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Background Aging and type 2 diabetes (T2DM) are associated with an increased risk of sarcopenia. Diagnosis of sarcopenia is commonly done using dual-energy X-ray absorptiometry (DXA) in specialized settings. Another available method for assessing body composition is direct segmental multi-frequency bioelectrical impedance analysis (DSMF-BIA). Here, we examine the accuracy of a DSMF-BIA (InBody-770) for assessing body composition in older adults with T2DM when compared to DXA. Methods Eighty-four obese/overweight older adults (49 women, 71 ± 5 years) with T2DM who were recruited for the CEV-65 study and had both DSMF-BIA and DXA assessments at baseline were included. The analysis included Bland–Altman plots and intra class correlation coefficients. Sub-analyses were performed according to gender and following 10 weeks of interventions (diet, circuit training, and Empagliflozin). Results The leg lean mass results according to DSMF-BIA and DXA were 14.76 ± 3.62 kg and 15.19 ± 3.52 kg, respectively, with no difference between devices according to Bland–Altman analyses (p = 0.353). Assessment of appendicular skeletal mass index did not differ between DSMF-BIA and DXA (7.43 vs. 7.47 kg/m2; p = 0.84; ICC = 0.965, p p = 0.595). Gender and treatment interventions did not modify the accuracy of the DSMF-BIA when compared to DXA. Conclusions In older adults with T2DM the degree of agreement between DSMF-BIA and DXA, was high, supporting the use of DSMF-BIA to measure muscle mass.

Background: Migraine is known to mildly increase the risk for ischemic stroke and is associated with vascular MRI markers. However, the potential effect of chronic headache (CH) on stroke outcomes has not been studied. Objective: We aimed to assess the interrelation between CH and post-stroke cognitive impairment. Methods: Data from 455 patients with a first ever stroke from the TABASCO study was available. All patients underwent 3T brain MRI, blood analysis, and a serial cognitive assessment at baseline and 6, 12, and 24 months after. Results: Eighty-five (18.7%) patients reported suffering from CH, of whom 53 (62.4%) reported symptoms of photophobia or nausea, and 34 (40%) reported an aura. CH was associated with female sex, lower prevalence of T2DM (p

Introduction Poor outcomes of coronavirus disease 2019 (COVID‐19) have been linked to diabetes but its relation to pre‐infection glycemic control is still unclear. Methods To address this question we report here the association between pre‐infection HemoglobinA1c (A1C) levels and COVID‐19 severity as assessed by need for hospitalization in a cohort of 2068 patients with diabetes tested for COVID‐19 in Leumit Health Services, Israel, between February 1 and April 30, 2020. Using the LHS integrated electronic medical records system we were able to collect a large amount of clinical information including age, sex, socioeconomic status, weight, height, body mass index, A1C, prior diagnosis of ischemic heart disease, depression/anxiety, schizophrenia, dementia, hypertension, cerebrovascular accident, congestive heart failure , smoking and chronic lung disease. Results Of the patients included in the cohort, 183 (8.85 %) were diagnosed with COVID‐19 and 46 were admitted to hospital. More hospitalized patients were female, came from higher socioeconomic background and had a higher baseline A1C. A prior diagnosis of cerebrovascular accident and chronic lung disease conferred an increased risk of hospitalization but not obesity or smoking status. In a multivariate analysis, controlling for multiple prior clinical conditions, the only parameter associated with a significantly increased risk for hospitalization was A1C≥9%. Conclusion Using pre‐infection glycemic control data we identify A1C as a clear predictor of COVID‐19 severity. Pre‐infection risk stratification is crucial to successfully manage this disease, efficiently allocate resources and minimize the economic and social burden associated with an undiscriminating approach. This article is protected by copyright. All rights reserved.

Objective To examine the effect of a novel antistigma intervention curriculum (ASIC) in reducing stigma toward psychiatry among medical students. Methods Medical students from 8 hospitals in central Israel were divided into intervention (n = 57) and control (n = 163) arms. The students completed the 30-item Attitudes Toward Psychiatry (ATP-30) and the Attitudes Toward Mental Illness (AMI) scales at psychiatry rotation onset and conclusion. The ASIC was designed to target prejudices and stigma through direct informal encounters with people with serious mental illness (SMI) during periods of remission and recovery. Supervised small-group discussions followed those encounters to facilitate processing of thoughts and emotions that ensued and to discuss salient topics in psychiatry. The study was conducted between November 2017 and July 2018. Results Significant between-group differences were found at endpoint for attitudes toward psychiatry and psychiatric patients (P < .001). Although changing attitudes toward psychiatry as a career choice was not part of the ASIC, a significant between-group difference emerged by endpoint (P < .001). Conclusions Implementation of an ASIC that includes contact with individuals with lived SMI experience followed by supervised small-group discussions is effective in reducing stigma in medical students' perceptions of people with mental illness and psychiatry. Further evaluation is warranted with regard to the long-term destigmatizing effects of an ASIC. Trial Registration ClinicalTrials.gov identifier: NCT03907696.

Aim To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla; 100 U/mL) with originator insulin glargine, Lantus (Sa-Gla), in people with type 1 diabetes mellitus (T1DM). Materials and methods This phase 3, randomized, active-controlled, open-label, 52-week study (ClinicalTrials.gov NCT02059161) enrolled 508 people with T1DM (HbA1c ≤11.0%; 97 mmol/mol) taking basal and prandial insulin. Participants were randomized 1:1 to once-daily Mk-Gla (n = 245) or Sa-Gla (n = 263). Dose titration of basal insulin was by a pre-breakfast plasma glucose dosing algorithm. The primary efficacy objective was assessment of the non-inferiority of HbA1c change from baseline (margin of 0.40% [4.4 mmol/mol]) for Mk-Gla compared with Sa-Gla over 24 weeks. The primary safety objective was assessment of anti-insulin antibody development over 24 weeks. Results The least squares (LS) mean HbA1c change from baseline at week 24 was -0.62 (95% CI -0.79, -0.45)% (-6.8 [-8.7, -4.9] mmol/mol) and -0.66 (-0.82, -0.50)% (-7.2 [-9.0, -5.4] mmol/mol) for Mk-Gla and Sa-Gla. The LS mean HbA1c difference was 0.04 (-0.11, 0.19)% (0.4 [-1.2, 2.0] mmol/mol) for Mk-Gla minus Sa-Gla, meeting the primary and secondary objective criteria for non-inferiority and equivalence. Week 24 mean insulin glargine dose for Mk-Gla and Sa-Gla was 0.46 and 0.48 U/kg, respectively. Similarity of HbA1c response and basal insulin dose trajectory persisted over the 52 weeks. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins over the 52-week study duration. Conclusions Mk-Gla and Sa-Gla exhibited similar efficacy and safety over 52 weeks in people with T1DM. ClinicalTrials.gov: NCT02059161.

