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MicroRNAs (miRNAs, miR) are endogenous short RNA sequences that regulate a wide range of physiological and pathophysiological processes. Several miRNAs control the formation of new blood vessels either by increasing or by inhibiting angiogenesis. Here, we investigated the possible role of the miR-106b� 25 cluster in postnatal neovas- cularization and in regulation of the angiogenic properties of adult bone marrow-derived stromal cells. Methods and results To study the effect of miR-106b� 25 deletion on neovascularization, we used a miR-106b� 25 knockout (KO) mouse model. After inducing hindlimb ischaemia, we showed that vascularization in ischaemic mice devoid of miR-106b� 25 is impaired, as evident from the reduced blood flow on laser Doppler perfusion imaging. The miR-106b� 25 cluster was also shown here to be an essential player in the proper functioning of bone marrow-derived stromal cells through its regulation of apoptosis, matrigel tube formation capacity, cytokine secretion, and expression of the stem-cell marker Sca-1. In addition, we showed that capillary sprouting from miR-106b� 25 KO aortic rings is diminished. Conclusion These results show that the miR-106b� 25 cluster regulates post-ischaemic neovascularization in mice, and that it does so in part by regulating the function of angiogenic bone marrow-derived stromal cells and of endothelial cells.

Background: Most studies on the prevalence of flexible pes planus (FPP) have been conducted in pediatric populations and older adults. There is limited comparable information on these parameters for the adolescent age group. The purpose of this study was to report the prevalence of FPP and its association with body mass index (BMI), body height, and gender among healthy and fit adolescents. Methods: The data for this study were derived from a medical database containing records of 17-year-old males and females before their recruitment into mandatory military service. Information on the disability codes associated with FPP according to the Regulations of Medical Fitness Determination was retrieved. Logistic regression models were used to assess the association between BMI, body height, and gender to various grades of FPP severity. Results: The study cohort included 825 964 adolescents (467 412 males and 358 552 females). The prevalence was 12.4% for mild FPP and 3.8% for severe FPP among the males and 9.3% and 2.4%, respectively, for the females. An increased BMI was associated with FPP in both males (overweight: odds ratio [OR] 1.385, confidence interval [CI] 1.352-1.419, P < .001; obese: OR 1.765, CI 1.718-1.813, P < .001) and females (overweight: OR 1.408, CI 1.365-1.620, P < .001; obese: OR 1.549, CI 1.481-1.620, P < .001). Body height was associated with a decreased risk of FPP when the highest height quintile was compared with the lowest height quintile in both males (OR 0.782, CI 0.762-0.802, P < .001) and females (OR 0.730, CI 0.707-0.754, P < .001) for all FPP severity grades. Conclusions: There was a greater prevalence of FPP among males compared with females in a general healthy adolescent age group. FPP was associated with increased BMI and shorter body height for all grades of FPP severity. Level of Evidence: Level II, diagnostic study.

OBJECTIVE Association between white blood cell (WBC) count and diabetes risk has been recently suggested. We assessed whether WBC count is an independent risk factor for diabetes incidence among young healthy adults. RESEARCH DESIGN AND METHODS WBC count was measured in 24,897 young (mean age 30.8 ± 5.36 years), normoglycemic men with WBC range of 3,000 to 12,000 cells/mm3. Participants were periodically screened for diabetes during a mean follow-up of 7.5 years. RESULTS During 185,354 person-years of follow-up, diabetes was diagnosed in 447 subjects. A multivariate model adjusted for age, BMI, family history of diabetes, physical activity, and fasting glucose and triglyceride levels revealed a 7.6% increase in incident diabetes for every increment of 1,000 cells/mm3 (P = 0.046). When grouped in quintiles, a baseline WBC count above 6,900 cells/mm3 had an independent 52% increase in diabetes risk (hazard ratio 1.52 [95% CI 1.06–2.18]) compared with the lowest quintile (WBC CONCLUSIONS WBC count, a commonly used and widely available test, is an independent risk factor for diabetes in young men at values well within the normal range.

