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Clinical Science | October 1998
A Multi-center Study of Intrathecal Neostigmine for Analgesia following Vaginal Hysterectomy
Gabriela R. Lauretti, MD, MSc, PhD; David D. Hood, MD; James C. Eisenach, MD; Ben L. Pfeifer, MD, PhD
(Lauretti) Assistant Professor, Discipline of Anesthesiology, Department of Surgery, Orthopedics and Traumatology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
(Hood) Associate Professor, Department of Anesthesiology, Wake Forest University School of Medicine.
(Eisenach) Professor and Francis M. James, III, Chair for Anesthesiology Research, Wake Forest University School of Medicine and Bowman Gray School of Medicine.
(Pfeifer) Director of Clinical Research, Department of Anesthesiology, University of Kentucky.
Anesthesiology 10 1998, Vol.89, 913-918. doi:
INTRATHECAL injection of neostigmine produces analgesia in animals, [1] human volunteers, [2] and patients with acute postoperative [3] and chronic [4] pain. Human volunteers achieve dose-dependent analgesia from doses more than 100 [micro sign]g. [2] Intrathecal neostigmine probably produces analgesia by inhibiting the breakdown of spinally released acetylcholine, and spinal acetylcholine release is increased in the presence of pain. [5] As a result, it might be expected that the potency of intrathecal neostigmine will increase in the postoperative period, and this was observed in animals. [6]
Few dose-response data exist for intrathecal neostigmine for postoperative analgesia. Intrathecal neostigmine, at a dose of 50 [micro sign]g, produced no postoperative analgesia compared with placebo in women undergoing vaginoplasty in one study, [7] whereas 100 [micro sign]g was more effective than placebo in another study. [8] A dose-response study in women undergoing vaginoplasty showed prolongation of time-to-first-rescue medication after 200 [micro sign]g, but not after 100 or 50 [micro sign]g neostigmine. [3] That study, however, included only six patients per group, and the resultant low statistical power may explain the lack of a statistically significant effect of 100 and 50 [micro sign]g neostigmine, despite the two- and fivefold increases in the mean time-to-first- rescue medication observed. A larger study with 15 patients per group showed a dose-independent reduction in morphine use after administration of 25, 50, and 100 [micro sign]g intrathecal neostigmine compared with a control after lower-extremity orthopedic surgery. [9] The primary purpose of the current study was to determine, using a multiple-institution study design with more than 20 patients per group, whether small doses of intrathecal neostigmine (25, 50, and 75 [micro sign]g) produce dose-dependent analgesia in patients after surgery.
The study protocol was approved by the human investigation committees of Wake Forest University School of Medicine (Coordinating Center), the University of Sao Paulo, and the University of Kentucky. After giving informed consent, 92 women classified as physical status 1 or 2 by the American Society of Anesthesiologists who were scheduled for total vaginal hysterectomy during spinal anesthesia were studied at the three university centers. Women older than 70 yr; those with known hypersensitivity to bupivacaine, neostigmine, propofol, or morphine; those with bradyarrhythmia; and those unable to understand the consent process or the use of the patient-controlled analgesia device were excluded.
The study was performed in a prospective, randomized, double-blind, placebo-controlled manner. Investigators at the coordinating center prospectively assigned neostigmine group quotas based on a computer-generated randomized balanced design and the anticipated availability of potential study patients. The number of patients observed was determined previously to be adequate to show a 25% linear dose-dependent reduction in morphine use (highest dose compared with placebo), an increase in the percentage incidence of nausea after surgery from 10% for placebo to 40% at the highest dose, a reduction in visual analog pain score (VAS) of 1.8 cm, and an increase in the VAS nausea score by 2 cm.
No premedication was administered on the night before surgery, although benzodiazepine was not discontinued in any patients who were routinely receiving it at night. The concept of a VAS, which consisted of a 10-cm line, with 0 signifying "no nausea" or "no pain at all" and 10 representing "the worst possible nausea or vomiting" or "the worst possible pain," was introduced the day before surgery. On the day of surgery, an intravenous catheter was inserted, and midazolam, up to 4 mg in 0.5-mg increments, was administered intravenously in the holding room as needed for anxiolytic' purposes. Lactated Ringer's solution, 15 ml/kg, was infused over 30-60 min before intrathecal drug injection. Lumbar puncture was performed in the operating room with the patient in the lateral decubitus position, using either a 25- or 27-gauge Whitacre needle at the L3-L4 or L4-L5 interspace. After free flow of clear cerebrospinal fluid was obtained, the study solution was injected, with the needle orifice facing the ceiling. The final volume of 3 ml was injected at 1 ml per 10 s. Patients received 2 ml bupivacaine, 0.75%, in dextrose plus either 1 ml saline or an equal volume of saline containing 25, 50, or 75 [micro sign]g neostigmine. The neostigmine study solution was prepared immediately before lumbar puncture by a local anesthesiologist who was not involved in the study, and the investigator (blinded to the study solution content) added this 1 ml of solution to the bupivacaine solution. All centers used the same preparation of neostigmine (IMS Ltd, El Monte, CA). Patients were positioned supine immediately after injection and in the lithotomy position within 15 min of spinal injection. After adequate sensory blockade from spinal bupivacaine was established, all patients received propofol by constant intravenous infusion that was titrated to deep sedation during surgery.
Sensory level to pinprick was assessed every 5 min for 15 min after spinal injection, when patients arrived in the recovery room, and every 30 min until discharge. At these times in the recovery room, motor strength in the lower extremities were assessed by a four-point scale (0 = able to move normally, 1 = subjective weakness, 2 = able to move feet but not flex knees, 3 = unable to move lower extremities). Blood pressure was monitored noninvasively every 5 min during surgery, and heart rate and oxyhemoglobin saturation were continuously monitored throughout surgery. Blood pressure and heart rate were recorded before drug injection, at 5-min intervals during surgery, at 15-min intervals after surgery until 3 h from the time of intrathecal injection, hourly until recovery room discharge, then every 6 h until 24 h after injection. A decrease in mean arterial pressure of more than 20% below preanesthetic baseline level was treated by 5-mg intravenous increments of ephedrine and by intravenous fluid administration. Decreases in heart rate of less than 50 beats/min were treated with 0.25-mg increments of atropine administered intravenously. Nausea at any time during the study was treated with either 2-4 mg ondansetron or 20 mg metoclopramide administered intravenously.
Any intraoperative pain was treated with intravenous fentanyl in 25-[micro sign]g increments. Pain was assessed by the 10-cm VAS at arrival in the recovery room and every 30 min until discharge and was treated with intravenous patient-controlled morphine, with initial settings of a 2-mg dose, 10-min lockout, and an hourly limit of 12 mg. The VAS was also recorded at discharge from the recovery room and 24 h after the study solution was injected. At these same times, patients rated their nausea on a 10-cm VAS scale.
Data are presented as mean +/− SD or median and quartiles, as appropriate. Groups were compared for demographic data, and the duration of surgery and time in the recovery room were determined by one-way analysis of variance. The time-to-first-patient-controlled analgesia use was compared among groups using the Kaplan-Meier analysis and the Wilcoxon's rank sum. The incidence of adverse events and adjuvant drug use were compared among the groups by chi-squared analysis. Blood pressure, heart rate, and VAS scores were compared among the groups by two-way analysis of variance for subsequent measures. Categoric scale data and cumulative morphine use for 8 h after intrathecal injection (the expected duration of drug action) were compared among the groups using the Kruskal-Wallis test followed by the Wilcoxon's rank sum test. P values were corrected by post hoc tests, and a level of 0.05 was considered significant.
Sixty patients were observed at the University of Sao Paulo, 23 were observed at Wake Forest University School of Medicine, and 9 were observed at the University of Kentucky. Demographic characteristics, duration of surgery, duration of stay in the recovery room, or intraoperative fluid or drug administration did not differ in the neostigmine-dose groups (Table 1). Blood pressure or heart rate before intrathecal injection or after bupivacaine injection did not differ in the groups (Figure 1). Similarly, blood pressure or heart rate in the recovery room or for the subsequent 24 h (data not shown) did not differ. The incidence of treatment with ephedrine for hypotension did not differ between saline control treatment (25%) and neostigmine treatment (25%), and it did not differ with neostigmine dose (25% after placebo, 36% after 25 [micro sign]g, 27% after 50 [micro sign]g, 13% after 75 [micro sign]g; P = 0.18 by chi-squared analysis). The incidence of treatment for bradycardia did not differ between saline control treatment (0%) and neostigmine treatment (9%), and it did not differ with neostigmine dose (5% after 25 [micro sign]g, 14% after 50 [micro sign]g, and 9% after 75 [micro sign]g). Neostigmine did not affect the onset of sensory blockade from intrathecal bupivacaine (Table 2).
Table 1. Demographic and Intraoperative Characteristics
Full Size | Slide (.ppt)
Table 2. Sensory Block to Pinprick and Motor Blockade after Intrathecal Injection
Figure 1. Mean arterial blood pressure (upper) and heart rate (lower) after injection at time 0 of intrathecal bupivacaine; 15 mg with 1 ml saline ([black square]); or 25 [micro sign]g, ([white square]), 50 [micro sign]([black circle]), or 75 [micro sign]g ([white circle]) neostigmine. Data are mean +/− SD of 22 to 24 patients. The groups did not differ.
Only the 75-[micro sign]g dose of neostigmine increased the nausea score in the recovery room (Figure 2). Similarly, the incidence of treatment for nausea was greater in patients who received neostigmine (61%) than in those who did not (29%). However, the incidence of nausea treatment was unrelated to neostigmine dose (the incidence of nausea treatment was 54% after 25 [micro sign]g, 64% after 50 [micro sign]g, and 64% after 75 [micro sign]g).
Figure 2. Nausea scores on a 10-cm visual analog scale at admission to the postanesthesia care unit for the following 2 h, at time of discharge from the postanesthesia care unit, and at 24 h after surgery. Data are median +/− 25th and 75th percentiles of patients receiving intrathecal saline ([black square]) or 25 [micro sign]g ([white square]), 50 [micro sign]g ([black circle]), or 75 [micro sign]g ([white circle]) neostigmine. *P < 0.05 versus control.
The analgesic effect of intrathecal neostigmine was dose independent. All doses of neostigmine reduced VAS pain scores in the recovery room to a similar degree (Figure 3). All doses of neostigmine prolonged the time-until-first-morphine-dose by a similar amount. The time-to-first-morphine-dose (median, 25th to 75th percentiles) was 3 h (3 to 4 h) after saline administration, 4 h (4 to 6.5 h) after 25 [micro sign]g neostigmine administration, 4 h (3 to 5.5 h) after 50 [micro sign]g, and 6 h (4 to 8.5 h) after 75 [micro sign]g (P < 0.05 for all neostigmine groups vs. saline by Kaplan-Meier analysis). Similarly, there was a dose-independent reduction in patient-controlled analgesia morphine use during the first 8 h after intrathecal injection of neostigmine (Figure 4).
Figure 3. Pain scores on a 10-cm visual analog scale at admission to the postanesthesia care unit, for the following 2 h, at time of discharge from the postanesthesia care unit, and at 24 h after surgery. Data are median +/− 25th and 75th percentiles of patients receiving intrathecal saline ([black square]) or 25 [micro sign]g ([white square]), 50 [micro sign]g ([black circle]), or 75 [micro sign]g ([white circle]) neostigmine. *P < 0.05 versus all neostigmine groups.
