12 known alcoholics without any evidence for an ischemic impact we could affirm that total necrosis may fit into the spectrum of Wernicke's encephalopathy. Our findings demonstrate that the morphological changes in the mamillary bodies due to thiamine deficiency and those due to hypoxia-ischemia may be identical." One more with added overview ideas. The Role of Thiamin in High Calorie Malnutrition http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=4&cad=rja&uact=8&ved=0CDwQFjAD&url=http%3A%2F%2Faustinpublishinggroup.com%2Fnutrition-food-sciences%2Fdownload.php%3Ffile%3Dfulltext%2Fajnfs-v3-id1061.pdf&ei=p_WTVYvIBsvz-AHnooPIAg&usg=AFQjCNG1J8HNREc00AMQZZLU-7vCQjc1jQ&bvm=bv.96952980,d.cWw The fact fat is a toxin repository is also of note. Some this relates a good bit with a lot Dr. Seneff mentions in one of her reports. The proposed effect of Glyphoste effecting gut bacterial composition and subsequent sulfate and phenol levels and function do ties together a great deal of the things That I had believed and documented. Glyphosate's Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern http://www.mdpi.com/1099-4300/15/4/1416/pdf The tremendous amount of system interaction in physiology does make this whole process so daunting that attempting to find key areas that point to the etiology of ASD's a vast challenge. How each person's system handles toxicity from chemicals, and in relation metals, along with degrees and type of exposure along with how the fetus's genetics may respond to the mother's status at least raises the question about how morning sickness and things like leptin and ghrelin levels may be involved. Adipose tissue, esp. visceral fat, relates to neuroendocrine and lymphoid function and bear on energy production and metabolism and involve the hypothalmus. Fatty acid metabolism and peroxisomal function and disorders and perturbed function in these systems would certainly present as areas related to the hormonal, immune and energy production and nutrition all intricately related to the changes in, and processes in pregnancy. How morning sickness severity or lack thereof relates to possible abilities of dealing with toxins or a sensitivity to them and how this bears on the development of the fetus is compelling in my view. It may be that severe morning sickness in some cases helps in fetal development in ways or in some may be a sign of a pathology or even some of both. Yet, there appears to be a relationship. The fact the brain uses so much energy and is mainly fat also buttress the ides of studying the finding of altered leptin and ghrelin levels in autism and their changes in pregnancy. How this relates to fatty acid metabolism, an area that many of us already believe to be a factor, is also somewhat researched and seems to tie into all of this. Solving the Autism Puzzle – The Fatty Acid Question and "Big, Fat Neurons"! http://www.ageofautism.com/2009/07/solving-the-autism-puzzle-the-fatty-acid-question-and-big-fat-neurons.html When you consider detoxifying enzymes, esp. the cytochrome P450 enzymes as Stephanie Seneff has reported on related to Glyphoste the problems with toxicity in pregnancy you also wonder how morning sickness relates to these matters. Adipose Tissue Immune Response: Novel Triggers and Consequences for Chronic Inflammatory Conditions NOVEL TRIGGERS OF ADIPOSE TISSUE IMMUNE RESPONSE Aryl Hydrocarbon Receptor Agonists "The rapid increase in the number of people with obesity and obesity-induced chronic inflammatory diseases is now attributed to intricate cross talk between genetic makeup and so termed environmental "obesogens" [96]. Among these, more than 20 chemicals have been shown to cause long-term weight gain based on exposures during critical periods of development. Smoking and nicotine, persistent organophosphate pesticides, flame retardants, plasticizers and plastics, and fungicides, for example, have all been linked to obesity in animals. These highly lipophilic toxicants have very long half-lives that allow them to accumulate in the food chain. Western style diet, based on high consumption of animal fat, increases human exposure to these ubiquitous toxicants. The dioxin and dioxin-like pollutants are among the most dangerous. Due to their long half-life and lipophilicity, they accumulate in adipocytes and participate in the pathophysiology of obesity and obesity-associated chronic inflammatory diseases [97, 98] through activation of the aryl hydrocarbon receptor (AhR) [99, 100]. AhR is a ligand-activated transcription factor with important roles not only in the xenobiotic metabolism but in developmental and normal physiology as well. This particular receptor is ubiquitously present in adipocytes and, most importantly, in all the cells that participate in the immune system responses [101, 102]. Moreover, the preadipocytes that differentiate into mature adipocytes in the presence of even low levels of these toxic AhR ligands produce significantly more inflammatory cytokines such as TNF-α, IL-6, and chemokine MCP-1 [103]. Long-term exposure of mice to dioxin-like AhR agonists led to increased visceral adipose tissue mass, ectopic fat deposition in the liver (hepatic steatosis) and peritoneal cavity, and abnormal serum lipid profile similar with the metabolic syndrome [98]. Importantly, under the same treatment, AhR KO mice appear resistant to obesity and its metabolic consequences. Consistent with these observations, ApoE−/−mice that received dioxin-like PCBs (AhR agonists) developed atherosclerosis, as early event in the pathogenesis of abdominal aortic aneurysms (AAAs) [98]." The things I have mentioned are only the broadest associations and often I just post these broad matters as to allow others to simply see the concept. If I post something too intricate or lengthy I doubt any would delve into reading these posts. I have looked at the systems in depth and there is a lot of reasonableness to connect toxins, enzyme function and attendant metabolic and immune effects in gestation and even morning sickness to these functions. Posted by: Visitor \| June 29, 2015 at 09:33 AM I appreciate it, too, Visitor. I'm just not as fast at absorbing and processing it all as you are. I'm still intrigued about the intersection of some stuff you've found and the information both Teresa Conrick and Eileen Nicole Simon post, combined with vitamin (prehormone D3) and their combined roles, and the new lymph findings take it all to another level. Re: lymph around the head/brain area, brings to mind discussions I've read on sites about cranialsacral therapy and people that find it helpful. Obviously oxygen is critical in the body for certain chemical reactions to occur properly so any challenges to that need to be remedied, and then there has to be an ONGOING way to remove the toxic byproducts of that. I read periodic stuff about advance glycation endpoints, etc, and see interesting info in the Anti-Aging medicine movement/organizations and their work on telomeres. I haven't checked to see if there have been any studies done on autistic children on what their telomeres look like comparatively. And I also want to look into the Heritage Study about VO2max non-responders, which have found that going beyond a certain level of exercise actually causes health problems, ie, their stuff may have clues as to the existance of a subgroup of people epigenetically at a loss to properly process oxygen based reactions in the body and/or manage its byproducts, which to me would be them at a higher risk for ANY other environmental challenges, including vaccine adverse reactions(thrombocytopenia, for example)that might normally cause only minimal or transient damage in people that are NOT VO2max non-responders. I think the morning sickness leptin/ghrelin stuff is intriguing but haven't read through the science - my primary question there is do any of those studies look at the diets of the women who do or do not have morning sickness. It goes against my intuition to think that those with morning sickness miscarry less than those without. Personally, I interpret most and maybe all physical discomforts as symptoms of reaction against an existing problem/imbalance not some mysterious preventive mechanism. For instance, if HCG is present in higher levels early on in a pregnancy and morning sickness got its name from brief mild nausea in the am, HCG may be cyclical not just from a trimester standpoint, but from a daily cyclical standpoint, just like cortisone in the body and melatonin, for example (both known to be affected by diet, and of course various stressors). What would cause HCG & leptin & ghrelin to NOT to maintain their natural cycles? Is there some molecular mimicry going on there or something? What effect does a healthy/unhealthy microbiome have on hormone cycles? We know the gut microbiome creates seratonin - what does it do for these other hormones? There are many questions and not enough time in the day - and all of it needs to be conveyed somehow to the public and politicians, but at $35 per article in general, the big corporations have it shut down tight. Posted by: Jenny \| June 27, 2015 at 08:56 AM I appreciate that Donna K. Glad to know someone is maybe getting something from this. Always interested in seeing what new info or insights you have come across to contribute. Thank you. Posted by: Donna K \| June 24, 2015 at 06:28 PM This quote is related the 2nd post back on leptin and related matters. I have been looking at ghrelin for a long time and had missed this report until recently. Then whole report is well worth reading. Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation "Numerous hormone studies have been undertaken in children with autism; however, to our knowledge, this study is the first in which ghrelin was measured. Plasma levels of both AG and DG were significantly reduced in the autism group compared with healthy controls. This result can be attributed to local factors affecting ghrelin-secreting cells and to hormonal influences. Gastrointestinal (GIT) problems are frequent in autism, including dysbiosis, chronic GIT inflammation and chronic fungal, viral and bacterial infections19. These disorders could affect the gastric mucosa and interfere with the normal function of ghrelin-secreting cells. Furthermore, ghrelin deficiency by itself can affect the gastric mucosa, as ghrelin is known for its role in maintaining mucosal health and integrity20. Thus, a loss of mucosal health and integrity could result in a further decrease in plasma ghrelin levels. Alterations in plasma ghrelin levels may also be part of the extensive, well-studied hormonal dysregulation that characterizes autism, particularly the dysregulation of TT, FT, leptin and GH. In agreement with the findings of the current study, previous studies have shown that androgen levels are significantly higher in autism patients11. At the same time, it is well established that ghrelin plasma levels are negatively correlated with high plasma testosterone levels12. The current study confirms the negative correlation between FT and DG. This correlation may indicate that the reduced plasma level of ghrelin in autistic children is in part a consequence of suppression by elevated androgens. Another hormone that has been studied in autism is leptin. Its relevance to ghrelin function comes from the observation that elevated plasma leptin levels are associated with reduced plasma ghrelin levels14, 15. This finding is in agreement with the results of the current study, which revealed a significant elevation of leptin and a reduction of ghrelin levels in the autism group. In support of this notion, Komori et al. provided a novel molecular link between leptin and ghrelin signaling, namely, the leptin-induced negative regulatory element-binding protein (NREBP), which suppresses ghrelin signalling21. The high serum leptin levels in the current study is consistent with other studies that reported a significant elevation of leptin levels in autistic children14, 22. The elevation of leptin levels can be explained in part by the observed significant elevation of androgen levels in autistic children. Both animal and human studies have shown that adipocytes have androgen receptors (ARs), and androgens are known to modulate the plasma leptin level23, 24. Consistent with these reports, the current study revealed a significant positive correlation between leptin and FT. The significant elevation of leptin levels in autism may also be a consequence of the significant decrease in GH levels in autistic children, as will be discussed later. Alterations in the levels of both ghrelin and leptin are known to be associated with adiposity25, 26. As can be noted from the anthropometric data in the current study, the only significant difference between the autism and control groups was in body weight, which was significantly higher in the autism group. To exclude the effect of weight on the levels of these hormones, we excluded four children with high body weight from the autism group to create a group that was age-, sex- and weight-matched with the controls, as shown in Table 3. As presented in Table 3, there were significant reductions in both AG and DG plasma levels, with a significant increase in the plasma leptin level in the autism group compared with weight-matched controls." http://www.nature.com/srep/2014/140926/srep06478/full/srep06478.html They are showing the pieces, but haven't much of a clue about the triggers or causes. A very good overview though. The Many Roads To Mitochondrial Dysfunction In Neroimmune And Neuropsychiatric Disorders This addresses autism with a specific idea about metals/toxicity and enzyme function. Since my wife had such severe morning sickness{hyperemesis gravidarum} I am also proposing a relationship in the chemistry and functions believed to be involved with it and a relationship with autism that may exist in her as well as possibly mothers of children who have autism. 1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D. "To investigate vitamin D-related control of brain-expressed genes, candidate vitamin D responsive elements (VDREs) at -7/-10 kb in human tryptophan hydroxylase (TPH)2 were probed. Both VDREs bound the vitamin D receptor (VDR)-retinoid X receptor (RXR) complex and drove reporter gene transcription in response to 1,25-dihydroxyvitamin D3 (1,25D). Brain TPH2 mRNA, encoding the rate-limiting enzyme in serotonin synthesis, was induced 2.2-fold by 10 nM 1,25D in human U87 glioblastoma cells and 47.8-fold in rat serotonergic RN46A-B14 cells. 1,25D regulation of leptin (Lep), encoding a serotoninlike satiety factor, was also examined. In mouse adipocytes, 1,25D repressed leptin mRNA levels by at least 84%, whereas 1,25D induced leptin mRNA 15.1-fold in human glioblastoma cells. Chromatin immunoprecipitation sequencing analysis of the mouse Lep gene in response to 1,25D revealed a cluster of regulatory sites (cis-regulatory module; CRM) at -28 kb that 1,25D-dependently docked VDR, RXR, C/EBPβ, and RUNX2. This CRM harbored 3 VDREs and single C/EBPβ and RUNX2 sites. Therefore, the expression of human TPH2 and mouse Lep are governed by 1,25D, potentially via respective VDREs located at -7/-10 kb and -28 kb. These results imply that vitamin D affects brain serotonin concentrations, which may be relevant to psychiatric disorders, such as autism, and may control leptin levels and affect eating behavior." Leptin and leptin receptor levels in pregnant women with hyperemesis gravidarum "Objective: To investigate the association between the leptin, leptin receptor and hormone levels and hyperemesis gravidarum, and to determine whether these two parameters may be early markers for hyperemesis gravidarum. Methods: The study group consisted of 18 pregnant women with hyperemesis gravidarum and the control group consisted of 18 healthy pregnant women. Demographic characteristics were recorded and body mass index (BMI) values were calculated for all the pregnant women. Serum leptin, leptin receptor, insulin, cortisol, thyroid hormone and human chorionic gonadotrophin (hCG) levels were measured. Results: When the two groups were compared with respect to leptin levels, the group with hyperemesis gravidarum was found to have significantly higher leptin levels (P = 0.037). No intergroup differences were observed in serum cortisol, insulin, hCG, thyroid hormone levels or BMI values. In the group with hyperemesis gravidarum, an inverse correlation was detected between cortisol and leptin (r = –0.762, P < 0.01), and hCG and thyroid-stimulating hormone (r = –0.503, P < 0.05), whereas a significant correlation was detected between insulin and leptin (r = 0.538, P < 0.05), leptin and BMI (r = 0.711, P < 0.01), and between TT3 and hCG (r = 0.605, P < 0.01). Conclusion: It was concluded that leptin could play a role in, and be defined as, a marker of hyperemesis gravidarum." http://onlinelibrary.wiley.com/doi/10.1111/j.1479-828X.2006.00590.x/abstract;jsessionid=6CC380C381CED0856437BEBB659FA705.f04t03 Hyperemesis gravidarum - Wiki "Intravenous fluids[edit] IV hydration often includes supplementation of electrolytes as persistent vomiting frequently leads to a deficiency. Likewise, supplementation for lost thiamine (Vitamin B1) must be considered to reduce the risk of Wernicke's encephalopathy.[20] A and B vitamins are depleted within two weeks, so extended malnutrition indicates a need for evaluation and supplementation. In addition, electrolyte levels should be monitored and supplemented; of particular concern are sodium and potassium." "Signs and symptoms[edit] When hyperemesis gravidarum is severe or inadequately treated, it may result in the following:[1] ##Loss of 5% or more of pre-pregnancy body weight ##Dehydration, causing ketosis,[3] and constipation ##Nutritional disorders such as vitamin B1 (thiamine) deficiency, vitamin B6 deficiency or vitamin B12 deficiency ##Metabolic imbalances such as metabolic ketoacidosis[1] or thyrotoxicosis[4]"... "Causes[edit] There are numerous theories regarding the cause of HG, but the cause remains controversial. It is thought that HG is due to a combination of factors which may vary between women and include: genetics,[1] body chemistry, and overall health.[8] One factor is an adverse reaction to the hormonal changes of pregnancy, in particular, elevated levels of beta human chorionic gonadotropin (hCG).[9][10] This theory would also explain why hyperemesis gravidarum is most frequently encountered in the first trimester (often around 8–12 weeks of gestation), as hCG levels are highest at that time and decline afterward. Another postulated cause of HG is an increase in maternal levels of estrogens (decreasing intestinal motility and gastric emptying leading to nausea/vomiting).[1] Pathophysiology[edit] Although the pathophysiology of HG is poorly understood, the most commonly accepted theory suggests that levels of hCG are associated with it.[11] Leptin may also play a role." https://en.wikipedia.org/wiki/Hyperemesis_gravidarum Wernicke–Korsakoff syndrome "One as-yet-unreplicated study has associated susceptibility to this syndrome with a hereditary deficiency of transketolase, an enzyme that requires thiamine as a coenzyme.[17]" https://en.wikipedia.org/wiki/Wernicke%E2%80%93Korsakoff_syndrome Wernicke's encephalopathy _ Wiki "Pathophysiology[edit] Thiamine deficiency and errors of thiamine metabolism are believed to be the primary cause of Wernicke encephalopathy. Thiamine, also called B1, helps to break down glucose. Specifically, it acts as an essential coenzyme to the TCA cycle and the pentose phosphate shunt. Thiamine is first metabolised to its more active form, thiamine diphosphate (TDP), before it is used. The body only has 2–3 weeks of thiamine reserves, which are readily exhausted without intake, or if depletion occurs rapidly, such as in chronic inflammatory states or in diabetes.[6][34] Thiamine is involved in:[34][42] 1.Metabolism of carbohydrates, creating energy. 2.Production of neurotransmitters including glutamic acid and GABA. 3.Lipid metabolism, necessary for myelin production. 4.Amino acid modification. Probably linked to the production of taurine, of great cardiac importance.[43][44] 5.Neuromodulation.[45] Neuropathy[edit] The primary neurological-related injury caused by thiamine deficiency in WE is three-fold: oxidative damage, mitochondrial injury leading to apoptosis, and directly stimulating a pro-apoptotic pathway.[45] Thiamine deficiency affects both neurons and astrocytes, glial cells of the brain. Thiamine deficiency alters the glutamate uptake of astrocytes, through changes in the expression of astrocytic glutamate transporters EAAT1 and EAAT2, leading to excitotoxicity. Other changes include those to the GABA transporter subtype GAT-3, GFAP, glutamine synthetase, and the Aquaporin 4 channel.[46"... "Other nutritional abnormalities should also be looked for, as they may be exacerbating the disease.[28][58] In particular, magnesium, a cofactor of transketolase which may induce or aggravate the disease.[34] Other supplements may also be needed, including: cobalamin, ascorbic acid, folic acid, nicotinamide, zinc,[59][60] phosphorus (dicalcium phosphate)[61] and in some cases taurine, especially suitable when there cardiocirculatory impairment.[62][63] Patient-guided nutrition is suggested. In patients with Wernicke-Korsakoff syndrome, even higher doses of parenteral thiamine are recommended." https://en.wikipedia.org/wiki/Wernicke%27s_encephalopathy Morning sickness - Wiki Morning sickness as a defense mechanism[edit] "Morning sickness is understood as an evolved trait that protects the fetus against toxins ingested by the mother.[6] [7] Many plants contain chemical toxins that serve as a deterrent to being eaten. Adult humans, like other animals, have defenses against plant toxins, including extensive arrays of detoxification enzymes manufactured by the liver and the surface tissues of various other organs. In the fetus, these defenses are not yet fully developed, and even small doses of plant toxins that have negligible effects on the adult can be harmful or lethal to the embryo.[8] Pregnancy sickness causes women to experience nausea when exposed to the smell or taste of foods that are likely to contain toxins injurious to the fetus, even though they may be harmless to her. There is considerable evidence in support of this theory, including:[9][10] ##Morning sickness is very common among pregnant women, which argues in favor of its being a functional adaptation and against the idea that it is a pathology. ##Fetal vulnerability to toxins peaks at around 3 months, which is also the time of peak susceptibility to morning sickness. ##There is a good correlation between toxin concentrations in foods, and the tastes and odors that cause revulsion. Women who have no morning sickness are more likely to miscarry.[11] This may be because such women are more likely to ingest substances that are harmful to the fetus.[12]" https://en.wikipedia.org/wiki/Morning_sickness The role of trace elements, thiamin (e) and transketolase in autism and autistic spectrum disorder. "Although there has been much research into autism or autistic spectrum disorder (ASD), there is room for considerable conjecture regarding the etiology of these developmental brain disorders. ASD is marked by a complex interaction between environmental factors and genetic predisposition, including epistasis. This manuscript argues that changes in oxidative metabolism, thiamine homeostasis, heavy metal deposition and cellular immunity have a role in the etiopathogenesis of autism and ASD. Recent findings from our group and others provide evidence for abnormal thiol metabolism, marked by significant alteration in the deposition of several trace heavy metal species. Together with these, we find differences in thiamine homeostasis in ASD patients, which can be corrected by supplementation. We hypothesize that altered thiol metabolism from heavy metal toxicity, one of the key mechanisms for oxidative stress production, may be responsible for the biochemical alterations in transketolase, dysautonomia and abnormal thiamine homeostasis. Although it is unknown why these particular metals accumulate, we suspect that children with ASD and forms of autism may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. We maintain mercury accumulation is evidence of altered clearance. Together with concomitant oxidative stress, these findings may offer an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Regardless of the exact cause, these factors may be more important to the etiology of this symptomatically diverse disease spectrum. Here, we offer insight into new avenues of exploration as well as the development of novel treatment approaches for these growing and devastating diseases." Altered Heavy Metals and Transketolase Found in Autistic Spectrum Disorder http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=4&cad=rja&uact=8&ved=0CDoQFjADahUKEwjm1vK99JHGAhVKoIAKHU9hAFI&url=http%3A%2F%2Fwww.researchgate.net%2Fprofile%2FMark_Obrenovich%2Fpublication%2F51491219_Altered_heavy_metals_and_transketolase_found_in_autistic_spectrum_disorder%2Flinks%2F09e41508337d93a026000000&ei=MuF-Veb1HcrAggTPwoGQBQ&usg=AFQjCNFi_qMQq5HQLaU4Pei6Q0gaj7eR7g&bvm=bv.95515949,d.eXY Well, on a simpler note -- maybe by parental instinct there are so many trampolines in back yards. Of all the toys to have, I have often wondered how those became so popular. I will be the first to admit that my parental instincts really stink as I kept allowing vaccinations after tons of reactions. But an up note; They did have a bouncing horse or two. I am also wondering whether heavy metals, mercury and aluminum of course being of interest, would be present in lymph fluid longer than in blood, possibly leading to a new lab test that could indicate heavy metal overload, different from or supporting provoked urine tests. Could be a better indicator of how efficiently or not a body rids itself of toxins, and therefore offer insight about whether a person could be severely damaged by vaccines or not. Have you been up on some of the ideas on oxygen that you mentioned or were you just surmising that it was a logical idea. On one sight I linked in another article the author indeed mentions the idea of oxygen related to lymphatic circulation. I am aware that some have called these quack ideas, but they also did not know about these new lymph vessels. Some quacks are looking better all the time. Even though the author here also did not know of these new found vessels the association was not excluded as apparently other evidence indicated the importance. Activating Lymphatics Improves Detoxification In The Brain "The brain depends on proper circulation to detox acidic cellular waste from its tissues. Even though the brain has no lymph vessels the membranes that surround the spinal cord and brain has lymph vessels. By manually activating the lymphatics in the neck and face you dramatically improve circulation and reabsorption of cerebrospinal fluid and cellular waste into the lymphatic system. This improved circulation delivers oxygen and nutrition to the cells while improving cellular detoxification throughout the body." "My point, if you have a young child with autism like behavior, you need to see that acid is a contributing factor in their cognitive problems, digestive issues, skin irritations, aggression, hyperactivity or lethargy. The first step should be to balance their pH and activate the lymphatic system. Start with Epsom salt and baking soda baths, alkalizing supplements, systemic enzymes, probiotics, and some type of lymph drainage therapy to open the lymph-brain connection." http://lymphman.com/Blog/tabid/197/articleType/ArticleView/articleId/97/categoryId/19/Autism-Christianson-Syndrome-Logs-Jamming-The-River.aspx The mechanical assistance that could move the lymphatic system along is reasonable as a therapeutic idea. The fact that the immune system and brain function have been so compelling in study and observation to some has had some element of problem due to how this is/was occurring. The blood brain barrier has seemed a possible route, and still may be, for some of the interplay, but this news of these lymphatic vessels gives a new route to consider strongly. There is still some element of uncertainty about the extent these vessels could impact the brain as there is little known about them at this point. Yet, the plausible effects are hard not to be very interested about. I don't know about oxygen availability, but I will be looking more into this. As for now this seems to be interesting to a good number who are also of the mind that the immune system is related to Autism. That is good to me. This is also an area that has already be in view by some studying Autism, though the vessels found is a new thing. Please share what you find here as I will do the same. Discovery of brain-immune link could advance understanding of autism https://www.autismspeaks.org/science/science-news/discovery-brain-immune-link-could-advance-understanding-autism Activating the Lymphatic System Can Help Autism Spectrum Disorders http://lymphman.com/Blog/tabid/197/articleType/ArticleView/articleId/21/Activating-the-Lymphatic-System-Can-Help-Autism-Spectrum-Disorders.aspx Helping autism spectrum disorders by opening the lymph/brain connection http://www.naturalhealingnews.com/helping-autism-spectrum-disorders-by-opening-the-lymphbrain-connection/#.VXOjFU3bJaQ Lymphatic Therapy http://www.autismone.org/content/lymphatic-therapy Visitor re: lymph propulsion cessation: I had started pondering last year that in certain cancer therapies, trampolining or vibration is deemed important - to force the lymph fluid to move when it otherwise might. I thought that the movement would be very similar to children with autism responding well to horse riding therapy and could explain the nature of those benefits. If so, once again, the solution points to the problem. I also wonder if / what lymph propulsion cessation might do re: oxygen availability in the body, if anything. Posted by: Jenny \| June 06, 2015 at 08:20 PM N-iminoethyl-L-lysine mentioned in the abstract in the last post is in view here. This is focusing on Alzheimer, but may relate to inflammation in other neurological conditions like Autism. N-iminoethyl-L-lysine improves memory and reduces amyloid pathology in a transgenic mouse model of amyloid deposition. "A large body of evidence suggests the importance of inflammation and oxidative or nitrosative stress in Alzheimer's disease (AD) pathogenesis. Inflammatory stimuli upregulate transcription of inducible nitric oxide synthase (iNOS), which can lead to the production of nitric oxide and other reactive nitrogen species. We previously found that genetic deletion of iNOS in mice overexpressing the amyloid precursor protein (APP) and presenilin-1 (PS1) reduced mortality, nitrosative stress, amyloid plaque burden, microgliosis, astrocytosis, and peri-plaque tau phosphorylation. We therefore examined the effects of N6-(1-iminoethyl)-L-lysine (L-NIL), a pharmacological iNOS inhibitor, or d-NIL, its enantiomeric control, in a transgenic mouse model of amyloid deposition. Tg19959 mice carry human APP with two mutations and develop amyloid plaques and memory impairment starting at 3-4 months of age. Mice were given L-NIL or D-NIL in the drinking water from 1 month of age and assessed behaviorally and histopathologically at 8 months of age. We found that L-NIL administration reduced disinhibition in the elevated plus maze, improved spatial memory performance in the Morris water maze, and decreased cortical amyloid deposition as well as microglial activation in 8-month-old Tg19959 mice. These findings are consistent with previous reports demonstrating that iNOS inhibition ameliorates AD pathogenesis." The following may be of relevance here. Nitric Oxide Can Regulate Gene Expression Ridiculous to speculate I guess, but concerning the last post here is an early Idea. Cytokines are systemic effectors of lymphatic function in acute inflammation. "The response of the lymphatic system to inflammatory insult and infection is not completely understood. Using a near-infrared fluorescence (NIRF) imaging system to noninvasively document propulsive function, we noted the short-term cessation of murine lymphatic propulsion as early as 4h following LPS injection. Notably, the effects were systemic, displaying bilateral lymphatic pumping cessation after a unilateral insult. Furthermore, IL-1β, TNF-α, and IL-6, cytokines that were found to be elevated in serum during lymphatic pumping cessation, were shown separately to acutely and systemically decrease lymphatic pulsing frequency and velocity following intradermal administration. Surprisingly, marked lymphatic vessel dilation and leakiness were noted in limbs contralateral to IL-1β intradermal administration, but not in ipsilateral limbs. The effects of IL-1β on lymphatic pumping were abated by pre-treatment with an inhibitor of inducible nitric oxide synthase, L-NIL (N-iminoethyl-L-lysine). The results suggest that lymphatic propulsion is systemically impaired within 4h of acute inflammatory insult, and that some cytokines are major effectors of lymphatic pumping cessation through nitric oxide-mediated mechanisms. These findings may help in understanding the actions of cytokines as mediators of lymphatic function in inflammatory and infectious states." Curious as to what this may eventually show, but it is interesting. Missing link found between brain, immune system http://medicalxpress.com/news/2015-06-link-brain-immune.html New hope for autism: Canadian researcher reports to Sweden's Nobel Forum "Autism rates have skyrocketed from 1 in 10,000 a half a century ago to 1 in 68 persons today. Expert opinion and funding to date has mostly focused on genetic causes and have attempted to explain the increase as better reporting of autism cases. MacFabe's research points strongly in another direction: changes in our gut bacteria. Dr. MacFabe and his colleagues have shown that compounds, known as short chain fatty acids, which are produced by bacteria found in our intestines affect brain function and behaviour. Collaborating with Dr. Richard Frye of the University of Arkansas, their research has shown that these compounds affect the efficiency of mitochondria, the energy storehouse of cells. Work with Dr. Bistra Nankova of New York Medical College has revealed that these fatty acid products can also act as epigenetic modulators, in effect acting as "switches" for many autism associated genes known to affect neural development and transmission, but also those involved in inflammation and energy metabolism, also reported in autism. MacFabe, whose work has been featured on CBC Television's The Nature of Things, says these associated autism genes need not only be irreversibly damaged but can actually be switched on and off by compounds produced by autism associated intestinal bacteria. This provides an important link between the gut and the brain in autism. It also lends credibility to reports from parents who often see a connection between digestive upsets and autism symptoms in their children, he says. Such symptoms include impaired language, repetitive behaviours, restricted interests, social impairment and self-injurious behaviour, but often of a variable course or severity. Dr. Suzanne Lewis, Director of the Autism Spectrum Interdisciplinary Research (ASPIRE) Program, Department of Medical Genetics, University of British Columbia has worked collaboratively with Dr. MacFabe for the past six years. Dr. Lewis states: "Genetic changes alone cannot explain the rising rate of autism within one generation. We need to look at environmental factors that can impact autism behaviours, for which a growing evidence points to changes involving the gut microbiome." http://www.prnewswire.com/news-releases/new-hope-for-autism-canadian-researcher-reports-to-swedens-nobel-forum-295188121.html Posted by: Visitor \| March 05, 2015 at 02:53 PM Biochemical, Histopathological and Morphological Profiling of a Rat Model of Early Immune Stimulation: Relation to Psychopathology. "Perinatal immune challenge leads to neurodevelopmental dysfunction, permanent immune dysregulation and abnormal behaviour, which have been shown to have translational validity to findings in human neuropsychiatric disorders (e.g. schizophrenia, mood and anxiety disorders, autism, Parkinson's disease and Alzheimer's disease). The aim of this animal study was to elucidate the influence of early immune stimulation triggered by systemic postnatal lipopolysaccharide administration on biochemical, histopathological and morphological measures, which may be relevant to the neurobiology of human psychopathology. In the present study of adult male Wistar rats we examined the brain and plasma levels of monoamines (dopamine, serotonin), their metabolites, the levels of the main excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid and the levels of tryptophan and its metabolites from the kynurenine catabolic pathway. Further, we focused on histopathological and morphological markers related to pathogenesis of brain diseases - glial cell activation, neurodegeneration, hippocampal volume reduction and dopaminergic synthesis in the substantia nigra. Our results show that early immune stimulation in adult animals alters the levels of neurotransmitters and their metabolites, activates the kynurenine pathway of tryptophan metabolism and leads to astrogliosis, hippocampal volume reduction and a decrease of tyrosine hydroxylase immunoreactivity in the substantia nigra. These findings support the crucial pathophysiological role of early immune stimulation in the above mentioned neuropsychiatric disorders." I wonder if vaccines fit in their idea of "perinatal immune challenges"? Posted by: Visitor \| January 21, 2015 at 05:04 PM Treating the brain and the immune system in tandem "For years, studies have shown that patients with a wide range of mental illnesses tend to have signs of inflammation, the body's natural response against infection and injury. But lately, scientists have been zeroing in on an explanation. They're accumulating evidence to suggest that infection, autoimmune diseases and environmental factors such as stress or diet can trigger the immune system to go awry, causing it to damage the brain instead of attacking foreign pathogens. The result: an array of psychiatric conditions, including schizophrenia, autism spectrum disorder, Alzheimer's disease, depression and anorexia nervosa." "This hypothesis does not suggest immune responses are at the root of all psychiatric cases. Rather, it points to the idea that common mental illnesses have multiple causes, a haywire immune system being just one. The immune hypothesis is nevertheless a paradigm shift that not only offers a tangible, biological basis for subsets of many previously inexplicable psychiatric conditions, it raises the possibility of successfully diagnosing, treating and perhaps even preventing them by homing in on the immune system and managing inflammation. Although the research is still in its early days, there's a growing sense of excitement over the prospect that certain individuals may regain mental health with antibiotics, intravenous immunoglobulin (IVIG) treatments (infusions of antibodies) and possibly dietary changes, instead of traditional psychiatric drugs and brain stimulation treatments." "I think we're on the cusp of something that's really huge and truly revolutionary in the way in which we ... both diagnose people, as well as to make them better," says Mady Hornig, associate professor of epidemiology at the Columbia University Medical Center, whose research focuses on the role of microbes and immune factors in neuropsychiatric illness." "Scientists are now recognizing that a host of external stimuli can disrupt the normal crosstalk between the brain and the immune system. Those stimuli can include stress, changes in the microbiome (the universe of microbes that live in our bodies), and certain viruses and bacteria." "It's believed this disruption can affect the brain, and thereby behaviour. In PANDAS, it is suggested that streptococcal bacteria may mimic brain proteins, prompting the body to produce antibodies that mistakenly target the brain." "So why doesn't everyone infected with strep throat come down with the same neurological and psychiatric symptoms that O'Donnell's daughter experienced? The answer may lie in genetics. Hornig explains that some individuals may be more genetically susceptible to producing a faulty immune response." "What is so remarkable and so exciting to researchers is that if certain neuropsychiatric disorders are triggered by external stimuli, it means they can be controlled, Hornig says. However, she adds, since genetics likely play a role, susceptible individuals could be vulnerable to falling ill again whenever they encounter such triggers." "A month after her symptoms disappeared, O'Donnell's daughter experienced a relapse of Tourette and OCD-like behaviour, and again tested positive for strep. Though she fully recovered a second time, O'Donnell notes that her child has since shown other signs of potential immune-related sensitivities. For example, she experienced a bout of anxiety after an unidentified viral infection. Meanwhile, recent dietary changes aimed at reducing inflammation, specifically eliminating gluten, seemed to alleviate her anxiety." "Anything that your immune system sees as an invader, whether it's gluten or a bee sting or whatever, or a virus or a bacteria, you now have to be careful and watching for almost a mental health symptom," O'Donnell says."... "It probably brings us closer to hammering in the idea that mental illness is a disease," she says. "It's a disease we don't fully understand." "Each new finding, however, is tempered with caution. "Using nationwide data from Denmark, Benros found a strong link between infection and autoimmune diseases and mood disorders. People who had visited the hospital for an infection at any time had a 62-per-cent higher risk of later being diagnosed with depression or bipolar disorder. Those who were hospitalized for autoimmune diseases had a 45-per-cent risk of subsequent depression or bipolar disorder."... "This suggests the need for immunopsychiatry, a new approach that recognizes the immune system and the brain are inexorably linked and should be treated in tandem, he adds." "I am one of the believers who thinks that the body is one big entity that shouldn't be split into different disciplines," Sakic says. "The problem is it's way more complex than we like to think." http://www.theglobeandmail.com/life/health-and-fitness/fitness/treating-the-brain-and-the-immune-system-in-tandem/article22491754/ Considering the role of the immune system and increasing evidence of microbiome effect in autism this may shed more light on heritability and environment in the demographics of autism. Environment, not genes, plays starring role in human immune variation, study finds The power of environment "Examining differences in the levels and activity states of these components within pairs of monozygotic and dizygotic twins, the Stanford scientists found that in three-quarters of the measurements, nonheritable influences — such as previous microbial or toxic exposures, vaccinations, diet and dental hygiene — trumped heritable ones when it came to accounting for differences within a pair of twins. This environmental dominance was more pronounced in older identical twins (age 60 and up) than in younger twins (under age 20)"... "Nonheritable influences, particularly microbes, seem to play a huge role in driving immune variation," said Davis. "At least for the first 20 or so years of your life, when your immune system is maturing, this amazing system appears able to adapt to wildly different environmental conditions. A healthy human immune system continually adapts to its encounters with hostile pathogens, friendly gut microbes, nutritional components and more, overshadowing the influences of most heritable factors." https://med.stanford.edu/news/all-news/2015/01/environment-not-genes-plays-starring-role-in-immune-variation.html A number of those with autism display psychotic traits according to studies. A lot of of effected brain areas are the same in both conditions.Some of the cause for both conditions may overlap. When and how much "damage" is occurring could be the difference with autism and psychotic disorders. Gray matter loss and inflamed brain associated with development of psychosis "Thirty-five individuals ultimately converted to psychosis and they showed a steeper rate of thinning in prefrontal cortex compared with those who did not convert and the healthy control group. Importantly, this tissue loss was not explained by exposure to antipsychotic drugs." "Because this differential rate of tissue loss was observed among subjects who had never been exposed to psychiatric drugs, we can conclude that the brain changes are part of the natural course of the disorder rather than being a consequence of treatment," explained Cannon." "Interestingly, the tissue loss observed in the converters was correlated with levels of proinflammatory cytokines in plasma, suggesting the presence of systemic neuroinflammation." "The findings are also important in showing that markers of proinflammatory cytokines at the baseline assessment predicted the rate of gray matter loss among the individuals who converted to psychosis, suggesting that activation of microglia was involved in the tissue loss," he added. "This could mean that psychosis is associated with an abnormal acceleration in the processes underlying normal synaptic pruning during late adolescence/early adulthood, or that some kind of immune-related process is involved in psychosis onset, or both." "Inflammation is increasingly recognized as a contributing factor to the emergence of progression of disease in every organ in the body," said Dr. John Krystal, Editor of Biological Psychiatry. "This report suggests that neuroinflammation may be a process that in some cases 'tips people over' from the at-risk state into psychosis." http://medicalxpress.com/news/2015-01-gray-loss-inflamed-brain-psychosis.html Psychosis and autism: magnetic resonance imaging study of brain anatomy Overlapping developmental brain abnormalities "People with autism-spectrum disorder already have significant developmental abnormalities in brain regions typically affected in psychosis (e.g temporal and frontal lobes), therefore it may be more difficult to detect subtle additional differences associated with further neuropsychiatric disorder." http://bjp.rcpsych.org/content/194/5/418.long Toddlers' Autistic Behaviors Linked to Preteen Psychosis "Autistic-like behaviors in toddlers might predict psychotic events in adolescence, a retrospective study has determined." "Speech problems and ritualistic behaviors in 3- and 7-year-olds showed a particularly strong influence, increasing the risk of psychosis in preteens by up to 300%, Rhys Bevan Jones, Ph.D., and colleagues wrote in the March issue of Schizophrenia Research (Schizophr Res. 2012;135:164-9)." "In the study, nearly 20% of children with these characteristics at age 7 went on to develop psychotic episodes by age 12." "The findings of this study suggest that clinicians should ask about psychotic experiences in those with autistic traits," wrote Dr. Jones of Cardiff (Wales) University. "Clinicians should also assess for traits of autism in those who develop psychotic experiences (23% of those with psychotic experiences in adolescence had at least one autistic trait at the age of 3, and 10% had at least one psychotic trait at the age of 7). Clinical care is likely to be enhanced by careful consideration of premorbid and comorbid autistic traits that might be impacting on patient function." "It is also possible that [autism spectrum disorders] and psychotic disorders represent part of the same disorder that is manifest differently at different stages of development." http://www.familypracticenews.com/news/child-adolescent-medicine/single-article/toddlers-autistic-behaviors-linked-to-preteen-psychosis/8c4a550248.html Mounting Research Shows Gut-Brain Connection "The work of these three researchers (some of the studies on mice) raises the possibility that brain disorders, including anxiety, depression, and autism, may be treated through the gut, which is a much easier target for drug delivery than the brain." "The human body contains trillions of microbes, collectively called the microbiome. In just one person's body, they are estimated to weigh two to six pounds — up to twice the weight of the average human brain." "Most reside in the gut and intestines, where they can help us to digest food, synthesize vitamins, and fight off infection. But their influence seems to reach the brain in a powerful way." "The big question right now is how the microbiome exerts its effects on the brain," said Christopher Lowry, Associate Professor of Integrative Physiology at the University of Colorado, Boulder..." "Dr. Sarkis Mazmanian, a Louis & Nelly Soux Professor of Microbiology at the California Institute of Technology, is investigating the connection between gut bacteria, gastrointestinal disease and autism, a neurodevelopmental disorder." "He has found that the gut microbiome communicates with the brain through molecules that are produced by gut bacteria and then enter the bloodstream. These molecules are strong enough to change the behavior of mice." "We've shown, for example, that a metabolite produced by gut bacteria is sufficient to cause behavioral abnormalities associated with autism and with anxiety when it is injected into otherwise healthy mice," said Mazmanian." "There is still much more work to be done to understand the gut-microbiome-brain connection, the researchers said. Mazmanian's lab is also exploring whether the microbiome plays a role in neurodegenerative diseases such as Alzheimer's and Parkinson's." "There are flash bulbs going off in the dark, suggesting that very complex neurodegenerative disorders may be linked to the microbiome. But once again this is very speculative. These seminal findings, the flash bulbs, are only just beginning to illuminate our vision of the gut-microbiome-brain connection," said Mazmanian." http://psychcentral.com/news/2015/01/12/mounting-research-shows-gut-brain-connection/79804.html We are less crazy as the days go by. My wife was diagnosed with RA, but with diet mod and immune modulation we have reversed it to a very large degree. That was a few years ago. The effects in some autism will be more clear soon it seems. Joint Pain, From the Gut "It's become more and more clear that these microbes can affect the immune system, even in diseases that are not in the gut," says Veena Taneja, an immunologist at the Mayo Clinic in Rochester, Minnesota, who has found clear differences in the bacterial populations of mice bred to be genetically prone to rheumatoid arthritis. In those more susceptible to the disease, a species of bacteria from the Clostridium family dominates. In mice without arthritis, other strains flourish, and the Clostridium strains are scarce...." "This is frontier stuff," says Scher, the director of the NYU's Microbiome Center for Rheumatology and Autoimmunity. "This is a shift in paradigm. By including the microbiome, we've added a new player to the game." "In fact, these bacteria have a powerful vested interest in controlling how our bodies respond to interlopers. Blaser and others say that it appears that many of the bugs that live inside us have thrived by modulating the immune system to avoid being recognized—and attacked—as invaders; in essence, these organisms train immune cells not to be trigger-happy. A microbiome with the wrong sorts of bugs, or the wrong ratio of bugs—a situation known as dysbiosis—may unbalance this immune system, causing immune cells to assault not only bacteria, but also the body itself." "Microbes are especially influential in the gut, which houses two-thirds of the body's immune cells. As the pathway for digestion, the gastrointestinal tract must deal with a constant stream of food-related foreign microbes, which must be monitored and, if they are harmful, destroyed. To do this, our intestines have developed an extensive immune system, whose effects reach far beyond the gut. Immune cells in the gut seem to be able to activate inflammatory cells throughout the body, including in joints." http://www.theatlantic.com/health/archive/2015/01/joint-pain-from-the-gut/383772/ Peripheral Blood Monocytes and innate immune dysregulation in ASD-IS or ASD-Inflammatory Subtype. So, peripheral blood cytokines and non IgE food allergy are proposed as possible bio markers that appear to effect behavior according to this study. This has to be effecting the brain too and suggests dealing with these elements in the periphery can be beneficial in this sub type. I am guessing this is a fairly large group in the ASD world. Cytokine profiles by peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype? "In summary, studies of purified PB Mo from ASD-IS children indicate that they have dysregulated innate immune responses. Specifically, these relate to the production of IL-1ß and IL-10, revealing significant changes in 'flare' versus 'non-flare' states. These responses, for the most part, were not observed in ASD/non-ASD controls. These results indicate that further analysis of the regulatory mechanisms of PB Mo in ASD-IS subjects may lead to the identification of biomarkers and even treatment options for ASD-IS subjects who typically do not respond well to the first-line therapeutic measures." Understanding why some of the immune genes are constantly turned on will be key it appears, but they did say that mutations are not the reason as I suspected they were not. This is a good read and seems on track. Again, etiology is a ways off in their pursuit it seems. Postmortem brains point to molecular signature of autism "The new study suggests that autism-linked mutations tend to strike genes involved in neurons' functions. By contrast, the activation of microglia-related genes appears to be unrelated to mutations." http://sfari.org/news-and-opinion/news/2014/postmortem-brains-point-to-molecular-signature-of-autism Have read this in the past, but it should be pinned somewhere. The Danger of Excessive Vaccination During Brain Development http://articles.mercola.com/sites/articles/archive/2008/03/14/the-danger-of-excessive-vaccination-during-brain-development.aspx This article may be controversial, but in my wife's case it is confirming information of her condition. It deals with autism and perception of self. Autism markers found in CMU study of brain activity "For example, thinking about the word "hug" evoked activity in the posterior midline region of the brain in "neurotypical" individuals — where activation is associated with the "self factor," or thoughts of oneself. The study investigated this verb and other similar verbs because in autism social interactions are believed to be experienced in an altered way. The new results now identify what the alteration is: People with autism think about social interactions without including thoughts of themselves." "The machine learning program was able to accurately classify people as having autism or not by assessing whether or not the self factor was activated during functional magnetic resonance imaging of their brains as they thought about the social-interaction verbs." https://www.post-gazette.com/news/health/2014/12/16/Autism-markers-found-in-Carnegie-Mellon-University-CMU-study-of-brain-activity/stories/201412160003 Years ago when first documenting my wife's condition I wrote this in a list of her physical and mental markers: "11. Lack of self, only reacting to others in a patterned way, she had no motives or feelings of her own and was often just operating at the prompting of others." "14. Avoidance of eye contact especially during serious conversation {this trait was something I noticed from the time we were married and probably not noticed by others in that it occurred in relation to my trying to get her to make decisions or give opinions concerning matters that revolved around self; i.e. why do you like or dislike this, that, or someone and why did you do this or that." "Over time, with hundreds of hours of counseling and my constantly teaching her about social interaction and logical thinking, she has developed a self. But this counseling /therapy would have been useless without dealing with the maze of biological problems she had and changing her diet." Many things were part of her recovery, but this self aspect is exactly in sync with what she was like. There are other foods and a few drugs mentioned in literature that ameliorate microglial inflammation, but apparently some drugs are untested or produce bad long term effects. Apparently there are systemic ways of tempering microglial activation as many have seen their children recover without any of these substances being used, only diet and other supplements. Dr. Datis Kharraaian; said that once the T Cells of the body get the immune cells of the brain going there is no shutting these brain immune cells -- glial cells off. Three was No known drug. He said though that certian types of foods would; Reveratorol, turmeric and luteolin I went to a concert a couple of years in a role when my kids were teenagers to see Michael Smith. He is wonderful. Posted by: Benedetta \| December 15, 2014 at 07:24 PM My sister sent me this song and I would like to share. https://www.youtube.com/watch?v=Vm2T8Xqbt6A Yes, I do remember the studies done about the stuff they got out of broccoli. Thanks for reminding me. That is a big push in nutrition right now . Another report on the "Inflammation" study: Researchers: 'Inflammation Is A Marker For Autism — Could Treating Inflammation Eliminate Symptoms?' "The idea that treating inflammation will mitigate the symptoms of autism is in no way novel. Vast numbers of parents of children with autism have claimed diets that treat inflammation have helped their children, though the idea has been ridiculed over the years. Now researchers are finally able to explain some of the complexities of autism-related inflammation, and are setting their sights on advanced scientific research into the possibility of treating autism symptoms by treating inflammation itself." http://www.inquisitr.com/1676403/researchers-inflammation-is-a-marker-for-autism-could-treating-inflammation-eliminate-symptoms/ "vast numbers of parents" --- uh huh. ROS and Brain Diseases: The Good, the Bad, and the Ugly "The key trigger to this neuroprotective cascade is the binding of Nrf2 to the antioxidant response elements (AREs) [140–142]. Therefore, exogenous Nrf2/ARE activators may represent powerful drugs to activate the antioxidant and defensive acting genes. The Nrf2/ARE pathway can be pharmacologically activated both by natural products such as sulforaphane [143, 144], polyphenols, epigallocatechin 3-gallate (EGCG), and curcumin [145] and synthetic drugs including triterpenoids and N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-trimethylphenoxy) acetamide, known as CPN-9 [146]." http://www.hindawi.com/journals/omcl/2013/963520/ This is likely known among readers here, but Sulforaphane Improves Autism Symptoms "What the authors concluded was that the activity of sulforaphane in terms of activating the Nrf2 pathway was likely the reason for its success. The Nrf2 gene pathway, when activated, dramatically reduces inflammation in the brain while increasing antioxidant protection. Sulforaphane is a powerful activator of Nrf2 and this is the reason we have included it in Nrf2 Advantage. Nrf2 Advantage has become one of my top nutritional supplements that we use in our clinic." http://www.drperlmutter.com/chemical-present-broccoli-vegetables-may-improve-autism-symptoms/ The immune system and the brain seem to have a feedback relationship. If Olmesartan does not directly activate NRF2{their is some evidence it does} than the control of other mediators{cytokines} may be ameliorate the inflammation in some. The report does not mention what drug depleted the microglia or if it would be safe use in humans. You may have gathered that I believe Olmesartan does something to curb the brain inflammation, but I don't know. I only know what I have seen and that is not enough to translate it to others though I would love to see this drug tried for a few months as it is generally safe. Thanks Visitor for bringing this research to our attention. Wonder what kind of drug it was? I wonder if it is some kind of psych drug that we are using already. Long term use shrinks the brains. There is a lot of talk about anti - inflammatory food right now. They said there was no drug known to stop inflammation of the brain - just certain types of foods. Maybe no safe drugs??? The actual study is does not say what the reports on it say exactly. It only says it is possible the downstream mechanisms may be altered. I guess that means it does not actually say the inflammation is definitely caused by these common upstream genes or mutations. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism "Despite the extreme genetic heterogeneity observed in autism, it is possible that common downstream mechanisms may be altered10. Thus, there has been an effort to use transcriptomics to identify and dissect molecular pathways that may be altered in autism spectrum disorder (ASD)." http://www.nature.com/ncomms/2014/141210/ncomms6748/full/ncomms6748.html Posted this ealier,but this relates to the latest on microglia and behavior.{mice} The next hot topic in autism research? Immune cells "To test more directly whether microglia are involved in social behavior, Kipnis' team looked at a different kind of mice — an inbred model called BTBR that is known to be asocial. After four weeks of consuming a drug that depletes microglia, the animals' social behaviors improved. As soon as they stopped taking the drug, the microglia repopulated and the social deficits returned. This suggests that microglia are somehow involved in the animals' social deficits, although exactly how is as yet unclear." http://sfari.org/news-and-opinion/conference-news/2014/society-for-neuroscience-2014/the-next-hot-topic-in-autism-research-immune-cells I another report on the new "brain inflammation" report it says: "There are many different ways of getting autism, but we found that they all have the same downstream effect," says Prof. Dan Arking regarding his research team's finding that brains affected by autism share a pattern of inflammation as a result of increased immune responses." All these ways of getting autism lead to this "pattern of inflammation as a result of increased immune responses"? Also, this is supposedly caused by an "upstream mutation related to all these ways of "getting autism"? Something doesn't fit. Maybe a more common trigger is causing this constant gene expression and immune response. Concerning the last post quote I doubt this part{quote below} is true, at least a mutation causing this without environmental factors. ""This is a downstream consequence of upstream gene mutation." Yes, that is the one I listened to. Thanks for finding the study Nick. Hope you had a good Thanksgiving. Posted by: Benedetta \| November 27, 2014 at 10:03 PM I watched this by Dr Datis Kharrazian: https://www.youtube.com/watch?v=Am7kr-vP0Ys It was quite interesting and makes sense. Some ideas, like gluten and molecular mimicry, I have long known about. I saw the part about the 3 "foods" that can shut down glial cells. It could that they are the only things that will work for now, and luteolin is what Dr. Theoharides has suggested as a substance to use in some autism cases. Have been studying the effect of ARB's on glial cell activation. They might be able to arrest some aspects of activation. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications. "Direct blockade of AT1 receptors in target cells within the brain parenchyma also play a major role. Neuronal AT1 receptors are selectively localized in many brain areas located inside the blood-brain barrier (Jöhren and Saavedra, 1996; Mendelsohn et al., 1984). AT1 receptors have been clearly identified, within the brain and spinal cord parenchyma, not only in neurons but also in astrocytes and resident microglia (Pavel et al., 2008; Imboden et al., 2009; Tang et al., 2009; Lanz et al., 2010; Wosik et al., 2007). Enhanced AT1 expression in brain neurons has been described, both in vivo and in vitro, in rodent models of genetic hypertension (Saavedra et al., 1986; Yang and Raizada, 1998). More recently, enhanced AT1 receptor expression has been reported in brain lesions of patients suffering from multiple sclerosis (Platten et al., 2009). A complete RAS has been described in cultured microglia, and ARBs reduce LPS-induced inflammation in these cells (Miyoshi et al., 2008). Since ARBs have been shown to cross the blood-brain barrier and to inhibit neuronal AT1 receptors not accessible to circulating Angiotensin II (Nishimura et al., 2000a), it is likely that inhibition of AT1 receptors located in neurons, microglia and astrocytes play a significant role in the anti-inflammatory effects of ARBs."... "Brain Angiotensin II, through AT1 receptor stimulation, is a master regulator of the cerebral circulation and of the central response to stress and inflammation. Excessive AT1 receptor stimulation contributes to determine the extent of allostatic load. Inhibition of brain AT1 receptor activity may be achieved with the use of orally administered ARBs, of tested efficacy in the treatment of cardiovascular disease and a good margin of safety. ARB treatment is neuroprotective: reduces brain ischemia, stress-related disorders and brain inflammation, and increases the lifespan. Preclinical data in rodent models has translational value, as indicated by increasing evidence of beneficial effects of ARBs in brain disorders, such as recent reports of significant decrease in stroke, protection of cognition, and amelioration of Alzheimer's disease, depression and stress. The anti-ischemic, anti-stress and anti-inflammatory effects of ARBs indicate that these compounds may be considered as contributors to the therapy of a wide range of conditions, including mood disorders and neurodegenerative diseases of the brain. It is hoped that in the near future ARBs will be tested, in controlled and carefully designed clinical trials, for the therapy of neurological and psychiatric disorders." There are multiple ways to activate glial cells and what works in attenuating them is complex and I am still trying to understand this system. It appears that Pardo himself was involved in trialing minocycline for 6 months in some with Autism. The outcome does not really address whether neuroinflammation is a problem, but rather the failure of minocycline to reduce the markers of neuroinflammation. Some neurotrophic growth factors were modulated. As a far as cytokines and chemokines the snippet below illuminates the lack of effect. I guess they thought minocycline was safe, how about trying something else? that actually effects the immune mediators? A pilot open-label trial of minocycline in patients with autism and regressive features Cytokines and Chemokine profiles 'There were no significant changes in the quantitative assessment of cytokines and chemokines in both serum and CSF as measured by multiplexed microbead array technology (Luminex™). Expression of chemokines, such as CCL2 (MCP-1) or cytokines such as TNF-α, CD40L, IL-6, IFN-γ and IL-1β, well recognized immune mediators implicated in inflammatory mechanisms, were not affected in serum or CSF when pre- and post-treatment levels of these proteins were compared (Table 3). Only the chemokine CXCL8 (IL-8) in serum was significantly reduced after treatment (P = 0.047) (Figure 1A); seven of ten patients had reduction in the serum level of CXCL8 (IL-8)"... "The trial revealed no significant effects of minocycline on the profile of immune mediators implicated in inflammatory mechanisms in either the serum or CSF of treated children with the exception of a reduction in the levels of CXCL8 (IL-8), a chemokine that appears to have neuroprotective effects [41] and regulates the release of MMPs [42]." http://www.jneurodevdisorders.com/content/5/1/9 If you happen to read this, what is trans-indolylacrylglycine. Is is a bacterial{closridial} metabolite of tryptophan? The BBB and gut barrier function are still poorly studied it seems. The cytokines Il-6 and Il-1b can cross the BBB in any event. These cytokines and other immune components are correlated in enough studies to merit a lot of attention. I may get around to listening to those "digestive sessions" too. Thanks for the thoughts. p.s. Neuroinflammation still lingers as a central player. Pardo with John Hopkins history has tempered focus on microglia in his latest release on the subject, but I think that is simply to dissuade any experimental "treatments" targeting them. I tend to think that is wise at this point of understanding. Nick; I spent a few days listening to the digestive session u tubes hosted by Sean from Underground Wellness. Sean has a lot of things on health and calls in all kinds of experts to interview them. . One expert he interviewed was Dr. Datis Kharrazian. He was saying something like you the study that you just last posted. Zonnulin opens up the gut and it also opens up the blood brain barrier too. He says if the outside world turns on the zonnulin and opens up the gut it opens up the blood brain barrier too. TO close the gut is to close the BBB. As far back as 30 years ago they were saying if a baby had colic that, that baby had a good chance of having a bad reaction to a vaccine. Ones that Mother's noticed. I bet this is the study that he got his information from. They also talk about the Vegus nerver a lot, and how messages are sent from the stomach to the brain. That is no surprise to me though since in 2000, my son and I traveled one cold snowy night 2 hours away to hear about vegus nerve stimulation. They implant an instrument close to the nerve and when an epileptic feels a seizure coming on they push a button some where and it gives the vegaus nerve a little shock. He said that once the brain's immune system it turned on -it is not turned off easily. There are foods that will do this resveratrol, turmeric and luteolin. Of course Dr. Wakefeild has had to live through terrible frustration of all of them smirking low lifes saying the gut is not attached to the brain -- and Dr. Wakefleld pointing out that beer that goes to the gut effects the brain. This is in mice...but interesting. If the BBB is not as strong in those that might be affected then environmental triggers, gut microbiome metabolites, and immune/allergic responses may interact in brain function and development. {selective qutoes from} Mother's Microbes Protect Baby's Brain "It's also known, he said, "that [gut] microbes could modulate brain function and development." Pettersson and his colleagues therefore wondered whether the effect of gut microbes on the brain might be manifested in part by control of the BBB." This increased barrier permeability was associated with low expression and disorganization of tight junction proteins and was shown by additional methods to persist into adult life. That is, pups that were born to germ-free mothers and that remained germ-free throughout life had leakier BBBs as adults. "The interesting thing here is that it is [controlled by] the mother's microbiome," said John Cryan, chair of anatomy and neuroscience at University College Cork in Ireland. "We largely think of the influence of the microbiome as having a postnatal effect, but here they show clearly that even before the animals get exposed to microbes, the fact that their mothers are germ-free is already impacting on their development," he said. "In the adult mice, transplantation of fecal matter from animals with normal microbiomes into the germ-free animals, not only corrected the expression of BBB tight junction proteins but reduced barrier permeability, the team showed. A similar effect was obtained by giving the germ-free mice bacteria-derived short chain fatty acids, suggesting that the production of metabolites may be part of the mechanism by which the bacteria control barrier integrity." Although the precise mechanisms remain to be determined, said Cryan, "we know that the microbiota is critical for the developing brain and now we know it is also critical for the blood-brain barrier." "Therefore," he added, "anything that threatens the microbiota homeostasis could potentially threaten the integrity of the blood-brain barrier." "Indeed, "anything that happens to the mother during pregnancy that can have a negative effect on her intestinal bacteria could adversely affect the development of the fetal brain," speculated Stephen Collins, director of the Farncombe Family Digestive Health Research Institute at McMaster University in Ontario. "For example, antibiotic usage during pregnancy theoretically—if these results can be extrapolated to humans—could actually have some impact on brain development." http://www.the-scientist.com/?articles.view/articleNo/41476/title/Mother-s-Microbes-Protect-Baby-s-Brain/ If the 80% detection rate is accurate and the bio-markers mentioned are actually involved{they are in my view in many cases} then this is in part a verification of biomedical approaches.{diet, gluten, carnitine} Company hopes test will revolutionize autism diagnosis, treatment "If we can understand which biomarkers signal a child who's not able to process those things well, then we might be able to suggest that may be the first line of defense," Donley said. Defenses that are similar to doctors discovering high blood sugar in someone with diabetes and changing their diet or adding insulin. This autism blood test is looking for problems like a carnitine deficiency, which helps break down fat, or negative gluten reactions. "And if we can change diet we should see an improvement both in those antibodies and the behavior that's associated with autism," Donley said." http://www.channel3000.com/health/Company-hopes-test-will-revolutionize-autism-diagnosis-treatment/29787960 Jerry says he is not on the spectrum...surprise. Cesarean birth alters immune system, social behavior in mice "Babies born vaginally are thought to receive two crucial exposures in the birth canal: microbes and extreme stress. Researchers suspect that this journey helps prime the infants' immune systems and stress responses for the rest of their lives..." "They found that compared with this control group, the C-section mice show several symptoms reminiscent of autism, including repetitive behavior, anxiety and mild social deficits..." "Cells from the spleen of these mice produce excess levels of pro-inflammatory cytokines — signaling molecules of the immune system — such interleukin 1 beta, TNF-alpha and IL-6. Cytokines, including IL-6 in particular, have been linked to autism-like features in mouse models of autism and in people with the disorder..." "The researchers don't know why or how C-sections lead to changes in behavior. One hypothesis, the so-called 'leaky gut' theory, suggests that because of an altered immune system, microbes and other molecules in the gut somehow seep into the peripheral circulation and eventually reach the brain, altering behavior..." "As with many studies linking the gut, immune system and brain, many parts of the story are not yet worked out. All three systems feed back on one another across development, making it difficult to tease out cause and effect. "They don't have the mechanism — that's what's missing," Foster says." http://sfari.org/news-and-opinion/conference-news/2014/society-for-neuroscience-2014/cesarean-birth-alters-immune-system-social-behavior-in-mice Clearly this is not about c-sections causing Autism, but microbes and altered immune systems being clues to developmental issues. Interesting, it is intuitive to think about the effects of adjuvants long term on the immune system too. Microglia are discussed..worth a read. "The next hot topic in autism research? Immune cells" "The link between the brain and the immune system is in fact somewhat intuitive: "When you get sick, you don't feel well," says Anthony Filiano, a postdoctoral fellow in Kipnis' lab who presented the new findings. "But the fact that the immune system can contribute to normal brain function is fairly new. And it's really neat because the immune system is a lot easier to treat than synapses in the brain." You are welcome Donna and Jenny. Thank you Visitor for the information. I am very interested in tryptophan metabolism in ASD since one of the initial urine labs performed for my child revealed a high result for tIAG trans-indolylacrylglycine. The lab was also looking for any opioid peptide metabolites, which in my child's case was negligible. Another urinalysis at the time identified high microbial metabolites from clostridia. My child suffered a significant regression with significant GI issues as a toddler and I am always interested in any new research that investigates this particular aspect. Posted by: Donna \| November 12, 2014 at 05:31 PM Metabolomics as a Tool for Discovery of Biomarkers of Autism Spectrum Disorder in the Blood Plasma of Children "Previous metabolic studies of ASD have used biological matrices such as cells, organelles, urine and blood, and have implicated a wide range of metabolites including fatty acids, sterols, intermediary metabolites, phospholipids, and molecules associated with oxidative stress [12]–[16]. Two recent reports highlight the potential use of metabolomic analysis of urine to identify signatures of ASD. One study used 1H-NMR methods and showed changes in metabolites associated with the tryptophan/nicotinic acid metabolic pathway, sulphur and amino acid pathways, as well as microbial metabolites implicating the involvement of microbial metabolism in the etiology of ASD [16]. Ming et al. used a combination of liquid- and gas-chromatography based mass spectrometry methods to identify changes in a number of amino acids and antioxidants such as carnosine, as well as confirming the changes associated with altered gut microbiomes. "This potential connection between the gut microbiome and ASD is also receiving considerable attention [55]. Metabolomic studies of urine from individuals with ASD have identified molecules associated with the microbiome such as dimethylamine, hippuric acid and phenylacetylglutamine [16], [17]. We observed decreased plasma levels of p-hydroxyphenyllactate, a metabolite associated with bifidobacteria and lactobacilli that is known to serve as an antioxidant both in the circulation and tissues [56]. We have yet to identify other microbiome related metabolites." "Metabolomics determines changes in small molecule metabolites that are reactants and products of endogenous biochemical processes as well as small molecules derived from diet, the gut microbiome and contact with the environment. Perturbations in their abundance can result not only from genomic and proteomic influences, but from environmental and epigenetic influences as well." Interesting - thanks for posting, visitor Posted by: Jenny \| November 04, 2014 at 08:41 PM Neuroprotective Effects of Angiotensin Receptor Blockers. Century-old drug reverses signs of autism in mice http://news.sciencemag.org/biology/2014/06/century-old-drug-reverses-signs-autism-mice The article has a link to the researcher's {Robert K. Naviaux} original theory, one I linked to in this thread last year. I am waiting for conclusive proof that living pathogens are causing, contributing to, or perpetuating a number of conditions, or part of these conditions per Marshall, but this theory fits the picture and the cell danger scenario with inflammation. Here is the link from within the article. p.s. Yes, they are mice, not people. Metabolic features of the cell danger response That study I linked was from a population in Finland with higher CRP. It was Finland that was having increasing rates of Type 1 Diabetes. The idea this was a true increase was something Dr. Noel Rose mentioned in his talk on autoimmune conditions linked in this thread elsewhere. In the gut bug thread I mentioned that vaccines could be opening the door for organisms to become pathogenic for the host due to the deregulation of the immune system. Finland is one population and CRP increases may be widespread, but many of the organisms are not easily cultured or known. Time will tell, but the microbiome shift as immune systems are altered alters the whole person in many cases{disease in many cases}. Age of Autism put an article up on this website of a rsearch paper -- were the researchers said they found that when a woman had the flu while pregnant that she had a better chance of having a baby with autism. What they found -- it was not a virus or bacteria -- or any certian pathogen but rather the Mother's own immune system reaction that was causing her baby to be more prone to autism. In the last meeting at the IACC at the very end -- Lyn Redwood brought up this research paper -and told them that if it was an immune reaction rather than the pathogen itself perhaps flu shots for pregnant women was not a good ides- but their eyes became shifty and they just set there like knots on the log. Since I had taken a break the following article and study have likely been seen here at AoA and I am not aware of it, but inflammation is in view here and it points out a study relating C-reactive protein and possible linkage to Autism. That was discussed a good bit at the very first part of this thread. Inflammation and the Origin of Autism http://www.healthline.com/health-news/connection-between-inflammation-and-autism-052214 Elevated maternal C-reactive protein and autism in a national birth cohort A S Brown, A Sourander, S Hinkka-Yli-Salomäki, I W McKeague, J Sundvall and H-M Surcel "Autism is a complex neuropsychiatric syndrome with a largely unknown etiology. Inflammation during pregnancy may represent a common pathway by which infections and other insults increase risk for the disorder. Hence, we investigated the association between early gestational C-reactive protein (CRP), an established inflammatory biomarker, prospectively assayed in maternal sera, and childhood autism in a large national birth cohort with an extensive serum biobank. Other strengths of the cohort included nearly complete ascertainment of pregnancies in Finland (N=1.2 million) over the study period and national psychiatric registries consisting of virtually all treated autism cases in the population. Increasing maternal CRP levels, classified as a continuous variable, were significantly associated with autism in offspring. For maternal CRP levels in the highest quintile, compared with the lowest quintile, there was a significant, 43% elevated risk. This finding suggests that maternal inflammation may have a significant role in autism, with possible implications for identifying preventive strategies and pathogenic mechanisms in autism and other neurodevelopmental disorders." http://www.nature.com/mp/journal/v19/n2/full/mp2012197a.html Edit last post: Compare that with the inflammation/disease ideas in the Discovery Journal paper, like this quote: {actual quote from that paper not correct in last post} "Since the immune system strives to target the persistent microbes but never fully succeeds, a stalemate results, a low grade inflammation accumulates." {pardon me} Inflammation may help explain depression, diabetes link "Death rates are up to twice as high among people with depression and diabetes as those with diabetes alone, Ismail said. "The conventional wisdom is that this is a consequence of the psychological burden of having diabetes," she said. "If that's the case, if you treat the depression, the diabetes control should improve." But it does not, Ismail said. So she began to wonder if inflammation, often seen in people with diabetes, could help explain both conditions and the worse outcomes. "It's a bit like an engine," Ismail said. "You're running a bit higher. So there's this constant low-grade inflammation and that's causing damage to your brain, your pancreas and to your vascular system."" http://www.reuters.com/article/2014/06/06/us-diabetes-depression-idUSKBN0EH1P720140606 "So there's this constant low-grade inflammation and that's causing damage to your brain, your pancreas and to your vascular system." The last link on Inflammation and the microbiome has a interesting background. Dr. Noel Rose of John Hopkins apparently invited this papers submission. Here is what Trevor Marshall said: A couple of months ago we received an invitation from Noel Rose (head of Autoimmunology at Johns Hopkins) to write a paper for Discovery Medicine, a journal affiliated with Johns Hopkins. We did, and it has just been published: http://www.discoverymedicine.com/Amy-D-Proal/2014/05/22/inflammatory-disease-and-the-human-microbiome/ ..Trevor.. « Older \| Newer » Benedetta on On Sanctity of Human Life Sunday Let's Make Vaccines Part of the Conversation? Magpie on Autism and Housing Dangerous Logic an Article by Amy Lutz in Psychology Today michael on Autism and Housing Dangerous Logic an Article by Amy Lutz in Psychology Today