Background: The chemokine eotaxin-2 is a potent chemoattractant for inflammatory cells, the predominants of which are eosinophils. Human and murine atherosclerotic plaques are known to exhibit inflammatory phenotypes where a complex interaction of cytokine and chemokines plays a role. We tested the hypothesis that eotaxin-2 (eo-2) plays a causative role in the initiation and progression of experimental atherosclerosis. Methods and Results: Sera collected from atherosclerotic ApoE knockout (KO) mice, exhibited significantly higher levels of eo-2 compared to sera collected from their background age matched C57BL/6 litters by ELISA. Moreover, levels of eo-2 were higher in old atherosclerotic ApoE KO mice than in young animals. Similarly, the expression level of the eo-2 receptor, CCR3, was increased in splenocytes of old ApoE compared to the young littermates. Administration of polyclonal blocking antibodies to eotaxin-2 resulted in a significant reduction of early atherosclerotic plaques in ApoE KO mice whereas prolonged treatment of mice with advanced plaques led to atheroma stabilization. A monoclonal antibody (D8) prepared against eo-2 attenuated adhesion of lymphocytes to fibronectin and potently inhibited their migration towards VEGF. Monoclonal blocking antibodies to eo-2 also significantly reduced atherosclerotic plaques in ApoE KO mice. Conclusion: Eo-2 serum levels are elevated in sera of ApoE KO mice with experimental atherosclerosis and its blockade is associated with reduced fatty streak accumulation and increased plaque stabilization.

To investigate the association between occupational risk factors and the incidence of knee disorders in a young adult population.Israeli recruits to the Israel Defense Forces go through a rigorous medical investigation. Study participants were classified by prior knee condition status and divided into 5 categories of prospective occupational exposure to physical activity according to their assigned military duties, and were then followed for 30 months for the development of severe knee disorders (SKD). Logistic regression analysis was used to estimate the occupational risks for incident SKD, adjusted for any previous mild or moderate disorder, body mass index, and body height at induction.The study population consisted of 76,491 males. SKD developed in 615 (0.8%). Compared to administrative workers as referents, a higher risk of developing SKD was manifest among high intensity combat occupations, (odds ratios [OR] 2.15), those in moderate intensity combat occupations (OR 2.57) and maintenance (OR 1.59). Drivers did not demonstrate increased risk of knee disorders compared to referents.Occupational factors during military service are associated with incident SKD, even when taking into account previous knee disorders, body mass index, and height, which also had independent effects in our study population.

Obesity has been linked to various malignancies, but a clear relation of overweight with urothelial cancer has not been established. We assessed the association between adolescent obesity and future risk for urothelial cancer. Medical data on 1,110,835 Israeli adolescents examined for fitness for military duty between 1967 and 2005 were linked to the National Cancer Registry in this nationwide population-based cohort study. We used Cox proportional hazards modeling to estimate the covariate-adjusted hazard ratio (HR) for urothelial cancer associated with BMI measured at age 17. The mean follow-up of 17.6 ± 10.8 years reflected 19,576,635 person years, during which 661 examinees developed urothelial cancer of the bladder, ureter, or renal pelvis. BMI ≥ 85 th standard percentile in adolescence significantly predicted increased risk of urothelial cancer with a HR (adjusted for year of birth, education and religiosity) of 1.42 (95% confidence interval (CI), 1.13-1.77, P = 0.002). Similar results were observed using the ≥ 25 kg/m(2) definition of overweight (HR = 1.36 (95% CI, 1.08-1.72), P = 0.008). Incidence of urothelial cancer was significantly lower in the more educated and among those who attended religious schools. Overweight in adolescence is related to increased risk of future urothelial cancer. In view of the growing incidence of both urothelial cancer and adolescent obesity, our study suggests an avenue for possible prevention of urothelial cancer.

Starting well before Independence in 1948, and over the ensuing six decades, Israel has built a robust, relatively efficient public system of health care, resulting in good health statistics throughout the life course. Because of the initiative of people living under the British Mandate for Palestine (1922-48), the development of many of today's health services predated the state's establishment by several decades. An extensive array of high-quality services and technologies is available to all residents, largely free at point of service, via the promulgation of the 1994 National Health Insurance Law. In addition to a strong medical academic culture, well equipped (albeit crowded) hospitals, and a robust primary-care infrastructure, the country has also developed some model national projects such as a programme for community quality indicators, an annual update of the national basket of services, and a strong system of research and education. Challenges include increasing privatisation of what was once largely a public system, and the underfunding in various sectors resulting in, among other challenges, relatively few acute hospital beds. Despite substantial organisational and financial investment, disparities persist based on ethnic origin or religion, other socioeconomic factors, and, regardless of the country's small size, a geographic maldistribution of resources. The Ministry of Health continues to be involved in the ownership and administration of many general hospitals and the direct payment for some health services (eg, geriatric institutional care), activities that distract it from its main task of planning for and supervising the whole health structure. Although the health-care system itself is very well integrated in relation to the country's two main ethnic groups (Israeli Arabs and Israeli Jews), we think that health in its widest sense might help provide a bridge to peace and reconciliation between the country and its neighbours.