Background Albuminuria is an established marker for endothelial dysfunction and cardiovascular risk in diabetes and prediabetes. Exercise induced albuminuria (EiA) appears earlier and may be a more sensitive biomarker for renal endothelial damage. We sought to examine the association between EiA, parameters of the metabolic syndrome, A1C levels, exercise ECG test results and sex related differences in a large cohort of healthy, pre-diabetic and diabetic subjects. Methods A total of 3029 participants from the Tel-Aviv Medical Center Inflammation Survey cohort (mean age 46 years, 73% men) were analyzed. Multiple physiologic and metabolic parameters including A1C were collected and albuminuria was measured in all subjects before and immediately after completing an exercise ECG test. Results Exercise increased urinary albumin to creatinine ratio (ΔEiA) by 2.8 (0–13.6) mg/g for median (IQR) compared to rest albuminuria (p 6.5% had an increased risk of higher ΔEiA (p 13 mg/g (top quartile) we found that women with ΔEiA > 13 mg/g were at greater risk for abnormal exercise ECG findings, (OR = 2.7, p = 0.001). Conclusion Exercise promotes excessive urinary albumin excretion in dysmetabolic patients. In women, a significant correlation exists between ΔEiA and A1C levels. A cutoff of ΔEiA > 13 mg/g in women may be used to identify populations at risk for abnormal exercise ECG test findings and perhaps increased cardiovascular risk. Future studies will be needed to further validate the usefulness of ΔEiA as a biomarker for cardiovascular risk in women with and without diabetes.

This study was designed to improve blood glucose level predictability and future hypoglycemic and hyperglycemic event alerts through a novel patient-specific supervised-machine-learning (SML) analysis of glucose level based on a continuous-glucose-monitoring system (CGM) that needs no human intervention, and minimises false-positive alerts. The CGM data over 7 to 50 non-consecutive days from 11 type-1 diabetic patients aged 18 to 39 with a mean HbA1C of 7.5% ± 1.2% were analysed using four SML models. The algorithm was constructed to choose the best-fit model for each patient. Several statistical parameters were calculated to aggregate the magnitudes of the prediction errors. The personalised solutions provided by the algorithm were effective in predicting glucose levels 30 minutes after the last measurement. The average root-mean-square-error was 20.48 mg/dL and the average absolute-mean-error was 15.36 mg/dL when the best-fit model was selected for each patient. Using the best-fit-model, the true-positive-hypoglycemia-prediction-rate was 64%, whereas the false-positive- rate was 4.0%, and the false-negative-rate was 0.015%. Similar results were found even when only CGM samples below 70 were considered. The true-positive-hyperglycemia-prediction-rate was 61%. State-of-the-art SML tools are effective in predicting the glucose level values of patients with type-1diabetes and notifying these patients of future hypoglycemic and hyperglycemic events, thus improving glycemic control. The algorithm can be used to improve the calculation of the basal insulin rate and bolus insulin, and suitable for a closed loop "artificial pancreas" system. The algorithm provides a personalised medical solution that can successfully identify the best-fit method for each patient.

BACKGROUND In contrast to earlier assumptions that the "ideal worker" should embrace traditional notions of career success, there is growing recognition that possessing holistic career values may be beneficial in the work domain as well. However, there is little empirical evidence to support this argument. We hypothesised that individuals who at the time of their university graduation possessed holistic career values would display stronger personal life satisfaction 20 years later, which in turn would enhance their work engagement (i.e. an individual's perceptions of the extent to which the work environment possesses engaging characteristics). METHODS Data from a longitudinal study of 158 university students who completed two questionnaires, one in 1992 and the other 20 years later, supported our hypotheses. RESULTS We found that individuals who possessed holistic career values displayed stronger personal life satisfaction 20 years later, which in turn enhanced their work engagement. We further found that this indirect effect of holistic career values on work engagement (through personal life satisfaction) is conditionally moderated by work-family interference. CONCLUSIONS Cultivating a holistic career perspective among employees is beneficial for both employee well-being (i.e. personal life satisfaction) and the flourishing of their organisations (i.e. work engagement).

Background Increasing evidence suggests that metabolism affects brain physiology. Here, we examine the effect of GLP-1 on simple visual-evoked functional Magnetic Resonance Imaging (fMRI) responses in cortical areas. Methods Lean (n = 10) and nondiabetic obese (n = 10) subjects received exenatide (a GLP-1 agonist) or saline infusion, and fMRI responses to visual stimuli (food and nonfood images) were recorded. We analysed the effect of exenatide on fMRI signals across the cortical surface with special reference to the visual areas. We evaluated the effects of exenatide on the raw fMRI signal and on the fMRI signal change during visual stimulation (vs rest). Results In line with previous studies, we find that exenatide eliminates the preference for food (over nonfood) images present under saline infusion in high-level visual cortex (temporal pole). In addition, we find that exenatide (vs saline) also modulates the response of early visual areas, enhancing responses to both food and nonfood images in several extrastriate occipital areas, similarly in obese and lean participants. Unexpectedly, exenatide increased fMRI raw signals (signal intensity during rest periods without stimulation) in a large occipital region, which were negatively correlated to BMI. Conclusions In both lean and obese individuals, exenatide affects neural processing in visual cortex, both in early visual areas and in higher order areas. This effect may contribute to the known effect of GLP1 analogues on food-related behaviour.

Background A giant congenital cervical teratoma is often highly vascularized; thus, in addition to a life-threatening airway occlusion at birth it comprises a high risk for significant and lethal blood loss during resection. In the case presented, an endovascular embolization of the carotid artery that supplied a giant congenital cervical teratoma was done as part of a three-stage treatment soon after birth and contributed to an overall good outcome. Embolization in cases of cervical teratomas was not described previously. Case presentation We present a case of a preterm newborn from a Sephardic jewish origin with a giant, highly vascularized, congenital cervical teratoma that was managed successfully in three stages: (1) delivery by an ex utero intrapartum treatment procedure after extensive preoperative planning and followed by tracheostomy, (2) endovascular embolization of the carotid artery that supplied the tumor in order to decrease blood loss during resection, and (3) complete surgical resection. The parents were involved in all the ethical and medical decisions, starting just after the cervical mass was diagnosed prenatally. Conclusion The management of giant congenital cervical teratoma is often challenging from both a medical and ethical prospective. Meticulous perinatal planning and parents’ involvement is crucial. Endovascular embolization of the tumor feeding vessels can significantly improve the resection outcome and overall prognosis.

Less attention has been given to the detection and nutritional status and needs of obese frail/sarcopenic older subjects. The aim of this study was to characterize the nutritional composition in older (≥65 years), frail-prone, obese subjects (defined by either waist circumference [WC] or body mass index [BMI]).A cross-sectional study with analysis of the national survey "Mabat Zahav". Random sample of 1751 community dwelling Israeli older adults (≥65 years). Eleven nutritional factors formerly linked to frailty were a-priori selected based on the current literature. Data was extracted from a 24-hour dietary recall. Adherence for each nutritional factor was defined using the Dietary Reference Intakes (DRI), and aggregated into a sum score of the overall adherence (ranging from "0" to "11", where "fair" adherence was defined as ≥6; inadequate adherence otherwise). Frailty likelihood was estimated using a validated non-direct model, and associations of nutritional factors with frailty-likelihood in obese vs non-obese individuals were examined. Additionally, a decision tree procedure based on machine learning was applied in order to capture nutritional factors related to frailty, stratified by gender, as well as by WC and/or BMI.Overall, the prevalence rates of frailty and pre-frailty were 7.1 and 57.6%, respectively. A "fair nutritional adherence" was less common among frail-prone compared to robust subjects (23.1% vs. 32.1%; p 0.0001). The intake of most frailty-related nutritional factors did not co-segregate according to the presence of abdominal or BMI-defined obesity. Still, compared to robust normal/overweight subjects, frail-prone obese (by BMI) individuals had a higher rate of inadequate nutritional adherence (odds-ratio 1.842; p 0.05). Of all 11 nutritional factors, folate in obese women and vitamin A (as retinol) and calcium in non-obese and obese men, respectively, were recognized as the most prominent predictors of frail-prone prevalence by the machine learning process. Although BMI was more closely associated with impaired intake of the 11 selected nutritional components than WC, this association was eliminated when frailty status, low income and education were considered.Frail-prone subjects differed from robust subjects in their nutritional intake. Nutritional inadequacies related to frailty-likelihood were mostly seen among obese women and non-obese men. In the prediction of inadequate adherence to the DRI of 11 nutritional components, obesity is a weaker predictor than frailty, lower education and low income in older Israeli adults.