Covid Watch: Your Covid Vaccination Questions Answered (2) – Vaccination Basics 9th January 2021 11th January 2021 These questions are answered by Dr Catherine Beanland, Portcullis Surgery; Dr Caron Morton, Station Drive Surgery; Rachel Robinson, Director of Public Health for Shropshire. If we are given the first dose with one vaccine and the second with the other, how might this alter the effectiveness of vaccination? Why is the second dose being delayed and do we have to have it? Why are individuals not first screened for pre-existing immunity with an antibody test before being offered the vaccine? Should people who have had Covid-19 still have a vaccination? Must I have a vaccination if it is offered, especially if everyone else I know is vaccinated? What are the risks or restrictions for people who have significant allergies or a fever? I have an autoimmune condition. I am taking immunosuppressants. Can I still be vaccinated? What are the side effects of vaccination? This article is the second in a series. Andy Boddington and Tracey Huffer, Shropshire Councillors for Ludlow North and East Q5. If we are given the first dose with one vaccine and the second with the other, how might this alter the effectiveness of vaccination? The preferred option is that people have the same vaccine for both doses. Due to supply constraints this may not always be possible. The Pfizer and Oxford vaccines both result in a specific part of the virus (known as the spike protein) being recognised by your immune system, triggering antibodies and developing immunity. Further research into this is already underway but you are still likely to produce a good immune response even if the second dose of vaccine is different from the first. Q6. Why is the second dose being delayed and do we have to have it? Like all viruses, the coronavirus will not disappear although, in time, populations will become more immune to it. The imperative is to get as many people vaccinated as possible. A single dose offers a high level of immunity though not as high as two doses. Covid-19 is a highly transmissible disease and the priority is to give as many people as much immunity we can as quickly as we can. The second dose is essential to ensure that we achieve maximum immunity as quickly as possible. We know that a high proportion of patients develop adequate immunity after the first dose, some develop a moderate immunity and a small proportion a low immunity. The second dose acts as a booster for those with good immunity and ensures the two other smaller groups have suitable immunity. The current advice is that a second vaccination should be administered approximately 12 weeks after the first jab. Q7. Why are individuals not first screened for pre-existing immunity with an antibody test before being offered the vaccine? Should people who have had Covid-19 still have a vaccination? The benefits of having the vaccine outweigh the need to screen. Not all tests give the correct result and we do not yet know for how long the vaccines will give immunity. The additional resources that would be required for mass screening would detract from the pressing need for vaccination. Covid-19 vaccination will be offered to you regardless of whether you have already had a Covid-19 infection. The trials of the vaccines have not revealed any safety issues with people who have had Covid-19 receiving the vaccine. Q8. Must I have a vaccination if it is offered, especially if everyone else I know is vaccinated? Vaccination is not compulsory. Vaccination protects both you and those around you, reducing the spread of the virus. When enough people are vaccinated it will create 'herd immunity' protecting those people who cannot get vaccinated, for example because they are too young or have a health condition. By remaining unvaccinated, you increase the possibility of contacting Covid-19, getting sick yourself, perhaps seriously so and spreading it to others. That will increase the pressure on health services. Q9. What are the risks or restrictions for people who have significant allergies or a fever? Anyone who has had a severe allergic reaction which has required hospitalisation or has had to use adrenalin to counter an allergic reaction should discuss having the vaccine with their GP or pharmacist before attending their vaccination appointment. Those with penicillin allergies can have the vaccine. A mild fever or infection, such as a cold, are not reasons to delay vaccination. Ring 111 if your temperature is 37.8°C or greater and do not leave your home. Q10. I have an autoimmune condition. I am taking immunosuppressants. Can I still be vaccinated? Neither vaccine is a live vaccine. This makes it safe for patients who are immunocompromised, including those on high dose steroids, disease modifying and biologic therapies such as methotrexate and rituximab, anyone with haematological malignancy, anyone undergoing chemotherapy or radiotherapy and transplant recipients. There is a possibility that the vaccine may not stimulate as strong an antibody response in immunosuppressed people but this is expected to still be better than not having been vaccinated. National guidance specifically identifies immunosuppressed people as a priority clinical risk group that should receive the immunisation. Q11. What are the side effects of vaccination? Some people will suffer side effects as the vaccine prepares the body to fight the disease. A sore arm and a light fever are common and some people may have flu-like symptoms. Fatigue and headaches are also known side effects. In a small number of people, these side effects may interfere with daily activities. These side effects only last for 48 hours at the most. Should they last longer, contact 111 for advice. Serious side effects are extremely rare. Local experience with the Pfizer vaccine suggests side effects are minor and mostly limited to a sore arm and light fever. coronavirusCovidQ&A Covid Watch: Your Covid Vaccination Questions Answered (1) –The Virus and the Vaccines Covid Watch: Your Covid Vaccination Questions Answered (3) – Vaccination Delivery Covid Watch: Your questions on vaccination answered – print edition Covid Watch: Your Covid Vaccination Questions Answered – Introduction and Index 2 thoughts on "Covid Watch: Your Covid Vaccination Questions Answered (2) – Vaccination Basics" andybodders says: 10th January 2021 at 10:42 am This article gives a useful briefing on the advantages and consequenses of delaying the second vaccine dose. https://theconversation.com/delaying-the-second-covid-vaccine-dose-a-medical-expert-answers-key-questions-152771 Heather Aston says: Many thanks to you & the panel. Of my personal contacts only two octogenarians, living in the community in Ludlow, ie not a care home, have received two doses of the COVID vaccine. They are both registered with a practice in Herefordshire. Have any of our residents in the Ludlow community, above 70 years of age received their 1st vaccine? And when will it be available? Please complete the Captcha *
Identification of Managerial Competencies in Knowledge-based Organizations Original Title: Identification of Managerial Competencies in K-Based Organizations Uploaded by Alexandru Ionuţ Pohonţu Description: zzz saveSave Identification of Managerial Competencies in K-Bas... For Later Files 2-Lectures Chapter 1 employee performance at super asia Plastic Money PPT Slides - Chap1 Cds Session 1 Bio Medical Waste competency reflections hrd_ch_4 lo3pct julien 3 9 Bio Medical Waste Management & Hygiene in Healthcare Environment zavala emma competencyreflections GOVERNMENT AND PRIVATE SECONDARY SCHOOL TEACHERS IN DISTRICT SRINAGAR, KASHMIR Principles of Management Slides bio-medical waste Management Orientation Lecture HR_Effectiveness.pps Management in a Dynamic Environment A Bit Explaination Mgt Knigov Martina, Urbancov Hana, Fejfar Ji Managerial competencies identification and development are important tools of human resources management that is aimed at achieving strategic organizational goals. Due to current dynamic development and changes, more and more attention is being paid to the personality of managers and their competencies, since they are viewed as important sources of achieving a competitive advantage. The objective of this article is to identify managerial competencies in the process of filling vacant working positions in knowledge-based organizations in the Czech Republic. The objective was determined with reference to the Czech Science Foundation GACR research project which focuses on the identification of managerial competencies in knowledge-based organizations in the Czech Republic. This identification within the frame of the research project is primarily designed and subsequently realised on the basis of content analysis of media communications such as advertisements - a means through which knowledge-based organizations search for suitable candidates for vacant managerial positions. The first part of the article deals with theoretical approaches to knowledge-based organizations and issues on competencies. The second part evaluates the outcomes of the survey carried out, and also summarizes the basic steps of the application of competencies. The final part summarizes the benefits and difficulties of applying the competency-based approach as a tool of efficient management of organizations for the purpose of achieving a competitive advantage. Key words: Manager, competencies, managerial competencies, knowledge-based organizations, human resource management, competitive advantage At present, knowledge management presents management based on knowledge applied by knowledge-based organizations. Globalization makes distances shorter and triggers the need for global thinking. Technologies and financial capital are moving into the background and need to be used in compliance with knowledge. Non-tangible assets and the ability to use them in practice are crucial for organizations. Knowledge in knowledge-based organizations is held by people, and therefore attention has to be paid to the identification and development of their competencies. Managerial competencies identification and its development are important tools of human resources management targeted at achieving the strategic goals of the organization. Managerial competencies, i. e. behaviour necessary to reach the required level of a managers performance, in combination with efficient organization management thus become a key factor of success and subsequently also a competitive advantage. Journal of Competitiveness Vol. 4, Issue 1, pp. 129-142, March 2012 ISSN 1804-171X (Print), ISSN 1804-1728 (On-line), DOI: 10.7441/joc.2012.01.10 2. THEORETICAL SOLUTIONS 2.1 Knowledge-Based Organizations Knowledge-based organizations (Perez-Bustamante, 1999) are organizations applying a knowledge-based approach to the organization. This approach perceives organizations as a means for the development, integration, preservation, sharing and application of knowledge. In literature we can also come across the following terms: the knowledge creating company (Nonaka & Takeuchi, 1995), the knowledge organization, the organization of knowledge, the knowing organization (Choo, 1998). According to Calabrese (2006), the twenty-first century has surfaced the need for more flexible and responsive knowledge-based organizations capable of rapidly adjusting to the increasing rate of change and demands in both products and services. Wu, Ong, and Hsu (2008) add that knowledge-based organizations allocate resources to intangible assets in the rapidly changing and highly competitive business environment in order to gain competitive advantages. Based on the analysis of secondary data sources (Nonaka & Takeuchi, 1995; Choo, 1998; Truneek, 2003; Bartk, 2006; Calabrese, 2006; Bure, 2007; Medzihorsk & Medzihorsk, 2007; Sldeek, 2007; Wu et al., 2008) by means of the method of comparison, the following general characteristics of knowledge-based organization were identified (see Tab. 1). Tab. 1 General characteristics of a knowledge-based organization. Source: Authors elaboration. Knowledge-Based Organization Creates, integrates, preserves, shares and applies knowledge; is efficient, innovative, flexible and proactive; is customer focused; uses ITs; has a strong and open corporate culture; implements knowledge processes; exploits knowledge resources; manages risks; implements project management; places emphasis on education and organizational learning; disposes of knowledge employees; is process-oriented; supports teamwork; encourages participation in management. Hess and Bacigalupo (2010) add that knowledge-based organizations may benefit from the utilization of behaviours most often attributed to emotional intelligence, and emotional intelligence may be redefined as a process rather than an outcome for organizational development. Given the presence and complexities of internal and external influences, the manager is often faced with the prospect of reacting to constant changes in the internal and external environ130 Journal of Competitiveness ment. In order to be effective in that regard the manager must possess the characteristics most often associated with the description of emotional intelligence: self-awareness, self-regulation, motivation, empathy and social skill. Additionally, the manager must be effective at spreading these same characteristics throughout the knowledge organization, since having these skills concentrated in a single individual within the organization is not optimal. Therefore, how to identify managerial competencies has become one of most important issues. In compliance with the resource-based approach to achieve a competitive advantage, i. e. perceiving an organization as a unique set of resources and competencies based on which a strategy for the best possible use of opportunities is defined, it is necessary for organizations to identify, evaluate and develop key managerial competencies in order to achieve a competitive advantage. On the other hand, organizations have to dispose of knowledge permitting them to identify these managerial competencies. Identified managerial competencies, just like knowledge, become valuable sources for achieving a competitive advantage. 2.2 Competency-Based Approach Competency is a commonly used term for peoples asserting of their working potential in real activities. At present, there are many definitions of this term. In principle, there are two main meanings on which individual definitions of competencies are generally based. The first characterises competencies as a power and a scope of authority associated with a certain person or body. The second meaning of competencies refers to the capacity, i.e. abilities to perform a certain activity, to have certain general and specific characteristics and skills, to be qualified in the given area. Generally it can be said that it is a set of specific knowledge, abilities, skills, traits, motives, attitudes and values essential for the personal development and successful participation of each person in an organization. That in fact means behaviour necessary for achieving the required level of performance. This refers to the performance aspect of a competency determined by the level of inputs (knowledge, abilities, skills, traits, motives, attitudes and values) and measured by the analysis of outputs (real behaviour and results). According to its development, it is possible to divide competencies into three main development phases. The first phase consists of individual competencies (White, 1959; McClelland, 1973; Boyatzis, 1982; Schroder, 1989; Woodruffe, 1992; Spencer & Spencer, 1993; Carroll & McCrackin, 1997). The second phase is based on the possibility of managing competencies in an organization by means of competency models (Mansfield, 1996; McLagan, 1997; Lucia & Lepsinger, 1999; Rothwell & Lindholm, 1999). The third phase is the identification of core competencies, a sum of organization key organizational competencies that may be exploited to gain competitive advantage (Prahalad & Hamel, 1990; Ulrich & Lake, 1991; Gallon, Stillman, & Coates, 1995; Coyne, Hall, & Clifford, 1997; Rothwell & Lindholm, 1999; Delamare & Wintertone, 2005). The survey concentrated on the managerial competencies. Managerial competencies are a specific type of individual competencies. Based on a survey, Boyatzis (1982) defined competencies as a human ability to behave in a way to meet job requirements in parameters given by the organizations environment and thus to achieve the required results. In his work he defined threshold competencies as competencies crucial for managerial work, however, not having any significant causal relationship to its efficiency and better results. Managerial competencies are activities, knowledge, skills or attitudes and perhaps also personal characteristics necessary to improve management performance. Schroder (1989) uses a similar classification of competencies and distinguishes between basic competencies and high performance competencies. Basic competencies are defined as knowledge and skills essential for the performance of a managers job. They relate to specific tasks and guarantee managers personal efficiency. High performance competencies are relatively stable manifestations of behaviour thanks to which the entire teams led by the manager accomplish excellent above standard results. High performance competencies are further subdivided into cognitive, motivational, directional and performance competencies. According to Spencer and Spencer (1993), managerial competencies are a specialized subset of the competencies, expressing the intention to have certain specific effects. These specific intentions are particularly important for managers. Hogg (1993) adds that managerial competencies lead to the demonstration of skills and abilities, which result in effective performance within an occupational area. According to Boyatzis (2008), research published over the last 30 years or so shows that outstanding managers appear to require the threshold clusters of competencies (expertise and experience, knowledge, an assortment of basic cognitive competencies) and the clusters of competencies differentiating outstanding from average performers (cognitive competencies, emotional intelligence competencies, social intelligence competencies). Additionally, the literature also identifies other components of managerial competencies which also contribute significantly to career success (Tate, 1995; Carroll & McCrackin, 1997; Woodall & Winstanley, 1998; Lucia & Lepsinger, 1999; Winterton & Winterton, 1999; Birdir & Pearson, 2000; Sanghi, 2007; Horng, Hsu, Liu, Lin & Tsai, 2011). Managerial competencies that are required for normal and superior performance determine managerial competency models. These performance-based competencies are assessed through observed behaviours (Chong 2011). 3. OBJECTIVES AND METHODOLOGY The objective of the article is to identify managerial competencies in the process of filling vacant working positions in knowledge-based organizations in the Czech Republic. The objective has been determined with reference to the Czech Science Foundation GACR research project focusing on the identification of managerial competencies in knowledge-based organizations in the Czech Republic. This identification within the frame of the research project is primarily designed and subsequently realised on the basis of content analysis of media communications such as advertisements, by means of which knowledge-based organizations search for suitable candidates for vacant managerial positions. Its aim is to identify which managerial competencies are required in Czech advertisements for new positions, verify these competencies through semi-structured interviews with selected managers and compare them with managerial competencies specified in technical literature and other surveys. The article is organized as follows. The first part of the article deals with theoretical approaches to knowledge-based organizations and competencies issues. The second part evaluates the outcomes of the survey carried out, and also summarizes the basic steps of competence application. The final part summarizes the benefits and difficulties of applying the competencybased approach as a tool of efficient management of organizations for the purpose of achieving a competitive advantage. 132 Journal of Competitiveness The article has been produced on the basis of the analysis of secondary sources of data, in particular research studies focusing on the competency-based approach. Primary data is derived from the survey carried out that was focused on the identification of managerial competencies in knowledge-based organizations. The conception of the survey was based on theoretical input on the importance and utilization of competencies for an organizations management and development. The survey was primarily formed by a quantitative content analysis of media communications through which knowledge-based organizations in the Czech Republic search for suitable candidates to fill vacant managerial positions. The approach of organizations to managerial competencies was further examined by means of semi-structured interviews with 14 managers, the aim of which was to gain a deeper insight into the issue. The questions for semi-structured interviews were determined, ordered and formulated, but respondents were given relative freedom with responses. Each interview took from 30 to 45 minutes. Selected respondents were in middle and top management positions and during the first contact confirmed that their organizations satisfied the characteristics of a knowledge-based organization. As soon as it was determined that no new information on the subject examined was provided and that the data obtained started to repeat, interviews were interrupted. 4.1 Evaluation of the Survey The identification of managerial competencies in the process of filling vacant positions in knowledge-based organizations in the Czech Republic represents one of the phases of the research which is realised within the frame of the Czech Science Foundation GACR research project. This identification was carried out by means of content analysis of media communications. For the purposes of the survey, an advertisement was defined as a short text message published in the press or on the Internet. The survey covered selected advertisements through which knowledge-based organizations search for suitable candidates to fill vacant managerial positions during the monitored period. The basic set consisted of all knowledge-based organizations in the Czech Republic. The selection set consisted of knowledge-based organizations chosen for the survey. The main methodological requirement was that the selection set was a representative sample of the basic set. According to Pavlica (2000), this can be a problem that is not always easy to solve. The aim is to ensure that the sample set is as close to the basic set as possible in all characteristics examined. To create the selection set, the method of intentional choice was applied in which the researcher is led by his/her experience, intuition, conception and sometimes also his/her possibilities. The sample set is built of individuals that the researcher considers suitable for the survey (Pavlica, 2000). Due to the fact that technical literature does not define any methodology that would specify the process of selection of knowledge-based organizations, it was necessary to establish selection criteria. The proposed selection criteria were determined based on the identified characteristics of knowledge-based organizations. The main criterion for the purpose of the survey was that organizations had to create, integrate, store, share and apply knowledge. The content analysis covered a three-month period. In total, 650 advertisements were analysed of which only 185 satisfied the required criteria, i.e. they were advertisements published by knowledge-based organizations searching for suitable candidates for vacant managerial positions. Manager was defined as a person who is entrusted with a team of collaborators with the help of which s/he implements the set goals. The content analysis revealed that all manag ers were required to have knowledge and experience in the given sector, a university degree plus knowledge of at least one world language. These three competencies were mentioned in all advertisements analysed, therefore they were taken as basic competencies and were not included in the more detailed evaluation. The list of individual managerial competencies was developed based on competencies that appeared in the advertisements analysed. If any of the managerial competencies was missing in the list, the list was extended accordingly. Thus, in the course of the survey, the list of managerial competencies was gradually completed and the absolute frequency of individual competency occurrence was filled in. In the final stage of the survey individual managerial competencies started to repeat and finally it was no longer necessary to extend the list. Tab. 2 shows the order of the desired managerial competencies according their frequency of occurrence both in absolute and relative values. The most common requirements found in the analysed advertisements were as follows: experience in leadership (88%), communication skills (59%), time flexibility (37%), presentable behaviour and presentation skills (37%), reliability and responsibility (32%), organizational skills (31%), independence (30%), self-confidence (29%), dynamic person with a proactive approach (28%), negotiation skills (24%), analytical skills (19%), hardworking (19%), goal-oriented (16%) and stress resistance (14%). Other requirements mentioned in the advertisements were, for example, knowledge in the area of project management (and its application in managerial work), loyalty, creativity, accuracy, systems thinking, decision-making skills, willingness to learn, sense of purpose and processoriented. It is also possible to create competencies clusters, e. g. the following managerial competencies could be clustered together: communication skills and negotiation skills; dynamic person with a proactive approach, goal-oriented and sense of purpose; analytical skills and decision-making skills; systems thinking and process-oriented. Journal of Competitiveness Tab. 2 Order of managerial competencies according to the frequency of their occurrence in absolute and relative values. Source: Authors elaboration. Order Competencies 1. 2. 3. Number Percentage Experience in leadership 162 88 % Communication skills 110 59 % Time flexibility 69 37 % Presentable behaviour and 68 4. 37 % presentation skills 5. Reliability and responsibility 60 32 % Organizational skills 58 31 % 6. 7. Independence 55 30 % 8. Self-confidence 53 29 % Dynamic person with a 9. 52 28 % proactive approach 10. Negotiation skills 45 24 % 11. Analytical skills 36 19 % 12. Hardworking 35 19 % 13. Goal-oriented 30 16 % 14. Stress resistance 26 14 % 15. Project management skills 20 11 % Loyalty 18 10 % 16. 17. Creativity 16 9% 18. Accuracy 12 6% 19. Systems thinking 11 6% 20. Decision-making skills 10 5% 21. Willingness to learn 8 4% 22. Sense of purpose 7 4% 23. Process-oriented 3 2% The maximum number of competencies mentioned in one advertisement was 13 (3 basic plus 10 specific competencies), the minimum number of competencies, on the contrary, being 4 (3 basic plus 1 specific competencies). The average number of specific competencies was 5. Determining the optimal number of competencies is crucial for the development of a competency model. The survey indicated that knowledge-based organizations in the Czech Republic reached consensus only as regards basic managerial competencies necessary for the performance of managerial work, i.e. knowledge and experience in the given sector, a university degree and knowledge of one world language. As far as other competencies are concerned, there was no unified consensus. Other important competencies include, for example, experience in leader ship, communication skills, flexibility, presentable behaviour, responsibility and organizational skills. Other forms of employee recruitment (e.g. through personnel agencies) have not been included in the survey because the research within the GACR research project focuses primarily on a content analysis of media communications. The approach of organizations to managerial competencies was also examined through semistructured interviews with 14 managers. The summary of findings obtained to present reveals that the issue of managerial competencies is important, yet quite complex. The managers interviewed agree with the definition of managerial competencies which specifies them as a set of specific knowledge, abilities, skills, traits, motives, attitudes and values that a manager needs to be able to achieve the requested (superior) level of performance. However, they find it difficult to specify individual competencies and subsequently to work with them and in particular to measure them. In their opinion, managerial competencies are closely connected with the content of work of each manager, despite the fact that they represent a specific type of individual competencies associated with the managerial position. The survey carried out confirmed that there was no unified consensus as regards the list of competencies that a manager needed to possess in order to be able to do his/her job at the required level. The efficiency of a manag ers work is evaluated in a broader context unlike, for example, in case of an expert. Were the interviewed managers to specify managerial competencies in more detail, they most frequently mentioned analytical skills, interpersonal skills, decision-making skills, process orientation, independence, loyalty, empathy, self-regulation, stress resistance and motivation. All the contacted managers agreed with the opinion that each individual could contribute to an organizations development not just by their common predispositions, but in particular by their specifics that differentiated them from others, i.e. their specific knowledge, abilities, skills, traits, motives, attitudes and values, i.e. individual competencies. The source of success of any organization is its ability to increase the quality of labour, i.e. human, potential and exploit it to improve productivity and to enhance its performance. Knowledge-based organizations are aware of the fact that human potential cultivation is a never-ending process. Therefore they attempt to improve its activities in compliance with modern management trends that also include the competency-based approach. Within the scope of these activities they focus in particular on the development of capable individuals, support the personal development of employees that finally contributes to the development of the whole organization. To manage and develop human resources, however, means to pay attention to them at a strategic level. It is very difficult to gain a competitive advantage without any vision, long-term goals and a human resources development strategy. The identification of competencies is one of the crucial steps in competency-based approach application. An efficient use of managerial competencies in the process of human resources management in an organization depends on how successfully managerial competencies are identified and transformed in the resulting behaviour description. The identification of managerial competencies cannot be perceived as a separate factor, but in connection with other steps leading to the development of a managerial competency model. 4.2 Managerial Competencies and Knowledge-Based Organizations Development When working with competencies, it is convenient to use the job analysis and make a comparison with the performance characteristic directed at management through preset goals and defined by the behaviour necessary for achieving the required level of performance. For a better identification of managerial competencies, the job analysis may be supplemented by structured interviews, expert panels, resource panels (Mansfield 2005) and direct observations. Identified competencies have to be precisely named and described and the required work behaviour for the given competency has to be defined. These competencies are subsequently used to create a competency model. A managerial competency model contains key characteristics required to achieve the required level of a managers performance. According to McClelland (1973), different competencies predict outstanding performance in different roles, and that there is a limited number of competencies that predict outstanding performance in any given job or role. Should more competencies be required, it is suitable to create competency clusters. The measure of managerial competencies enables comparing the defined behaviour with the real one, i.e. the goal is to determine whether the required level of a competency is sufficient. Each competency is evaluated according to the set criteria using a pre-defined scale. The description of individual levels starts from negative manifestations of behaviour and continues to higher levels and up to the superior level of the given competency. Each level of the competency has to be described through such manifestations of behaviour to be unambiguously distinguishable from the previous level. On the basis of the defined behavioural scale, the levels of managerial competencies are subsequently measured. Simultaneously, it is possible to determine the relevance of managerial competencies using weights. The level of managerial competencies may be graphically represented by a polygon. There are a number of methods used for managerial competency measurement that differ in terms of their suitability, precision, and the level of difficulty of their implementation. They include review performance methods, such as the 360-degree method, role-playing, storytelling, direct observation, development centres, skill tests, questionnaires, and competency-based interviews. The choice of a suitable method depends on the type of competency measured, i.e. the method selected needs to measure the level of the given competency as precisely and reliably as possible. It is convenient to combine the recommended methods. Regular evaluation allows for the identification of the difference between the required and the real states of the measured level of managerial competencies and defining the goals to be achieved by the relevant employee. Provided the requested level of competencies is achieved, the outcomes of the evaluation serve as background information for planning of the personal development of an individual that is targeted at career growth. Such an individual development plan has to specify particular goals and steps leading to the efficient development of an employee. Apart from the individual development plan, organizations may also use other methods of managerial skill development, such as coaching, role-playing, storytelling or action learning, the advantage of which is that it permits solving real problems in real time and involve individual, group and organizational skills and knowledge. A complete competency framework helps employers plan for future development, identify a suitable career path and cultivate related competencies (Noe, 2008). Managerial competencies identification and development has a number of advantages for organizations; it broadens the labour potential of managers and thus also the possibilities for dynamic development of work teams and subsequently of the organization as a whole. In order to achieve this effect, the development programme of an organization has to have a clear and systematic conception that would take into account expected future changes. Individual steps of working with managerial competencies leading to the achievement of strategic goals of an organization are depicted in Fig. 1. 1. Job analysis 2. Managerial competencies identification 3. Competency model development 4. Competencies level measuring and evaluation 5. Competencies development 6. Carrier management 7. Checking of goals achievement Fig. 1 Process of working with managerial competencies. Source: Authors elaboration. In compliance with the resource-based approach to the creation of a competitive advantage, in the 21st century it is the people who, thanks to their competencies, represent the main source of achieving a competitive advantage. Therefore organizations need to support and develop talented managers and thus prepare them for current and future challenges and more and more frequent changes in both the external and internal environment of their organizations and help them respond to them. Mansfield (2005) stated that in recent years, organizations have begun to use competency models in new ways. Many organizations that have redesigned their work processes and restructured their jobs have developed competency models for newly designed jobs for which there are few, if any, job incumbents with experience. These new competency models, of necessity, describe emerging and anticipated skill requirements, rather than skills that have been effective in the past. Many organizations have taken a one size fits all approach to competency modelling, by developing one competency model, usually for leaders, and applying this model to a large set of jobs, sometimes even non-managerial ones. Other organizations have moved in the opposite direction, by simultaneously developing multiple competency models for different jobs within an organization. There have also been changes in the workplace which affect competency model building. Because organizations are changing more rapidly, the shelf life of a competency model has diminished. At present, a number of organizations are aware of the competency-based approach, however, they are often unable to utilize competencies appropriately. Simultaneously, there is not a common consensus as regards the competencies that managers have to possess to perform his/her work at the required (superior) level. In practice, therefore, managerial competencies are often connected with an organizations values rather than individual work positions. An efficient utilization of a competency-based approach is dependent on the correct identification of managerial competencies and the subsequent development of a suitable competency model as well as their measuring, evaluation and development. Difficulties may occur in any phase of this process. Within the context of competency measuring and evaluation, it is important how competencies are transformed into the description of the final behaviour that is characteristic of them. This behaviour shows what is meant by the required performance for each competency and the pre-set weights also play a role. Another problem is that the conclusions made based on testing in development centres derive from the current performance as competencies are connected with the observed behaviour. It means that if a competency is defined as a set of specific knowledge, abilities, skills, traits, motives, attitudes and values important for personal development and the successful involvement of each person in an organization, then all aspects of a competency are displayed indirectly, through behaviour. This is also confirmed by Burgoyne (1989), who explained the difficulties in identifying managerial competencies. These include: measurability and divisibility of competencies; generalising skills over different categories of manager; the changing nature of managing; accommodating different styles and strategies of managing; and how individual competence contributes to and integrates into organizational competence. On the contrary, the benefit of the competency-based approach is that it focuses on one specific individual, not a work position, which complies with the philosophy of human resources management. In this conception, human resources management means taking concentrated and targeted care of employees. Organizations have to focus this care not only on training and personal development, but also on career growth (in compliance with the Maslows hierarchy of needs). Simultaneously, it is necessary to take into consideration an organizations employee together with all their social relationships in which the personal characteristics of other employees are reflected and to encourage their attempts to improve and develop. The survey showed that knowledge-based organizations in the Czech Republic realise the significance of application of managerial competencies in management, but at the same time refer to possible problems associated with competency-based approach implementation. In their opinion these problems lie in particular in the non-cohesive definition of managerial competencies as well as their specification and measuring. The survey carried out confirmed that there was no unified consensus as regards the list of competencies that a manager needed to possess in order to be able to do his/her job at the required level. For these reasons knowledge-based organizations are recommended to develop their own managerial competency model (so called the tailored approach (Rothwell & Lindholm, 1999)) reflecting their specific needs. This is also confirmed by Lucia and Lepsinger (1999), according to which certain competencies, such as consumer focus or problem-solving skills, might be generic across several organizations, but the behaviours relating to those competencies can still vary widely from one organization to another, just as they may vary from one role or job or level in a organization to another. In compliance with the resource-based approach to competitive advantage development, it is the people/employees who become, due to their competencies, an important source for achieving a competitive advantage. The value of the managerial competencies model consists in its application and may be identified in particular in the following areas: (1) recruitment, (2) employee evaluation, (3) training, (4) employee development, (5) carrier management, (6) adaptation to changes, (7) enhancement of productivity of labour and (8) an organizations performance. It works best if applied in all areas of an organizations human resources management. In the fully integrated human resources management system employing the competency-based approach, competencies represent a key prerequisite for efficient performance. Acknowledgement The article originated as a part of the grant project of the Czech Science Foundation GACR GP402/09/P616 Use of Competencies in Knowledge-Based Organization and is associated with the research project of the Czech University of Life Sciences in Prague entitled Information and Knowledge Support of Strategic Management (MSM6046070904). 1. Bartk, J. (2006). Skryt bohatstv firmy. Prague: Alfa Publishing. 2. Birdir, K. & Pearson, T. (2000). Research Chefs Competencies: A Delphi Approach. International Journal of Contemporary Hospitality Management, 12(3), 205-209. http://dx.doi.org/10.110 8/09596110010309989 3. Boyatzis, R. E. (1982). The Competent Manager: A Model for Effective Performance. New York: John Villey & Sons. 4. Boyatzis, R. E. (2008). Competencies in the 21st Century. Journal of Management Development, 27 (1), 5-12. http://dx.doi.org/10.1108/02621710810840730 5. Bure, V. (2007). Znalostn management a proces jeho zavdn. Prague: Grada Publishing. 6. Burgoyne, J. (1989). Creating the Managerial Portfolio: Building on Competency Approaches to Management Development. Management Education and Development, 20 (1), 56-61. 7. Calabrese, F. A. (2006). Knowledge-based Organizations in Context. The Journal of Information and Knowledge Management Systems, 36 (1), 12-16. 8. Carroll, A. & McCrackin, J. (1998). The Competent Use of Competency Based Strategies for Selecting and Development. Performance Improvement Quarterly, 11 (3), 45-63. http://dx.doi. org/10.1111/j.1937-8327.1998.tb00099.x 9. Chong E. (2011). Managerial Competencies and Career Advancement: A Comparative Study of Managers in Two Countries. Journal of Business Research. In Press. http://dx.doi.org/10.1016/ j.jbusres.2011.08.015 10. Choo, CH. W. (1998). The Knowing Organization: How Organizations Use Information to Construct Meaning, Create Knowledge, and Make Decisions. Oxford: Oxford University Press. 11. Coyne, K. P., Hall, S. J. D. & Clifford, P. G. (1997). Is Your Core Competence a Mirage? The McKinsey Quarterly, 1, 40-54. 12. Delamare Le Deist, F. & Wintertone, J. (2005). What Is Competence? Human Resource Development International, 8 (1), 2746. http://dx.doi.org/10.1080/1367886042000338227 13. Gallon, M. R., Stillman, H. M. & Coates, D. (1995). Putting Core Competency Thinking into Practice. Research Technolog y Management, 38 (3), 20-8. 14. Hess, J. D. & Bacigalupo, A. C. (2010). The Emotionally Intelligent Leader, the Dynamics of Knowledge-Based Organizations and the Role of Emotional Intelligence in Organizational Development. On the Horizon, 18 (3), 222-229. http://dx.doi.org/10.1108/1074812101107267 2 15. Hogg, B. (1993). European Managerial Competencies. European Business Review, 93 (2), 21-26. http://dx.doi.org/10.1108/EUM0000000001914 16. Horng, J. S., Hsu, H., Liu, Ch. H., Lin, L. & Tsai, Ch. Y. (2011). Competency Analysis of Top Managers in the Taiwanese Hotel Industry. International Journal of Hospitality Management, 30, 1044-1054. http://dx.doi.org/10.1016/j.ijhm.2011.03.012 17. Lucia, A. D. & Lepsinger, R. (1999). The Art and Science of Competency Models: Pinpointing Critical Success Factors in Organizations. San Francisco: Jossey-Bass/Pfieffer. 18. Mansfield, R. S. (1996). Building Competency Models: Approaches for HR Professionals. Human Resource Management, 35 (1), 7-18. http://dx.doi.org/10.1002/(SICI)1099050X(199621)35:1<7::AID-HRM1>3.0.CO;2-2 19. Mansfield, R. S. (2005). Practical Questions in Building Competency Models. Retrieved from http:// workitect.performatechnologies.com/pdf/PracticalQuestions.pdf 20. McClelland, D. C. (1973). Testing for Competence Rather Than for Intelligence. American Psychologist, 28, 1-14. http://dx.doi.org/10.1037/h0034092 21. McLagan, P. (1997). Competencies: The Next Generation. Training & Development, 51 (4), 4047. 22. Medzihorsk, . & Medzihorsk, J. (2007). Uplatnn psychickch a asocilnch faktor v managementu rozvoje znalostnch organizac . Prague: PYRAMIDA. 23. Noe, R. A. (2008). Employee Training and Development. New York: McGraw-Hill. 24. Nonaka, I. & Takeuchi, H. (1995). The Knowledge-Creating Company. How Japanese Companies Create the Dynamics of Innovation. New York: Oxford University Press. 25. Pavlica, K. et al. Sociln vzkum, podnik a management. Prague: Ekopress, 2000. http://dx.doi. org/10.1108/13673279910259358 26. Perez-Bustamante, G. (1999). Knowledge Management in Agile Innovative Organisations. Journal of Knowledge Management, 3 (1), 6-17. http://dx.doi.org/10.1108/13673279910259358 27. Prahalad, C. K. & Hamel, G. (1990). The Core Competence of the Corporation. Harvard Business Review, 68 (3), 79-91. 28. Rothwell, W. J. & Lindholm, J. E. (1999). Competency Identification Modelling and Assessment in the USA. International Journal of Training and Development, 3 (2), 90-105. http://dx.doi. org/10.1111/1468-2419.00069 29. Sanghi, S. (2007). The Handbook of Competency Mapping. New Delhi: Sage Publications India. 30. Schroder, H. M. (1989). Managerial Competence: The Key to Excellence: A New Strateg y for Management Development in the Information Age. London: Kendall & Kent Publications. 31. Sldeek, M. (2006). zen znalost v praxi. Modern zen, 2006 (6), 8-10. 32. Spencer, L. M. & Spencer S.M. (1993). Competence at Work. New York: John Wisley & Sons. 33. Tate, W. (1995). Developing Managerial Competence. Hampshire: Gower Publishing Limited. 34. Truneek, J. (2003). Znalostn podnik ve znalostn spolenosti. Prague: Professional Publishing. 35. Ulrich, D. & Lake, D. (1991). Organizational Capability: Creating Competitive Advantage. Academy of Management Executive, 5 (1), 77-92. 36. White, R. (1959). Motivation Reconsidered: the Concept of Competence. Psychological Review, 66 (5), 279333. http://dx.doi.org/10.1037/h0040934 37. Winterton, J. & Winterton, R. (1999). Developing Managerial Competence. London: Routledge. http://dx.doi.org/10.4324/9780203264492 38. Woodall, J. & Winstanley, D. (1998). Management Development: Strateg y and Practice. Oxford: Blackwell. 39. Woodruffe, C. (1992). What is Meant By a Competency. In R. Boam & P. Sparrow (Eds.), Designing and Achieving Competency, (pp.16-29). London: McGraw-Hill. 40. Wu, L. Ch., Ong, Ch. S. & Hsu, Y. W. (2008). Knowledge-Based Organizations Evaluation. Decision Support Systems, 45, 541-549. http://dx.doi.org/10.1016/j.dss.2007.06.013 Contact information Ing. Martina Knigov, Ph.D., Ing. Hana Urbancov Czech University of Life Sciences in Prague, Faculty of Economics and Management Department of Management Kamck 129, 165 21 Prague 6 Suchdol Czech Republic Tel.: +420 22438 2037, +420 22438 2026, E-mail: [email protected], [email protected] Ing. Ji Fejfar, Ph.D. Czech University of Life Sciences in Prague, Faculty of Economics and Management Department of Systems Engineering Kamck 129, 165 21 Prague 6 Suchdol Czech Republic Tel.: +420 22438 2181 E-mail: [email protected] JEL Classification: M12, J24 142 Journal of Competitiveness Competence (Human Resources) Survey Methodology Documents Similar To Identification of Managerial Competencies in K-Based Organizations Devesh Pratap Singh Michelle Lagos Sardar Zaryab Jahandar Dogar Monika Suthar Priyanka Joshi Sepe Kapfo kritishah2997 Hiral Soni Sreejith Aravindakshan Anonymous CwJeBCAXp acb562 faridkhan Raul Nocete HadiBies Chantal Mangion EmelldaMa Gohan Son Vardhan Reddy ch01 Management Tushar Tandel Ch01p org management saynas8781 ASTD Survey Results _Training Professionals urdestiny performance management 2010 for portfoliodocx Lecture-2 & 3 Management Bilal Hanif Management and Managers fatimaBAALA KPMG Graduate Application and Interview Process stillnexxt 2-Lectures Chapter 1 DRathika Sanjana Ganesh More From Alexandru Ionuţ Pohonţu IJEBMRLeadership.pdf Alexandru Ionuţ Pohonţu PwC Report - Retail.pdf bun1 Dana Beatrice Prague.enemark.com2Seminar.june2007 IPC322E-IR-F3660_web oecd 2003 The Influence of Tacit Knowledge and Collective Mind on Strategic Planning Sainio Henri ABDENNADHER Reviziurea Regulamentului European Privind Procedurilor de Insolvența A Business Plan for the Language Interpreter Center Forbes Thesis Dissertations Ungh Yup Hyun 0817 The Integrated Logistics Management System CASE STUDY Gejo Varkey Logistics and Supply Chain Management in the Hotel Industry- Impa 2535_1268748912 LDM_BRI(2014)140709_REV1_EN Basnet Perception and Predictors of Consumers Purchase Intentions for Store Brands - Evidence From Malaysia Liew2020 13 Yi Ching Tsai Khushi Awan J. 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Is the flu more deadly than COVID-19 for children? Dr. Jay Bhattacharya was quoted in this recent Foundation for Economic Education article: In a debate last week with pro-lockdown Harvard epidemiologist, Marc Lipsitch, Dr. Bhattacharya acknowledged that COVID-19 "is an absolutely deadly disease for people who are older and for people who have certain chronic conditions." He explained that there is a 95 percent COVID-19 survival rate for people 70 and older, while for people who are under 70, there is currently a 99.95 percent survival rate. Dr. Bhattacharya said: "For children the flu is worse. We've had more flu deaths of children this year than Covid deaths." Dr. Bhattacharya who made the claim is also an important signee of the Great Barrington Declaration, which argues for focused protection, and which also states on the website that (without proof): Fortunately, our understanding of the virus is growing. We know that vulnerability to death from COVID-19 is more than a thousand-fold higher in the old and infirm than the young. Indeed, for children, COVID-19 is less dangerous than many other harms, including influenza. I know that Covid is hitting the older people disproportionately hard, but is it true that it hit less hard on children than flu? covid-19 flu GravitonGraviton Allegedly the corona thing is still 'new'. That makes it worse to ascertain "worse", since we may indeed know too little about certain aspects in the long run to judge any wobbly "worse" qualifier. So, why not stick to this 'hard number': is it true that "we" (to which location do they refer?) saw more flu deaths than covid deaths in people aged 1–18? – LangLаngС The question title is about deaths, but the ending question about "hitting" demographics harder than others compels me to point out that death is only one possible complication for COVID-19. The long term effects are still unknown, but so far what we have seen indicates worse health after recovery than the flu. – Logarr Isn't this use of 'deadly'/'hit less hard' ambiguous? Total deaths or death rate? Imagine virus A is rare but kills 99% of children who catch it compared to virus B which is common and kills less than 0.01% of children who catch it. A kills 100 kids and B kills 1000 - which one hits children harder? – Rob P. @RobP.: Yeah, that's why I had to qualify what my answer was based on. The CFR for many forms of Ebola is incredibly high (90% for some strains). But it's also far less dangerous to everyone (at least in the U.S.) than COVID-19, simply because it's not very contagious. It doesn't really matter if the flu kills a higher percentage of the children who get it, if, under normal circumstances, far fewer children contract it in the first place (and of course, we have a vaccine for the flu, so responsible parents can dramatically reduce the risk of dying from the flu w/o masking/distancing/closures). – ShadowRanger Perhaps worth noting that viruses can have serious long-term health effects that are not trivial to identify. We've only recently found out that measles and flu are much more dangerous than previously known because of their long-term effects on immune reaction and heart disease respectively, and these are diseases that have been with us for a long time. The short-term effects of COVID-19 in children seem relatively mild, but nobody knows what the long-term effects might be. – Geoffrey Brent Says the WHO since March 2020: Children are important drivers of influenza virus transmission in the community. For COVID-19 virus, initial data indicates that children are less affected than adults and that clinical attack rates in the 0-19 age group are low. Further preliminary data from household transmission studies in China suggest that children are infected from adults, rather than vice versa. While the range of symptoms for the two viruses is similar, the fraction with severe disease appears to be different. For COVID-19, data to date suggest that 80% of infections are mild or asymptomatic, 15% are severe infection, requiring oxygen and 5% are critical infections, requiring ventilation. These fractions of severe and critical infection would be higher than what is observed for influenza infection. Those most at risk for severe influenza infection are children, pregnant women, elderly, those with underlying chronic medical conditions and those who are immunosuppressed. For COVID-19, our current understanding is that older age and underlying conditions increase the risk for severe infection. And true, show the most up to date statistics from the CDC, if we concentrate on mortality: — Deaths involving coronavirus disease 2019 (COVID-19), pneumonia, and influenza reported to NCHS by sex and age group. United States. Week ending 2/1/2020 to 11/7/2020. on: "Weekly Updates by Select Demographic and Geographic Characteristics. Provisional Death Counts for Coronavirus Disease 2019 (COVID-19)", cdc.org When comparing these numbers it should be noted: It is extremely remarkable that in 2020 influenza testing was as ever further increased, but the flu season was much lower than expected, with the southern hemisphere even skipping the flu season entirely: Globally, despite continued or even increased testing for influenza in some countries, influenza activity remained at lower levels than expected for this time of the year. In the temperate zone of the northern hemisphere, influenza activity remained below inter-seasonal levels, though sporadic influenza detections were reported in some countries. In the temperate zones of the southern hemisphere, no influenza detections were reported across countries. — WHO: Global Influenza Programme — Influenza update - 380 — 09 November 2020, based on data up to 25 October 2020 Meaning the CDC table may show a somehow inflated number of covid deaths due to counting and reporting issues, but the also slightly imprecise numbers for influenza deaths are also much lower than usual currently. Similarities: Both COVID-19 and flu illness can result in severe illness and complications. Those at highest risk include: Older adults, People with certain underlying medical conditions, Pregnant people, Differences: The risk of complications for healthy children is higher for flu compared to COVID-19. Influenza is dangerous for children but the current mortality rate for Covid in children is almost 0.0%. Or, in the words of a trustworthy state public health agency: Children are not considered to be at risk of serious illness Even if they have one of the conditions or illnesses that increase the risk for adults and older people, children are very unlikely to become seriously ill. — Our World in Data: Mortality Risk of COVID-19 But this may still change. While the above numbers still hold true for the vast majority of countries in Europe, for example Sweden and Germany, there appear some statistical outliers. While for influenza the attack rate in younger patients is generally much higher than for coronavirus, in influenza we also see the severity changing according to location, season and virus subtype. For England – in this year – and note that the infinitesimally small number stats for children are within the group "<65" COVID-19 mortality rates were higher than influenza and pneumonia rates for 2020 and the five-year average for all age groups in England Age-standardised and age-specific mortality rates for deaths due to influenza and pneumonia, and COVID-19, England, occurring between 1 January and 31 August 2020 and registered by 5 September 2020 - Deaths due to coronavirus (COVID-19) compared with deaths from influenza and pneumonia, England and Wales: deaths occurring between 1 January and 31 August 2020 Comparison of deaths from the coronavirus (COVID-19) with deaths from influenza (flu) and pneumonia. Includes deaths by date of death occurrence and breakdowns by sex and age. For New York City alone we see in a comparison for strong flu seasons and covid: Notwithstanding the substantial burden of less severe infections due to both influenza and COVID-19 in different age groups, and the possibility that risk of death may vary over time, the higher age-specific mortality in the young in both the 1918–19 and 2009 influenza pandemics compared with COVID-19 is an important factor for decisions about whole-of-population versus age-targeted vaccination strategies. — David J Muscatellod & Peter B McIntyred: "Comparing mortalities of the first wave of coronavirus disease 2019 (COVID-19) and of the 1918–19 winter pandemic influenza wave in the USA", Int J Epidemiol. 2020 Sep 15. doi: 10.1093/ije/dyaa186 People <65 years old have 16–100 fold lower risk of COVID-19 deaths than older people. Age risk gradients are less steep in India and Mexico. Absolute risks of COVID-19 in the population are low for people <65 years old. COVID-19 deaths occur sparsely in people <65 without underlying conditions. People <65 years old have very small risks of COVID-19 death even in pandemic epicenters and deaths for people <65 years without underlying predisposing conditions are remarkably uncommon. Strategies focusing specifically on protecting high-risk elderly individuals should be considered in managing the pandemic. COVID-19 may thus be yet another disease with a profile dependent on inequalities and generating even more inequalities. The difference in the proportion of deaths in people <65 years old across different US locations may be due to chance, or may reflect genuine differences in the proportion of deaths occurring in nursing homes and/or the proportion of deaths occurring in younger populations of disadvantaged people, differences in reporting of COVID-19 deaths, or other unclear reasons. Of interest, influenza deaths seem to have a similar difference in age distribution between the USA and European countries like Italy: a larger proportion of influenza deaths in the USA tend to be in the <65 age group (Estimated Influenza, 2018), as compared with Italy (Rosano et al., 2019). Of course, a major difference between influenza and COVID-19 is that the latter typically does not cause deaths in otherwise healthy children, in contrast to influenza (Wang et al., 2020b). — John P.A. Ioannidis & Cathrine Axfors Despina G. Contopoulos-Ioannidis: "Population-level COVID-19 mortality risk for non-elderly individuals overall and for non-elderly individuals without underlying diseases in pandemic epicenters" Environmental Research, Volume 188, September 2020. doi Influenza is least dangerous for young adults, but more dangerous for children and elderly people. Influenza virus accounted for 7% of ALRI cases, 5% of ALRI hospital admissions, and 4% of ALRI deaths in children under 5 years. About 23% of the hospital admissions and 36% of the in-hospital deaths were in infants under 6 months. […] A large proportion of the influenza-associated burden occurs among young infants and in low-income and lower middle-income countries. — Wang et al.: "Global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: a systematic review and modelling study", Lancet Glob Health 2020; 8: February 20, 2020, doi. US Mortality (42 states and NYC reported): Children were 0.00%-0.18% of all COVID-19 deaths, and 16 states reported zero child deaths In states reporting, 0.00%-0.13% of all child COVID-19 cases resulted in death — Children and COVID-19: State-Level Data Report, AAP Report Nov 2020 While the CDC reports around 200 yearly influenza deaths in children with an estimate of 600 'true' cases due to underreporting (CDC Flu & Young Children), with actual data for 2020 still listed as insufficient: — Influenza-Associated Pediatric Mortality, CDC FluView That is: for the start of the year we saw some pediatric influenza deaths (a 'record' of >170 for season 19/20) but for the season that just started now we have today: "No influenza-associated pediatric deaths occurring during the 2020-2021 season have been reported." That makes the other initial claim of 'more very young persons died so far from flu than from covid' true: while the 'everyone now has corona' season of 2020 so far within the age bracket of 0–24 had a reported death toll of covid deaths excluding inluenza (table 1) at 155, in the US the overall very mild flu season of 2019/20 took the lives as reported of finally in week 38 at 188 pediatric deaths (Compared for example to 2009 influenza-related pediatric deaths of even 317). Meaning a low prevalence influenza took more young lives in absolute numbers than the high prevalence corona outbreak. That well may change for the absolute numbers, since flu seems to remain at very low activity compared to corona which remains at a somewhat higher activity level. But the relative risk is unlikely to change: at similar virus activity the flu is more dangerous than corona for children. LangLаngСLangLаngС I honestly don't know how to read the first Table ( table 1). It says for under 1 year, "All Deaths involving Covid 19" is 26, and "All Deaths involving Influenza with or without Covid" is 16, for other age group, the "deaths involving Influenza is lumped together with deaths from Covid", so how does all that translate to the conclusion that "Influenza is more deadly than Covid for young age"? – Graviton Also, your other stats and table don't seem to directly address the claim that "Influenza is more deadly than Covid for young age". @LangLаngС: Your link from the text "the flu season was much lower than expected" is written with a very conspiracy theory-style tone to it (is it really so surprising that the flu, a disease which spreads less effectively than COVID and even in normal years has limited spread in Spring/Summer, might be controlled even better as a side-effect of anti-COVID measures like masks, distancing and lockdowns?). It doesn't seem necessary to support your post (the WHO quote covers it), and the post would probably be improved by not linking rambling conspiracy theories involving flu testing. You're significantly overstating annual flu deaths. 188/600 is a "high" water mark, not a "normal" mark - it is the second highest number reported since 2004/05. The current CDC table for COVID-19 pediatric cases is close to that (and likely has as many, or more, "hidden" cases as does influenza). There is not nearly enough evidence for a True here - it's still very unclear which is worse. The contribution of children to the spread: children still have limited exposure to infection, and become infected less frequently. When infected, they are generally less sick than adults. Six months into the pandemic, children have not shown any evidence of being a significant factor in its propagation & Why young children seem less likely to spread the new coronavirus to others is unclear … children tend to transmit less virus … risk of infection at school is low, Update 2021-03-24: Based on new data through "End Week" 3/13/2021: the CDC tallied total COVID-19 death toll among children since the beginning of the pandemic (which has now had meaningful cases in the U.S. for almost precisely a year) is up to 273 (76 in 0-4 range, 197 in 5-18 range). By itself, this doesn't meaningfully change the original answer (273 still falls within the 37 to 600 range where we couldn't give a definitive answer without a head-to-head comparison), but: It is higher than the officially reported pediatric death toll for any typical flu season (so if the rate of missed deaths was even remotely similar, more children died of COVID-19 this past year than in any typical flu season). The same mitigation measures (or lack thereof) have now been in place during a flu season as well, so we have one cold/flu season in which both COVID-19 and the flu were operating, and both were subject to all the same mitigations aside from vaccines (no pediatric COVID-19 vaccine has been approved yet; they've barely started testing them). With that in mind, the new comparison is: COVID-19 killed 273 children in the U.S. this past year, 138 of them between early November (when the data from the original answer was pulled) and mid-March (current data at time of writing), a period encompassing the height of most flu seasons (the flu season typically extending a month further on either side, but with fewer deaths on either end). The flu killed one child in the U.S during this past flu season (6-9 for the past year depending on whether you start from March or April, counting deaths from the tail of the previous flu season). Even if we assume it was a low danger flu strain circulating this year (comparable to the one that only caused 37 pediatric deaths in a prior year), the anti-COVID-19 mitigations we made reduced the flu death toll by over 97% for this past flu season; even with inconsistent mitigations, the flu was effectively zero threat to children (the flu season basically didn't happen in either hemisphere this past year thanks to said mitigations), while COVID-19 remained a threat. So under the criteria of "which kills the most children under similar circumstances" the answer is clearly COVID-19. Even if the flu has a higher case fatality rate among children (there's no strong evidence on this either way, and it varies by strain), COVID-19 is clearly much more contagious; at any given time, your average currently uninfected child has a dramatically higher risk of dying of COVID-19 than the typical seasonal flu over the course of the following year, simply because they're far more likely to catch it, and it's lethal enough. Original answer (still relevant for context and explanation): "Is it true that it hit less hard on children than flu?" Short answer up front: To the best of our knowledge, subject to the conditions we've been able to observe (vaccines for flu, lockdowns, distancing and masking for COVID-19), COVID-19 is, so far, a similar level of threat to children as typical seasonal flus; more deadly than some flu years, less deadly than others. This is a hard question to answer definitively, since the death toll from the flu varies significantly from year to year. According to the CDC, the pediatric death toll from seasonal flu during the typical flu season has varied from 37 to 188 per year since 2004 (the 2009 H1N1 pandemic was an outlier, in that it had a total of 358 pediatric flu-related deaths between April 2009 to September 2010, a period of 18 months, and most of them occurred outside "typical" flu season). That said, the CDC is suspicious of the completeness of their pediatric flu death reports, and believes, based on statistical modeling, that the year with 188 deaths actually involved ~600 pediatric deaths. If we focus on seasonal flu in general, we can say roughly, that if the annual pediatric COVID-19 death toll: Is below 37, then COVID-19 is less dangerous than seasonal flus Is between 37 and 600, then COVID-19, under existing mitigation strategies, may be less dangerous to children than some flu seasons, and probably more dangerous than others. Is above 600, then COVID-19 is more dangerous to children than typical seasonal flus. Note that this is not saying whether the child is more at risk once infected; that's much harder to determine (especially with the high rate of asymptomatic COVID-19 cases in children). If COVID-19 has a lower case fatality rate, but is sufficiently more infectious such that more children die of it, I'd argue it remains more of a threat to children than the flu for the same reason that we consider the flu a greater threat to U.S. children than we do Ebola; sure, many forms of Ebola are incredibly deadly if you catch it, but it doesn't spread easily enough to actually infect that many people under conditions in most developed countries. Given those bounds, based on the CDC's raw data focused on deaths aged 0-18: we can see that the United States has had 135 COVID-19 deaths in the 0-18 range (42 among the 0-4 group, 93 among the 5-18 group). Thus, all we can say right now is what I said in the short answer: To the best of our knowledge, subject to the conditions we've been able to observe, COVID-19 is, so far, of a similar level of threat to children as typical seasonal flus; more deadly than some, less deadly than others. The qualifiers are needed because: With lockdowns (including school closures), masking, and distancing, we're not observing COVID-19 as it would behave "naturally" (e.g. under the "focused protection" scenario proposed by your source). Thanks to vaccines, we don't observe seasonal flus as they'd behave "naturally" either; approximately 80% of observed pediatric flu deaths occurred in unvaccinated or under-vaccinated (two shots are suggested the first year you receive a flu vaccine) children, even though unvaccinated children are in the minority. We still haven't seen how COVID-19 behaves over the course of a full cold season (Fall-Winter), which we can expect to be worse than other seasons based on the typical behavior of coronaviruses. Issue #3 should be answerable by sometime next Spring (looking at a full year's death toll during a period where COVID-19 was fairly widespread). But #1 and #2 are harder to account for. Pediatric flu vaccination rates in the 2017-2018 flu season (when 188 pediatric flu deaths were reported, and 600 estimated) were 57.9% overall (higher for 6 mo.-4 y.o. groups, lower for teens), and given ~80% of deaths typically occur in the unvaccinated group, one could reasonably assume the flu would kill significantly more children if the vaccine did not exist. Beyond that, lack of a vaccine would increase the number of infected individuals spreading the flu, thereby increasing the number of cases, so it's not as simple as just applying the death rate from the unvaccinated group to the vaccinated group to estimate overall death toll, you'd have to guess at how much more community spread you'd see without the vaccine. Similarly, while there is no vaccine for COVID-19, it does appear that mitigation (lockdowns, distancing, masking) reduced COVID-19 spread (and masking in particular appears to reduce severity as well), so it's nearly impossible to state with certainty how many more children would have died from COVID-19 if we'd just ignored it and gone about our lives. ShadowRangerShadowRanger "We still haven't seen how COVID-19 behaves over the course of a full cold season (Fall-Winter)" waves from Southern Hemisphere @Oddthinking: Well, one, COVID-19 was still getting going in southern Fall, so it's not a full season there either (though it's much closer). Two, even if was a full season, I have the problem of not knowing which countries have good historical pediatric flu death data and "bad enough" COVID control protocols to make them useful for determining COVID risk. Brazil probably fits the latter category, but if it fits the former, I don't speak Portuguese well enough to find the info. New Zealand probably hits the former, but not the latter. Maybe Australia, but I can't find the data there either. @Oddthinking ShadowRanger is generally correct, though I wouldn't call it "cold season". The Southern Hemisphere, broadly, only experienced their initial wave of COVID-19 in their fall-winter. Thankfully, a vaccine will be available just as cases would start to pick up in your fall-winter 2021. – De Novo I'm going to have to downvote this for an invalid comparison in the update: 2020-2021 flu season is well-know to have been extremely atypical. @Mark: That's the whole point. Unless your argument is that, by sheer coincidence unrelated to COVID, the flu had its weakest year in history, it's fairly clear it's atypical because the flu is more susceptible to anti-COVID measures than COVID itself is (almost certainly because COVID is more contagious). So, under equivalent circumstances (mitigations, masking, lockdowns, inconsistently applied), we have our only apples-to-apples comparison, and COVID "wins". It seems it might depend on the age sub-group, at least in France. Although data is so sparse that it comes down to a handful of actual deaths from either disease in adolescents, the number of deaths for Covid-19 beat that for influenza in that group in a statistically significant manner, at least in this comparison, which used the 2018-2019 flu season for comparison: Of the patients hospitalised, the proportion of paediatric patients (<18 years) was smaller for COVID-19 than for influenza (1227 [1·4%] vs 8942 [19·5%]), but a larger proportion of patients younger than 5 years needed intensive care support for COVID-19 than for influenza (14 [2·3%] of 613 vs 65 [0·9%] of 6973). In adolescents (11–17 years), the in-hospital mortality was ten-times higher for COVID-19 than for influenza (five [1·1% of 458 vs one [0·1%] of 804), and patients with COVID-19 were more frequently obese or overweight. [...] In children, although the rate of hospitalisation for COVID-19 appears to be lower than for influenza, in-hospital mortality is higher; however, low patient numbers limit this finding. I'm not sure why they didn't mention the other age groups in the abstract (perhaps the data is even more sparse, so not statistically significant as a difference--actually that's the case see table further below), but they do have this graph across age groups under 18, and it seems Covid-19 beat influenza in all of them for in-hospital mortality (2nd plot below) and for the ICU support fraction in the younger groups (1st plot): They also give the raw number in an appendix, together with some statistical tests for the significance of the difference observed: As seen in that table, the p-value for the difference is indeed not significant for the other children-age groups (except 11-17) with respect to mortality, but clearly there's a trend for Covid-19 being more deadly even in children under 11, if they are hospitalized with it. Alas they don't mention how many children had been vaccinated against influenza, only that "influenza vaccination coverage against seasonal influenza in France was 29·7% for those under 65 years", which isn't too insightful for children in particular... In the conclusion section they say Although children seemed to have a lower risk of being hospitalised for COVID-19 (as shown here by the low rate of hospitalisation for COVID-19 compared with seasonal influenza in patients younger than 18 years), the in-hospital mortality of these children was more than four-times higher than it was for children with influenza. I think by "children" they mean all under 18 in that para. To wit: there were 9 Covid-19 deaths among 1,227 cases in under 18 y.o. and 16 deaths among 8,942 cases of flu in the same age group. That gives 0.73% (hospitalized) CFR for Covid-19 in under 18 y.o. and 0.18% for flu. The ratio of these two percentages is approximately 4. They do note that there's a potential source of uncertainty here because influenza testing isn't as widespread/standardized even in hospitals: testing practices for influenza are likely to be highly variable across hospitals, whereas practices for COVID-19 may be more standardised (eg, all hospitalised patients require testing). So if the CFR is narrowly defined for those hospitalized but we assume much higher attack rate of non-symptomatic or at least non-hospitalized children with Covid-19, it could be the case that the CFR is higher for Covid-19 than for flu even in children, but the IFR is not. At least in France. Unfortunately, the IFR is notoriously difficult to measure when there is a large fraction of asymptomatic presentations. An editorial in the same journal issue points to another study with similar findings in Brazil (note the statistically significant difference in deaths--also this paper was on pediatric patient only, so they often drop the qualifier in the text) The risk of death was comparable between the influenza and ORV group, but the SARS-CoV-2 group had more than three times the risk compared to the other two groups (adjusted OR=3.74 [CI 2.5-5.6], p<0.001) (Table 2). The latter study has a somewhat similar disclaimer as to the relevance to broader/milder cases (which are not be hospitalized and may not be well accounted for): We must emphasize that the clinical presentation and outcomes described in this study concern only a subset of pediatric COVID-19 patients: hospitalized children and adolescents with severe symptoms. Therefore, our results cannot be generalized to all children with COVID-19. Large population studies are needed to evaluate the broad impact of COVID-19 on children's health. Not the answer you're looking for? Browse other questions tagged covid-19 flu . Do most locations have an infection fatality rate less than 0.20% from Covid-19 (and less than 0.05% for those under 70 y.o.)? Was the 2009 swine flu pandemic five times deadlier to children under 18 than COVID-19? Is COVID-19 more dangerous than typical annual coronavirus variants? Did lockdowns limit the spread of COVID-19? Does flu vaccine make us more vulnerable to COVID-19? Are unusually many people dying after being vaccinated for COVID-19? Were summer colds up in 2021?
Children and COVID-19 Common Questions from Parents In the past 18 months, we all have experienced a lot of new challenges. Whether it be social distancing, adapting to remote work environments, encouraging masking, or witnessing the most extensive mass vaccination effort in history — one would think these obstacles encompass all the struggles we face. But there is a segment of the population often left out of the conversation when it comes to COVID-19 safety — and that is the nearly 50 million children in our country between the ages of 2-11. This segment of our population is also the group that is unvaccinated yet still in large group settings amid a variant outbreak. With the school year now in full swing, we wanted to answer the most common questions parents may have about their children's safety and going back to school. Question 1: Why is it taking so long for vaccines to be approved for younger children, and when can we expect it? For parents, the safety of your child is your number one concern. Likewise, the same could be said about researchers' study of vaccines. Scientists are dedicated to ensuring that vaccines for children are highly safe and efficacious before administering them. Clinical trials for children ages 5-11 are currently in progress for all three vaccines. These trials occur in a step-down manner, meaning that once a vaccine is approved for children 5-11, researchers will begin trials for children 2-4. So far, out of the three vaccines in the U.S., the Pfizer vaccine is the closest to submitting authorization requests to the FDA. Both Pfizer and Moderna have noted that they are spending extra time reviewing data before submitting it to the FDA due to caution surrounding a single health concern called myocarditis. Myocarditis, while being extremely rare, is defined as the inflammation of the heart muscle. From those vaccinated, this issue has most commonly been seen among younger males in their teens and early 20s. In CDC data from males vaccinated 12+, the cases of myocarditis per age group are as follows: 12-29 years old: 40.6 cases per million vaccines administered (rate of occurrence: .00004%) 30 and older: 2.4 cases per million vaccines administered (rate of occurrence: .000002) Question 2: How dangerous is the virus to children under 12? COVID-19 and its newer variant, Delta, still largely spare most children. While kids can be infected, most have asymptomatic or mild cases (for those who get mild cases, most recover within a week). While a majority of kids are spared, severe cases are rare but do exist. Currently, 1% of children infected will be hospitalized, and of those kids hospitalized, .1% will die from COVID. Kids hospitalized from COVID: 1% = 1 in a 100 infections Kids who die after hospitalization: .0001% = 1 in a 10,000 infections Question 3: I am (or have been) pregnant. Does the vaccine pass on antibodies to the newborn through the placenta or breast milk? This is an area where we are beginning to see preliminary data. A few weeks ago, the CDC, for the first time in the pandemic, strongly encouraged pregnant women to receive the vaccine after finding no evidence of adverse impacts to either the mother or baby. Furthermore, research now shows that the mother, after being fully vaccinated, does pass on antibodies through the placenta as well as in her breast milk. For more information on COVID and the vaccines, visit our COVID FAQs or Vaccine FAQs page. Testing is critical in our fight against COVID-19 Keep your children safe and have them tested frequently. Information provided by the Centers for Disease Control and Prevention, Harvard Medical, MIT Medical, John Hopkins Medical, The Mayo Clinic, and science reporter Emily Anthes from the New York Times.