Figure 4. Cumulative intravenous patient-controlled analgesia morphine use after intrathecal injection of saline ([black square]) or 25 [micro sign]g ([white square]), 50 [micro sign]g ([black circle]), or 75 [micro sign]g ([white circle]) neostigmine. Dose-independent reduction in morphine use by neostigmine (P < 0.001). Data are median +/− 25th and 75th percentiles.
This is the first, large, dose-response study of low doses of intrathecal neostigmine for postoperative analgesia, and it provides new information regarding dose-related analgesia, nausea, and hemodynamic actions of this agent in different patient populations at the three sites.
Intrathecal neostigmine, at a dose of 100 [micro sign]g, produces mild analgesia (30-40% reduction in pain scores to a noxious cold stimulus) lasting 3 or 4 h in volunteers, whereas 50 [micro sign]g produces no detectable analgesia. [2] However, a painful stimulus, such as occurs after surgery, might increase the apparent potency of neostigmine. This is confirmed by studies with sheep that showed an increase in acetylcholine concentrations in lumbar cerebrospinal fluid during painful electrical stimulation. [5] In addition, the antinociceptive effect of intrathecal neostigmine is enhanced in the first 2 days after lumbar laminectomy surgery in sheep. [6] The current study showed significant analgesia, as defined by a reduction in morphine use, with administration of 25-50 [micro sign]g intrathecal neostigmine in women after surgery, suggesting that a similar phenomenon may occur in humans.
An alternative explanation to the effect of small doses of neostigmine in the current study relates to the mechanisms of action of systemic opioids in producing analgesia. Intravenous morphine injection is thought to activate descending spinal inhibitory pathways, some of which are noradrenergic, and, as such, morphine injection increases concentrations of norepinephrine in lumbar cerebrospinal fluid in animals and humans. [10] Spinally released norepinephrine produces analgesia in part by activating spinal cholinergic neurons to release acetylcholine, and, as such, intravenous morphine increases cerebrospinal concentrations of acetylcholine. [10] All patients in the current study received intravenous morphine by patient-controlled analgesia, and it is possible that smaller doses of intrathecal neostigmine were more effective in these patients than in others because the patients were receiving morphine, which stimulated acetylcholine release on which neostigmine could act.
Regardless of the mechanism, the current study suggests that doses of intrathecal neostigmine of less than 50 [micro sign]g reduce intravenous morphine requirements for 8 h after vaginal hysterectomy. Previous literature does not consistently report a dose-dependent analgesic effect of neostigmine. As reviewed previously, large doses (200 [micro sign]g) uniformly produce analgesia, but also nausea. With one exception, [3] 100 [micro sign]g neostigmine also produces analgesia, but in most cases it is associated with an increased incidence of nausea. The current study corresponds with previous data from open-label studies in women after cesarean section, [11] and in patients after orthopedic procedures, [9] that doses of more than 100 [micro sign]g also may be effective. The clinical usefulness of this reduction in morphine use for 8 h may be limited. Preliminary data suggest that a much longer duration of analgesia can be obtained by coadministration of intrathecal neostigmine with morphine, [3] reflecting the synergistic interaction between these agents by intrathecal administration. [1]
Intrathecal neostigmine produces nausea in volunteers and patients at doses >or= to 100 [micro sign]g. [2] The current study suggests that doses as small as 25 [micro sign]g may increase the requirements for antiemetic treatment. It is conceivable that the use of propofol during surgery for sedation reduced nausea after intrathecal neostigmine from what would be seen with concomitant propofol administration.
Intrathecal neostigmine administration diminishes hypotension from spinal bupivacaine [12,13] and from clonidine [14] in animals and from epidural clonidine in humans. [15] The mechanism of this interaction is thought to be augmentation by neostigmine of stimulation from spinally released acetylcholine on preganglionic sympathetic neurons. This stimulation may counteract the sympatholytic actions of the local anesthetic, bupivacaine, or of the [Greek small letter alpha]2-adrenergicagonist clonidine. We did not observe a reduced incidence of hypotension in women receiving neostigmine, suggesting that clinically useful doses of intrathecal neostigmine would not affect intrathecal bupivacaine-induced hypotension.
In conclusion, 25-75 [micro sign]g intrathecal neostigmine produces a dose-independent reduction in morphine use for 8 h after vaginal hysterectomy and a dose-independent increase in the need for antiemetic treatment. These data suggest that intrathecal neostigmine alone is unlikely to produce complete analgesia after surgery and that even doses less than 50 [micro sign]g may increase the incidence of postoperative nausea.
Naguib M, Yaksh TL: Antinociceptive effects of spinal cholinesterase inhibition and isobolographic analysis of the interaction with [micro sign] and [Greek small letter alpha]2receptor systems. Anesthesiology 1994; 80:1338-48
Hood DD, Eisenach JC, Tuttle R: Phase I safety assessment of intrathecal neostigmine in humans. Anesthesiology 1995; 82:331-43
Lauretti GR, Reis MP, Prado WA, Klamt JG: Dose-response study of intrathecal morphine versus intrathecal, neostigmine, their combination, or placebo for postoperative analgesia in patients undergoing anterior and posterior vaginoplasty. Anesth Analg 1996; 82:1182-7
Klamt JG, Dos Reis MP, Neto JB, Prado WA: Analgesic effect of subarachnoid neostigmine in two patients with cancer pain. Pain 1996; 66:389-91
Eisenach JC, Detweiler DJ, Tong CY, D'Angelo R, Hood DD: Cerebrospinal fluid norepinephrine and acetylcholine concentrations during acute pain. Anesth Analg 1996; 82:621-6
Bouaziz H, Tong C, Eisenach JC: Postoperative analgesia from intrathecal neostigmine in sheep. Anesth Analg 1995; 80:1140-4
Lauretti GR, Azevedo VMS: Intravenous ketamine or fentanyl prolongs postoperative analgesia after intrathecal neostigmine. Anesth Analg 1996; 83:766-70
Lauretti GR, Lima ICPR: The effects of intrathecal neostigmine on somatic and visceral pain: Improvement by association with a peripheral anticholinergic. Anesth Analg 1996; 82:617-20
Lauretti GR, Mattos AL, Reis MP, Prado WA: Intrathecal neostigmine for postoperative analgesia after orthopedic surgery. J Clin Anesth 1997; 9:473-7
Bouaziz H, Tong CY, Yoon Y, Hood DD, Eisenach JC: Intravenous opioids stimulate norepinephrine and acetylcholine release in spinal cord dorsal horn-Systematic studies in sheep and an observation in a human. Anesthesiology 1996; 84:143-5
Krukowski JA, Hood DD, Eisenach JC, Mallak KA, Parker RL: Intrathecal neostigmine for post-cesarean section analgesia: Dose response. Anesth Analg 1997; 84:1269-75
Carp H, Jayaram A, Morrow D: Intrathecal cholinergic agonists lessen bupivacaine spinal-block-induced hypotension in rats. Anesth Analg 1994; 79:112-6
Rose G, Xu ZM, Tong CY, Eisenach JC: Spinal neostigmine diminishes, but does not abolish, hypotension from spinal bupivacaine in sheep. Anesth Analg 1996; 83:1041-5
Williams JS, Tong C, Eisenach JC: Neostigmine counteracts spinal clonidine-induced hypotension in sheep. Anesthesiology 1993; 78:301-7
Hood DD, Mallak KA, Eisenach JC, Tong CY: Interaction between intrathecal neostigmine and epidural clonidine in human volunteers. Anesthesiology 1996; 85:315-25
Gabriela R. Lauretti, David D. Hood, James C. Eisenach, Ben L. Pfeifer; A Multi-center Study of Intrathecal Neostigmine for Analgesia following Vaginal Hysterectomy . Anesthesiology 1998;89(4):913-918.
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Robert M. Watkins
Robert M. Watkins comes (home) to Mallard Creek Presbyterian from California where he was the General Presbyter for the Presbytery of Sacramento. He has served in this position since January 2016. Before that, Rob served as a Pastor and Associate Pastor for 25 years. His ministry began as Pastor in Ludlow, Kentucky at First Presbyterian Church, then as an Associate Pastor in North Carolina, serving First Presbyterian-Gastonia and then here at Mallard Creek Presbyterian Church, and then as Pastor in Augusta, Georgia at the Covenant Presbyterian Church.
Rob was born in Virginia, but grew up in Statesville, North Carolina. Rob attended Davidson College and Union Seminary in Richmond, VA. Rob is married to the Rev. Alison Messick-Watkins, They have two children—Perry and Chelsea They also have one dog, Hazel.
Alison Messick-Watkins
Parish Associate
An ordained PCUSA pastor, Alison has ministered to a variety of people and in a variety of settings. Prior to joining the MCPC staff, Alison served in the Sacramento Presbytery as part-time chaplain at University Retirement Community in Davis, California, and part-time pastor of Journey Presbyterian Church. For the majority of her over 25 years of ministry experience, Alison worked as a Pastoral Psychotherapist in private practice.
Alison holds a Master of Divinity degree from Union Theological Seminary in Virginia, a Master of Arts in Pastoral Psychotherapy from The Athenaeum of Ohio, and a Bachelor of Arts from Centre College in Kentucky. She is a Fellow in the American Association of Pastoral Counselors, and has completed three units of Clinical Pastoral Education.
In her free time, you can usually find Alison in one of three places: on a long walk with her husband, Rob, and their pup, Hazel; in her backyard, tending to her garden; or gathered around the table for a home cooked meal with her adult children and their significant others.
Andrea Thomas
Director of Children & Youth Ministries
Andrea holds a Master's Degree in Theology and Ministry from Boston College and a Bachelor's Degree in Psychology from Garner Webb. She has completed a Chaplaincy residency in Clinical Pastoral Education at Wake Forest Baptist Medical Center and has been an Associate Chaplain at CaroMont Regional Medical Center in Gastonia, where she specialized in mental health advocacy with kids and teens. She is married to Carson and they have a dog named Nellie. She is also a registered Yoga instructor. She loves science fiction, women's spirituality, and brussels sprouts. She is passionate about helping youth and children come to know the love of Christ through love of neighbor in the community of the church and through acts of service outside the church walls.
Shawn Watkins
Shawn joined Mallard Creek Presbyterian in December of 2015 and cares for the many details that are involved in assisting the church body. After spending 17 years with Love, Inc. a Christian nonprofit, her compassion and love for people is something that she is excited to continue utilizing with the MCPC family. Shawn and her husband, Lynn, have four children, 2 sons in laws and 1 grandson. In her spare time, she enjoys gardening, biking and traveling to see family.
David Barnaba
Director of Music Ministries
David is our Director of Music Ministries at Mallard Creek. David is no stranger to working in music, and has grown up in a musical family. His Grandfather played in many bands, and his mother is a private piano instructor in South Carolina. David is a graduate of the Crane School of music in Potsdam, NY and has a degree in music education. He is a full-time elementary music teacher at Pitts School Road Elementary, is married to his wife Tara, and has 2 daughters, Clara and Scarlett.
Cathy Marlor
Cathy has worked for churches and nonprofits for the past 30 years. She and her husband, Mike have 3 sons, 2 beautiful daughter in-laws, 3 adorable grandchildren and one dog. In their free time, Cathy and Mike enjoy camping in the NC mountains.
Kristy Maddux
Kristy Maddux has a Bachelor of Science degree in Business Administration from WVU. After moving to Charlotte, Kristy became an assistant teacher at MCPC Preschool and loved it so much that she is starting her 24th year on the MCPCP team. Kristy and her husband, Mike, have three adult children, 1 daughter-in-law, 1 granddaughter, 2 miniature dachshunds, and 4 grand dogs. She is also a member of Mallard Creek Presbyterian Church, where she is a deacon, enjoys helping out, and caring for those in need. In her spare time, Kristy loves to cook, read, attend yard sales, watch college basketball and football, take care of her grand baby, and spend time with her family.