Background Treatment of the older diabetic individual comprises a therapeutic challenge. Currently little scientific evidence exists depicting the best approach to type 2 diabetes treatment in this growing sub-population of patients. The purpose of this study is to assess the effects of a modified plant-based Mediterranean diet (“vegeterranean” diet), circuit resistance training (CRT) and empagliflozin, separately or in combination, on body composition and physical function in older subjects with type 2 diabetes. The rationale for this study is to assess three interventions associated with a negative energy/caloric balance (increased caloric use in exercise, caloric restriction in the “vegeterranean” diet and caloric wasting by glycosuria with empagliflozin), their interaction and effect on body composition and physical function. Methods One hundred and twenty men and women ≥65 years of age with type 2 diabetes, and low levels of physical activity will be randomized (1:1:1 manner, gender stratified) for 10 weeks to one of 3 parallel arms: CRT consisting of 3 home sessions/week; ad-libitum plant-based Mediterranean diet (limited consumption of eggs, dairy and fish, avoidance of red meat and poultry) or empagliflozin 10 mg/day. After 10 weeks CRT will be added to the empagliflozin and diet arms for an additional 10 weeks. Allocation concealment and blinding of primary outcome assessors will be implemented. Efficacy will be determined by assessment of lean body mass, body weight, frailty and functional status, sarcopenia, HbA1c and quality of life questionnaires. Safety will be evaluated by routine monitoring of adverse events. This study was approved by the Tel-Aviv Sourasky Medical Center Institutional Review Board. Discussion The combination and comparison of these diverse interventions to metabolic control may lead to better understanding of their mechanism of action with potential clinical implications in older individuals. Also, this study will provide evidence of the effectiveness of these interventions on delaying the progression from diabetes to sarcopenia and/or frailty. Trial registration ClinicalTrials.gov PRS: NCT03560375. Last registration date (last update): 06/06/2018. The trial was a-priori registered before actual recruitment of subjects. Electronic supplementary material The online version of this article (10.1186/s12877-019-1219-7) contains supplementary material, which is available to authorized users.

The larval developmental sites of Culicoides species were assessed from 1155 samples collected during the years 1969-2003. Culicoides circumscriptus was most prolific in mud with medium organic matter with proportional representation of 55.8%. Culicoides imicola breeds mainly in damp mixture of rotten, decomposed animal dung with or without some mud, with proportional representation of 97.2%. Culicoides obsoletus was found mostly in rotten banana stumps, with proportional representation of almost 100%. Culicoides puncticollis was found in mud with a medium amount of organic matter with proportional representation of 35.6%. Culicoides distinctipennis showed 22.2% proportional representation for mud poor in organic matter. Culicoides schultzei gr. was most prolifically in mud rich in organic matter with proportional representation of 6.2%. Culicoides cataneii was most prolifically in mud with a medium amount of organic matter with proportional representation of 1.8%. Maximum duration time to emergence from the larval developmental sites ranged from seven weeks in C. obsoletus to fourteen weeks in C. circumscriptus and nine weeks in C. imicola. All the studied species breed throughout the year. Significant innate differences in the proportions of the sexes were found in the emergence of six species.

Aim To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla) and Lantus (Sa-Gla) in people with type 2 diabetes mellitus (T2DM). Materials and methods This Phase 3, randomized, active-controlled, open-label, 24-week clinical trial (ClinicalTrials.gov number NCT02059187) enrolled 531 participants with T2DM (HbA1c ≤11.0%) either eligible for or currently taking basal insulin (≥10 U/day). Participants were randomized 1:1 to once-daily Mk-Gla (n = 263) or Sa-Gla (n = 263). Titration of insulin was guided by a fasting plasma glucose (FPG)-based dosing algorithm. The primary efficacy objective was to demonstrate the non-inferiority of change from baseline in HbA1c (margin of 0.40% [4.4 mmol/mol]) with Mk-Gla versus Sa-Gla after 24 weeks. The primary safety objective was anti-insulin antibody development after 24 weeks. Results For Mk-Gla and Sa-Gla, the least squares (LS) mean HbA1c change from baseline (95% CI) was -1.28 (-1.41, -1.15)% (-14.0 [-15.4, -12.6] mmol/mol) and -1.30 (-1.43, -1.18)% (-14.2 [-15.6, -12.8] mmol/mol). The LS mean HbA1c difference (Mk-Gla minus Sa-Gla) was 0.03 (-0.12, 0.18)% (0.3 [-1.4, 1.9] mmol/mol), meeting non-inferiority and equivalence (secondary objective) criteria. Insulin doses, FPG, and seven-point plasma glucose profiles were similar between groups. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins. The efficacy and safety of Mk-Gla and Sa-Gla were similar both in participants who were insulin-treated or insulin-naive at baseline. Conclusions Mk-Gla and Sa-Gla demonstrated similar efficacy and safety over 24 weeks of treatment in people with T2DM.

Internal mammary lymph node (IMN) chain assessment for breast cancer is controversial; however, current oncologic data have shed new light on its importance. Metastatic involvement of the IMN chain has implications for staging, prognosis, treatment, and survival. Here, we analyzed our data gathered during sampling of the IMN and the oncologic treatment changes that resulted from our findings. A retrospective chart review was performed on 581 patients who underwent free-flap breast reconstruction performed by the senior author. All dissected IMNs were submitted for pathological examination. Patient demographics, oncologic data, and the results of IMN sampling were reviewed. 581 patients undergoing 981 free flaps were identified. A total of 400 lymph node basins were harvested from 273 patients. Of these, nine had positive IMNs. Two of these nine patients had positive IMNs of the contralateral nonaffected breast. Five patients had positive axillary lymph nodes. Four patients had multifocal tumors, one of which was bilateral. Seven patients had an increase in cancer stage as a result of having positive IMNs. Six patients had a change in treatment: two patients required additional chemotherapy, one received adjuvant radiation therapy, and three necessitated both supplemental chemotherapy and radiation. Opportunistic biopsy of the IMN while dissecting the recipient vessels is simple and results in no added morbidity. We recommend that biopsy of the IMN chain be performed whenever internal mammary vessels are dissected for microsurgical anastomosis in breast cancer patients. Positive IMN involvement should encourage thorough oncological workup and treatment reevaluation. Case series.