Menopause management can help women adjust and find treatment options to reduce the severity of symptoms through the stages of this life change. Menopause is a natural condition that involves the loss of hormone function as women age. Typically, menopause affects women between the ages of 40 and 60. Medical professionals can help guide you through this transition with personalized menopause management. There are three main stages of menopause: perimenopause, menopause and post-menopause. In perimenopause, the body's hormone and estrogen levels begin to drop. Symptoms like menstrual irregularity, hot flashes and mood changes may begin to appear. Since you can still become pregnant at this stage, it is important to continue to use birth control. It can take three to five years for your body to reach menopause, which is when you have your last menstrual period. When you have not had a period for 12 consecutive months, you are then in post-menopause. It's difficult to predict exactly when you will begin to experience menopausal symptoms. Depending on your family history and individual health status, you will be affected at different times, and your symptoms will vary. Your health care provider will be able to counsel you on your treatment options, including the benefits and drawbacks of hormone therapy, which may involve the use of either synthetic estrogen or progesterone. You also may decide to investigate whether prescription pills or low-dose birth control pills can help relieve symptoms. Menopause management includes professional recommendations on lifestyle changes to help reduce stress and increase overall health — two changes that can help ease menopausal symptoms. Form a plan to increase exercise and change your diet. By decreasing alcohol and caffeine consumption, adding more fruits and vegetables and reducing the amount of fat and overall calories you eat, your health will improve and you will find the side effects of menopause may be less disruptive to your daily life. Just as each woman will experience menopause differently, every woman also needs personalized care to help navigate this natural transition. Discuss your needs with Rocky Mountain Women's Health Center and receive the compassionate, caring assistance you need with menopause management.
Magnetic separation and HGMS processes have been used extensively in the processing of minerals (14), and more recently for water treatment and environmental applications (15). This research differs significantly from common magnetic separation and HGMS processes. For this, we have studied the silica enrichment process using a magnetic separation. Moreover, a leaching process by using hydrochloric acid has been studied under various experimental conditions; the parameters studied were hydrochloric concentration, temperature, and time of contact. Recovery of alumina from magnetic separation tailings of red mud has been investigated by Na 2CO 3 solution leaching. X ray diraction (XRD) results show that most of the alumina is present as 12CaO198;7Al 2O 3 and CaO198;Al 2O 3 in the magnetic separation tailings. The shrinking core model was employed to describe the leaching kinetics. Results showed that by the integrated modeling of leaching and adsorption with regard to formed and adsorbed complexes, the leaching and adsorption processes can be predicted with errors less than 5%. leaching and adsorption magnetic separator overall service Everest Nepal Restaurant Ore Flotation Separator Ore . Service support. Mineral Dressing Test Mine Design A wet permanent magnetic separator for separating strong magnetic minerals. Adsorption of Copper and Zinc in Bentonite Clay.HAMDI A.M.Sequential leaching of the adsorbed ions revealed that the amounts of desorbed ion are linearly Sanchez G A,Ayuso E A and Blas O J,Clay Minerals,1999,34,469 477.5. A surface ion imprinted magnetic silica sorbent for the separation and determination of leaching silver in antibacterial food contact products. Guo Qiang Xiang, Yu Long Ma, Jun Feng Yang, Fan Wang, Jin Rong Wang, Bo Wang . Henan University of Technology, Lianhua Road, High Tech Zone, Zhengzhou, Henan 450001, China. antimony ore leaching and adsorption egypt Effect of Metal Impurities on Adsorption of Gold by CDC Stacks Oct 3,1989and mineral resources and works to assure that their development is inantimony,arsenic,cobalt,copper,iron,nickel,thallium,and zinc maycyanide leach solutions,have on the adsorption of gold by activated carbon. the process. Furthermore, magnetic separation method is also beneficial with regard to the environment because it does not result in the production of contaminants such as flocculants . This makes magnetic nanoparticles as excellent candidate for combining metal binding and selective adsorption properties with ease of phase separation. magnetic separator leaching and adsorption new Magnetic Separation of Ore, Roller Magnetic Separator, Wet . Counter flow type permanent magnetic drum separator slurry flows over against drum, which create great conditions for cleaning of non magnetic ores. Feb 15, 20180183;32;A wide variety of gold separation equipment options are available to you, such as gravity separator, flotation separator, and magnetic separator. Get Price China small scale mining equipment wholesale [ Leaching and adsorption of gold CIP production line] Adding carbon in the leaching tank; the carbon absorbs gold becoming gold loaded carbon. Adsorption and ion exchange processes can recover dissolved metals from solutions, separate one metal from another in leach liquors, and remove impurities from aqueous streams. Adsorption on activated carbon is the most widely used method to recover gold from cyanide solutions. Accepted Manuscript Superior lithium adsorption and required magnetic separation behavior of iron doped lithium ion sieves; This content will become publicly available on September 9, 2019. Superior lithium adsorption and required magnetic separation behavior of iron doped lithium ion sieves. The magnetic separation performed ahead of leaching has been efficient by means of buffering the high pH via washing out the soluble salts and the excess of bases and applied after leaching has facilitated the removal of secondary liberated gangue minerals in the non magnetic fraction. Through the experiment, the first is pre discarding tailings by centrifuge, and then the gold is recovered by cyanidation leaching with using of H 2 O 2 to increase the rate of gold dissolution. The golds leaching rate can reach 97.60%. The qualified iron concentrate can be got from leaching slag and gravity tailings by magnetic separation.
Tranilast is an allergy medium-blockers, inhibit allergens and other stimuli cause mast cell degranulation and the release of allergy mediators reaction. Having a cell membrane stabilizing mast cells and basophils, preventing degranulation. Thereby inhibiting the release of histamine and serotonin substance of anaphylaxis, the IgE antibodies cause allergic skin reaction and experimental rats significantly inhibited asthma is an allergic disease pathogenesis for the cause of therapeutic drugs. Except tranilast with other antihistamine that tranilast suppressed due to the treatment of allergic reactions, can effectively prevent the occurrence and development of allergic reactions. And antihistamines, corticosteroids compared to the side effects, allergic reactions significant effect. 1, TNL can inhibit mast cells and basophils phosphodiesterase that elevated levels of intracellular cyclic AMP, reduce free calcium into the cell, cell membrane stability, prevent degranulation and histamine release and other chemical media. 2, reduce serum IgE levels: The IgE binds to the antigen can mast cells to release histamine and serotonin and other chemicals. TNL is not only a mast cell stabilizer, is also likely to produce IgE plasma cell lines inhibited. If you have more interest in our pharmaceutical raw materials such as Mesalazine API supplier China, please take a view at our site and contact us to get more information.
Q & M Dental Group has entered into a Collaboration Agreement with IMUE to develop an AI-enhanced dental treatment decision support system for the management of common dental problems. The clinical management of dental problems is highly dependent on the diagnoses of the dentists which require a great deal of knowledge of, amongst other factors, the various risk factors, treatment plans, treatment outcomes, individual patient's conditions, and incidence and progression rates. As dentists are limited by and differ in their cognitive functions, these factors combined may result in a divergence in diagnoses and subsequent treatment plans made by different dentists. The AI-enhanced dental treatment decision support system will put in place the best dental expertise that not only provide the most appropriate treatment but also automate and optimize the involvement of human judgement. Q & M continues to launch initiatives to convert these challenges into advantages, further improving the quality of treatments received by patients and patient experience. The AI Project is focused on the development of AI algorithms to intelligently assist dental treatment decision-making. The end product will produce the most comprehensive treatment plans in the best interests of the patients and will aid the dentists in ensuring early and/or complete detection of dental problems. Further, it can be used as an adjunct training tool which Q & M can leverage upon in the continuing education of its pool of more than 200 dentists. International Medical University (IMU) is the largest private premier higher learning educational institution in Malaysia owned and operated by IMUE, a company incorporated in Malaysia. The development of the AI system will involve expertise from IMU School of Dentistry, responsible for the development of the evidence-based decision tree, and the IMU Institute for Research, Development and Innovation, in-charge of getting results into the AI system and validating them. The evidence-based decision tree will be developed based on available research sourced by lecturers in IMU and strengthened by anonymized data. These will then be further verified by a panel of dental specialists at Q & M. The AI system will draw on the dental knowledge and expertise of Q & M, which has the largest collective of qualified dentists and dental specialists in private dental healthcare in Singapore. The system will be able to provide evidence-based treatment plans that further enhances the insight of the dentist as well as increases patient confidence in Q & M. It will also reinforce dentists' ability to discuss preventive measures with patients, to reduce the risk of patients contracting further common dental problems by analyzing the patients' profile in real-time. Q & M will own the rights to the technology and the AI Project will be funded through internal resources. Q & M is also in the process of registering a patent for this AI-enhanced dental treatment decision support system. Dr Ng Chin Siau, Group CEO of Q & M commented, "The welfare of our patients is paramount. This AI-enhanced support system will help further develop our patient-centric approach which respects patient autonomy by increasing their understanding about their own health. Our patients will be able to receive personalized diagnoses and treatment plans which take into account their own specific characteristics. Patients will also receive advice on preventive measures to minimize the risk of succumbing to oral diseases in the future.
BACKGROUND: The self-expandable metallic stent (SEMS) has been widely used for unresectable malignant biliary obstruction but eventually becomes occluded by tumor ingrowth/overgrowth and sludge. Therefore, we aimed to determine the therapeutic effectiveness of secondary stents and to find differences according to various combinations of the first and second stents for the management of occluded SEMSs in patients with malignant distal biliary obstruction. METHODS: Between 1999 and November 2008, 77 patients with malignant biliary obstruction underwent secondary biliary stent placement as "stent-in-stent" at three university hospitals in Korea (40 covered, 26 uncovered, and 11 plastic stents). The membrane of the covered SEMS was regarded as the barrier against tumor ingrowth. We categorized the patients into three groups based on whether the covered SEMS was either the first or the second stent: membrane-SEMS (18 covered-covered; 9 covered-uncovered; 22 uncovered-covered SEMS), bare-SEMS (17 uncovered-uncovered SEMS), and plastic stent (3 covered-plastic; 8 uncovered-plastic). RESULTS: The median patency of second stents was 138, 109, and 88 days (covered, uncovered, and plastic stents). The second covered SEMSs had a significantly longer patency than plastic stents (p=0.047). In a multivariate analysis including membrane-SEMS, bare-SEMS, and plastic stent groups, the bare-SEMS had a worse cumulative stent patency (HR=2.04, CI=1.08-3.86) and survival time (HR=2.37, CI=1.25-4.49) than the membrane-SEMS. Patients with ampulla of Vater cancer had better stent patency (HR=0.27, CI=0.08-0.98) and survival (HR=0.17, CI=0.04-0.77) than those with other pancreatobiliary malignancies. In addition, antitumor treatment prolonged survival time (HR=0.50, CI=0.26-0.99). CONCLUSIONS: The placement of additional biliary stents using the "stent-in-stent" method is an effective treatment for an occluded metallic primary stent. In addition, double biliary SEMS placement using at least one covered SEMS (in the primary and/or secondary procedure) might provide longer cumulative stent patency and survival than using uncovered SEMSs in both procedures.
Innis SM, Elias SL. Intakes of essential n-6 and n-3 polyunsaturated fatty acids among pregnant Canadian women. Am J Clin Nutr. 2003 Feb;77(2):473-8. BACKGROUND: Fetal growth requires n-3 docosahexaenoic acid (DHA), which is derived from the essential n-3 fatty acids in the maternal diet. DHA is accumulated in the developing brain and is critical for normal neural and visual function. Available estimates suggest that 67 mg DHA/d is accumulated by the fetus during the third trimester of gestation. Little is known about n-3 fatty acid intakes in pregnant women, although human milk concentrations of DHA have decreased in recent years. OBJECTIVE: We prospectively determined the n-3 and n-6 fatty acid intakes of 55 pregnant Canadian women. DESIGN: A food-frequency questionnaire was completed at 28 and 35 wk, and plasma n-3 and n-6 fatty acids were measured at 35 wk gestation. The fatty acid composition of approximately 500 foods was analyzed to allow analysis of dietary intakes from specific foods. RESULTS: Intakes, as a percentage of energy, were (macro x +/- SEM) total fat, 28.0 +/- 3.6%; saturated fat, 9.8 +/- 0.3%; monounsaturated fat, 11.2 +/- 0.4%; polyunsaturated fat, 4.7 +/- 0.2%; linoleic acid, 3.9 +/- 0.2%; and alpha-linolenic acid, 0.54 +/- 0.05%. The daily intakes (range) were 160 +/- 20 (24-524) mg DHA/d, 121 +/- 8 (15-301) mg arachidonic acid/d, and 78 +/- 2 (4-125) mg eicosapentaenoic acid/d. The plasma phospholipids had (mg/100 g fatty acid) 5.0 +/- 0.18 DHA, 8.7 +/- 0.18 arachidonic acid, and 0.52 +/- 0.32 eicosapentaenoic acid. CONCLUSION: The low intake of DHA among some pregnant women highlights the need for studies to address the functional significance of maternal fat intakes during pregnancy on fetal development.
There are many different types of vision problems that could be affecting your eyesight. But, for the purposes of this guide, we will be focusing on four of the most common causes of impaired vision. These, along with many other vision impairments, are treated with care and precision by the eye care providers at Yin Eyecare in Overland Park. In reality, most people have some degree of astigmatism, which is usually present at birth and is believed to be hereditary. In minor cases, treatment may not be required but is certainly beneficial. Moderate to severe astigmatism can be treated with corrective eyewear or refractive surgery, such as LASIK. If you are mildly farsighted, your eye care provider may not recommend corrective treatment at all. However, if you are moderately or severely hyperopic, you may have several treatment options available, including eyeglasses and contact lenses. Your eye care provider at Yin Eyecare will help you determine the best treatment option for you. Nearsightedness is diagnosed during routine eye exams and possible treatments include eyeglasses, contacts, refractive surgeries, such as LASIK and photorefractive keratotomy (PRK). Dr. Yin will suggest the best treatment option for you. Unfortunately, presbyopia is an inevitable part of aging and cannot be prevented by diet, lifestyle or visual habits. However, it is treatable with several types of corrective lenses, including progressives, bifocals and trifocals, single-vision reading glasses, multifocal contact lenses and monovision contact lenses. Your eye care provider at Yin Eyecare will work with you to diagnose your vision problem and suggest the best treatment option for your eyes at our optometric office in Overland Park. For more information, schedule an appointment with Cynthia Yin, O.D..
Medrad® Stellant® CT Injection System with Certegra® Workstation – First Medical International Corp. Intelligent, Intuitive, Innovative: Confidence Through Patient-centered Care and Efficiency. The Medrad® Stellant® CT injection system with Certegra® Workstation delivers new levels of efficiency and patient-centered care in CT imaging. An integral part of Bayer's CT imaging solution, the scalable informatics ready solution offers radiation dose management and Contrast Dose Management™ options—complete with injector interfacing between the scanner, PACS, RIS, and speech recognition systems. We support our CT solution with VirtualCare® Remote Support and flexible support service programs to meet your changing needs. The Certegra® Workstation is the cornerstone of the Bayer Certegra® @ Point of Care application, the industry's first1 Contrast Dose Management™ Solution. The data you need is centrally mobilized and instantly available.
Concussion as a multi-scale complex system: An interdisciplinary synthesis of current knowledge Erin S. Kenzie, Elle L. Parks, Erin D. Bigler, Miranda M. Lim, James C. Chesnutt, Wayne Wakeland Traumatic brain injury (TBI) has been called "the most complicated disease of the most complex organ of the body" and is an increasingly high-profile public health issue. Many patients report long-term impairments following even "mild" injuries, but reliable criteria for diagnosis and prognosis are lacking. Every clinical trial for TBI treatment to date has failed to demonstrate reliable and safe improvement in outcomes, and the existing body of literature is insufficient to support the creation of a new classification system. Concussion, or mild TBI, is a highly heterogeneous phenomenon, and numerous factors interact dynamically to influence an individual's recovery trajectory. Many of the obstacles faced in research and clinical practice related to TBI and concussion, including observed heterogeneity, arguably stem from the complexity of the condition itself. To improve understanding of this complexity, we review the current state of research through the lens provided by the interdisciplinary field of systems science, which has been increasingly applied to biomedical issues. The review was conducted iteratively, through multiple phases of literature review, expert interviews, and systems diagramming and represents the first phase in an effort to develop systems models of concussion. The primary focus of this work was to examine concepts and ways of thinking about concussion that currently impede research design and block advancements in care of TBI. Results are presented in the form of a multi-scale conceptual framework intended to synthesize knowledge across disciplines, improve research design, and provide a broader, multi-scale model for understanding concussion pathophysiology, classification, and treatment. https://doi.org/10.3389/fneur.2017.00513 Models of injury Multi-scale 10.3389/fneur.2017.00513 Dive into the research topics of 'Concussion as a multi-scale complex system: An interdisciplinary synthesis of current knowledge'. Together they form a unique fingerprint. Traumatic Brain Injury Medicine & Life Sciences 100% Brain Concussion Medicine & Life Sciences 64% Research Design Medicine & Life Sciences 40% Lenses Medicine & Life Sciences 24% Public Health Medicine & Life Sciences 18% Clinical Trials Medicine & Life Sciences 16% Kenzie, E. S., Parks, E. L., Bigler, E. D., Lim, M. M., Chesnutt, J. C., & Wakeland, W. (2017). Concussion as a multi-scale complex system: An interdisciplinary synthesis of current knowledge. Frontiers in Neurology, 8(SEP), [513]. https://doi.org/10.3389/fneur.2017.00513 Concussion as a multi-scale complex system : An interdisciplinary synthesis of current knowledge. / Kenzie, Erin S.; Parks, Elle L.; Bigler, Erin D.; Lim, Miranda M.; Chesnutt, James C.; Wakeland, Wayne. In: Frontiers in Neurology, Vol. 8, No. SEP, 513, 28.09.2017. Kenzie, ES, Parks, EL, Bigler, ED, Lim, MM, Chesnutt, JC & Wakeland, W 2017, 'Concussion as a multi-scale complex system: An interdisciplinary synthesis of current knowledge', Frontiers in Neurology, vol. 8, no. SEP, 513. https://doi.org/10.3389/fneur.2017.00513 Kenzie ES, Parks EL, Bigler ED, Lim MM, Chesnutt JC, Wakeland W. Concussion as a multi-scale complex system: An interdisciplinary synthesis of current knowledge. Frontiers in Neurology. 2017 Sep 28;8(SEP). 513. https://doi.org/10.3389/fneur.2017.00513 Kenzie, Erin S. ; Parks, Elle L. ; Bigler, Erin D. ; Lim, Miranda M. ; Chesnutt, James C. ; Wakeland, Wayne. / Concussion as a multi-scale complex system : An interdisciplinary synthesis of current knowledge. In: Frontiers in Neurology. 2017 ; Vol. 8, No. SEP. @article{b5714b8f2ad04530b264629e6b4bf27d, title = "Concussion as a multi-scale complex system: An interdisciplinary synthesis of current knowledge", abstract = "Traumatic brain injury (TBI) has been called {"}the most complicated disease of the most complex organ of the body{"} and is an increasingly high-profile public health issue. Many patients report long-term impairments following even {"}mild{"} injuries, but reliable criteria for diagnosis and prognosis are lacking. Every clinical trial for TBI treatment to date has failed to demonstrate reliable and safe improvement in outcomes, and the existing body of literature is insufficient to support the creation of a new classification system. Concussion, or mild TBI, is a highly heterogeneous phenomenon, and numerous factors interact dynamically to influence an individual's recovery trajectory. Many of the obstacles faced in research and clinical practice related to TBI and concussion, including observed heterogeneity, arguably stem from the complexity of the condition itself. To improve understanding of this complexity, we review the current state of research through the lens provided by the interdisciplinary field of systems science, which has been increasingly applied to biomedical issues. The review was conducted iteratively, through multiple phases of literature review, expert interviews, and systems diagramming and represents the first phase in an effort to develop systems models of concussion. The primary focus of this work was to examine concepts and ways of thinking about concussion that currently impede research design and block advancements in care of TBI. Results are presented in the form of a multi-scale conceptual framework intended to synthesize knowledge across disciplines, improve research design, and provide a broader, multi-scale model for understanding concussion pathophysiology, classification, and treatment.", keywords = "Complex, Concussion, Models of injury, Multi-scale, Networks, Systems science, Traumatic brain injury", author = "Kenzie, {Erin S.} and Parks, {Elle L.} and Bigler, {Erin D.} and Lim, {Miranda M.} and Chesnutt, {James C.} and Wayne Wakeland", note = "Publisher Copyright: {\textcopyright} 2017 Kenzie, Parks, Bigler, Lim, Chesnutt and Wakeland.", doi = "10.3389/fneur.2017.00513", journal = "Frontiers in Neurology", number = "SEP", T1 - Concussion as a multi-scale complex system T2 - An interdisciplinary synthesis of current knowledge AU - Kenzie, Erin S. AU - Parks, Elle L. AU - Bigler, Erin D. AU - Lim, Miranda M. AU - Chesnutt, James C. AU - Wakeland, Wayne N1 - Publisher Copyright: © 2017 Kenzie, Parks, Bigler, Lim, Chesnutt and Wakeland. N2 - Traumatic brain injury (TBI) has been called "the most complicated disease of the most complex organ of the body" and is an increasingly high-profile public health issue. Many patients report long-term impairments following even "mild" injuries, but reliable criteria for diagnosis and prognosis are lacking. Every clinical trial for TBI treatment to date has failed to demonstrate reliable and safe improvement in outcomes, and the existing body of literature is insufficient to support the creation of a new classification system. Concussion, or mild TBI, is a highly heterogeneous phenomenon, and numerous factors interact dynamically to influence an individual's recovery trajectory. Many of the obstacles faced in research and clinical practice related to TBI and concussion, including observed heterogeneity, arguably stem from the complexity of the condition itself. To improve understanding of this complexity, we review the current state of research through the lens provided by the interdisciplinary field of systems science, which has been increasingly applied to biomedical issues. The review was conducted iteratively, through multiple phases of literature review, expert interviews, and systems diagramming and represents the first phase in an effort to develop systems models of concussion. The primary focus of this work was to examine concepts and ways of thinking about concussion that currently impede research design and block advancements in care of TBI. Results are presented in the form of a multi-scale conceptual framework intended to synthesize knowledge across disciplines, improve research design, and provide a broader, multi-scale model for understanding concussion pathophysiology, classification, and treatment. AB - Traumatic brain injury (TBI) has been called "the most complicated disease of the most complex organ of the body" and is an increasingly high-profile public health issue. Many patients report long-term impairments following even "mild" injuries, but reliable criteria for diagnosis and prognosis are lacking. Every clinical trial for TBI treatment to date has failed to demonstrate reliable and safe improvement in outcomes, and the existing body of literature is insufficient to support the creation of a new classification system. Concussion, or mild TBI, is a highly heterogeneous phenomenon, and numerous factors interact dynamically to influence an individual's recovery trajectory. Many of the obstacles faced in research and clinical practice related to TBI and concussion, including observed heterogeneity, arguably stem from the complexity of the condition itself. To improve understanding of this complexity, we review the current state of research through the lens provided by the interdisciplinary field of systems science, which has been increasingly applied to biomedical issues. The review was conducted iteratively, through multiple phases of literature review, expert interviews, and systems diagramming and represents the first phase in an effort to develop systems models of concussion. The primary focus of this work was to examine concepts and ways of thinking about concussion that currently impede research design and block advancements in care of TBI. Results are presented in the form of a multi-scale conceptual framework intended to synthesize knowledge across disciplines, improve research design, and provide a broader, multi-scale model for understanding concussion pathophysiology, classification, and treatment. KW - Complex KW - Concussion KW - Models of injury KW - Multi-scale KW - Networks KW - Systems science KW - Traumatic brain injury U2 - 10.3389/fneur.2017.00513 DO - 10.3389/fneur.2017.00513 JO - Frontiers in Neurology JF - Frontiers in Neurology IS - SEP
Our Delivery of Pharmacy Services in Residential Care Online Training Programme aims to provide pharmacists with the information they require to provide pharmacy services to residents in care settings. Our Management of Benzodiazepines and Z-drugs Training Programme aims to educate healthcare professionals on the legislation pertaining to benzodiazepines and the implications that has on the management of benzodiazepines in practice. Our Diagnosis and Treatment of an Acute Asthmatic Attack and the Supply and Administration of Salbutamol Training Programme enables pharmacists to diagnose and treat an acute asthmatic attack and supply and administer salbutamol in an emergency situation. Following a recent change to legislation, ( SI 449 of 2015 ), Cardiopulmonary Resuscitation (CPR) training is mandatory for all pharmacists wishing to supply and administer certain medicines. A list of Upcoming CPR Courses can be found in the Courses & Events menu. Our Developing Effective Communication Skills Online Course aims to enable pharmacists to consider the communication styles, approaches and techniques that are most effective in dealing with the different stakeholders they are engaged with in their daily practice. See more in the Online Courses section. Our online Diabetes Training Programme will give you the knowledge to deliver evidence-based care to patients with diabetes. All the information that you require to navigate through the core stages of the 2018/19 ePortfolio Review can be found here, including information on timelines, ePortfolio Review Information Events and support resources.
designed to target and destroy cancer cells. negative blood or urine pregnancy test. over 1 hour. This will be followed by an infusion into a vein of cisplatin over 2 hours. or until your doctor thinks it is no longer benefiting you. tests. The imaging tests include a chest x-ray and a CT scan of the head and neck area. on the status of the disease. You may continue receiving OSI-774 for as long as your cancer responds to study treatment. significant side effects or your medical condition worsens. patients who have relapsed. Its use in this study is considered investigational. of 50 patients taking part in this study. cavity, oropharynx, hypopharynx, or larynx. therapy, they must be off therapy for at least 6 months. 4. Be >= 18 years of age. or metastatic head and neck cancer. 2. Patients may not be receiving any other investigational agents. would confound the evaluation of neurologic and other adverse events. composition to OSI-774 or other agents used in the study. 5. Patient has received prior biologic therapy targeting EGFR. 6. Signs or symptoms of acute infection requiring systemic therapy. that may impair patient's understanding of the informed consent. 8. Requires total parenteral nutrition with lipids. 10. Histology other than squamous cell carcinoma. 11. Refusing to sign the informed consent. 12. History of severe hypersensitivity reaction to Taxotere®. 13. Pre-existing peripheral neuropathy NCI CTC grade 2 or worse. unknown Class agent with the potential for teratogenic or abortifacient effects. apply to other agents used in this study. receiving combination anti-retroviral therapy when indicated. To learn if giving the new drug, Tarceva® (OSI-774), in combination with Platinol® (cisplatin) and Taxotere® (docetaxel) is effective in the treatment of metastatic or recurrent head and neck cancer.
Home bclforge.com Overall health a books review of asexuality as a handicap and the A books review of asexuality as a handicap and the Topic: Sexual desire Dowload now Smoking cigarettes Nursing staff Gawain Green Completely happy Healthy balanced Clampdown dominance Klux Klan Urban centers Health safety Good person Conventional paper Economic system Insurance plan Various people believe that embedded in parts of the individual psyche is the innate wish to breed, breeding is how organisms pass on their inherited genes, so it may make sense which a creature's main goal is always to reproduce. Because of this, humans happen to be sexual creatures as well, and having kids is the existence goal of numerous. Asexuality difficulties this notion, however. Asexuality is defined as the lack of sexual desire or disinterest in having sex. It might be evaluated through three different means: intimate behavior, sex attraction, and identity (Brotto, Knudson, Inskip, Rhodes, Erskine, 2010). Around 1% worldwide identifies since asexual, which makes it one of the littlest sexual details (Bogaert, 2004). Due to the perception that individuals should the natural way have sex, asexuality has been negatively stigmatized, thought to either be considered a physical or perhaps psychological disorder. This books review will probably be reviewing this question: Is definitely asexuality a disability? The actual the two unique? Understanding the characteristics of asexuality has both biological and interpersonal benefits. Much of the research in back of asexuality tries to characterize it as being a biological problems or mental disorder. Below this view, asexuality is viewed as a disorder which should be treated, just like through hormone therapy or perhaps therapysuch just like hyposexual desire disorder (American Psychiatric Relationship, 1994). Yet , if various asexuals will not experience distress or broken interpersonal associations, should it still be classified being a disorder? If perhaps not a disorder, should asexuality even be remedied? A more deeply understanding of the origins of asexuality conserve valuable resources for those who do feel distress about their state. On top of that, identifying asexual qualities and the technology behind it can reduce the adverse social stigma attached to without having sexual wants. Much of this discrimination also stems from the queer community's long record with discrimination and institutionalization (Conrad Schneider, 1994). Having an personality allows one to connect with all their community and face day-to-day struggles with a supportive group behind them. There is certainly very little analysis regarding asexuality. This may be thanks, I believe, to the fact that the concept of asexuality as a sexual orientation features only recently become a subject of discussion. During the past, the fact that some almost never felt lovemaking attraction was of tiny note, instead, these emotions were associated with a sense of inability or of "being cracked. " As the asexual labeled has simply recently started to become more popular, very few persons may not even be aware that asexuality exists in the first place. One more why there may be so little studies that self-identified asexuals make-up such a small portion of the population, only about 1% (Bogaert, 2004). This provides fewer opportunities to get asexual subject matter and selection interviews, as they are harder to come across. Most of the research which i have come across pertaining to asexuality have had little sample sizes, especially with types of self-identified asexuals. Instead, many investigations have resorted to using online forms, tapping into well-known asexual areas such as The Asexual Visibility and Education Network (AVEN). Founded in 2001 by David Jay, the site states the goals as "creating acceptance by the general public and exploration of asexuality and facilitating the growth of an asexuado community" ("AVEN"). AVEN seeks to provide information not only to asking asexuals, but for their families and community as well. Studies have shown that asexual-identified individuals are incredibly open to working together with researchers to be able to progress their scientific understanding (Brotto, Knudson, Inskip, Rhodes, Erskine, 2010). The paper "Asexuality: Classification and Characterization" by Prause and Graham (2007) created an online questionnaire used by 1, 146 individuals (N = forty one self-identified asexuals). This set of questions asked inquiries regarding intimate history, intimate excitation and inhibition, sexual interest, and a great open-response section regarding asexuality. Asexuals reported less sex history with partners, significantly less sexual fermentation, and less arousability or desire. Surprisingly, they were doing not substantially differ from non-asexuals in regards to sex inhibition or perhaps desire to masturbate. This indicates the fact that primary characteristic of asexuality is lack of sexual desire. Although this newspaper does focus on the differences between sexuals and asexuals, that primarily concentrates on this concept exclusively and does not discuss the effect asexality has on the self-identified asexuals' lives. Asexuality may frequently at times be confused with other similar internal or natural disorders. Among these circumstances are hypoactive sexual desire disorder and lovemaking aversion disorder. Hypoactive sexual interest disorder, or perhaps inhibited sexual interest, was a sex dysfunction defined by the Analysis and Record Manual of Mental Disorders Fourth Copy (DSM-IV) being a lack of desire for sexual activities for six months or longer. In the Diagnostics and Statistical Manual of Mental Disorders Fifth Copy (DSM-V) the disorder was erased and replaced with male hypoactive sexual interest disorder and female sexual interest/arousal disorder. It is important to note that to be marked as a disorder, it must cause extreme distress for the person or sociable difficulties. There has been much demonstration as to the introduction of these disorders into the DSM-V, primarily coming from asexual activists who believe that this condition is just like the addition of homosexuality in the DSM until 1973. There are a handful of studies seeking to exploration the internal characteristics of asexuality, and what separates it apart from a mental disorder. One particular highly regarded analyze surrounding asexuality is Bogaert's (2004) "Asexuality: Prevalence and Associated Elements in a National Probability Sample". In this analyze, the author looks for to explore some of the shared features between a sample of 18, 000 Uk asexuals. Bogaert found that some of the prevalent characteristics contain gender (being a woman), short size, low economic status, low religiosity, a later menarche, low education, and poor health. This analyze suggests that that we now have, in fact , numerous psychosocial and biological factors that can lead to one being asexual. However , in his paper Bogart (2004) exclusively refers to asexuality because those who have by no means felt sex attraction prior to, excluding significant components such as sexual patterns and personality from his operational classification focusing on desire alone. 2 yrs later, Bogaert (2006) proceeded to write "Toward a Conceptual Understanding of Asexuality". This paper focuses on a number of the concepts lurking behind asexuality, talking about the similarities and differences between the libido and disorders such as hypoactive sexual desire disorder or sex aversion disorder. Bogaert (2006) concludes that asexuality must not necessarily end up being correlated with a psychological or biological disorder. In the newspaper "Asexuality: a mixed-methods approach" by Brotto, Knudson, Inskip, Rhodes, Erskine (2010), two studies had been conducted to increase understand asexuality. The 1st study analyzed relationship characteristics, sexual difficulties and distress, psychopathology, frequency of sexual actions, interpersonal functioning, and alexithymia in 187 self-reported asexuals from AVEN in an online questionnaire. Results found that their sex responses were not deemed while distressing and this masturbation rates for asexual men had been similar to reports from sex men. Interpersonal withdrawal was the most enhanced personality range, but sociable interaction was average. The 2nd study delved deeper in to these outcomes by selecting fifteen asexuals via mobile phone. Results identified that there have been not larger rates of psychopathology amongst asexuals and that the individuals evaluated were highly against asexuality being seen as a sexual desire disorder. A limitation on this study was that only people from IGUE were questioned. Because these individuals have seemingly acknowledged their asexuality, right now there may have been instances of selection opinion. A lack of sexual desire has not simply been suggested as a emotional disorder, but as a biological condition as well. Milligan and Neufeldt (2001) in "The Myth of Asexuality: A Survey of Social and Empirical Evidence" discusses the connection between people who have disabilities and asexuality, referencing the concern a large number of authors and advocacy organizations feel about all of them being viewed as asexual beings and thus faulty to be passionate partners. The authors discuss the studies behind why people with disabilities are connected with asexuality and how much more function is needed in the field to further the understanding of the lives of men and women with problems and asexuality. While it is usually argued that ascribing asexuality to disabled people is definitely problematic, much of this comes from the ethnical belief that asexuality can be negative or a disorder in itself. Brotto and Yuletide (2010) likewise approached the thought of sexual malfunction in asexuals in their conventional paper "Physiological and subjective lovemaking arousal in self-identified asexual women". In this study, the authors sought whether or not asexual women experienced psychophysiological lovemaking responses, computing arousal in both sexual and asexuado women when it comes to erotic and nonerotic movies. Results identified that there was clearly normal subjective and physiological arousal potential in the asexual women. That is why, the creators chose to never identify asexuality as a sexual dysfunction. However , it should be noted that study pertained only to female subjects, guy sexual and asexual subjects were not analyzed for arousability, leaving room for further exploration to be performed. Overall, research is suggesting that asexuality is usually neither a psychological disorder nor a sexual disorder. While asexuals tend to often share prevalent characteristics which include being girl and a later menarche, Anthony Bogaert suggests that you will find not enough features to distinctively describe asexualiy as a disorder (Bogaert, 2005, 2006). Research also reveal that asexuals do not feel extreme levels of distress more than their insufficient sexuality, neither is there a trend of psychopathology between them (Brotto, Knudson, Inskip, Rhodes, Erskine, 2010). In accordance with the biological part, Milligan and Neufeldt (2001) have asserted that asexuality as a great orientation is different from the not enough sexual actions exhibited simply by those with problems, citing the incorrect correlation people often bring between the two. Finally, Brotto and Yule (2010) selected not to define asexuality as being a sexual problems due to the fact that asexual women have normal very subjective and physiological capacity to always be aroused by erotic content material. Although a decrease in sexual desire can be a sign of physiological distress (such as with hypothyroidism) or internal distress (as with mood-hampering disorders including depression), there will be a crystal clear distinction among outside elements affecting sexual interest and asexuality. Conditions just like hypoactive sexual interest disorder are marked simply by extreme levels of distress. It should be noted, however , that asexual-identified individuals do not feel this relax upon coming to terms with their sexuality (Brotto, Knudson, Inskip, Rhodes, Erskine, 2010). There is certainly still much research to become done in relation to asexuality as a intimate orientation, but its recent introduction on the internet will with any luck , attract even more attention to this little comprehended label. 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Sex Qs Early Signs of HIV Medically reviewed by Michaela Murphy, PA-C — Written by Daniel Yetman — Updated on December 13, 2021 Early HIV symptoms AIDS symptoms Stages of HIV HIV transmission Testing and Diagnosis HIV is a virus that weakens your immune system. It's transferred through bodily fluids like semen, vaginal fluids, and blood. When it comes to HIV transmission, it's important to know what early symptoms to look for. Early detection of HIV can help ensure prompt treatment to control the virus and prevent progression into stage 3 HIV. Stage 3 HIV is more commonly known as AIDS. Early treatment using antiretroviral drugs makes the virus undetectable, which can prevent transmission to other people. In this article, we examine the early symptoms of HIV and symptoms that may develop as the disease progresses. Early symptoms of HIV The early signs of HIV, also known as acute retroviral syndrome, may appear as symptoms similar to those caused by the flu. These can include: tiredness or fatigue muscle and joint pain ulcers in the mouth ulcers on the genitals Early HIV symptoms generally develop within 2 to 4 weeks of transmission. Some people may not experience any early symptoms after they've contracted HIV. It's important to remember that these early HIV symptoms are also associated with common illnesses and health conditions. To be sure of your HIV status, consider speaking with a healthcare professional about testing options. A lack of symptoms can last for as long as 10 to 15 years. But this doesn't mean that the virus is gone. HIV is a manageable health condition. But left untreated, HIV can progress to stage 3 even if no symptoms are present. That's why it's so important to get tested. Symptoms of AIDS Symptoms that indicate HIV may have progressed to stage 3 include: high fevers chills and night sweats breathing problems and persistent coughing severe weight loss white spots in the mouth genital sores unexplained fatigue Depending on the phase of HIV, symptoms can vary. The first stage of HIV is known as acute or primary HIV infection. It's also called acute retroviral syndrome. During this stage, some people experience common flu-like symptoms that may be hard to distinguish from a gastrointestinal or respiratory infection. The next phase is the clinical latency stage. The virus becomes less active, though it's still in the body. During this stage, people experience no symptoms while the viral infection progresses at very low levels. This period of latency can last a decade or longer. Many people show no symptoms of HIV during this entire 10- to 15-year period. The final phase of HIV is stage 3. During this phase, the immune system is severely damaged and is vulnerable to opportunistic infections. Once HIV progresses into stage 3, symptoms associated with infections may become apparent. These symptoms can include: Symptoms associated with HIV itself, like cognitive impairment, can also become apparent. Is there a period when the virus isn't transmittable? HIV is transmittable soon after it's introduced into the body. During this phase, the bloodstream contains higher levels of HIV, which makes it easy to transmit it to others. Since not everyone has early symptoms of HIV, getting tested is the only way to know if the virus has been contracted. An early diagnosis also allows an HIV-positive person to begin treatment. Proper treatment can eliminate their risk of transmitting the virus to their sexual partners. When it comes to HIV symptoms, remember that it's not always HIV itself that makes people feel sick. Many HIV symptoms, particularly the most severe ones, arise from opportunistic infections. The germs responsible for these infections are generally kept at bay in people who have an intact immune system. But when the immune system is impaired, these germs can attack the body and cause illness. People who show no symptoms during early-stage HIV may become symptomatic and begin to feel sick if the virus progresses. When to seek medical care Early diagnosis is key. If you think you've been exposed to HIV or have an encounter that put you at risk for HIV, you should seek medical care right away with a primary care doctor, urgent or walk-in clinic, or, if those are not available to you, a local emergency room. Doctors can give you a medication called post-exposure prophylaxis after exposure to reduce your chances of developing HIV. But this medication needs to be taken within 72 hours of exposure. Ideally, you'd start taking it within the first 24 hours. If you think you were exposed to HIV in the past – for example, if a former sexual partner tells you they have HIV – it's critical to seek medical care as soon as possible. The sooner you find out you have HIV, the sooner you can start treatment. The Centers for Disease Control and Prevention (CDC) recommends everybody between the ages of 13 to 64 gets tested for HIV at least once. Getting tested for HIV HIV testing is important. Someone living with HIV who isn't getting treatment can still transmit the virus, even if they have no symptoms. Others may pass the virus to others through an exchange of bodily fluids. But today's treatment can effectively eliminate the risk of transmitting the virus to a person's HIV-negative sexual partners. According to the CDC, antiretroviral therapy can lead to viral suppression. When someone with HIV can maintain an undetectable viral load, they can't transmit HIV to others. The CDC defines an undetectable viral load as fewer than 200 copies per milliliter (mL) of blood. Taking an HIV test is the only way to determine whether the virus is in the body. There are known risk factors that increase a person's chance of contracting HIV. For example, people who've had sex without a condom or shared needles may want to consider seeing their healthcare professional about getting tested. Last medically reviewed on December 13, 2021 A Timeline of HIV Symptoms Erythema Multiforme Information and Treatment Synovial Fluid Analysis What Is Paraparesis and How Is It Treated? Unlike other viruses, HIV is a progressive disease in which symptoms and severity vary between people. We explain the common symptoms of each stage. Medically reviewed by Cynthia Cobb, DNP, APRN, WHNP-BC, FAANP Erythema multiforme (EM) is a skin condition that takes the form of bull's-eye-like lesions. Most of the time, it's minor and caused by an infection… Paraparesis means partial inability to move your legs. It's not the same thing as paraplegia. Here's why it happens, what to expect, and more. Medically reviewed by Daniel Murrell, MD Read about the most common HIV symptoms, from rash to fever, and which might affect a person in the early (acute) stage of HIV. Find out what symptoms… How to Apply for Disability Benefits Due to HIV HIV can cause health issues which may significantly impact your daily life. Here's what to know about applying for disability status with this… What Are the Early Signs and Symptoms of HIV in Men? The symptoms of HIV vary as much man-to-man, as between two people of different genders. Our guide can be useful for folks all across the gender… FDA Approves First Injectable HIV Prevention Drug Apretude is designed to be taken every 2 months. Experts say this will increase adherence to HIV prevention drug treatments. Humanizing HIV: The Young Activists Fighting for an End to HIV/AIDS Knowledge about HIV/AIDS is low among today's youth. Despite this, these four young activists are working to empower their peers with information… Pediatricians Recommend Routine HIV Screening for Youths as Early as 15READ MORE
Isolation of high-quality RNA, including miRNA, from microscopic woody apple bud meristem using laser capture microdissection-based method. It is often challenging to study the expression of microRNAs (miRNAs) or genes in less accessible inner tissues of tree species rich in polyphenols or polysaccharides. Here, we report a laser capture microdissection (LCM)-based method for efficient and cost-effective isolation and expression analysis of miRNAs and genes in the meristem tissue of woody apple bud. The tissue fixation, processing, infiltration, and sectioning steps were optimized for LCM-based excision and subsequent RNA isolation. Further, we have confirmed that RNA isolated from LCM-derived apple bud meristem contained miRNAs and was of good quantity and quality, sufficient for downstream expression analysis. The online version of this article ( https://doi.org/10.1007/s00425-019-03127-0) contains supplementary material, which is available to authorized users. SV acknowledges Department of Science and Technology-Science and Engineering Research Board (DST-SERB), Govt. of India, for National-Postdoctoral Fellowship (N-PDF file no. PDF/2016/002423). AKS and VG acknowledge funding from Department of Biotechnology (DBT), Govt. of India (research grant no. BT/PR12766/BPA/118/63/2015). We acknowledge LCM facility, other central instrument facility and internal grant of NIPGR. We thank Dr. Mohar Singh, ICAR-NBPGR, Regional Station Shimla, India for giving us access to collect apple bud samples. We thank the lab members (Shalini and Archita) for critical reading of the manuscript and valuable comments.
Integrated care for your whole body! We are passionate about helping people improve their health and physical well being through a variety of treatments provided by our team of dedicated practitioners. We understand that although our patients may be diagnosed with the same condition they respond very differently to treatments. For this reason, we tailor a specific plan of action to meet their needs, goals, and unique medical and physical condition. We have successfully treated patients with headaches, neck and back pain, shoulder pain, knee pain, osteoarthritis, fatigue, allergy problems, and many other related conditions. We aim to educate our patients about their condition in order to motivate them to take a more active and responsible role in restoring and maintaining their own health. By also educating them on natural solutions to many common health conditions, we hope they will become more informed consumers. Finding healthcare providers who understand changing health care needs and the most current techniques and approaches to addressing health problems can be a daunting task. We hope that you will find this site helpful in learning more about our approach to natural pain relief and integrative medicine, as well as the ways that it can improve the quality of your life. Learn more about the types of low back and neck pain we treat. Our staff is here to help. Find out about our non-surgical knee treatments. Splitting, stabbing, throbbing or aching? Find out how we can help! A car accident is a major event and the trauma that comes from them could be significant. We can help get you out of pain faster and ensure there are no underlying injuries.
• What is the chance my cancer will be cured if I get no additional treatment after surgery? • How much could this be improved if I take chemotherapy, endocrine therapy or both? • Does my cancer have a specific marker called "HER2?" If so, how does this change my treatment options? • If I need chemotherapy, how many sessions will there be, and how long will each session last? What are the side effects? Will I have to take off work, and if so, for how long? • Where has my cancer spread? What does this mean? • How can my symptoms be treated? • How much will the treatment improve my odds of living longer? What are the side effects, and which treatment will give me the best quality of life? • Which clinical trials are appropriate for me? Clinical trials are available for both early- and advanced-stage cancers and offer excellent opportunities to improve upon standard treatments. Read the informed consent document closely with family or friends before making a final decision, and do not be afraid to seek a second opinion from another cancer center.
Human T-lymphotropic virus style="background:#Template:Taxobox colour;"\|Human T-lymphotropic virus style="background:#Template:Taxobox colour;" \| Virus classification Group: Group VI (ssRNA-RT) Family: Retroviridae Subfamily: Orthoretrovirinae Genus: Deltaretrovirus Species: Simian T-lymphotropic virus Serotypes 2 HTLV-I 2.1 Prevalence 2.2 Transmission 2.3 Opportunistic infections 2.3.1 Mechanism 3 HTLV-II 4 HTLV-III and HTLV-IV Human T-lymphotropic virus (HTLV) is a human, single-stranded RNA retrovirus that causes T-cell leukemia and T-cell lymphoma in adults and may also be involved in certain demyelinating diseases, including tropical spastic paraparesis. Adult T-lymphotropic virus (ATLV) is a strain of this disease that affects primarily adults. A closely related virus is bovine leukemia virus BLV. HTLV-I HTLV-I is an abbreviation for the human T-cell lymphotropic virus type 1, also called the Adult T-cell lymphoma virus type 1, a virus that has been seriously implicated in several kinds of diseases including HTLV-I-associated myelopathy, Strongyloides stercoralis hyper-infection, and a virus cancer link for leukemia (see adult T-cell leukemia/lymphoma). Between one in twenty and one in twenty-five infected persons are thought to develop cancer as a result of the virus. HTLV was discovered in 1977 in Japan. The virus was first isolated by Drs. Bernard Poiesz and Francis Ruscetti and their co-workers in the laboratory of Robert C. Gallo at the NCI.[1] It was the first identified human retrovirus. Infection with HTLV-I, like infection with other retroviruses, probably occurs for life and can be inferred when antibody against HTLV-1 is detected in the serum. HTLV-I infection in the United States appears to be about half as prevalent as HIV infection among IV drug users and about one-tenth as prevalent in the population at large. Although little serologic data exist, prevalence of infection is thought to be highest among blacks living in the Southeast. A prevalence rate of 30% has been found among black intravenous drug abusers in New Jersey, and a rate of 49% has been found in a similar group in New Orleans.[2] It is possible that prevalence of infection is increasing in this risk group. HTLV-I infection in Australia is very high among the Indigenous peoples of central and northern Australia, with a prevalence rate of 10-30%. It is also high among the Inuit of Northern Canada.[1] Studies of HTLV-I antibody indicate that the virus is endemic in southern Japan, in northeastern Iran [3], in Peru, in the Pacific coast of Colombia and Ecuador, in the Caribbean, and in Africa. Transmission of HTLV-I is believed to occur from mother to child via breastfeeding; by sexual contact; and through exposure to contaminated blood, either through blood transfusion or sharing of contaminated needles. The importance of the various routes of transmission is believed to vary geographically. In Japan, the geographic clustering of infection and the rarity of unprotected sexual contact suggest that the virus is more dependent on mother-to-child transmission.[4] In the Caribbean, the geographic distribution of the virus is more uniform, and it is more common among those with many sexual partners, indicating that sexual transmission is more common.[5] Individuals infected with HTLV-1 are at risk for opportunistic infections, diseases not caused by the virus itself, but by alterations in the host's immune functions. HTLV-1, unlike the distantly related retrovirus HIV, has an immunostimulating effect, which, however, turns out to be immunosuppressive. The virus activates a subset of T-helper cells called Th1 cells. The result is a proliferation of Th1 cells and overproduction of Th1 related cytokines (mainly IFN-gamma and TNF-alpha). Feedback mechanisms of these cytokines cause a suppression of the Th2 lymphocytes and a reduction of Th2 cytokine production (maily IL-4, IL-5, IL-10 and IL-13). The end result is a reduction in the ability of the infected host to mount an adequate immune response to invading organisms that require a predominantly Th2 dependant response (these include parasitic infections and production of mucosal and humoral antibodies). In the central Australian Aboriginal population, HTLV-1 is thought to be related to their extremely high rate of death from sepsis. It is particularly associated with bronchiectasis, a chronic lung condition predisposing to recurrent pneumonia. It is also associated with chronic infected dermatitis, often superinfected with Staphylococcus aureus and a severe form of Strongyloides stercoralis infection called hyper-infection which may lead to death from polymicrobial sepsis. HTLV-1 is also associated with adult T cell leukemia/lymphoma, and has been quite well studied in Japan. The time between infection and onset of cancer also varies geographically. It is believed to be about sixty years in Japan, and less than forty years in the Caribbean. The cancer is thought to be due to the pro-oncogenic effect of viral DNA incorporated into host lymphocyte DNA, and chronic stimulation of the lymphocytes at the cytokine level may play a role in development of malignancy. The malignancy ranges from a very indolent and slowly progressive lymphoma to a very aggressive and nearly uniformaly lethal proliferative lymphoma. Treatment varies depending on the type of disease and varies from careful observation to aggressive chemotherapy and antiretroviral agents. HTLV-1 is also associated with a progressive demyelinating upper motor neurone disease known as HAM/TSP for HTLV-1 associated myelopathy/Tropical Spastic Paparparesis characterized by sensory and motor deficits, particularly of the lower extremities, incontinence and impotence. [6] Less that 2% of infected individuals develop HAM/TSP, but this will vary dramatically from one geographic location to another. HTLV-II A virus closely related to HTLV-I, HTLV-II shares approximately 70% genomic homology (structural similarity) with HTLV-I. It is found predominantly in IV drug users and Native Americans, as well as Caribbean and South American Indian groups. HTLV-II has not been clearly linked to any disease, but has been associated with several cases of myelopathy/tropical spastic paraparesis (HAM/TSP)- like neurological disease. HTLV-III and HTLV-IV The terms "HTLV-III" and "HTLV-IV" have been used to describe recently characterized viruses.[7][8] These viruses were discovered in 2005 in rural Cameroon, and were apparently transmitted from monkeys to hunters of monkeys through bites and scratches. HTLV-III is similar to STLV-III (Simian T-lymphotropic virus 3), but HTLV-IV does not resemble any known virus. It is not yet known how much further transmission has occurred among humans, or whether the viruses can cause disease. The use of these names can cause some confusion, because the name HTLV-III was the former name of HIV in early AIDS literature, but has since fallen out of use.[9]. Also, the name HTLV-IV has been used to describe HIV-2.[10] Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis. 2007 7(4):266-81. ↑ Poiesz BJ, Ruscetti FW, Reitz MS, Kalyanaraman VS, Gallo RC. Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with Sezary T-cell leukaemia. Nature 1981;294(5838):268-71. ↑ Cantor et al., 1991. HTLV I/II seroprevalence and HIV/HTLV coinfection among United States intravenous drug users. J. Acquired Immune Defic-iency Syndrome. 4, 460-7. ↑ Sabouri, AH. (2005). "Differences in viral and host genetic risk factors for development of human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis between Iranian and Japanese HTLV-1-infected individuals". J Gen Virol. 86 (3): 773–81. PMID 15722539. ↑ Tajima, K. (1988). "The third nation-wide study on adult T-cell leukaemia/lymphoma (ATL) in Japan: characteristic patterns of HLA antigen and HTLV-I infection in ATL patients and their relatives. The T- and B-cell Malignancy Study Group". Int J Cancer. 41 (4): 505–12. PMID 2895748. ↑ Clark J, Saxinger C, Gibbs W, Lofters W, Lagranade L, Deceulaer K, Ensroth A, Robert-Guroff M, Gallo R, Blattner W (1985). "Seroepidemiologic studies of human T-cell leukemia/lymphoma virus type I in Jamaica". Int J Cancer. 36 (1): 37–41. PMID 2862109. CS1 maint: Multiple names: authors list (link) ↑ Osame, M. (1986). "HTLV-I associated myelopathy, a new clinical entity". Lancet. 3 (1): 1031–2. PMID 2871307. ↑ Mahieux R, Gessain A (2005). "New human retroviruses: HTLV-3 and HTLV-4". Med Trop (Mars). 65 (6): 525–8. PMID 16555510. ↑ Calattini S, Chevalier S, Duprez R, Afonso P, Froment A, Gessain A, Mahieux R (2006). "Human T-cell lymphotropic virus type 3: complete nucleotide sequence and characterization of the human tax3 protein". J Virol. 80 (19): 9876–88. PMID 16973592. CS1 maint: Multiple names: authors list (link) ↑ Human+T-Lymphotropic+Virus+Type+III at the US National Library of Medicine Medical Subject Headings (MeSH) ↑ Human+T+Lymphotropic+Virus+Type+IV at the US National Library of Medicine Medical Subject Headings (MeSH) med/1038 at eMedicine - "human T-cell lymphotrophic virus" International Retrovirology Association Human+T-lymphotropic+virus+1 at the US National Library of Medicine Medical Subject Headings (MeSH) de:HTLV it:HTLV sv:HTLV Template:Jb1 Template:WH Template:WikiDoc Sources Retrieved from "https://www.wikidoc.org/index.php?title=Human_T-lymphotropic_virus&oldid=716702" Retroviruses This page was last edited 18:20, 4 September 2012 by wikidoc user WikiBot.
Fine lines and wrinkles are an unwelcome part of the aging process. These skin conditions grow increasingly visible as we get older, sometimes leading us to feel older than we actually are. Although most people simply live with it, others seek methods that address these skin concerns without the need for surgery. Although cosmetic surgery often offers dramatic results, it can come at a cost. Not only can surgical procedures be expensive, they often involve extensive recovery periods and downtimes. Some people prefer methods that appear more natural. One such technique is a dermal filler called Restylane®. Most people have never heard of hyaluronic acid, but it turns out to be a major contributor to the appearance and health of your skin. Hyaluronic acid encourages your skin cells to take in water. As a result, your skin appears more moist and plump. Unfortunately, as you age, your skin begins receiving less and less hyaluronic acid, and the effects start to show as dry, thinner skin that displays more fine lines and wrinkles. Restylane® is a type of dermal filler containing hyaluronic acid. It involves an injection of the gel into your skin to replace the lost hyaluronic acid. This makes the process work in reverse. Your skin takes in moisture and gains volume, smoothing away fine lines and wrinkles and moisturizing your skin from the inside out. The results of a Restylane® treatment can be seen immediately and will continue to develop over the course of the following hours and days. Your results will also appear completely natural, since we are only restoring hyaluronic acid, resulting in the appearance of a younger version of yourself. It is important, however, to realize that the results of treatment with Restylane® are not permanent. Although your results should last for several months, at some point you will need follow-up treatments to maintain them, since the injected hyaluronic acid will be gradually absorbed and broken down by your body. Different fillers are good for different areas. Restylane® is particularly effective at treating the areas under the eyes, since it draws in less water that could make under-eye bags worse. Another advantage to Restylane® treatment is that very few side effects are associated with the process. There is no downtime or recovery period involved with Restylane® treatment. You may go home or return to work immediately after your session. Talk to the team at Grossman Dermatology to learn more information about how Restylane® can benefit you. We offer a variety of different dermal fillers at our offices in Santa Monica and New York City. Contact us today to schedule your consultation!
iQuest Avenda wins FDA IDE nod for AI-enabled prostate cancer therapy Avenda Health announced that it received FDA investigational device exemption (IDE) for its FocalPoint ablation system power by iQuest. The IDE will allow Avendra to combine the two technologies in a randomized, controlled trial to show superiority over the standard of care for the treatment of prostate cancer. iQuest uses artificial intelligence (AI) and deep learning to map prostate cancer and provide physicians with a precise location of cancer within the gland, plus a better understanding of the extent of the disease to help with treatment planning. According to a news release, a retrospective study of 50 patients demonstrated that iQuest improved tumor margin creation over conventional treatment planning from 56% to 80%. California-based Avenda designed its FocalPoint laser ablation system to treat localized prostate cancer in-office while preserving quality of life. Avendra's system received FDA breakthrough device designation last year. "Our mission is to advance prostate cancer therapy so patients no longer need to choose between treatment or quality of life," said Dr. Shyam Natarajan, co-founder and CEO of Avenda Health. "Using the latest deep learning technology, iQuest gives physicians and their patients more insights to identify the best treatment on an individual basis. We're thrilled to receive IDE approval so we can further prostate cancer research for the millions of men affected each year." Avenda, a spinout of UCLA with support from a National Cancer Institute grant, aims for its FocalPoint system to re-imagine laser ablation to enable a prostate cancer treatment outside an MRI under ultrasound guidance in a doctor's office. The company said it is building a "more personalized and targeted standard of care for prostate cancer." "This clinical trial will play a key role in advancing our breakthrough technology to improve prostate cancer care," said Brittany Berry-Pusey, Avenda co-founder and COO. "With no new FDA approvals for the treatment of localized prostate cancer in more than four decades, we look forward to working alongside our clinical sites to collect the data necessary to bring iQuest and FocalPoint to market and into the patient care environment." News, Recognition First AI-Powered Precision Oncology Platform for Prostate Cancer Care, iQuestTM, Receives FDA Clearance Avenda's Platform for Personalized Prostate Cancer Mapping Earns FDA Clearance iQuest™ is FDA cleared under K221624. Please consult the indications for use. Avenda Health, the logo, and all product and service names on this site are trademarks of Avenda Health unless otherwise noted. No use is permitted without prior written authorization. ©2023 Avenda Health. All rights reserved. Privacy Policy • Terms of Use
Do you have any physical impairment and have had a diagnosis of cancer, currently in remission or six months beyond treatment? Are you an adult living anywhere in the UK? If the answer is yes, please take a moment to consider participating in an interview study funded by Tenovus Cancer Care. The aim of the Challenges of Cancer and Disability Study, CoCaDS, is to improve cancer care for disabled people. It is carried out by researchers at the School of Healthcare Sciences, Cardiff University. If you are interested, please contact Dikaios Sakellariou at [email protected] or 07511554462 (text or voice).