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Талассеми́и  — это наследственные заболевания крови, для которых характерно снижением выработки гемоглобина. Симптомы зависят от типа патологии и могут варьироваться от незначительных до тяжелых. Часто наблюдается анемия от легкой до тяжелой степени (низкий уровень эритроцитов или гемоглобина), что может приводить к ощущению усталости. Также могут наблюдаться проблемы с костями, увеличение селезенки, желтизна кожи и слизистых, а также потемнение мочи. У детей может наблюдаться замедление роста.

Талассемии — это генетические нарушения. Существует два основных типа:  и . Тяжесть альфа- и бета-талассемии зависит от того, сколько из четырех генов альфа-глобина или двух генов бета-глобина отсутствует. Диагноз обычно ставится с помощью анализов крови, включая общий анализ крови, специальные и генетические тесты. Диагноз может быть поставлен до рождения с помощью пренатального тестирования.

По состоянию на 2015 год талассемия встречается примерно у 280 миллионов человек, из которых около 439 000 человек страдают тяжелым заболеванием. Эта патология наиболее распространена среди людей греческого, итальянского, ближневосточного, южноазиатского и африканского происхождения. Мужчины и женщины имеют одинаковые показатели заболеваемости. В 2015 году патология привела к гибели 16 800 человек по сравнению с 36 000 смертей в 1990 году. Люди с легкой степенью талассемии, аналогично пациентам с серповидно-клеточной анемией, имеют некоторую защиту от малярии, что объясняет, почему они чаще встречаются в тех регионах, в которых существует  малярия.

Признаки и симптомы

 Перегрузка железом (гемохроматоз): у людей с талассемией может возникать перегрузка железом либо из-за самой патологии, либо из-за частых гемотрансфузий. Избыток железа может привести к повреждению сердца, печени и эндокринной системы, включая железы, вырабатывающие гормоны, регулирующие процессы во всем организме. Повреждение характеризуется чрезмерными отложениями железа. Без адекватной железохелатирующей терапии почти у всех пациентов с бета-талассемией накапливаются потенциально фатальные уровни железа.
 Инфекция: люди с талассемией имеют повышенный риск инфекций. Это особенно вероятно, если селезенка была удалена.
 Деформации костей: Талассемия может вызвать гиперплазию костного мозга, что вызывает нарушения структуры костей, особенно лица и черепа. Гиперплазия костного мозга также делает кости тонкими и ломкими, увеличивая риск переломов костей.
 Увеличение селезенки (спленомегалия): селезёнка помогает бороться с инфекцией и фильтрует старые или поврежденные клетки крови. Талассемия часто сопровождается разрушением большого количества эритроцитов, и удаление этих клеток вызывает увеличение селезенки. Спленомегалия может усугубить анемию и сократить срок жизни перелитых эритроцитов. Серьезное увеличение селезенки может потребовать ее удаления.
 Замедление темпов роста: анемия может привести к замедлению роста ребенка. Половое созревание также может быть задержано у детей с талассемией.     Проблемы с сердцем: такие заболевания, как застойная сердечная недостаточность и нарушения сердечного ритма, могут быть связаны с тяжелой талассемией.

Структурная биология гемоглобина
Нормальные гемоглобины человека представляют собой тетрамерные белки, состоящие из двух пар глобиновых цепей, каждая из которых содержит одну альфа-подобную (α-подобную) цепь и одну бета-подобную (β-подобную) цепь. Каждая цепь глобина связана с железосодержащим фрагментом гема. На протяжении всей жизни синтез альфа-подобных и бета-подобных (также называемых неальфа-подобными) цепей уравновешивается, так что их соотношение относительно постоянно и избытка какого-либо типа нет. Специфические альфа- и бета-подобные цепи, входящие в состав гемоглобина, строго регулируются во время развития:

 Эмбриональные гемоглобины экспрессируются уже на четвертой-шестой неделе эмбриогенеза и исчезают примерно на восьмой неделе беременности, поскольку они замещаются фетальными гемоглобинами.  Эмбриональные гемоглобины включают:         Hb Гоувер-1, состоящий из двух ζ-глобинов (зета-глобинов) и двух ε-глобинов (эпсилон-глобинов) (ζ2ε2)         Hb Гоувер-2, состоящий из двух альфа-глобинов и двух эпсилон-глобинов (α2ε2)         Hb Портланд, состоящий из двух дзета-глобинов и двух гамма-глобинов (ζ2γ2)
 Фетальный Hb (Hb F) вырабатывается примерно с 8-ой недель беременности до рождения и составляет примерно 80% гемоглобина у доношенных новорожденных. Он снижается в течение первых нескольких месяцев жизни и в норме составляет <1% от общего гемоглобина к периоду раннего детства. Hb F состоит из двух альфа-глобинов и двух гамма-глобинов (α2γ2).
 Взрослый Hb (Hb A) является преобладающим гемоглобином у детей в возрасте шести месяцев и старше; он составляет 96-97% общего гемоглобина у лиц без гемоглобинопатии и состоит из двух альфа-глобинов и двух бета-глобинов (α2β2).
 Hb A2 — это второстепенный гемоглобин взрослого человека, который обычно составляет примерно 2,5–3,5% от общего гемоглобина, начиная с шестимесячного возраста. Состоит из двух альфа-глобинов и двух дельта-глобинов (α2δ2).

Причина
Талассемия имеет аутосомно-рецессивный тип наследования. Как α-, так и β-талассемии часто наследуются по аутосомно-рецессивному типу. Сообщалось о случаях доминантно наследуемой α- и β-талассемии, первый из которых был в ирландской семье с двумя делециями 4 и 11 bp. в экзоне 3, прерванными вставкой 5 bp. в гене β-глобина. Для аутосомно-рецессивных форм заболевания оба родителя должны быть носителями, чтобы ребенок был поражен. Если оба родителя несут признаки гемоглобинопатии, риск рождения больного ребенка составляет 25% для каждой беременности.

Гены, вовлеченные в талассемию, контролируют производство здорового гемоглобина. Гемоглобин связывает кислород в легких и высвобождает его, когда эритроциты достигают периферических тканей, таких как печень. Связывание и высвобождение кислорода гемоглобином необходимы для выживания.

Эволюция
Наличие единственного генетического варианта талассемии может защитить от малярии и, таким образом, может быть преимуществом. Люди, у которых диагностирована гетерозиготная (носительство) β-талассемия, имеют некоторую защиту от ишемической болезни сердца.