Aim To evaluate the efficacy and safety of ertugliflozin and sitagliptin co‐administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin. Methods In this study (http://Clinicaltrials.gov NCT02099110), patients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) with metformin ≥1500 mg/d (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100) or to co‐administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26. Results At Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (−1.5%) and E15/S100 (−1.5%) than with individual agents (−1.0%, −1.1% and −1.1% for E5, E15 and S100, respectively; P < .001 for all comparisons). HbA1c

OBJECTIVE We have previously shown that chronic inflammation results in immunosuppression associated with CD247 downregulation in T lymphocytes. Type 2 diabetes mellitus (T2DM) is known to be associated with chronic inflammation. We therefore sought to examine CD247 expression levels in patients with T2DM and to assess whether it can serve as a diagnostic and prognostic biomarker for disease complications and outcomes. RESEARCH DESIGN AND METHODS Peripheral blood samples from 75 T2DM patients and 40 healthy control subjects were collected and analyzed for the expression level of CD247 in T lymphocytes. Subjects with T2DM underwent a medical interview with physical examination and were followed for an additional average of 19.2 ± 0.9 months to determine the occurrence of major adverse disease end points. The relationship between the level of CD247 expression and disease status at the time of blood draw and the ability of the marker to identify future complications was evaluated. RESULTS We observed a significant reduction in CD247 expression levels in T lymphocytes of T2DM patients when compared with healthy volunteers. CD247 downregulation was associated with disease severity, complications, and the occurrence of future cardiovascular events, suggesting its potential use not only as a diagnostic but also as a prognostic biomarker. CONCLUSIONS Our results suggest the use of CD247 as a biomarker in diabetic patients for evaluating the state of chronic inflammation that contributes to morbidity and mortality in this disease and for the prediction of future cardiovascular events.

Aims To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin. Materials and Methods In this double-blind randomized study (Clinicaltrials.gov NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53-91 mmol/mol] receiving metformin ≥1500 mg/d and sitagliptin 100 mg/d; estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2) were randomized to ertugliflozin 5 mg once-daily, 15 mg once-daily or placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52. Results A total of 464 patients were randomized (mean baseline HbA1c, 8.0% [64.3 mmol/mol]; eGFR, 87.9 mL/min/1.73 m2). After 26 weeks, placebo-adjusted least squares (LS) mean changes in HbA1c from baseline were −0.7% (−7.5 mmol/mol) and −0.8% (−8.3 mmol/mol) for ertugliflozin 5 and 15 mg, respectively (both P

The notion of service has been receiving increasing attention in organizational psychology literature in recent years, due to the client-oriented managerial movement. Yet, little to no attention has been paid to the service notion in educational psychology despite its high relevance to educational settings, given the pressure to be more service-oriented and possess a client-focused state of mind. The present study explores the notion of service in school domains by examining the joint effects of climate for service and the internal service in schools on teachers' work attitudes: work engagement, job satisfaction, and intention to leave their work. The notion of climate for service emphasizes the school's attitude of teachers as service providers to its clients (students and their parents); internal climate emphasizes the school's attitude of providing service to its teaching staff. The study was conducted via a sample of 423 teachers from 30 different schools in Israel. We hypothesized that the indirect relationship between the climate for service and teachers' job satisfaction and intention to leave work would be mediated by teacher work engagement. Our findings supported this hypothesis. Moreover, this indirect relationship via teacher work engagement was demonstrated most strongly when the internal service quality received was high, providing teachers with the capability to deliver what the service climate motivates them to do. Therefore, service-oriented resources-both climate for service and internal service-may be crucial in affecting teachers work attitudes and should be specifically targeted by principals and other educational decision makers.

Background and Purpose— Type 2 diabetes mellitus (T2DM) is associated with diseases of the brain, kidney, and vasculature. However, the relationship between T2DM, chronic kidney disease, brain alterations, and cognitive function after stroke is unknown. We aimed to evaluate the inter-relationship between T2DM, impaired renal function, brain pathology on imaging, and cognitive decline in a longitudinal poststroke cohort. Methods— The TABASCO (Tel Aviv brain acute stroke cohort) is a prospective cohort of stroke/transient ischemic attack survivors. The volume and white matter integrity, ischemic lesions, and brain and hippocampal volumes were measured at baseline using 3-T MRI. Cognitive tests were performed on 507 patients, who were diagnosed as having mild cognitive impairment, dementia, or being cognitively intact after 24 months. Results— At baseline, T2DM and impaired renal function (estimated creatinine clearance [eCCl] Conclusions— T2DM and impaired renal function are independently associated with abnormal brain structure, as well as poorer performance in cognitive tests, 2 years after stroke. The presence of both conditions quadruples the risk for cognitive decline. T2DM and lower eCCl have an independent and additive effect on brain atrophy and the risk of cognitive decline. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01926691.

Background We previously reported that induced pluripotent stem cell–derived cardiomyocytes manifest beat rate variability (BRV) resembling heart rate variability (HRV) in the human sinoatrial node. We now hypothesized the BRV-HRV continuum originates in pacemaker cells. Objective To investigate whether cellular BRV is a source of HRV dynamics, we hypothesized 3 levels of interaction among different cardiomyocyte entities: (1) single pacemaker cells, (2) networks of electrically coupled pacemaker cells, and (3) the in situ sinoatrial node. Methods We measured BRV/HRV properties in single pacemaker cells, induced pluripotent stem cell–derived contracting embryoid bodies (EBs), and electrocardiograms from the same individual. Results Pronounced BRV/HRV was present at all 3 levels. The coefficient of variance of interbeat intervals and Poincare plot indices SD1 and SD2 for single cells were 20 times greater than those for EBs ( P in situ heart (the latter two were similar; P > .05). We also compared BRV magnitude among single cells, small EBs (~5–10 cells), and larger EBs (>10 cells): BRV indices progressively increased with the decrease in the cell number ( P 2+ handling markedly augmented BRV magnitude, revealing a unique bimodal firing pattern, suggesting that intracellular mechanisms contribute to BRV/HRV and the fractal behavior of heart rhythm. Conclusion The decreased BRV magnitude in transitioning from the single cell to the EB suggests that the HRV of in situ hearts originates from the summation and integration of multiple cell-based oscillators. Hence, complex interactions among multiple pacemaker cells and intracellular Ca 2+ handling determine HRV in humans and cardiomyocyte networks.

Sudden cardiac death caused by ventricular arrhythmias is a disastrous event, especially when it occurs in young individuals. Among the five major arrhythmogenic disorders occurring in the absence of a structural heart disease is catecholaminergic polymorphic ventricular tachycardia (CPVT), which is a highly lethal form of inherited arrhythmias. Our study focuses on the autosomal recessive form of the disease caused by the missense mutation D307H in the cardiac calsequestrin gene, CASQ2. Because CASQ2 is a key player in excitation contraction coupling, the derangements in intracellular Ca(2+) handling may cause delayed afterdepolarizations (DADs), which constitute the mechanism underlying CPVT. To investigate catecholamine-induced arrhythmias in the CASQ2 mutated cells, we generated for the first time CPVT-derived induced pluripotent stem cells (iPSCs) by reprogramming fibroblasts from skin biopsies of two patients, and demonstrated that the iPSCs carry the CASQ2 mutation. Next, iPSCs were differentiated to cardiomyocytes (iPSCs-CMs), which expressed the mutant CASQ2 protein. The major findings were that the β-adrenergic agonist isoproterenol caused in CPVT iPSCs-CMs (but not in the control cardiomyocytes) DADs, oscillatory arrhythmic prepotentials, after-contractions and diastolic [Ca(2+) ](i) rise. Electron microscopy analysis revealed that compared with control iPSCs-CMs, CPVT iPSCs-CMs displayed a more immature phenotype with less organized myofibrils, enlarged sarcoplasmic reticulum cisternae and reduced number of caveolae. In summary, our results demonstrate that the patient-specific mutated cardiomyocytes can be used to study the electrophysiological mechanisms underlying CPVT.