The secular trend of increasing weight may lead to a decline in height gain compared with the genetic height potential. The impact of weight on height in healthy male and female adolescents compared with their genetic height was assessed.Height and weight were measured in Israeli adolescent military recrutees aged 16-19 years between 1967 and 2013. The study population comprised 355,229 recrutees for whom parental height measurements were documented. Subjects were classified into four body mass index percentile groups according to the U.S. Centers for Disease Control and Prevention body mass index percentiles for age and sex:5th (underweight), 5th-49th (low-normal), 50th-84th (high-normal), and ≥85th (overweight-obese). Short stature was defined as height ≤ third percentile and tall stature as height ≥ 90th percentile for age and sex.Overweight-obese females had a 73% increased risk for short stature (odds ratio [OR]: 1.73, 95% confidence interval [CI] = 1.51-1.97, p.001). Conversely, underweight females had a 56% lower risk of short stature (OR: .44, 95% CI = .28-.70, p = .001) and a twofold increased risk for being tall (OR: 2.08, 95% CI = 1.86-2.32, p.001). Overweight-obese males had a 23% increased risk of being short (OR: 1.23, 95% CI = 1.10-1.37, p.001). Underweight females were on average 4.1 cm taller than their mid-parental height.Overweight-obese males and females had an increased risk of being short, and underweight females were significantly taller compared with their genetic height. The significantly increased height among underweight healthy females may reflect a potential loss of height gain in overweight-obese females.

In light of the worldwide increase in childhood obesity, we examined the association between body-mass index (BMI) in late adolescence and death from cardiovascular causes in adulthood.We grouped data on BMI, as measured from 1967 through 2010 in 2.3 million Israeli adolescents (mean age, 17.3±0.4 years), according to age- and sex-specific percentiles from the U.S. Centers for Disease Control and Prevention. Primary outcomes were the number of deaths attributed to coronary heart disease, stroke, sudden death from an unknown cause, or a combination of all three categories (total cardiovascular causes) by mid-2011. Cox proportional-hazards models were used.During 42,297,007 person-years of follow-up, 2918 of 32,127 deaths (9.1%) were from cardiovascular causes, including 1497 from coronary heart disease, 528 from stroke, and 893 from sudden death. On multivariable analysis, there was a graded increase in the risk of death from cardiovascular causes and all causes that started among participants in the group that was in the 50th to 74th percentiles of BMI (i.e., within the accepted normal range). Hazard ratios in the obese group (≥95th percentile for BMI), as compared with the reference group in the 5th to 24th percentiles, were 4.9 (95% confidence interval [CI], 3.9 to 6.1) for death from coronary heart disease, 2.6 (95% CI, 1.7 to 4.1) for death from stroke, 2.1 (95% CI, 1.5 to 2.9) for sudden death, and 3.5 (95% CI, 2.9 to 4.1) for death from total cardiovascular causes, after adjustment for sex, age, birth year, sociodemographic characteristics, and height. Hazard ratios for death from cardiovascular causes in the same percentile groups increased from 2.0 (95% CI, 1.1 to 3.9) during follow-up for 0 to 10 years to 4.1 (95% CI, 3.1 to 5.4) during follow-up for 30 to 40 years; during both periods, hazard ratios were consistently high for death from coronary heart disease. Findings persisted in extensive sensitivity analyses.A BMI in the 50th to 74th percentiles, within the accepted normal range, during adolescence was associated with increased cardiovascular and all-cause mortality during 40 years of follow-up. Overweight and obesity were strongly associated with increased cardiovascular mortality in adulthood. (Funded by the Environment and Health Fund.).