Bone morphogenetic protein \| Article about Bone morphogenetic protein by The Free Dictionary https://encyclopedia2.thefreedictionary.com/Bone+morphogenetic+protein (redirected from Bone morphogenetic protein) Also found in: Dictionary, Thesaurus, Medical, Acronyms, Wikipedia. Related to Bone morphogenetic protein: Bone morphogenetic protein 4, Bone morphogenetic protein 7 Bône: see AnnabaAnnaba , formerly Bône (bōn), city (1998 pop. 348,554), capital of Annaba prov., extreme NE Algeria, a port on the Mediterranean Sea. One of the country's leading ports, the city is also an important administrative, commercial, and industrial center. ..... Click the link for more information. , Algeria. hard tissue that forms the skeletonskeleton, in anatomy, the stiff supportive framework of the body. The two basic types of skeleton found among animals are the exoskeleton and the endoskeleton. The shell of the clam is an exoskeleton composed primarily of calcium carbonate. ..... Click the link for more information. of the body in vertebrate animals. In the very young, the skeleton is composed largely of cartilage and is therefore pliable, reducing the incidence of bone fracture and breakage in childhood. The inorganic, or mineral, content of bone is mainly calcium, phosphate and carbonate minerals. The organic content is a gelatinous material called collagen. As the body grows older, decreases in bone mass may lead to an increased vulnerability to fractures. Bone fractures heal naturally, although they are often aided through restriction of movement in the affected area. Bones assume a variety of sizes and shapes; however, all bone tissue has a three-layered composition. A spongy layer forms the interior. Long bones (such as those in the arms and legs) are hollow, the inner spaces being filled with marrow (see bone marrowbone marrow, soft tissue filling the spongy interiors of animal bones. Red marrow is the principal organ that forms blood cells in mammals, including humans (see blood). In children, the bones contain only red marrow. ..... Click the link for more information. ), important in the formation of blood cells. Surrounding the spongy, inner layer is a hard, compact layer that functions as the basic supportive tissue of the body. The outer layer is a tough membrane called the periosteum, which sheaths most bones. Although bone appears solid, it contains numerous microscopic canals permitting the passage of blood vessels and nerve fibers. Two types of bone are present in most bones: compact, which constitutes the shaft, and cancellous, an extremely strong variety which makes up the enlarged ends of the bone. See also osteoporosisosteoporosis , disorder in which the normal replenishment of old bone tissue is severely disrupted, resulting in weakened bones and increased risk of fracture; osteopenia results when bone-mass loss is significant but not as severe as in osteoporosis. The hard connective tissue that, together with cartilage, forms the skeleton of humans and other vertebrates. It is made of calcium phosphate crystals arranged on a protein scaffold. Bone performs a variety of functions: it has a structural and mechanical role; it protects vital organs; it provides a site for the production of blood cells; it serves as a reserve of calcium. See Connective tissue There are two types of bone in the skeleton: the flat bones (for example, the bones of the skull and ribs) and the long bones (for example, the femur and the bones of the hand and feet). Both types are characterized by an outer layer of dense, compact bone, known as cortical bone, and an inner spongy bone material made up of thin trabeculae, known as cancellous bone. Cortical bone consists of layers of bone (lamellae) in an orderly concentric cylindrical arrangement around tiny Haversian canals. These interconnecting canals carry the blood vessels, lymph vessels, and nerves through the bone and communicate with the periosteum and the marrow cavity. The periosteum is a thin membrane covering the outer surface of bone and consisting of layers of cells that participate in the remodeling and repair of bone. The cancellous bone is in contact with the bone marrow, in which much of the production of blood cells takes place. The interface between the cancellous bone and the marrow is called the endosteum, and it is largely at this site that bone is removed in response to a need for increased calcium elsewhere in the body. Bone is formed by the laying down of an osteoid matrix by osteoblasts, the bone-forming cells, and the mineralization of the osteoid by the development and deposition of crystals of calcium phosphate (in the form of hydroxyapatite) within it. It is the mineral, organized in a regular pattern on a collagen scaffold, that gives bone its stiffness. Osteoid contains largely fibers of type I collagen and lesser amounts of numerous noncollagenous proteins. Although the role of these proteins in bone is not well understood, it is thought that their particular combination in bone gives this tissue the unique ability to mineralize. It is clear that these proteins interact with each other and that collagen and several of the noncollagenous proteins can bind to specialized receptors on the surface of bone cells. This binding is important for the adhesion of the cells to the bone matrix, and also delivers behavioral signals to the cells. See Collagen The primary cell types in bone are those that result in its formation and maintenance (osteoblasts and osteocytes) and those that are responsible for its removal (osteoclasts). Osteoblasts form from the differentiation of multipotential stromal cells that reside in the periosteum and the bone marrow. Under the appropriate stimuli, these primitive stromal cells mature to bone-forming cells at targeted sites in the skeleton. Under different stimuli, they are also capable of developing into adipocytes (fat cells), muscle cells, and chondrocytes (cartilage cells). Osteocytes, which are osteoblasts that become incorporated within the bone tissue itself, are the most numerous cell type in bone. They reside in spaces (lacunae) within the mineralized bone, forming numerous extensions through tiny channels (cannaliculi) in the bone that connect with other osteocytes and with the cells on the endosteal surface. Osteocytes are therefore ideally placed to sense stresses and loads placed on the bone and to convey this information to the osteoblasts on the bone surface, thus enabling bone to adapt to altered mechanical loading by the formation of new bone. Osteocytes are also thought to be the cells that detect and direct the repair of microscopic damage that frequently occurs in the bone matrix due to wear and tear. Failure to repair the cracks and microfractures that occur in bone, or when this microdamage accumulates at a rate exceeding its repair, can cause the structural failure of the bone, such as in stress fractures. A large number of molecules that regulate the formation and function of osteoblastic cells have been identified. Circulating hormones, such as insulin, growth hormone, and insulinlike growth factors, combine with growth factors within the bone itself, such as transforming growth factor beta (TGFβ) and bone morphogenetic proteins (BMPs), to influence the differentiation of osteoblasts. Osteoclasts are typically large, multinucleated cells, rich in the intracellular machinery required for bone resorption. This is accomplished when the cells form a tight sealing zone by attachment of the cell membrane against the bone matrix, creating a bone-resorbing compartment. Into this space, the cell secretes acid to dissolve the bone mineral, and enzymes to digest the collagen and other proteins in the bone matrix. The removal of bone by osteoclasts is necessary to enable the repair of microscopic damage and changes in bone shape during growth and tooth eruption. Osteoclast-mediated bone resorption is also the mechanism for releasing calcium stored in bone for the maintenance of calcium levels in the blood. Most agents that promote bone resorption act on osteoblastic cells, which in turn convey signals to osteoclast precursors to differentiate into mature osteoclasts. These agents include the active form of vitamin D, parathyroid hormone, interleukin-1, interleukin-6, and interleukin-11, and prostaglandins such as prostaglandin E2. Differentiation to fully functional osteoclasts also requires close contact between osteoclast precursors and osteoblastic cells. This is due to a molecule called osteoclast differentiation factor (ODF) which is located on the surface of osteoblasts, binds to receptors on the surface of osteoclast precursor cells, and induces their progression to osteoclasts. Flat bones and long bones are formed by different embryological means. Formation of flat bones occurs by intramembranous ossification, in which primitive mesenchymal cells differentiate directly into osteoblasts and produce bony trabeculae within a periosteal membrane. The initial nature of this bone is relatively disorganized and is termed woven bone. Later, this woven bone is remodeled and replaced by the much stronger mature lamella bone, consisting of layers of calcified matrix arranged in orderly fashion. Long bones are formed by intracartilaginous development in which the future bone begins as cartilage. The cartilage template is gradually replaced by bone in an orderly sequence of events starting at the center of the growing bone. Cartilage remains at the ends of long bones during growth, forming a structure at each end termed the growth plate. Cartilage cells (chondrocytes) that arise in the growth plates proliferate and add to the length of the bone. This occurs during a complex series of events, with expansion both away from and toward the center of the bone. When the bone achieves its final length in maturity, expansion from the growth plate ceases. Cartilage persists at the ends of the long bones in a specific form called articular cartilage, which provides the smooth bearing surfaces for the joints. Bone is a dynamic tissue and is constantly being remodeled by the actions of osteoclasts and osteoblasts. After bone removal, the osteoclasts either move on to new resorption sites or die; this is followed by a reversal phase where osteoblasts are attracted to the resorption site. It is thought that growth factors that are sequestered in an inactive form in the bone matrix are released and activated by the osteoclast activity and that these in turn promote fresh osteoid production by the recruited osteoblasts. The new osteoid eventually calcifies, and in this way the bone is formed and replaced in layers (lamellae), which are the result of these repeated cycles. In growing bone, the activities of bone cells is skewed toward a net increase in bone. However, in healthy mature bone there is an equilibrium between bone resorption and bone formation. When the equilibrium between these two cell types breaks down, skeletal pathology results. The most common bone disease is osteoporosis, in which there is a net loss of bone due to osteoclastic bone resorption that is not completely matched by new bone formation. The best-understood cause of osteoporosis is that which occurs in women due to the loss of circulating estrogen after menopause. Another cause of osteoporotic bone loss is seen in disuse osteoporosis. Just as bone can respond to increased loading with the production of additional bone, bone is also dependent on regular loading for its maintenance. Significant bone loss can occur during prolonged bed rest or, for example, in paraplegia and quadriplegia. Likewise, an unloading of the skeleton (due to a lack of gravitational pull) in space flight results in severe bone loss in astronauts unless the effects of gravity are simulated by special exercises and devices. See Osteoporosis Many metabolic and genetic diseases can affect the amount and quality of bone. Metabolic diseases such as diabetes, kidney disease, oversecretion of parathyroid hormone by the parathyroid glands, anorexia nervosa, and vitamin D-dependent rickets may cause osteopenias (the reduction in bone volume and bone structural quality). Immunosuppressive therapy in organ transplant patients can lead to reduced bone mass, as can tumors of bone and other sites. Tumors can produce substances that cause the activation of osteoclastic bone resorption. In the genetically based disease osteogenesis imperfecta, mutations in the gene for type I collagen result in the production of reduced amounts of collagen or altered collagen molecules by osteoblasts. Other common diseases of the skeleton are diseases of the joints, such as rheumatoid arthritis and osteoarthritis. See Thyroid gland the principal element of the vertebrate skeleton. Bones, the joints and ligaments joining the skeletal bones, and the muscles attached to the bones by tendons together make up the locomotor apparatus. Bones are classified as long, or tubular (for example, the humerus and the femur), flat (for example, the bones of the skull), or short (for example, the vertebrae). The middle section of the long bones is called the diaphysis. The two ends are called the epiphyses. The articulations are either immobile (synarthroses; for example, cranial sutures) or mobile (joints, or diarthroses; for example, the articulations of the limbs). Bones consist of bony tissue, periosteum, marrow, blood and lymphatic vessels, nerves, and, in many cases, cartilage. Bony tissue, the main constituent, forms lamellae; the bone is considered compact or cancellous (spongy) according to the density of these lamellae. In long bones, the shaft is predominantly of the compact type of bony tissue, where the arrangement of lamellae depends chiefly on the distribution of the bone-feeding blood vessels in the haversian canals. In short bones and in the epiphyses of long bones, cancellous tissue is predominant; here, Table 1. Classification of boiler units according to parameters and output Parameters of superheated steam Rated steam output (tons/hr) Pressure (MN/m2 [kgf/cm2]) Primary superheated steam Secondary superheated steam Unit with natural circulation, with and without superheating. . . . . . . . . . 4 (40) 440 — 6.5, 10, 15, 20, 25, 35, 50, 75 10 (100) 540 — 60, 90, 120, 160, 220 14 (140) 570 — 160, 210, 320, 420, 480 Unit with natural circulation, with superheating and intermediate superheating of steam. . . . . . . . . . 14 (140) 570 570 320, 500, 640 Flow-through unit with superheating and intermediate superheating of steam. . . . . . . . . . 25.5 (255) 585-565 570 950; 1,600; 2,500 there are honeycomblike cavities, filled with marrow, between the lamellae or trabeculae. The trabeculae are arranged in the direction of greatest pressure and tension, ensuring maximum tensile strength with a minimum of material. Bones are covered with periosteum, which contains blood vessels and nerves. Bone is a variety of connective tissue. Insoluble salts (chiefly hydroxylapatite) constitute about 50 percent of its bulk. Bone cells, or osteocytes, lie embedded in the bone cavities (lacunae). They are linked to one another by thin processes in the canaliculi, through which they are supplied with nutrients. The intercellular substance of bony tissues consists of tightly packed collagen fibers (on the surface of which are hydroxylapatite crystals), polysaccharides, and proteins. The formation and calcification of the intercellular substance are brought about by osteoblasts, which become embedded in the intercellular substance during the course of osteogenesis (to become the osteocytes). Bony tissue is the body's main calcium depot, and it is active in calcium metabolism. Calcium is released by the resorption and bound by the formation of bony tissue. These processes occur during the reconstruction of bony tissue, which occurs constantly and throughout life. The shape of bone changes with changing mechanical loads. Bony tissue in the human skeleton is almost completely reconstructed every ten years; multinuclear cells called osteoclasts are involved in the resorption. Bone is classified as coarse-fibrous or fine-fibrous (lamellate) according to the arrangement of the collagen fiber in the ground substance. In coarse-fibrous bone the fibers are arranged randomly, but in fine-fibrous bone they form plates, or lamellae, in which most of the fibers are arranged in the same direction. Bones develop either from the embryonic connective tissue, mesenchyma, or directly (secondary, or cover, bone, such as the frontal and parietal bones), or by passing through a cartilaginous stage (primary, or substitution, bone, such as the humerus and the femur). Secondary bone, in terms of vertebrate evolution, developed from dermal scales that sank beneath the skin; primary bone originated as an ossification of cartilaginous endo-skeleton. The development of secondary bone involves the formation of a skeletogenous rudiment, a collection of mesenchymal cells that eventually become osteoblasts and form bone. In the development of primary bone, the initial formation in the skeletogenous rudiment is a cartilaginous model of the future bone. The model is replaced subsequently by bony tissue, and the cartilage disintegrates. The coarse-fibrous bone formed in the rudiment is replaced by fine-fibrous bone in some amphibians and reptiles, most birds, and mammals. The process of bone formation usually intensifies dramatically when a tubular bone is fractured. A chondro-osseous callus forms to reunite the fragments. The shape of the bone is restored in the course of further reconstruction. Bone can form in adult vertebrates, including man, not only as part of the skeleton but also in any connective tissue (ectopic osteogenesis). Zavarzin, A. A., and A. V. Rumiantsev. Kurs gistologii, 6th ed., chapter 6. Moscow, 1946. Ivanov, G. F. Osnovy normal'noi anatomii cheloveka, vols. 1–2. Moscow, 1949. Fridenshtein, A. la. Experimental'noe vneskeletnoe kosteoobrazovanie. Moscow, 1963. A. IA. FRIDENSHTEIN What does it mean when you dream about bones? Bones can obviously represent death, either literal or metaphorical. They can also symbolize a state of reduction or deprivation (as in being "stripped to the bare bones" and being left with a "skeleton crew"). Less ominously, bones may simply refer to the structure of something. [bōn] (anatomy) One of the parts constituting a vertebrate skeleton. (histology) A hard connective tissue that forms the major portion of the vertebrate skeleton. 1. any of the various structures that make up the skeleton in most vertebrates 2. the porous rigid tissue of which these parts are made, consisting of a matrix of collagen and inorganic salts, esp calcium phosphate, interspersed with canals and small holes <a href="https://encyclopedia2.thefreedictionary.com/Bone+morphogenetic+protein">bone</a> Amvrosievka Camp Atlanthropus Auditory Capsule Baikal Neolithic Cultures bone char Bone Dysplasias bone house bone meal Bone Tools Complications with the use of bone morphogenetic protein 2 (BMP-2) in spine surgery. The use of bone morphogenetic protein in spinal transforaminal lumbar interbody fusion: our experience Oocyte bone morphogenetic protein 15, but not growth differentiation factor 9, is increased during gonadotropin-induced follicular development in the immature mouse and is associated with cumulus oophorus expansion. Short term organ culture of mouse ovary in the medium supplemented with bone morphogenetic protein 15 and follicle stimulating hormone: a morphological, hormonal and molecular study Differential gene expression of bone morphogenetic protein 15 and growth differentiation factor 9 during in vitro maturation of porcine oocytes and early embryos. Role of growth differentiation factor 9 and bone morphogenetic protein 15 in ovarian function and their importance in mammalian female fertility--a review Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex. Posible papel del gen noggin en el desarrollo mandibular Quantitative analysis of bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) gene expressions in calf and adult bovine ovaries. Investigation of BMP15 gene polymorphism by PCR-SSCP in Arabic sheep breed population in khuzestan province Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. BMP-2 Polymorphism c.893TGreater thanA (rs235768) Does Not Affect Bone Mineral Density in Female Population of Lahore Bone morphogenetic protein 7 (BMP7) expression is a potential novel prognostic marker for recurrence in patients with primary melanoma. Bone morphogenetic protein levels in osteoarthritis/ Osteoartritte kemik morfogenik protein duzeyleri Bone Morphogenetic Proteins (BMPs) are a group of growth factors and cytokines which were originally discovered by their ability to induce formation of bone and cartilage, but are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue architecture throughout the body (2). Bone morphogenetic proteins: a new vista in bone regeneration Possible involvement of bone morphogenetic protein 2 in heterotopic ossification in metastatic lesion from urothelial carcinoma of bladder. Coordination of bone morphogenetic protein 2 (BMP2) and aberrant canonical Wnt/[beta]-catenin signaling for heterotopic bone formation in adrenal myelolipoma: A case report s bone morphogenetic protein (BMP) portfolio of development programs and associated intellectual property. Bioventus now the proud owner of Pfizer's BMP portfolio Comparison of the osteogenic activity of bone morphogenetic protein (BMP) mutants. Periplasmic expression of a novel human bone morphogenetic protein-7 mutant in Escherichia coli More recently a man-made version of a growth factor called bone morphogenetic protein has been used. Now, ultrasound shockwave therapy to heal fractures that won't join up Bondiuzhskii Bond-Lassell bond-line formula Bondone, Giotto di Bondopaddhai, Manik Bond's law Bond's third theory Bonds, Barry Lamar bondstone Bone Age bone ash bone bed bone chert bone coal bone oil bone seeker Bone, Eleanor "Ray" Bone, Henry bonecrusher disease bonedome bone-dry wood Bonellidae Boner, Ulrich Bones, Brom boneset Bonfante, Giuliano Bonfim Festival Bong, Richard Bongo, Albert-Bernard Bongo, Ali Bongo, Omar Bonham State Park Bonheur, Rosa Bone Mineral Content Index bone mineral content normalized for bone width Bone Mineral Densitometry bone mineral density Bone Mineral Density at Lumbar Spine Bone Mineral Density Distribution bone mineral density expressed as standard deviation score Bone Mineral Density Measurement bone modeling bone modelling Bone morephenic peptide Bone morephenic peptides Bone morphogenetic protein 10 bone morphogenetic protein 2B Bone morphogenetic protein 8A bone morphogenetic protein and associated noncollagenous proteins Bone Morphogenetic Protein I Bone Morphogenetic Protein Receptor Bone morphogenetic protein receptor type II bone morphogenetic protein receptor type-1A bone morphogenetic protein receptor type-1B bone morphogenetic protein receptor type-2 bone morphogenetic protein receptor, type IA bone morphogenetic protein receptor, type IB
Brain tumours may occur at any age, and do not appear to show predilections for ethnic groups or gender. Though there may be certain associations between the occurrence of brain tumours and a history of exposure to harmful factors including radiation and certain chemicals, as well as possible genetic predisposition, the reason for their occurrence remains largely unexplained. Benign brain tumours are generally not infiltrative in character, grow relatively slowly, and are usually amenable to complete surgical removal, and sometimes to non-surgical treatment alone. They do not show a tendency towards recurrence, recur if at all after an interval of many years, and usually do not recur with malignant change. Though they carry a generally good prognosis in terms of life expectancy and a better quality of life following treatment, depending on location, permanent disabilities may occur. Malignant brain tumours are generally infiltrative in character, grow relatively quickly, and usually require more than surgical treatment alone. Surgical treatment, when possible, is often followed by radiotherapy and/or chemotherapy. They carry a relatively negative prognosis in all respects, and some sort of permanent disability to various extents usually remains following treatment. Primary brain tumours refer to those which arise within the brain and its membranes itself, or from primitive developmental residual remnants and they do not usually metastasise outside the central nervous system. The majority of primary brain tumours, however, are either progressively malignant, or recurrent with increasing grades of malignancy in spite of early diagnosis or initial low-grade histology and systematic treatment. They are characterised by direct damage to normal brain tissue stemming from malignant change and infiltration of neighbouring, sensitive structures. Secondary brain tumours refer to metastases from malignant tumours in other areas of the body.
Tadalafil or generic Cialis 2.5 mg and 5 mg are daily use tablets comes from Canada manufactured by Mylan. It is a clinically proven, low-dose tablets used for the treatment of erectile dysfunction (or impotence) and the frustrated urinary symptoms of benign prostatic hyperplasia (BPH). The side effects of Tadalafil are mild, the common effects including diarrhea, headache, insomnia, nausea, flu-like symptoms, or sore throat.
science illustration illustration, writing, and design Fiction Writing Samples — http://medium.com/@ren.t.graham Opioid Crisis in the US It's no secret that the United States is broiling in the midst of an opioid epidemic. Even though it took until 2017 for the US Department of Health and Human Services to officially declare the opioid crisis a public health emergency, the escalating overdose risk has been going on since the late 1990s. Patients want to trust their physicians when it comes to prescribed medication, but for decades, doctors have been pressured by big pharmaceutical companies to over-prescribe opioid painkillers. Pharmaceutical companies with profits in mind over patient wellness guaranteed that opioid painkillers were non-addictive and safe for use. With no other affordable pain relief options at their disposal, doctors became reliant on prescribing economical opioid painkillers for patients with chronic pain, acute muscle soreness, and for those in recovery after surgery. When it comes to chronic diseases like cancer, even stronger opioids are needed to help patients manage pain. The synthetic opiate fentanyl was created for this express purpose. Fentanyl is 50 to 100 times more potent than morphine, which makes it incredibly dangerous if abused. Because it produces a more powerful psychoactive effect and requires less product for the same high, fentanyl is much cheaper to manufacture and distribute than traditional opioids. While fentanyl is an economic boon for illegal drug manufacturers looking to ship more product, it has led to a market saturated in heroin, cocaine, and other opiates that have been mixed with huge portions of fentanyl, often unbeknownst to the user. Fentanyl overdoses present a unique challenge to treat because of the drug's strength, and oftentimes multiple doses of the rescue medication naloxone are needed to reverse them. So who is most at risk for opiate overdose? Nearly 80 percent of opioid overdoses in the United States can be attributed to white, low income Americans, and are especially prevalent in the Appalachian "Rust Belt" region of the country. There are a variety of socioeconomic factors at play here, but the lack of available jobs has certainly been a major contributor to the widespread depression of the region. Low income Americans that are unable to afford the tuition costs associated with a college degree are less likely to be able to find work, integrate, and uplift, and thus more likely to turn to illicit drugs as a kind of emotional salve. Military veterans are another demographic where opioid abuse is rampant. Without access to necessary therapeutic treatments for chronic pain or PTSD that developed as a result of military service, many veterans account for a disproportionately high number of opioid-related deaths. To really drive home the scale of the epidemic, consider that more than 130 people in the United States die every day from opioid overdoses, and that in 2017 alone, there were 47,000 opioid-related deaths. The economic burden of the opioid crisis is over $78 billion a year, including the tallied costs of healthcare, lost productivity, addiction treatment, and criminal justice involvement. With 1 in 3 Medicare beneficiaries receiving a prescription of an opioid painkiller in 2016 and 30 percent of patients misusing their opioid prescriptions, overdose fatalities are only projected to rise. While the news certainly seems dire, there are a variety of things that can be done to combat the epidemic. First and foremost, it's important to ensure that proper justice is dealt to pharmaceutical companies who were well aware of the dangers of their painkillers and continued to aggressively market them to medical professionals anyway. Next, it's essential to create infrastructure to provide long term support for those suffering from opiate addiction. Safe injection clinics destigmatize addiction and simultaneously provide around-the-clock nurse supervision and naloxone treatment in the instance that an opioid overdose were to occur. If implemented, safe injection clinics can provide sufferers with informed options moving forward to treat addiction. Lastly, it's critical to invest in new pain management research to find other methods of management that don't rely on addictive medication. With these three key avenues funded and in place, physicians, politicians, and healthcare advocates will be able to create a safer place for vulnerable groups of people suffering not just from the effects of opiates, but from addictions of all kinds. Exam Room Sterilization: A Troubling History If you had been wheeled into a surgeon's operating theater before 1885, it was as good as a coin flip to determine the odds of your post-surgery survival. Even relatively minor injuries like compound fractures could lead to fierce sepsis complications. Surgeons believed that infection spread through a mechanism known as miasma--or "bad air"--and the only precaution that they took against it was to keep operating areas well-ventilated, presumably so all that "bad air" could escape. It didn't help that many surgeons would readily don garments splashed with pus and dried blood from previous procedures, and that neither hands nor surgical instruments were washed before or after an operation. Maybe most egregious of all, in some rural areas, it was common practice to apply a poultice of warm cow dung directly to the wound site to promote healing. At this time, Victorian-era doctors were only just grappling with the concept of germ theory, with many of them entirely dismissive of the idea that invisible microbes could be floating around in the air. Before there was a strong antiseptic foothold in the medical community, surgeons felt that germ theory was about as scientific as spiritualism and its claims of ghostly encounters and wisdom beyond the grave delivered via possessed planchette. There is, however, a long pre-germ theory history of people trying to tamper the spread and scope of infection. Ancient Egyptians used pitch or tar, resins, and aromatic herbs to ward off the spread of disease during body embalming. In 500 BC, Persians were aware that silver in drinking vessels could be used to preserve the purity of the water stored within. Even the Romans knew to sterilize medical implements by heating them over a fire or boiling them in a large cauldron of water before use. This knowledge, however, was lost, along with many things in the middle ages. As the bubonic plague spread across the European continent, stupefied healers tried desperately to burn sulfur and wood with the intent of chasing away the devouring sickness with little success. It wasn't until 1883 when Joseph Lister, a British surgeon, discovered a document on the existence of microbes, a research piece published as Recherches sur la putrefaction by French chemist Louis Pasteur. With the newfound backdrop of microbe theory, Lister hypothesized that this same microscopic life might also be responsible for the rapid spread of infection after surgery. To test his theory, he used carbolic acid--now more typically known as phenol--to sterilized medical implements, garments, the patient's wound site, and his own hands before operating. The results were immediate. In his practice alone, mortality from post-surgical infection dropped by nearly 40 percent. In modern medicine, there are plenty of options for physicians when it comes to keeping exam and operating rooms as sterile as possible. We are lucky to have disposable garments, high-powered autoclaves and dry heat sterilizers, as well as germicidal cleaners to keep surfaces clean and hostile to microbial life. Without the pioneering efforts of undaunted germ theorists like Lister and Pasteur, we would not enjoy such high standards of sterilization in physician offices today. The Science of Paralysis and the Central Nervous System Nearly 5.6 million people in the US alone live with paralysis of some kind day to day, which works out to nearly 1 in every 50 people. Despite being such a common medical condition, the exact mechanism underlying paralysis is varied, complex, and as with most symptoms originating in the brain, not especially well understood. The most common types of conditions that can lead to long-term paralysis include spinal cord injuries, broken neck, nerve-damaging diseases, and autoimmune diseases. The initial cause of these conditions are numerous. Everything from stroke to car crash to workplace injury to progressive autoimmune disease can result in living with paralysis. Paralysis can be localized--as in only occurring in a specific region like a limb or the face--or generalized in form. Generally paralysis is considered a chronic, life-long condition, but there are certain select circumstances where it can be temporary and symptoms can improve over time. But how does something like paralysis occur? To answer that, it's important to understand the central nervous system. Essentially, the central nervous system is made up of a combination of the brain and the spinal cord, and operates by way of nerve cells, or neurons, that make up a web of interconnected signal relays throughout the body. To understand how monumental the central nervous system is to the body consider this statistic: the brain itself utilizes about 20 percent of the total oxygen breathed in, all while accounting for only 2 percent of the body's total mass. Consisting of over 100 billion inter-meshed neurons, the brain is rightly viewed as one of, if not the most complex organ in the human body. The central nervous system is responsible for controlling all manner of physical responses in the body, both conscious movement and internal processes such as breathing, heart rate, hormone release, and body temperature. In order for the electrical relay to function properly, neurons must be protected by healthy glial cells. Glial cells, or neuralgia, support nerve cells in a variety of ways, including as an anchor between neurons and the blood supply, supporting the creation of the myelin sheaths that insulate electrical signals, providing a scaffolding on which neurons can grow, and in lining brain ventricles to supply cerebrospinal fluid. When there is significant damage to any portion of the central nervous system, that is when paralysis is likely to occur. A damaged neuron can no longer transmit a signal up or down the neuron chain between the brain and the limbs, so motor control is effectively dampened or entirely silenced. There are, however, a multitude of options for paralysis treatment and support. Mobility equipment such as wheelchairs, limb braces, and exterior supports can help people living with paralysis to remain autonomous and active. Physiotherapy with a trained physical therapist can aid in maintaining limb strength and muscle mass. Occupational therapy provides a way for people living with paralysis to adapt to everyday life at home and work through tasks that may prove challenging. And of course there is a whole market of medicine designed to relieve pain, stiffness, and muscle spasms associated with paralysis. As an emerging field of study, neurologists and physicians alike are sure to discover further therapeutic options in the future to augment and improve everyday life for people living with paralysis. History of Medicinal Honey Virtually every civilization has utilized honey for its medicinal properties, going back as far as 8,000 BCE. The Assyrians and Chinese used it as a topical solution for wounds, and almost all Egyptian medicine contained honey mixed with wine and milk. The ancient Greeks mixed together a tincture of vinegar and honey to treat pain from wound sites, especially common as a remedy for a soldier's war injuries. There are myriad illustrious passages in the Qur'an detailing the significance of honey as a remedy for any ailment. While it might not be a cure-all for everything, there is good reason for honey's reputation of ambrosia-like properties throughout medical history. Honey's antimicrobial properties were first verified in 1892 and since then it has gone on to perform well in a variety of clinical trials. An inhibitory effect has been shown in over 60 species of bacteria, including aerobes and anaerobes as well as both gram-positive and gram-negative bacteria. This is an especially useful trait considering the growing microbial resistance to antibiotics. So how does honey work as a natural bactericidal agent? When applied topically, honey draws moisture out of the wound area, dehydrating any growing bacterial strains. Honey's sugar content is also high enough to prove toxic for microbes and hinders colony growth, and its low pH discourages bacteria that has trouble growing in an acidic environment. As a triple threat, honey also contains an enzyme called glucose oxidase, which gradually breaks down its sugars to generate hydrogen peroxide that acts as a third antibacterial agent. A variety of clinical evidence suggests that topical application of honey forms a protective, non-adhesive barrier dressing and can stimulate healing while reducing scarring potential. Further study needs to be done, but it seems as though honey also has a positive effect on several other conditions, including gastrointestinal tract disease, fungal infection, and may be useful as anti-inflammatory. Another boon that honey offers is its relative safety. Allergy potential is low in the general population, barring infants that may be sensitive to botulism. Although science has shined light on the fallacies of ancient practices like bloodletting and the theory of the four humors, honey has remained a mainstay in wound care application since ancient times. As more research is done, honey may reveal itself to contain even more medicinal benefits than science is already aware of, pushing it closer and closer to that glittering ideal medicine outlined in the passages of the Qur'an. The History of X-Rays Perhaps the most useful advancement in medical technology, x-rays have not been inextricably linked with the medical and dental communities all that long. In 1895, Wilhelm Conrad Roentgen, a German physicist and mechanical engineer, was at work in his laboratory, toying with a cathode-ray tube. Cathode-ray tubes were popular experimental tools at the time in electromagnetic field research, and so Roentgen was perfectly in his element as he evacuated air in the tube and experimented with high voltage application to its contents. To Roentgen's surprise, when he covered the tube with dense black paper to block out its light, some objects nearby remained illuminated with a ghostly phosphorescence. After further study--most famously in producing the world's first x-ray radiographic print with the glowing bones in his wife's hand--Roentgen determined that he had stumbled upon an invisible ray, a kind of light ray outside the sliver of the electromagnetic spectrum that humans can see with the naked eye. It didn't take long for the medical community to latch onto x-rays as an invaluable diagnostic tool. Because they were able to provide a complete view of the bone without having to sever or puncture skin, they allowed physicians to have an almost omnipotent view of a patient's body. Within a month of their initial discovery, surgeons had already implemented x-rays into their surgical procedure routines. Having an x-ray done even became something of a fad for the general public for awhile, with everyday consumers using coin operated mechanisms at penny arcades to take radiographs of hands and feet as quick, touristy mementos. There were, of course, downsides to allowing consumers to cheerfully dish out a dose of radiation at their own discretion, though the risks associated with x-rays weren't fully realized until the mid-20th century. During the atomic era, when governments around the world were myopically focused on building and refining weaponized uranium, the effects of excess radiation on human health came to the scientific forefront. Radiation strips cells, shreds DNA, and rends cellular function out of its normal parameters. Unchecked, x-rays are capable of doing the same. Presently, x-ray radiograms still stand out as a hallmark of medical innovation. Physicians and dental professionals alike use them routinely to diagnose bone health, foresee cavities and hairline fractures, and to provide general, non-invasive visual support during an exam. With the advent of personal computers, physicians have been able to digitize x-ray radiographs and store high resolution digital files with ease. Linear accelerators allow physicians to generate penetrating radiation for use in precise, high quality diagnostic imaging. And the technology itself has improved since Roentgen's crude cathode-ray tube experiment, too. Man-made isotopes are far more powerful than those that occur naturally, and offer x-ray technicians a wide array of energy levels and half-lives to work with during imaging. As a miracle of modern medicine, x-rays have come a long way. From a dim experimental laboratory curiosity in Germany during the late 19th century, to a routine full-mouth prognostic panel at dentist offices worldwide, x-rays are and will continue to be an invaluable diagnostic tool. Healthcare-Acquired Infections: How to Keep Facilities Safe There is a silent killer in healthcare facilities that has been largely untreated. One in ten patients in acute hospital care environments develop some kind of healthcare-acquired infection during their stay. As the 6th leading cause of death in the United States, healthcare-acquired infections cost the health industry upwards of $88 billion annually and contribute up to a 6 percent mortality rate in hospitals countrywide. The greatest microbiological threats attributed to these infections are methicillin-resistant Staphylococcus aureus, S. epidermidis, and multi-drug resistant gram-negative aerobes. Most healthcare-acquired infections are associated with invasive medical devices and complications from surgical procedures. Catheter use, which is extensive in the health industry and especially in the ICU and long term care facilities, contributes to a significant portion of healthcare-acquired infections. Gram-negative bacteria in particular is associated with both ventilator contamination and complications from unsanitary catheter care. Pneumonia typically arises from comprised ventilators, whereas urinary tract and bloodstream infections commonly stem from lack of catheter sterilization. Considering that these infections arise during or shortly after medical stay, the patient's immune system is at its most vulnerable in this critical time period. For the elderly, infirm, and younger populations of hospital patients, these sterility compromises can be life-threatening. Fortunately, there are steps to take to keep hospitals, intensive care units, and long term healthcare facilities free of these infectious agents. The hand hygiene of hospital staff goes a long way towards preventing microbial spread. Utilizing sterile gloves, aseptic handling techniques, antimicrobial flushes, and 2 percent chlorhexidine skin preparation provide an ideal defense against infection. With reduced drug longevity due to growing microbial resistance and the high capital costs required for new drug development, cutting infection off at the pass with safe handling techniques is the best method forward towards reducing hospital-acquired infections. Living with Arthritis: Mechanism, Symptoms, and Long Term Care Often seen as a hallmark of age, arthritis affects nearly 50 million adults in the United States alone. Though it is generally associated with an older population, there are roughly 300,000 children in the U.S. who are also living with arthritis. The surprising truth here is that what we know as 'arthritis' is not even a single disease, but a set of symptoms associated with several different kinds of disease. There are four distinct categories that most types of arthritis fall under, and over a hundred even more specialized subcategories that arthritis can break into from there. For the sake of brevity and simplicity, we'll only go over the four major categories here: degenerative arthritis, inflammatory arthritis, infectious arthritis, and metabolic arthritis. Degenerative arthritis, or osteoarthritis, is the most globally prevalent of all types of arthritis, and occurs most frequently in the wrists, legs, and hips. Because these regions are typically associated with movement, it's natural that there is a higher degree of cartilage rubbing in these areas. Over time, when the cartilage cushioning between bones is completely rubbed down and worn away, the bones begin to rub and shift against one another. This can cause stiffness, both acute and chronic pain, decreased range of motion, and can contribute to an inability to do day-to-day activities that were once a staple part of a person's life. As far as management techniques for osteoarthritis are concerned, there are a plethora of options. Finding ways to balance periods of activity and rest, practicing therapeutic muscle strengthening exercises, utilizing hot/cold therapy products, and taking over-the-counter pain relief medication can all contribute to successful osteoarthritis management. The second type of arthritis is inflammatory, or rheumatoid arthritis. This is when the immune system is working improperly and mistakenly attacks joints, which in turn causes uncontrolled inflammation and pain. Over time, this immune system assault on vulnerable structures can cause internal organ damage, vision loss, and joint erosion. For this reason, it's important to treat suspected cases of rheumatoid arthritis with quick, aggressive treatment methods. Disease-modifying antirheumatic drugs, or DMARDs, are often the best treatment option when it comes to facilitating disease remission. As another form arthritis can take, infectious arthritis is just as straightforward as it sounds. Bacteria, viruses, or fungi can infiltrate and infect sensitive joints and trigger severe inflammation and pain. The most common microbial offenders in this case are salmonella, shigella, chlamydia, gonorrhea, and hepatitis C. Luckily, infectious arthritis is relatively easy to treat, and a course of antibiotics usually takes care of the unpleasant symptoms. The last category of arthritis we'll discuss here is metabolic arthritis, also known colloquially as gout. Gout occurs when there is a significant build-up of uric acid--a byproduct of the metabolic breakdown of purine nucleotides. When uric acid begins to adhere to the joints, it crystallizes and forms painful, icicle-like spears along the joint fissure. Generally gout is affected by diet, weight, and exercise, and so following a healthy day-to-day regimen can prevent and manage gout flare-ups fairly effectively. Early diagnosis of arthritis symptoms generally results in a better pain management outcome for patients. The doctor may order blood, urine, joint fluid, and/or x-ray tests in order to effectively determine if a patient is suffering from arthritis. X-rays in particular are easily able to provide a direct view of possible joint narrowing and osteophyte formation in osteoarthritis cases. On the treatment side of things, physical therapists are able to provide care and therapeutic guidance for maintaining range of motion and joint limberness over the long term. With arthritis diagnosis numbers growing annually, it's important to remain proactive in reaching out for support and an expert opinion on concerning symptoms. Remember, early therapeutic care can lead to a lifetime of pain-free arthritis management. The Ancient and Surprising History of Surgery While it may seem intuitive to describe surgery as a 'modern' medical practice, its origins in fact can be traced back thousands of years, deep into the Pre-Classical and even Neolithic era. The earliest recorded archaeological evidence for surgical practice is an astounding 12000 BCE. To put a time frame like this in perspective, writing wasn't developed until 2600 BCE in Egypt. Early people were practicing rudimentary surgery before recorded history! Prehistoric surgery focused around a practice called trepanation, which involves scooping or drilling a hole into the skull of the patient. This ancient practice was used as a panacea for everything from relieving migraine or intracranial swelling, cleaning out fractured skull fragments from a war injury, and even as a means of managing misunderstood mental health conditions that were viewed as a malignant spirit trapped within the patient's cranial cavity. In 500 BCE, the first example of plastic surgery sprung up in India. Having one's nose cut off was a common punishment for a past crime, and so reformed felons would have their noses reconstructed via early rhinoplasty to avoid the social stigma. Surgery in Ancient Greece included a variety of makeshift surgical work including the setting of broken bones, bloodletting, the draining of lungs from patients suffering from pneumonia, and the severing of gangrenous limbs. The Mayans were really at the forefront of global surgical practice at this time and performed routine dentistry, filling in cavity with flecks of jade, turquoise, quartz, or hematite. The Incas had master surgeons specializing in head injuries and cranial surgery, and records show they had a substantially better success rates than surgeons during the American Civil War, nearly 500 years later. Another major leap forward was in 900 AD, with the highly esteemed 'father of surgery' Al-Zahrawi, and his all-encompassing surgical text Kitab al-Tasrif. It was a cutting-edge compendium on every known practice and procedure, including orthopedics, military surgery, and ear, nose, and throat surgery. A combination of Al-Zahrawi's collected knowledge and local folk remedies remained the go-to surgical manual for nearly eight hundred years. Up until the 18th century, there was no formal medical training in Europe, and so most surgeons learned their trade through apprenticeship, much like one might learn blacksmithing or another artisan skill. In fact, because surgeons were seen as 'lesser' physicians during this period of time, many women were trained and practiced as surgeons. It wasn't until the 1700s, with the development of medical colleges and academic institutions, that women were then excluded from practicing. As far as patient care was concerned, it really wasn't until modernity that a surgical procedure became anything short of horrific to experience. With little regard for infection control, pain management, bodily fluid contamination, or proper wound maintenance, being a patient before modern anesthetic was akin to torture. Many physicians believed it was important to keep patients alert and awake during surgery, and would periodically rouse the patient if it appeared they were in danger of losing consciousness. Opium and alcohol were used as analgesics only sparingly, and never in quantities large enough to diminish patient consciousness. Japanese surgeons were the first to implement true general anesthetic in the early 1800s, at which point ether, chloroform, and locally-administered cocaine became more commonplace globally as anesthetic for patients in the operating room. While far from a modern practice, surgery has grown and developed to be a vastly safer and more pleasant patient experience over the millennia, all thanks to talented medical pioneers and advocates all over the world. Social Media Ad Copy Examples Shop QuickMedical's wide range of patient aid products, perfect for long-term care facilities, clinics, and hospital use. Provide patients with welcoming hygiene care essentials away from home, including wipes, body wash, deodorant, and disposable razors, among dozens of other product categories. The Mediana DT-100 Smart Thermometer offers non-contact infrared temperature measuring with a rapid response time. Using heat mapping technology, the DT-100 is next step in hygienic, easy-to-use patient temperature measuring. Shop today! Electrode Prep Products from Parker Labs ensure a conductive connection between skin and the electrodes, and transmit electrical impulses clearly for ECG, TENS, muscle stimulation and other procedures. Parker Labs Electrode Prep Products are offered in gels and creams, and are ideal for hospitals, electrotherapy clinics, and other medical facilities. QM Elite nitrile gloves are multi-purpose, with applications extending from laboratory use to routine medical exams. With textured fingertips to provide dexterity support and a range of size options, look no further for your clinic's new favorite exam glove. copyright ren graham 2019. all rights reserved.
Surgeon negligence claims and surgical errors compensation Home Medical Negligence Surgery Poor surgical treatment can lead to devastating consequences. Search for more specific surgical negligence types that have affected you. Search: Surgical mesh, Urology, Wrong site surgery All Surgical cases we deal with: Failure To Remove Foreign Objects Keyhole Surgery Claiming for surgical negligence Surgery is a daunting prospect, no matter what. It's natural to feel anxious and many of us will find ourselves imagining all of the worst-case scenarios. While we can always hope that these scenarios never become reality, the unfortunate truth is that injury sustained as a result of medical negligence during surgery is one of the most common causes for making a claim. If you have suffered an injury during a surgical procedure, it's time to get in touch. With no upfront fees or payments necessary, Your Legal Friend is here to help. Your surgeon has a duty to treat you appropriately and you have the right to expect that he will be as capable as a reasonable and responsible surgeon who performs the operation that you need. If the outcome of your surgery is not what you expected you may have a negligent medical treatment. Complications that arise during surgery or develop at a later stage may be the result of negligence. Your doctor or specialist should have explained to you the risks of the surgery and all possible outcomes before surgery takes place. If he has not you may not had the correct surgery or you may not have given your informed consent. If you or a member of your family have suffered an unexpected outcome a loss, following surgery you will need to seek specialist lawyer who is an expert in complex cases arising from surgical negligence. The specialist lawyers at Your Legal Friend will help you find out what went wrong, what can be done to put it right and claim compensation. We know that you have been let done by a professional and we will treat you be with sympathy and provide you with straight forward easy to understand advice. We have years of experience working on medical negligence cases, involving everything from cervical to cardiac surgery. From a legal point of view, we know how complicated these cases can be. More importantly, we understand that they can leave the victim feeling incredibly vulnerable, even embarrassed. The psychological and emotional effects of medical negligence are often just as damaging as the physical impact which is why we are committed to guiding you through every step of the process. We will ensure that your claim is handled carefully and professionally by specialist solicitors, while working alongside medical experts in the surgical field to guarantee the best results for you. Watch some helpful related videos What are the key stages where surgical negligence may be found? What are common surgical negligence claims? To bring a successful surgical negligence claim, What is it necessary to prove? What is the time limit for making a claim for surgical negligence? How much compensation can I claim for surgical negligence? What is anesthesia awareness? What is the difference between 'general' and 'local' anesthetic What are some factors affecting anesthetic dosage? What are some common anesthesia risk factors? What further errors are associated with anesthesia? What are some post operation symptoms? Making a claim for clinical negligence in administering anesthetics What are the key stages where surgical negligence may be found? There are numerous types of surgical procedure and complications that might occur at a particular stage. To discover where a problem might have arisen during your treatment, we will look at four stages and each stage examined for potential medical negligence. Investigation and diagnosis, including delay Care after surgery What are common surgical negligence claims? Of the 4.6 million hospital admissions to the NHS in England each year requiring surgery the risk of a mistake taking place during a procedure is estimated by the NHS to be one in 20,000. Among the various types of surgical negligence claims that are commonly made are: Failure to fully and honestly discuss the risks and benefits of surgery and the alternatives. Misinterpreted scans Delay in surgery resulting in avoidable surgical complications. Poor surgical technique leading to injury. Damage to surrounding structures, tissues and nerves. Poor post-operative care. Anaesthetic complications including respiratory distress, stroke, cardiac arrest, brain damage, anaesthetic awareness, tooth and throat damage. Retained swabs and implements. Post-operative infection. Deep vein thrombosis (DVT), pulmonary embolism. To bring a successful surgical negligence claim, What is it necessary to prove? Whatever type of injury has been sustained, it must have been caused by unacceptably poor treatment It must have been avoidable with poor care It must have resulted in an injury If you have suffered an injury, which could not have been prevented with proper care , it will not be possible to bring a claim for surgical negligence. What is the time limit for making a claim for surgical negligence? When a mistake is alleged to have been made during a surgical procedure, which is believed was the cause of physical or psychological damage, it is vital to immediately seek expert legal advice from a medical negligence specialist. A claim for surgical negligence must be started in Court within 3 years from: The date of your injury The date when you first discovered your injury was the result of an action you now believe was negligent. How much compensation can I claim for surgical negligence? While no amount of compensation for surgical negligence will be able to reverse the pain that you have suffered and the stress caused, you may need support and care. Compensation that you are entitled to because of the lack of surgical care received will help. Compensation can be divided into two types: General Damages for the pain and suffering Financial loss The amount of compensation you receive will depend on the type of injury and personal circumstances, such as the consequences of the injury on your ability to work and care for your family. What is anesthesia awareness? Accidental awareness during general anaesthesia (AAGA) – more commonly referred to as 'anaesthesia awareness'- is a known and fortunately rare occurrence, in which a patient remembers awaking and being conscious of their surroundings during a surgical procedure but is unable to communicate to the medical staff. Specific sensations, which may be recalled include, tugging, stitching, pain, paralysis and choking accompanied by feelings of panic, extreme fear, suffocation and even of dying. What is the difference between 'general' and 'local' anesthetic A general anaesthetic - is intended to make a patient completely unconscious for the duration of the procedure, or A local anaesthetic is applied to numb a specific body area only. Problems associated with anaesthetics Anaesthesia is consultant-led. This means a senior doctor is present for more than eight in ten of all occasions when anaesthetics are administered and for three in every four occasions when they are administered "out of hours". The proper A duty of care and a high standard of skill is expected to be maintained throughout. What are some factors affecting anesthetic dosage? A range of factors are calculated in the level of anaesthetics administered, including: Patient weight Relevant medical history Current techniques enable anaesthetists to try and give patients the minimum level of anaesthetic required to reduce the risk of complications, especially if deeper anaesthetic levels may need to be used. Difficulties or complications may arise during surgery if: Anaesthetics were incorrectly or poorly administered The patient was not properly monitored during anaesthesia A drop in blood pressure was either not noted or failed to be prevented Faulty equipment is used Medical training was inadequate The patient has high drug tolerance levels and this was not recognised What are some common anesthesia risk factors? While anaesthetic failures most often occur before surgery starts or after it finishes, patients are at higher risk of experiencing anaesthesia awareness: During a caesarean section If they are obese Have breathing / airway restrictions at the start of anaesthesia Anaesthetics are administered to prevent feeling any sensation or pain, and often also includes a muscle relaxant, which may leave a patient unable to move or make any signal whatsoever. Patients given muscle relaxants for particular types of surgery, such as cardiothoracic operations and caesarean sections are at a higher risk of suffering complications. What further errors are associated with anesthesia? Anaesthetic Nerve / Spinal Cord Injuries Anaesthetics can be mistakenly injected into the spinal cord or into nerves causing severe, painful injuries and leaving a patient with a serious disability. Anaesthetic Brain Damage and Stroke A failure by the anaesthetist to correctly regulate a patient's blood pressure can cause severe brain damage or a stroke. What are some post operation symptoms? While research has shown that most incidence of anaesthesia awareness are brief and not a cause for concern, around five in ten episodes have led to patient distress and four in ten cause longer-term psychological harm. A small number of patients who experience anaesthesia awareness may develop post-traumatic stress disorder (PTSD) and levels of associated anxiety behaviour, including severe phobias, nightmares, insomnia and in very extreme cases, attempted suicides. Making a claim for clinical negligence in administering anesthetics The Royal College of Anaesthetists (RCoA) and the Association of Anaesthetists of Great Britain and Ireland (AAGBI) have recommended that before surgery a 'check list' for ensuring the correct administering of anaesthetics should be carried out. However, in any clinical negligence claim it is necessary to prove: Whatever type of injury has been sustained, it must have been avoidable 'at the time and in the circumstances' with proper care Due to the negligence of a person who owed you a duty of care Due to the negligence of a person who demonstrated a lack of skill Mr Lapworth's story In this story, we hear from Kenneth Lapworth who tragically lost his wife Elaine to cancer which developed after their local NHS Trust failed to arrange regular check-ups for her condition. VIEW ALL SURGERY
108 1 g contains 200 mg of amoxicillin as amoxicillin trihydrate. 165 Amoxicillin is a broad-spectrum semi-synthetic penicillin. It exerts bactericidal action on many gram-positive and gram-negative organisms, is stable in gastric acid and is well resorbed from the gastrointestinal tract, achieving rapidly high blood- and tissue levels. Its resorption and antimicrobial action are superior to that of ampicillin. Unlike with ampicillin, resorption of Simivet<b><sup>®</sup></b> is not diminished by food in gastrointestinal tract. 317 - prophylaxis and treatment of chronic respiratory disease complex (CRD) in poultry. 412 - hypersensitivity to penicillin antibiotics, which is extremely rare. 469 Simivet<b><sup>®</sup></b> 20% soluble powder is given mixed with feed or dissolved in drinking water, milk or milk substitute. Always prepare a fresh solution. To ensure the intake of medicated drinking water, the animals should be restricted from other sources of liquid 2 hours prior to treatment and during it. 545 Average dose of amoxicillin for majority of animals is 6-10 mg/kg of b. w., i. e. 1 g of Simivet<b><sup>®</sup></b> 20% soluble powder per 20-33 kg of b. w. every 12 hours. One levelled teaspoonful of powder contains 4 g of the preparation, which is sufficient for the animal weighing 80-130 kg (e. g. calf). 583 When preparing medicated feed (e. g. for swine) mix 200-320 g of powder with 100 kg of feed, which makes 400-640 ppm of amoxicillin trihydrate. 877 Relevant to severity of the infection, the treatment lasts for 3-5 days, i. e. at least 1 additional day upon remission of clinical symptoms. Gram-negative infections and severe diseases, particularly acute infections, are treated with higher doses without any risk of side effects. 934 In the ruminants with functionally developed forestomach, systemic infections are not treated with oral amoxicillin. 972 Sick animals taking scarce water and feed should be treated by parenteral route. 1010 If after three days of treatment there is no apparent improvement, causative organism is probably amoxicillin-resistant, which requires institution of another antimicrobial. 1162 Store in a dry place at room temperature (up to 25°C). Keep away from children. 1333 Bags with 100 g and 1000 g.
The CIRS Model 002H5 IMRT Phantom for Film and Ion chamber Dosimetry is designed to address the complex issues surrounding commissioning and comparison of treatment planning systems while providing a simple yet reliable method for verification of individual patient plans and delivery. The 002H5 is homogeneous and elliptical in shape. It properly represents human anatomy in size and proportion. It measures 30 cm long x 30 cm wide x 20 cm thick (PA). The phantom is constructed of proprietary tissue equivalent epoxy materials. Linear attenuations of the simulated tissues are within 1% of actual attenuation for bone and water from 50 keV to 15 MeV. Water equivalent interchangeable rod inserts accommodate ionization chambers allowing for point dose measurements in multiple planes within the phantom.* The phantom also supports radiographic or GafChromic® film at mid-plane in the phantom for analysis of dose distributions. Additional inserts are available to support a variety of other detectors including TLD's, MOSFET, and diodes. CIRS IMRT phantoms are manufactured from tissue equivalent materials that mimic within 1% from 50 keV to 15 MeV for accurate simulation from CT planning to treatment delivery. The interchangeable rod design allows the phantom to accommodate a multitude of dose measurement devices such as ion chambers, TLD, diodes and MOSFET's in the same location within the phantom.* Phantom cross sections accommodate GafChromic(r) or standard ready-pack films. Refer to the cavity and plug code list for available chamber cavities. The CIRS line of IMRT phantoms is compatible with the RIT 113 software for film to plan analysis.
Pediatric Dermatology Consult A 7-month-old male presents with perioral rash and fever Publish date: March 12, 2020 Safiyyah Bhatti, MD Lawrence F. Eichenfield, MD A 7-month-old male with a past medical history of atopic dermatitis presented to the ED with worsening perioral, facial, and posterior neck rash and 3 days of fevers with decreased oral intake and urine output. Mother reports that he has had eczema on his cheeks and others areas of the body intermittently, but over the last week the eczema on his bilateral cheeks had an acute flare. She used hydrocortisone 2.5% ointment and Vaseline, and the rash initially improved over 4 days, but on the fifth day it started to gradually worsen, and became more erythematous and inflamed. Keflex and mupirocin were prescribed, and after 2 days of treatment the patient developed a fever of 102°F with poor oral intake and decreased urine output. Exam revealed perioral pink papules coalescing into plaques, some with honey-colored crust, and several pink papules of the face and neck. There were no intraoral lesions. Mother denied exposure to anyone else sick or with rash. What's your diagnosis? Hand, foot, and mouth disease Eczema herpeticum Bacterial superinfection Primary varicella infection Patients with atopic dermatitis are at risk for developing the herpes simplex virus (HSV)–related skin complication "eczema herpeticum," also known as Kaposi's varicelliform eruption. Eczema herpeticum is characterized by cutaneous pain and vesicular skin lesions, most commonly secondary to infection with HSV-1. The condition may affect individuals with atopic dermatitis or other inflammatory skin disorders. Eczema herpeticum develops when the virus infects large areas of skin, rather than being confined to a small area as in the common cold sore. Eczema herpeticum often appears on the face and neck, although it can appear anywhere on the body. In some cases, the rash may be difficult to distinguish from a patient's baseline eczema if the latter is poorly controlled. Skin symptoms of eczema herpeticum include clusters of small blisters that are itchy and painful; vesicles that appear red, purple, or black; purulent blisters; or crusting. Classically, the morphology of vesicles or crusted lesions shows a "cluster of grapes" appearance. Eczema herpeticum may present with a high fever, chills, and swollen lymph glands. Courtesy Dr. Lawrence F. Eichenfield While a clinical diagnosis based on the history, physical findings, and morphologic appearance of the rash is reasonable, testing may confirm the diagnosis. The most sensitive and specific tests are polymerase chain reaction sequencing for HSV, direct fluorescent antibody stain, and/or viral culture, while Tzanck smear may show characteristic histologic changes. Treatment is with oral antiviral therapy and treatment of the eczema. Hand, foot, and mouth disease (HFMD) is a common viral illness usually affecting infants and children. The infection often involves the hands, feet, mouth, and sometimes, the genitals and buttocks. The viral exanthem is most commonly caused by the coxsackievirus, of the enterovirus family. Coxsackievirus A16 and enterovirus A71 are the serotypes that are most commonly implicated as the causative agents. HFMD initially presents with a low-grade fever, reduced appetite, and general malaise. About 1-2 days later, the child may develop painful mouth sores with an exanthem that involves the dorsum of the hands, soles of the feet, buttocks, legs, and arms. The exanthem consists of vesicles surrounded by a thin halo of erythema, eventually rupturing and forming superficial ulcers with a gray-yellow base and erythematous rim. The exanthem is itchy, and can be macular, papular, or vesicular. The lesions are nonpruritic, and typically not painful. The diagnosis of HFMD usually is made clinically, although a physician can swab the mouth or get a stool sample for polymerase chain reaction, which will show the virus; treatment is supportive. In children with atopic dermatitis, lesions also can tend to concentrate in areas previously or currently affected by the dermatitis, similar to eczema herpeticum, and the terms eczema coxsackium or atypical HFMD are applicable. In young adults, the disease may present with erythematous papulovesicular lesions on the face, oral mucosa, extensor surfaces of the upper and lower extremities, and palms and soles; confluent, hemorrhagic, and crusted lesions also can be seen on the extremities. Systemic symptoms usually subside in a few days; the skin lesions resolve without scarring in days to weeks. Dr. Safiyyah Bhatti Secondary bacterial infection is not uncommon in eczema herpeticum patients, reflecting common Staphylococcus aureus infection in atopic dermatitis patients. Streptococcus also may be seen as a concurrent infection. Treatment of secondary bacterial infection may be considered based on clinic context and culture. Impetiginized eczema also is in the differential diagnosis of eczema herpeticum. S. aureus and Streptococci are the most important causative organisms. Lesions can manifest as a single red papule or macule that quickly becomes vesicular or eroded. Subsequently, the content dries, forming honey-colored crusts. Impetigo may resolve spontaneously, although in the context of infected eczema both topical anti-inflammatory agents (e.g. topical corticosteroids) along with systemic antibiotics may be a reasonable treatment option. Although our patient had honey-colored crusting, the wound culture showed normal bacterial flora. Dr. Lawrence F. Eichenfield Primary varicella infection causes acute fever and rash, with an initial exanthem of disseminated pruritic erythematous macules that progress beyond the papular stage, forming clear, fluid-filled vesicles (like dewdrops on a rose petal). In children, the rash presents on the stomach, back, and face, and then spreads to other parts of the body. Blisters also can arise inside the mouth. In this patient, perioral HSV PCR 1 was positive, and wound culture showed normal oral flora with no organisms or white blood cells seen. The patient responded well to oral acyclovir, and treatment of his underlying atopic dermatitis with low-potency topical corticosteroids. Dr. Bhatti is a research fellow in pediatric dermatology at Rady Children's Hospital and the University of California, San Diego. Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children's Hospital–San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. Neither of the physicians had relevant financial disclosures. Email them at [email protected]. Can Fam Physician. 2012 Dec;58(12):1358-61. William L Weston, MD., William Howe, MD. UpToDate. Treatment of atopic dermatitis (eczema). Christine Johnson, MD, Anna Wald, MD, MPH. UpToDate. Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection. Robert Sidbury, MD, MPH. UpToDate. Atypical exanthems in children. National Eczema Association. Eczema herpeticum. Centers for Disease Control and Prevention. Symptoms and diagnosis of hand, foot, and mouth disease (HFMD). Coronavirus outbreak prompts cancellation of AAD annual meeting