Background Diabetes mellitus, characterized by chronic hyperglycemia, is known to have a deleterious effect on erythrocyte structure and hemodynamic characteristics, which eventually contribute to diabetes-associated vascular complications. Protein kinase C alpha (PKCα) is a major regulator of many metabolic processes and structural changes in erythrocytes, and may play a significant role in the development of hyperglycemia-mediated cellular abnormalities. Aim We hypothesized that acute hyperglycemic stress may affect erythrocyte structure and metabolic properties through its effect on PKCα membrane content and activity. Results Erythrocytes, from healthy individuals acutely exposed to a glucose enriched media, showed a significant decrease in the membranous fraction of PKCα and its phosphorylation (p = 0.005 and p = 0.0004, respectively). These alterations correlated with decreased affinity of PKCα to its membrane substrates (4.1R and GLUT1) and reduced RBC deformability (p = 0.017). Pre-activation of erythrocytes with PKC activator, PMA, minimized the effect of glucose on the membrane PKCα fraction and RBC deformability (p > 0.05). Conclusions Acute glycemia-induced inhibition of PKCα membranous translocation and activation is associated with reduced erythrocyte membrane deformability.

OBJECTIVE This study examined the effect of exenatide on brain activity measured by functional (f)MRI and on insulin secretion in lean and obese normal-glucose-tolerant individuals. RESEARCH DESIGN AND METHODS The brain fMRI signal in response to high-calorie-content food pictures was measured with and without intravenous exenatide infusion in 10 lean and 10 obese healthy volunteers. Insulin secretion was measured with a two-step (+100 and +200 mg/dL) hyperglycemic clamp with exenatide and with saline infusion. RESULTS The brain fMRI signal in response to food pictures in amygdala, insula, hippocampus, and frontal cortex was significantly greater in obese versus lean individuals. Intravenous exenatide significantly inhibited the fMRI signal in response to food pictures in obese individuals but did not affect the brain fMRI signal in lean subjects. Conversely, exenatide infusion caused an 18.5-fold increase in insulin secretion in lean individuals compared with an 8.8-fold increase in obese subjects. No significant correlation was observed between inhibition of the brain fMRI signal and increase in insulin secretion during exenatide infusion. CONCLUSIONS Exenatide causes greater augmentation in insulin secretion in lean compared with obese individuals but inhibits the brain response to food pictures only in obese individuals.

Gonadotropin-releasing hormone agonist (GnRHa) trigger instead of human chorionic gonadotropin in the context of ovarian hyperstimulation syndrome (OHSS) prevention has been used for >20 years. In its first decade it did not gain popularity because it cannot work in GnRHa-based ovarian stimulation protocols. The introduction of GnRH antagonists has revolutionized our ability to eliminate OHSS completely because patients at high risk for OHSS can be triggered with GnRHa. This has been documented in randomized prospective studies, in which none of the patients randomized to the agonist trigger arm developed OHSS. In other words, GnRHa proved to be a potent tool that, truly remarkably, never fails. Although there is some debate concerning the clinical outcome of these cycles, data so far indicate that aggressive luteal support can ensure a good outcome. Moreover, the large number of frozen embryos in these cycles results in excellent per-oocyte retrieval pregnancy rates. In summary, GnRHa ovulatory trigger is the ultimate tool for complete OHSS prevention. GnRH antagonist-based ovarian stimulation protocols should be considered in OHSS high-risk patients so GnRHa trigger can be used if needed.

Background: Complex wounds of the pelvis and perineum commonly occur as a result of primary and secondary ablative procedures for colorectal and gynecologic malignancies, particularly following previous radiation therapy to these regions. In certain instances, the more traditional flaps such as the vertical rectus abdominis and gracilis flaps are either unavailable or unsuitable for the reconstruction of particular defects. The posterior thigh flap has been described previously for pelvic defects but has not become as widely accepted as other regional flaps. Methods: This study sought to retrospectively review the authors' experience with the posterior thigh flap as an alternative to these more commonly performed transfers for difficult wounds of the perineum and pelvic structures. A total of 27 posterior thigh flaps were used in 19 patients for complex perineal wound closure. Results: Successful transfer of the posterior thigh flap was noted in 26 of 27 flaps (11 unilateral and eight bilateral), with only one flap failure (3.7 percent). Primary wound healing was ultimately achieved in all patients; however, early wound-healing complications were common (53 percent). Secondary procedures were necessary in seven patients (37 percent), with only one patient requiring a secondary flap procedure. Conclusions: The authors found the posterior thigh flap to be a useful and reliable flap for coverage of complex perineal wounds. This was particularly true for those patients in whom a laparotomy was best avoided and those who have had both urinary and fecal diversion.

A study was carried out to assess the effects of immediate postoperative oral rehydration in 51 unpremedicated women undergoing caesarean section under epidural anesthesia. The patients were randomly assigned to 2 groups: group 1 (n = 22)--fasting at least until 24 hours after the end of the operation, and group 2 (n = 29)--receiving immediate oral intake of fluids (water, tea or coffee with sugar) without limitation of quantity. The 2 groups were compared for the occurrence of postoperative nausea and vomiting, onset of peristalsis, rectal gas emission, first bowel movement, and possible complications. The results demonstrate no significant differences between the parturients who drank immediately postoperatively as compared to those in whom oral fluid intake was delayed for 24 hours or more. It is concluded that immediate postoperative oral rehydration had no harmful effect upon peristalsis post-caesarean section.

Aims FFA and FFA metabolites cause insulin resistance and impair beta cell function. The goal of our research was to examine whether elevation of plasma FFA impairs mitochondrial function and alters PGC-1α promoter methylation. Methods In this uncontrolled, change from baseline study design, insulin sensitivity and glucose-stimulated insulin secretion were measured in 9 normal glucose tolerant subjects before and after 3 day lipid infusion to elevate plasma FFA concentration. Vastus lateralis muscle biopsies were obtained and mitochondrial function, PGC-1α expression, and PGC-1α promoter methylation were quantitated. Results Increased plasma FFA (440±93 μmol/Lto 997±242 μM, p

Haemorrhagic tendency, including frequent epistaxis and easy bruising, has been observed in patients with beta thalassaemia major. Disturbances in the coagulation system were also described in this condition, which probably resulted from liver damage associated with this disease. There was, however, no quantitative or qualitative correlation between the haemorrhagic manifestations on the one hand and the abnormalities in the clotting mechanism on the other. Platelet functions were studied in 15 patients with beta thalassaemia major and in 5 with thalassaemia minor. In most of the thalassaemia major patients and in some with thalassaemia minor, diminished platelet aggregation to ADP, collagen, ristocetin and epinephrine was found. These anomalies could not be corrected by the resuspension of the thalassaemic platelets in normal plasma.