Патофизиология
В норме большая часть гемоглобина взрослого человека (HbA) состоит из четырех белковых цепей, двух α- и двух β-цепей глобина, расположенных в виде гетеротетрамера. При талассемии у пациентов обнаруживаются дефекты α- или β-глобиновой цепи, вызывающие образование аномальных эритроцитов.

Талассемии классифицируют в зависимости от того, какая цепь молекулы гемоглобина поражена. При α-талассемии нарушается продукция цепи α-глобина, а при β-талассемии – продукция цепи β-глобина.

Цепи β-глобина кодируются одним геном на хромосоме 11; Цепи α-глобина кодируются двумя тесно сцепленными генами на 16-й хромосоме. Таким образом, у нормального человека с двумя копиями каждой хромосомы два локуса кодируют β-цепь, а четыре локуса кодируют α-цепь. Делеция одного из α-локусов широко распространена у лиц африканского или азиатского происхождения, что повышает вероятность развития у них α-талассемии. β-талассемии распространены не только у африканцев, но и у греков и турок.

Альфа-талассемия
Связана с мутациями в генах HBA1 и HBA2. Есть всего 4 локуса, кодирующего α-цепи. Наличие мутации в одном из локусов приводит к минимальным клиническим проявлениям. Нарушения в двух локусах выражаются лёгкой формой анемии. При мутациях в трёх локусах возникает значительное уменьшение продукции α-глобина. При этом избыточные цепи β-глобина образуют нестабильные тетрамеры — гемоглобин Н. Эта форма носит также название гемоглобинопатии Н. Характер заболевания может варьироваться от лёгкой до тяжёлой картины гипохромной микроцитарной анемии. Присутствие мутаций во всех четырёх аллелях альфа-глобина не совместимо с жизнью. Ребёнок с такой патологией погибает внутриутробно или вскоре после рождения. Из пуповинной крови таких детей можно выделить гемоглобин Барта. Альфа-талассемия часто встречается у людей из Юго-Восточной Азии, Ближнего Востока, Китая и у лиц африканского происхождения.

Бета-талассемия
Бета-талассемия возникает из-за мутаций в гене HBB на хромосоме 11, которые также наследуются по аутосомно-рецессивному типу. Тяжесть заболевания зависит от характера мутации и наличия мутаций в одном или обоих аллелях.

Мутированные аллели называются β+, когда частично сохраняется функция (либо белок имеет пониженную функцию, либо он функционирует нормально, но вырабатывается в уменьшенном количестве) или βo, когда функционирующий белок не вырабатывается.

Положение обоих аллелей определяет клиническую картину:

    Большая β-талассемия (средиземноморская анемия или анемия Кули) вызывается генотипом βo/βo. Функциональные β-цепи не образуются, поэтому сборка гемоглобина А невозможна. Это наиболее тяжелая форма β-талассемии;

    Промежуточная бета-талассемия вызывается генотипом β+/β0 или β+/β+. В этой форме вырабатывается некоторое количество гемоглобина А;

    Малая β-талассемия вызывается генотипом β/βo или β/β+. Только один из двух аллелей β-глобина содержит мутацию, поэтому продукция β-цепи не сильно нарушена, и патология может протекать относительно бессимптомно.

Бета-талассемия чаще всего встречается у людей средиземноморского происхождения. В меньшей степени могут быть затронуты представители Китая, другие выходцы из Азии и афроамериканцы.

Дельта-талассемия
Помимо альфа- и бета-цепей, присутствующих в гемоглобине, около 3% взрослого гемоглобина состоит из альфа- и дельта-цепей. Как и при бета-талассемии, могут возникать мутации, влияющие на способность этого гена продуцировать дельта-цепи.

Комбинированные гемоглобинопатии
Талассемия может сосуществовать с другими гемоглобинопатиями. Наиболее распространенными из них являются:

    Гемоглобин Е/талассемия: распространен в Камбодже, Таиланде и некоторых частях Индии, клинически подобен большой β-талассемии или промежуточной талассемии.

    Гемоглобин S / талассемия: распространена среди населения Африки и Средиземноморья, клинически похожа на серповидноклеточную анемию с дополнительным признаком спленомегалии.

    Гемоглобин C/талассемия: распространенная среди населения Средиземноморья и Африки гемоглобин C/β0 талассемия вызывает умеренно тяжелую гемолитическую анемию со спленомегалией; талассемия с гемоглобином C / β + вызывает более легкое заболевание.

    Гемоглобин D/талассемия: часто встречается в северо-западной части Индии и Пакистана (регион Пенджаб).

Диагностика
Талассемию можно диагностировать с помощью полного анализа крови, электрофореза гемоглобина или высокоэффективной жидкостной хроматографии, а также при тестировании ДНК. Электрофорез гемоглобина малодоступен в развивающихся странах, но индекс Ментцера также можно использовать для диагностики талассемии; это не окончательный тест, но он может указывать на возможность талассемии. Индекс Ментцера можно рассчитать на основании полного результата анализа крови.

Профилактика
Американский колледж акушеров и гинекологов рекомендует всем людям, планирующим забеременеть, пройти обследование на наличие талассемии. Генетическое консультирование и генетическое тестирование рекомендуются семьям, у которых есть признаки талассемии.

На Кипре существует политика скрининга для снижения заболеваемости талассемией, которая с момента реализации программы в 1970-х годах (включая пренатальный скрининг и аборты) сократила число детей, рожденных с этим заболеванием, с одного на каждые 158 рождений почти до нуля. В Греции также есть программа скрининга для выявления людей, которые являются носителями патологии.

В Иране в качестве добрачного скрининга в первую очередь проверяют индексы эритроцитов мужчины. Если выявляется микроцитоз (средний уровень гемоглобина в клетках < 27 пг или средний объем эритроцитов < 80 мкл), женщина проходит обследование. Если микроцитоз определяют у обоих исследуемых, измеряют их концентрации гемоглобина А2. Если оба имеют концентрацию выше 3,5% (диагностический признак талассемии), их направляют в местный назначенный медицинский пункт для генетического консультирования.

В Индии  как правительство, так и неправительственные организации организуют крупномасштабные информационные кампании для продвижения добровольного добрачного скрининга, при этом браки между носителями категорически не приветствуются.

Лечение
Легкая талассемия: люди с признаками талассемии не нуждаются в последующем медицинском наблюдении после постановки первоначального диагноза. Людей с  β-талассемии следует предупредить, что их состояние может быть неправильно диагностировано как более распространенная железодефицитная анемия. Им следует избегать рутинного приема добавок железа, но дефицит железа может развиться во время беременности или в результате хронического кровотечения. Консультирование показано всем лицам с генетическими нарушениями, особенно когда в семье существует риск тяжелой формы заболевания, которую можно предотвратить.

Лечение зависит от типа и тяжести заболевания. Лечение пациентов с более тяжелым заболеванием часто включает регулярные переливания крови, хелатирование железа и прием фолиевой кислоты. Хелатирование железа можно проводить с помощью дефероксамина, деферасирокса или деферипрона. Иногда вариантом может быть трансплантация костного мозга. Осложнения могут включать перегрузку железом из-за переливаний с последующими заболеваниями сердца или печени, инфекциями и остеопорозом. Если селезенка становится чрезмерно увеличенной, может потребоваться её хирургическое удаление. Больные талассемией, которые плохо реагируют на переливание крови, могут принимать гидроксимочевину или талидомид, а иногда и то и другое вместе. Гидроксимочевина — единственный одобренный FDA препарат для лечения талассемии. У пациентов, которые принимали 10 мг/кг гидроксимочевины каждый день в течение года, уровень гемоглобина был значительно выше, и это было хорошо переносимым лечением для пациентов, которые плохо реагировали на переливания крови. Другой индуктор гемоглобина включает талидомид, хотя он не был испытан в клинических условиях. Комбинация талидомида и гидроксимочевины привела к значительному повышению уровня гемоглобина у пациентов, зависимых от переливания крови, и пациентов, не зависимых от переливания крови.

Анемия
Людям с тяжелой формой талассемии требуется лечение. Схема переливания крови является первой эффективной мерой продления жизни.

Терапия гормоном роста
Имеются некоторые свидетельства того, что заместительная терапия гормоном роста может способствовать увеличению скорости роста детей с талассемией .

Перегрузка железом
Многократные переливания крови могут привести к перегрузке железом. Перегрузку железом, связанную с талассемией, можно лечить с помощью хелатотерапии с помощью  дефероксамина, деферипрона или деферасирокса. Эти методы лечения привели к увеличению продолжительности жизни больных большой талассемией.

Дефероксамин эффективен только в виде ежедневных инъекций, что усложняет его длительное использование. Однако это недорого и безопасно. Побочные эффекты включают первичные кожные реакции вокруг места инъекции и потерю слуха.

Деферасирокс и деферипрон являются пероральными препаратами, общие побочные эффекты которых включают тошноту, рвоту и диарею. Деферасирокс эффективен не для всех пациентов и может не подходить для пациентов с серьезными сердечными проблемами, связанными с перегрузкой железом, в то время как деферипрон, по-видимому, является наиболее эффективным средством при поражении сердца. Кроме того, стоимость деферасирокса также значительна.

В рандомизированных контролируемых исследованиях нет данных, подтверждающих необходимость приема добавок цинка для больных талассемией.

Трансплантация костного мозга
Трансплантация костного мозга может дать возможность излечения молодых людей, у которых есть HLA-совместимый донор. Показатели успеха достигли диапазона 80–90%. Смертность от процедуры составляет около 3%. Нет рандомизированных контролируемых исследований, в которых проверялась бы безопасность и эффективность трансплантации костного мозга от неидентичного донора у лиц с β-талассемией, зависящих от переливания крови.

Реакция «трансплантат против хозяина» (РТПХ) является одним из побочных эффектов трансплантации костного мозга. Необходимы дальнейшие исследования, чтобы оценить, можно ли использовать мезенхимальные стромальные клетки для профилактики или лечения БТПХ.