Objective Apolipoprotein A–V plays an important role in reducing plasma triglyceride levels. We hypothesized that expression of apoA–V would inhibit atherogenesis in apoE −/− mice fed chow diet which is a known model of hypercholesterolemia. Our aim was to study this protective effect and to explore possible mechanisms. Methods and results ApoA–V +/+ ApoE −/− mice expressing human apolipoprotein A–V ( h apoA–V) were generated and compared to apoE −/− mice. Atherosclerotic aortic sinus lesion area was 70% smaller in h apoA–V +/+ apoE −/− . This was accompanied by a 58% reduction in lesion macrophage content. Furthermore, advanced atherosclerotic lesions in h apoA–V +/+ apoE −/− mice showed features of a more stable plaque, manifested by 59% and 37% higher collagen and α-actin content, respectively. Plasma triglyceride and cholesterol levels in h apoA–V +/+ apoE −/− mice were 47% and 33% lower, respectively. These were associated with a 33% reduction in very low density lipoprotein triglyceride production and 2-fold acceleration in triglyceride-rich lipoprotein clearance in h apoA–V +/+ apoE −/− mice. In addition, h apoA–V +/+ apoE −/− mice showed enhanced insulin sensitivity (25% and 15% improvement in glucose tolerance and insulin responsiveness, respectively). Finally, h apoA–V +/+ apoE −/− displayed a milder systemic inflammatory response compared to apoE −/− mice, manifested by 22%, 65% and 15% lower plasma levels of TNFα, IL-1β and IL-6, respectively. Conclusions We showed that human apolipoprotein A–V is a potent modulator of atherosclerosis in mice through multiple modes of action. These findings may identify apoA–V as a potential therapeutic target for treatment of atherosclerosis.

Despite having a similar large extent of atherosclerotic coronary affliction, some patients suffer of recurrent cardiac events, whereas others remain asymptomatic.We hypothesized the existence of a systemic "signature" that could distinguish "vulnerable" patients with preexisting coronary atherosclerosis from those having similar risk factors and atheromatous burden, but no history of clinically evident plaque rupture/erosion.Twenty three patients who had at least two prior myocardial infarctions ("vulnerable group") were matched in respect to their background and coronary atherosclerosis extent with twenty one patients without a history of previous myocardial infarction who underwent routine coronary angiography before valvular surgery. We studied a panel of cytokines, antibodies and hormones including IL-6, IL-10, IL-12, antibodies to β2 glycoprotein I (β2GPI), antibodies to oxidized-LDL, adiponectin and resistin, along with levels of circulating EPCs and Tregs.A significantly higher level of Treg cells was present in the control (73.4%±4) than in the "vulnerable patient" group (62.2%±10.7), p0.001. IL-10 level was also significantly higher in the control than in the vulnerable patients (2.6±1.2 pg/ml versus 0.9±0.1 pg/ml respectively, p=0.03). There was no significant difference in the circulating levels of the other cytokines, hormones or EPCs between the two groups.Regulatory T cells and serum IL-10 may discriminate "vulnerable" versus stable patients and may have a protective role against plaque rupture in patients with coronary atherosclerosis.

Familial dilated cardiomyopathy is a major cause of advanced heart failure and heart transplantation. In most families, the disease-causing mutation is unknown, and relatives should therefore undergo periodic screening to facilitate early diagnosis and therapy. In the present study, we describe a novel titin truncation mutation causing adult-onset familial dilated cardiomyopathy in an Israeli Arab family. The family members underwent physical examination, electrocardiography, and Doppler echocardiography. Linkage to candidate loci was performed, followed by gene sequencing. We identified 13 clinically affected family members (8 men and 5 women, mean age 47 ± 12 years). Compared with their healthy first-degree relatives, the affected relatives had a larger end-diastolic left ventricular dimension (60 ± 10 vs 49 ± 4 mm, p