The clinical and research value of human embryonic stem cells (hESC) depends upon maintaining their epigenetically naïve, fully undifferentiated state. Inactivation of one X chromosome in each cell of mammalian female embryos is a paradigm for one of the earliest steps in cell specialization through formation of facultative heterochromatin. Mouse ES cells are derived from the inner cell mass (ICM) of blastocyst stage embryos prior to X-inactivation, and cultured murine ES cells initiate this process only upon differentiation. Less is known about human X-inactivation during early development. To identify a human ES cell model for X-inactivation and study differences in the epigenetic state of hESC lines, we investigated X-inactivation in all growth competent, karyotypically normal, NIH approved, female hESC lines and several sublines. In the vast majority of undifferentiated cultures of nine lines examined, essentially all cells exhibit hallmarks of X-inactivation. However, subcultures of any hESC line can vary in X-inactivation status, comprising distinct sublines. Importantly, we identified rare sublines that have not yet inactivated Xi and retain competence to undergo X-inactivation upon differentiation. Other sublines exhibit defects in counting or maintenance of XIST expression on Xi. The few hESC sublines identified that have not yet inactivated Xi may reflect the earlier epigenetic state of the human ICM and represent the most promising source of NIH hESC for study of human X-inactivation. The many epigenetic anomalies seen indicate that maintenance of fully unspecialized cells, which have not formed Xi facultative heterochromatin, is a delicate epigenetic balance difficult to maintain in culture.

The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue- nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.

A law permitting couples to conceive biological children through surrogacy was legislated in Israel in March 1996. The Rambam Medical Center has established the only nonprofit Surrogate Parenting Center at a public hospital in Israel. The multidisciplinary teamwork at the Center is case managed by a social worker. An important role of the social work intervention is consultation and support for the couple and the surrogate at all stages of the process. The case study presented in the article illustrates the need for sensitive and professional intervention due to the complexity of the surrogacy process and the crisis it involves for both the surrogate and the couple. In light of the growing parenting surrogacy cases in the United States, Europe, and Israel, a structured social work intervention model is described, which may be implemented at public or private surrogate parenting centers.

Applications for intense pulsed light (IPL) for hair removal are gaining favor among other methods, including lasers, because of its noninvasive nature, versatility regarding different skin and hair types, safety, and ease of use. Hair removal using IPL was performed from January 2002 to December 2003 on 108 consecutive patients. Eighty of these patients answered a questionnaire and were enrolled in the study group. The investigated parameters were hair and skin type, number of pulses, fluence, pulse duration, pulse delay, the filters used, and the treated area. The patient assessment of improvement (satisfaction) rate was graded from 1 to 5 points: 1, worse; 2, no improvement; 3, mild improvement; 4, good result; and 5, excellent result. The patients had between 1 and 13 treatments most of them during 2 to 6 sessions. Sixty-seven percent of the patients reported no complications. Prolonged erythema for more than 7 days was reported by 16.25%, blisters by 6.25%, temporary hyperpigmentation by 8.75%, leukotrichia was present in 1 case, and 1 case of persistent hypopigmentation was noted in a young girl. An increased number of complications and a decreased satisfaction rate were noted with higher skin types, but it was not statistically significant. Patients who underwent fewer treatments (1-3 treatments) were more satisfied compared with those who had more than 7 treatments (P < 0.02). Sixty percent of the patients rated their satisfaction to be good to excellent and 65% would ill recommend this treatment to their friends. To minimize the complication rate the authors found that the preset parameters should be adjusted at every treatment session according to the skin response at the previous one. Permanent hair removal cannot be guaranteed and it is not possible to predict the improvement rate. Nevertheless, based on patient satisfaction rate in this study, the authors recommend using IPL for hair removal.

The mechanisms underlying the immunomodulatory effects of mesenchymal stem cells (MSCs) have been investigated under extreme conditions of strong T cell activation, which induces the rapid death of activated lymphocytes. The objective of this study was to investigate these mechanisms in the absence of additional polyclonal activation. In co-cultures of peripheral mononuclear blood cells with human MSCs (hereafter referred to as hMSCs), we observed a striking decrease in the level of CD8 expression on CD8+ cells, together with decreased expression of CD28 and CD44, and impaired production of IFN-gamma and Granzyme B. This effect was specific to hMSCs, because it was not observed with several other cell lines. Downregulation of CD8 expression required CD14+ monocytes to be in direct contact with the CD8+ cells, whereas the effects of hMSCs on the CD14+ cells were essentially mediated by soluble factors. The CD14+ monocytes exhibited a tolerogenic pattern when co-cultured with hMSCs, with a clear decrease in CD80 and CD86 co-stimulatory molecules, and an increase in the inhibitory receptors ILT-3 and ILT-4. CD8+ cells that were preconditioned by MSCs had similar effects on monocytes and were able to inhibit lymphocyte proliferation. Injection of hMSCs in humanized NSG mice showed similar trends, in particular decreased levels of CD44 and CD28 in human immune cells. Our study demonstrates a new immunomodulation mechanism of action of hMSCs through the modulation of CD8+ cells towards a non-cytotoxic and/or suppressive phenotype. This mechanism of action has to be taken into account in clinical trials, where it should be beneficial in grafts and autoimmune diseases, but potentially detrimental in malignant diseases.

Treatment with intensive chemotherapy regimens is frequently complicated by severe thrombocytopenia. During the period of severe thrombocytopenia, anticoagulant treatment is not uncommonly indicated for thromboembolic events or thromboprophylaxis in these patients. We report 10 hematological patients treated with intensive chemotherapy protocols that were anticoagulated with enoxaparin for catheter related central venous thrombosis and thromboprophylaxis. During the period of severe thrombocytopenia the dosages of enoxaparin were reduced and no major bleeding occurred. Based on our experience we suggest that reduced dosages of low molecular weight heparins may be used relatively safely during transient severe thrombocytopenia.

The authors' experience using intense pulsed light for skin rejuvenation is summarized and analyzed with regard to its efficacy, safety, and complications. Rejuvenation using intense pulsed light was performed on 59 patients over a 6-month period (January of 2002 to July of 2002); these patients served as the study group. The areas treated were the face, neck, chest, hands, and legs. The parameters used during the procedure, patient satisfaction, and complications are described. Ninety-five percent of the patients included in the study had one or two sessions. Good to very good results were reported by 93.1 percent. Most patients had minor side effects and only three patients (5 percent) experienced complications (hyperpigmentation or scars). Intense pulsed light is an effective and safe method for skin rejuvenation. Its efficacy is mainly manifested by eliminating senile pigmentation and telangiectasias and a achieving a younger and fresher appearance of the skin. Although in the literature intense pulsed light skin rejuvenation is mainly reported for the face, the authors have obtained good results by using it for other areas of the body. The majority of the patients were satisfied. The authors conclude that intense pulsed light skin rejuvenation is a safe and effective method for facial and nonfacial rejuvenation.

SummaryThe general safety and efficacy of intravenous immunoglobulin (IGIV) as treatment for idiopathic thrombocytopenic purpura (ITP) has been well-studied. The current study compares the safety and efficacy of a novel IGIV (IGIV-C; Gamunex®, 10%) with a licensed solvent/detergent-treated product (IGIV-S/D; Gamimune®N, 10%) in treatment of ITP. Ninety-seven pediatric and adult patients with acute and chronic ITP were treated in a multi-center, prospective, randomized, double-blind parallel group, non-inferiority trial at 26 international sites. Baseline data (age, duration of ITP, platelet counts, previous treatment) were comparable between groups. Patients were treated with 1 g/kg/day of IGIV-C or IGIV-S/D for 2 days. The primary endpoint, proportion of patients whose platelet counts increased from ≤20 × 109/L to ≥50 × 109/L within 7 days after dosing, was achieved by 35/39 (90%) and 35/42 (83%) of patients treated with IGIV-C and IGIV-S/D, respectively. A secondary endpoint, maintaining platelet counts ≥50 × 109/L for ≥7 days, was achieved by 29/39 (74%) of IGIV-C and 25/42 (60%) IGIV-S/D treated patients. Compared with IGIV-S/D, fewer patients treated with IGIV-C received corticosteroids beyond day 7 (p = 0.02). Efficacy was independent of the presence of isoantibodies or blood type, supporting mechanisms of effect different from anti-D treatments. Adverse events were generally mild and occurred with similar frequency in each group. Viral safety monitoring for HIV, HCV, HBV and Parvovirus B19 showed no seroconversions on study. In conclusion, IGIV-C is as safe and efficacious as IGIV-S/D in treatment of ITP.