Если у пациента нет HLA-совместимого совместимого донора, может быть предпринята попытка трансплантации костного мозга от гаплоидентичной матери ребенку (несовместимый донор). В исследовании с участием 31 человека выживаемость без талассемии составила 70 %, отторжение — 23 %, а смертность — 7 %. Наиболее положительные результаты, как правило, наблюдаются у очень молодых людей.

Эпидемиология
Альфа-талассемия распространена в Западной Африке и Южной Азии. Бета-талассемия часто встречается в странах Средиземноморья, Западной Азии, Северной Африки и на территории Поволжья в России. Это регионы, где распространена малярия. Гетерозиготные носители мутаций в генах альфа- и бета цепей гемоглобина являются более устойчивыми к малярийному плазмодию. Имеются очаги талассемии в Азербайджане, в равнинных районах которого гетерозиготная бета-талассемия наблюдается у 7—10 % населения.

Примерно 1,5% населения мира (80–90 миллионов человек) являются носителями β-талассемии. Однако точные данные о частоте переносчиков среди многих групп населения отсутствуют, особенно в развивающихся регионах мира, о которых известно или ожидается, что они сильно пострадают. Из-за распространенности заболевания в странах, где мало что известно о талассемии, доступ к надлежащему лечению и диагностике может быть затруднен. Хотя в развивающихся странах есть некоторые диагностические и лечебные учреждения, в большинстве случаев они не предоставляются государственными службами и доступны только пациентам, которые могут себе это позволить. В целом более бедные слои населения имеют доступ только к ограниченным диагностическим средствам и переливаниям крови. В некоторых развивающихся странах практически нет средств для диагностики или лечения талассемии.

Этимология и синоним
Слово талассемия (/θælɪˈsiːmiə/) происходит от греческого thalassa (θάλασσα), «море», и новолатынского -emia (от греческого сложного корня -aimia (-αιμία), от haima (αἷμα), «кровь "). Он был придуман потому, что состояние под названием «средиземноморская анемия» было впервые описано у людей средиземноморской национальности. «Средиземноморская анемия» была переименована в большую талассемию после того, как генетика стала лучше изучена. Слово талассемия впервые было использовано в 1932 году.

Исследования

Генная терапия
Изучаются возможности генной терапии при талассемии. Процедура включает сбор гемопоэтических стволовых клеток (ГСК) из крови больного человека. Затем к HSC добавляют ген бета-глобина с использованием лентивирусного вектора. После разрушения костного мозга пострадавшего дозой химиотерапии (схема миелоаблативного кондиционирования) измененные ГСК вводятся обратно пострадавшему, где они приживаются в костном мозге и размножаются. Это потенциально приводит к прогрессирующему увеличению синтеза гемоглобина А2 во всех последующих развивающихся красных кровяных тельцах с результирующим исчезновением анемии.

Хотя одному человеку с бета-талассемией больше не требовалось переливание крови после лечения в рамках исследовательского испытания, по состоянию на 2018 год это лечение не было одобрено.

Индукция HbF
Индукция HbF представляет собой попытку реактивировать транскрипцию фетального глобинового гена. Усилия включают попытку разрушить промотор фетального глобинового гена.

Примечания

Ссылки
 Талассемия
 Фонд анемии Кули
 «Зинтегло»: генная терапия бета-талассемии

Наследственные болезни
Заболевания крови

redpajama_set_name: RedPajamaWikipedia


text:
Mighty Heroes REQUIRE Mighty Villains
Every Novel Needs a Mighty Hero
Hero, heroine, anti-hero... whichever approach you're taking, you're molding a story around someone your readers will learn to love, admire - maybe even envy.
But no matter whether your protagonist is an underdog, an overlord, or an everyman, there's one element to their character every protagonist needs: Strength.
I've done a previous post about strength - about how strength shouldn't be defined purely as physical, or a fearless desire to kick a$$, especially in female characters. Strength in a character can be demonstrated through intellect, moral nobility, a willingness to sacrifice for others, problem solving, perserverance in the face of extreme danger or opposition... the list is endless.
But in my opinion, there's one aspect of building a strong hero that's easy to overlook - yet, without it your book risks disappointing readers:
No One Looks Strong When the Opposition is Weak
I'm about to over-simplify to make the point. But go with me...
Your hero is a grown man, physically strong and mentally adept. If you pit him against the average weedy teenager in an arm-wrestling competition, there's little tension. The way the world works, the man is expected to win - and in fact, if he took too much pleasure in beating a young guy, he'd look like a jerk.
So, in order for the grown man's success to be cheer-worthy, he has to win an arm-wrestling competition over someone who, at the very least, is evenly matched in strength and skill.
And yet... so many villains I read (especially in early drafts of manuscripts, or novice stories) are dim-witted, weak or easily defeated in comparison to the hero / heroine. They make stupid decisions, put themselves into situations that make it easy for the hero to thwart them, and reveal their plans without being asked. And that's a huge, huge problem. Because as a reader I want to admire the hero! I want to feel satisfied by his / her win. I want to feel like we diced with death to achieve it.
I don't want to walk into a conflict thinking "can we just get this over with...?"
But in one published book I read, that's exactly what happened. I'll lay this out for you as an example:
Fantasy hero in medieval-esque world finds himself faced with a supernatural being which has a physical body, but doesn't appear to be restrained by simple things like physics. It can move like lightening, slip through tiny holes, kill a human with it's bare hands easily, and has zero conscience. It also can't be touched by the supernatural power used by some characters in the book.
In fact, on a physical level, this thing appears to significantly outweigh our admirable and amusing hero.
The hero can't use the power. His weapons are a long spear he uses as a quarterstaff, an innate and extremely accurate ability to throw knives, general athletic ability and speed, along with a deep-seated survival instinct. He is also in possession of an medallion that, when it touches the fantasy creature, burns its skin.
Now... over the course of THREE BOOKS this thing has hunted our hero. It's shown up at the most inopportune moments, demonstrated incredible power and stealth, and always been turned away at the last possible moment, the hero only surviving by the a miniscule thread of luck and skill.
This thing has vowed to kill our hero -- is under the instruction of the darkest power in the land -- and has recently revealed that he knows about the hero's secret wife and adopted son and vowed to kill them too.
So you can imagine after THREE BOOKS and tremendous forshadowing, not to mention several close calls in the last few chapters, the final confrontation between this thing and the hero is a highly anticipated read.
But you know what happened?
After three books of threats, dozens of secondary murders, and a relentless hunt drawing ever closer to the hero, the creature takes one look at a weapon the hero produces, whines "HOW?!" and runs - right in the direction the hero wants him to go: Right into a room where the hero has arranged for a power-drawn precipice.
Hero gives a couple pithy comments, then tips the creature over the edge into an endless nothing.
Seriously?!
I waded through THREE BOOKS of encounters to watch this thing go all wide-eyed and shaky at the end?
No! No, no, no, no. I did NOT.
I waded through three books to watch this thing go mental. I waded through three books to watch it almost win, then be defeated by the narrowest margin possible - with the hero almost dying in the process. I waded through three books to watch A REAL, FRIGGIN' FIGHT TO THE DEATH.
I waded through three books to be convinced that all was lost, the hero would lose, his much loved wife and son would be killed too -- and then to jump for joy when the hero pulled it all out of the hat in a way I could never anticipate.
I did NOT wade this far to watch this apparently indestructable, undefeatable, undeniably evil thing turn into a trembling coward of dubious intelligence.
I. Did. Not.
So, dear writer friends, take this advice from my reader self: If you want me to admire your hero, make sure he / she is facing off with a truly frightening villain who puts everything they have into winning. Because unless I feel like victory is hard won, frankly, it doesn't feel like victory at all.
Your Turn: Have you ever been disappointed by a villian's villainy? Or have you read a truly TERRIBLE villain who provided the perfect foil to an admirable hero?
Note: This post previously appeared in January 2012
Labels: Character Development
Michael Offutt, Phantom Reader January 8, 2012 at 2:51 PM
Not to use a biblical example but what you're saying is the world prefers David vs. Goliath; not Goliath kicking David's butt.
Sierra Gardner January 8, 2012 at 3:00 PM
I REALLY appreciate this post because I've been struggling with how to make my 'villain' scary and powerful enough while still enabling my hero to win. Thanks for reminding me not to take the easy road =)
Lorelei Bell January 8, 2012 at 3:06 PM
Unbelevable. Since we don't know if this book was an Indi or actually has a publisher... matters not. This writer has no idea how to end a series--a trillogy, I guess. And it sounds a little Harry Potter-esque, to me.
You're absolutely right, Aimee. The villain can't just go "oops, sorry to have bothered you" and go on his merry way... or be confronted by something that could have happened in the very first book and saved you the time and trouble of wading through three such books. I would want to scream, myself into next Tuesday.
I also agree with you about the heroine not just being a kick a$$ lady that has various ways of killing demons, vampires and the like. It's almost like everyone is copying everyone else.
Great endings must be equal to the great conflicts in the book. And for me, the heroine can be a little klutsy, not quite sure of herself and yet can be strong of character, smart, wanting to right wrongs, and isn't a push-over.
AimeeLSalter January 8, 2012 at 10:49 PM
Lorelei - I didn't give more detail on the book(s) or the story because I don't want to deride anyone specifically. But I will say that these three books over which the characters conflict aren't the only three books, nor is this the only hero. So I suspect someone got a little lazy.
This is a traditionally published book from a BIG house. The further I read into the series, the more convinced I am that the entire epic has such a strong following that the publishers got lazy and greedy, stringing the story out to squeeze more books from it. There's a serious difference in the standard of storytelling in these later books than in the earlier ones.
(And if any future commentors recognize the story - please don't name it. I used this as an example for analysis purposes, not to string up an author / publishing house).
Jemima Pett January 11, 2012 at 1:08 PM
Interesting and useful article. And here am I puzzling over my hero's next exploit. You are absolutely right, if he is going to overcome the odds, the odds have to be difficult to overcome, worthy of his battling. Food for thought indeed. Thanks!
SF March 11, 2013 at 11:21 AM
Yikes! I'm currently working on my villain(s), so this was a great post to come across. :)
AimeeLSalter March 11, 2013 at 1:28 PM
Glad to help, Susan!
Wow - that really bummed you out. But I agree. It has to be right down to the wire to get the payoff. I feel your pain!
Intangible Hearts March 15, 2013 at 7:52 AM
Guy sold you three books. That's the point isn't it? Not for me, but for some who want to make money. That's the question-'why do you write?' Do you write for profit or because you have an incredible story with fabulous characters?
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Most of the trademark owners in the Arab region are not aware of the real value for their trademark(s); they do not know the potential revenue that this intangible asset could bring to their business. Due to their lack of awareness, they overlook this value when they establish their firms, leading to "miss-protecting" their trademark in this respect.
This ignorance makes them vulnerable to trademark infringements, acquiescence of their brand, and could lead to lost profits as a result.
On the other hand, the local consumers may not be aware of the Arabic brands, their producers, or their quality.
This practice has made our regional market a playground for black-market and infringers, who in their turn, help to increase corruption, counterfeiting of famous products, and killing the commercial economical cycle in the market.
We aim to serve the community and create a better environment for better competition.
This can help you expand your business and trademark; our project will tell you how known your brand is! Increase the protection level of your brand by making it a well-known trademark.
Upon participating, trademarks will receive free, high-end promotion; making the un-known trademarks popular and visible. And any trademarks that meet the criteria of the top 50 marks, will then be listed on the list of the Top Brands in the MENA region and published globally.
Claim your lost profit, this process will create a link between trademarks and the original owners of these trademarks, thus creating customers awareness and loyalty. Customers will ask for your product or service instead of being deceived by fakers.
Customers will be more familiar with brands and will reach a degree where they can distinguish between a counterfeit product and the genuine product. They will be more knowledgeable about the origins of a certain brand, thus, reducing the chances of being a victim of fake products.
Having said that, a loyalty-bridge will be established between customers and those brands as a result of taking the ultimate advantage that a product can deliver.
Enhancing the spread of the local trademarks.
Creating knowledge for alternative local trademarks.
Generate better quality goods and services.
Roll up the economic cycle.
Knowing the popularity of a trademark aids in establishing plans and strategies to develop the product and increase the sales.