Children's Health DefenseFollow4,27498,015 Mission: End childhood health epidemics by exposing causes, eliminating harmful exposures; seeking justice for injured and establishing safeguards. Children's Health Defense@ChildrensHD· Don't miss #TheDefender's MOST READ NEWS OF THE WEEK! READ + SHARE Most Read News of the Week childrenshealthdefense.salsalabs.org Journalist Laura Bult traveled to NC to better understand the human health + environmental impact of the state's massive pig farms, each of which house tens of thousands of hogs + produce an estimated 10,000 gallons of waste /day. @voxdotcom #TheDefender North Carolina's 2,000 Massive Industrial Pig Farms Wreak Havoc on Human Health Vox journalist Laura Bult traveled to North Carolina to better understand the human health and environmental impact of the state's massive pig f... childrenshealthdefense.org Fight censorship. 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Source: Children's Health Defense August 6, 2019 at 11:26 am. … and For Some Outcomes Infants of Unvaccinated Moms Fared Better By the Children's Health Defense Team Public health officials and doctors, ever more insistent that pregnant women get flu shots, are frustrated that fewer than four in ten American moms-to-be avail themselves of the recommendation. Policy-makers' disappointment stems not just from their zeal to achieve the Healthy People 2020 goal of 80% coverage of pregnant women but also from their recognition that women who go along with vaccine recommendations during pregnancy are more acquiescent about vaccinating their newborn infants as well. In their surprisingly frank conclusions, not only do the researchers report that influenza vaccination during pregnancy was ineffective in lowering risk for the four outcomes, but—ever so cautiously—they also note that the vaccinated infants fared worse. Yet maternal worries about vaccine-related harm to the fetus are widespread and operate as a principal barrier to higher pregnancy vaccine uptake. Envisioning a day when "even more vaccines" will be added to the maternal vaccine schedule, researchers are studying how to improve uptake and design more persuasive "communication interventions." Their messaging generally emphasizes a twofold rationale for prenatal flu shots. The first and primary stated aim is to prevent influenza in mothers and babies—but researchers also assert that by preventing such infections, they may be able to prevent unwanted fetal outcomes thought to be linked to influenza infection during pregnancy. A research team out of South Africa has just published a paper examining the second rationale, comparing four outcomes—fetal death, low birth weight, small for gestational age birth and preterm birth—for infants whose mothers received flu shots or a placebo. In their surprisingly frank conclusions, not only do the researchers report that influenza vaccination during pregnancy was ineffective in lowering risk for the four outcomes, but—ever so cautiously—they also note that the vaccinated infants fared worse. Unexpectedly (to the researchers), they also found that the average gestational age at birth was lower in the vaccinated versus placebo group—a statistically significant result indicative of a greater risk of preterm birth. The 2011–2012 South Africa study was one of three large double-blind, randomized, placebo-controlled trials of influenza vaccination during pregnancy funded by the Bill & Melinda Gates Foundation (BMGF). As originally described in 2014 in the New England Journal of Medicine, over 2,000 mothers received either trivalent inactivated influenza vaccines or placebo between 20 and 36 weeks of pregnancy—in other words, in their second or third (but not first) trimester of pregnancy. (In the U.S., which encourages flu shots during any trimester of pregnancy, studies have identified a heightened risk of autism in the children of women vaccinated during the first trimester.) The researchers followed up on fetal outcomes when the infants reached 24 weeks of age. Overall, the investigators found "no significant vaccine efficacy" with respect to any of the fetal outcomes. Unexpectedly (to the researchers), they also found that the average gestational age at birth was lower in the vaccinated versus placebo group—a statistically significant result indicative of a greater risk of preterm birth. Of note, the study used an inert saline placebo. This is unusual in the context of vaccine clinical trials, which nearly always compare one group that receives the vaccine of interest against another group that receives a different vaccine (called an "active comparator"). The use of active comparators can "increase the occurrence of harms in the comparator groups and thereby [mask] harms caused by the…vaccines" being studied. In contrast, an inert placebo enhances the likelihood of detecting differences between groups, if any are present. Overall, the investigators found "no significant vaccine efficacy" with respect to any of the fetal outcomes. Unexpectedly (to the researchers), they also found that the average gestational age at birth was lower in the vaccinated versus placebo group—a statistically significant result indicative of a greater risk of preterm birth. Although most of the study's other findings did not attain statistical significance, the pattern of results showed, in another writer's words, tendencies that were "not reassuring." Across all analyses, the percentages and rates of fetal death, preterm birth, low birth weight and small for gestational age birth were higher in the vaccine group than in the placebo group. Couching their conclusions with caveats, the authors explain: [W]e found a slight, though non-significant decrease in the birth weight of infants in the vaccinated group…as well as a non-significant increase in fetal deaths among [influenza]-vaccinated mothers. […] We point this out only as a cautionary word and suggest this observation be explored carefully in larger studies of vaccine safety data bases. … maternal hospitalizations for infections were "numerically higher" in the vaccinated group, as were severe neonatal infections. Weak, inconsistent and biased evidence In 2017, researchers who carried out a systematic review found that "comparative studies of adverse birth outcomes following maternal influenza disease are limited in quantity and have produced inconsistent findings." In a 2019 paper, an Italian researcher agrees, arguing that it is inappropriate to recommend across-the-board influenza vaccination of all pregnant women in the absence of "strong and consistent" randomized clinical trial evidence—particularly if one also acknowledges that current evidence often exhibits bias. Making specific reference to the South Africa clinical trial, the author notes that the trial "was funded by BMGF and by public sponsors, with the principal investigator in financial relationships with the vaccine producer, and two authors with other influenza vaccine producers." The author describes other results from the South Africa trial that, while again not attaining statistical significance, "were not in the expected/hoped direction." For example, maternal hospitalizations for infections were "numerically higher" in the vaccinated group, as were severe neonatal infections. Overall, the trial produced only "18 less influenza illnesses in vaccinated mothers and their children, to be weighted…against 9 more maternal hospitalization for any infection and 6 more neonatal hospitalization due to sepsis within 28 days of birth." In addition to the South Africa trial, the Italian author mentions several other randomized controlled trials (RCTs) in low-income countries that compared influenza vaccination during pregnancy against meningococcal or pneumococcal vaccination; even with an active comparator, the author suggests that these trials [hyperlinks added] do not support influenza vaccination during pregnancy: The first and larger trial substantially disregarded an alarming excess of infant deaths and serious "presumed/neonatal infections" in the influenza vaccine group. Even in the other small RCT the fetal plus infant deaths were nonsignificantly higher in the influenza vaccine group. In a last large trial the tendency for miscarriage, stillbirth, congenital defects, and infant deaths at 0-6 months were not in favour of the vaccine group. These countries are not comparable to high-income ones, but one could expect that their poverty and demographic conditions would magnify the benefits of influenza vaccination, not the opposite. A 2013 study that evaluated adverse pregnancy outcomes following influenza vaccination of pregnant women found that "low-risk" women (that is, women without medical complications or co-morbidity) who received the vaccine during the 2009–2011 influenza seasons had an increase in a composite measure of adverse outcomes (miscarriage, fetal demise, preterm birth and neonatal demise) compared to unvaccinated pregnant women—"even after adjusting for confounding factors." Reluctant to accept the implications of their findings, the authors stated, "We do not believe that influenza vaccination causes adverse pregnancy outcomes in low-risk women; instead our findings likely represent the result of selection bias and residual confounding." The same kind of avoidance was apparent in a study that investigated risks for preterm delivery and birth defects following influenza vaccination in three consecutive seasons beginning in 2011. Although the researchers found that women in the vaccinated group had a shorter gestational duration and their infants had an elevated risk of a rare abdominal wall defect called omphalocele, the investigators concluded that their results were "generally reassuring" and that "[t]he few risks that were observed are compatible with chance." … no vaccines have ever been approved by the Food and Drug Administration (FDA) specifically for use during pregnancy to protect the infant. A questionable policy Researchers have speculated that influenza infection during pregnancy could be associated with adverse birth outcomes due to "mechanisms such as maternal fever and inflammation," and they note that "[i]mmunological responses, such as elevated pro-inflammatory cytokine levels…are recognised as an important pathway to preterm birth." What they generally do not acknowledge is that prenatal vaccination also introduces immune activation risks—and these risks remain scandalously understudied. Instead of bemoaning pregnant women's "suboptimal" flu shot uptake—or dismissing the risks to a developing fetus from vaccinating the mother during pregnancy as "theoretical"—researchers and policy-makers should be putting their poorly supported pregnancy vaccination recommendations on hold. And members of the public should remember that no vaccines have ever been approved by the Food and Drug Administration (FDA) "specifically for use during pregnancy to protect the infant." The post Flu Shots During Pregnancy Failed to Lower the Risk of Fetal Death, Preterm Birth and Low Birth Weight appeared first on Children's Health Defense. © 06 Aug 2019 Children's Health Defense, Inc. This work is reproduced and distributed with the permission of Children's Health Defense, Inc. Want to learn more from Children's Health Defense? Sign up for free news and updates from Robert F. Kennedy, Jr. and the Children's Health Defense. Your donation will help to support us in our efforts. 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Mesenchymal precursor cells in the blood of normal individuals Nathan J Zvaifler1, Lilla Marinova-Mutafchieva2, Gill Adams2, Christopher J Edwards2, Jill Moss3, Jan A Burger1 & Ravinder N Maini2,3 Arthritis Research & Therapy volume 2, Article number: 477 (2000) Cite this article Statement of findings Mesenchymal precursor cells found in the blood (BMPCs) of normal persons adhere to plastic and glass and proliferate logarithmically in DMEM-20% fetal calf serum (FCS) without growth factors. They form cells with fibroblast-like and stromal morphology, which is not affected by eliminating CD34, CD3, or CD14 cells. Osteogenic supplements (dexamethasone, ascorbic acid, and β-glycerophosphate) added to the culture inhibited fibroblast formation, and BMPCs assumed the cuboidal shape of osteoblasts. After 5 days in supplemented medium, the elutriated cells displayed alkaline phosphatase (AP), and the addition of bone morphogenetic protein (BMP)2 (1 ng) doubled AP production (P < 0.04). Two weeks later, 30% of the cells were very large and reacted with anti-osteocalcin antibody. The same cultures also contained sudanophlic adipocytes and multinucleated giant cells that stained for tartrate-resistant acid phosphatase (TRAP) and vitronectin receptors. Cultured BMPCs immunostain with antibodies to vimentin, type I collagen, and BMP receptors, heterodimeric structures expressed on mesenchymal lineage cells. In addition, BMPCs stain with anti-CD105 (endoglin), a putative marker for bone-marrow mesenchymal stem cells (MSCs). Adult human bone marrow contains a minority population of MSCs that contribute to the regeneration of tissues such as bone, cartilage, muscle, ligaments, tendons, fat, and stroma. Evidence that these MSCs are pluripotent, rather than being a mixture of committed progenitor cells each with a restricted potential, includes their rapid proliferation in culture, a characteristic morphology, the presence of typical marker proteins, and their consistent differentiation into various mesenchymal lineages. These attributes are maintained through multiple passages and are identifiable in individual stem cells. Since stem cells are present in both the bone marrow and other tissues, we thought it possible that cells with a similar appearance and pluripotent mesenchymal potential would be present in the blood. We applied techniques used successfully with marrow MSCs to identify similar cells in elutriation fractions of normal human blood. BMPCs were elutriated by diluting the buffy coats from 500 ml of anticoagulant-treated, platelet-depleted blood 1:4 in RPMI-1640 medium (RPMI) and layering 25-ml portions over 20 ml of Lymphoprep™. These samples were centrifuged at 2000 rpm for 20 min. The leukocyte-rich interface cells were collected, made up to 20 ml in RPMI, and separated by density-gradient centrifugation. The interface cells, now depleted of red blood cells, were collected, resuspended in 50 ml of sterile RMPI and 5% heat-inactivated FCS, and introduced into the sample line of the flow system of a Beckman JE-50 cell elutriator charged with elutriation buffer. The chamber was centrifuged at 25 000 rpm at 10°C and the flow rate adjusted to 12 ml/min. After about 150 ml had been collected, the flow rate was increased by 1 ml/min. Fractions nos. 1-6 (flow rates of 12-16 ml/min) contained most of the lymphocytes. Monocytes usually appeared in fractions 6 or 7 (as determined by flow cytometric analysis in a fluorescence-activated cell sorter (FACS). BMPCs were concentrated in fractions 7 and 8, along with monocytes and lymphocytes. Elutriation fractions with more than 50% and less than 75% monocytes were collected and concentrated by centrifugation at 1200 rpm for 5 min, and the cell pellets were combined, reconstituted in DMEM plus 20% sterile heat-inactivated FCS, counted, washed in medium, repelleted, and then resuspended in DMEM to 5 × 106/ml and dispensed into either tissue-culture plastic slides or glass chamber slides. Cells thus obtained were observed in time-lapse cinematography, assayed for proliferation, and examined immunohistologically and histochemically, and their ability to become fibroblasts, osteoclasts, osteoblasts, and adipocytes was documented. BMPCs were found in elutriation fractions containing less than 30% T cells and more than 60% monocytes from the blood of more than 100 normal persons. BMPCs adhered to plastic and glass and proliferated logarithmically in DMEM-20% FCS without added growth factors. The initial elutriate had only small, round, mononuclear cells; upon culture, these were replaced by fibroblast-like cells and large, round, stromal cells. The formation of cells with fibroblast-like and stromal morphology was not affected by eliminating CD34, CD3, or CD14 cells from the elutriation fraction. Osteogenic supplements (dexamethasone, ascorbic acid, and β-glycero-phosphate) added to the culture inhibited fibroblast formation, and BMPCs assumed the cuboidal shape of osteoblasts. After 5 days in supplemented medium, the elutriated cells displayed AP and its production was doubled by the addition of BMP2 (1 ng) (P < 0.04). Two weeks later, 30% of the cells were very large and reacted with anti-osteocalcin antibody. The same cultures contained two other types of cell: sudanophlic adipocytes and multinucleated giant cells, which stain for TRAP and vitronectin receptors (attributes of osteoclasts). Cultured BMPCs were immunostained by antibodies to vimentin, type I collagen, and BMP receptors (heterodimeric structures expressed on mesenchymal lineage cells). The cultured cells also stained strongly for the SH-2 (endoglin) antigen, a putative marker for marrow MSCs. BMPCs express the gene for SDF-1, a potent stroma-derived CXCα chemokine. In the circulation of normal individuals is a small population of CD34- mononuclear cells that proliferate rapidly in culture as an adherent population with a variable morphology, display cytoskeletal, cytoplasmic, and surface markers of mesenchymal precursors, and differentiate into several lineages (fibroblasts, osteoblasts, and adipocytes). These are all features found in bone-marrow-derived MSCs. Therefore, autologous blood could provide cells useful for tissue engineering and gene therapy. In addition, the demonstration of similar cells in the inflammatory joint fluids and synovium of patients with rheumatoid arthritis (RA) suggests that these cells may play a role in the pathogenesis of RA. Bone marrow is a complex tissue containing hematopoietic cell progenitors and their progeny and a connective-tissue network of mesenchymally derived cells known as stroma. Marrow stroma includes a subpopulation of undifferentiated cells that are capable of becoming one of a number of phenotypes, including chondrocytes, osteoblasts, adipocytes, fibroblasts, possibly muscle cells, and the reticular cells that support hematopoietic cell differentiation [1,2]. Extensive experimentation has defined conditions for the isolation, propagation, and differentiation in vitro and in vivo of the stromal cells referred to as MSCs. They are a population of firmly adherent cells with a high proliferative capacity and potential for self-renewal. Their developmental potential is retained even after repeated subcultivation in vitro, supporting their designation as stem cells [3]. Identification of MSCs in situ has been difficult, partly because they have few unique products or molecular markers. A series of monoclonal antibodies (SH antibodies) purportedly specific reagents have been used to isolate MSCs from a population of bone-marrow cells [1,3]. The one used most often (SH-2) was recently shown to react with endoglin (CD105), a member of the transforming growth factor (TGF)-β receptor family usually found on the endothelium of postcapillary venules [4]. Two other reagents may be more specific. One consists of a group of antibodies to BMP receptors (BMPRs) present on embryonic mesenchyme and postnatally on osteoblasts and chondrocytes [5]. Another antibody, Stro-1 made against marrow fibroblastic cells, blocks hematopoiesis in vitro by interfering with the interaction of reconstituted human hematopoietic stem cells (HSCs) and stromal cells [6]. Attempts to demonstrate MSCs in peripheral blood have been unrewarding, except for a report by Fernandez et al [7], who identified cells with the features of MSCs in growth-factor-mobilized peripheral-blood cells from breast-cancer patients. Low-density mononuclear cells grown for 1 week in tissue culture with fetal calf serum (FCS) become adherent fibroblast-like cells and a few were large, flat, round cells. Immunohistology and flow cytometric analysis in a fluorescence-activated cell sorter (FACS) revealed fibronectin and three types of collagen (I, III, and VI) in the cytoplasm of the cultured cells. They expressed adhesion ligands and antigens recognized by SH-2 and SH-3 monoclonal antibodies. No stromal cells were demonstrated in normal peripheral-blood cells not mobilized by granulocyte-macrophage CSF [7]. Bucala et al [8] separated human blood cells by density centrifugation, cultured them on a fibronectin matrix, and identified a population of circulating cells that had fibroblast properties and a distinctive phenotype (collagen+/vimentin+/ CD34+). This novel circulating cell, termed a fibrocyte, has both mesenchymal and hematopoietic features. Now we report for the first time that cells with the morphology and phenotype of mesenchymal precursors are normally present in the circulation. Hereafter these are referred to as `blood-derived mesenchymal precursor cells' (BMPCs). The observations that support these conclusions and the significance of the findings are discussed. Reagents and laboratory ware Dexamethasone, ascorbic acid-2 phosphate, β-glycerophosphate, bovine serum albumin (BSA), and FCS were purchased from Sigma Diagnostics (St Louis, MO, USA); penicillin, streptomycin, DMEM, and RPMI-1640 from Biowhittaker (Watersville, MD, USA); Lymphoprep™ from Nycomed, Oslo, Norway. Monoclonal antibodies were purchased from commercial vendors unless otherwise stated: CD3, IgG1; CD68, IgG1; CD34, IgG1; CD45, IgG1, D105, IgG1; and IgG2a controls (Dako Corporation, Carpinteria, CA, USA); anti-HLA-DR, IgG2a; CD14, IgG2b; CD34, IgG1 (Becton Dickinson, San Jose, CA, USA); anti-vimentin, IgG1; IgG2b control (Serotec, Kidlington, Oxfordshire, UK); anti-VCAM-1, IgG1; anti-αvβ3 (vitronectin receptor), IgG1 (Pharmingen, San Diego, CA, USA); anti-collagen-type-1, IgG1 (Sigma Diagnostics); anti-osteocalcin, IgG1 (ABOC-5021, Haematologic Technologies, Essex Junction, VT, USA) anti-IgG1. Stro-1 is a culture supernatant, monoclonal IgM, from Developmental Studies Hybridoma Bank, University of Iowa (Iowa City, IA, USA). Biotinylated mouse Ig, streptavidin/horseradish peroxidase conjugate, diamino benzidine, and Vectastain ABC were from Vector (Burlingame, CA, USA). Tissue-culture treated glass slides, Petri dishes, and six-well tissue-culture plates and eight-chamber tissue culture slides (Falcon) were from Becton Dickinson Labware (Franklin Lakes, NJ, USA); 12-well sterile glass slides were from ICN (Costa Mesa, CA, USA). Elutriation procedure for BMPCs Anticoagulant-treated, platelet-depleted buffy coat was obtained in sterile packages from the North London Blood Transfusion Service. About 50 ml of the buffy coat was diluted 1:4 in RPMI and 25 ml was layered over 20 ml of Lymphoprep™ in a 50-ml conical centrifuge tube. The tubes (approximately eight) were centrifuged at 2000 rpm for 20 min. The supernatant was discarded and leukocyte-rich interface cells were collected and combined. These were made up to 20 ml in RPMI and layered again over Lymphoprep™ and centrifuged at 2000 rpm for 20 min more. The buffy coat, now depleted of red blood cells, was collected from the interface, resuspended in 50 ml of sterile RMPI and 5% heat-inactivated FCS, and introduced into the sample line of the flow system of a Beckman JE-50 cell elutriator which had been charged with elutriation buffer. The chamber was centrifuged at 25 000 rpm at 10°C and the flow rate adjusted to 12 ml/min. The eluate fractions were collected in sterile, conical, 50-ml tubes. After about 150 ml had been collected, the flow rate was increased by 1 ml/min. Fractions nos. 1-6 (flow rates of 12-16 ml/min) contained most of the lymphocytes. Monocytes usually made their appearance (as determined by FACS analysis) in fraction 6 or 7. In fractions 7 and 8, monocytes constituted up to two thirds of the cells, and BMPCs were concentrated in these fractions. Elutriation fractions containing more than 50% and less than 75% monocytes were concentrated by centrifugation at 1200 rpm for 5 min, and the cell pellets were combined, reconstituted in DMEM plus 20% sterile heat-inactivated FCS (hereafter referred to as complete medium, unless otherwise stated), counted in a hemocytometer, washed in DMEM medium, repelleted, resuspended to 5 × 106/ml, and dispensed into either plastic tissue-culture slides or glass chamber slides. More than 100 consecutive buffy coats from normal individuals were processed by this method and cultured. In every case, the appropriate elutriation fractions had cells with the BMPC morphology. Cell-proliferation assay The BMPC-rich elutriation fractions were plated at 5 × 105 in 500 μl of complete medium in polystyrene chambers on treated glass tissue-culture slides (Falcon). At various times, cultures were rinsed twice with Tyrode's balanced salt solution, fixed with 1% glutaraldehyde (v/v) in Tyrode's for 15 min, rinsed twice with deionized water, and air-dried. Cultures were then stained with 0.1% crystal violet (w/v) in deionized water for 30 min and washed 3 times with deionized water; the crystal-violet dye was extracted by rocking the cultures gently in 1% Triton X-100 for 4 h at room temperature and read at 595 nm on a microplate reader (BioRad, Hercules, CA, USA). Absorbance values (optical densities; ODs) were converted into absolute cell numbers on the basis of established standard curves [9]. BMPC-rich elutriation fractions (500 μl, containing 5 × 106 cells per ml) or other sources of BMPCs were placed into the wells of sterile, 12-well multitest slides (ICN) in complete medium and left to adhere at 37°C for 4 h. The slides were then placed into 100 × 20 mm Petri dishes containing 5-7 ml DMEM-20% FCS. The nonadherent cells floated off, while mesenchymal cells adhered, spread, and grew. Their daily progress was assessed by phase-contrast microscopy. The medium was changed every 3 to 5 days and the cells were studied after 5-7 days. The growing, adherent cells were rinsed in phosphate-buffered saline (PBS), fixed in ice-cold 4% paraformaldehyde for 20 min, and then washed in PBS. All further incubations and washes were carried out using PBS. Endogenous peroxidase activity was blocked with 0.1 mol sodium azide containing 1% hydrogen peroxide, and the specimens were incubated with 10% normal goat serum, 2% normal rat serum, and 1% bovine serum albumin for 30 min at room temperature to eliminate non-specific binding. Specimens were then incubated with primary antibodies at 4°C overnight and were then incubated with a biotinylated secondary antibody (Vector). The antibody-biotin conjugates were detected with an avidin-biotin-peroxidase complex (Vector), applied for 30 min at room temperature. A color reaction was developed with 3-amino-9-ethylcarbazole and specimens were lightly counterstained with Mayer's hematoxylin. Controls included normal rabbit or mouse IgG, 1% BSA in PBS, or, in the case of BMPR antibodies, preabsorbed with the respective peptide used for immunization. Quantification of BMPCs by immunohistochemistry BMPC-rich elutriation fractions (5 × 105 cells in 500 μl of complete medium) were placed into the chambers of sterile, eight-chamber, treated glass tissue-culture slides. Two to 4 h later, nonadherent cells were removed. Cultures were fed every 3 days. At regular intervals, the slides were rinsed in PBS, fixed in ice-cold 4% paraformaldehyde for 20 min, washed in PBS, stained with anti-BMPR antibodies, and visualized by the ABC immunoperoxidase method described above. The specimens were examined using an Olympus BH-2 microscope and analyzed by computer image analysis (AnalySIS, Soft Imaging System GmbH, Münster, Germany). Six digital images (400×) per specimen were recorded and quantitative analysis was performed according to the color cell separation. Images chosen at random were analyzed and the data are presented as the mean of the total number of cells per six images examined at 400×. Slender cells with a small, centrally localized nucleus were scored as fibroblast-like. Large, round cells and intermediate-sized cells with more cytoplasm and a large, round nucleus were scored as large cells. Anti-BMPR antibodies Rabbit polyclonal antibodies to BMPRs were provided by K Funa (Göteborg University, Gothenburg, Sweden). Polyclonal rabbit antisera were prepared using synthetic peptides corresponding to the intracellular transmembrane portions of the types IA, IB, and II BMPRs [10]. The antisera were affinity-purified and tested for specificity by immunoprecipitation of cross-linked complexes of cultured cells transfected with receptor complementary deoxyribonucleic acids (cDNAs) [11]. Magnetic antibody-coated-bead separation (MACS) was performed in accordance with the manufacturer's recommendations (Miltenyi Biotec, Inc., Auburn, CA, USA). Elutriation fractions with 50-75% monocytes were centrifuged at 900 × g, washed with MACS buffer (PBS pH7.2, + 0.5% SSA + 2 mmol EDTA) and counted in a hemocytometer. The cell pellet was resuspended in 80 μl MACS buffer per 107 total cells, and 20 μl of MACS antibody-coated beads was added to the cells, mixed, and incubated for 15 min at 6-12°C. The cells were washed with a 20-fold volume of MACS buffer, spun, and resus-pended in 500 μl buffer. The cell suspension was applied to a positive selection column washed previously with 1 ml MACS buffer and placed in a magnetic separator and the cells were eluted. The column was rinsed four times with 500 μl buffer and the cells that passed through were combined as the antigen-free fraction. The column was removed from the magnetic separator, 1 ml of buffer was added to the column, and the positive cells were flushed out with a syringe plunger. This was repeated with another 1 ml of buffer. The elutriated cells were combined as the antigen-containing fraction. Alkaline phosphatase activity of circulating BMPCs BMPC-rich elutriation fractions were prepared from four individual blood packs as described and plated into four-well chamber slides (Lab-Tek) at 5 × 106 cells per ml in DMEM-10% FCS. After 24 h at 37°C, the nonadherent cells were removed and new medium was added containing BMP2 (a gift from the Genetics Institute, Cambridge, MA, USA) at concentrations of 0, 1, 10, or 100 ng/ml. The cells were incubated at 37°C in 5% CO2 and the medium was changed every 5 days. Supernatants were taken at 5, 10, and 15 days and stored at -20°C for later analysis. AP activity in the supernatants was estimated using a p-nitro-phenol colorimetric assay. Cell supernatants were assayed for AP activity in 50 mmol glycine, 0.05% Triton X-100, 4 mmol MgCl2, and 5 mmol p-nitrophenol phosphate, pH10.3, for 15 min at 37°C (Sigma Diagnostics, St Louis, MO). OD was measured at 405 nm and compared with that of standards. Stromal-cell-derived factor (SDF)-1 RT-PCR RNA was isolated from BMPCs cultured for 7-12 days using the Qiagen RN Easy kit (Qiagen, Santa Clarita, CA, USA). RNA was then used for the first-strand cDNA synthesis in the SuperScript Preamplification System (GIBCO, BRL, Rockville, MD, USA) in accordance with the manufacturer's instructions. SDF-1 specific primers: 5'-GAGGATCCGACGGGAAGCCC-GTCAGC; 3'-GAA-TTCACATCTTGAACCTCTTG. The annealing temperature was 58°C and the reaction proceeded for 35 cycles. The glyceraldehyde-3-phosphate dehydrogenase (GA3PD) gene was included as a reverse transcriptase polymerase chain reaction (RT-PCR) control and performed under similar conditions to normalize for the amount of RNA. Reaction products were analyzed in 2% agarose gel containing 0.25 mg/ml ethidium bromide. Data analysis and statistics Results are shown as the standard error about the mean (SEM) of at least three experiments each. For statistical comparison between groups, the Student paired t test or Bonferroni t test was used. Analyses were performed using the Biostatistics software developed by Stanton A Glantz (UC San Francisco, CA, USA). Flow cytometry data were analyzed using the FlowJo software. BMPCs selected by elutriation of normal human blood When the elutriated cells from the fractions between the smaller T cells and the larger, more granular monocytes were cultured in complete medium without any other supplements, they appeared small and round on examination by phase-contrast microscopy. Some of them were nonadherent (presumably T lymphocytes) and were removed with the initial feeding of the culture. After 72 h, elongated cells with a fibroblast-like morphology and large cells with a clear, thin, adherent cytoplasm around a central nucleus made their appearance. Over the ensuing 7-14 days, they became the predominant cells in the culture (Fig. 1a). At higher magnification they could often be seen to have a splayed, spreading cap at the end and a small, central nucleus. Another cell population, consisting of larger and wider cells, with more cytoplasm and a larger nucleus, was intermediate in morphology between the large, round cells and the thinner, fibroblast-like cells (Fig. 1b). Culture conditions modified the morphology of the elutriated cells. Adding dexamethasone (100 nmol) at the initiation of the culture significantly reduced (by 60% ± 10%) the total number of cells at the 7th to 10th days and decreased the formation of fibroblast-like cells (data not shown). Cultures supplemented with a mixture of 100 nmol dexamethasone, 0.05 mmol ascorbic acid-2-phosphate, and 10 mmol β-glycerophosphate (conditions that favor the development of osteoblasts) developed only round or cuboidal cells, and not fibroblast-like ones (Fig. 1c). Dexamethasone alone added at days 6 to 8 reduced fibroblast numbers, but not the total cell numbers (data not shown). BMPC-rich elutriation fractions observed in time-lapse cinematography Clusters of small round cells formed within 24 h. Cell processes occasionally extended from them, but these retracted minutes later (Fig. 2a). Individual cells were motile and often left the field, but the clusters remained intact. After 72 h, a few cells with a fibroblast-like morphology could be seen beneath and at the edges of the clusters. The fibroblast-like cells were much larger than the initial cells and quite mobile, extending and retracting usually about a broad, fixed cup, or pseudopod. By 6 days, a significant portion of the cells retained their elongated form and looked like the cells in Fig. 2b. Large, round cells were also present. Thus, it appears that BMPCs in the circulation were present as small, round mononuclear cells and their subsequent morphology and function were dictated by culture conditions. Cell numbers in the BMPC-rich elutriation fraction from 500 ml of normal human blood Elutriation fractions were selected for quantification of BMPCs based on cell size (intermediate between lymphocytes and monocytes) and granularity (FACS). This population comprised less than 35% lymphocytes and more than 50% monocytes. Nineteen consecutive samples had an average total cell number of 2.14 ± 0.22 (SEM) × 107, of which 64.4% ± 1.5% (SEM) were monocytes. A sub-population, estimated as 0.3-0.7% of the starting elutriation fractions, was judged to consist of BMPCs on the basis of their morphology, their strong adherence to plastic or glass, and their ability to proliferate in DMEM-20% FCS without added growth factors (ie <1% of the starting 2 × 107 elutriated cells represents 1000 to 10 000 BMPCs). Therefore, it is likely that 500 ml of normal blood will have several thousand BMPCs. Cultures were established with 5 × 105 cells from the elutriation fractions and proliferation was measured on days 3, 10, and 17. Nonadherent cells were removed in the first 24 h and the cultures were fed twice weekly. The cells grew logarithmically, with an approximate doubling time of 2.5 days. By day 17, the initial 5 × 105 cells multiplied to 6.7 × 107 (Table 1). The culture conditions are not conducive to growth of lymphocytes or monocytes; therefore, by week 3, most of the proliferating population in cultures were mesenchymal cells (<20% CD14-staining cells; data not shown). Cells from a BMPC-rich elutriation fraction of healthy human blood were cultured in DMEM-20% FCS. At days 3, 5, 8, and 11 the cultured cells were fixed, stained with anti-BMPR antibodies, and quantified with an autoanalyzer (described in Methods). The results are presented in Fig. 3 as the means of the total number of cells in six individual images. Big cells plus fibroblast-like cells constituted 37% to 59% of the total. Cells with a fibroblast-like morphology varied from 21% to 34% of the BMPCs. The 1:2 ratio of fibroblast-like to big cells remained relatively stable over 11 days of culture, even as the total cell numbers increased (see Table 1). Immunohistology of BMPCs Elutriated cells were grown on sterile 12-well glass slides (ICN) in DMEM-20% FCS and 6 to 12 days later the cells were fixed, stained, and examined by immunohistology (Table 2). The large cells and the fibroblast-like cells stained with antibodies to both vimentin and collagen type I. They were also identified by antibodies to one or the other chain (type IA and type II) of the BMPR (Fig. 4a), but did not react with an anti-type-IB-receptor-chain antibody. Monoclonal Stro-1 antibody stained most of the large BMPCs and a few of the fibroblast-like cells, while anti-CD105 reacted with both populations (Fig. 4b). BMPCs stained strongly with anti-CD44 antibody. Conventional T-cell (CD3), monocyte (CD14, CD68), and B-cell (CD20) antibodies stained neither of the two BMPC populations, nor did they react to anti-LCA (CD45), anti-VCAM (CD106), or MHC-Class II (anti-DR). Cell separation by magnetic beads to analyze the contribution of CD34+ progenitors, monocytes, and T lymphocytes to BMPC formation BMPC-rich elutriation fractions were incubated with magnetic beads coated with specific antibodies and subsequently separated into adherent (antigen-enriched) and nonadherent (antigen-depleted) populations. These were cultured in complete medium in six-well plates and observed daily by phase-contrast microscopy. The CD34-depleted fraction always developed many examples of both types of mesenchymal cells (seven experiments). The fibroblast-like cells appeared in the CD34-depleted cultures at the same time as in untreated controls (usually day 3 or 4). There were not enough CD34+ cells to establish cultures. A representative experiment is shown in Table 3. In two additional experiments, the cells from the elutriation fraction were exposed to CD34 beads and the negative fraction was separated again on fresh CD34 beads. There was no reduction in the time of appearance or number of fibroblast-like cells. Thus, although BMPCs were present in an elutriation fraction that contained CD34+ cells, the two types of cell could be distinguished from one another. Findings with anti-CD14 beads were somewhat different. Both CD14+ and CD14- eluates developed fibroblast-like cells in culture, but the numbers were less than in unfractionated controls. In four of five experiments, the fibroblast-like cells in the CD14+ fraction appeared sooner and in greater numbers than the CD14-fraction. In all instances, however, each fraction contained both large, round cells and fibroblast-like cells and their numbers become more equal with time (usually by day 13). A representative experiment is shown in Table 3. When the CD14+ and CD14- populations were combined, the number of fibroblast-like cells and their time of appearance was the same as in unfractionated controls. T-cell depletion had no effect on the number, morphology, or time of appearance of mesenchymal cells (data not shown). Pluripotent BMPC-fibroblast, osteoblast, and adipocyte formation BMPC-rich elutriation fractions cultured in complete medium supported growth of fibroblasts (spindle-shaped cells stained by antibodies to vitronectin and type I collagen). When the same elutriated cells were supplemented with dexamethasone, ascorbic acid, and β-glycerophosphate their morphology altered, and they became uniform, polygonal cells reminiscent of osteoblasts (Fig. 1c). By 10 days, many of the cells stained for AP (not shown). Over the next 1 to 2 weeks, a subpopulation (approximately 30%) of large cells (which were 3- to 6-fold bigger than monocytes) developed. They accumulated an ill-defined pericellular matrix and the osteoblast-specific protein osteocalcin (Fig. 5a and b). In the same supplemented cultures were sudanophilic adipocytes (Fig. 5a). Another large cell present after 1 week in the supplemented cultures had multiple nuclei (Fig. 6a) and stained for tartrate-resistant acid phosphatase (TRAP) and the vitronectin receptor (Fig. 6b), which are features of osteoclasts (OCs). OCs developed in the supplemented BMPC cultures because both monocytes and stem cells (and/or pre-osteoblasts) were present together in the elutriated cells. Alkaline phosphatase production BMPC-rich elutriation fractions from four separate blood packs were cultured in complete medium with varying concentrations of BMP2 for 5 days and AP in the supernatants was measured (Fig. 7). The lowest concentration of BMP2 (1 ng/ml) caused a significant increase in AP activity (P = 0.004). This represents an increased AP production per cell, because BMP2 had no effect on BMPC proliferation over 5 days (data not shown). Stromal-cell-derived factor 1 SDF-1 is a potent CXCα chemokine produced by bone-marrow spindle-shaped stromal cells and other cells of mesenchymal origin, but not blood leukocytes [12,13]. RT-PCR analysis for SDF-1 mRNA expression in two cDNA samples of cultured BMPCs (lanes 2 and 3) and in a cDNA from RA synoviocytes (lane 4) are shown in Fig. 8. Each sample displayed an amplification of a PCR fragment of the expected size for SDF-1 (296 bp) and was similar to the positive control (lane 5), a sequenced plasmid containing human SDF-1β cDNA. Appearance of cells isolated from a BMPC-rich elutriation fraction of healthy human blood and cultured in DMEM-20% FCS for 8 days (a, b). At this time, the predominant cells consist of both fibroblast-like cells with a central nucleus, filmy cytoplasm, and adherent pseudopods, and large, round cells with a thin, adherent cytoplasm and a round, central nucleus. Hematoxylin staining. (a) ×200; (b) ×400. (c) The appearance of cells isolated from the same BMPC-rich elutriation fraction of healthy human blood and cultured in DMEM-20% FCS supplemented at the initiation of culture with dexamethasone (10-7mol), ascorbic-acid-2-phosphate (0.05 mmol), and β-glycerophosphate (10 mmol) for 8 days. At this time, all the cells have a round or cuboidal morphology with a centrally placed nucleus. ×200. Compare with the nonsupplemented cultures in (a). Time-lapse video cinematography of a BMPC-rich elutriation fraction cultured in DMEM-20% FCS observed by phase-contrast microscopy. At day 2 (a), there are small, round cells in clusters and a few cells with pseudopods. By day 6 (b), there are many large, fibroblast-like cells and large, round, stromal cells arising from a cluster of small, round cells. BMPC-rich elutriation fraction from healthy human blood cultured in DMEM-20% FCS. Cells were fixed, stained with anti-BMPR 1A antibody (see Methods), and analyzed on days 3, 5, 8, and 11. BMPCs were determined by morphology (fibroblast-like [hatched bars] or big cells [filled bars]) and immunoperoxidase staining. Results are presented as the means of total number of cells in six individual images. ×400. Computer image analysis (AnalySIS). BMPC-rich elutriation fraction cultured on a sterile glass slide in DMEM-20% FCS and allowed to proliferate. (a) On day 7, the slide was washed and the cells were fixed and stained with anti-BMPR Type 1A antibody. In the background are many unstained, small, mononuclear cells. Two types of cell are stained: one looks like a fibroblast, and the other is a large, round cell with an adherent cytoplasm. (b) A similar culture on day 12, stained with anti-endoglin (CD105) antibody. The cytoplasm of almost all the large mesenchymal cells shows stippled staining with perinuclear accentuation. BMPC-rich elutriation fraction cultured in DMEM-20% FCS supplemented with dexamethasone, ascorbic acid, and β-glycerophosphate (as described in Fig. 1). After 20 days, about one-third of the cells are very large. Their cytoplasm stains with an anti-calcitonin antibody. Immunoperoxidase staining is also observed in the matrix formed around some of the largest cells. In the same supplemented cultures are large cells containing neutral lipid (Sudan IV; red stain). (a) Shows both anti-calcitonin-stained cells (arrows) and sudanophilic cells (arrowheads) in the same supplemented cultures (×250) and (b) is at higher magnification (×400) showing a cell and its surrounding matrix stained with an anticalcitonin antibody (arrow). BMPC-rich elutriation fraction cultured in DMEM-20% FCS supplemented with dexamethasone, ascorbic acid, and β-glycerophosphate (as described in Fig. 1) and examined daily thereafter. (a) By day 7 there are many large, multinucleated cells (phase-contrast microscopy). (b) These cells stain with an anti-vitronectin receptor antibody (×250). BMPC-rich elutriation fractions (n = 4) cultured in DMEM-20% FCS with varying concentrations of BMP2 for 5 days. Supernatants were collected and analyzed for alkaline phosphatase activity (AP; the release of pNP is a measure of AP activity). The lowest concentration of BMP2 (1 ng/ml) caused a significant increase in AP activity. **P > 0.004. RT-PCR analysis for expression of mRNA for (a) the chemokine SDF-1 and (b) the housekeeping gene GA3PD in cultured BMPCs (GA42, GA43), and a rheumatoid arthritis synovial fibroblast line (RA505 passage 4). Note the similar RT-PCR fragment size in the samples to that in an SDF-1 plasmid (lane 5) included as a positive control. Conditions for RT-PCR and the primers used are described in the methods section. Table 1 Proliferation of BMPCs Table 2 Antibody profile of BMPCs (at days 7-10) Table 3 Outcome of separation of BMPC-rich elutriation fraction using magnetic beads coated with specific antibodies The abilities to self-replicate and to give rise to daughter cells that undergo an irreversible terminal differentiation are features of stem cells [14,15]. The best-characterized are HSCs and their progeny. Friedenstein et al proposed a similar scheme for mesenchymal cells and showed that bone marrow contained primitive cells that could generate progenitors committed to one or another mesenchymal line [2]. Such cells are called MSCs [1]. Conditions that direct marrow MSCs along myogenic [16], adipogenic [17,18], osteogenic [18,19,20], chondrogenic [19,21], and stromal pathways [22] have been defined. For instance, exposure of fibroblast-like marrow MSCs in vitro to optimal concentrations of dexamethasone, ascorbic acid and β-glycerophosphate induces a cuboidal morphology, upregulates AP and osteocalcin expression, and a mineralized (hydroxyapatite) matrix [20]. Lineage differentiation signals can be subtle. Dexamethasone at 10-9mol/l supports adipocyte differentiation, whereas osteogenesis is favored at 10-7 mol/l [19]. Human marrow MSCs obtained by Ficoll density gradient fractionation (1.078 g/ml) and cultured in 25% serum (half horse and half fetal calf) supplemented with hydrocortisone (1 μmol) gives rise to a heterogeneous population, in which fibroblast-like cells do not predominate [22]. Separation of the same population of marrow MSCs on a Percoll density gradient (1.090 g/ml) and culture in carefully selected 10% FCS resulted in a homogeneous population of spindle-shaped fibroblast cells. The higher-density Ficoll may isolate cells that sediment through the Percoll solution used for the marrow MSC isolation. Elutriation, as used in this investigation, probably selects a somewhat different population. The CD34 status of mesenchymal cells is disputed [7,8]. A minority of adult marrow cells express CD34. The antigen is present on pluripotent HSCs, and all unipotent myeloid and erythroid-colony-forming cells [23], but CD34 is also recognized on vascular endothelial cells, basement-membrane structures, and dendritic and perifollicular cells in human skin [24,25]. Simmons and Torok-Storb separated human marrow cells on the basis of their CD34 expression [26]. More than 95% of the detectable colony forming unit fibroblasts were recovered in the adherent CD34+ population, but their CD34 density was much less than on CD34 high HSCs. Furthermore, only 5% of the CD34+ marrow cells reacted with the monoclonal antibody Stro-1, which identifies marrow MSCs [6]. All these studies were done on marrow MSCs before culture, because after culture in vitro, the same stromal cells no longer react with anti-CD34 antibodies [26]. Likewise, although CD34+ cells are identified in tissue sections of human umbilical vein endothelial cells, they are not found in vitro [27]. These and other reports suggest the CD34 glycoprotein is either down-regulated or modified in vitro to a form that is not reactive with the usual anti-CD34 antibodies [23]. Therefore, the failure of Fernandez et al to demonstrate CD34 on circulating stromal cells mobilized by growth factors was probably because the cells had been in culture for 10 days [7]. Similarly, the inability of Majumdar et al to demonstrate CD34 staining was on first-passage marrow MSCs [22]. In vitro culture conditions, however, cannot explain our failure to eliminate BMPCs in fresh elutriation fractions with anti-CD34-coated magnetic beads, a technique widely used to harvest CD34+ HSCs from growth-factor-mobilized human blood. The absorptions were performed on fresh BMPC-rich elutriation fractions. Therefore, BMPCs either lack CD34 or have only a very low density of this glycoprotein. The CD34+ cells called fibrocytes, which are present in monocyte fractions of human blood and develop a fibroblast morphology when grown on fibronectin, have features identical to those of circulating vascular endothelial cell progenitors [28] and are probably not BMPCs. Bone morphogenetic proteins (BMPs) were originally identified as proteins that induced bone formation at extraskeletal sites [29]. Currently, there are 20 or more known BMPs, all members of a larger TGF-β superfamily. BMPs are involved in morphogenesis and embryogenesis, influencing bone, cartilage, and skeletal formation [29,30,31,32]. Much of this information comes from animal cells and embryos, but the addition of BMP2 to cultured postnatal human bone marrow `preosteoblastic' cells in the presence of β-glycerophosphate and ascorbic acid increases the gene message and protein production of AP, osteopontin, bone sialoprotein, osteocalcin, and α-1 collagen [33]. BMPCs develop into osteocalcin-producing cells (Fig. 5a) and make increased amounts of AP in response to BMP2 (Fig. 7). This cannot be explained by proliferation, because BMP2 reduces the number of marrow MSCs in either serum or serum-free conditions [33]. BMPRs belong to the TGF-β receptor family of serine/threonine kinases [34]. Both type I and type II BMPRs bind their respective ligands, but heterodimerization is required for a signal to be transduced [34,35]. For instance, coexpression of type II BMPR with either IA or IB BMPR increases ligand-binding affinity and dramatically enhances biologic activity [11]. Human marrow MSCs express BMP2/4 type I and II receptors as shown in studies employing BMP2 as ligand in the presence or absence of a 100-fold excess of a competitor [33]. BMP structure is conserved across species, and antibodies to type I and typeII receptors react equally well with murine and human mesenchymal cells, but not with hematopoietic cells [34]. This is consistent with our findings that polyclonal antibody to BMPRs can be used to identify BMPCs and constitutes strong evidence that the circulating cells described in this report are mesenchymal precursors. BMPCs stain with the Stro-1 monoclonal antibody made against human bone-marrow stromal cells [6]. Stro-1+ cells cultured in an osteogenic medium exhibit three markers of differentiated bone: AP; 1,25-dihydroxyvitamin-D3-dependent induction of osteocalcin; and a mineralized matrix (hydroxyapatite) [36,37]. Stro-1 is expressed by BMPCs, but the antibody also stains pericytes, cells that surround small-vessel endothelium. Pericytes, which are of mesodermal origin, can also differentiate into a variety of cell types, including osteoblasts and adipocytes (reviewed in [38]). The reactivity of pericytes with BMPR antibodies is not known, but we have used BMPR antibodies to analyze mesenchymal cells in synovial tissues. The antibodies identify large cells in the inflamed joint lining, but they do not stain blood vessels of either normal or inflamed synovium (Marinova-Mutafchieva, personal communication). SH-2, a proprietary antibody developed against isolated bone marrow MSCs [1,3], was not available when these studies were performed. When SH-2 was identified as endoglin (CD105) [4], the cells in a BMPC-enriched elutriation fraction of blood were examined with an anti-CD105 monoclonal antibody. The strong cytoplasmic staining of the large blood mesenchymal cells (Fig. 4b) is more evidence of the great similarity of marrow MSCs and circulating BMPCs. Progenitor and precursor B cells require close contact with marrow MSCs for growth and maturation. Mouse marrow MSCs contain the gene for a protein (termed either stromal-cell-derived factor 1 (SDF-1) or pre-B-cell-growth-stimulating factor (PBSF) [12,13]. SDF-1 is a powerful CXC chemokine that recruits circulating lymphocytes, monocytes, and CD34+hematopoietic progenitors, but not neutrophils [39,40]. PBSF is responsible for converting `early' B cells into immunoglobulin-producing cells [41]. SDF-1 mRNA is constitutively expressed in many tissues, unlike other chemokines, which are only induced [41,42]. SDF-1 is expressed in marrow MSCs, dermal fibroblasts, and synovial fibroblasts, but not HSCs. The demonstration of constitutive expression of SDF-1 mRNA in cultured BMPCs (Fig. 8) and as protein in supernatants from cultured BMPCs (data not presented) is additional evidence that BMPCs are of mesenchymal lineage. Human OCs arise from HSCs in close proximity to stromal cells or from blood monocytes. The OC is a TRAP-positive, large, multinucleated cell with receptors for calcitonin and vitronectin (αvβ3) (Fig. 5a) and the capacity to form resorption lacunae in bone slices [43]. Osteoblast production and OC production are tightly linked and regulated. Osteoblasts facilitate OC formation by providing physical support and critical soluble factors [43]. Our observation of spontaneous formation of cells with the morphology and phenotype of OCs in monocyte-rich (65%) elutriation fractions is best explained by the simultaneous presence of BMPCs in the same fractions. More than 100 normal individuals had CD34- mononuclear cells in a fraction of elutriated blood cells that fulfilled criteria for mesenchymal precursors or stem cells. They proliferated rapidly in culture, had an adherent, spread morphology, displayed cytoskeletal, cytoplasmic, and surface markers of mesenchymal precursors, and had a capacity for differentiation into fibroblast, osteoblast, and adipocyte lineages. Thus, autologous blood could be an important source of cells for tissue engineering and gene therapy [44,45,46]. In addition, the finding of similar cells in the inflammatory joint fluids and synovial tissues of patients with RA suggests they may play a role in the pathogenesis of this disease [47]. Caplan AI: Mesenchymal stem cells. J Orthop Res. 1991, 9: 641-650. Friedenstein AJ, Gorskaja JF, Kulagina NN: Precursor cells of mechanocytes. ExpHematol. 1976, 4: 267-274. Bruder SP, Jaiswal N, Haynesworth SE: Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. J Cell Biochem. 1997, 64: 278-294. 10.1002/(SICI)1097-4644(199702)64:2<278::AID-JCB11>3.0.CO;2-F. Barry FP, Boynton RE, Haynesworth S, Murphy JM, Zaia J: The monoclonal antibody SH-2, raised against human mesenchymal stem cells, recognizes an epitope on endoglin (CD105). Biochem Biophys Res Commun. 1999, 265: 134-139. 10.1006/bbrc.1999.1620. Rosen V: Signaling pathways in skeletal formation. A role for BMP receptors. In Ann NY Acad Sci No 785: Molecular and Developmental Biology of Cartilage. Edited by de Crombrugghe B. 1996, 56-59. Simmons PJ, Torok-Storb B: Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody Stro-1. Blood. 1991, 78: 55-62. Fernandez M, Simon V, Herrera G, Cao C, Del Favero H, Minguell JT: Detection of stromal cells in peripheral blood progenitor cell collections from breast cancer patients. Bone Marrow Trans. 1997, 20: 265-271. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A: Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994, 1: 71-81. Westergren-Thorsson G, Onnervik PO, Fransson LA, Malmstrom A: Proliferation of cultured fibroblasts is inhibited by L-iduronate containing glycosaminoglycan. J Cell Physiol. 1991, 147: 523-530. Ten Dijke P, Yamashita H, Ichigo H, Franzer P, Laiho M, Miyazono K, Helden CH: Characterization of type I receptors for transforming growth factor-beta and activin. Science. 1994, 264: 101-104. Ten Dijke P, Yamashita H, Sampath TK, Reddi AH, Estevez M, Riddle DL, Ichijo H, Heldin CH, Miyanzono K: Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem. 1994, 269: 16985-16988. Tashiro T, Tada H, Heilker R, Shirozu R, Nakano T, Honjo T: Signal sequence trap: a cloning strategy for secreted proteins and type I membrane proteins. Science. 1993, 61: 600-603. Shirozu M, Nakano T, Inazawa J, Tashiro K, Tada H, Shinohara T, Honjo T: Structure and chromosomal location of the human stromal derived factor-1. Genomics. 1995, 28: 495-500. 10.1006/geno.1995.1180. Owen J: Marrow stromal cells. Cell Sci (Suppl). 1988, 10: 63-76. Dennis JE, Merream A, Awadallah A, Yoo JU, Johnstone B, Caplan A: A quadripotential mesenchymal progenitor isolated from the marrow of an adult mouse. J Bone Mineral Res. 1999, 5: 700-709. Ferrari G, Cusella-de Angelis G, Coletta M, Paolucci E, Stornaueolo A, Cassu G, Mavilio F: Muscle regeneration by bone-marrow-derived myogenic progenitors. Science. 1998, 279: 1528-1530. Kelly KA, Gimble JM: 1,215-Dihydroxy vitamin D inhibits adipocyte differentiation and gene expression in murine bone marrow stromal cell clones and primary cultures. Endocrinology. 1998, 139: 2622-2628. Grigoriadis AE, Heersche JN, Aubin JE: Differentiation of muscle, fat, cartilage and bone from progenitor cells present in a bone marrow-derived clonal cell population. Effect of dexamethasone. J Cell Biol. 1988, 106: 2139-2151. Thies RS, Baudy M, Ashton B, Kurtzberg L, Wozney J, Rosen V: Recombinant human bone morphogenetic protein-2 induces osteoblast differentiation in W-20-17 stromal cells. Endocrinology. 1992, 130: 1318-1324. Jaiswal N, Haynesworth SE, Caplan AI, Bruder SP: Osteogenic differentiation of purified, culture expanded human mesenchymal stem cells in vitro. J Cell Biochem. 1997, 64: 295-312. 10.1002/(SICI)1097-4644(199702)64:2<295::AID-JCB12>3.3.CO;2-6. Yoo JU, Barethel TS, Nishimura L, Solchaga L, Caplan AI, Goldberg VM, Johnstone G: The chondrogenic potential of human bone-marrow-derived mesenchymal progenitor cells. J Bone Joint Surg (Am). 1998, 80: 1745-1757. Majumdar MD, Thiede MA, Mosca JD, Moorman M, Gerson SL: Phenotypic and functional comparison of cultures of marrow derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol . 1998, 176: 57-66. 10.1002/(SICI)1097-4652(199807)176:1<57::AID-JCP7>3.0.CO;2-7. van de Rijn M, Rouse RV: CD34. A review. Applied Immunohistochem. 1994, 2: 71-80. Nickoloff BJ: The human progenitor cell antigen (CD34) is localized on endothelial cells, dermal dendritic cells and perifollicular cells in formalin fixed normal skin. Arch Dermatol. 1991, 127: 523-529. Brown J, Greaves MF, Molgaard HV: The gene encoding the stem cell antigen CD34 is conserved in the mouse and expressed in hematopoietic cell lines, brain and embryonic fibroblasts. Inter Immunol. 1991, 3: 75-184. Simmon PJ, Torok-Storb B: CD34 expression by stromal precursors in normal adult human bone marrow. Blood. 1991, 78: 2848-2853. Fina L, Molgaard H-V, Robertson D, Bradley NJ, Monaghan P, Delia D, Sutherland DR, Baker M, Greaves MF: Expression of the CD34 gene in vascular endothelial cells. Blood. 1990, 75: 2417-2426. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner J: Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997, 275: 964-967. Reddi AH: Regulation of cartilage and bone differentiation by bone morphogenetic proteins. Curr Opin Cell Biol. 1992, 4: 850-855. Wang EA, Rosen V, D'Allesandro JS, Bauduy M, Cordes P, Harada T, Isreal DJ, Hiwick RM, Kerns KM, La Pan P, Luxenberg DP, McQuaid D, Nove J, Wozney JM: Recombinant human bone morphogenetic protein induces cartilage and bone differentiation. Proc Natl Acad Sci USA. 1990, 87: 2220-2224. Enomoto-Iwamoto M, Iwamoto M, Mukudai Y, Kawakami Y, Nohno T, Higuchi Y, Takemoto S, Ohuchi H, Noji S, Kurisu K: Bone morphogenetic protein signaling is required for maintenance of differentiated phenotype, control of proliferation, and hypertrophy in chondrocytes. J Cell Biol . 1998, 140: 409-418. Lyons KM, Pelton RW, Hogan BL: Organogenesis and pattern formation in the mouse: RNA distribution patterns suggest a role for bone morphogenetic protein 2 (BMP 2-A). Development. 1990, 109: 833-844. Lecanda F, Avioli LV, Cheng SL: Regulation of bone matrix protein expression and induction of differentiation of human osteoblasts and human bone marrow stromal cells by bone morphogenetic protein. Cell Biochem. 1997, 67: 386-396. Yamashita H, Ten Dijke P, Heldin C-H, Miyazono K: Bone morphogenetic protein receptors. Bone. 1996, 19: 569-574. 10.1016/S8756-3282(96)00259-1. Massague J: TGF-beta signaling: receptors, transducers and Mad proteins. Cell. 1996, 85: 947-950. Gronthos S, Greaves SE, Ohta S, Simmons PJ: The STRO-1 fraction of adult human bone marrow contains the osteogenic precursors. Blood. 1994, 84: 4164-4173. Stewert K, Screen J, Jeffries CM, Walsh S, Beresford JN: Coexpression of the STRO-1 antigen and alkaline phosphatase in cultures of human bone and marrow cells. J Bone Miner Res. 1996, 11: 208-211. Doherty MJ, Canfield AE: Gene expression during vascular pericyte differentiation. Crit Rev Eukaryotic Gene Expr. 1999, 9: 1-17. Bleul CC, Fuhlbrigge RC, Casanovas JM, Aiuti A, Springer TA: A highly efficacious lymphocyte chemoattractant, stromal cell derived factor 1 (SDF-1). J Exp Med. 1996, 184: 1101-1109. Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC: The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med. 1997, 185: 111-120. Nagasawa T, Kikutani H, Kishimoto T: Molecular cloning and structure of a pre-B cell growth-stimulating factor. Proc Natl Acad Sci USA. 1994, 91: 2305-2309. Nagasawa T, Hirota S, Tachibana N, Takakura S, Nishikawa Y, Kitamura N, Yoshida H, Kikutani T, Kishimoto T: Defects of B cell lymphopoiesis and bone marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996, 382: 635-638. Suda T, Takahashi N, Martin TJ: Modulation of osteoclast differentiation. Endocr Rev. 1992, 13: 66-80. Prockop DJ: Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997, 276: 71-74. Gerson SL: Mesenchymal stem cells: no longer second class citizens. Nature Med. 1999, 5: 262-264. Pittinger MP, Mackay AM, Beck SC, Jaiswal RM, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak D: Multilineage potential of human mesenchymal stem cells. Science. 1999, 284: 143-147. 10.1016/S0304-3940(00)00981-2. Marinova-Mutafchieva L, Taylor P, Funa K, Maini RN, Zvaifler NJ: Mesenchymal cells expressing bone morphogenetic protein receptors are present in the rheumatoid arthritis joint. Arthritis Rheumat . 2000, This work was done at the Kennedy Institute of Rheumatology, London, while the first author (Nathan J Zvaifler) was on sabbatical leave from the University of California, San Diego. He is grateful to the members of the faculty and staff who facilitated these studies, especially the students and research staff in Professor Marc Feldmann's laboratory for their expertise in elutriation, M Kahan for cytofluorography, and S Quarantino, F Brennan, and Y Chernajovsky for helpful suggestions and discussion. Jennifer Allen provided excellent secretarial services. This work was supported by the Arthritis Research Campaign Core Grant to the Kennedy Institute and by the National Institutes of Health grants nos. AR40770 and AR45347 (NJ Zvaifler). Department of Medicine, University of California, San Diego, CA, USA Nathan J Zvaifler & Jan A Burger Kennedy Institute of Rheumatology, London, UK Lilla Marinova-Mutafchieva, Gill Adams, Christopher J Edwards & Ravinder N Maini Department of Pathology and Medicine, Imperial College School of Medicine, Charing Cross Hospital, London, UK Jill Moss & Ravinder N Maini Nathan J Zvaifler Lilla Marinova-Mutafchieva Gill Adams Christopher J Edwards Jill Moss Jan A Burger Ravinder N Maini This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zvaifler, N.J., Marinova-Mutafchieva, L., Adams, G. et al. Mesenchymal precursor cells in the blood of normal individuals. Arthritis Res Ther 2, 477 (2000). https://doi.org/10.1186/ar130 Revised: 10 July 2000 bone marrow progenitor cells bone morphogenetic protein receptors mesenchymal precursor cells SDF-1
Identification of partial sweeps, which include both hard and soft sweeps that have not currently reached fixation, provides crucial information about ongoing evolutionary responses. To this end, we introduce a deep learning approach that uses a convolutional neural network for image processing, which is trained with coalescent simulations incorporating population-specific history, to discover selective sweeps from population genomic data. This approach distinguishes between completed versus partial sweeps, hard versus soft sweeps, and regions directly affected by selection versus those merely linked to nearby selective sweeps. We perform several simulation experiments under various demographic scenarios to demonstrate the performance of our deep learning classifier partialS/HIC, which exhibits unprecedented resolution for detecting partial sweeps. We also apply our method to whole genomes from eight mosquito populations sampled across sub-Saharan Africa by the Anopheles gambiae 1000 Genomes Consortium, elucidating both continent-wide patterns as well as sweeps unique to specific geographic regions. These populations have experienced intense insecticide exposure over the past two decades, and we observe a strong overrepresentation of sweeps at insecticide resistance loci. Our analysis thus provides a catalog of candidate adaptive loci that may aid mosquito control efforts. More broadly, the success of our supervised machine learning approach introduces a powerful method to distinguish between completed and partial sweeps, as well as between hard and soft sweeps, under a variety of demographic scenarios. As whole-genome data rapidly accumulate for a greater diversity of organisms, partialS/HIC addresses an increasing demand for useful selection scan tools that can track in-progress evolutionary dynamics. Author Summary Recent successful efforts to reduce malaria transmission are in danger of collapse due to evolving insecticide resistance in the mosquito vector Anopheles gambiae. We aim to understand the genetic basis of current adaptation to vector control efforts by deploying a novel method that can classify multiple categories of selective sweeps from population genomic data. In recent years, there has been great progress made in the identification of completed selective sweeps through the use of supervised machine learning (SML), but SML techniques have rarely been applied to partial or ongoing selective sweeps. Partial sweeps represent an important facet of evolution as they reflect present-day selection and thus may give insight into future dynamics. However, the genomic impact left by partial sweeps is more subtle than that left by completed sweeps, making such signatures more difficult to detect. To this end, we extend a recent SML method to partial sweep inference and apply it to elucidate ongoing selective sweeps from Anopheles population genomic samples.
Homeopathic treatments may be the drug of choice for certain members of the British Royal Family, but researchers in Australia have dismissed claims to their effectiveness. The latest report from Australia's National Health and Medical Research Council (NHMRC) warns people that they 'may put their health at risk', should they choose homeopathic remedies. Homeopathy is based on the premise of treating 'like for like', and uses minute, highly diluted doses of the substance that causes the illness, as a remedy. Treatments can come prepared in a variety of methods, including solutions, pills, sprays, creams and ointments. Homeopaths believe that the minute dose retains a 'memory' of the original substance, which then goes on to trigger a healing response in the body. Advocates of homeopathy recommend that it can be used to treat both acute and chronic conditions, and is used globally by over 200 million people. How was the Australian Homeopathic report conducted? The report looked at 225 previous studies dating back to 1997, to test the effectiveness of homeopathy on a number of health condition. The research team rated each study for reliability from one – very strong – to four – very weak. The team only used studies which included controlled trials, in other words, those with a comparison group who were not given homeopathic treatment. The council assessed the effectiveness of the homeopathic treatments based on three criteria. The past studies were reviewed using an independent contractor. Independent evaluation of information was provided by homeopathy interest groups and the public. Worldwide clinical practice guidelines and government reports on homeopathy, were taken into consideration. What did the Australian Homeopathic Report reveal? The report found that there is no decisive evidence to suggest that homeopathy is more effective than placebos in either easing patients or treating their symptoms. The report did find evidence that homeopathy was more effective than placebos for conditions such as ADHD, bruising, HIV, chronic fatigue, ulcers and depression. However, the council decided that the original experiments had not been properly conducted and so deemed the final results unreliable. The council advised that for any treatment to be effective it had to outweigh any benefits from a placebo effect. Not only that, but these benefits should improve a person's general health. The benefits from treatments should also not be attributed to chance, and remain consistent throughout several studies. Professor Anderson concluded: "From this review, the main recommendation for Australians is that they should not rely on homeopathy as a substitute for proven, effective treatments.
Inflammation drives the development or severity of a large number of diseases (e.g., atherosclerosis, asthma, ulcerative colitis, postmenopausal osteoporosis, sleep disorders). Variation in genes that encode proteins regulating inflammation may underlie a large proportion of interindividual variation in susceptibility to numerous diseases. Furthermore, variation in the production or function of cytokines can cause variation in inflammatory responses that in turn influences the progression of inflammatory disease. Examples of genetic variation in inflammation are abundant. For example, a single nucleotide polymorphism in the human caspase-12 proenzyme confers hyporesponsiveness to LPS-stimulated cytokine production that manifests clinically as increased susceptibility to severe sepsis and mortality (Saleh et al. 2004). Similarly, a polymorphism in TNF-a promoter region is associated with increased TNF-a production in response to LPS and increased risk of sepsis-related morbidity and mortality (Bessler, Osovsky, and Sirota 2004; Hartel, von Puttkamer, Gallner, Strunk, and Schultz 2004; Lorenz, Mira, Frees, and Schwartz 2002; Strunk and Burgner 2006), an IL-6 polymorphism is associated with higher risk of bacterial sepsis (Heesen, Kunz, Bachmann-Mennenga, Merk, and Bloemeke 2003), and certain IL-1ß polymorphisms correlate with susceptibility to Helicobacter pylori infection and gastric cancer, Alzheimer's disease, and possibly rheumatoid arthritis (Cantagrel et al. 1999; El Omar, Chow, Mccoll, Fraumeni, and Rabkin 2000; Hamajima et al. 2001; Mcgeer and Mcgeer 2001). Receptors for inflammatory mediators also show genetic variation. For example, toll-like receptor 4 (TLR4), which mediates the effects of LPS, has two missense single nucleotide polymorphisms are associated with differences in susceptibility to sepsis (Agnese et al. 2002; Barber, Aragaki, Rivera-Chavez, Purdue, Hunt, and Horton 2004; Child et al. 2003). The impact of genetic variation on the inflammatory response is perhaps best illustrated in mice. C3H/HeJ mice, for example, are hyporesponsive to Escherichia coli LPS because they bear a mutation in the TLR4 gene that is not present in related strains (e.g., C3H/HeOuJ and C3H/HeN) (Qureshi et al. 1996; Vallance, Deng, Jacobson, and Finlay 2003). The cytokine responses (TNF-a, IL-1, IL-6) of C3H/HeJ mice treated with LPS are similar those of in humans with TLR4 mutations (Kuhns, Priel, and Gallin 1997; Poltorak et al. 1998). As a second example, C57BL/6J and A/J mice injected with LPS demonstrate different numbers of infiltrating polymorphonuclear leucocytes (PMN) in liver and lungs, serum levels of IL-1P and IL-6 are higher in C57BL/6J mice than in A/J mice, A/J mice have higher levels of TNF-a, and mortality is higher in the C57BL/6J strain (De Maio, Mooney, Matesic, Paidas, and Reeves 1998). In contrast to LPS, A/J mice are far more susceptible to infection with C. albicans than are C57BL/6J mice (Marquis, Montplaisir, Pelletier, Auger, and Lapp 1988; Tuite, Elias, Picard, Mullick, and Gros 2005). Genetic variation in the sensitivity and immune responses of different mouse strains to microbial challenge is a likely factor in the changes in vigilance associated with infectious and inflammatory disease. In considering the genetics of inflammation and its relationship to disease, three questions warrant attention: (a) will identified polymorphisms significantly impact the inflammatory process, (b) will the impact on inflammation be clinically relevant, and (c) does genetic information suggest therapeutic measures that may reduce clinical morbidity and mortality (Kornman 2006). Functional genetic polymorphisms in the cytokine response both under normal conditions and after inflammation may influence both the disease process and the sleep.
This is an early view in BI. About the most ever studied invasive tree. Abstract The potential for populations of exotic invasive plants to differ in their response to stressful environmental conditions is an underexplored issue in determining invasive species' range limits. Introduced genotypes may differ in response to climatic, edaphic, or biotic factors within their introduced range leading to differences in potential ranges among populations. potential for expansion into areas with more severe winters. Differences among introduced populations should be considered when evaluating the potential range expansion of Chinese tallow and other invasive species.
The Neuroimaging Core is a Core that leverages neuroimaging expertise in molecular, functional, and structural imaging to serve the neuroimaging research needs of the Massachusetts ADRC (MADRC). The Neuroimaging Program was previously embedded within the Clinical Core, but given the growing number of MADRC affiliated neuroimaging based research projects and the increasing importance of neuroimaging in NIH and industry supported multi-center AD studies, we have expanded into a fully fledged Neuroimaging Core to provide cutting-edge support to ongoing and new neuroimaging projects. Aim 1: To support the neuroimaging components of MADRC affiliated research studies, implement standardized MRI and PET acquisition protocols and provide expertise on image analysis for Projects 1 and 2, affiliated R01, R21, and PPG imaging studies and MADRC pilot projects. Aim 2: To support neuroimaging acquisition for multi-center AD research studies, neuroimaging data for Alzheimer's Disease Neuroimaging Initiative (ADNI), Dominantly Inherited Alzheimer Network (DIAN), Neuroimaging in FTD (NIFD), NIH and industry sponsored multi-center clinical trials. Aim 3: To acquire, catalogue, and store multi-modality image datasets from MADRC Longitudinal Cohort (LC) subjects, links to available imaging data. Aim 4: To facilitate the implementation of amyloid imaging and novel PET tracers into MADRC-affiliated research studies, support for utilizing new radiopharmaceuticals, including markers for tau, inflammation, and mGluR5 receptors. Aim 5: To implement sensitive analytic techniques for volumetric MRI, ctical thinning in AD and FTD subtypes to aid in early detection and differential diagnosis. Aim 6: To optimize and validate innovative imaging techniques for early AD research, or "task-free" functional connectivity MRI and "connectome" measures of white matter fiber tracts. Aim 7: To provide neuroimaging expertise and education imaging research, and guidance to clinicians and the lay public regarding media reports on advances in neuroimaging research and the appropriate use of new neuroimaging techniques in clinical practice.