Bleeding is the most serious adverse event of oral anticoagulants and is a major cause of morbidity and mortality in such patients. Rapid reversal of anticoagulation in bleeding patients or prior to urgent surgery is mandatory. The therapeutic options in these situations include administration of fresh frozen plasma (FFP), and recently of prothrombin complex concentrates (PCCs). However, viral safety and thrombogenicity of PCCs remain issues of concern. In the present study, we administered Octaplex, a new solvent/detergent (S/D) treated and nanofiltered PCC, to excessively anticoagulated bleeding patients or to anticoagulated patients facing urgent surgery. Ten excessively anticoagulated patients with major bleeding and 10 anticoagulated patients awaiting surgery (median age 72.5 (43-83) years, 9 females) received a median dose of 26.1 IU/kg body weight (BW) of Octaplex for reversal of anticoagulation. Response to Octaplex was rapid with decline of INR within 10 min after Octaplex administration (from 6.1+/-2. to 1.5+/-0.3). Clinical response was graded as good in most patients (85%) and as moderate in the rest. Octaplex administration was uneventful in all patients. Following Octaplex administration, a small increase in F1+2 levels was observed in bleeding patients, whereas D-dimer level did not change significantly. We conclude that Octaplex is effective and safe in situations where rapid reversal of anticoagulation is needed.

Objective To investigate the effect of triggering oocyte maturation with GnRH agonist on corpus luteum function by measuring luteal phase levels of inhibin A and pro-αC. Design Prospective randomized trial. Setting In vitro fertilization (IVF) program at a university hospital. Patient(s) Infertile women undergoing IVF-ET treatment. Intervention(s) Controlled ovarian hyperstimulation with FSH and GnRH antagonist, triggering of final oocyte maturation with either hCG (n = 8) or GnRH agonist (n = 8), IVF-ET, and collection of blood samples every 2–3 days during the luteal phase. Main outcome measure(s) Luteal phase serum levels of inhibin A and pro-αC, P, and E 2 . Result(s) Levels of inhibin A, pro-αC, estrogen, and P were significantly lower from day 4 to day 14 after triggering final oocyte maturation by GnRH agonist compared with hCG. Maximal luteal serum inhibin A and pro-αC levels were 91.5 ± 23.6 and 184.1 ± 23.5 pg/mL in the GnRH agonist–treated women compared with 464.7 ± 209.1 and 7,351.6 ± 934.3 pg/mL in women treated with hCG. Conclusion(s) Triggering final oocyte maturation with GnRH agonist instead of hCG in IVF cycles dramatically decreases luteal levels of inhibins, reflecting significant inhibition of the corpus luteum function. This effect may explain, at least in part, the mechanism of ovarian hyperstimulation syndrome prevention by the use of GnRH agonist.

Thromboembolic disease is a rare, but important, complication of pregnancy that remains a leading non-obstetric cause of maternal death. The prevention and management of venous thromboembolism (VTE) in pregnant women is a complex area of medicine: a balance must be found between protecting the health of the mother and minimizing the risk to the unborn fetus. Until now, unfractionated heparin has been regarded as the drug of choice for the prevention and treatment of VTE during pregnancy. However, because of its significant side effects (osteoporosis and heparin-induced thrombocytopenia), the inconvenient mode of administration and need for monitoring, unfractionated heparin is now being replaced by low-molecular-weight heparin (LMWH). There is a convincing body of clinical evidence from well-designed studies and prospective case series that supports the efficacy and safety of LMWH in pregnant women. There are also encouraging observations on the efficacy of LMWH in the prevention of severe obstetric complications, which are frequently associated with inherited or acquired thrombophilias. The recently-published guidelines of The American College of Chest Physicians (ACCP), summarized in this review, allows the development of higher clinical standards. However, there is concern over the greater cost of LMWH compared with unfractionated heparin and oral anticoagulants, and cost-effectiveness studies are needed.

OBJECTIVE: To determine the risk of thrombophilias in women with unexplained intrauterine fetal deaths (IUFD). METHODS: All women with IUFD at 27 weeks’ gestation or greater were initially assessed during a period of 26 months. Subjects with multiple pregnancies, congenital anomalies, intrauterine infection, chorioamnionitis, immune hydrops, diabetes mellitus, previous thromboembolism, and severe hypertensive disease were excluded. The remaining 40 women with unexplained IUFD (study group) were matched for age and ethnicity with 80 healthy women who had at least one normal pregnancy (control group). All participants were tested at least 2 months after delivery for mutations of factor V Leiden, prothrombin gene, methylenetetrahydrofolate reductase, and for deficiencies of protein S, protein C, and antithrombin III. They were also tested and found to be negative for anticardiolipin antibodies. RESULTS: The gestational age at delivery and birth weight were significantly lower in the study group. The prevalence of inherited thrombophilias was 42.5% in the study group compared with 15% in the control group (odds ratio 2.8, 95% confidence interval 1.5, 5.3, P = .001). The prothrombin mutation and protein S deficiency rates were significantly higher in the study group (odds ratio 2.3, 95% confidence interval 1.3, 4.0, and odds ratio 3.2, 95% confidence interval 2.4, 4.1, respectively). CONCLUSION: Third-trimester IUFD is significantly associated with thrombophilias. These findings suggest that thrombophilia work-ups should be part of IUFD investigations and may have therapeutic and prognostic implications in future pregnancies.

Increased red cell aggregability might have unfavorable rheological effects in the microcirculation. It has been suggested that thrombolysis-related hypofibrinogenemia might be associated with a reduced erythrocyte adhesiveness/aggregation. We followed the reduction in erythrocyte adhesiveness/aggregation using a simple slide test and image analysis that measures the spaces that are formed between the aggregated erythrocytes. A significant (p = 0.01) reduction in the degree of erythrocyte adhesiveness/aggregation was noted in patients with acute myocardial infarction who received thrombolysis as opposed to individuals with Braunwald Class IIIB unstable angina who had normal fibrinogen concentrations. No change was found in the Westergren erythrocyte sedimentation rate, which is an indirect method to detect changes in aggregability of red blood cells. The present study shows the superiority of using a direct measurement of red blood cell adhesiveness/aggregation. This extremely rapid, cheap and almost bedside methodology to detect changes in erythrocyte adhesiveness/aggregation might be useful to detect changes of hemorheological relevance following thrombolysis.