The shoulder is the hub of upper limb movement, in a very important core position! Any upper limb training action will use the shoulder joint, no matter how you practice chest, practice back, practice shoulder, practice your hand, and even the lower body of the deadlift need to use the shoulder joint!
During exercise, the shoulder is the most vulnerable part of the injury, if your shoulder is hurt! Then you will give up all the upper limb training!
Preventing problems before they happen is what we should do! Therefore, when training upper body muscles/single training shoulder muscles, be sure to pay great attention to the warmth of the shoulders before training.
1. Stand up, keep your body straight, and don't swing back and forth.
1. Also adopt a standing posture, adopt a standing posture, stand upright, and grasp the elastic band with both hands and lift it higher than the shoulder!
2. Use the shoulders to clip back and pull the elastic band down and the top of the action will squeeze your shoulder blades tightly together!
1. The feet are wider, one foot is on one end of the elastic band, and the opposite side is grasping the elastic band.
2. Start the shoulders and move outwards sideways!
The elastic band is fixed at the back, then take a few steps forward, and grasp the elastic band on the side of the body with one hand.
Start the shoulders and lift the side up, lift your head!
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text:
Gideon Stein (born December 19, 1971, in Washington, D.C.) is an American entrepreneur and education activist. He is the Chairman of Write Label, a crowd-sourced platform for short-form writing, president of The Moriah Fund, Chairman of Chalkbeat, and a member of the board of directors of New Classrooms, and Narrative 4. He is the former vice chairman of the board of Success Academy Charter Schools, a high-performing charter school management organization in New York City.

Education
Stein graduated with honors from Wesleyan University with a degree in economics and history. He attended St Edmund Hall at Oxford University as a visiting scholar in development economics and European history.

Career
Stein is the CEO of Write Label, a crowd-sourced platform for short-form writing. He was the founder and CEO of LightSail Education, an adaptive literacy solution for K-12. Stein was the founder, chairman and CEO of Omnipod, Inc., a leading on-demand provider of real-time messaging to the enterprise market, until its sale in 2005 to MessageLabs Group, Ltd., one of the world's largest private software companies (and now a division of Symantec). Stein was a founding partner of MR Ventures, a private investment firm with a portfolio of companies concentrated in media, commerce and software. Stein also served on the board of directors of the Real Silk Investment Company, a publicly traded regulated investment company, until its sale to Lord Abbett Affiliated Funds.

Philanthropy
In May 2019, Stein became the President of his family's private foundation, The Moriah Fund. Stein is a board member of New Classrooms. He serves as the Chairman of Chalkbeat, a leading non-profit education news outlet for New York City, Denver, Indianapolis, Memphis, Chicago, Philadelphia, Newark, and Detroit. He is on the board of directors of Narrative 4, a global empathy building organization, as well as on the board of directors for University Prep Public Schools.

References

1971 births
Living people
Wesleyan University alumni
People from Washington, D.C.


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Slater and Gordon lawyer wins national legal award
Slater and Gordon's Melinda Griffiths has won the Regional/Suburban Lawyer of the Year prize at the Lawyers Weekly Australian Law Awards 2017.
The Wollongong Principal Lawyer was one of seven Slater and Gordon lawyers nominated for an award at a ceremony held in Sydney on Friday 1 September.
Ms Griffiths specialises in Motor Vehicle Accident and Public Liability claims and also has extensive experience working in historic childhood sexual abuse cases.
She said while it was a complete shock to hear her name announced at the ceremony, it was a wonderful testament to the hard work put in by her team.
"It was just amazing. Words couldn't describe the feeling when they called my name – it was very special and an honour to win," Ms Griffiths said. "The past 12 months have been extremely rewarding for me and my team, and I definitely wouldn't have achieved this honour without their hard work.
"I have worked in the Wollongong and Illawarra region for more than 20 years and I'm extremely passionate about this community and its people."
Slater and Gordon lawyers Martin Rogalski (Queensland), Rebekah Lovely (Queensland) and Heather McKinnon (NSW) were also nominated for the same award.
Marko Eric (Victoria) was nominated for the Senior Associate of the Year prize, while Serina Dowding (Victoria) and Rebecca Lanza (Victoria) were both nominated for the Legal Support Professional of the Year award.
Slater and Gordon Chief Executive Officer Hayden Stephens congratulated Ms Griffiths on the honour, highlighting her commitment and passion for supporting her clients.
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Mr Stephens also congratulated the other six nominees, paying tribute to their dedication and hard work over the past 12 months.
In March this year, Ms Griffiths was elected President of the Wollongong and District Law Society. She had served in various roles within the group for the previous five years. She was also nominated for the same Lawyers Weekly Australian Law Award in 2016.
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Many bicycle accidents involve falling heavily on the shoulder which can result in a fractured collar bone (clavicle). A fractured clavicle is extremely painful initially, but it very rarely involves surgery and usually heals within 6 weeks.
Generally, you'll be in a 'sling' for the first few days as the initial phase of recovery involves rest and pain control. After the first few days, the pain begins to decrease and you can begin to ride on a stationary trainer without bearing any weight on your affected shoulder/arm. You can keep your arm in the sling for comfort. This allows you to maintain your fitness during your recovery. After a few days, you can begin to put some weight on your arm and gradually increase as tolerated. Be aware, too much too soon can result in delayed healing and prolong your recovery. As a general rule, if it hurts, you're doing too much. An indoor trainer (not rollers!) can be boring but experience has shown that a solid indoor training program with intervals can bring you back stronger than your were before your crash. You can't change the fact that your crashed and broke your collar bone, but your can focus on the future and come back stronger!
Doing a physical therapy program to maintain the range of motion in the shoulder joint and strengthen the shoulder muscles is a good idea. You can use light, free-weights or rubber-band cords to strengthen the rotator cuff muscles and muscles surrounding the shoulder. Start slowly with low resistance/weights and gradually increase as tolerated by pain. This will help stabilize your shoulder when riding hard and theoretically can protect you in the event of another fall. You can also work on stretching for your legs to improve your flexibility and exercises for your abdominal and back muscles to improve your core strength during this time.
If all is going well and you are healing as expected you can begin to ride on the road with a training partner or alone at 2-3 weeks when you have full motion, full strength and no pain. You shouldn't attempt to ride in a large group or race until the bone is completely healed and you have been cleared by your doctor. Adequate bone healing is confirmed on x-ray. This usually takes between 6-8 weeks. There should be no pain with direct pressure over the fracture site. You should be able to ride in and out of the saddle, sprint, corner and distribute equal amounts of weight through your injured shoulder without any pain. It is important to be sure your can handle your bike safely before returning to competition.
It is likely that there will be a sizeable 'bump' at the site of the fracture. Although this sometimes looks weird, you don't have to worry because this is common and is the 'callus' or site of bone healing. Through a process known as 'remodeling' this will improve over time, but you will likely have some mild deformity, as a badge of honor, for the rest of your cycling days. Although a fractured clavicle is scary and painful initially, with a proper rehabilitation program you can maintain your fitness and return to racing safely and effectively in a fairly short period of time.
Ride smart, ride safe, ride swiftly!


This came up on OGR several years back but has long disappeared from their archive window. Apparently an engine needing maintenance might emit blue smoke. As a quick experiment I inserted a Blue LED into the smoke stream. The surface-mount 0603-size (60 mil x 30 mil) LED needs to be small enough so as not to materially obstruct the flow. Obviously this is a steamer and the thin magnet wire would need to run under the shell. There are many not-so-trivial logistical issues of how to integrate this, but for proof of concept it looked pretty good IMHO.