Counting the costs: Comparing depot medroxyprogesterone acetate and norethisterone oenanthate utilisation patterns in South Africa Jennifer Smit1,2,3, Andrew Gray2, Lynn McFadyen1,2,3 & Khangelani Zuma4 BMC Health Services Research volume 1, Article number: 4 (2001) Cite this article In South Africa, where health care resources are limited, it is important to ensure that drugs provision and use is rational. The Essential Drug List includes depot medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-EN) as injectable progestagen-only contraceptives (IPCs), and both products are extensively used. Objectives and Methods Utilisation patterns of the injectable contraceptive products DMPA and NET-EN are compared in the context of current knowledge of the safety and efficacy of these agents. Utilisation patterns were analysed by means of a Pareto (ABC) analysis of IPCs issued from 4 South African provincial pharmaceutical depots over 3 financial years. A case study from rural KwaZulu-Natal, South Africa, is used to examine utilisation patterns and self-reported side effects experienced by 187 women using IPCs. IPCs accounted for a substantial share of total state expenditure on drugs. While more DMPA than NET-EN was issued, NET-EN distribution from 2 depots increased over the 3-year period. Since DMPA was cheaper, if all NET-EN clients in the 1999/2000 financial year (annualised) had used DMPA, the 4 depots could have saved 4.95 million South African Rands on product acquisition costs alone. The KZN case study showed slightly more NET-EN (54%) than DMPA (46%) use; no significant differences in self-reported side effects; and that younger women were more likely to use NET-EN than DMPA (p = 0.0001). Providing IPCs on the basis of age is not appropriate or cost effective. Rational use of these products should include consideration of the cost of prescribing one over another. Affordability of drugs by developing countries is currently a topic of heated debate. In South Africa, where financial resources for health care are limited, and where health care costs are expected to soar as the HIV epidemic escalates, it becomes increasingly important to ensure that all drugs are rationally provided and used. The injectable progestagen-only contraceptives (IPCs) depot medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-EN) are by far the most widely utilised contraceptives in South Africa, especially amongst younger users and women living in rural areas [1]. Both drugs are on the South African Essential Drug List [2] and are available free of charge at public sector primary health care facilities. Although not extensively documented, it is claimed that there has been a shift away from the predominant use of DMPA, which is given every 12 weeks, to NET-EN, given every 8 weeks, especially amongst younger, nulliparous women [3, 4]. Combined injectable contraceptives (CICs), which contain a combination of oestrogen and progestagen, are not registered for use in South Africa. The World Health Organisation's general criteria - safety, affordability, necessity and efficacy - for inclusion on the Model List of Essential Drugs (EDL) [5] provide a useful basis upon which to make decisions about drug selection and rational use. Taking into account published findings on efficacy, reversibility, side effects and safety, this paper analyses IPC supply patterns and costs from four pharmaceutical depots, and describes a case study of IPC utilisation patterns and side effects in a rural sub-district of KwaZulu-Natal, South Africa. Based on these analyses, appropriate recommendations for the rational use of IPCs are made. What the literature tells us Published clinical trials and reviews on efficacy, side effects, reversibility and safety of DMPA and NET-EN were sought by means of computerized and hand searches. Copies of relevant publications and citations from these publications were obtained and reviewed. Relevant international and South African policy documents were also reviewed. This extensive search revealed that: DMPA is better researched than NET-EN, few studies directly compare DMPA and NET-EN, few clinical trials have been undertaken in Southern Africa, few clinical studies have been undertaken amongst young users, and most published studies, upon which review after review are based, were undertaken in the 1970s and early 1980s. Methodological differences in subject recruitment, exclusion criteria, frequency and nature of procedures for follow-up, types of observations made, method of recording, methods of analysis and large intersite variability in some studies, make it difficult to evaluate the published data. Trussel et al. provide a useful account of difficulties in analysing and comparing contraceptive efficacy trials [6]. Nevertheless, to the extent that this is possible, a comparative synopsis of the efficacy, side effects, delay in return to fertility and safety of DMPA and NET-EN is provided in this section. It is not the purpose of this paper to provide a detailed review, but merely to highlight relevant findings. The authors can be contacted for a more extensive bibliography. Both IPCs are demonstrably highly effective. There are minor differences in published efficacy rates of both drugs depending on the study, timing of the first injection, the population, body weight, dosage regimen and provider training. An illustration of the high efficacy of these two products is provided by a World Health Organisation (WHO) comparative trial [7]. According to this study the efficacy of DMPA given every 90 days and NET-EN given every 60 days are comparable, with a cumulative 2-year pregnancy rate of 0.4 per 100 woman-years. In an evaluation of 5 large controlled multicentre studies, Kaunitz [8] reported that there were only 24 pregnancies among 7 849 women using DMPA for 122 496 patient-months. Trussel et al. [6] provide "summary estimates of contraceptive failure" and give the lowest expected, and typical percentage, of accidental pregnancies in the United States, during the first year of use, as 0.3 for DMPA and 0.4 for NET-EN (unspecified dose interval). There is little direct comparative data on the reversibility of DMPA and NET-EN. While return to fertility is reported by some reviewers to be more rapid with NET-EN [9, 10], more recently, Bigrigg et al. [11] in examining early data, suggest that there is no delay in return to fertility with DMPA use, if one considers the methodological bias of early studies, which did not take in to account the date of the last DMPA injection. They state further that "if there is a delay it is not statistically significant and is less than 30 days". Kaunitz gives the shortest reported time before fertility is returned with DMPA, as 4 months after the last injection i.e. 4 weeks after the due date of the next injection [8] and, according to Hatcher et al. return to fertility is delayed by DMPA for about 4 months longer on average, compared with the combined oral contraceptive method, intrauterine contraceptive device, and condoms [12]. The poor side effect profile of progestagen-only injectables is extensively documented. The most frequently reported side effects, and those most likely to result in discontinuation, are menstrual disturbances such as amenorrhoea, irregular bleeding and heavy bleeding [3, 13]. Menstrual irregularities are reported to occur more often with DMPA than with NET-EN use. For instance, the WHO clinical trial undertaken in 1983 compared menstrual disturbances resulting from DMPA given at 90-day intervals, with NET-EN given every 60 days and with NET-EN given every 60 days for 6 months and then every 84 days [7]. Significantly less amenorrhoea was reported by NET-EN users (on both dosage regimens), than by DMPA users. Amenorrhoea was also found to result in significantly higher discontinuation rates with DMPA users than with NET-EN. During the first six months of use, both dosage regimens of NET-EN were reported to result in more defined cyclic patterns and fewer prolonged bleeding and spotting episodes than DMPA, but similar discontinuation rates were found with the two products. However, in a study undertaken in Egypt, despite the more frequent occurrence of menstrual irregularities with DMPA, better one-year continuation rates were found with DMPA than with NET-EN [14]. Weight gain is also a commonly reported side effect and in comparing DMPA and NET-EN, the findings on weight gain appear to be similar. A multinational WHO comparative clinical trial found no statistical difference in weight gain between NET-EN and DMPA (both administered at 12 week intervals) after a year of use - the weight gain with NET-EN was reported as 1.5 kg and with DMPA was 2.0 kg [15]. Headache was the most common non-menstrual side effect reported in this comparative trial and was more frequently reported by DMPA users than NET-EN users, however, it is important to note that in this study, NET-EN was administered every 12 weeks. IPCs are considered to be relatively safe contraceptive methods [16, 17] and recent studies indicate that there is little reason to be concerned about either DMPA or NET-EN causing an increased risk of breast cancer [18]. However, the possible effect of DMPA on bone density, particularly in adolescents and long-term users is cause for concern [19]. Little is published on the possible effect of NET-EN on bone density. Findings from prospective studies in progress are awaited. The World Health Organization's Medical Eligibility Criteria for Contraceptive Use classifies DMPA and NET-EN together, and makes no differentiation between the two in regard to their side effects or contraindications [20]. The only restriction this document makes about age, for IPC use, is that "For women under 16 years of age, there are theoretical concerns regarding hypo-oestrogenic effects...." p.54. The WHO states further that there is no need to restrict use of progestagen-only contraceptive methods for nulliparous women. The Primary Health Care Essential Drugs List for South Africa provides no guidelines with respect to the circumstances under which DMPA rather than NET-EN should be prescribed (or vice versa) [2]. Supply patterns and costs Consumption figures of IPC stock issued from provincial pharmaceutical depots were requested from the Deputy Director, Procurement of the South African National Department of Health. Data for DMPA and NET-EN were made available for the KwaZulu-Natal (KZN), Guateng and Free State Provincial Pharmaceutical depots and for the Port Elizabeth depot, which serves the western part of the Eastern Cape Province. These four provinces (of nine South African provinces) represent over 50% of the total South African population. Gauteng has a mostly urban population and KZN and Eastern Cape are more rural. The following data were analysed for financial years 1997/8, 1998/9, and for 1/04/99 to 7/12/99 of the 1999/2000 financial year: Position number on Pareto (ABC) analyses for DMPA and NET-EN. An ABC analysis is a method which ranks drugs according to their annual usage (unit cost times annual consumption). Class A items are the 10 to 20 % which account for 75 to 80% of the funds spent. Class B items have an intermediate contribution to total expenditure, whereas Class C items (the majority of items) account for a small percentage of funds spent. ABC analyses are used to identify priority cost drivers for intervention [21]. Number of units of each item issued in the same time period per depot. Total cost of each item per time period per depot (at constant 1999 prices). Current and previous tender prices for DMPA and NET-EN. Note exchange rate: 1 British Pound ≈ 11 South African Rands. Case study: use patterns and side effects Prevalence of IPC use was determined by means of a community-based cross-sectional survey undertaken in a rural sub-district in northern KZN, South Africa. Commencing from a randomly selected starting point, every second household was chosen until 40% of households in the sub-district had been visited. In this way, 849 households of an estimated 2088 were selected and, one woman from each household, in the age range 15 to 49, was randomly selected for interview. Verbal and written explanations of the study were provided to each woman selected (in Zulu and/or English) and consent to participate in the study was requested. In all, 848 women were interviewed and no-one refused to participate. Prior to commencing the survey, workshops and meetings were held to introduce the study to local traditional leaders, community health workers, and health service providers. Ethical clearance for the study was provided by the Ethics Committee of the University of Durban-Westville. Each woman selected was asked if she was currently using an IPC and those who were, were asked whether they were using DMPA or NET-EN. Data were collected by means of an extensive structured interview, including questions on demographic characteristics, reasons for method selection, and problems and side effects experienced. Interviews were conducted in Zulu, between September and December 1998. They were conducted during the day from Mondays to Fridays, but where a selected woman was not home, a revisit was made in the evening or on a Saturday. Data were coded, double entered and analysed using Epi-Info Version 6.43 and the SAS Version 6.12. Cost of injectable contraceptive products DMPA products issued at primary health care outlets in the three financial years analysed were obtained from the original patent holder (Pharmacia-Upjohn) and a generic manufacturer (Aspen Pharmacare). NET-EN was available only from the innovator (Schering). Table 1 shows that the acquisition cost of a vial of both DMPA and NET-EN products increased every year, and that the cost of both DMPA products rose particularly steeply. In the 1999/2000 financial year, the generic product, was almost the same price as the innovator product. Their costs were exactly the same in the 1999/2000 fiscal year. Table 1 Acquisition costs of injectable contraceptive products: 1997/8, 1998/9, 1999/2000 Since DMPA is given less frequently than NET-EN, cost per couple years of protection (CYP) provides a more accurate cost comparison of DMPA and NET-EN. Based on the 1999/2000 state tender prices for the DMPA and NET-EN innovator products, the cost per couple year was SAR28.68 for NET-EN (6 vials per year) and SAR19.12 for DMPA (4 vials per year). If the calculation were based on the DMPA generic product price, use of DMPA would be even cheaper (SAR17.16). It should be noted that the cost of syringes, needles and swabs, personnel costs and client transport and time were not included in the calculations. These costs can be considerable and are obviously higher for NET-EN because it is administered more frequently. Analysis of annual expenditure on DMPA and NET-EN In all 4 depots, both IPCs consumed an important share of total drug expenditure (table 2). A Pareto analysis shows that both DMPA and NET-EN appeared in the top 10 in each year (based on actual volumes multiplied by constant 1999 prices), with the exception of NET-EN in KZN where it was19th in 1997/8, 1998/9 and 1999/2000. More was spent on NET-EN than DMPA in Gauteng in all 3 years, but less in the other 3 depots. Only in 1998/9 in the Port Elizabeth area was more spent on NET-EN than DMPA. Total annualised expenditure on both products in the 4 depots in 1999/2000 was projected to be SAR28.77 million. Table 2 Pareto analysis of injectable contraceptive products: 1997/8, 1998/9, 1999/2000 Ratio of NET-EN:DMPA issued The ratios of NET-EN:DMPA issued from the 4 depots were calculated based on CYP rather than on number of vials issued. As shown in Figure 1, DMPA was increasingly used in Port Elizabeth where the ratio of NET-EN:DMPA decreased from 0.64 in 1997/8 to 0.57 in 1999/2000. In Free State the market share was more or less stable (0.42, 0.44, 0.40). A similar picture emerged in KZN (0.22, 0.23, 0.25), with some increase in NET-EN use. However, in Gauteng, while DMPA was still used most, NET-EN use was clearly increasing (0.67, 0.73, 0.81). Ratio of NET-EN:DMPA issued from the four pharmaceutical depots in 1997/8, 1998/9, 1999/2000 Counting the cost of injectable contraceptive product choice If all NET-EN clients in the 1999/2000 financial year (annualised) had been given DMPA instead, the 4 depots together might have saved SAR4.95 million. Conversely, if NET-EN had been issued to all DMPA clients, then the estimated additional cost in the same year for the 4 depots would have been SAR9.35 million. Savings and additional costs would be increased if other costs (surgical supplies, personnel costs, client transport etc.) were included. The savings are calculated on the annualised total CYP for innovator versions of both DMPA and NET-EN. If the price of the cheaper generic preparation of DMPA had been used in the calculation, the savings would have been greater. To illustrate the potential savings or additional costs further, in KZN, a 9.0% saving on the expected 1999/2000 annual IPC drug bill might have been effected if only DMPA had been supplied. On the other hand, if only NET-EN had been available, the additional load would have been 36.5%. In Gauteng, the savings or additional costs could have been 18.3% and 22.6% respectively. Injectable contraceptive prevalence and cost All respondents (848) were African, Zulu-speaking women in the age range 15-49 years. Of these, 187 (22.1%) were using an injectable contraceptive method, either the innovator product of DMPA or NET-EN. Forty-six per cent (86) of the IPC users were using DMPA and 54% (101) were using NET-EN. The mean age of DMPA users was 29.6 years (median 29, range 18-49) and that of NET-EN users was 23.2 (median 23; range 17-37). Younger women were thus more likely to use NET-EN than DMPA (p = 0.0001). The age distribution of DMPA and NET-EN users is shown in Figure 2. The mean length of use was 2.2 years (range 0.1 to 11). Age distribution of DMPA and NET-EN users The ratio of NET-EN:DMPA users in this rural sub-district was 1.2 to 1. Based on 1999/2000 product costs, by supplying only DMPA, a saving of 21.3% on the annual drug bill for IPCs could have been achieved by the local health facility. On the other hand, if only NET-EN had been supplied, the annual IPC cost would have increased by 18.1%. These figures are based on product costs alone. Reasons for product choice Current users were asked, by means of an open-ended question, why they preferred the injectable product they were using, and the following findings are of note: Many DMPA users (42.4%) indicated that they preferred this product because it was "stronger". On the other hand, NET-EN was favoured by 36.0% of those using it as it was regarded as "weaker" or "lighter". Concern about delayed return to fertility with DMPA was expressed by 5.0% of NET-EN users and 14.0% indicated that they chose NET-EN because it did not delay return to fertility. The idea that the NET-EN is for younger women or teenagers and DMPA for older women was expressed by 14.6% of the IPC users. This preference is clearly reflected in the age distribution of DMPA & NET-EN users depicted in Figure 2. Recommendation by health worker was given as one of the most common reasons for product choice (21.1%). Relatively few women (6.5%) mentioned that concern about side effects influenced choice of either product. Side effects with injectable contraceptives IPC users were asked to indicate what side effects, if any, they were experiencing with DMPA or NET-EN by responding to a list of 22 possible side effects. Consistent with the international literature, many women reported menstrual irregularities such as amenorrhoea, spotting, heavy periods or irregular periods (table 3). Other side effects commonly reported were vaginal wetness and weight gain. The side effect profile for DMPA or NET-EN users was similar with no significant differences found between users of the two products in terms of their experience of side effects. Table 3 Side effects most frequently reported by DMPA and NET-EN users In highlighting key issues in financing family planning services in Sub-Saharan Africa, Janowitz et al. make the following statement "Given limited resources, the universal provision of methods based on demand and without regard to cost will restrict the number of individuals whose need for family planning services can be met" p. 64 [22]. The balancing of needs and resources becomes even more challenging when attempting to meet reproductive health needs more broadly. For instance, in developing countries like South Africa many drugs, such as antiretrovirals for the management of HIV, are not available through the public sector. Careful analysis of current expenditure on drugs is thus required so that resources are allocated to meet changing therapeutic needs. Findings presented in this paper show that IPCs account for a substantial share of the total state expenditure on drugs in South Africa. Of the two IPCs available on the EDL, DMPA is a cheaper option than NET-EN, even if only considering acquisition costs. Analysis of supply patterns from the 4 pharmaceutical depots shows that if all NET-EN clients had been given DMPA, between 9.0% and 18.3% of the expected annual drug bill for IPCs could have been saved per depot. Rational use of drugs cannot however be based on cost alone and clinical criteria, such as efficacy, safety, and acceptability of side effects, must also be considered. The context within which contraception is provided should also be taken into account. An extensive review of the literature on IPCs shows little difference between NET-EN and DMPA in terms of efficacy, safety, reversibility and side effect profile. However, a systematic comparative review has not been published and little clinical data on African women are available. NET-EN appears to have a slightly better side effect profile and a slightly shorter delay in return to fertility. DMPA is marginally more effective and is more convenient as users only have to return to the clinic every 12 weeks rather than after 8 weeks, as is the case for NET-EN users. As noted earlier, no differentiation in regard to side effects or contraindications of the two products is made by the WHO in terms of its medical eligibility criteria for contraceptive use [20]. Findings from the KZN case study show that slightly more NET-EN was used than DMPA. No significant differences were found in self-reported experience of side effects. What does emerge clearly is that NET-EN is viewed as the product of choice for young women and DMPA for older women. This is reflected in reasons given for product preference by clients, and in the age distribution of DMPA and NET-EN users. Further, health workers appear to play an important role in decision-making about which IPC product is provided. That different products are considered to be more appropriate for different age groups may be linked to the perception that DMPA is "stronger" while NET-EN is "weaker", and may well be related to concerns about delay in return to fertility after IPC use, particularly with DMPA. This is consistent with results from a study undertaken in the Northern Province of South Africa where providers were found to recommend NET-EN for younger women based on their perception that DMPA use may result in permanent infertility, whilst NET-EN was considered ".... less strong and 'usually reversible' " p. 13 [4]. Age as a criterion for prescribing one or other IPC product is not supported by the literature, and some policy documents and publications specifically debunk the notion that IPCs should be restricted according to age. For instance, Lande recommends that: "Providers may need to reassure clients and the public that injectables do not cause infertility but to note that women should expect a wait of some months after stopping injectables to become pregnant. Service policies based on a fear of infertility - in particular, age and parity restrictions - can be dropped p.7 [23]. The second draft of the South African Department of Health's Draft National Framework & Guidelines for Contraceptive Services explicitly states that: "Young clients should not be prevented from using either DMPA or NET-EN because of their age." p.64 [24]. If one were to embrace the WHO promoted Essential Drugs concept [5] the decision about which IPC to supply should be made on cost since DMPA and NET-EN have comparable efficacy and safety profiles. Based on the cost analysis presented in this paper, DMPA should be the product selected. However, reducing contraceptive options flies in the face of progressive reproductive health policies which promote expansion of contraceptive choice. For instance, the WHO "is giving priority to improving access to high-quality care in family planning through a variety of strategies" p.2, and lists one of these strategies as "promoting the widest availability of different contraceptive methods so that people may select what is most appropriate to their needs and circumstances" p.2 [20]. The Programme of Action adopted at the International Conference on Population and Development held in Cairo in 1994 recommended that family planning programmes should "Recognize that appropriate methods for couples and individuals vary according to their age, parity, family-size preference and other factors, and ensure that women and men have information and access to the widest possible range of safe and effective family-planning methods in order to enable them to exercise free and informed choice" p.39/132 [25]. The Population Council's new approach to contraceptive introduction in developing countries involves an assessment of the context of contraceptive use in that country, on the basis of which "recommendations for upgrading contraceptive services - which could include introducing new methods, improving the utilisation of existing ones, and/or removing one or more from the method mix". p.1 [26]. The injectable contraceptive method is an important option in South Africa, since many women choose this method because its use does not require partner knowledge or consent [27]. The review of the literature shows that menstrual irregularities are reported to occur more often with DMPA than with NET-EN use. In cases where side effects such as amenorrhoea are particularly problematic with DMPA, NET-EN may be a good alternative. By providing NET-EN explicitly as a second-line option, the range of contraceptive products would be restricted, but not reduced. Conclusions and Recommendations Providing IPCs on the basis of age is not appropriate or cost effective. Training of health workers and counselling of clients to correct this misconception is clearly required. Where clients require immediate return to fertility upon discontinuing contraception, neither IPC preparation is ideal. Since DMPA is a cheaper option than NET-EN, health worker training about the rational use of injectable contraceptives should include consideration of the cost implications of prescribing one product over another. DMPA should be considered as the first option, but where DMPA is not well tolerated, NET-EN should be available as a second option. It is also recommended that a comparative systematic review of DMPA and NET-EN be undertaken. Based on the outcome of this review, consideration may be given to conducting a comparative clinical trial of NET-EN and DMPA when used by African women. Consideration should be given to encouraging the registration of the combined injectable contraceptive in South Africa, which has a better side effect profile than the IPCs [28]. This would be an expensive option thus combined injectable contraceptives should only be provided where side effects with the IPCs are intolerable. A better contraceptive option, especially for young people, might however be the male or female condom with back up of emergency contraceptive pills to provide dual protection against unwanted pregnancy and HIV and other sexually transmitted infections. CYP: couple years of protection DMPA: depot medroxyprogesterone acetate EDL: essential drugs list KZN: IPCs: injectable progestagen-only contraceptives NET-EN: norethisterone oenanthate SAR: Department of Health of South Africa, Medical Research Council and Macro International: South Africa demographic and health survey 1998. Preliminary report. Pretoria, South Africa: Department of Health. 1999 National Department of Health: South African standard treatment guidelines and essential drugs list for South Africa. Primary health care. South Africa: National Department of Health. 1998 Beksinska ME, Rees VH, Nkoyane T, McIntyre JA: Compliance and use behaviour, an issue in injectable as well as oral contraceptive use? A study of injectable and oral contraceptive use in Johannesburg. British Journal of Family Planning. 1998, 24(1): 21-3. Wood K, Maepa J, Jewkes R: Adolescent sex and contraceptive experiences: perspectives of teenagers and clinic nurses in the Northern Province. Pretoria, South Africa: Medical Research Council. 1997 Kanji N, Hardon A, Harnmeijer JW, Mandani M, Walt G: Drugs policy in developing countries. London: Zed Books. 1992 Trussell J, Hatcher RA, Cates W, Stewart FH, Kost K: A guide to interpreting contraceptive efficacy studies. Obstetrics and Gynecology. 1990, 76: 558-67. WHO Special Programme of Research Development and Research Training in Human Reproduction, Task Force on Long-Acting Agents for the Regulation of Fertility: A multinational comparative clinical trial of long-acting injectable contraceptives: Norethisterone enanthate given in two dosage regimens and depot-medroxyprogesterone acetate. Final report. Contraception. 1983, 28: 1-21. Kaunitz AM: Clinical use of depo-provera (medroxyprogesterone acetate) for contraception. A current perspective of scientific, clinical and social issues. In Proceedings of an International Symposium 19-20 November 1992. Edited by Zambrano D. Johannesburg, South Africa: Upjohn,. 1992 Fraser IS, Weisberg E: Fertility following discontinuation of different methods of fertility control. Contraception. 1982, 26: 389-415. Howard G, Blair M, Fotherby K, Elder MG, Bye P: Seven years clinical experience of the injectable contraceptive, norethisterone oenanthate. The British Journal of Family Planning. 1985, 11: 9-16. Bigrigg A, Evans M, Gbolade B, Newton J, Pollard L, Szarewski A, Thomas C, Walling M: Depo Provera. Position paper on clinical use, effectiveness and side effects. British Journal of Family Planning. 1999, 25: 69-76. Hatcher RA, Rinehart W, Blackburn R, Geller JS, Shelton JD: The essentials of contraceptive technology. Baltimore: Johns Hopkins University of Public Health, Population Information Program,. 1997 Fraser IS: Menstrual changes associated with progestogen-only contraception. Acta Obstetricia et Gynecolologica Scandnavicia. 1986, 134: 21-7. Salem HT, Salah M, Aly MY, Thabet AI, Shaaban MM, Fathalla MF: Acceptability of injectable contraceptives in Assiut, Egypt. Contraception. 1988, 38: 697-710. World Health Organisation Expanded Programme of Research Development and Research Training in Human Reproduction: Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids: Norethisterone oenanthate and medroxyprogesterone acetate. 2. Bleeding patterns and side effects. Contraception. 1978, 17: 395-406. Fraser IS: A health perspective of hormonal contraceptives. Acta Obstetricia et Gynecologica Scandinavica. 1986, 134: 33-43. Kaunitz AM: Long-acting injectable contraception with depot medroxyprogesterone acetate. American Journal of Obstetrics and Gynecology. 1994, 170: 1543-49. Shapiro S, Rosenberg L, Hoffman M, Truter H, Cooper D, Rao S, Dent D, Gudgeon A, van Zyl J, Katzenellenbogen J, Baillie R: Risk of breast cancer in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen contraceptives. American Journal of Epidemiology. 2000, 151: 396-403. Watts NB: Spinal bone density in women using depot medroxyprogesterone contraception. Obstetrics and Gynecology. 1998, 92: 569-73. 10.1016/S0029-7844(98)00270-1. World Health Organisation: Improving access to quality care in family planning. Medical eligibility criteria for contraceptive use. Geneva: World Health Organisation. 1996 Quick JD, Rankin JR, Laing RO, O'Conner RW, Hogerzeil HV, Dukes MNG, Garnett A (eds): Managing drug supply. The selection, procurement, distribution and use of pharmaceuticals,. 2nd ed. West Hartford, Connecticut, USA: Kumarian Press,. 1997 Janowitz B, Measham D, West C: Issues in the financing of family planning services in Sub-Saharan Africa. USA: Family Health International,. 1999 Lande RE: New era for injectables. Baltimore, Maryland, USA, Population Information Program, Center for Communication Programs, The Johns Hopkins School of Hygiene and Public Health. Population Reports. 1995, , Series K, No 5 Department of Health: National Framework & Guidelines for Contraceptive Services. Republic of South Africa. Second Draft. Pretoria, South Africa: Department of Health,. 1999 United Nations Population Information Network: Report of the International Conference on Population and Development, Cairo, 5-13 September 1994. New York, United Nations Publications,. 1994, [http://www.undp.org/popin/icpd/conference/offeng/poa.html] Population Council: Contraceptive introduction. Expanding contraceptive choice: Findings from Zambia. Population Briefs, Spring. 1996, 2: 2-[http://wwwpopcouncil.org/publications/popbriefs/pb2%282%29%5F4.html] Kaufman CE: Reproductive control in South Africa. Policy Research Division Working Paper, No 97. New York: Population Council. 1997 Kaunitz AM, Garceau RJ, Cromie MA: Comparative safety, efficacy, and cycle control of Lunelle™ monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) and Ortho-Novum 7/7/7 oral contraceptive (norethindrone/ethinyl estradiol triphasic). Lunelle Study Group. 1999, 60: 179-87. 10.1016/S0010-7824(99)00083-9. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/content/backmatter/1472-6963-1-4-b1.pdf This study was supported by the Wellcome Trust (Grant Number 050522/Z/97/Z). We thank Mr J van den Berg (Deputy Director: Procurement, National Department of Health) and Mr A Odendaal (Systems Manager, Co-ordinating Committee for Medical Procurement) for providing access to the data from the pharmaceutical depots and for the initial Pareto analysis. Have you in the past five years received reimbursements, fees, funding, or salary from an organisation that may in any way gain or lose financially from the publication of this paper? A travel grant was awarded to the main author of this paper in March 1997 by the manufacturer of the generic depot medroxyprogesterone acetate product - one of the drugs mentioned in this manuscript. Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper? No. Do you have any other financial competing interests? No. Are there any non-financial competing interests you would like to declare in relation to this paper? No. Africa Centre for Population Studies and Reproductive Health, Mtubatuba, South Africa Jennifer Smit & Lynn McFadyen Pharmaceutical Policy Practice Group, School of Pharmacy and Pharmacology, University of Durban-Westville, Durban, South Africa Jennifer Smit, Andrew Gray & Lynn McFadyen Division of HIV Prevention and Vaccine Research, South African Medical Research Council, Durban, South Africa Biostatistics Unit, South African Medical Research Council, Durban, South Africa Khangelani Zuma Jennifer Smit Andrew Gray Lynn McFadyen Correspondence to Jennifer Smit. Smit, J., Gray, A., McFadyen, L. et al. Counting the costs: Comparing depot medroxyprogesterone acetate and norethisterone oenanthate utilisation patterns in South Africa. BMC Health Serv Res 1, 4 (2001). https://doi.org/10.1186/1472-6963-1-4 DOI: https://doi.org/10.1186/1472-6963-1-4 DMPA Menstrual Irregularity Injectable Contraceptive Supply Pattern
The infants school I attended insisted that I should eat separately from the other children as "sandwiches from home" were not part of the curriculum. Some of my earliest memories were of sitting alone in an empty classroom, quaking at the sound of footsteps in the corridor. I was born in 1967 at the Woolwich Hospital for Mothers and Babies. Shortly after my birth, I became seriously ill and it was clear that all was by no means well. The doctors at my local hospital were unable to diagnose the problem and my condition was deteriorating fast. My father, a scientist, was, by a happy accident of fate, conducting research into lipids at the Lister Institute in London. Having identified Professor Lloyd at Great Ormond Street Hospital as the authority on lipid-related metabolic conditions, he asked for me to be transferred immediately by ambulance to Great Ormond Street where, after a lengthy review of my condition and the genetic make-up of my parents, the cause was identified: I had type 1 hyperlipoproteinemia. One of the main signs was the milky consistency of my pupils, an indication of my inability to digest fat. From that point onwards, I made a gradual recovery and, the story goes that I spent 99 days in hospital, returning home on the 100th day, extremely fragile but alive! My parents were stringent in their observance of my strict non-fat diet and in my indoctrination that fat was my enemy. They were both intelligent, diligent and clear-thinking and were determined that I should not be made to feel different or marginalised. My mother tirelessly prepared non-fat delicacies so that, at children's parties, I would have my own sandwiches and cakes. At school, I would have separate, carefully prepared sandwiches, although the attitude of the school was a little less flexible. The infants school I attended insisted that I should eat separately from the other children as "sandwiches from home" were not part of the curriculum. Some of my earliest memories were of sitting alone in an empty classroom, quaking at the sound of footsteps in the corridor. Despite this somewhat unpropitious start, the rest of my childhood went remarkably smoothly. I was swiftly removed from the infant school with its Draconian rules and spent the following years in a more understanding environment where the psychological impact of my condition was minimised. My university years were largely incident-free and a nine-year spell in Italy expanded my culinary repertoire. The demanding nature of the condition meant that all my friends and family experienced my condition first hand and evenings in restaurants and even drinks in bars needed to be navigated with the appropriate care, with all those present participating in the explanations to bemused chefs! In my later life I sometimes ask myself, how has it affected me? Whilst many of my friends have been more daring in their travel plans, I have been conditioned by the limitations of my diet and have preferred only to take calculated risks. I have come to realise that travelling in comfort is a necessity for my condition as "slumming it" is not an option; the stakes are just too high. Time is also an essential factor as the availability of ready-made foods is limited: I now have a cook who helps me prepare my non-fat dishes and cakes and I feel physically stronger as a result. It is also an immense psychological relief to know that my needs are taken care of. I have never had any incidents of pancreatitis, as often happens to sufferers of the condition, and I intend to keep it that way. All in all, I have led a trouble-free life, given the constraints of my condition, and consider myself lucky to have had such a caring and loving family and friends who ensured that I did not feel marginalised. I realise that not every case is like mine as it is a condition fraught with complexity, both from a physical and psychological perspective
Correlation of resting elbow angle with spasticity in chronic stroke survivors Minal Y. Bhadane1,2, Fan Gao3, Gerard E. Francisco1,2, Ping Zhou1,2,4 and Sheng Li1,2* 1Department of Physical Medicine and Rehabilitation, The University of Texas Health Science Center at Houston, Houston, TX, USA 2NeuroRehabilitation Research Laboratory, The NeuroRecovery Research Center at TIRR Memorial Hermann Research Center, Houston, TX, USA 3The University of Texas Southwestern Medical Center, Dallas, TX, USA 4Guangdong Work Injury Rehabilitation Center, Guangzhou, China Objective: To evaluate whether resting joint angle is indicative of severity of spasticity of the elbow flexors in chronic stroke survivors. Methods: Seventeen hemiparetic stroke subjects (male: n = 13; female: n = 4; age: 37–89 years; 11 right and 6 left hemiplegia; averaged 54.8 months after stroke, ranging 12–107 months) participated in the study. The number of subjects with modified Ashworth scale score (MAS) = 0, 1, 1+, 2, and 3 was 3, 3, 5, 3, and 3, respectively. In a single experimental session, resting elbow joint angle, MAS, and Tardieu scale score (Tardieu R1) were measured. A customized motorized stretching device was used to stretch elbow flexors at 5, 50, and 100°/s, respectively. Biomechanical responses (peak reflex torque and reflex stiffness) of elbow flexors were quantified. Correlation analyses between clinical and biomechanical assessments were performed. Results: Resting elbow joint angle showed a strong positive correlation with Tardieu R1 (r = 0.77, p < 0.01) and a very strong negative correlation with MAS (r = −0.89, p < 0.01). The resting angle also had strong correlations with biomechanical measures (r = −0.63 to −0.76, p < 0.01). Conclusion: Our study provides experimental evidence for anecdotal observation that the resting elbow joint angle correlates with severity of spasticity in chronic stroke. Resting angle observation for spasticity assessment can and will be an easy, yet a valid way of spasticity estimation in clinical settings, particularly for small muscles or muscles which are not easily measurable by common clinical methods. Post-stroke spasticity is one of the most physically debilitating conditions that interfere with functional improvement (1, 2). Prevalence estimates of spasticity are highly variable, ranging from 20 to 46% (3–6). Spasticity significantly affects their quality of life, thus causing a significant burden for survivors and caregivers (2, 7). Spasticity, commonly defined as "a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes ('muscle tone') with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex, as one component of the upper motor neuron syndrome" (8). It can be easily recognized, but difficult to objectively quantify because of its multifactorial nature (1, 9). Measuring spasticity using reliable and valid tools is important for treatment planning rationale and also to evaluate treatment efficacy (10–13). Clinical scales including the Ashworth (14, 15) and Modified Ashworth (MAS) (16) are commonly used for assessment of spasticity. But these scales do not capture other symptoms and signs of the upper motor neuron syndrome, such as co-contraction during movements or spasms (12, 17). The Tardieu Scale is considered as a more appropriate clinical measure of spasticity as it involves assessment of resistance to passive movement at both slow and fast speeds (18, 19). Even though reliability and validity of these clinical scales have been studied in many research studies, it is still controversial (16, 17, 20, 21). Laboratory tests, such as motorized stretching (22–25) and electrophysiological measurements, have higher accuracy but they are time consuming, expensive, and cannot be easily implemented in clinical environment (26–28). These approaches require specialized motor-driven mechanical systems that are not only space-prohibitive in a rehabilitation clinic, but require significant training and ongoing technical maintenance. Although these studies have given insight into neurophysiological aspects of spasticity, these techniques are unlikely to be widely adopted by clinics for routine use. Also except for commonly studied joints (elbow, wrist, knee, and ankle), it is difficult to apply these methods to spastic muscles in the neck and trunk areas, as well as those crossing the joint and changing their direction, e.g., posterior tibialis muscle. Hence, there is a clear need to explore alternative ways to incorporate assessment of spasticity into clinical practice. It is a common clinical observation that altered resting posture of the trunk and joint correlates with spasticity of the respective muscles. Accordingly, the objective of this study was to evaluate whether resting joint angle is indicative of severity of spasticity of the elbow flexors in chronic stroke survivors by correlating resting joint angle with other frequently used clinical (MAS, Tardieu) and biomechanical methods for assessment of spasticity. Seventeen hemiparetic stroke subjects (age: 37–89 years; 11 right and 6 left hemiplegia; averaged 54.8 months after stroke, ranging 12–107 months) participated in the study. Table 1 displays characteristics of the subjects. Inclusion criteria were: (1) hemiplegia secondary to a single ischemic or hemorrhage stroke; (2) at least 6 months post-stroke; (3) elbow flexor spasticity of the impaired side less than 4 (rated by MAS); (4) able to understand and follow instructions related to the experiment; and (5) able to give informed written consent. The exclusion criteria were: (1) a history of multiple strokes or bilateral involvement; (2) presence of contracture that would limit full elbow range of motion on the impaired side. The number of subjects with MAS = 0, 1, 1+, 2, and 3 was 3, 3, 5, 3, and 3, respectively. The experiment was approved by the UTHealth Committee for the Protection of Human Subjects. All subjects gave written informed consent prior to participation. Table 1. Characteristics of stroke subjects (F: female, M: male, angle in degrees, fully extended position of the elbow was considered as 180°, age in years, post stroke months, ROM: range of motion). The study had two sets of measurements, including clinical assessment and biomechanical measurements. The following clinical assessments were performed on each subject: (1) passive range of motion; (2) active range of motion; (3) MAS: resistance to passive elbow flexion was assessed by stretching the muscle at a moderate speed and scoring the resistance using MAS; (4) Tardieu scale (Tardieu R1): angle measured at a fast speed when the muscle reaction was first felt (if there was no muscle reaction, Tardieu angle was considered as 180°); and (5) resting angle (R): to evaluate gravity effect. The fully extended position of the elbow was defined as 180°. For clinical measurements, subjects were explicitly instructed to stand and relax the affected arm as much as they could. The measurements were taken after they were standing upright still for at least 1 min. Subjects were allowed to take support of a person/chair/walker/cane with the unaffected arm. Biomechanically, responses to constant velocity stretch of elbow flexors were measured. We adopted our previous experimental setup (29). The subjects were seated on a height adjustable chair. The arm to be tested was secured firmly on a customized apparatus with a servomotor. The shoulder was positioned at ∼45° of abduction and 30° of flexion. The center of the elbow joint was aligned with the axis of rotation of the servo motor. The forearm was firmly secured using four vertical plates at the proximal and distal forearm (Figure 1). The subjects were instructed to naturally relax the wrist, hand, and fingers without additional support during external stretching. This arrangement prevented translation and rotation of the arm. The other arm of the subject rested alongside the body. Figure 1. Experimental setting and representative torque–angle profiles at different speeds. Subjects completed a single session during which the elbow joint of the impaired side was passively stretched at different velocities. Only the affected side was tested. A total range of 60° stretch was utilized with the end position (E) at 10° beyond the resting angle (R) (E = R + 10). The initial position (I) was I = E − 60°. For patients with resting angle close to or more than 170°, the end position (E) was considered to be at 180° making the initial position (I) of 120°. Goniometer was used to position arm at the initial angle. The end joint angle was set at 180°, if the resting angle was 170° or greater. The trial began with the elbow at the initial position (I), and then a constant velocity extension movement was imposed at the elbow until the elbow reached the predetermined end position (E). The elbow was then held in the end position for 2 s and returned to the initial position at the same velocity. A rest period of about 30 s was allowed between trials to allow adequate recovery and to minimize the influence of stretch history on the response to the subsequent stretch. Subjects were instructed to relax during the trials, neither supporting nor opposing the joint extension. Three velocities of 5, 50, and 100°/s were used with three trials at each velocity. Torque was measured with a torque sensor (Model TRS 500, Transducers Techniques, CA, USA). An angular motion recorded using encoder (HD FHA-25C-50-US250, Standard Incremental, 2500 pulses per revolution). All signals were digitized at 1000 samples/s on a PC computer with a data acquisition board (National Instruments, Austin, TX, USA) using custom LabView software (National Instruments). Data was saved for offline analysis using a customized MATLAB (The MathWorks Inc.) program. Angle and torque signals were analyzed to determine biomechanical response of stretch in the spastic elbow flexors. The torque signal was filtered using a 100-point moving window median filter to remove outlier noise evident in the raw data. Mean of initial 100 ms data was subtracted from complete data set to remove any DC bias. To avoid data variation as a result of anthropometry spread between subjects, torque was normalized by individual body weight. To characterize the pattern of the response, average torque was calculated across all three trials for each speed (Figure 1). For each subject, peak torque was calculated for all speeds between the start and end of rotation. Reflex torque was calculated by subtracting torque response at 5°/s from those at 50 and 100°/s (23). The reflex stiffness was computed by finding slope from the linear regression of reflex torque–angle profile. The limits to finding slope were decided to be 25 and 75% of the maximum torque for a given trial (23). Linear regression analysis was performed on torque and stiffness data with resting angle, Tardieu R1, and MAS. Correlations between clinical assessment (MAS, Tardieu R1, and resting angle) and biomechanical measures (peak reflex torque and reflex stiffness) were analyzed using Spearman's coefficient (r). Furthermore, a repeated measures one-way analysis of variance (ANOVA) was used to analyze the effect of velocity on peak torque with a factor of VELOCITY. Statistical significance was set at p < 0.05. Velocity-Dependent Responses Overall, we observed velocity-dependent mechanical responses. Figure 1 shows representative torque–angle profile recorded for all three speeds. Figure 2 demonstrates comparative torque–angle data for patients representing each of the five MAS levels. Photos of patients in standing positions used for resting joint angle measurement are shown in first row. The torque–angle curve increased sharply at the beginning of the stretch due to inertial effects and then settled into a constant slope. Effect of speed on torque amplitude was apparent in Figures 1 and 2. A repeated one-way ANOVA showed a main effect of VELOCITY for peak torque response (F[3,14] = 15.63, p < 0.0001) (Figure 3A). Figure 3B shows the direct relationship between stiffness in elbow flexors and velocity. Similarly, there was a main effect of VELOCITY (F[3,14] = 12.68, p = 0.0002). Figure 2. (A) A stroke patient (representing each MAS score group) standing in a relaxed position; (B) resting angle in degrees; (C) MAS score; (D) Tardieu R1 angle in degrees; (E) torque–angle response (mean of three trials) for the speeds 5, 50, and 100°/s for each subject of a representing MAS score group. Figure 3. (A) Normalized peak torque and (B) stiffness at three speeds. Mean and SEs are plotted. * represents statistical significance. Correlations between Clinical and Biomechanical Assessments The resting angle showed a strong positive correlation with the Tardieu R1 angle (r = 0.77, p < 0.01) and a strong negative correlation with MAS (r = −0.89, p < 0.01) (Figure 4). The resting angle also showed strong correlations with peak reflex torque (r ranged from −0.639 to −0.700, p < 0.01) and reflex stiffness (r ranged from −0.716 to −0.763, p < 0.01) (Table 2). All clinical measures, the resting angle (r ranged from −0.63 to −0.76, p < 0.01), MAS (r ranged from 0.79 to 0.84, p < 0.01), and the Tardieu R1 angle (r ranged from −0.58 to −0.63, p < 0.05) showed strong correlations with biomechanical measurement (peak reflex torque and reflex stiffness) (Table 2). Figure 4. Correlations between the resting angle and clinical measurements (A) MAS and (B) Tardieu R1 angle. Because of same measures for some cases, there are less data points (cases) on the figure than the actual number of cases. Refer to Table 1 for details. Table 2. Correlations among resting angle, Tardieu R1 angle, MAS and biomechanical parameters: peak reflex torque and reflex stiffness. Given the constraints of a clinical environment, technique for spasticity assessment must be clinically valid and easy to implement. In this study we evaluated relation between the severity of spasticity at the elbow joint and the resting joint angle. The results of the biomechanical tests in this study provide experimental evidence that resting joint angle can be used to estimate post-stroke spasticity. Strong Correlations between Biomechanical and Clinical Parameters Our results of velocity-dependent peak torque and reflex stiffness were consistent with previous reports (15, 22–24, 27). There were controversial reports of relations between biomechanical measures and clinical scale (15, 26–28, 30, 31). In a study of 14 stroke subjects, reflex stiffness measured at 90° of elbow flexion for all subjects had very weak correlation (r = 0.2) with MAS (15). In contrast, when passive stretches were applied to the full comfortable range of motion of the elbow joint, reflex torque and stiffness had strong correlations with the Ashworth scale score in a group of 16 stroke subjects (27). Our findings were consistent with the latter study (27, 30), showing strong correlations between biomechanical measures and clinical measures. Though commonly used as in the above cited studies, we are aware of the limitation of the use of parametric statistics for non-linear data, such as the MAS and Tardieu scales. Biomechanical measures of spastic muscles are length-dependent in stroke subjects (15, 24). Measurement at a standardized joint angle does not reflect pathological state of patients with different severities of spasticity. The resting joint angle may represent a reference for the new equilibrium point of the neuromuscular system after stroke (25). Thus, biomechanical measures obtained from passive stretch with reference to the resting angle are comparable across subjects and show strong correlations with other clinical measures. Insight into Pathophysiology of Spasticity Despite the advances in the treatment of spasticity, there are several gaps in research and clinical practice, foremost of which is the relative deficiency of knowledge of the pathophysiology of spasticity. It is well accepted that there is hyperexcitability of the stretch reflex in spasticity (32–36). Excitability of the spinal stretch reflex arc is maintained by a balanced descending regulation and normal intraspinal processing. Therefore, stretch reflex hyperexcitability in post-stroke spasticity could be mediated by two categories of mechanisms: abnormal descending regulations and/or abnormal intraspinal processing of stretch reflex. Accumulated evidence suggest that abnormal intraspinal processing likely results from plastic rearrangement secondary to abnormal descending regulation; in contrast, imbalanced descending inhibitory and excitatory inputs, particularly reticulospinal hyperexcitability, as a result of unmasking after stroke is the primary underlying mechanism for spasticity [see reviews in Ref. (37)]. Acoustic startle reflex is a brainstem reflex which is primarily medicated by the reticulospinal pathway. In a recent study, reticulospinal hyperexcitability, as reflected by exaggerated acoustic startle reflex responses, was only seen in stroke survivors with elbow flexor spasticity, but not in those without (flaccid or fully recovered) (38). Furthermore, the reticulospinal pathway also plays an important role in maintaining joint position and posture against gravity (39). Altered reticulospinal excitability and its anti-gravity effect could lead to a new neuromuscular balance, reflecting a shift in reference configuration after stroke (25, 40). This new balance could be reflected by a change in the resting angle of a joint. The results of high correlations between severity of spasticity and resting joint angle, thus, suggest that spasticity is strongly related to reticulospinal hyperexcitability and its anti-gravity effects. Clinical Significance of Resting Joint Angle Our results revealed that there existed overall strong correlations between resting joint angle and other frequently used clinical (MAS, Tardieu R1 angle) and biomechanical (stretch reflex response) measurements. As such, our study provides evidence that resting joint angle correlates with severity of post-stroke spasticity in elbow flexors. This finding is clinically useful in that the resting angle could be easily and objectively quantified. No subjective interpretation is involved, for example, a subjective feeling of "catch" in other clinical scales. Therefore, resting joint angle could be used as objective outcome measures for treatment, e.g., before and after botulinum toxin injections. Resting angle is particularly helpful for muscles which are not easily measurable by common clinical methods, such as spastic sternocleidomastoid muscles. However, the results may not be applicable to weight-bearing joints, where ground reaction force may alter joint position independent of spasticity's effect. Soft tissue contractures are often present in spastic muscles (41). They may partially account for the joint abnormality as well. Another limitation of this study is a small sample size. Future study with a large sample size is needed. To summarize, our study provides experimental evidence for anecdotal observation that resting elbow joint angle correlates with severity of spasticity in chronic stroke. This study was supported in part by an NIH grant R01NS060774. 1. Scanlan SM, McGuire J. Effective collaboration between physician and occupational therapist in the management of upper limb spasticity after stroke. Top Stroke Rehabil (1998) 4:1–13. doi:10.1310/GALH-DAXM-8HE8-P4E4 2. Wissel J, Manack A, Brainin M. Toward an epidemiology of poststroke spasticity. Neurology (2013) 80:S13–9. doi:10.1212/WNL.0b013e3182762448 3. Watkins C, Leathley M, Gregson J, Moore A, Smith T, Sharma A. Prevalence of spasticity post stroke. Clin Rehabil (2002) 16:515–22. doi:10.1191/0269215502cr512oa 4. Lundström E, Terént A, Borg J. Prevalence of disabling spasticity 1 year after first-ever stroke. Eur J Neurol (2008) 15:533–9. doi:10.1111/j.1468-1331.2008.02114.x 5. Sommerfeld DK, Gripenstedt U, Welmer A-K. Spasticity after stroke: an overview of prevalence, test instruments, and treatments. Am J Phys Med Rehabil (2012) 91:814–20. doi:10.1097/PHM.0b013e31825f13a3 6. Opheim A, Danielsson A, Alt Murphy M, Persson HC, Sunnerhagen KS. Upper-limb spasticity during the first year after stroke: stroke arm longitudinal study at the University of Gothenburg. Am J Phys Med Rehabil (2014) 93:884–96. doi:10.1097/PHM.0000000000000157 7. Zorowitz RD, Gillard PJ, Brainin M. Poststroke spasticity sequelae and burden on stroke survivors and caregivers. Neurology (2013) 80:S45–52. doi:10.1212/WNL.0b013e3182764c86 8. Lance JW. Pathophysiology of spasticity and clinical experience with baclofen. In: Feldman RG, Young RR, Koella WP, editors. Spasticity: Disordered Motor Control. Chicago: Year Book Medical Publishers (1980). p. 185–203. 9. Brashear A, Elovic E. Spasticity: Diagnosis and Management. New York: Demos Medical Publishing (2010). 10. Decq P, Filipetti P, Lefaucheur J-P. Evaluation of spasticity in adults. Operat Tech Neurosurg (2004) 7:100–8. doi:10.1053/j.otns.2005.02.003 11. Pandyan AD, Gregoric M, Barnes MP, Wood D, Van Wijck F, Burridge J, et al. Spasticity: clinical perceptions, neurological realities and meaningful measurement. Disabil Rehabil (2005) 27:2–6. doi:10.1080/09638280400014576 12. Fleuren JF, Voerman GE, Erren-Wolters CV, Snoek GJ, Rietman JS, Hermens HJ, et al. Stop using the Ashworth scale for the assessment of spasticity. J Neurol Neurosurg Psychiatry (2010) 81:46–52. doi:10.1136/jnnp.2009.177071 13. Francisco GE, McGuire JR. Poststroke spasticity management. Stroke (2012) 43:3132–6. doi:10.1161/STROKEAHA.111.639831 14. Ashworth B. Preliminary trial of carisoprodol in multiple sclerosis. Practitioner (1964) 192:540–2. 15. Alibiglou L, Rymer WZ, Harvey RL, Mirbagheri MM. The relation between Ashworth scores and neuromechanical measurements of spasticity following stroke. J Neuroeng Rehabil (2008) 5:18. doi:10.1186/1743-0003-5-18 16. Ghotbi N, Ansari NN, Naghdi S, Hasson S. Measurement of lower-limb muscle spasticity: intrarater reliability of modified modified Ashworth scale. J Rehabil Res Dev (2011) 48:83–8. doi:10.1682/JRRD.2010.02.0020 17. Pandyan A, Johnson G, Price C, Curless R, Barnes M, Rodgers H. A review of the properties and limitations of the Ashworth and modified Ashworth scales as measures of spasticity. Clin Rehabil (1999) 13:373–83. doi:10.1191/026921599677595404 18. Haugh A, Pandyan A, Johnson G. A systematic review of the Tardieu scale for the measurement of spasticity. Disabil Rehabil (2006) 28:899–907. doi:10.1080/09638280500404305 19. Patrick E, Ada L. The Tardieu scale differentiates contracture from spasticity whereas the Ashworth scale is confounded by it. Clin Rehabil (2006) 20:173–82. doi:10.1191/0269215506cr922oa 20. Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther (1987) 67:206–7. 21. Li S, Chang SH, Francisco GE, Verduzco-Gutierrez M. Acoustic startle reflex in patients with chronic stroke at different stages of motor recvoery: a pilot study. Top Stroke Rehabil (2014) 21:358–70. doi:10.1310/tsr2104-358 22. Kamper DG, Rymer WZ. Quantitative features of the stretch response of extrinsic finger muscles in hemiparetic stroke. Muscle Nerve (2000) 23:954–61. doi:10.1002/(SICI)1097-4598(200006)23:6<954::AID-MUS17>3.0.CO;2-0 23. Kamper D, Schmit B, Rymer W. Effect of muscle biomechanics on the quantification of spasticity. Ann Biomed Eng (2001) 29:1122–34. doi:10.1114/1.1424918 24. Li S, Kamper DG, Rymer WZ. Effects of changing wrist positions on finger flexor hypertonia in stroke survivors. Muscle Nerve (2006) 33:183–90. doi:10.1002/mus.20453 25. Calota A, Feldman AG, Levin MF. Spasticity measurement based on tonic stretch reflex threshold in stroke using a portable device. Clin Neurophysiol (2008) 119:2329–37. doi:10.1016/j.clinph.2008.07.215 26. Jobin A, Levin MF. Regulation of stretch reflex threshold in elbow flexors in children with cerebral palsy: a new measure of spasticity. Dev Med Child Neurol (2000) 42:531–40. doi:10.1111/j.1469-8749.2000.tb00709.x 27. Starsky AJ, Sangani SG, McGuire JR, Logan B, Schmit BD. Reliability of biomechanical spasticity measurements at the elbow of people poststroke. Arch Phys Med Rehabil (2005) 86:1648–54. doi:10.1016/j.apmr.2005.03.015 28. Kumar RT, Pandyan AD, Sharma AK. Biomechanical measurement of post-stroke spasticity. Age Ageing (2006) 35:371–5. doi:10.1093/ageing/afj084 29. Li S, Liu J, Bhadane M, Zhou P, Rymer WZ. Activation deficit correlates with weakness in chronic stroke: evidence from evoked and voluntary EMG recordings. Clin Neurophysiol (2014) 25:2413–7. doi:10.1016/j.clinph.2014.03.019 30. de Vlugt E, de Groot JH, Schenkeveld KE, Arendzen JH, van der Helm FC, Meskers CG. The relation between neuromechanical parameters and Ashworth score in stroke patients. J Neuroeng Rehabil (2010) 7:35. doi:10.1186/1743-0003-7-35 31. Mullick AA, Musampa NK, Feldman AG, Levin MF. Stretch reflex spatial threshold measure discriminates between spasticity and rigidity. Clin Neurophysiol (2013) 124:740–51. doi:10.1016/j.clinph.2012.10.008 32. Brown P. Pathophysiology of spasticity. J Neurol Neurosurg Psychiatry (1994) 57:773–7. doi:10.1136/jnnp.57.7.773 33. Gracies JM. Pathophysiology of spastic paresis. II: emergence of muscle overactivity. Muscle Nerve (2005) 31:552–71. doi:10.1002/mus.20285 34. Nielsen JB, Crone C, Hultborn H. The spinal pathophysiology of spasticity – from a basic science point of view. Acta Physiol (2007) 189:171–80. doi:10.1111/j.1748-1716.2006.01652.x 35. Mukherjee A, Chakravarty A. Spasticity mechanisms – for the clinician. Front Neurol (2010) 1:149. doi:10.3389/fneur.2010.00149 36. Burke D, Wissel J, Donnan GA. Pathophysiology of spasticity in stroke. Neurology (2013) 80:S20–6. doi:10.1212/WNL.0b013e31827624a7 37. Li S, Francisco G. New insights into the pathophysiology of post-stroke spasticity. Front Hum Neurosci (2015) 9:192. doi:10.3389/fnhum.2015.00192 38. Li F, Wu Y, Li X. Test-retest reliability and inter-rater reliability of the modified Tardieu scale and the modified Ashworth scale in hemiplegic patients with stroke. Eur J Phys Rehabil Med (2014) 50:9–15. 39. Drew T, Prentice S, Schepens B. Cortical and brainstem control of locomotion. Prog Brain Res (2004) 143:251–61. doi:10.1016/S0079-6123(03)43025-2 40. Calota A, Levin MF. Tonic stretch reflex threshold as a measure of spasticity: implications for clinical practice. Top Stroke Rehabil (2009) 16:177–88. doi:10.1310/tsr1603-177 41. Ada L, O'Dwyer N, O'Neill E. Relation between spasticity, weakness and contracture of the elbow flexors and upper limb activity after stroke: an observational study. Disabil Rehabil (2006) 28:891–7. doi:10.1080/09638280500535165 Keywords: stroke, spasticity, resting angle, MAS, Tardieu Citation: Bhadane MY, Gao F, Francisco GE, Zhou P and Li S (2015) Correlation of resting elbow angle with spasticity in chronic stroke survivors. Front. Neurol. 6:183. doi: 10.3389/fneur.2015.00183 Received: 24 April 2015; Accepted: 10 August 2015; Laszlo Csiba, University of Debrecen, Hungary Katharina Stibrant Sunnerhagen, Sahlgrenska University Hospital, Sweden Zsuzsanna Vekerdy-Nagy, University of Debrecen, Hungary Zoltan Jenei, University of Debrecen, Hungary Copyright: © 2015 Bhadane, Gao, Francisco, Zhou and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Sheng Li, NeuroRehabilitation Research Laboratory, Department of Physical Medicine and Rehabilitation, The University of Texas Health Science Center – Houston, 1333 Moursand Avenue, Houston, TX 77030, USA, [email protected]
Author(s): Buijck, B.I. ; Zuidema, S.U. ; Eijk, M. van ; Bor, H. ; Gerritsen, D.L. ; Koopmans, R.T.C.M. OBJECTIVES: Geriatric patients' physical disabilities, dependency on care, and possible psychological ill-being may negatively affect both the patient's quality of life and the informal caregiver burden. Focusing on this interrelationship which can be particularly prominent in geriatric patients with stroke, the objective of this study was to identify determinants of patients' quality of life and informal caregiver burden. METHOD: This is a prospective, multicentre, cohort study. Data were collected in 84 geriatric home-dwelling patients with stroke three months after their rehabilitation period in skilled nursing facilities (SNFs). We assessed patients' quality of life, depressive complaints, neuropsychiatric symptoms, balance, (instrumental) activities of daily living, and informal caregiver burden. Linear regression models were constructed to study the association between the variables. RESULTS: For several domains, high quality of life of these geriatric patients was associated with high functional independence, less neuropsychiatric symptoms, and less depressive complaints. Informal caregiver burden was not associated with patients' quality of life, but patients' neuropsychiatric symptoms were a significant determinant of high informal caregiver burden. CONCLUSION: The presence of neuropsychiatric symptoms (more specifically depressive complaints) negatively affects the quality of life of geriatric patients. Their neuropsychiatric symptoms also affect caregiver burden. Health care professionals in SNFs can play an important role in providing the necessary psychosocial support and aftercare.
Univ. of Sao Paulo, Polytechnic School, Dept. of. Mining and Petroleum. The image analysis coupled with Energy Dispersive Spectrometry (EDS) analysis on a Scanning Electron Microscope (SEM) was applied to the characterization of a Zn and Pb ore as an efficient tool for mineral quantification and for the assessment of the degree of mineral liberation. Screened size fractions of mineral particles were mounted on polished thin sections and, later on, analyzed by a SEM coupled with an EDS. This is important for the discrimination of different mineral phases, particularly when two minerals have similar average atomic numbers, such as willemite and pyrite. Two images per field were collected - backscattered electrons image and a multi-element X-ray dot mapping images. The results were utilized for quantification and liberation analysis of two valuable minerals in the ore -sphalerite and galena. H. Kahn, E. Mano and M. Tassinari, "Image Analaysis Coupled With A SEM-EDS Applied To The Characaterization Of A Zn-Pb Partially Weathered Ore," Journal of Minerals and Materials Characterization and Engineering, Vol. 1 No. 1, 2002, pp. 1-9. doi: 10.4236/jmmce.2002.11001. Gabas, S.G. Análise de Imagens Aplicada à Caracterizacao de Minérios – Análise Modal e Liberacao. Dissertacao de Mestrado, Escola Politécnica da Universidade de Sao Paulo (1999). Kahn, H.; Sant'Agostino, L.; Mano, E.S., Tassinari, M.M. (1998) Acta Microscopica. 7-A: 241-244.
I read this article and found it very interesting, thought it might be something for you. The article is called Sense.ly Integrates Mayo Clinic's Triage Algorithms To Enhance Their Virtual Nurse App and is located at https://hitconsultant.net/2017/05/10/sensely-integrates-mayo-clinics-triage-algorithms/. Sense.ly, a San Francisco, CA-based virtual medical assistant application for patient engagement and chronic disease monitoring has announced an agreement with Mayo Clinic. As part of the agreement, Sensely will integrate Mayo Clinic's triage algorithms and clinical expertise with Sense.ly's proven, empathy first, patient engagement platform to support of optimal health outcomes for individuals. The Sense.ly virtual medical assistant app combines innovative avatar-based technology, advanced sensor capabilities, and telemedicine features that generate actionable, real-time data and intelligent analytics, enabling clinicians to make better, timelier care decisions. Supporting more than 20 conditions and protocols, Sensely offers therapeutic help with expertise and empathy. Sense.ly's healthcare solutions have achieved remarkable results regarding patient compliance, reduction of readmissions, and lowering of costs. "We are collaborating on solutions that would allow people to receive trusted health guidance and information, leading to more appropriate diagnosis and treatments. This new digital solution can help reduce the burden on the healthcare's most expensive services, such as emergency rooms and clinical office visits. With research showing that 65 percent of ER visits are avoidable, it's crucial for digital healthcare to continue to evolve at a rapid pace," said Sensely's founder and CEO Adam Odessky in a statement. « Digital Health Disruption: Will Wearables Transform Healthcare Delivery?
Nephrology is a branch of internal medicine that specializes in the study of the function and diseases of the kidney. Your child's two kidneys are bean-shaped organs that not only filter blood and getting rid of waste products, but also control blood pressure, balance levels of electrolytes and stimulate the production of red blood cells. The kidneys are located near the middle of the back, just below the rib cage, one on each side of the spine. What is the difference between renal and kidney? The terms are interchangeable and mean the same thing. What does a kidney transplant mean? A kidney transplant, also known as a renal transplant, is the process of replacing a current, failing kidney with a healthy, donated kidney. The transplant requires careful preparation and quality follow-up care. Children usually require a kidney transplant when their kidneys fail to work properly or are expected to fail. How does the transplant process work? Before the transplant, Miller Children's ensures the child and family understand as much as possible about the process. The Miller Children's renal care team holds a pre-evaluation session with the child and their family before working with organizations that handle the organ donation process. Once the child and family understand the process, Miller Children's collaborates with a transplant center, such as UCLA or CHLA, to set an appointment. Our nurse specialist will work with the transplant center to prepare authorizations and provide medical information such as history, x-rays and lab results. After the transplant procedure, the patient continues follow-up care with the transplant team. Sometimes, the child's care may be transferred back to Miller Children's for follow-up care. Dialysis is a procedure that is performed routinely on patients whose kidneys no longer work properly. A special machine is used to remove wastes, toxins and fluid from the blood that is normally eliminated by the kidneys. Length of treatment depends on the condition and health of the child. Some minor injuries, such as sports injuries, require dialysis for a short time to help fully heal the damaged kidney. For chronic renal failure, children usually stay on dialysis until a kidney transplant is performed. Dialysis may be needed for some children after transplant until the new kidney is fully working. During dialysis, the renal nurses and nephrologist will teach your child and family about a new diet your child may need, medicine and other areas of kidney care. It is very important that you ask questions about your child's visit to Miller Children's Nephrology Center. Miller Children's values your input as a parent and wants you to make informed decisions for your child. No question is too small or unimportant.