The efficacy of oral anticoagulants (OAC) in reducing the incidence of stroke in elderly patients with atrial fibrillation (AF) has been well documented. The intensity of OAC therapy and deviations in the prothrombin time (PT) are the strongest risk factor for bleeding complications in elderly patients. The aim of this study was to evaluate a more rigorous regulation of OAC by the use of a portable whole blood PT-monitor (CoaguChek) in elderly patients with AF (age 65–80 years). The study group consisted of 20 patients, of whom 17 were evaluable , which were trained to use to CoaguChek monitor and adjust their anticoagulant dose for 12 months. The control group, 20 patients matched for age, gender and the duration of OAC treatment, were tested in an anticoagulant clinic and their OAC dose was adjusted by a physician. To validate the PT-monitor results, the patients performed a total of 129 simultaneous venous blood PT tests at various time points. The correlation coefficient R2 was 0.707 indicating the accuracy of the CoaguChek results. The self-managed patients perform more frequent measurements 46 ± 8.9 vs. 15.7 ± 3.1 PT tests per patient. They demonstrated a within the therapeutic range INR in 80.5% of the tests (95% confidence interval, 76.5–84.1%) as compared to 72.4% (95% confidence interval, 68.5–76.5%) in the control group (p = 0.057). The median value for all CoaguChek International Normalized Ratio (INR) recordings was within therapeutic range in the self-management group as well as in the control group. There were fewer INR results below or above the therapeutic range in the study group. None of the patients had hemorrhagic or thrombotic events during the study. Overall, the study group expressed high satisfaction from using the home monitor. We conclude that home PT monitoring and self-management of OAC are feasible in a motivated population of elderly patients with atrial fibrillation and are probably cost effective.

Maternal infection is associated with oxidative stress (OS) and inflammatory responses. We have previously shown that maternal exposure to lipopolysaccharide (LPS) at E18 alters the subsequent offspring immune response. As immune responses are mediated, in part, by OS, we sought to determine if maternal inflammation during pregnancy programs offspring OS and C-reactive protein (CRP) levels. Pregnant Sprague-Dawley rats received intraperitoneal (i.p.) injections of saline or LPS at 18 days’ gestation (n= 4), and pups delivered spontaneously at term. At postnatal day 24, male and female offspring received i.p. injection of LPS. Serum lipid peroxides formation (PD) and CRP levels were determined before and at 4 h following the LPS injection. Pups of LPS-exposed dams had significantly higher basal OS (PD 29.4 ± 5.4v.10.1 ± 4.8 nmol/ml) compared with controls. In response to LPS, CRP levels (20.4 ± 2.8v.5.7 ± 1.0 ng/ml) were significantly higher among pups of LPS-exposed dams than controls. Prenatal maternal exposure to LPS increases baseline OS levels in neonates and CRP levels in response to LPS. These results suggest that maternal inflammation during the antenatal period may induce long-term sequelae in the offspring that may predispose to adult disease.

Insulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic insulin clamp with muscle biopsy, and 3) 1H-magnetic resonance spectroscopy of tibialis anterior muscle before and after acipimox (250 mg every 6 h for 12 days). ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively. Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral glucose tolerance tests and insulin clamp in obese NGT and T2DM subjects and 2) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P < 0.001). Mitochondrial ATP synthesis rate increased by >50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin-resistant individuals is, at least in part, reversible.

OBJECTIVE: To compare placental pathology between women with and without thrombophilia who had severe preeclampsia, intrauterine growth retardation, severe abruptio placentae, or stillbirth. METHODS: After delivery, 68 women with singleton pregnancies with one of the above complications were evaluated for an inherited thrombophilia: factor V Leiden, methylenetetrahydrofolate reductase and prothrombin gene mutation, and deficiencies of protein S, protein C, and antithrombin III. Thirty-two women were thrombophilic (group A), and 36 women were not (group B). There was no difference in maternal age, parity, and type of pregnancy complication. A single pathologist examined each placenta. RESULTS: The gestational age at delivery, birth weight, and placental weight were significantly lower in group A. Three parameters showed significant differences between the groups: thrombophilic women had a higher number of villous infarcts (P < .01), more multiple infarcts (P < .05), and a higher incidence of placentas with fibrinoid necrosis of decidual vessels (P < .05). CONCLUSION: Placentas of women with severe complications and thrombophilia have an increased rate of vascular lesions.

Background: We designed a study to assess the safety and long-term efficacy of laparoscopic splenectomy (LS) for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). Methods: Over a period of 55 months, 104 patients underwent LS for chronic ITP. The perioperative course was documented and the long-term follow-up data were recorded. Results: The mean age was 36.9 years (range, 8-83) and 72 patients were female. Patients were operated on with a mean platelet count of 110,000/ml. Fifty-one patients were operated on with a platelet count of < 100,000; 18 of them had a count of < 50,000/ml and 11 had a count of < 10,000/ml. There were no conversions to laparotomy. Bleeding occurred in 14 patients, and five of them received a blood transfusion. The mean operating time was 56.5 min (range, 25-240). There were minor complications in five patients and major complications in three. The mean hospital stay was 2.1 days (range, 0-13). Over a mean follow-up period of 36 months (range, 4-62), all but four patients were available for follow-up. Eighty-four patients are in complete remission. Seven patients are in partial remission, with a platelet count of 50,000-100,000 \ml without medical treatment. Eleven patients did not respond or relapsed following a short initial response; three of them underwent later removal of an accessory spleen, two with partial response. All but two relapses occurred within 70 days of the operation. Conclusion: LS is safe and effective for the treatment of chronic ITP and yields excellent long-term results. Until another form of treatment emerges, LS should be considered the treatment of choice for this disease and recommended to the patient at an early stage of the disease.

Cyclizine is an antihistamine with sedative effect used to treat motion sickness. A few studies have reported on cyclizine abuse among teenagers, and cyclizine abuse has been reported among opioid dependants receiving methadone, with the combination having been reported to produce strong psychoactive effects. Few reports exist on the possible toxic effects of cyclizine, and it is regarded as a safe drug most often sold as a non-prescription/over-the-counter drug. Very few cases of fatalities resulting from cyclizine overdose can be found in the literature. We present a case where a 22-year-old female was found unconscious and intoxication with drugs and alcohol was suspected. Whole blood from the femoral vein, urine and stomach content were collected during autopsy and screened for drugs of abuse and medicinal drugs. GC–MS screening of the stomach contents revealed presence of cyclizine and meclozine. Cyclizine and meclozine concentrations in blood were determined using a UPLC–MS-MS method. Quantification of femoral blood revealed a high concentration of cyclizine (16 mg/L), a low concentration of meclozine (0.2 mg/L) and ethanol 0.16 g/dL. No other medicinal drugs or drugs of abuse were detected. We report on a case of suicide where cyclizine was found to be the principal drug and question the safety of this drug.

It has been reported recently that obstetric complications are associated with thrombophilias. Our objective was to investigate the association between pregnancy complications and the guanine 20210 adenine (G20210A) mutation in prothrombin gene.Two hundred and twenty-two women (study group) with obstetric complications were tested for the prothrombin mutation. Indications for testing were: severe preeclampsia, mild preeclampsia, intrauterine growth retardation, severe abruptio placentae, unexplained stillbirth, second trimester loss, and three or more consecutive spontaneous abortions. We also tested 156 healthy women who had at least one normal pregnancy and comprised the control group.Demographic data of the study and control groups were similar. Twenty-eight women of the study group (13%) were found to be heterozygous carriers of the 20210 variant of the prothrombin gene compared to five (3.2%) of the control group, p=0.001, odds ratio (OR) 2.9; 95% confidence interval (CI) 1.3-6.5. Compared to the control women, the prothrombin gene mutation was significantly more prevalent in women with IUGR, abruptio placentae, and second trimester loss but not in women with mild or severe preeclampsia, stillbirth and habitual abortion.Our data demonstrate that the mutation in the prothrombin gene is associated with specific pregnancy complications.