Every year a new generation of Samsung tablets hits the market. The 4th generation of Galaxy Tab which was recently launched comes with a more powerful configuration, Android 4.4 and some other improvements on the design and software part.
We will review below the Galaxy Tab 4 10.1 T530 model with Wi-Fi and 16 GB internal memory.
We are dealing with a completely redesigned tablet which comes in 2 basic colours for now (black and white). The new Galaxy Tab is lighter, thinner and has a completely remodelled casing. Compared to the rounded shape of Tab 3, the new Samsung tablet comes in a perfectly rectangular shape and straight corners.
Its weight has been reduced to 480 grams which allows us to use it more without our hand getting tired, and also the back is made of a matte plastic material (not glossy as we have seen on the previous versions).
Basically the Tab 4 has been rethought in terms of ergonomics: to be light when you hold it and use it for long periods of time without becoming uncomfortable.
Another piece of news refers to the tablet's commands which is the repositioning of the lower left button (next to the physical Home button). Up until now, for most Samsung tablets this button opened the editing menu of the Home screen, however on the Tab 4 this button opens the recently used apps, in order to help us quickly resume our work.
Although, the case and weight of the tablet are strong points, the display – even if it is bright and has a vivid colour palette – doesn't impress. Even though we are talking about a quite generous screen (10.1 inch) and we would have expected to see Full HD, Samsung used the same mediocre resolution of 1280 x 800 pixels on the Galaxy Tab 4. This adversely affects the visual impact and though I have always praised the screens used by this manufacturer for their luminosity, colours and great viewing angles, the new Tab 4 gets a black ball/ minus on this.
It was expected that Galaxy Tab 4 have some upgrades worthy of 2014.
The tablets CPU is a Quad-Core APQ 8026 with a frequency of 1.2 Ghz and only 1,5 Gb of RAM.
I am sure you are wondering why they didn't opt for 2 or 3 GB of RAM? They say that 1.5 GB are enough for Internet, multimedia and other usual apps. At the same time better specs would have placed the tablet closer to the top of the rank (Note and Tab Pro) affecting the sales segment on that category …business is business right? The internal memory has stayed the same of 16 GB on the Galaxy Tab 4 T530 and by means of a memory card it can be expanded to up to 64 GB ( microSD slot ).
To conclude the configuration changes support the use of stronger, more demanding apps and allow the latest version of Android 4.4. installed to run smoothly.
After we have reviewed the appearance and components it is time we talk about the interface and apps. As previously stated the new Galaxy Tab 4 de 10.1 inch is equipped with Android 4.4 which ensures stability and very good security and connectivity options offered by the latest version of the operating system developed by Google.
Nonetheless, Samsung has adapted the new OS to its own style and further implemented the Touch Wiz interface which isn't the same anymore. The lower left button now opens recently used programs .
The new Galaxy Tab allows working with 2 apps simultaneously : by dragging your finger from right to left an editable menu will appear where we can run our favourite papps. The screen can be split into 2 equal parts or we can devote a larger share of the screen to a certain app by simply moving with our finger the dividing line of the two apps, either to the left or to the right. This working method is very interesting in our opinion.
Another novelty is that the new Galaxy Tab 4 can be used by more than one user, in fact we may have up to 8 users each with its own profile, own settings and own apps without affecting the activities of others in any way. We can have a profile and account for our child who wants to play or study, and the apps on our profile will not suffer any changes. I am sure many of you needed such a feature.
Multitasking and multiple profiles aren't the only news but they seemed like the most important to us. Moving on , Galaxy Tab 4 10.1 inch also comes with GPS , Bluetooth v4.0 and Wi-Fi a/b/g/n .
As for video we have 3 Mp web camera on the back and 1,3 Mp in the front – specs which aren't different from the Galaxy Tab 3 model.
The 6800 mAh battery has been properly chosen especially if we consider the size of the screen and the fact that according to the manufacturer it should allow up to 10-12 hours of use.
I will conclude with what I have already stated: evolution not revolution.
The new Galaxy Tab 4 10.1 manages to surprise us with its design and distance itself from the classical Samsung design line allowing an easier use of the tab for a longer period of time. The display is one of its major minuses, the low resolution being a factor in diminishing the visual quality of this model. The performance of the tablet is good but not extraordinary.
The new Galaxy Tab 4 is designed for those who want a compact tablet for common applications, some games and small business applications. I would say for multimedia as well but then we would have to deal with the problem of screen resolution again.
Certainly, if we look at the price of this product we see that it is a fair one and upon further consideration it is actually lower than the launching price of the previous model (Galaxy Tab 3) so I tend to think that this model will be a best buy due to its price and the brand of the manufacturer.


text:
Cigar Editorial: When is a 90 not a ...
Cigar Editorial: When is a 90 not a 90
October 26, 2017 Aaron Loomis Cigar Editorials, Editorials No comments
For the most part, people tend to think "a cigar rating is a cigar rating"; but looking into the numbers, this isn't actually the case. With Cigar Aficionado utilizing the 100 point scoring system that was very successfully used for wine, it made sense that many other cigar media entities would use the same scoring format as it is very familiar to people as a rating system. Other than the system's basic structure, how various sites/magazines work within it are different. With those differences, and taste being very subjective, it's only logical that the results would be different.
With this possibility, we were very interested in digging into the numbers to be able to clearly see what these differences were rather than just being speculative. What it shows is that each site/magazine uses the ratings in their own individual ways.
What we did was identify some of the more popular media outlets that utilize the 100 point system. If an outlet was not included, it was either due to the fact that their full library of scores are not available online, they do not have at least a 3 year history of reviews, they are not consistent with giving scores as part of reviews or that we were just not aware of the brand.
We collected all review scores from the most recent 3 year window. Different brands have different review frequency so there are some wide ranges in the number of reviews included, but over a 3 year window, it provides ample data to be able to do some analysis. With this data, the average score was determined as well as a simple histogram mapping out the quantity of reviews that were given a particular score. From there, we were able to make some observations from the data which is shared below.
We'll start with Cigar Aficionado since the magazine began earlier than any of the other entities in this article and, like it or not, is still the standard where ratings and scores are compared. The average score across 2,245 reviews is 89.1. There were 443 reviews that were given an 89, 418 were given a 90 and 352 were given an 88. With the bulk of reviews getting an 89 or 90, cigars need to score 91 or higher to start differentiating themselves from the pack. This makes sense as they use the 91 point marker as a cutoff for cigars to qualify for their cigar of the year ranking. On both sides of their most frequent ranking of 89, they produce scores on the higher side 13% more than they do on the lower side.
Blind Man's Puff
Blind Man's Puff has multiple reviewers on each review which uses a formula to generate the overall score. The overall score is what was used to generate this data. The average score across 382 reviews is 90.2. There were 94 reviews that received a 90, 81 were given a 91 and 72 were given an 89. With the bulk of reviews getting a 90 or 91, cigars need to score 92 or higher to start differentiating themselves from the pack. On both sides of their most frequent ranking of 90, they produce scores on the higher side 30% more than they do on the lower side.
Cigar Coop consists of a single reviewer which takes the variation from multiple reviewers out of the equation. The average score across 656 reviews is 90.8. There were 146 reviews that received a 91, 144 were given a 90 and 133 were given a 92. With the bulk of reviews getting between a 90 and 92, cigars need to score 93 or higher to start differentiating themselves from the pack. On both sides of the most frequent ranking of 91, he produces scores on the lower side 21% more than he does on the higher side.
Cigar Dojo
Cigar Dojo has a team of reviewers but just a single person on each review. The average score across 209 reviews is 90.2. There were 41 reviews that received a 90, 28 were given a 92 and 27 were given a 91. There were also two other scores that were very close which were 88 and 89 both having 23 reviews each. The score distribution is pretty unique as there is a clear high frequency of 90, but 88 to 93 are all pretty equal. With the bulk of reviews getting a 90 and an even spread for secondary scores between 91 and 93, it's not as easy to draw a direct correlation of where the tipping point is for cigars to differentiate themselves from the pack. On both sides of the most frequent ranking of 90, they produce scores on the higher side 27% more than they do on the lower side.
Halfwheel
Halfwheel has a team of reviewers but just a single person on each review. The average score across 911 reviews is 86.7, quite a bit lower than the rest of the media outlets. There were 103 reviews that received an 88, 96 were given an 87 and 93 were given an 89. What's interesting is that there is a bit of a gap between what the average rating is compared to what the most given score is. The gap is larger than a full point, so it's not something just occurring from rounding. Part of this reason is that the site is the only one from this group to publish any scores below a 74. There are 20 scores below a 74 with the lowest being a 50. With the bulk of reviews getting an 87 to 91, cigars need to score 92 or higher to start differentiating themselves from the pack. On both sides of the most frequent ranking of 88, they produce scores on the lower side 25% more than they do on the higher side.
The Cigar Authority
The Cigar Authority reviews primarily come from a single person, but there are a couple of reviews from others mixed in, so the variation is very low in regards to consistency. The average score across 600 reviews is 91.6. There were 117 reviews that received a 92, 116 were given a 91 and 105 were given a 90. With the bulk of reviews scoring between a 90 and 93, cigars need to score 94 or higher to start differentiating themselves from the pack. On both sides of the most frequent ranking of 92, they produce scores on the lower side 54% more than they do on the higher side.
Tiny Tim's Cigar World
Tiny Tim consists of a single reviewer which takes the variation from multiple reviewers out of the equation. The average score across 230 reviews is 91.7. There were 67 reviews that received a 92, 45 were given a 91 and 43 were given a 93. With the bulk of reviews scoring between a 91 and 93, cigars need to score 94 or higher to start differentiating themselves from the pack. On both sides of the most frequent ranking of 92, he produces scores on the lower side 30% more than he does on the higher side.
The score of 90 has seemed to be the magic number that people look for to determine when a cigar is "good". We think it goes back to the 100 point scoring system in school where a 90 and above was an A. In seeing that the majority of the entities here give a 90 or above as their most frequent rating it may need to be determined if most of the cigars out there, or at least those being rated, are considered "good", if the score that consumers use needs to be bumped up or if reviewers need to adjust their ratings to bring the scale back down.
As far as we know, none of these brands only review cigars they like or that are going to score above a certain threshold, so that shouldn't be one of the traits that shows a higher average rating. It may be possible that some of the brands don't publish some (or a lot of) lower scoring cigars they review and that could be a trait that leads to a higher leaning average score.
As you can tell by the scores given across the brands, a 90 is not a 90. It's not enough just to know that someone is using a 100 point system, you also need to know their tendencies to get a feel for where they score most often to truly gain value from the score given. It's most likely that the words in the review are more objective than the numbers given and it would be much easier to discern the value of the review from reading the notes than just looking at the score.
In the end, it probably doesn't matter to most people that there are differences in scoring between brands just as there are lots of people that pay no attention to the words in reviews and look solely at the score given. This was an interesting exercise for us as we were pretty sure there was a difference just based on casual comparisons and we're glad we went through it to get the data to back it up. For the others that are into such things, we hope you find the article interesting.
You can find the follow up to this article with opinions here.
Aaron LoomisCigar Editorial: When is a 90 not a 90 10.26.2017
Cigar Editorial: When is a 90 not a 90 – 3 Years Later
Cigar Editorial: When is a 90 not a 90 – 1 Year Later