Chemical stability of chalcogenide infrared glass fibers Pierre Lucas, Allison A. Wilhelm, Marcelo Videa, Catherine Boussard-Plédel, Bruno Bureau Infrared fibers from the chalcogenide family are becoming increasingly prevalent for applications in optical sensing and imaging. In this work, we study the chemical stability of these fibers during long-term storage in air and medium term immersion in water comparable to normal usage conditions during optical monitoring in aqueous environments. A detailed study of surface oxidation in Te-As-Se fibers shows that the oxidation is limited to a superficial layer and progress at a rate of about 20 Å per year. While the elemental glass is insoluble in water, the oxide layer solubilizes rapidly and can lead to surface pitting after oxide removal. The dissolution process is complete after about 2 h of immersion in water. The elemental glass on the other end is chemically stable in water and no significant oxidation process can be detected by cyclic voltammetry. Finally the useful optical properties of these fibers are essentially unchanged after extended storage or immersion in water despite surface oxide or surface pitting. Corrosion Science https://doi.org/10.1016/j.corsci.2008.04.020 Chemical stability Glass fibers Pitting A. Glass B. AFM B. IR spectroscopy B. XPS C. Oxidation Lucas, P., Wilhelm, A. A., Videa, M., Boussard-Plédel, C., & Bureau, B. (2008). Chemical stability of chalcogenide infrared glass fibers. Corrosion Science, 50(7), 2047-2052. https://doi.org/10.1016/j.corsci.2008.04.020 Chemical stability of chalcogenide infrared glass fibers. / Lucas, Pierre; Wilhelm, Allison A.; Videa, Marcelo; Boussard-Plédel, Catherine; Bureau, Bruno. In: Corrosion Science, Vol. 50, No. 7, 07.2008, p. 2047-2052. Lucas, P, Wilhelm, AA, Videa, M, Boussard-Plédel, C & Bureau, B 2008, 'Chemical stability of chalcogenide infrared glass fibers', Corrosion Science, vol. 50, no. 7, pp. 2047-2052. https://doi.org/10.1016/j.corsci.2008.04.020 Lucas P, Wilhelm AA, Videa M, Boussard-Plédel C, Bureau B. Chemical stability of chalcogenide infrared glass fibers. Corrosion Science. 2008 Jul;50(7):2047-2052. https://doi.org/10.1016/j.corsci.2008.04.020 Lucas, Pierre ; Wilhelm, Allison A. ; Videa, Marcelo ; Boussard-Plédel, Catherine ; Bureau, Bruno. / Chemical stability of chalcogenide infrared glass fibers. In: Corrosion Science. 2008 ; Vol. 50, No. 7. pp. 2047-2052. @article{79bcac7342c5499fa3413b4ad12a2f3c, title = "Chemical stability of chalcogenide infrared glass fibers", abstract = "Infrared fibers from the chalcogenide family are becoming increasingly prevalent for applications in optical sensing and imaging. In this work, we study the chemical stability of these fibers during long-term storage in air and medium term immersion in water comparable to normal usage conditions during optical monitoring in aqueous environments. A detailed study of surface oxidation in Te-As-Se fibers shows that the oxidation is limited to a superficial layer and progress at a rate of about 20 {\AA} per year. While the elemental glass is insoluble in water, the oxide layer solubilizes rapidly and can lead to surface pitting after oxide removal. The dissolution process is complete after about 2 h of immersion in water. The elemental glass on the other end is chemically stable in water and no significant oxidation process can be detected by cyclic voltammetry. Finally the useful optical properties of these fibers are essentially unchanged after extended storage or immersion in water despite surface oxide or surface pitting.", keywords = "A. Glass, B. AFM, B. IR spectroscopy, B. XPS, C. Oxidation", author = "Pierre Lucas and Wilhelm, {Allison A.} and Marcelo Videa and Catherine Boussard-Pl{\'e}del and Bruno Bureau", doi = "10.1016/j.corsci.2008.04.020", journal = "Corrosion Science", T1 - Chemical stability of chalcogenide infrared glass fibers AU - Lucas, Pierre AU - Wilhelm, Allison A. AU - Videa, Marcelo AU - Boussard-Plédel, Catherine AU - Bureau, Bruno N2 - Infrared fibers from the chalcogenide family are becoming increasingly prevalent for applications in optical sensing and imaging. In this work, we study the chemical stability of these fibers during long-term storage in air and medium term immersion in water comparable to normal usage conditions during optical monitoring in aqueous environments. A detailed study of surface oxidation in Te-As-Se fibers shows that the oxidation is limited to a superficial layer and progress at a rate of about 20 Å per year. While the elemental glass is insoluble in water, the oxide layer solubilizes rapidly and can lead to surface pitting after oxide removal. The dissolution process is complete after about 2 h of immersion in water. The elemental glass on the other end is chemically stable in water and no significant oxidation process can be detected by cyclic voltammetry. Finally the useful optical properties of these fibers are essentially unchanged after extended storage or immersion in water despite surface oxide or surface pitting. AB - Infrared fibers from the chalcogenide family are becoming increasingly prevalent for applications in optical sensing and imaging. In this work, we study the chemical stability of these fibers during long-term storage in air and medium term immersion in water comparable to normal usage conditions during optical monitoring in aqueous environments. A detailed study of surface oxidation in Te-As-Se fibers shows that the oxidation is limited to a superficial layer and progress at a rate of about 20 Å per year. While the elemental glass is insoluble in water, the oxide layer solubilizes rapidly and can lead to surface pitting after oxide removal. The dissolution process is complete after about 2 h of immersion in water. The elemental glass on the other end is chemically stable in water and no significant oxidation process can be detected by cyclic voltammetry. Finally the useful optical properties of these fibers are essentially unchanged after extended storage or immersion in water despite surface oxide or surface pitting. KW - A. Glass KW - B. AFM KW - B. IR spectroscopy KW - B. XPS KW - C. Oxidation U2 - 10.1016/j.corsci.2008.04.020 DO - 10.1016/j.corsci.2008.04.020 JO - Corrosion Science JF - Corrosion Science 10.1016/j.corsci.2008.04.020
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Commission Directive 2008/128/EC of 22 December 2008 laying down specific purity criteria concerning colours for use in foodstuffs (Codified version) (Text with EEA relevance) OJ L 6, 10.1.2009, p. 20–63 (BG, ES, CS, DA, DE, ET, EL, EN, FR, IT, LV, LT, HU, MT, NL, PL, PT, RO, SK, SL, FI, SV) No longer in force, Date of end of validity: 30/11/2012; Repealed by 32012R0231 . Latest consolidated version: 07/02/2011 ELI: http://data.europa.eu/eli/dir/2008/128/oj Language 1 Bulgarian (bg) Spanish (es) Czech (cs) Danish (da) German (de) Estonian (et) Greek (el) English (en) French (fr) Italian (it) Latvian (lv) Lithuanian (lt) Hungarian (hu) Maltese (mt) Dutch (nl) Polish (pl) Portuguese (pt) Romanian (ro) Slovak (sk) Slovenian (sl) Finnish (fi) Swedish (sv) Language 2 Please choose Bulgarian (bg) Spanish (es) Czech (cs) Danish (da) German (de) Estonian (et) Greek (el) English (en) French (fr) Italian (it) Latvian (lv) Lithuanian (lt) Hungarian (hu) Maltese (mt) Dutch (nl) Polish (pl) Portuguese (pt) Romanian (ro) Slovak (sk) Slovenian (sl) Finnish (fi) Swedish (sv) L 6/20 COMMISSION DIRECTIVE 2008/128/EC of 22 December 2008 laying down specific purity criteria concerning colours for use in foodstuffs (Codified version) (Text with EEA relevance) THE COMMISSION OF THE EUROPEAN COMMUNITIES, Having regard to the Treaty establishing the European Community, Having regard to Council Directive 89/107/EEC of 21 December 1988 on the approximation of the laws of the Member States concerning food additives authorized for use in foodstuffs intended for human consumption (1), and in particular Article 3(3)(a) thereof, Commission Directive 95/45/EC of 26 July 1995 laying down specific criteria concerning colours for use in foodstuffs (2) has been substantially amended several times (3). In the interests of clarity and rationality the said Directive should be codified. It is necessary to establish purity criteria for all colours mentioned in European Parliament and Council Directive 94/36/EC of 30 June 1994 on colours for use in foodstuffs (4). It is necessary to take into account the specifications and analytical techniques for colours as set out in the Codex Alimentarius as drafted by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Food additives prepared by production methods or starting materials significantly different from those evaluated by the Scientific Committee for Food or different from those mentioned in this Directive should be submitted for safety evaluation by the European Food Safety Authority with emphasis on the purity criteria. The measures provided for in this Directive are in accordance with the opinion of the Standing Committee on the Food Chain and Animal Health. This Directive should be without prejudice to the obligations of the Member States relating to the time-limits for transposition into national law of the Directives set out in Annex II, Part B, HAS ADOPTED THIS DIRECTIVE: The purity criteria referred to in Article 3(3)(a) of Directive 89/107/EEC for colours mentioned in Directive 94/36/EC are set out in Annex I hereto. Directive 95/45/EC, as amended by the Directives listed in Annex II, Part A, is repealed, without prejudice to the obligations of the Member States relating to the time-limits for transposition into national law of the Directives set out in Annex II, Part B. References to the repealed Directive shall be construed as references to this Directive and shall be read in accordance with the correlation table in Annex III. This Directive shall enter into force on the 20th day following that of its publication in the Official Journal of the European Union. This Directive is addressed to the Member States. Done at Brussels, 22 December 2008. For the Commission (1) OJ L 40, 11.2.1989, p. 27. (2) OJ L 226, 22.9.1995, p. 1. (3) See Annex II, Part A. (4) OJ L 237, 10.9.1994, p. 13. A. GENERAL SPECIFICATIONS FOR ALUMINIUM LAKES OF COLOURS Aluminium lakes are prepared by reacting colours complying with the purity criteria set out in the appropriate specification monograph with alumina under aqueous conditions. The alumina is usually freshly prepared undried material made by reacting aluminium sulfate or chloride with sodium or calcium carbonate or bicarbonate or ammonia. Following lake formation, the product is filtered, washed with water and dried. Unreacted alumina may also be present in the finished product. HCl insoluble matter Not more than 0,5 % Ether extractable matter Not more than 0,2 % (under neutral conditions) Specific purity criteria for the corresponding colours are applicable. B. SPECIFIC CRITERIA OF PURITY E 100 CURCUMIN CI Natural Yellow 3, Turmeric Yellow, Diferoyl Methane Curcumin is obtained by solvent extraction of turmeric i.e. the ground rhizomes of natural strains of Curcuma longa L. In order to obtain a concentrated curcumin powder, the extract is purified by crystallisation. The product consists essentially of curcumins; i.e. the colouring principle (1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-dien-3,5-dione) and its two desmethoxy derivatives in varying proportions. Minor amounts of oils and resins naturally occuring in turmeric may be present. Only the following solvents may be used in the extraction: ethylacetate, acetone, carbon dioxide, dichloromethane, n-butanol, methanol, ethanol, hexane. Dicinnamoylmethane Colour Index No Chemical names 1,7-Bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione 1-(4-Hydroxyphenyl)-7-(4-hydroxy-3-methoxy-phenyl-)hepta-1,6-diene-3,5-dione 1,7-Bis(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione Content not less than 90 % total colouring matters E1 cm 1 %1 607 at ca 426 nm in ethanol Orange-yellow crystalline powder Maximum in ethanol at ca 426 nm 179 °C-182 °C Solvent residues Ethylacetate Not more than 50 mg/kg, singly or in combination Dichloromethane: not more than 10 mg/kg Not more than 3 mg/kg Not more than 10 mg/kg Heavy metals (as Pb) E 101 (i) RIBOFLAVIN Lactoflavin Isoalloxazine 7,8-Dimethyl-10-(D-ribo-2,3,4,5-tetrahydroxypentyl)benzo(g)pteridine-2,4(3H,10H)-dione 7,8-dimethyl-10-(1′-D-ribityl)isoalloxazine Content not less than 98 % on the anhydrous basis E1 cm 1 % 328 at ca 444 nm in aqueous solution Yellow to orange-yellow crystalline powder, with slight odour The ratio A375/A267 is between 0,31 and 0,33 in aqueous solution Maximum in water at ca 444 nm [α]D20 between – 115° and – 140° in a 0,05 N sodium hydroxide solution Loss on drying Not more than 1,5 % after drying at 105 °C for 4 hrs Sulfated ash Primary aromatic amines Not more than 100 mg/kg (calculated as aniline) E 101 (ii) RIBOFLAVIN-5′-PHOSPHATE Riboflavin-5′-phosphate sodium These specifications apply to riboflavin 5′-phosphate together with minor amounts of free riboflavin and riboflavin diphosphate Monosodium (2R,3R,4S)-5-(3′)10′-dihydro-7′,8′-dimethyl-2′,4′-dioxo-10′-benzo[γ]pteridinyl)-2,3,4-trihydroxypentyl phosphate; monosodium salt of 5′-monophosphate ester of riboflavin For the dihydrate form C17H20N4NaO9P·2H2O For the anhydrous form C17H20N4NaO9P Content not less than 95 % total colouring matters calculated as C17H20N4NaO9P·2H2O Yellow to orange crystalline hygroscopic powder, with slight odour and a bitter taste [α]D20 between + 38° and + 42° in a 5 molar HCl solution Not more than 8 % (100 °C, 5 hrs in vacuum over P2O5) for the dihydrate form Not more than 25 % Inorganic phosphate Not more than 1,0 % (calculated as PO4 on the anhydrous basis) Subsidiary colouring matters Riboflavin (free) Not more than 6 % Riboflavine diphosphate Not more than 70 mg/kg (calculated as aniline) E 102 TARTRAZINE CI Food Yellow 4 Tartrazine consists essentially of trisodium 5-hydroxy-1-(4-sulfonatophenyl)-4-(4-sulfonatophenylazo)-H-pyrazole-3-carboxylate and subsidiary colouring matters together with sodium chloride and/or sodium sulfate as the principal uncoloured components. Tartrazine is described as the sodium salt. The calcium and the potassium salt are also permitted. Monoazo Trisodium-5-hydroxy-1-(4-sulfonatophenyl)-4-(4-sulfonatophenylazo)-H-pyrazole-3-carboxylate C16H9N4Na3O9S2 Content not less than 85 % total colouring matters calculated as the sodium salt Light orange powder or granules Yellow solution in water Water insoluble matter Organic compounds other than colouring matters: 4-hydrazinobenzene sulfonic acid 4-aminobenzene-1-sulfonic acid 5-oxo-1-(4-sulfophenyl)-2-pyrazoline-3-carboxylic acid 4,4′-diazoaminodi(benzene sulfonic acid) Tetrahydroxysuccinic acid Total not more than 0,5 % Unsulfonated primary aromatic amines Not more than 0,01 % (calculated as aniline) Not more than 0,2 % under neutral conditions E 104 QUINOLINE YELLOW CI Food Yellow 13 Quinoline Yellow is prepared by sulfonating 2-(2-quinolyl) indan-1,3-dione. Quinoline Yellow consists essentially of sodium salts of a mixture of disulfonates (principally), monosulfonates and trisulfonates of the above compound and subsidiary colouring matters together with sodium chloride and/or sodium sulfate as the principal uncoloured components. Quinoline Yellow is described as the sodium salt. The calcium and the potassium salt are also permitted. Chinophthalone The disodium salts of the disulfonates of 2-(2-quinolyl) indan-1,3-dione (principal component) C18H9N Na2O8S2 (principal component) 477,38 (principal component) Quinoline Yellow shall have the following composition: Of the total colouring matters present: not less than 80 % shall be disodium 2-(2-quinolyl) indan-1,3-dione-disulfonates not more than 15 % shall be sodium 2-(2-quinolyl) indan-1,3-dione-monosulfonates not more than 7,0 % shall be trisodium 2-(2-quinolyl) indan-1,3-dione-trisulfonate E1 cm 1 % 865 (principal component) at ca 411 nm in aqueous acetic acid solution Yellow powder or granules Maximum in aqueous acetic acid solution of pH 5 at ca 411 nm 2-methylquinoline-sulfonic acid 2,6-dimethyl quinoline 2,6-dimethyl quinoline sulfonic acid 2-(2-quinolyl)indan-1,3-dione E 110 SUNSET YELLOW FCF CI Food Yellow 3, Orange Yellow S Sunset Yellow FCF consists essentially of disodium 2-hydroxy-1-(4-sulfonatophenylazo) naphthalene-6-sulfonate and subsidiary colouring matters together with sodium chloride and/or sodium sulfate as the principal uncoloured components. Sunset Yellow FCF is described as the sodium salt. The calcium and the potassium salt are also permitted. Disodium 2-hydroxy-1-(4-sulfonatophenylazo)naphthalene-6-sulfonate C16H10N2Na2O7S2 E1 cm 1 % 555 at ca 485 nm in aqueous solution at pH 7 Orange-red powder or granules Maximum in water at ca 485 nm at pH 7 Orange solution in water 1-(Phenylazo)-2-naphthalenol (Sudan I) Not more than 0,5 mg/kg 3-hydroxynaphthalene-2,7-disulfonic acid 6-hydroxynaphthalene-2-sulfonic acid 6,6′-oxydi(naphthalene-2-sulfonic acid) E 120 COCHINEAL, CARMINIC ACID, CARMINES Carmines and carminic acid are obtained from aqueous, aqueous alcoholic or alcoholic extracts from Cochineal, which consists of the dried bodies of the female insect Dactylopius coccus Costa. The colouring principle is carminic acid. Aluminium lakes of carminic acid (carmines) can be formed in which aluminium and carminic acid are thought to be present in the molar ratio 1:2. In commercial products the colouring principle is present in association with ammonium, calcium, potassium or sodium cations, singly or in combination, and these cations may also be present in excess. Commercial products may also contain proteinaceous material derived from the source insect, and may also contain free carminate or a small residue of unbound aluminium cations. Cochineal: 215-680-6; carminic acid: 215-023-3; carmines: 215-724-4 7-β-D-glucopyranosyl-3,5,6,8-tetrahydroxy-1-methyl-9,10-dioxoanthracene-2-carboxylic acid (carminic acid); carmine is the hydrated aluminium chelate of this acid C22H20O13 (carminic acid) 492,39 (carminic acid) Content not less than 2,0 % carminic acid in the extracts containing carminic acid; not less than 50 % carminic acid in the chelates. Red to dark red, friable, solid or powder. Cochineal extract is generally a dark red liquid but can also be dried as a powder. Maximum in aqueous ammonia solution at ca 518 nm Maximum in dilute hydrochloric solution at ca 494 nm for carminic acid E 122 AZORUBINE, CARMOISINE CI Food Red 3 Azorubine consists essentially of disodium 4-hydroxy-3-(4-sulfonato-1-naphthylazo) naphthalene-1-sulfonate and subsidiary colouring matters together with sodium chloride and/or sodium sulfate as the principal uncoloured components. Azorubine is described as the sodium salt. The calcium and the potassium salt are also permitted. Disodium 4-hydroxy-3-(4-sulfonato-1-naphthylazo) naphthalene-1-sulfonate Content not less than 85 % total colouring matters, calculated as the sodium salt Red to maroon powder or granules Red solution in water 4-aminonaphthalene-1-sulfonic acid E 123 AMARANTH Amaranth consists essentially of trisodium 2-hydroxy-1-(4-sulfonato-1-naphthylazo) naphthalene-3,6-disulfonate and subsidiary colouring matters together with sodium chloride and/or sodium sulfate as the principal uncoloured components. Amaranth is described as the sodium salt. The calcium and the potassium salt are also permitted. Trisodium 2-hydroxy-1-(4-sulfonato-1-naphthylazo) naphthalene-3,6-disulfonate C20H11N2Na3O10S3 Reddish-brown powder or granules 7-hydroxynaphthalene-1,3-6-trisulfonic acid E 124 PONCEAU 4R, COCHINEAL RED A CI Food Red 7, New Coccine Ponceau 4R consists essentially of trisodium 2-hydroxy-1-(4-sulfonato-1-naphthylazo) naphthalene-6,8-disulfonate and subsidiary colouring matters together with sodium chloride and/or sodium sulfate as the principal uncoloured components. Ponceau 4R is described as the sodium salt. The calcium and the potassium salt are also permitted. Content not less than 80 % total colouring matters, calculated as the sodium salt. Reddish powder or granules E 127 ERYTHROSINE CI Food Red 14 Erythrosine consists essentially of disodium 2-(2,4,5,7-tetraiodo-3-oxido-6-oxoxanthen-9-yl) benzoate monohydrate and subsidiary colouring matters together with water, sodium chloride and/or sodium sulfate as the principal uncoloured components. Erythrosine is described as the sodium salt. The calcium and the potassium salt are also permitted. Xanthen Disodium 2-(2,4,5,7-tetraiodo-3-oxido-6-oxoxanthen-9-yl)benzoate monohydrate C20H6I4Na2O5.H2O Content not less than 87 % total colouring matters, calculated as the anhydrous sodium salt E1 cm 1 %1 100 at ca 526 nm in aqueous solution at pH 7 Red powder or granules. Inorganic iodides calculated as sodium iodide Subsidiary colouring matters (except fluorescein) Tri-iodoresorcinol 2-(2,4-dihydroxy-3,5-diodobenzoyl) benzoic acid From a solution of pH from 7 through 8, not more than 0,2 % Aluminium Lakes The hydrochloric acid insoluble matter method is not applicable. It is replaced by a sodium hydroxide insoluble matter, at not more than 0,5 %, for this colour only. E 128 RED 2G CI Food Red 10, Azogeranine Red 2G consists essentially of disodium 8-acetamido-1-hydroxy-2-phenylazonaphthalene-3,6-disulfonate and subsidiary colouring matters together with sodium chloride and/or sodium sulfate as the principal uncoloured components. Red 2G is described as the sodium salt. The calcium and the potassium salt are also permitted. Disodium 8-acetamido-1-hydroxy-2-phenylazo-naphthalene-3,6-disulfonate Red powder or granules 5-acetamido-4-hydroxynaphthalene-2,7-disulfonic acid 5-amino-4-hydroxynaphthalene-2,7-disulfonic acid E 129 ALLURA RED AC Allura Red AC consists essentially of disodium 2-hydroxy-1-(2-methoxy-5-methyl-4-sulfonato-phenylazo) naphthalene-6-sulfonate and subsidiary colouring matters together with sodium chloride and/or sodium sulfate as the principal uncoloured components. Allura Red AC is described as the sodium salt. The calcium and the potassium salt are also permitted. Disodium 2-hydroxy-1-(2-methoxy-5-methyl-4-sulfonatophenylazo) naphthalene-6-sulfonate Dark red powder or granules 6-hydroxy-2-naphthalene sulfonic acid, sodium salt 4-amino-5-methoxy-2-methylbenezene sulfonic acid 6,6-oxybis (2-naphthalene sulfonic acid) disodium salt From a solution of pH 7, not more than 0,2 % E 131 PATENT BLUE V CI Food Blue 5 Patent Blue V consists essentially of the calcium or sodium compound of [4-(α-(4-diethylaminophenyl)-5-hydroxy-2,4-disulfophenyl-methylidene)2,5-cyclohexadien-1-ylidene] diethylammonium hydroxide inner salt and subsidiary colouring matters together with sodium chloride and/or sodium sulfate and/or calcium sulfate as the principal uncoloured components. The potassium salt is also permitted. Triarylmethane The calcium or sodium compound of [4-(α-(4-diethylaminophenyl)-5-hydroxy-2,4-disulfophenyl-methylidene) 2,5-cyclohexadien-1-ylidene] diethyl-ammonium hydroxide inner salt Calcium compound: C27H31N2O7S2Ca Sodium compound: C27H31N2O7S2Na Calcium compound: 579,72 Sodium compound: 582,67 Dark-blue powder or granules Maximum in water at 638 nm at pH 5 Blue solution in water 3-hydroxy benzaldehyde 3-hydroxy benzoic acid 3-hydroxy-4-sulfobenzoic acid N,N-diethylamino benzene sulfonic acid Leuco base From a solution of pH 5 not more than 0,2 % E 132 INDIGOTINE, INDIGO CARMINE Indigotine consists essentially of a mixture of disodium 3,3′dioxo-2,2′-bi-indolylidene-5,5′-disulfonate, and disodium 3,3′-dioxo-2,2′-bi-indolylidene-5,7′-disulfonate and subsidiary colouring matters together with sodium chloride and/or sodium sulfate as the principal uncoloured components. Indigotine is described as the sodium salt. The calcium and the potassium salt are also permitted. Indigoid Disodium 3,3′-dioxo-2,2′-bi-indolylidene-5,5′-disulfonate Content not less than 85 % total colouring matters, calculated as the sodium salt; disodium 3,3′-dioxo-2,2′-bi-indolylidene-5,7′-disulfonate: not more than 18 % Excluding disodium 3,3′-dioxo-2,2′-bi-indolylidene-5,7′-disulfonate: not more than 1,0 % Isatin-5-sulfonic acid 5-sulfoanthranilic acid E 133 BRILLIANT BLUE FCF Brilliant Blue FCF consists essentially of disodium α-(4-(N-ethyl-3-sulfonatobenzylamino) phenyl)-α-(4-N-ethyl-3-sulfonatobenzylamino) cyclohexa-2,5-dienylidene) toluene-2-sulfonate and its isomers and subsidiary colouring matters together with sodium chloride and/or sodium sulfate as the principal uncoloured components. Brilliant Blue FCF is described as the sodium salt. The calcium and the potassium salt are also permitted. Disodium α-(4-(N-ethyl-3-sulfonatobenzylamino) phenyl)-α-(4-N-ethyl-3-sulfonatobenzylamino) cyclohexa-2,5-dienylidene) toluene-2-sulfonate E1 cm 1 %1 630 at ca 630 nm in aqueous solution Reddish-blue powder or granules Sum of 2-, 3- and 4-formyl benzene sulfonic acids 3-((ethyl)(4-sulfophenyl) amino) methyl benzene sulfonic acid Not more than 0,2 % at pH 7 E 140 (i) CHLOROPHYLLS CI Natural Green 3, Magnesium Chlorophyll, Magnesium Phaeophytin Chlorophylls are obtained by solvent extraction of natural strains of edible plant material, grass, lucerne and nettle. During the subsequent removal of solvent, the naturally present co-ordinated magnesium may be wholly or partly removed from the chlorophylls to give the corresponding phaeophytins. The principal colouring matters are the phaeophytins and magnesium chlorophylls. The extracted product, from which the solvent has been removed, contains other pigments such as carotenoids as well as oils, fats and waxes derived from the source material. Only the following solvents may be used for the extraction: acetone, methyl ethyl ketone, dichloromethane, carbon dioxide, methanol, ethanol, propan-2-ol and hexane. Chlorophylls: 215-800-7, chlorophyll a: 207-536-6, Chlorophyll b: 208-272-4 The major colouring principles are: Phytyl (132 R,17S,18S)-3-(8-ethyl-132-methoxycarbonyl-2,7,12,18-tetramethyl-13′-oxo-3-vinyl-131-132-17,18-tetrahydrocyclopenta [at]-porphyrin-17-yl)propionate, (Pheophytin a), or as the magnesium complex (Chlorophyll a) Phytyl (132 R,17S,18S)-3-(8-ethyl-7-formyl-132-methoxycarbonyl-2,12,18-trimethyl-13′-oxo-3-vinyl-131-132-17,18-tetrahydrocyclopenta[at]-porphyrin-17-yl)propionate, (Pheophytin b), or as the magnesium complex (Chlorophyll b) Chlorophyll a (magnesium complex): C55H72MgN4O5 Chlorophyll a: C55H74N4O5 Chlorophyll b (magnesium complex): C55H70MgN4O6 Chlorophyll b: C55H72N4O6 Chlorophyll a (magnesium complex): 893,51 Chlorophyll a: 871,22 Chlorophyll b (magnesium complex): 907,49 Chlorophyll b: 885,20 Content of total combined Chlorophylls and their magnesium complexes is not less than 10 % E1 cm 1 % 700 at ca 409 nm in chloroform Waxy solid ranging in colour from olive green to dark green depending on the content of co-ordinated magnesium Maximum in chloroform at ca 409 nm Propan-2-ol E 140 (ii) CHLOROPHYLLINS CI Natural Green 5, Sodium Chlorophyllin, Potassium Chlorophyllin The alkali salts of chlorophyllins are obtained by the saponification of a solvent extract of natural strains of edible plant material, grass, lucerne and nettle. The saponification removes the methyl and phytol ester groups and may partially cleave the cyclopentenyl ring. The acid groups are neutralized to form the salts of potassium and/or sodium. Only the following solvents may be used for the extraction: acetone, methyl ethyl ketone, dichloromethane, carbon dioxide, methanol, ethanol, propan-2-ol and hexane. The major colouring principles in their acid forms are: 3-(10-carboxylato-4-ethyl-1,3,5,8-tetramethyl-9-oxo-2-vinylphorbin-7-yl)propionate (chlorophyllin a) 3-(10-carboxylato-4-ethyl-3-formyl-1,5,8-trimethyl-9-oxo-2-vinylphorbin-7-yl)propionate (chlorophyllin b) Depending on the degree of hydrolysis the cyclopentenyl ring may be cleaved with the resultant production of a third carboxyl function. Magnesium complexes may also be present. Chlorophyllin a (acid form): C34H34N4O5 Chlorophyllin b (acid form): C34H32N4O6 Chlorophyllin a: 578,68 Chlorophyllin b: 592,66 Each may be increased by 18 daltons if the cyclopentenyl ring is cleaved. Content of total chlorophyllins is not less than 95 % of the sample dried at ca 100 °C for 1 hour. Dark green to blue/black powder Maximum in aqueous phosphate buffer at pH 9 at ca 405 nm and at ca 653 nm E 141 (i) COPPER COMPLEXES OF CHLOROPHYLLS CI Natural Green 3, Copper Chlorophyll, Copper Phaeophytin Copper chlorophylls are obtained by addition of a salt of copper to the substance obtained by solvent extraction of natural strains of edible plant material, grass, lucerne, and nettle. The product, from which the solvent has been removed, contains other pigments such as carotenoids as well as fats and waxes derived from the source material. The principal colouring matters are the copper phaeophytins. Only the following solvents may be used for the extraction: acetone, methyl ethyl ketone, dichloromethane, carbon dioxide, methanol, ethanol, propan-2-ol and hexane. Copper chlorophyll a: 239-830-5; copper chlorophyll b: 246-020-5 [Phytyl (132 R,17S,18S)-3-(8-ethyl-132-methoxycarbonyl-2,7,12,18-tetramethyl-13′-oxo-3-vinyl-131-132-17,18-tetrahydrocyclopenta[at]-porphyrin-17-yl)propionate] copper (II) (Copper Chlorophyll a) [Phytyl (132 R,17S,18S)-3-(8-ethyl-7-formyl-132-methoxycarbonyl-2,12,18-trimethyl-13′-oxo-3-vinyl-131-132-17,18-tetrahydrocyclopenta[at]-porphyrin-17-yl)propionate] copper (II) (Copper chlorophyll b) Copper chlorophyll a: C55H72Cu N4O5 Copper chlorophyll b: C55H70Cu N4O6 Copper chlorophyll a: 932,75 Copper chlorophyll b: 946,73 Content of total copper chlorophylls is not less than 10 %. Waxy solid ranging in colour from blue green to dark green depending on the source material Maximum in chloroform at ca 422 nm and at ca 652 nm Copper ions Not more than 200 mg/kg Total copper Not more than 8,0 % of the total copper phaeophytins E 141 (ii) COPPER COMPLEXES OF CHLOROPHYLLINS Sodium Copper Chlorophyllin, Potassium Copper Chlorophyllin, CI Natural Green 5 The alkali salts of copper chlorophyllins are obtained by the addition of copper to the product obtained by the saponification of a solvent extraction of natural strains of edible plant material, grass, lucerne, and nettle; the saponification removes the methyl and phytol ester groups and may partially cleave the cyclopentenyl ring. After addition of copper to the purified chlorophyllins, the acid groups are neutralized to form the salts of potassium and/or sodium. Only the following solvents may be used for the extraction: acetone, methyl ethyl ketone, dichloromethane, carbon dioxide methanol, ethanol, propan-2-ol and hexane. 3-(10-Carboxylato-4-ethyl-1,3,5,8-tetramethyl-9-oxo-2-vinylphorbin-7-yl)propionate, copper complex (Copper chlorophyllin a) 3-(10-Carboxylato-4-ethyl-3-formyl-1,5,8-trimethyl-9-oxo-2-vinylphorbin-7-yl) propionate, copper complex (Copper chlorophyllin b) Copper chlorophyllin a (acid form): C34H32Cu N4O5 Copper chlorophyllin b (acid form): C34H30Cu N4O6 Copper chlorophyllin a: 640,20 Copper chlorophyllin b: 654,18 Content of total copper chlorophyllins is not less than 95 % of the sample dried at 100 °C for 1 h. E1 cm 1 % 565 at ca 405 nm in aqueous phosphate buffer at pH 7,5 Maximum in aqueous phosphate buffer at pH 7,5 at ca 405 nm and at ca 630 nm Not more than 8,0 % of the total copper chlorophyllins E 142 GREEN S CI Food Green 4, Brilliant Green BS Green S consists essentially of sodium N-[4-(dimethylamino)phenyl] 2-hydroxy-3,6-disulfo-1-naphthalenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-methylmethanaminium and subsidiary colouring matters together with sodium chloride and/or sodium sulphate as the principal uncoloured compounds. Green S is described as the sodium salt. The calcium and the potassium salt are also permitted. Sodium N-[4-[[4-(dimethylamino)phenyl](2-hydroxy-3,6-disulfo-1-naphthalenyl)-methylene]2,5-cyclohexadien-1-ylidene]-N-methylmethanaminium; Sodium 5-[4-dimethylamino-α-(4-dimethyliminocyclohexa-2,5-dienylidene) benzyl]-6-hydroxy-7-sulfonato-naphthalene-2-sulfonate (alternative chemical name). C27H25N2NaO7S2 Dark blue or dark green powder or granules Blue or green solution in water 4,4′-bis(dimethylamino)-benzhydryl alcohol 4,4′-bis(dimethylamino)-benzophenone E 150a PLAIN CARAMEL Plain caramel is prepared by the controlled heat treatment of carbohydrates (commercially available food grade nutritive sweeteners which are the monomers glucose and fructose and/or polymers thereof, e.g. glucose syrups, sucrose, and/or invert syrups, and dextrose). To promote caramelization, acids, alkalis and salts may be employed, with the exception of ammonium compounds and sulphites. Dark brown to black liquids or solids Colour bound by DEAE cellulose Colour bound by phosphoryl cellulose Colour intensity (1) Total sulphur E 150b CAUSTIC SULPHITE CARAMEL Caustic sulphite caramel is prepared by the controlled heat treatment of carbohydrates (commercially available food grade nutritive sweeteners which are the monomers glucose and fructose and/or polymers thereof, e.g. glucose syrups, sucrose, and/or invert syrups, and dextrose) with or without acids or alkalis, in the presence of sulphite compounds (sulphurous acid, potassium sulphite, potassium bisulphite, sodium sulphite and sodium bisulphite); no ammonium compounds are used. More than 50 % Not more than 0,3 % (2) 0,3-3,5 % (2) Sulphur bound by DEAE cellulose Absorbance ratio of colour bound by DEAE cellulose Absorbance ratio (A 280/560) Greater than 50 E 150c AMMONIA CARAMEL Ammonia caramel is prepared by the controlled heat treatment of carbohydrates (commercially available food grade nutritive sweeteners which are the monomers glucose and fructose and/or polymers thereof, e.g. glucose syrups, sucrose, and/or invert syrups, and dextrose) with or without acids or alkalis, in the presence of ammonium compounds (ammonium hydroxide, ammonium carbonate, ammonium hydrogen carbonate and ammonium phosphate); no sulphite compounds are used. Ammoniacal nitrogen 4-methylimidazole Not more than 250 mg/kg (2) 2-acetyl-4-tetrahydroxy-butylimidazole Not more than 10 mg/kg (2) Absorbance ratio of colour bound by phosphoryl cellulose E 150d SULPHITE AMMONIA CARAMEL Sulphite ammonia caramel is prepared by the controlled heat treatment of carbohydrates (commercially available food grade nutritive sweeteners which are the monomers glucose and fructose and/or polymers thereof (e.g. glucose syrups, sucrose, and/or invert syrups, and dextrose) with or without acids or alkalis in the presence of both sulphite and ammonium compounds (sulphurous acid, potassium sulphite, potassium bisulphite, sodium sulphite, sodium bisulphite, ammonium hydroxide, ammonium carbonate, ammonium hydrogen carbonate, ammonium phosphate, ammonium sulphate, ammonium sulphite and ammonium hydrogen sulphite). Nitrogen/sulphur ratio of alcohol precipitate Absorbance ratio of alcohol precipitate (3) Absorbance ratio (A 280/560) Not more than 50 E 151 BRILLIANT BLACK BN, BLACK PN CI Food Black 1 Brilliant Black BN consists essentially of tetrasodium-4-acetamido-5-hydroxy-6-[7-sulfonato-4-(4-sulfonatophenylazo)-1-naphthylazo] naphthalene-1,7-disulfonate and subsidiary colouring matters together with sodium chloride and/or sodium sulfate as the principal uncoloured components. Brilliant Black BN is described as the sodium salt. The calcium and the potassium salt are also permitted. Bisazo Tetrasodium 4-acetamido-5-hydroxy-6-[7-sulfonato-4-(4-sulfonatophenylazo)-1-naphthylazo] naphthalene-1,7-disulfonate E1 cm 1 % 530 at ca 570 nm in solution Black powder or granules Black-bluish solution in water Not more than 10 % (expressed on the dye content) 4,4′-diazoaminodi-(benzenesulfonic acid) E 153 VEGETABLE CARBON Vegetable black Vegetable carbon is produced by the carbonization of vegetable material such as wood, cellulose residues, peat and coconut and other shells. The raw material is carbonised at high temperatures. It consists essentially of finely divided carbon. It may contain minor amounts of nitrogen, hydrogen and oxygen. Some moisture may be absorbed on the product after manufacture. Content not less than 95 % of carbon calculated on an anhydrous and ash-free basis Black powder, odourless and tasteless Insoluble in water and organic solvents When heated to redness it burns slowly without a flame Ash (Total) Not more than 4,0 % (ignition temperature: 625 °C) Polyaromatic hydrocarbons The extract obtained by extraction of 1 g of the product with 10 g pure cyclohexane in a continuous extraction apparatus shall be colourless, and the fluorescence of the extract in ultraviolet light shall not be more intense than that of a solution of 0,100 mg of quinine sulfate in 1 000 ml of 0,01 M sulphuric acid. Not more than 12 % (120 °C, 4 hrs) Alkali soluble matter The filtrate obtained by boiling 2 g of the sample with 20 ml N sodium hydroxide and filtering shall be colourless E 154 BROWN FK CI Food Brown 1 Brown FK consists essentially of a mixture of: sodium 4-(2,4-diaminophenylazo) benzenesulfonate sodium 4-(4,6-diamino-m-tolylazo) benzenesulfonate disodium 4,4′-(4,6-diamino-1,3-phenylenebisazo)di (benzenesulfonate) disodium 4,4′-(2,4-diamino-5-methyl-1,3-phenylenebisazo)di (benzenesulfonate) trisodium 4,4′,4″-(2,4-diaminobenzene-1,3,5-trisazo)tri-(benzenesulfonate) and subsidiary colouring matters together with water, sodium chloride and/or sodium sulfate as the principal uncoloured components. Brown FK is described as the sodium salt. The calcium and the potassium salt are also permitted. Azo (a mixture of mono-, bis- and trisazo colours) A mixture of: C12H11N4NaO3S Of the total colouring matters present the proportions of the components shall not exceed: Red-brown powder or granules Orange to reddish solution m-phenylenediamine and 4-methyl-m-phenylenediamine Not more than 0,35 % Unsulfonated primary aromatic amines other than m-phenylene diamine and 4-methyl-m-phenylene diamine Not more than 0,007 % (calculated as aniline) E 155 BROWN HT Brown HT consists essentially of disodium 4,4′-(2,4-dihydroxy-5-hydroxymethyl-1,3-phenylene bisazo) di (naphthalene-1-sulfonate) and subsidiary colouring matters together with sodium chloride and/or sulfate as the principal uncoloured components. Brown HT is described as the sodium salt. The calcium and potassium salt are also permitted. Disodium 4,4′-(2,4-dihydroxy-5-hydroxymethyl-1,3-phenylene bisazo)di (naphthalene-1-sulfonate) Content not less than 70 % total colouring matters calculated as the sodium salt. Maximum in water of pH 7 at ca 460 nm Brown solution in water Not more than 10 % (TLC method) Not more than 0,2 % in a solution of pH 7 E 160a (i) MIXED CAROTENES Plant carotenes CI Food Orange 5 Mixed carotenes are obtained by solvent extraction of natural strains of edible plants, carrots, vegetable oils, grass, alfalfa (lucerne) and nettle. The main colouring principle consists of carotenoids of which beta-carotene accounts for the major part. Alpha, gamma-carotene and other pigments may be present. Besides the colour pigments, this substance may contain oils, fats and waxes naturally occurring in the source material. Only the following solvents may be used in the extraction: acetone, methyl ethyl ketone, methanol, ethanol, propan-2-ol, hexane (4), dichloromethane and carbon dioxide. Carotenoid Beta-carotene: C40H56 Beta-carotene: 536,88 Content of carotenes (calculated as beta-carotene) is not less than 5 %. For products obtained by extraction of vegetables oils: not less than 0,2 % in edible fats. E1 cm 1 %2 500 at approximately 440 nm to 457 nm in cyclohexane Maximum in cyclohexane at 440 nm to 457 nm and 470 nm to 486 nm Algal carotenes Mixed carotenes may also be produced from natural strains of the algae Dunaliella salina, grown in large saline lakes located in Whyalla, South Australia. Beta-carotene is extracted using an essential oil. The preparation is a 20 to 30 % suspension in edible oil. The ratio of trans-cis isomers is in the range of 50/50 to 71/29. The main colouring principle consists of carotenoids of which beta-carotene accounts for the major part. Alpha-carotene, lutein, zeaxanthin and beta-cryptoxanthin may be present. Besides the colour pigments, this substance may contain oils, fats and waxes naturally occurring in the source material. Content of carotenes (calculated as beta-carotene) is not less than 20 % E1 cm 1 %2 500 at approximately by 440 nm to 457 nm in cyclohexane Natural tocopherols in edible oil E 160a (ii) BETA-CAROTENE These specifications apply predominantly to all trans isomer of beta-carotene together with minor amounts of other carotenoids. Diluted and stabilised preparations may have different trans-cis isomer ratios. Beta-carotene, beta, beta-carotene C40H56 Not less than 96 % total colouring matters (expressed as beta-carotene) Red to brownish-red crystals or crystalline powder Maximum in cyclohexane at 453 nm to 456 nm Carotenoids other than beta-carotene: not more than 3,0 % of total colouring matters Beta-carotene from Blakeslea trispora Obtained by a fermentation process using a mixed culture of the two sexual mating types (+) and (–) of natural strains of the fungus Blakeslea trispora. The beta-carotene is extracted from the biomass with ethyl acetate, or isobutyl acetate followed by isopropyl alcohol, and crystallised. The crystallised product consists mainly of trans beta-carotene. Because of the natural process approximately 3 % of the product consists of mixed carotenoids, which is specific for the product. Beta-carotene, beta,beta-carotene Red, brownish-red or purple-violet crystals or crystalline powder (colour varies according to extraction solvent used and conditions of crystallisation) Not more than 0,8 %, singly or in combination Isobutyl acetate: Not more than 1,0 % Isopropyl alcohol: Not more than 0,1 % Mycotoxins: Aflatoxin B1 Trichothecene (T2) Ochratoxin Zearalenone Microbiology: Not more than 100/g Absent in 25 g Absent in 5 g E 160b ANNATTO, BIXIN, NORBIXIN CI Natural Orange 4 Annatto: 215-735-4, annatto seed extract: 289-561-2; bixin: 230-248-7 Bixin 6′-Methylhydrogen-9′-cis-6,6′-diapocarotene-6,6′-dioate 6′-Methylhydrogen-9′-trans-6,6′-diapocarotene-6,6′-dioate Norbixin 9′Cis-6,6′-diapocarotene-6,6′-dioic acid 9′-Trans-6,6′-diapocarotene-6,6′-dioic acid Reddish-brown powder, suspension or solution maximum in dilute KOH solution at ca 482 nm Solvent extracted bixin and norbixin Bixin is prepared by the extraction of the outer coating of the seeds of the annatto tree (Bixa orellana L.) with one or more of the following solvents: acetone, methanol, hexane or dichloromethane, carbon dioxide followed by the removal of the solvent. Norbixin is prepared by hydrolysis by aqueous alkali of the extracted bixin. Bixin and norbixin may contain other materials extracted from the annatto seed. The bixin powder contains several coloured components, the major single one being bixin, which may be present in both cis- and trans- forms. Thermal degradation products of bixin may also be present. The norbixin powder contains the hydrolysis product of bixin, in the form of the sodium or potassium salts as the major colouring principle. Both cis- and trans-forms may be present. Content of bixin powders not less than 75 % total carotenoids calculated as bixin. Content of norbixin powders not less than 25 % total carotenoids calculated as norbixin E1 cm 1 %2 870 at ca 502 nm in chloroform E1 cm 1 %2 870 at ca 482 nm in KOH solution Alkali extracted annatto Water soluble annatto is prepared by extraction with aqueous alkali (sodium or potassium hydroxide) of the outer coating of the seeds of the annatto tree (Bixa orellana L.) Water soluble annatto contains norbixin, the hydrolysis product of bixin, in the form of the sodium or potassium salts, as the major colouring principle. Both cis- and trans- forms may be present. Contains not less than 0,1 % of total carotenoids expressed as norbixin Oil extracted annatto Annatto extracts in oil, as solution or suspension, are prepared by extraction of the outer coating of the seeds of the annatto tree (Bixa orellana L.) with edible vegetable oil. Annatto extract in oil contains several coloured components, the major single one being bixin, which may be present in both cis- and transforms. Thermal degradation products of bixin may also be present. Contains not less than 0,1 % of total carotenoids expressed as bixin E 160c PAPRIKA EXTRACT, CAPSANTHIN, CAPSORUBIN Paprika Oleoresin Paprika extract is obtained by solvent extraction of the natural strains of paprika, which consists of the ground fruits pods, with or without seeds, of Capsicum annuum L., and contains the major colouring principles of this spice. The major colouring principles are capsanthin and capsorubin. A wide variety of other coloured compounds is known to be present. Only the following solvents may be used in the extraction: methanol, ethanol, acetone, hexane, dichloromethane, ethyl acetate and carbon dioxide. Capsanthin: 207-364-1, capsorubin: 207-425-2 Capsanthin: (3R, 3′S, 5′R)-3,3′-dihydroxy-β,k-carotene-6-one Capsorubin: (3S, 3′S, 5R, 5R′)-3,3′-dihydroxy-k,k-carotene-6,6′-dione Capsanthin: C40H56O3 Capsorubin: C40H56O4 Capsanthin: 584,85 Capsorubin: 600,85 Paprika extract: content not less than 7,0 % carotenoids Capsanthin/capsorubin: not less than 30 % of total carotenoids E1 cm 1 %2 100 at ca 462 nm in acetone Dark-red viscous liquid Maximum in acetone at ca 462 nm Colour reaction A deep blue colour is produced by adding one drop of sulfuric acid to one drop of sample in 2-3 drops of chloroform E 160d LYCOPENE Natural Yellow 27 Lycopene is obtained by solvent extraction of the natural strains of red tomatoes (Lycopersicon esculentum L.) with subsequent removal of the solvent. Only the following solvents may be used: dichloromethane, carbon dioxide, ethyl acetate, acetone, propan-2-ol, methanol, ethanol, hexane. The major colouring principle of tomatoes is lycopene, minor amounts of other carotenoid pigments may be present. Beside the other colour pigments the product may contain oils, fats, waxes, and flavour components naturally occurring in tomatoes. Lycopene, ψ,ψ-carotene Content not less than 5 % total colouring matters E1 cm 1 %3 450 at ca 472 nm in hexane Dark red viscous liquid Maximum in hexane at ca 472 nm E 160e BETA-APO-8′-CAROTENAL (C30) These specifications apply to predominantly all trans isomer of β-apo-8′-carotenal together with minor amounts of other carotenoids. Diluted and stabilized forms are prepared from β-apo-8′-carotenal meeting these specifications and include solutions or suspensions of ß-apo-8′carotenal in edible fats or oils, emulsions and water dispersible powders. These preparations may have different cis/trans isomer ratios. Carotinoid β-apo-8′-carotenal, Trans-β-apo-8′carotene-aldehyde C30H40O Not less than 96 % of total colouring matters E1 cm 1 %2 640 at ca 460-462 nm in cyclohexane Dark violet crystals with metallic lustre or crystalline powder Maximum in cyclohexane at 460-462 nm Carotenoids other than β-apo-8′-carotenal: not more than 3,0 % of total colouring matters E 160f ETHYL ESTER OF BETA-APO-8′-CAROTENOIC ACID (C30) CI Food Orange 7, β-apo-8′-carotenoic ester These specifications apply to predominantly all trans isomer of β-apo-8′-carotenoic acid ethyl ester together with minor amounts of other carotenoids. Diluted and stabilized forms are prepared from β-apo-8′-carotenoic acid ethyl ester meeting these specifications and include solutions or suspensions of β-apo-8′-carotenoic acid ethyl ester in edible fats or oils, emulsions and water dispersible powders. These preparations may have different cis/trans isomer ratios. β-apo-8′-carotenoic acid ethyl ester, ethyl 8′-apo-β-caroten-8′-oate E1 cm 1 %2 550 at ca 449 nm in cyclohexane Red to violet-red crystals or crystalline powder Maximum in cyclohexane at ca 449 nm Carotenoids other than β-apo-8′-carotenoic acid ethyl ester: not more than 3,0 % of total colouring matters E 161b LUTEIN Mixed Carotenoids, Xanthophylls Lutein is obtained by solvent extraction of the natural strains of edible fruits and plants, grass, lucerne (alfalfa) and tagetes erecta. The main colouring principle consists of carotenoids of which lutein and its fatty acid esters account for the major part. Variable amounts of carotenes will also be present. Lutein may contain fats, oils and waxes naturally occurring in the plant material. Only the following solvents may be used for the extraction: methanol, ethanol, propan-2-ol, hexane, acetone, methyl ethyl ketone, dichloromethane and carbon dioxide 3,3′-dihydroxy-d-carotene Content of total colouring matter not less than 4 % calculated as lutein E1 cm 1 %2 550 at ca 445 nm in chloroform/ethanol (10 + 90) or in hexane/ethanol/acetone (80 + 10 + 10) Dark, yellowish brown liquid Maximum in chloroform/ethanol (10 + 90) at ca 445 nm E 161g CANTHAXANTHIN These specifications apply to predominantly all trans isomers of canthaxanthin together with minor amounts of other carotenoids. Diluted and stabilized forms are prepared from canthaxanthin meeting these specifications and include solutions or suspensions of canthaxanthin in edible fats or oils, emulsions and water dispersible powders. These preparations may have different cis/trans isomer ratios. β-Carotene-4,4′-dione, canthaxanthin, 4,4′-dioxo-β-carotene Not less than 96 % of total colouring matters (expressed as canthaxanthin) E1 cm 1 %2 200 at ca 485 nm in chloroform at 468-472 nm in cyclohexane at 464-467 nm in petroleum ether Deep violet crystals or crystalline powder Maximum in petroleum ether at 464-467 nm Carotenoids other than canthaxanthin: not more than 5,0 % of total colouring matters E 162 BEETROOT RED, BETANIN Beet Red Beet red is obtained from the roots of natural strains of red beets (Beta vulgaris L. var. rubra) by pressing crushed beet as press juice or by aqueous extraction of shredded beet roots and subsequent enrichment in the active principle. The colour is composed of different pigments all belonging to the class betalaine. The main colouring principle consists of betacyanins (red) of which betanin accounts for 75-95 %. Minor amounts of betaxanthin (yellow) and degradation products of betalaines (light brown) may be present. Besides the colour pigments the juice or extract consists of sugars, salts, and/or proteins naturally occurring in red beets. The solution may be concentrated and some products may be refined in order to remove most of the sugars, salts and proteins. Betalaine (S-(R′,R′)-4-(2-(2-Carboxy-5(β-D-glucopyranosyloxy)-2,3-dihydro-6-hydroxy-1H-indol-1-yl)ethenyl)-2,3-dihydro-2,6-pyridine-dicarboxylic acid; 1-(2-(2,6-dicarboxy-1,2,3,4-tetrahydro-4-pyridylidene)ethylidene)-5-β-D-glucopyranosyloxy)-6-hydroxyindolium-2-carboxylate Betanin: C24H26N2O13 Content of red colour (expressed as betanine) is not less than 0,4 % Red or dark red liquid, paste, powder or solid Not more than 2 g nitrate anion/g of red colour (as calculated from assay). E 163 ANTHOCYANINS Anthocyanins are obtained by extraction with sulphited water, acidified water, carbon dioxide, methanol or ethanol from the natural strains of vegetables and edible fruits. Anthocyanins contain common components of the source material, namely anthocyanine, organic acids, tannins, sugars, minerals etc., but not necessarily in the same proportions as found in the source material. 208-438-6 (cyanidin); 205-125-6 (peonidin); 208-437-0 (delphinidin); 211-403-8 (malvidin); 205-127-7 (pelargonidin) 3,3′,4′,5,7-Pentahydroxy-flavylium chloride (cyanidin) 3,4′,5,7-Tetrahydroxy-3′-methoxyflavylium chloride (peonidin) 3,4′,5,7-Tetrahydroxy-3′,5′-dimethoxyflavylium chloride (malvidin) 3,5,7-Trihydroxy-2-(3,4,5,trihydroxyphenyl)-1-benzopyrylium chloride (delphinidin) 3,3′4′,5,7-Pentahydroxy-5′-methoxyflavylium chloride (petunidin) 3,5,7-Trihydroxy-2-(4-hydroxyphenyl)-1-benzopyrilium chloride (pelargonidin) Cyanidin: C15H11O6Cl Peonidin: C16H13O6Cl Malvidin: C17H15O7Cl Delphinidin: C15H11O7Cl Petunidin: C16H13O7Cl Pelargonidin: C15H11O5Cl Cyanidin: 322,6 Peonidin: 336,7 Malvidin: 366,7 Delphinidin: 340,6 Petunidin: 352,7 Pelargonidin: 306,7 E1 cm 1 % 300 for the pure pigment at 515-535 nm at pH 3,0 Purplish-red liquid, powder or paste, having a slight characteristic odour Maximum in methanol with 0,01 % conc. HCl Cyanidin: 535 nm Peonidin: 532 nm Malvidin: 542 nm Delphinidin: 546 nm Petunidin: 543 nm Pelargonidin: 530 nm Not more than 1 000 mg/kg per percent pigment E 170 CALCIUM CARBONATE CI Pigment White 18, Chalk Calcium carbonate is the product obtained from ground limestone or by the precipitation of calcium ions with carbonate ions. Calcium carbonate: 207-439-9 Limestone: 215-279-6 White crystalline or amorphous, odourless and tasteless powder Practically insoluble in water and in alcohol. Dissolves with effervescence in diluted acetic acid, in diluted hydrochloric acid and in diluted nitric acid, and the resulting solutions, after boiling, give positive tests for calcium. Not more than 2,0 % (200 °C, 4 hours) Acid-insoluble substances Magnesium and alkali salts Antimony (as Sb) Copper (as Cu) Chromium (as Cr) Zinc (as Zn) Barium (as Ba) Not more than 100 mg/kg, singly or in combination E 171 TITANIUM DIOXIDE CI Pigment White 6 Titanium dioxide consists essentially of pure anatase and/or rutile titanium dioxide which may be coated with small amounts of alumina and/or silica to improve the technological properties of the product. Content not less than 99 % on an alumina and silica-free basis White to slightly coloured powder Insoluble in water and organic solvents. Dissolves slowly in hydrofluoric acid and in hot concentrated sulfuric acid. Loss on ignition Not more than 1,0 % on a volatile matter free basis (800 °C) Aluminium oxide and/or silicon dioxide Matter soluble in 0,5 N HCl Not more than 0,5 % on an alumina and silica-free basis and, in addition, for products containing alumina and/or silica, not more than 1,5 % on the basis of the product as sold. Water soluble matter Not more than 50 mg/kg by total dissolution Not more than 3 mg/kg by total dissolution E 172 IRON OXIDES AND IRON HYDROXIDES CI Pigment Yellow 42 and 43 CI Pigment Red 101 and 102 Iron Oxide Black CI Pigment Black 11 Iron oxides and iron hydroxides are produced synthetically and consist essentially of anhydrous and/or hydrated iron oxides. The range of hues includes yellows, reds, browns and blacks. Food quality iron oxides are primarily distinguished from technical grades by the comparatively low levels of contamination by other metals. This is achieved by the selection and control of the source of the iron and/or by the extent of chemical purification during the manufacturing process. hydrated ferric oxide, hydrated iron (III) oxide anhydrous ferric oxide, anhydrous iron (III) oxide ferroso ferric oxide, iron (II, III) oxide FeO(OH)·H2O Fe2O3 FeO·Fe2O3 FeO(OH) Yellow not less than 60 %, red and black not less than 68 % total iron, expressed as iron Powder; yellow, red, brown or black in hue Insoluble in water and in organic solvents Soluble in concentrated mineral acids By total dissolution E 173 ALUMINIUM CI Pigment Metal, Al Aluminium powder is composed of finely divided particles of aluminium. The grinding may or may not be carried out in the presence of edible vegetable oils and/or food additive quality fatty acids. It is free from admixture with substances other than edible vegetable oils and/or food additive quality fatty acids. Not less than 99 % calculated as Al on an oil-free basis A silvery-grey powder or tiny sheets Insoluble in water and in organic solvents. Soluble in dilute hydrochloric acid. The resulting solution gives positive tests for aluminium. Not more than 0,5 % (105 °C, to constant weight) E 174 SILVER Argentum, Ag Content not less than 99,5 % Ag Silver-coloured powder or tiny sheets E 175 GOLD Pigment Metal 3, Aurum, Au Content not less than 90 % Au Gold-coloured powder or tiny sheets After complete dissolution E 180 LITHOLRUBINE BK CI Pigment Red 57, Rubinpigment, Carmine 6B Lithol Rubine BK consists essentially of calcium 3-hydroxy-4-(4-methyl-2-sulfonatophenylazo)-2-naphthalenecarboxylate and subsidiary colouring matters together with water, calcium chloride and/or calcium sulfate as the principal uncoloured components. Calcium 3-hydroxy-4-(4-methyl-2-sulfonatophenylazo)-2-naphthalene-carboxylate C18H12CaN2O6S E1 cm 1 % 200 at ca 442 nm in dimethylformamide Red powder Maximum in dimethylformamide at ca 442 nm 2-Amino-5-methylbenzenesulfonic acid, calcium salt 3-hydroxy-2-naphthalenecarboxylic acid, calcium salt Not more than 0,01 % (expressed as aniline) (1) Colour intensity is defined as the absorbance of a 0,1 % (w/v) solution of caramel colour solids in water in a 1 cm cell at 610 nm. (2) Expressed on equivalent colour basis i.e. is expressed in terms of a product having a colour intensity of 0,1 absorbance units. (3) Absorbance ratio of alcohol precipitate is defined as the absorbance of the precipitate at 280 nm divided by the absorbance at 560 nm (1 cm cell). (4) Benzene not more than 0,05 % v/v. ANNEX II Repealed Directive with list of its successive amendments (referred to in Article 2) Commission Directive 95/45/EC (OJ L 226, 22.9.1995, p. 1) Commission Directive 1999/75/EC (OJ L 206, 5.8.1999, p. 19) (OJ L 190, 12.7.2001, p. 14) (OJ L 82, 21.3.2006, p. 10) List of time-limits for transposition into national law Time-limit for transposition 95/45/EC 1 July 1996 (1) 1999/75/EC 1 April 2005 (2) (1) According to Article 2(2) of Directive 95/45/EC, products put on the market or labelled before 1 July 1996 which do not comply with that Directive may, however, be marketed until stocks are exhausted. (2) According to Article 3 of Directive 2004/47/EC, products on the market or labelled before 1 April 2005 which do not comply with that Directive may be marketed until stocks are exhausted. Correlation table Directive 95/45/EC This Directive Article 1, first paragraph Article 1, second paragraph
Rapid advances in our understanding of the molecular basis of cancer development and progression over the past three decades have led to the design of new potential cancer therapies. High throughput target validation and expression studies are expected to yield a powerful arsenal of new cancer treatments, but untangling the complex pathways underlying the major cancer phenotypes remains a significant challenge. A considerable body of evidence in recent years implicates deregulated expression of a single multi-component enzyme, telomerase, as a causative factor at the heart of immortalization in the vast majority of human tumors. This review highlights the potential of telomerase as a target for novel cancer therapies. The potential of exploiting the selectivity of the telomerase family of genes within cancer cells to develop gene therapy strategies is discussed, and the progress towards translating these novel therapeutics from the laboratory to the clinic is reviewed. Keith, W., Bilsland, A., Hardie, M., and Evans, T.
Stratification is a natural occurrence in deep lakes and reservoirs. This phenomenon results in two distinct layers, the warmer, less dense epilimnion on top and the colder, denser, hypolimnion on the bottom. The epilimnion remains saturated with dissolved oxygen (DO) from mass transfer with the atmosphere, while the hypolimnion continues to undergo oxygen-depleting processes. During seasons of high oxygen demand the hypolimnion often becomes anoxic and results in the release of compounds, such as Iron, Manganese, Hydrogen Sulfide, and Phosphorous from the sediment. Iron, Manganese, and Hydrogen Sulfide can require addition Chlorine for water treatment plants, thus increasing cost and the potential production of DBPâ s, while the release of phosphorous results in algal blooms the following year. Spring Hollow Reservoir, located in Roanoke County, Virginia is a deep reservoir that undergoes stratification during the summer months. During 1997 Roanoke County purchased a bubble-plume diffuser from Tennessee Valley Authority (TVA) to oxygenate the hypolimnion to maintain long-term water quality. Spring Hollow currently operates the diffuser, with compressed air, during late summer months when DO levels in the hypolimnion reach approximately 4 mg/L. Observations during oxygenation have identified changing DO addition rates during diffuser operation and changing DO depletion rates following termination of oxygenation. Future research should focus on developing a quantitative understanding of the changing rates as they are related to diffuser induced oxygen demand.
Interleukin-2 in Renal Cell Carcinoma: A Has-Been or a Still-Viable Option? Modulation of the immune response plays an important role in the natural history of renal cell carcinoma. Spontaneous regression of metastases has been well documented in a small percentage of patients after they undergo de-bulking nephrectomy without any additional systemic intervention. The only logical explanation for these observations is "resetting" of the balance between tumor and the host immune system that, having been overwhelmed by the tumor burden, is able to function better after tumor de-bulking. Attempts to modulate the activity of the immune system "on demand" have included the use of vaccines, cytokines/lymphokines, adoptive cell transfer, monoclonal antibodies and most recently manipulation of immune checkpoint inhibitors. Here we review the data for infusional interleukin-2 in the management of advanced renal cell carcinoma and its role in current clinical practice.
Alar adjustment is a surgical procedure that reduces flared or wide nostrils. The outer edges of the nostrils are called the ala. Alar adjustment is typically performed along with width reduction. The surgeon removes a portion of tissue to adjust the level of tension that is leading to the excessive nostril width. The Weir technique is a specialized alar adjustment approach that involves a specific incision type. The surgeon removes tissue to develop a wedge-shaped void and then sutures it to create desirable contours. Certain ethnic patients tend to have wide nostrils along with a nasal flare. African American patients usually have this type of nasal anatomy. Some patients feel that their wide and/or flared nostrils distract from other facial features. This can have an adverse effect on an individual's self-esteem. Board certified facial plastic and reconstructive surgeon Dr. Eric Yavrouian provides nose reshaping surgery to patients in Glendale, Pasadena, Burbank, Greater Los Angeles, Beverly Hills, CA, and surrounding locations. The surgeon will remove a wedge of tissue from the side of the nostrils near the junction with the cheek in a procedure known as alarplasty. The wedge base will at the level of the alar rims, and the pointed apex will be near the sides where the nose connects to the cheek groove. The amount of tissue removal will depend on the width of the nostrils. Many rhinoplasty surgeons and patients try to measure the change in mm narrowing on the frontal view. However, this can be challenging as the wedge size that is removed does not accurately reflect the frontal narrowing distance. The surgeon will explain to the patient whether they need a minor, medium, or dramatic change. Most patients want a medium change. Patients should understand that it is always possible to remove more tissue later on if they feel that their nostrils are still excessively wide. But the excision of substantial amounts of tissue is difficult to reverse. Some nose surgeons use a suturing technique to draw the walls in medially. However, this can lead to bunching. Yet other surgeons only place incisions within the nostrils from fear of external scarring. But this technique does not create dramatic changes. Incisions placed on the outside of the nose heal well and can be made inconspicuously adjacent to the alar groove. A skilled rhinoplasty surgeon will make this incision in the area where the nostrils connect to the cheeks. This allows the scar to remain discreet within the natural crease between these regions. Alarplasty, or nostril narrowing, is an effective procedure that offers dramatic results without the need for a full rhinoplasty. The patient will experience some discomfort and pain in the nose region along with inflammation and puffiness during the initial few days of the recovery phase. The pain will gradually subside in two to three days. However, the inflammation will take more time to resolve. Patients typically experience minor bleeding in the incision areas. This bleeding typically resolves in around two days. The swelling on the face starts to subside in around a week and should be completely resolved by two weeks. The patient will need to visit the office to have their bandages taken off in around three days after the procedure. The surgeon will typically remove stitches at the end of the first week. Facial plastic and reconstructive surgeon Dr. Eric Yavrouian receives patients from Glendale, Pasadena, Burbank, Greater Los Angeles, Beverly Hills, CA, and nearby areas for nose surgery.
Today is July 9th of 2013. I celebrated my first year of clean time and sobriety. I did today what I have been doing for some time now. I got up at 06:30 and walked 2.3 miles, made some oatmeal for breakfast, made some juice out of a selection of fruits. I went to the local 1:00pm meeting I secretary and went after to meet a new sponsee. After that I came home and took a mild nap beginning with some meditation and when I awoke, I went to the 6:00 "circle" meeting and after that, I came home and made salmon for dinner followed by a healthy dose of Juice Plus. What is missing is the integration of an intimate walk with a "higher power". I am unclear what prevents me from such a connection other than just plain ole doubt and lack of faith. I prayed with my new sponsee today and asked God to please bless our relationship as I walked him through the 12 steps and asked God to teach us how to honor him through the relationship by showing us how to live well and healthy. Today I take ½ the usual dose of blood pressure medicine I used to take and although I struggle in the mornings with anxiety, it is not necessary for me to take any drugs for it nor do I crave anything. During the day, I have minor bouts of anxiety and experience what I have come to know as "cog fog". My recovery of late is much different in that I am not in a constant state of terror and fear as my mind and body undergo what I now know is the healing process but what felt more like "the dread before the dead". Today I awake with anxiety that prevents me from sleeping in past the 06:00 hour but is settled down by a brisk 2.3 mile walk with my dog. During the day, I experience anxiety from time to time and some minor bouts of nausea and heart palpitations. During the mid-afternoon, I get fatigue, especially in the summer heat and have learned to minimize exertion and meditate for 10-30 minutes, usually leading to a short rejuvenate nap. Another walk in the early evening helps eliminate evening anxiety. I go to fewer meetings than in early recovery but try to go to 3-5 meetings a week, sharing AA, NA and CR meetings. Once a week, I go to biofeedback and once every two weeks or there about, I go to restorative yoga. Every day, I juice fruits and vegetable, eat oatmeal, yogurt, salmon or tuna, and a variety of other healthy foods. I try to drink plenty of water but should probably drink more than I do. I avoid caffeine, soft drinks, red meat, and processed foods for the most part but am more relaxed about this than early in my recovery. The first year of recovery was about surrendering, acceptance, humility and determination. It took a few years to come to a place of admitting I was addicted to comfort first and then drugs to help me deal with uncomfortable situations. I used benzodiazepines because I was convinced prior to surrendering, that I suffered from a physical malady misunderstood and misdiagnosed by family, friends and the medical community. I thought the physical malady was my body's response to previous traumas. My body became anxious, panicky, nauseated and subdued. The benzodiazepines at first, dampened the physical symptoms and minimized the psychological impact, what I refer now to as "psychobabble". My denial of addiction was so strong that two psychiatric hospital commitments and two treatment center visits could not convince me that the things my body was going through were not so much the impact of childhood trauma but were the effects of inter-dose and acute withdrawal from long term use of benzodiazepines. In June of 2012, I asked my wife to recommit me to a treatment center and although I had not yet surrendered, I knew I had to do something because the physical and psychological symptoms were so out of control, no amount of benzodiazepines seemed to help. I understood that I needed to get off these medications for a couple of years and tried to wean myself off of them but could never reduce my dose below two milligrams per day and most days towards the end of my addiction required "as needed" doses to get by. At the treatment center in June, I was still in the better part of denial, telling those who asked that I was suffering from physical issues like panic attacks and anxiety but in the same breath, I explained I needed to come off the benzodiazepines because I came to realize that they were not helping me anymore. The treatment center started me on five milligrams of Klonopin and reduced my dose one milligram per day for five days. Within three days of not taking Klonopin, I was in inter-dose withdrawal and found it necessary to go to the emergency room in extreme anxiety and with serious psychological and physical symptoms. The ER doctor ordered one milligram of Ativan the first visit and within several minutes, my symptoms subsided. Why I did not understand at this point the obvious nature of my addiction is beyond me, but back to the treatment center I went and within three days, I was back in ER suffering the same symptoms. This time the treatment center insisted that I refuse all hospital attempts to inject me with benzodiazepines. I asked the ER doctor what was happening to me. I had difficulty talking, putting my words together. I was shaking out of control and was stuttering. He explained to me that I was in acute withdrawal as a result of long term exposure to benzodiazepines. He told me I had several weeks of physical symptoms to endure and months of psychological symptoms to endure as well. He recommended I take a shot of Hydroxyzine (Benadryl, Atarax, or Vistiril) and go back to treatment. I did. For the next three days I went through the excruciating process of "kicking" as my body and mind, deprived of the drug I had been accustomed to taking for almost 15 years, retaliated. One of the most profound things I discovered as part of recovery is that the most severe symptoms of withdrawal did not appear until about 3 months out. What disturbs me about this is that treatment centers usually release their patients from inpatient treatment between one and three months. As it was in my case, when I needed the help the most, I did not have it and when I tried to call the treatment center, no help was available to me because as they explained it to me, I was no longer a patient of the treatment center. I also discovered during the half way point of my first year of recovery, the supplements I was taking, hoping they would help me get through withdrawal with less symptoms proved to be inconclusive. I am sure there are benefits to some supplements but I cannot say with certainty that any one supplement brought about a better withdrawal experience. In fact, as I discovered in later months, magnesium and or niacin actually precipitated more severe heart palpitations. I can say with some confidence that Juice Plus did in fact have positive results in my recovery as I saw in my monthly blood test results. My cholesterol, triglycerides and blood pressure all dropped as did my weight as I exercised and changed my diet which included a daily dose of Juice Plus. My cholesterol was 260 pre-treatment and dropped to 180. My blood pressure which hovered around 160/110 in my addiction dropped over time to 100/70. My weight dropped from 242 to average around 195. One significant occurrence I became aware of as the months went by in recovery is that the windows, periods of relief, became more the norm while waves, periods of symptoms, lessened in severity and occurred less frequently.
Effect of bambara groundnut supplementation on the physicochemical properties of rice flour and crackers. This study evaluated the effect of bambara groundnut supplementation on the physicochemical properties of local rice flour and baked crackers. Bulk and true density, porosity, water absorption index, oil absorption capacity, pasting properties by RVA, morphological appearance by SEM, color by calorimetry, and textural properties by TA.XT2 analysis of wheat and two formulations of rice-legume flours and crackers were studied. Moisture (10.94%) and carbohydrate (77.42%) levels were significantly greater in wheat flour than the rice-legume flours, while the reverse was true for fat and ash. Also rice-legume flours had significantly greater water and oil absorption capacity and lower water solubility compared to wheat flour. Compared to wheat crackers, rice-legume crackers had greater fat and ash, 20.51 and 3.57%, respectively, while moisture was significantly lower in the rice-legume crackers by 41 to 58%. Rice legume crackers were significantly harder and had significantly increased spread ratio. The results obtained from the development of locally grown rice and underutilized legume bambara groundnut showed great promise in physicochemical and functional properties and may be a good replacement for wheat flour to serve as a gluten-free product.
The list is endless and there are no simple answers. Obesity in America and living room technology are on the rise, while government funding for physical education is declining. The global outlook for large-scale physical activity is uncertain. It is well-known that a minimum of 30 minutes per day of moderate intensity exercise in children and adults is beneficial for health (JAMA, 1996). A recent review of 104 physical activity questionnaires and 1965 exercise items by Williams et al. (2012) found that no questionnaires covered all types of physical activity categories. This illustrates how categorizing exercise into a one-size-fits-all package is difficult and involves activity identification, quantification, multi-level analysis and evaluation. The answer for "How much exercise training is enough?" is therefore, "It depends." The amount depends on the population, activity, assessment instrument, and outcome criteria. For example, enjoyment of activities with family, friends, or at school requires up to a well-rounded amount. If the goal is to enjoy a sport, then a mild to moderate amount will do. To compete or be the best at a sport, and in particular a high power output sport, a higher-intensity risk-reward balance exists between success or failure (including injuries). If there is no exercise training then the enjoyment and performance of sport, physical activity and quality of life will decline, while elevating the risk of health-related diseases. If exercise is healthy and relatively inexpensive, then why are fewer Americans exercising? One possibility is that technology has replaced much of the physical activity at home, play and work. As the current generation of family role models grows and develops in a high-tech world, less emphasis is placed on physical activity with large muscle groups. More time with personal, social and occupational technology (e.g. computer, cell phone, texting, video games and television) burns fewer calories versus physical activity. A progressive reduction in calorie burning with technology use eventually leads to weight gain and a higher risk of obesity with related complications. One solution is to set, assess, and update achievable and progressive physical activity goals. An example would be a goal per day, then per week and beyond. A small achievable goal could be parking farther from the store for a 2 to 3 minute walk to the entrance. The second week could be the same accompanied by a brisk walk. Another would be walking or other exercise during the lunch hour followed by a glass of juice or water instead of no exercise, fast food and relaxing. Trimming the waistline, and improving zip in sport and daily activities, work production, and quality of life are achievable with minimal effort and expense in a technology world. Dr. William W. Edwards, PhD, is the Chair of Sports Exercise Science at the United States Sports Academy. He has competed in road races and triathlons for over 20 years and worked with K-12, adult fitness, high-risk, and rehabilitation populations. He can be reached at [email protected]. NIH Consensus Development Panel on Physical Activity and Cardiovascular Health (1996). Physical activity and cardiovascular health. JAMA, 276, 241–246. Williams, K., Frei, A., Vetsch, A., Dobbels, F., Puhan, M.A., & Rüdell, K. (2012). Patient-reported physical activity questionnaires: A systematic review of content and format. Health and Quality of Life Outcomes, 10 (28), 1-18.
Doppler left ventricular filling characteristics in hypertensive left ventricular hypertrophy Senior R., Sridhara BS., Bhattacharya S., Raftery EB., Lahiri A. Impaired left ventricular filling in presence of normal systolic function is known to cause heart failure in patients with hypertensive left ventricular hypertrophy. To evaluate which of the Doppler parameters best detect diastolic abnormalities, 24 patients with hypertension and left ventricular hypertrophy with mean ± SD blood pressures of 163 ± 17/102 ± 7 mm Hg and left ventricular mass 150 ± 26 g/m2 were compared with 14 age-and sex-matched normals. Compared to normal values, all Doppler left ventricular filling parameters were significantly altered in hypertensive patients with left ventricular hypertrophy, i.e. deceleration time of early velocity (146 ± 14 vs. 185 ± 34 ms, p < 0.0005), ratio of late (A) and early (E) peak filling velocities (0.74 ± 0.16 vs. 1.30 ± 0.40, p < 0.0001), ratio of the integrals of A and E (0.50 ± 0.16 vs. 0.90 ± 0.47, p < 0.01), and isovolumic relaxation period (74 ± 6 vs. 121 ± 20 ms, p < 0.0001), respectively. Acceleration time of the early filling velocity did not show any significant difference. Abnormal isovolumic relaxation period was found to be significantly (p < 0.005) more prevalent in this group of hypertensive patients compared to other left ventricular filling parameters. We conclude that isovolumic relaxation period is the most common abnormality in patients with hypertensive left ventricular hypertrophy compared to the other commonly used Doppler left ventricular filling parameters. American Journal of Noninvasive Cardiology
Cannabis Daily CBD Restricts Tumor Growth In Cancer Patients, Finds New Study By Terry Hacienda, The Fresh Toast on Jan 11, 2022 Published in Cannabis Daily "I am skeptical when it comes to CBD treating depression or anxiety or financial distress or marriage problems," he says. "That's probably not all true. But now that we have some basic science that supports this therapy I think it is really exciting." "Overall, our novel findings support the possible therapeutic role of inhaled CBD as an effective, relatively safe, and easy to administer treatment adjunct for GBM with significant impacts on the cellular and molecular signaling of TME (tumor microenvironment) warranting further research," the authors conclude. In October 2021, doctors in the U.K. released an article documenting an elderly woman in her 80's who was diagnosed with lung cancer. The case, which was published in BMJ Case Reports, details her medical history which included high blood pressure, chronic obstructive pulmonary disease, and osteoarthritis. The woman admitted to smoking over one pack of cigarettes a week, both before and after her diagnosis. By June and July of 2018, the doctors tested her using a PET scan, MRI, CT scan, as well as a biopsy. They diagnosed her with Stage IIB of non-small cell lung cancer (NSCLC). By September 2019, the chest CT scan was repeated, showing 2 new nodules in the upper right lobe and left apex. She declined surgery to remove the lobe because of risks, and also declined radiofrequency ablation due to the side effects suffered by her late husband from radiation therapy. By this time, she admitted to starting CBD oil treatment with 0.5 ML 3x per day orally, then twice daily, after she was diagnosed. The CBD oil supplier advised her not to take the CBD oil with hot drink or food to avoid the feeling of being stoned, and she also reported a reduction in appetite with CBD oil. Despite that, she didn't make any changes in her lifestyle or diet, and even continued smoking a pack of cigarettes a week. "We were definitely not expecting to see such a striking tumor regression with no conventional cancer treatments and no other health or lifestyle changes…. Multiple studies so far in animal models have shown conflicting results, and with some cases reducing cancer cell growth and others finding an accelerating growth of cancer cells," commented lead author Dr. Kah Ling Liew. Dr. Jack Jacoub, a medical director at the MemorialCare Cancer Institute at Orange Coast Medical Center, and a medical oncologist, told Medical News Today, "It's definitely hypothesis provoking, and additional research is needed before it could become a recommended treatment option for patients with cancer. From the strength of a scientific evidence standpoint, a case report is about the weakest strength, and so you have to consider what you're reading in that context." Using Cannabis Together With Other Cancer Therapies While more research is needed in this area, there are already several promising studies that point towards CBD being effective especially when used in complement with other conventional cancer therapies. Additionally, radiation and chemotherapy are notorious for its side effects, oftentimes bad enough to discourage patients to continue therapy and affecting survival rates. The most common side effects are loss of appetite and nausea, leading to weight loss. Many studies prove the efficacy of cannabis in mitigating these side effects; CBD can suppress the anxiety associated with having cancer or going to chemotherapy and radiation treatments, while THC can improve appetite. If you want to consider using CBD in conjunction with other therapies to beat tumors, the best guidance is to always do this with the supervision of your physician. This article originally appeared on Cannabis.net and has been reposted with permission. The Fresh Toast is a daily lifestyle platform with a side of cannabis. For more information, visit www.thefreshtoast.com. The Fresh Toast More Cannabis Daily Can You Use Cannabis As A Study Aid? Cannabis Daily / January 11, 2022 Using cannabis as a study aid may not be for everyone, as there will always be others who prefer to do so sober or with caffeine, but it's certainly much safer compared to ADHD drugs This article originally appeared ...Read More COVID-19 Vaccinations Quadruple After Quebec Requires Them For Weed Purchases Quebec's decision to ask for vaccine passports in order to purchase alcohol and cannabis has resulted in a significant surge in vaccination appointments. The solution for pushing reluctant people to get their COVID-19...Read More This Airport Could Become First In World To Open Marijuana Shop On Friday, the Prince George Airport Authority in British Columbia welcomed a new business partner, which is pioneering cannabis for travel. By Nina Zdinjak A cannabis dispensary at an airport? Could this be true? Little Known Supplies That Are Essential For Keeping Glass Accessories Clean After your glass accessories have been properly cleaned with these items, don't be surprised when they feel like entirely new devices! One of the most effective ways to consume cannabis from both an economic and an ...Read More You Got Way Too High - How Can You Bring It Down A Notch? If you find yourself with more THC than you bargained for, here's what can you do to come back down to earth. The holidays are the...Read More Kansas Democrats Unveil Plan To Put Marijuana Legalization On 2022 Ballot If approved in the legislature and then by voters in November, the laws would take effect in July 2023. By Nicolas Jose Rodriguez Kansas Democratic leaders announced on Thursday that they will be introducing proposals ...Read More Adults Who Use Marijuana And Have This Condition Are More Likely To Develop Stroke Complication Cannabis And Inflammation — What's The Connection? Why Smoking Weed Won't Protect You From COVID-19 What's Your Sweet Spot For Vaping? An Easy Guide To Mod Settings
ICE IT -- Place an ice pack or cold towels on your face – 15 minutes on, 15 minutes off – for the first 6-8 hours. DON'T TOUCH -- Keep tongue and fingers away from the extraction site. BLEEDING – Saliva will be slightly streaked with blood for 1-2 days. If abnormal bleeding occurs, place moist gauze pad over extraction site and bite down for 30-40 minutes. Tea bags also help stop bleeding: place teabag in hot water for one minute, then bite down on the teabag until the bleeding stops. DIET – A liquid or soft diet is recommended for 24 hours. Drink lots of fluids. SWELLING & STIFFNESS – Swelling and stiffness are normal after dental surgery. Apply ice packs or cold towels to reduce swelling. RINSE MOUTH – Do not rinse mouth until the day after extraction. Rinse mouth with warm salt water (1/2 teaspoon salt to a glass of warm water). Repeat several times daily. MEDICATION – After dental surgery, it is normal to experience discomfort. If medication is prescribed, take as directed. NO SMOKING – Do not smoke. If you do smoke, don't do it for 48 hours following surgery. STRAWS – Do not use a straw for 48 hours following surgery. VITAMIN C – It's true, it promotes healing! Take plenty of Vitamin C before and after your surgery. CONCERNS – Call our office 248-398-6046 if any undue symptoms develop and we will schedule an appointment for you.