Studies over the years (such as this one) have shown repeatedly that children whose parents read to them have larger vocabularies than children who aren't regularly exposed to the written word. That message seems to be getting through: A new study from the Pew Research Center's Internet & American Life Project found that half of all parents with children under 12 say they read to them every day; another 26 percent say they read to their child a few times a week.
As one might expect, parents are more likely to read to children 5 and younger than to older kids — most of whom, presumably, can read on their own. Mothers are more likely than fathers to read to their child every day (55% vs. 45%) as are parents under 40 (55% vs. 43%), those with incomes over $50,000 (60% vs. 42%) and those with at least some college education (59% vs. 36%).


Carte de l'Egypte Ancienne et Moderne, dressee sur celle du R.P. Sicard et autres, assujetties aux observations astronomiques.
This is an exceptional 1753 map of Egypt by Rober de Vaugondy. Centered in the Nile River Delta, the map covers Egypt and part of the Red Sea. Details various Sheikdoms, Prefectures and Provinces throughout along with several ancient towns and oases along the Nile. The important ancient caravan route from the Red Sea port of Berenice to Coptos (Qift) is noted. The pyramids near Memphis are also identified. Several other important towns, mountains, rivers and other topographical details are noted.
Several archeological surveys have been undertaken to unearth the labyrinth, but so far no findings have been confirmed.
A highly decorative title cartouche depicting a sphinx and pyramids appears in the bottom left quadrant. Drawn by Robert de Vaugondy and published in the 1757 issue of his Atlas Universal. The Atlas Universal was one of the first atlases based upon actual surveys. Therefore, this map is highly accurate (for the period) and has most contemporary town names correct, though historic names are, in many cases, incorrect or omitted.
Very good. Minor wear along original centerfold. Original platemark visible. Some spotting and mold stains near top and bottom margins.
Rumsey 3353.097. Pedley, Mary Sponberg Belle et Utile: The Work of the Robert de Vaugondy Family of Mapmakers, 431.


text: Q: How was a place in OSM before some month? I am in need of looking how the place was before some months or year. I have been adding places and ways in OSM since two months in a particular place. But now, I need previous view of OSM before I started digitization. Is there any way?

redpajama_set_name: RedPajamaStackExchange


Frederick Victor Marshall was born in the 3rd quarter of 1887 in Wotton, Surrey to coachman John Marshall and Martha Briggs Marshall nee Stokes.
At the time of the 1891 Census, the family lived at Broadmoor Cottage, Wotton, Surrey. John was working as a coachman and Martha was at home. The household further comprised of their children: agricultural labourer William, stable boy Albert, Henry, Alice Kate, Samuel Stokes, Francis James, Rose Emily, Mary, Frederick Victor and Louise E. Marshall. John´s mother Mary Ann Marshall also lived in the cottage.
At the time of the 1901 Census, the family lived at 69 Orchard Road in Dorking. John Marshall was working as a coachman and Martha Briggs Marshall was at home. The household further comprised of their children: Rose Emily, Frederick, Louise and Daisy.
At the time of the 1911 Census, the family lived at 47 Falkland Road in Dorking. John was working as a cab driver and Martha was at home. Of their children: Samuel Stokes was working as a chauffeur, Frederick was a bricklayer´s labourer and Daisy was at school. The household further comprised of John´s son Francis James, his wife Jane Hannah and their children Francis Christian and Winifred Patty. The accomodation had four rooms. Martha stated that she had given birth to 15 children of whom 11 were still alive.
Frederick married Violet Amelia Jeffries, by Banns, on the 4th of January 1914 at St Martin´s church in Dorking. At the time of their marriage Frederick was working as a labourer and lived at 47 Falkland Road in Dorking. Violet lived at 29 Walton Road in Dorking.
Violet Jeffries was born about 1894 in Bromley, Hertfordshire to labourer Frederick Jeffries. She was baptised on the 18th of February 1894 at Holy Trinity church, Horsham, Sussex. At the time of the 1911 Census, Violet lived with her adoptive parents, brick setter, Frederick Etherington and Jane Etherington at 29 Walton Road in Dorking. At this time Violet was working as a domestic servant.
Frederick and Violet had two children: Margaret V. Marshall born in the 3rd quarter of 1914, Winifred N. Marshall, both born in the 4th quarter of 1916 in the Registration District of Dorking, Surrey.
Private Frederick Marshall enlisted into the army at Kingston upon Thames. His regiment was the East Surrey Regiment, and he was a member of the first Battalion. This wasn't a Territorial Army formation but one of the regular army formations. On January 12th 1916 this merged into the 95th Brigade in the 5th division.
The 5th division took over a section of front line between St Laurent Blangy and the southern edge of Vimy Ridge, in front of Arras in March 1916. The Attacks on High Wood, The Battle of Guillemont, The Battle of Flers-Courcelette, The Battle of Morval, The Battle of Le Transloy these were all phases of the battle of the Somme. By 5th October 1916, the Division had left the Somme and was holding a quieter line near Festubert. There was a constant threat from enemy artillery and sniper fire, but in comparison with the Somme, it was a relatively peaceful. However this is most likely where Private Frederick Marshall was killed despite the tranquillity of the front.
Frederick Victor Marshall died on the 5th of November 1916 in France.
Before he joined the Army he had been employed at the North Holmwood brickyard.
Fredrick Marshall is commemorated on the Loos Memorial, France.
Frederick Victor´s wife Violet re-married Frank Leslie Prince Marwood in the 4th quarter of 1917 in the Registration District of Dorking, Surrey. She later lived at 31 Wathen Road in Dorking.
Frederick´s father John Marshall was born about 1847 in Dorking, Surrey to agricultural labourer William Marshall, born about 1821 in Dorking, Surrey, and Mary Ann Marshall, born about 1816 in Dorking, Surrey. John Marshall was baptised on the 10th of October 1847 in the Poor Law Union of Dorking. At the time of the baptism the family lived at Logmore. At the time of the 1871 Census, widowed Mary Marshall lived with her son John Marshall at Broadmoor, Wotton, Surrey. John was working as an agricultural labourer.
Frederick´s mother Martha Briggs Stokes was born on the 31st of March 1852 in London, Middlesex to William Stokes and Martha Stokes. Martha was baptised on the 1st of August 1852 at Redenhall with Harleston, Norfolk, England.
John and Martha married, by Banns, on the 23rd of December 1871 at St Paul´s church, Hook. At the time of the marriage John Marshall lived at Wotton and was working as a labourer. Martha lived in the Parish of Kingston.
Frederick Victor Marshall had fourteen siblings of whom twelve are known: William J. Marshall born about 1873; Albert G. Marshall born about 1874; Ellen M. Marshall born about 1876; Ada A. Marshall born about 1877; Henry A. Marshall born about 1879; Alice Kate Marshall born about 1880; Samuel Stokes Marshall born about 1882; Francis James Marshall born about 1884; Rose Emily born about 1885; Mary F. Marshall born about 1886; Louise E. Marshall born about 1890, all born in Wotton, Surrey and Daisy Dorothy Marshall born about 1897 in Abinger, Surrey.
At the time of the 1881 Census, the family lived at Broadmoor, Wotton. John Marshall was working as an agricultural labourer and Martha. The household further comprised of John´s mother Mary Ann Marshall.


text:
by Melanie Jackson
Love Spell, August, 2003.
Paperback, 342 pages.
Subgenre: Paranormal
Io Cyphre is an undercover agent for HUG, Humans Under Ground. In her first serious assignment, she's sent to Goblin Town (a grimly fascinating alternate reality version of Detroit) to find out more about the Goblin Fruit, which is addicting and killing humans at an alarming pace. Since the Goblins arrived from France (described in a very funny backstory) America begrudgingly gave them asylum and they are now insidiously working their way into mainstream society. Io's co-agent on this mission is Jonathan "Jack" Frost, a dangerous death fey who is also a legendary operative. As Io and Jack delve deeper into the goblin's underground headquarters, they discover shocking secrets that could spell the end of humankind.
Like Laurell K. Hamilton, Melanie Jackson takes romance to a different, darker place with results that are both edgy and entertaining. In this first book of her new Wildside series, Jackson raises the bar for the genre. There is magic, passion and gritty crime drama, all set against a vivid and disturbing background. This is an imaginative and well-imagined story that should earn Melanie Jackson a large following.
Traveler is available for purchase on Amazon.com
Note: We may receive a commission from sales made through product links in this article.
This review was published in the September-October, 2003 of The Internet Writing Journal.
Copyright © Writers Write, Inc. All Rights Reserved.


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