Effects of dietary fat on gut microbiota and faecal metabolites, and their relationship with cardiometabolic risk factors: a 6-month randomised controlled-feeding trial Yi Wan1, Fenglei Wang1,2, Jihong Yuan3, Jie Li3, Dandan Jiang3, Jingjing Zhang4, Hao Li1, Ruoyi Wang1,2, Jun Tang1, Tao Huang5, Jusheng Zheng6, Andrew J Sinclair7, Jim Mann8, Duo Li1,9 1 Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China 2 Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, USA 3 No. 1 Department of Nutrition, Chinese People's Liberation Army General Hospital, Beijing, China 4 Department of Gastroenterology, School of Medicine, Zhejiang University, Hangzhou, China 5 Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China 6 Institute of Basic Medical Science, Westlake University, Hangzhou, China 7 Department of Nutrition, Dietetics and Food, Monash University, Melbourne, Australia 8 Department of Human Nutrition and Medicine, University of Otago, Otago, New Zealand 9 Institute of Nutrition and Health, Qingdao University, Qingdao, China Correspondence to Professor Duo Li, Institute of Nutrition and Health, Qingdao University, Qingdao 266071, China; duoli{at}qdu.edu.cn Objective To investigate whether diets differing in fat content alter the gut microbiota and faecal metabolomic profiles, and to determine their relationship with cardiometabolic risk factors in healthy adults whose diet is in a transition from a traditional low-fat diet to a diet high in fat and reduced in carbohydrate. Methods In a 6-month randomised controlled-feeding trial, 217 healthy young adults (aged 18–35 years; body mass index <28 kg/m2; 52% women) who completed the whole trial were included. All the foods were provided during the intervention period. The three isocaloric diets were: a lower-fat diet (fat 20% energy), a moderate-fat diet (fat 30% energy) and a higher-fat diet (fat 40% energy). The effects of the dietary interventions on the gut microbiota, faecal metabolomics and plasma inflammatory factors were investigated. Results The lower-fat diet was associated with increased α-diversity assessed by the Shannon index (p=0.03), increased abundance of Blautia (p=0.007) and Faecalibacterium (p=0.04), whereas the higher-fat diet was associated with increased Alistipes (p=0.04), Bacteroides (p<0.001) and decreased Faecalibacterium (p=0.04). The concentration of total short-chain fatty acids was significantly decreased in the higher-fat diet group in comparison with the other groups (p<0.001). The cometabolites p-cresol and indole, known to be associated with host metabolic disorders, were decreased in the lower-fat diet group. In addition, the higher-fat diet was associated with faecal enrichment in arachidonic acid and the lipopolysaccharide biosynthesis pathway as well as elevated plasma proinflammatory factors after the intervention. Conclusion Higher-fat consumption by healthy young adults whose diet is in a state of nutrition transition appeared to be associated with unfavourable changes in gut microbiota, faecal metabolomic profiles and plasma proinflammatory factors, which might confer adverse consequences for long-term health outcomes. Trial registration number NCT02355795; Results. intestinal microbiology gut inflammation What is already known on this subject? Rates of obesity and other cardiometabolic disorders in most developing countries have increased rapidly in parallel with a transition from the traditional lower-fat diet to a diet relatively high in fat but lower in carbohydrate. Gut microbiota dysbiosis has been shown to be associated with a high risk of obesity, type 2 diabetes and many other cardiometabolic diseases. Studies using rodent models suggest that a high-fat diet unbalances the gut microbiota and impairs the gut barrier, resulting in cardiometabolic diseases. Observational studies conducted in globally distinct human populations suggest that diet has a strong effect on the composition of gut microbiota and related faecal metabolomics, while evidence from dietary intervention studies suggests that the effect of diet on gut microbiota might be more modest. At the phylum level, the moderate-fat and higher-fat diets decreased the ratio of Firmicutes to Bacteroidetes after the intervention. At the genus level, the higher-fat diet decreased the abundance of Faecalibacterium, increased the abundance of Alistipes and Bacteroides, while the lower-fat diet increased the Faecalibacterium and Blautia abundance after the intervention. Concentration of faecal butyric acids was increased after the lower-fat diet intervention and decreased after the higher-fat diet intervention. The cometabolites p-cresol and indole were decreased after consumption of the lower-fat diet, while palmitic acid (C16:0), stearic acid (C18:0) and arachidonic acid were increased after the higher-fat diet consumption. Change in relative abundance of Blautia was negatively associated with the changes in serum total cholesterol, low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol, whereas the change in Bacteroides abundance was positively correlated with the changes in these three blood lipid markers. For circulating proinflammatory factors, the higher-fat diet was associated with increased plasma high sensitivity C-reactive protein and thromboxane B2 relative to the lower-fat diet, while leukotriene B4 and prostaglandin E2 in the lower-fat diet were decreased the most among the three diet groups. Our findings demonstrate that among healthy young adults whose diet is in a state of transition, a higher-fat diet had a notably unfavourable impact on gut microbial taxa, faecal metabolomic profiles and plasma proinflammatory biomarkers, whereas the lower-fat diet was associated with a more favourable profile of these biomarkers. These findings provide confirmatory evidence that nutritional guidelines in countries in a state of nutrition transition should advise against increasing intakes of dietary fat. The results might also have relevance in developed countries in which fat intake is already high. The parallel increases in dietary carbohydrate and the prevalence of obesity and type 2 diabetes (T2D) in the United States and some other Western countries have led to the suggestion that this dietary change, resulting from an increase in carbohydrate consumption and a reduction in total fat intake, might be a determinant of cardiometabolic disorders.1–3 By contrast in China, the nutritional transition from the traditional low-fat, high-carbohydrate diet to a diet relatively higher in fat and lower in carbohydrate has been associated with a dramatic increase in the risk of obesity, T2D and cardiovascular diseases in the past 30 years.4 5 We have previously shown in a randomised controlled-feeding trial that among healthy young adults, a lower-fat, higher-carbohydrate diet is likely to be associated with a lower risk of excessive weight gain and increase in waist circumference and a more favourable lipid profile than a higher-fat, lower-carbohydrate diet.6 There has been interest in the role of gut microbiota in the development of obesity and cardiometabolic diseases.7 Rodent studies have suggested that the high-fat Western-type diet has a strong effect on the genetic composition and metabolic activity of gut microbiota.8 9 Evidence has shown that in humans gut microbiota diversity and richness are reduced when comparing such high-fat diets with more traditional diets with relatively higher proportions of carbohydrate.10 11 Such diet-induced 'dysbiosis' in gut-associated microbial communities has been postulated as a major trigger of metabolic impairments associated with obesity.12 Much of the relevant existing literature on humans is based on observational studies and the relatively few short-term dietary intervention trials suggest that the effect of dietary change might be relatively modest.13–16 No information is available relating to healthy young people or to populations whose diet is in transition from that traditionally consumed to one associated with a high risk of cardiometabolic disease. Thus in a 6-month randomised controlled-feeding trial among healthy young adults, we compared a number of attributes of gut microbiota and faecal metabolomic profiles as well as markers of inflammation for diets of differing proportions of fat and carbohydrate. Study design and population This study investigated the gut microbiota, faecal metabolomic profiles response and their relationship with cardiometabolic risk factors in 217 healthy adults who had provided faecal samples in the Optimal Dietary Macronutrient Distribution in China trial.6 The trial was conducted at People's Liberation Army General Hospital in north China and Zhejiang University in south China and was approved by the ethics committees. Each participant provided written informed consent and received no financial compensation or gifts. The trial was registered at ClinicalTrials.gov, number NCT02355795. The primary aim of the trial was to determine whether the traditional lower-fat diet was more effective than a higher-fat diet at weight control among a healthy young population whose diet was in a state of nutrition transition. The study design, method and primary results have been described elsewhere.6 17 In brief, the trial involved screening 1145 potentially eligible adults in two centres from January 2015. The main inclusion criteria included body mass index <28 kg/m2, the lower cut-off point according to the Chinese obesity criteria. Key exclusion criteria were blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic, total cholesterol (TC) ≥6.19 mmol/L, low-density lipoprotein cholesterol (LDL-C) ≥4.12 mmol/L, fasting triglyceride ≥2.25 mmol/L and fasting glucose ≥6.11 mmol/L. Finally, 307 eligible participants were randomised (1:1:1) to one of three diets with differing proportions of dietary fat, stratified by study centre, age, sex and body mass index using a computer-generated random number list. After 6 months of controlled-feeding intervention, 245 participants (79.8%) completed the whole trial. Among them, a total of 217 participants who provided faecal samples at baseline and the end of the trial were included in the 16S rRNA sequencing. Additionally, 120 participants (n=40 in each diet group) with enough faecal samples after 16S rRNA sequencing were further included in the faecal metabolomic analysis. Study diets and intervention The three diets were isocaloric, the primary distinguishing feature being their fat and carbohydrate content. We achieved the required macronutrient distribution in the three diet groups by replacing a proportion of energy derived from carbohydrate (mainly white rice and wheat flour, the most consumed carbohydrate sources in Asia) with fats (mainly soybean oil, the most widely used edible oil in Asia). Otherwise, the menus for the three diet groups were almost identical. The intervention diets were a lower-fat diet (fat 20% and carbohydrate 66% energy, corresponding to the macronutrient distribution 30 years ago during which obesity was rare in China); a moderate-fat diet (fat 30% and carbohydrate 56% energy, comparable with current macronutrient intake in China and also the upper limit of fat intake recommended by the Chinese Nutrition Society) and a higher-fat diet (fat 40% and carbohydrate 46% energy, approximating the current consumption of Chinese residents of some megacities). Protein provided 14% energy in all three diets. In order to avoid an additional dietary variable, intake of dietary fibre on all the three diets was maintained at the baseline level of consumption, around 14 g/day. Details of the study diets are provided in the online supplementary table 1. Participants were provided with all of their food and most beverages throughout the intervention. During the controlled-feeding period, they were asked to complete a daily diary in which they recorded whether they had eaten all the study foods and provided a list of non-study foods eaten. Supplementary file 1 [gutjnl-2018-317609supp001.pdf] Blood specimen collection and assessment of proinflammatory factors Blood samples were collected by venepuncture after a 12-hour fast. Plasma and serum were centrifuged from the blood samples and immediately stored at −80°C for further analysis. Serum concentrations of clinical biomarkers, including lipid profiles, glucose and insulin, were measured as described previously.6 Plasma proinflammatory factor concentrations, including interleukin (IL)−1β, IL-6, IL-8, tumour necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), thromboxane B2 (TXB2) and leukotriene B4 (LTB4), were measured using ELISA kits (Cayman Chemical Co, Ann Arbour, Michigan, USA and MultiSciences Biotech Co, Hangzhou, China). In addition, high-sensitive C-reactive protein (hs-CRP) was measured by a latex-enhanced turbidimetric immunoassay method. All measurements were performed at the end of the study to minimise variability. 16S rRNA sequencing and measurement of faecal metabolomics Faecal samples were collected at baseline and the end of the 6-month intervention. Each faecal sample was snap frozen in liquid nitrogen within minutes of donation and then kept at −80°C. DNA was extracted from stool samples (200 mg) using QIAamp DNA Stool Mini Kit (Qiagen, Hilden, Germany) following the manufacturer's instructions, with additional homogenised steps in a bead beater (FastPrep, Thermo Electron Co, Boston, Massachusetts, USA). The V3-V4 hypervariable regions of the bacteria 16S rRNA gene were amplified with barcode-indexed primers 338F (5'-ACTCCTACGGGAGGCAGCAG-3') and 806R (5'-GGACTACHVGGGTWTCTAAT-3'). The purified amplicons were pooled in equimolar concentration and further paired-end sequencing was performed using an Illumina Miseq instrument (Illumina, San Diego, California, USA). Raw sequencing data have been deposited in the National Center for Biotechnology Information Sequence Read Archive database with accession number PRJNA480547. Targeted identification and measurement of faecal metabolomics were performed based on a validated method.18 Details of the 16S rRNA sequence data preparation and analysis as well as the quantitative measurement of faecal metabolomics are available in online supplementary materials. Descriptive statistics included crude comparison of demographic factors, clinical parameters and dietary intake among the three diet groups. Differences among diets for 6-month changes from baseline of proinflammatory markers were tested by analysis of variance or Kruskal-Wallis test based on whether the data were normally distributed. The α-diversity indices evaluating gut microbial community richness (the Ace and Chao1 estimators) and community diversity (the Shannon estimator) were calculated using Mothur.19 Principal coordinate analysis (PCoA) based on Bray-Curtis distance and permutational multivariate analysis of variance (PERMANOVA) were performed to compare the global microbiota composition before and after intervention in each group at phylum, genus and operational taxonomic unit (OTU) levels, respectively. Enterotypes were determined using the abundance of genus and OTUs separately using the methods suggested by Arumugam et al.20 In univariate analysis of gut microbiota and predicted Kyoto Encyclopaedia of Genes and Genomes (KEGG) biochemical pathways in each group, a paired t-test or a Wilcoxon matched-pairs test was adopted and p values were adjusted for multiple comparison using the Benjamini-Hochberg false discovery rate (FDR). Correlations between changes in cardiometabolic risk factors, including body weight, waist and lipid profiles selected based on the previous results,6 and changes in genus relative abundance, were calculated using Spearman's rank or Pearson's correlation depending on the distribution of the data. Orthogonal projection to latent structure-discriminant analysis (OPLS-DA) with unit variance scaling was performed to examine the overall microbial metabolites distribution before and after intervention in each group. The qualities of all OPLS-DA models were assessed with R2X (the total variation being explained by the model) and Q2 (denoting the predictability of the model). The significance of the models was further validated by cross-validation analysis of variance (CV-ANOVA). Univariate analysis was also conducted with p values adjusted for multiple testing by the Benjamini-Hochberg approach. Correlations between changes in faecal metabolites and changes in genus relative abundance, as well as proinflammatory markers were calculated by Spearman's rank test or Pearson's correlation test, when appropriate, in the full cohort. P values for the correlations between changes in faecal metabolites and changes in genus relative abundance were corrected for multiple comparisons. Analyses were also conducted to examine the difference in gut microbiota and faecal metabolomic profiles across groups. PCoA based on Bray-Curtis distance and PERMANOVA were performed to compare the global microbiota composition among the three groups at phylum, genus and OTU levels, at baseline and after intervention, respectively. OPLS-DA with unit variance scaling and CV-ANOVA were performed to examine the overall microbial metabolites distribution across the three groups at baseline and after intervention. For the significantly changed bacteria and faecal metabolites after FDR correction in each group, Wilcoxon test was further performed to compare the changes in values between the dietary groups. OPLS-DA and CV-ANOVA were performed with the software SIMCA-P +version 14.0, and all other statistical analyses were performed in R version 3.4. The main R packages used were 'ape' and 'vegan' for PCoA and PERMANOVA analyses and 'ade4' and 'clusterSim' for enterotype analysis. Characteristics of study participants No significant differences in anthropometric measurements or clinical parameters were observed among the three groups at baseline (n=217, table 1). Mean carbohydrate intake of the three groups was 55% energy at baseline and during the intervention period 67% energy in the lower-fat diet group, 57% energy in the moderate-fat diet group and 48% energy in the higher-fat diet group (online supplementary figure 1). Mean dietary fat consumption of the three groups was 32% at baseline, which changed to around 20%, 30% and 40% energy in the lower-fat diet group, moderate-fat diet group and higher-fat diet group, respectively, during the intervention period. Protein intake remained stable, at around 13–14% energy. After the 6-month controlled-feeding intervention, all groups lost weight, the reduction in the lower-fat diet group being significantly greater than in the higher-fat groups. Similarly, reduction in waist circumference, TC, high-density lipoprotein cholesterol (HDL-C), LDL-C and non-HDL-C for the lower-fat diet group were significantly greater than those observed in the higher-fat diet group. However, the change in ratio of TC to HDL-C among the groups did not differ significantly throughout the intervention period. Changes in anthropometric data and clinical parameters during the 6-month intervention among participants included in the gut microbiota study (n=217) are presented in online supplementary figure 2. Baseline characteristics of the participants included in the gut microbiota study (n=217) Effects of dietary interventions on gut microbiota The microbial community richness indicated by Ace and Chao1 estimators showed no significant changes among the three groups, whereas the community diversity estimated by the Shannon index was significantly increased in the lower-fat diet group relative to the higher-fat diet group (p=0.03) (figure 1A). No significant shift was observed on the three diets in the overall composition of the gut microbiota at phylum, genus and OTU levels as indicated by PERMANOVA analysis (figure 1B-D). Similarly, the enterotypes did not change significantly in any of the three groups (figure 2 and online supplementary figure 3). We further performed PCoA and PERMANOVA analyses among groups to investigate the potential differences at baseline and month 6. At phylum level, we observed no statistically significant differences among the three diet groups at baseline, but marginally significant differences at month 6 (p=0.08). However, at genus and OTU level, there were no significant differences among groups at baseline or month 6 (online supplementary figure 4). Univariate analysis at phylum level showed that the relative abundance of Bacteroidetes was significantly increased in the moderate-fat diet group after intervention (p=0.005 after FDR correction) (figure 3A). In the higher-fat diet group, the relative abundance of Firmicutes was decreased, while Bacteroidetes was increased after intervention (p<0.001 after FDR correction) (figure 3A). The ratio of Firmicutes to Bacteroidetes was significantly decreased in the moderate-fat and higher-fat diet group after intervention (p=0.004 for moderate fat diet group and p<0.001 for higher-fat diet group). Compared with the lower-fat diet, the higher-fat diet significantly increased the abundance of Bacteroidetes and decreased the abundance of the Firmicutes (all p<0.01, online supplementary figure 5). At genus level, the lower-fat diet resulted in a significant increase in relative abundance of Blautia (p=0.007) and Faecalibacterium (p=0.04) after the intervention; while the higher-fat diet led to a reduction in Faecalibacterium (p=0.04) and an increase in Alistipes (p=0.04) and Bacteroides (p<0.001), after FDR correction for multiple testing (figure 3B and online supplementary table 2). Compared with lower-fat diet, the higher-fat diet led to a significant decrease in Blautia and Faecalibacterium abundance, while there was a significant increase in the abundance of Alistipes and Bacteroides (all p<0.01, online supplementary figure 5). The change in relative abundance of Blautia was negatively associated with the changes in serum TC (r=−0.27, p<0.001), LDL-C (r=−0.26, p<0.001) and non-HDL-C (r=−0.24, p<0.001), whereas the change in Bacteroides was positively correlated with the changes in these three blood lipid markers (r=0.44, p<0.001 for TC; r=0.34, p<0.001 for LDL-C and r=0.40, p<0.001 for non-HDL-C, respectively) (figure 3C). No significant changes in KEGG database biochemical pathways were seen in the lower-fat and moderate-fat groups after intervention (online supplementary table 3). Among the nine most responding pathways (FDR corrected p<0.10) in the lower-fat group, lipopolysaccharide biosynthesis (ko00540) decreased to a notable degree (median fold change after intervention=0.75). In the higher-fat group, 29 pathways were identified as significantly responding to the higher-fat intervention after FDR correction (FDR corrected p<0.05). Among these, pathways with notable changes (median fold change after intervention ≤0.80 or ≥1.20) were steroid hormone biosynthesis (ko00140), lysosome pathway (ko04142), arachidonic acid metabolism (ko00590) and lipopolysaccharide biosynthesis (ko00540). All four pathways were significantly increased in the higher-fat group. Changes of global gut microbiota after intervention in each group. (A) α-Diversity at genus level estimated by Ace, Chao 1 and Shannon estimator. p<0.05, p<0.01. (B) Principal coordinate analysis (PCoA) score plots based on Bray-Curtis distance at phylum level. (C) PCoA score plots based on Bray-Curtis distance at genus level. (D) PCoA score plots based on Bray-Cutis distance at operational taxonomic unit (OTU) level. Clustering of gut microbiota into enterotypes at genus-level using Jensen-Shannon distance. (A) Two clusters exist most naturally in the dataset by the PAM method. The x-axis shows the cluster number, the y-axis shows the Calinski-Harabasz (CH) index. (B) Clustering of the first two principal components. (C) Relative abundance of bacterial taxa characteristic of each enterotype. Boxes represent the IQR and the line within represents the median. Whiskers denote the lowest and highest values within 1.5×IQR. (D) Proportions of enterotypes in each group before and after the intervention. No statistically significant changes were seen in each group before and after the intervention by χ2 tests. Analyses based on individual genera. (A) Changes of relative abundance of individual phylum before and after diet intervention. (B) Heatmap of the median fold changes in relative abundance of individual genera before and after the intervention. (C) Significant associations between changes in lipid profiles and changes in genus abundance as measured by the Spearman's correlations. p<0.01. FDR, false discovery rate. Effects of dietary interventions on faecal metabolomic profiles Significant shifts in the composition of faecal metabolites were observed after the lower-fat and higher-fat diets intervention (p=0.02 for lower-fat and p=0.01 for higher-fat diet) (figure 4A). Furthermore, no statistically significant differences were seen among groups at baseline (online supplementary figure 6). However, we observed significant differences among groups at month 6 (p=0.002, online supplementary figure 6). Further stratified analysis by metabolite categories showed that amino acid metabolites were significantly altered in the lower-fat group (p=0.001) and long-chain saturated fatty acids (with 14 or more carbons) were significantly altered in the higher-fat group (p<0.001) (online supplementary figure 7). In addition, total short-chain fatty acid (SCFAs) concentrations were significantly decreased in the higher-fat group, compared with other diet groups (p<0.001) (figure 4B). Individual metabolite analysis identified four significantly changed faecal metabolites, including three amino acid metabolites (p-cresol, indole and 3-indolepropionic acid) and one SCFA (butyric acid), in the lower-fat group after FDR correction (figure 4C and online supplementary table 4). Among these four metabolites, two were decreased (p-cresol and indole) and two were increased (3-indolepropionic acid and butyric acid). While in the higher-fat group, eight faecal metabolites including long-chain saturated fatty acids, SCFAs and amino acid metabolites were found to be significantly changed. Among them, three were decreased (butyric acid, valeric acid and ethylmethylacetic acid) and five were increased (indole, palmitic acid, stearic acid, arachidonic acid and indoleacetic acid). Compared with the lower-fat group, the higher-fat diet group significantly increased the faecal concentration of palmitic acid, stearic acid, arachidonic acid, indoleacetic acid, indole and p-cresol (all p<0.01), while significantly decreasing the faecal concentration of butyric acid, valeric acid and 3-indolepropionic acid (all p<0.05, online supplementary figure 8). Since arachidonic acid is the precursor of eicosanoids and other lipid mediators involved in the inflammation process, we specifically tested the correlation between changes in faecal arachidonic acid concentration and changes in plasma proinflammatory markers concentrations. The change in faecal concentration of arachidonic acid was found to be positively associated with the changes in plasma concentrations of PGE2 (r=0.35, p<0.001), TXB2 (r=0.28, p=0.002) and hs-CRP (r=0.20, p=0.03) (figure 4D). Additionally, Spearman correlation analysis showed that the change in Bacteroides was positively associated with the changes in palmitic acid (r=0.35, p=0.004), indole (r=0.39, p<0.001) and p-cresol (r=0.64, p<0.001); the change in Faecalibacterium was positively associated with the change in butyric acid (r=0.35, p=0.004); whereas the change in Ruminococcus was negatively associated with the change in p-cresol (r=0.32, p=0.01, figure 5). Faecal metabolomics changed after the intervention. (A) OPLS-DA score plots comparing the faecal metabolites before and after the intervention in each group. P values are evaluated by CV-ANOVA. (B) Faecal total short-chain fatty acids concentration before and after the intervention. p<0.05 and *p<0.01. (C) Heatmap of the median fold changes in faecal metabolite concentrations before and after the intervention. (D) Associations between change in faecal arachidonic acid concentration and changes in plasma proinflammatory marker levels. CV-ANOVA, cross-validation analysis of variance; FDR, false discovery rate; hs-CRP, high sensitivity C-reactive protein; IL, interleukin; LTB4, leukotriene B4; OPLS-DA, orthogonal projection to latent structure-discriminant analysis; PGE2, prostaglandin E2; TNF-α, tumour necrosis factor α; TXB2, thromboxane B2. Correlation between changes in faecal metabolites and changes in genus abundance. The heat-map shows the Spearman correlation coefficient between changes in faecal metabolite concentrations and changes in relative abundance of individual genera. The intensity of the colours represents the degree of association between changes in the concentration of faecal metabolites and changes in relative abundance of individual genera as measured by the Spearman's correlations. P values were corrected for multiple testing using the Benjamini-Hochberg false discovery rate. p<0.05, **p<0.01. TSCFA, total short-chain fatty acids. Effects of dietary interventions on inflammatory markers Plasma concentration of hs-CRP was significantly increased during the higher-fat diet intervention, compared with the moderate-fat (p for higher-fat vs moderate-fat <0.001) and lower-fat (p for higher-fat vs lower-fat <0.001) diet groups (table 2). Likewise, compared with the lower-fat diet, plasma concentration of the inflammatory mediators TXB2 was increased on the higher-fat diet (p for higher-fat vs lower-fat=0.02). Additionally, LTB4 and PGE2 were significantly decreased in the lower-fat diet group, when compared with moderate-fat diet group (p for lower-fat vs moderate-fat=0.006, 0.003, respectively) and higher-fat diet group (p for lower-fat vs higher-fat=0.02, <0.001, respectively). However, the changes in proinflammatory cytokines including IL-1β, IL-6, IL-8 and TNF-α showed no significant differences among the three groups after the 6-month diet intervention. Effects of dietary interventions on plasma proinflammatory markers (n=217) We believe that the present randomised, controlled-feeding trial, is the first study to investigate the effect of different proportions of dietary fat intake on gut microbiota, faecal metabolomic profiles and plasma inflammatory factors in healthy young adults drawn from a population whose diet is in a state of transition. The findings of our study suggest that although the three diets did not induce major changes of the global gut microbiota composition, the higher-fat diet had overall unfavourable effects on several important biomarkers, while the lower-fat diet with a macronutrient distribution corresponding to those consumed in China until some 30 years ago, appeared to have beneficial effects. Numerous rodent studies have reported that a high-fat diet might appreciably unbalance the gut microbiota composition.21 However, the effect of diet on the human gut is complex given the considerable individual variation in the response of the gut microbiota to dietary intervention.22 23 Our findings are in keeping with previous studies, which indicate that the overall structure of gut microbiota is principally influenced by long-term dietary intake.10 13–15 23 24 Short-term effects have mainly been reported in studies with small sample size,25 26 and characterised by extreme and unrealistic dietary intakes25 or when the subjects studied were at high cardiometabolic risk.27–29 A 10-day clinical trial with nine participants reported that the composition and function of the microbiota were rapidly changed when carbohydrates were eliminated from the diet, a dietary intervention which is neither sustainable nor desirable in the long term.25 In much more moderate dietary interventions that can be sustained in humans, high interindividual variations among subjects might have masked minor changes in distinct taxonomic groups.30 It has been reported that diet might have a greater influence on the metabolic activity of the gut microbiota than on its taxonomic composition.16 In accordance with this proposition, in our study diets differing in dietary fat content provoked a marked shift of faecal concentrations of metabolites produced by the gut microbiota. We found Blautia and Faecalibacterium, genera known to contain butyrate-producing bacteria, were increased in the lower-fat diet group. Blautia is a group of bacteria containing various acetate and butyrate producers and reported to have a lower relative abundance in patients with T2D than in healthy controls.31 32 Faecalibacterium contains anti-inflammatory and functionally important bacteria.33 Higher abundance of F. prausnitzii was associated with a reduction of systematic low-grade inflammation among obese subjects receiving bariatric surgery.34 Many previous studies have reported the benefits of dietary fibre on gut microbiota.35 In our study, the amount of carbohydrate was highest in the lower-fat diet group, mainly from white rice and wheat flour (bread). The proportion of resistant starch has been reported to be 3% in white rice and 2% in bread.36 37 Given that dietary fibre intake did not differ among the three groups, it is possible that the favourable effects of the lower-fat diet in our study might be due to the increased amount of resistant starch which can, like dietary fibre, be fermented by the gut microbiota, with associated health benefits. In contrast, the abundance of Faecalibacterium was decreased and Bacteroides and Alistipes were increased after the higher-fat diet intervention. Among the Chinese population, Bacteroides and Alistipes were found to be more abundant in patients with T2D than in subjects with normal glucose metabolism.38 These changes at genus level indicated that dietary fat content had a selective effect on the human gut microbiota, which might have clinical significance among healthy young adults. The higher-fat diet induced a reduction in faecal butyrate acid and SCFAs as opposed to the lower-fat diet group. This is probably due to the reduction in dietary carbohydrate intake.39 It has been suggested that the benefits of a 'healthy diet' are mediated via the anti-inflammatory effects of SCFAs and other bioactive compounds produced by the gut microbiota.40 Several observations in our study pointed towards an effect of gut microbiota-mediated proinflammatory factors. Among the individual genera which responded to the dietary intervention, the abundance of Faecalibacterium was directly related to the concentration of butyric acid, as suggested by the positive association between changes in butyrate concentration and the abundance of Faecalibacterium. A study using faecal microbiota transplantation from lean donors to insulin-resistant patients with metabolic syndrome demonstrated that faeces from lean subjects were associated with enhanced numbers of butyrate-producing bacteria and increased insulin sensitivity.41 In contrast, a significant reduction of dietary carbohydrates in omnivores led to much lower levels of faecal SCFAs and decreased bacterial numbers.39 The protective role of SCFAs against different types of disease is well documented; in particular, butyric acid can serve as the energy substrate for epithelial cells of the gut and confer anti-inflammatory effects.42 The reduction in SCFAs induced by the higher-fat diet was presumably detrimental for metabolic health. In addition to the reduction of SCFAs, the higher-fat diet induced significant alterations in long-chain fatty acids metabolism. The faecal concentrations of palmitic acid (C16:0) and stearic acid (C18:0) were significantly increased in the higher-fat group. Palmitic acid and stearic acid, the main saturated fatty acids, in food and tissues, have been considered to stimulate inflammatory signalling in macrophages, adipocytes, myocytes, hepatocytes, etc.43 Epidemiological studies showed that plasma phospholipid palmitic acid and stearic acid were positively associated with the incidence of T2D and cardiovascular diseases.44 Notably, the predicted lipopolysaccharide biosynthesis and arachidonic acid metabolism pathways were also increased in response to the higher-fat diet. Lipopolysaccharide is known to induce the release of arachidonic acid and its inflammation-involving metabolites, such as prostaglandins, thromboxane and leukotrienes.45 It should be noted that the intake of polyunsaturated fatty acids (PUFAs) was relatively high in the higher-fat diet group (24% of total energy) owing to exclusive use of soybean oil, which is rich in n-6 PUFA. A higher intake of n-6 PUFA has been reported to have proinflammatory effects.46 Consistent with the predicted pathway analysis, we found the faecal concentration of arachidonic acid (the precursor of proinflammatory compounds like PGE2, TXB2 and LTB4) was indeed increased in the higher-fat group. The positive association between changes in faecal arachidonic acid concentration and the changes in plasma levels of inflammatory makers—namely, PGE2 and TXB2, suggested a potential mechanism through which the amount of dietary fat consumption affects inflammation via gut microbiota. Interestingly, although the same amount and quality of protein was provided in each diet group, we found that the lower-fat diet group induced a significantly alteration in the amino acids metabolism, indicating enhanced protein degradation by the gut microbiota. The results reinforced the view that luminal substrate availability is also an important variable for fixing bacterial metabolite concentration.16 The lower-fat diet group induced reduction of faecal concentrations of indole and p-cresol, the host microbiota cometabolites derived from amino acids, while the higher-fat diet led to an increase in indole concentration. Indole is the precursor of indoxyl sulfate, which has been linked with hypertension and cardiovascular disease in people with chronic kidney disease.47 Likewise, p-cresol, the precursor of p-cresol sulfate, has been shown to act as an inhibitor of colonocyte oxygen consumption and as a genotoxic agent in vitro.48 Production rates of these potentially toxic compounds are found to be markedly lower in vegetarians than in people consuming an unrestricted diet.49 It has also been reported that bacterial diversity is higher among populations adopting a lower-fat diet like a vegetarian diet and can be modified through dietary intervention in obese subjects.50 It should be noted that the microbial α-diversity (indicated by the Shannon index) was increased in the lower-fat group compared with the higher-fat diet group. Increased diversity has been associated with improved health in the elderly, and reduction of gut microbial diversity has been linked to increased risk of gastrointestinal diseases and proinflammatory characteristics.14 51 Thus, in addition to increased SCFAs, our data suggest that the lower-fat diet can decrease the luminal concentration of these deleterious compounds while increasing the gut microbial α-diversity. Correlation analysis allowed us to identify several new bacterial genera potentially implicated in the host metabolic health. We observed negative associations of Blautia abundance with serum concentration of TC, LDL-C and non-HDL-C, whereas the opposite was seen for Bacteroides, a genus that we found to be increased after higher-fat consumption. A previous clinical trial reported that T2D and hyperlipidaemia patients were ameliorated by metformin and a herbal formula with increased abundance of Bautia, which was correlated significantly with the improvement in circulating glucose and lipids.52 Also, in line with a clinical trial in which Blautia was found to be negatively associated with TC and non-HDL-C, we observed similar negative associations between Blautia and blood lipid profiles.53 The enrichment of Blautia in the lower-fat group suggested that the diet-induced change in gut microbiota might be related to the host lipid homoeostasis in healthy young adults and possibly, be a future target for the management of subjects with cardiometabolic diseases. A limitation of this study was that faecal sampling was carried out only at baseline and at the end of the trial. A more complete picture of changes in gut microbiota would have been possible with more frequent sampling. In addition, all three groups lost weight and weight loss differed among groups after dietary intervention. Whether weight loss led to the changes in gut microbiota and faecal metabolomics or vice versa needs to be studied further. Another limitation relates to the generalisability of our study since our subjects were healthy young non-obese adults; the results might not apply to people at high risk of cardiometabolic diseases. The strengths of this study included the controlled-feeding design, the large sample size and the relatively long intervention period. In contrast to previous studies, we applied 16S rRNA amplicon profiling and quantitatively targeted bacterial metabolomics, which allowed us to understand both gut microbiota response and bacterial metabolites to gain more information about host–gut microbiota metabolic interactions in response to dietary fat content. In summary, compared with a lower-fat diet, long-term consumption of a higher-fat diet appears to be undesirable owing to changes in gut microbiota, faecal metabolomic profiles and proinflammatory factors for healthy young adults whose diet is in transition from the traditionally consumed lower fat, higher carbohydrate diet to one characterised by an appreciably higher fat content. These findings might also have relevance in developed countries in which fat intake is already high. We thank all the participants, the investigators, on-site staff, kitchen staff and all members of the Duo Li Laboratory for participating in scientific discussions about the manuscript. Austin GL , Ogden LG , Hill JO . Trends in carbohydrate, fat, and protein intakes and association with energy intake in normal-weight, overweight, and obese individuals: 1971-2006. Am J Clin Nutr 2011;93:836–43.doi:10.3945/ajcn.110.000141 Livesey G , Taylor R , Livesey H , et al . Is there a dose-response relation of dietary glycemic load to risk of type 2 diabetes? Meta-analysis of prospective cohort studies. Am J Clin Nutr 2013;97:584–96.doi:10.3945/ajcn.112.041467 Te Morenga L , Mallard S , Mann J . Dietary sugars and body weight: systematic review and meta-analyses of randomised controlled trials and cohort studies. BMJ 2012;346:e7492.doi:10.1136/bmj.e7492 Du SF , Wang HJ , Zhang B , et al . China in the period of transition from scarcity and extensive undernutrition to emerging nutrition-related non-communicable diseases, 1949-1992. Obes Rev 2014;15(Suppl 1):8–15.doi:10.1111/obr.12122 Zhai FY , Wang ZH , et al . Dynamics of the Chinese diet and the role of urbanicity, 1991-2011. Obesity Reviews 2014;15(Suppl. 1):16–26.doi:10.1111/obr.12124 Wan Y , Wang F , Yuan J , et al . Effects of macronutrient distribution on weight and related cardiometabolic profile in healthy non-obese chinese: a 6-month, randomized controlled-feeding trial. EBioMedicine 2017;22:200–7.doi:10.1016/j.ebiom.2017.06.017 Clemente JC , Ursell LK , Parfrey LW , et al . The impact of the gut microbiota on human health: an integrative view. Cell 2012;148:1258–70.doi:10.1016/j.cell.2012.01.035 Turnbaugh PJ , Ridaura VK , Faith JJ , et al . The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 2009;1:6ra14–14r.doi:10.1126/scitranslmed.3000322 Serino M , Luche E , Gres S , et al . Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut 2012;61:543–53.doi:10.1136/gutjnl-2011-301012 De Filippo C , Cavalieri D , Di Paola M , et al . Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A 2010;107:14691–6.doi:10.1073/pnas.1005963107 Ou J , Carbonero F , Zoetendal EG , et al . Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am J Clin Nutr 2013;98:111–20.doi:10.3945/ajcn.112.056689 Ley RE , Klein S , et al . Microbial ecology: human gut microbes associated with obesity. Nature 2006;444:1022–3.doi:10.1038/4441022a Wu GD , Chen J , Hoffmann C , et al . Linking long-term dietary patterns with gut microbial enterotypes. Science 2011;334:105–8.doi:10.1126/science.1208344 Claesson MJ , Jeffery IB , Conde S , et al . Gut microbiota composition correlates with diet and health in the elderly. Nature 2012;488:178–84.doi:10.1038/nature11319 Cotillard A , Kennedy SP , Kong LC , et al . Dietary intervention impact on gut microbial gene richness. Nature 2013;500:585–8.doi:10.1038/nature12480 Compher C , Chen EZ , et al . Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production. Gut 2016;65:63–72.doi:10.1136/gutjnl-2014-308209 . Optimal dietary macronutrient distribution in China (ODMDC): a randomised controlled-feeding trial protocol. Asia Pac J Clin Nutr 2017;26:972–80.doi:10.6133/apjcn.072017.06 Zhao L , Ni Y , Su M , et al . High throughput and quantitative measurement of microbial metabolome by gas chromatography/mass spectrometry using automated alkyl chloroformate derivatization. Anal Chem 2017;89:5565–77.doi:10.1021/acs.analchem.7b00660 Schloss PD , Westcott SL , Ryabin T , et al . Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol 2009;75:7537–41.doi:10.1128/AEM.01541-09 Arumugam M , Raes J , Pelletier E , et al . Enterotypes of the human gut microbiome. Nature 2011;473:174–80.doi:10.1038/nature09944 Murphy EA , Velazquez KT , Herbert KM . Influence of high-fat diet on gut microbiota: a driving force for chronic disease risk. Curr Opin Clin Nutr Metab Care 2015;18:515–20.doi:10.1097/MCO.0000000000000209 Walker AW , Ince J , Duncan SH , et al . Dominant and diet-responsive groups of bacteria within the human colonic microbiota. Isme J 2011;5:220–30.doi:10.1038/ismej.2010.118 Salonen A , Lahti L , Salojärvi J , et al . Impact of diet and individual variation on intestinal microbiota composition and fermentation products in obese men. Isme J 2014;8:2218–30.doi:10.1038/ismej.2014.63 Roager HM , Vogt JK , Kristensen M , et al . Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial. Gut 2019;68:83–93.doi:10.1136/gutjnl-2017-314786 David LA , Maurice CF , Carmody RN , et al . Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014;505:559–63.doi:10.1038/nature12820 Whisner CM , Martin BR , Nakatsu CH , et al . Soluble corn fiber increases calcium absorption associated with shifts in the gut microbiome: a randomized dose-response trial in free-living pubertal females. J Nutr 2016;146:1298–306.doi:10.3945/jn.115.227256 Xiao S , Fei N , Pang X , et al . A gut microbiota-targeted dietary intervention for amelioration of chronic inflammation underlying metabolic syndrome. FEMS Microbiol Ecol 2014;87:357–67.doi:10.1111/1574-6941.12228 Zhang C , Yin A , Li H , et al . Dietary modulation of gut microbiota contributes to alleviation of both genetic and simple obesity in children. EBioMedicine 2015;2:968–84.doi:10.1016/j.ebiom.2015.07.007 Xu J , Lian F , Zhao L , et al . Structural modulation of gut microbiota during alleviation of type 2 diabetes with a Chinese herbal formula. Isme J 2015;9:552–62.doi:10.1038/ismej.2014.177 Flint HJ , Scott KP , Louis P , et al . The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol 2012;9:577–89.doi:10.1038/nrgastro.2012.156 Park SK , Kim MS , Bae JW . Blautia faecis sp. nov., isolated from human faeces. Int J Syst Evol Microbiol 2013;63:599–603.doi:10.1099/ijs.0.036541-0 Inoue R , Ohue-Kitano R , Tsukahara T , et al . Prediction of functional profiles of gut microbiota from 16S rRNA metagenomic data provides a more robust evaluation of gut dysbiosis occurring in Japanese type 2 diabetic patients. J Clin Biochem Nutr 2017;61:217–21.doi:10.3164/jcbn.17-44 Pryde SE , Duncan SH , Hold GL , et al . The microbiology of butyrate formation in the human colon. FEMS Microbiol Lett 2002;217:133–9.doi:10.1111/j.1574-6968.2002.tb11467.x Furet JP , Kong LC , Tap J , et al . Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 2010;59:3049–57.doi:10.2337/db10-0253 Makki K , Deehan EC , Walter J , et al . The impact of dietary fiber on gut microbiota in host health and disease. Cell Host Microbe 2018;23:705–15.doi:10.1016/j.chom.2018.05.012 Yang CZ , Shu XL , Zhang LL , et al . Starch properties of mutant rice high in resistant starch. J Agric Food Chem 2006;54:523–8.doi:10.1021/jf0524123 Sajilata MG , Singhal RS , Kulkarni PR . Resistant starch? A review. Compr Rev Food Sci Food Saf 2006;5:1–17.doi:10.1111/j.1541-4337.2006.tb00076.x Qin J , Li Y , Cai Z , et al . A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012;490:55–60.doi:10.1038/nature11450 Belenguer A , Holtrop G , et al . Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces. Appl Environ Microbiol 2007;73:1073–8.doi:10.1128/AEM.02340-06 Fardet A . New hypotheses for the health-protective mechanisms of whole-grain cereals: what is beyond fibre? Nutr Res Rev 2010;23:65–134.doi:10.1017/S0954422410000041 Udayappan SD , Hartstra AV , Dallinga-Thie GM , et al . Intestinal microbiota and faecal transplantation as treatment modality for insulin resistance and type 2 diabetes mellitus. Clin Exp Immunol 2014;177:24–9.doi:10.1111/cei.12293 Ríos-Covián D , Ruas-Madiedo P , Margolles A , et al . Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol 2016;7:185.doi:10.3389/fmicb.2016.00185 Nguyen MT , Favelyukis S , Nguyen AK , et al . A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 2007;282:35279–92.doi:10.1074/jbc.M706762200 Fretts AM , Mozaffarian D , Siscovick DS , et al . Plasma phospholipid saturated fatty acids and incident atrial fibrillation: the Cardiovascular Health Study. J Am Heart Assoc 2014;3:e889.doi:10.1161/JAHA.114.000889 Shoeb M , Yadav UC , Srivastava SK , et al . Inhibition of aldose reductase prevents endotoxin-induced inflammation by regulating the arachidonic acid pathway in murine macrophages. Free Radic Biol Med 2011;51:1686–96.doi:10.1016/j.freeradbiomed.2011.07.024 Patterson E , Wall R , Fitzgerald GF , et al . Health implications of high dietary omega-6 polyunsaturated Fatty acids. J Nutr Metab 2012;2012:1–16.doi:10.1155/2012/539426 Barreto FC , Barreto DV , Liabeuf S , et al . Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 2009;4:1551–8.doi:10.2215/CJN.03980609 Andriamihaja M , Lan A , Beaumont M , et al . The deleterious metabolic and genotoxic effects of the bacterial metabolite p-cresol on colonic epithelial cells. Free Radic Biol Med 2015;85:219–27.doi:10.1016/j.freeradbiomed.2015.04.004 Patel KP , Luo FJ , Plummer NS , et al . The production of p-cresol sulfate and indoxyl sulfate in vegetarians versus omnivores. Clin J Am Soc Nephrol 2012;7:982–8.doi:10.2215/CJN.12491211 do Rosario VA , Fernandes R , Trindade EB . Vegetarian diets and gut microbiota: important shifts in markers of metabolism and cardiovascular disease. Nutr Rev 2016;74:444–54.doi:10.1093/nutrit/nuw012 Ott SJ , Musfeldt M , Wenderoth DF , et al . Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut 2004;53:685–93.doi:10.1136/gut.2003.025403 Tong X , Lian F , et al . Structural alteration of gut microbiota during the amelioration of human type 2 diabetes with hyperlipidemia by metformin and a traditional chinese herbal formula: a multicenter, randomized, open label clinical trial. MBio 2018;9:e2317–92.doi:10.1128/mBio.02392-17 Upadhyaya B , McCormack L , Fardin-Kia AR , et al . Impact of dietary resistant starch type 4 on human gut microbiota and immunometabolic functions. Sci Rep 2016;6:28797.doi:10.1038/srep28797 gutjnl-2018-317609.pdf YW and FW contributed equally. Contributors Conception and design of the study: DL, YW, and FW. Collection of data: JL, DJ, JY, JiZ, HL and RW. Analysis and interpretation of data: YW, FW, JT, TH and JuZ. Drafting of the manuscript: YW and FW. Critical revision of the manuscript for important intellectual content: AJS, JM, and DL. Administrative support and study supervision: DL and JY. All authors read, revised and approved the final draft. Funding This study was funded by the National Basic Research Program of China (2015CB553604) and China Postdoctoral Science Foundation (2018M642466). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. Patient consent Obtained. Ethics approval Institutional review board. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
Being physically active comes with a surplus of benefits that promotes productivity within the body and mind. In specific, physical activity can improve a child's overall way of life with autism spectrum disorder. Ranging from improved health benefits, to improving motor skills and overall functionality, staying active has the ability to make a difference in children's lives. According to the National Center for Biotechnology Information, the lack of leading an active lifestyle particularly leads children with ASD to have a higher exposure to screen related activities. Thus, such exposure can cause children to start away from physical activity. When it comes to the U.S. Department of Health and Human Services, they advise that children participate in fitness related activities for at least an hour to three hours a day, depending on their age. Despite this recommendation, it is particularly beneficial that children stay on the move as much as possible throughout the day. Aside from health complications such as cardiovascular diseases, children become exposed to an array of negative factors when they are not engaged in any or much exercise. Today, children are arguably spending a lot more time in front of a screen than ever before. Due to this, a child is more likely to watch television or spend their time on a digital device instead of being physically active. In particular, this rise in increased screen time can hinder a child on the spectrum by depleting them from social interactions where they can put their communication skills to practice. With this in mind, children with ASD may be more susceptible to senses of isolation if they are not active, as they tend to spend more time participating in independent activities. Furthermore, an increasingly high amount of stationary activities can cause children to avoid practicing their motor skills as a whole. Integrating fitness into a child's life on the spectrum has proven that it is able to enhance multiple aspects of their health. According to the Autism Research Institution, the integration of physical activity is capable of aiding mental health by showcasing an improvement in symptoms of anxiousness or high levels of stress, which can lead to another onset of problems in the future. Alongside these benefits, sleeping improvements are also an effect of physical activity. It has been proven that exercise leads to the production of melatonin; a chemical that is associated with the initiation of sleep. When a child is active throughout the day, they tend to use up more energy which may help them get a good night's rest and also help with their mood. Moreover, exercise is capable of enhancing a child's motor skills, which improves their quality of life at home and at school. Correspondingly, a combination of exercise at home and physiotherapy are a great way to focus on the improvement of motor skills on a deeper level. For example, sensory improvements can be achieved in the aspect of stabilizing coordination during activity and strengthening grasping skills with their hands. Through these acquisitions, children can learn to experience independence by gaining the skillset to do more things on their own without much difficulty. When it comes to promoting physical activity, parents or guardians may find it challenging to pinpoint where to start, or which activities suit their child best. In order to assess a more condensed and particular set of activities for a child with ASD, it is highly encouraged that a health care provider is involved in the process. It is important that each child is provided with different personalized options to stay active that work well with their abilities and level of participation. By involving a healthcare provider, the child will be able to engage in physical activity in ways that are tailored to their needs and capabilities without exposing them to activities that may be too difficult for them to partake in. Additionally, it should be noted that the physical activity plan should be structured in a manner that includes aerobic, muscle strengthening, and bone strengthening activities which work well with the child's limitations. Furthermore, an explorative review conducted by the University of California Santa Barbara noted that positive results are produced when a child is guided through activity with individualized attention. Likewise, using reinforcements can be an effective way of getting a child to participate during physical activity. A simple "good job!" or other encouraging phrases can give the child a sense of confidence to want to engage. In conclusion, the observation of multiple studies showed that profound levels of activity produced much more advanced results than those activities classified on the low-intensity scale. Although, it is important to begin at a level that is suitable for the child and then move forward with more advanced activities. "Autism Spectrum Disorder (ASD) and Sleep." Tuck Sleep, 10 May 2017, www.tuck.com/autism-spectrum-disorder-and-sleep/. Edelson, Stephen M. "Physical Exercise and Autism." DSM-V: What Changes May Mean \| Autism Research Institute, www.autism.com/treating_exercise. Lukas. "Children's Team Building on Green Grassland." Free Stock Photos, www.pexels.com/photo/action-activity-boy-children-296301/. Must, Aviva et al. "Barriers to Physical Activity in Children with Autism Spectrum Disorders: Relationship to Physical Activity and Screen Time" Journal of physical activity & health vol. 12,4 (2015): 529-34. Physical exercise and individuals with autism spectrum disorders: A systematic review. (2019). Santa Barbara, California: The Eli and Edythe L. Broad Asperger Research Center, University of California, pp.566-574.
Whitepaper: Structural variation in the human genome Structural variation accounts for much of the variation among human genomes. Structural variants of all types are known to cause Mendelian disease and contribute to complex disease. Learn how long-read sequencing is enabling detection of the full spectrum of structural variants to advance the study of human disease, evolution and genetic diversity. Webinar: Beginner's guide to PacBio SMRT Sequencing data analysis PacBio SMRT Sequencing is fast changing the genomics space with its long reads and high consensus sequence accuracy, providing the most comprehensive view of the genome and transcriptome. In this webinar, I will talk about the various data analysis tools available in PacBio's data analysis suite – SMRT Link – as well as 3rd party tools available. Key applications addressed in this talk are: Genome Assemblies, Structural Variant Analysis, Long Amplicon and Targeted Sequencing, Barcoding Strategies, Iso-Seq Analysis for Full-length Transcript Sequencing User Group Meeting: Improved assembly of segmental duplications using HiFi In this PacBio User Group Meeting presentation, Mitchell Vollger of the University of Washington used HiFi reads from SMRT Sequencing to study segmental duplications in the human genome. The technique significantly reduced the complexity of accurately mapping these nearly identical sequences throughout the genome; it also reduced the amount of compute power needed compared to a previous PacBio assembly using continuous long reads instead of circular consensus sequencing. Despite generating less data with the HiFi assembly, the team still resolved 30% more segmental duplications with the new approach. ASHG PacBio Workshop: Sequence with confidence – A new era of highly accurate long-read sequencing In this presentation, Emily Hatas of PacBio offers a look a how SMRT Sequencing has changed over the years as well as the most common applications in human genome analysis: high-throughput structural variant detection; comprehensive variant detection; and de novo assembly of reference genomes. Comprehensive variant detection in a human genome with PacBio high-fidelity reads Human genomic variations range in size from single nucleotide substitutions to large chromosomal rearrangements. Sequencing technologies tend to be optimized for detecting particular variant types and sizes. Short reads excel at detecting SNVs and small indels, while long or linked reads are typically used to detect larger structural variants or phase distant loci. Long reads are more easily mapped to repetitive regions, but tend to have lower per-base accuracy, making it difficult to call short variants. The PacBio Sequel System produces two main data types: long continuous reads (up to 100 kbp), generated by single passes over a long template,… Single molecule high-fidelity (HiFi) Sequencing with >10 kb libraries Recent improvements in sequencing chemistry and instrument performance combine to create a new PacBio data type, Single Molecule High-Fidelity reads (HiFi reads). Increased read length and improvement in library construction enables average read lengths of 10-20 kb with average sequence identity greater than 99% from raw single molecule reads. The resulting reads have the accuracy comparable to short read NGS but with 50-100 times longer read length. Here we benchmark the performance of this data type by sequencing and genotyping the Genome in a Bottle (GIAB) HG0002 human reference sample from the National Institute of Standards and Technology (NIST). We… High-quality human genomes achieved through HiFi sequence data and FALCON-Unzip assembly De novo assemblies of human genomes from accurate (85-90%), continuous long reads (CLR) now approach the human reference genome in contiguity, but the assembly base pair accuracy is typically below QV40 (99.99%), an order-of-magnitude lower than the standard for finished references. The base pair errors complicate downstream interpretation, particularly false positive indels that lead to false gene loss through frameshifts. PacBio HiFi sequence data, which are both long (>10 kb) and very accurate (>99.9%) at the individual sequence read level, enable a new paradigm in human genome assembly. Haploid human assemblies using HiFi data achieve similar contiguity to those using… Single Molecule Real-Time (SMRT) Sequencing of genes implicated in autosomal recessive diseases. In today's clinical diagnostic laboratories, the detection of the disease causing mutations is either done through genotyping or Sanger sequencing. Whether done singly or in a multiplex assay, genotyping works only if the exact molecular change is known. Sanger sequencing is the gold standard method that captures both known and novel molecular changes in the disease gene of interest. Most clinical Sanger sequencing assays involve PCR-amplifying the coding sequences of the disease target gene followed by bi-directional sequencing of the amplified products. Therefore for every patient sample, one generates multiple amplicons singly and each amplicon leads to two separate sequencing… High-throughput analysis of full-length proviral HIV-1 genomes from PBMCs. Background: HIV-1 proviruses in peripheral blood mononuclear cells (PBMCs) are felt to be an important reservoir of HIV-1 infection. Given that this pool represents an archival library, it can be used to study virus evolution and CD4+ T cell survival. Accurate study of this pool is burdened by difficulties encountered in sequencing a full-length proviral genome, typically accomplished by assembling overlapping pieces and imputing the full genome. Methodology: Cryopreserved PBMCs collected from a total of 8 HIV+ patients from 1997-2001 were used for genomic DNA extraction. Patients had been receiving cART for 2-8 years at the time samples were obtained.… New discoveries from closing Salmonella genomes using Pacific Biosciences continuous long reads. The newer hierarchical genome assembly process (HGAP) performs de novo assembly using data from a single PacBio long insert library. To assess the benefits of this method, DNA from several Salmonella enterica serovars was isolated from a pure culture. Genome sequencing was performed using Pacific Biosciences RS sequencing technology. The HGAP process enabled us to close sixteen Salmonella subsp. enterica genomes and their associated mobile elements: The ten serotypes include: Salmonella enterica subsp. enterica serovar Enteritidis (S. Enteritidis) S. Bareilly, S. Heidelberg, S. Cubana, S. Javiana and S. Typhimurium, S. Newport, S. Montevideo, S. Agona, and S. Tennessee. In addition,… Unique haplotype structure determination in human genome using Single Molecule, Real-Time (SMRT) Sequencing of targeted full-length fosmids. Determination of unique individual haplotypes is an essential first step toward understanding how identical genotypes having different phases lead to different biological interpretations of function, phenotype, and disease. Genome-wide methods for identifying individual genetic variation have been limited in their ability to acquire phased, extended, and complete genomic sequences that are long enough to assemble haplotypes with high confidence. We explore a recombineering approach for isolation and sequencing of a tiling of targeted fosmids to capture interesting regions from human genome. Each individual fosmid contains large genomic fragments (~35?kb) that are sequenced with long-read SMRT technology to generate contiguous long… An interactive workflow for the analysis of contigs from the metagenomic shotgun assembly of SMRT Sequencing data. The data throughput of next-generation sequencing allows whole microbial communities to be analyzed using a shotgun sequencing approach. Because a key task in taking advantage of these data is the ability to cluster reads that belong to the same member in a community, single-molecule long reads of up to 30 kb from SMRT Sequencing provide a unique capability in identifying those relationships and pave the way towards finished assemblies of community members. Long reads become even more valuable as samples get more complex with lower intra-species variation, a larger number of closely related species, or high intra-species variation. Here we… A comparison of assemblers and strategies for complex, large-genome sequencing with PacBio long reads. PacBio sequencing holds promise for addressing large-genome complexities, such as long, highly repetitive, low-complexity regions and duplication events that are difficult to resolve with short-read technologies. Several strategies, with varying outcomes, are available for de novo sequencing and assembling of larger genomes. Using a diploid fungal genome, estimated to be ~80 Mb in size, as the basis dataset for comparison, we highlight assembly options when using only PacBio sequencing or a combined strategy leveraging data sets from multiple sequencing technologies. Data generated from SMRT Sequencing was subjected to assembly using different large-genome assemblers, and comparisons of the results will be… Resolving KIR genotypes and haplotypes simultaneously using Single Molecule, Real-Time Sequencing The killer immunoglobulin-like receptors (KIR) genes belong to the immunoglobulin superfamily and are widely studied due to the critical role they play in coordinating the innate immune response to infection and disease. Highly accurate, contiguous, long reads, like those generated by SMRT Sequencing, when combined with target-enrichment protocols, provide a straightforward strategy for generating complete de novo assembled KIR haplotypes. We have explored two different methods to capture the KIR region; one applying the use of fosmid clones and one using Nimblegen capture. RNA sequencing: the teenage years. Over the past decade, RNA sequencing (RNA-seq) has become an indispensable tool for transcriptome-wide analysis of differential gene expression and differential splicing of mRNAs. However, as next-generation sequencing technologies have developed, so too has RNA-seq. Now, RNA-seq methods are available for studying many different aspects of RNA biology, including single-cell gene expression, translation (the translatome) and RNA structure (the structurome). Exciting new applications are being explored, such as spatial transcriptomics (spatialomics). Together with new long-read and direct RNA-seq technologies and better computational tools for data analysis, innovations in RNA-seq are contributing to a fuller understanding of RNA biology, from questions…
Hope this offer letter will receive you in your good health & spirit….. A couple of hours drive from Goa & almost 10 km before the powerful world famous Amrit Balaji temple, nestled amidst the quiet and peaceful area, lies Naturoveda Health & Naturopathy resort which takes a holistic approach to your well being, combine ancient therapies to encompass mind, body & spirit. From Nature cure treatment, to weight loss, stress reduction or pure pampering, guests are assured of a comfortable stay within our beautiful stress relieving environment. NaturoVeda offers a variety of nature care drug free treatments such as Naturopathy, Yoga, Ayurveda which address various ailments like Respiratory, Digestive, Metabolic, Cardiovascular, Neuro, Muscular Skeletal, Hormonal, Gynecological, stress, Diabetes, Hyper tension, paralysis & Sinusities along with common dilemma like Sleeplessness, Depression, Anxiety, Fat Analysis & Weight loss etc. While you are there, relax by swinging in Vrindawan lawns jhullas with peacock around you or explore the activities or simply pamper yourself with natural beauty and surrounding. We have combined the pleasure of good health & business with your moments of leisure. Please find our charges hereunder for your necessary action. For Detoxification / Rejuvenation Plan, we prefer minimum 7 days stays and it can be extended as per your choice, subject to availability. The above rates are inclusive of Comprehensive NATUROPATY & YOGA TREATMENT ( Jal Neti, Sutra Neti, Yogic Exercises/ Pranayam, Mud Patti, Mud Bath, Anema, Oil Massages, Powder Massages, Steam Bath, Water Sprinkler and much more……) under expert guidance. It is inclusive of regular Health Meals (Sprout / Juices /Lunch / Dinner ) also. We hereby offer you 40% Special Discount on above charges. One time Doctor's Consultation /Regn fee of Rs 2000/- per person is also applicable. You are required to deposit the requisite amount in the accounts detail given hereunder and intimate us to confirm your booking to our "NaturoVeda Naturopathy & Health Research Centre". In anticipation of your prompt response. 1) We book against payment of full basic charges. Amount to be deposited in bank account of " Naturoveda Private Limited, SBI, Mumba Branch, A/c No – 123456789124, IFC Code – SBIN0012345678. 2) Management reserves all the rights of booking & cancellation. 3) Please check the availability of dates from us before making your final plan to visit NaturoVeda. 4) Only those who are seriously interested in purification of soul , mind & body take the admission. Bookings once made cannot be cancelled. Dates can be adjusted on request of client at the discretion of management. 5) It is a centre for overall growth and relaxation of body through Naturopaty treatment, Yoga, Meditation, Pranayam, Vedic Treatment. Any critically / terminally ill patients should not take admission by suppressing their medical facts. Results of treatment is subjective and majorly depends on the cooperation, willingness & interest of the patients during their stay with us. 6) Any special treatment, if required / desired, will be charged extra with the prior approval of the client. 7) This offer letter is valid for 7 days from the date of this letter. 8) Credit Cards / Debit Cards are not accepted.
Does Vitamin D work on Covid after all? Israeli study finds nutrient big indicator of severity When? June 2021. By who? McGill University in Canada. What did scientists study? Genetic variants strongly associated with increased vitamin D levels in more than 4,000 people who were diagnosed with Covid and more than 1.2million uninfected people from 11 countries. What did they find? There was no evidence linking high vitamin D levels and a lower risk of contracting Covid. And among those who tested positive, there was no association between higher vitamin D and a lower likelihood of being hospitalised or becoming severely ill. What were the study's limitations? The study did not include individuals with vitamin D deficiency, so does not cover whether deficient patients could benefit. When? March 2021. By who? The University of Chicago. What did scientists study? The vitamin D levels for more than 3,000 people in Chicago and whether this increased their risk of catching Covid. What did they find? 30 ng/ml of vitamin D in the blood is usually considered sufficient. But Black people who had less than 40 ng/ml were 2.64 times more likely to test positive compared to those with levels more than 40 ng/ml. No statistically significant link was found between vitamin D levels and infection risk in white people. What were the study's limitations? It is unclear how vitamin D supports immune function and is only observational, so cannot determine that low vitamin D causes the increased risk of infection. When? December 2020. By who? King's College London. What did scientists study? 372,720 users of the Covid Symptom Study app in the UK, who had reported what supplements they were taking at the start of the pandemic. What did they find? Women taking vitamin D, multi-vitamins, omega-3 or probiotics appeared to be between nine and 14 per cent less likely to get Covid-19. This means that, if the average risk of getting Covid was one in 10, those taking supplements could see their risk fall to around one in 12. What were the study's limitations? Scientists were very unsure of the results and said the study did not prove that the pills actually protected women, but may have been a sign of generally healthier lifestyles. The expert who led the study said people shouldn't start trying to protect themselves with vitamins. When? October 2020. By who? University of Cantabria in Spain. What did the scientists study? 116 Covid patients at the Valdecilla Hospital What did they find? Eighty-two per cent were deficient in vitamin D, whereas just 18 per cent had adequate levels of the nutrient – a fourfold difference. This was compared to the 47 per cent of people who were deficient in a control group who did not have the infection. What were the study's limitations? The research does not prove that deficiency led to them falling ill enough to need hospital care. When? September 2020. By who? Cordoba University in Spain. What did scientists study? 50 Covid-19 hospital patients with Covid-19 were given vitamin D. Their health outcomes were compared with 26 volunteers in a control group who were not given the tablets. What did they find? Only one of the 50 patients needed intensive care and none died. Half of 26 virus sufferers who did not take vitamin D were later admitted to intensive care and two died. What were the study's limitations? Small pool of volunteers. Patients' vitamin D levels were not checked before admission. Comorbidities were not taken into consideration. By Who? University of Chicago. What did scientists study? 500 Americans' vitamin D levels were tested. Researchers then compared volunteers' levels with how many caught coronavirus. What did they find? 60 per cent higher rates of Covid-19 among people with low levels of the 'sunshine vitamin'. What were the study's limitations? Researchers did not check for other compounding factors. Unclear whether or not volunteers were vitamin D deficient at the time of their coronavirus tests. People's age, job and where they lived – factors which greatly increase the chance of contracting the virus – were not considered. By Who? Tehran University, in Iran, and Boston University. What did scientists study? Analysed data from 235 hospitalized patients with Covid-19. What did they find? Patients who had sufficient vitamin D – of at least 30 ng/mL— were 51.5 per cent less likely to die from the disease. They also had a significantly lower risk of falling seriously ill or needing ventilation. Patients who had plenty of the nutrient also had less inflammation – often a deadly side effect of Covid-19. What were the study's limitations? Confounding factors, such as smoking, and social economic status were not recorded for all patients and could have an impact on illness severity. When? July 2020. By Who? Tel Aviv University, Israel. What did scientists study? 782 people who tested positive for coronavirus had their vitamin d levels prior to infection assessed retrospectively and compared to healthy people. What did they find? People with vitamin D levels below 30 ng/ml – optimal – were 45 per cent more likely to test positive and 95 per cent more likely to be hospitalised. What were the study's limitations? Did not look at underlying health conditions and did not check vitamin D levels at the time of infection. By Who? Brussels Free University. What did scientists study? Compared vitamin D levels in almost 200 Covid-19 hospital patients with a control group of more than 2,000 healthy people. What did they find? Men who were hospitalised with the infection were significantly more likely to have a vitamin D deficiency than healthy men of the same age. Deficiency rates were 67 per cent in the COVID-19 patient group, and 49 per cent in the control group. The same was not found for women. What were the study's limitations? Independent scientists say blood vitamin D levels go down when people develop serious illness, which the study did not take into consideration. This suggests that it is the illness that is leading to lower blood vitamin D levels in this study, and not the other way around. By who? Inha University in Incheon, South Korea. What did scientists study? 50 hospital patients with Covid-19 were checked for levels of all vital vitamins and compared to a control group. What did they find? 76 per cent of them were deficient in vitamin D, and a severe vitamin D deficiency (<10 ng/dl) was found in 24 per cent of Covid-19 patients and just 7 per cent in the control group. Small sample size and researchers never accounted for vitamin levels dropping when they fall ill. By Who? Independent scientists in Indonesia. What did scientists study? Checked vitamin D levels in 780 Covid-19 hospital patients. What did they find? Almost 99% of patients who died had vitamin D deficiency. Of patients with vitamin D levels higher than 30 ng/ml – considered optimal – only per cent died. What were the study's limitations? It was not peer-reviewed by fellow scientists, a process that often uncovers flaws in studies. When? May 2020. By Who? University of Glasgow. What did scientists study? Vitamin D levels in 449 people from the UK Biobank who had confirmed Covid-19 infection. What did they find? Vitamin D deficiency was associated with an increased risk in infection – but not after adjustment for con-founders such as ethnicity. It led to the team to conclude their 'findings do not support a potential link between vitamin D concentrations and risk of Covid-19 infection.' What were the study's limitations? Vitamin D levels were taken 10 to 14 years beforehand. By Who? University of East Anglia. What did scientists study? Average levels of vitamin D in populations of 20 European countries were compared with Covid-19 infection and death rates at the time. What did they find? The mean level of vitamin D in each country was 'strongly associated' with higher levels of Covid-19 cases and deaths. The authors said at the time: 'The most vulnerable group of population for Covid-19 is also the one that has the most deficit in vitamin D.' What were the study's limitations? The number of cases in each country was affected by the number of tests performed, as well as the different measures taken by each country to prevent the spread of infection. And it only looked at correlation, not causation. By Who? Northwestern University. What did scientists study? Crunched data from dozens of studies around the world that included vitamin D levels among Covid-19 patients. What did they find? Patients with a severe deficiency are twice as likely to experience major complications and die. What were the study's limitations? 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