The increasing prevalence of adolescent obesity affects adult health. We investigated the association of adolescent overweight with pancreatic cancer incidence in a cohort of 720,927 Jewish Israeli men. Body mass index (BMI) was measured during a general health examination at ages 16–19 between the years 1967 and 1995. Overweight was defined as BMI ≥ 85th percentile of the reference US-CDC distribution in adolescence. Pancreatic cancer was identified by linkage with the Israel National Cancer Registry up to 2006. The mean follow-up period was 23.3 ± 8.0 years. During 16.8 million person-years, 98 cases of pancreatic cancer were detected. Using Cox proportional hazards modeling, overweight in adolescence predicted an increased risk of pancreatic cancer [hazard ratio (HR) = 2.09; 95% confidence interval (CI): 1.26–3.50, p = 0.005]. Compared with adolescents with ‘normal’ range BMI Z-scores (−1 to +1), adolescents with Z-scores > 1 showed significantly increased risk [HR, 2.28 (95% CI: 1.43–3.64), p = 0.001]. Lower education level (10 or less years of schooling vs. 11–12 years) was also associated with increased risk of pancreatic cancer [HR 1.90 (95% CI: 1.27–2.86, p = 0.002)], whereas height, country of origin and immigration status were not. Adolescent overweight is substantially associated with pancreatic cancer incidence in young to middle-aged adults. Applying our point estimates to the 16.8% prevalence of excess weight in Israeli adolescents in the past decade suggests a population fraction of 15.5% (95% CI: 4.2–29.6%) for pancreatic cancer attributable to adolescent overweight in Israel.

Background and Aims: The increasing prevalence of adolescent obesity affects adult health. We investigated the association of adolescent overweight with colorectal cancer incidence in a large cohort of males. Methods: Body mass index (BMI) was measured in 1.1 million Jewish Israeli males who underwent a general health examination at ages 16 to 19 between 1967 and 2005. Overweight was defined as BMI ≥ 85th percentile of the standard U.S. distribution in adolescence. Colorectal cancer was identified by linkage with the Israel National Cancer Registry up to 2006. The mean follow-up period was 17.6 ± 10.9 years, reflecting 19.5 million person-years. Cox proportional hazards modeling was used. Results: The prevalence of adolescent overweight increased from 9.9% to 16.8% in the first 10 and last 10 annual examination cohorts. Colon (n = 445) and rectal cancer (n = 193) cases were detected. Overweight predicted an increased risk of colon cancer [HR = 1.53; 95% confidence interval (CI), 1.17–2.02, P = 0.002] but not of rectal cancer (HR = 1.09; 95% CI, 0.38–1.73, P = 0.72). The risk was greatest for nonmucinous adenocarcinoma of the colon (HR = 1.68, 95% CI, 1.26–2.23, P = 0.001). The association of BMI ≥ 85th percentile with colon cancer was even more pronounced in analyses that were restricted to men followed until at least 40 years of age [N = 367,478; HR = 1.75 (95% CI, 1.33–2.3, P < 0.001)]. Conclusions: Adolescent overweight is substantially associated with colon cancer incidence in young to middle-aged adults. Impact: These long-term sequelae add to the urgency to seriously address increasing childhood and adolescent obesity with its attendant increasing population impact. Cancer Epidemiol Biomarkers Prev; 20(12); 2524–31. ©2011 AACR.

Low lymphocyte count has been considered a predictive marker of unfavorable outcomes for patients with heart failure (HF). Baseline blood samples for complete blood counts, differential counts, renal function tests. and lipid profile were prospectively obtained to assess the association between lymphocyte count and clinical outcomes in 305 patients with HF (average New York Heart Association [NYHA] class 2.8). The mean follow-up duration was 4.7 years (range 8 months to 8.4 years), and 111 patients (36%) died during the follow-up period. The mean lymphocyte count for the group was 1,803.64 ± 740.3, and the mean left ventricular ejection fraction (LVEF) was 37%. Patients with low lymphocyte counts (1,600 median count) after 8 years had significantly lower survival rates than those with lymphocyte counts ≥1,600 (58% vs 72%, p=0.012). The prediction of poorest survival was for patients in NYHA class III or IV and with lymphocyte counts1,600. Regression analysis showed that lymphocyte level, the LVEF, and NYHA class were predictors of mortality. Of these, NYHA class was the most prominent predictor, followed by lymphocyte count, which was even more significant than the LVEF (hazard ratio 0.76, p=0.037). In conclusion, the findings of this study demonstrate that total lymphocyte count is an important prognostic factor, inversely associated with predicted mortality. Although the total low lymphocyte count was correlated with a lower NYHA class and a lower LVEF, it emerged as an independent death risk factor in patients with chronic HF.

The association of body-mass index (BMI) from adolescence to adulthood with obesity-related diseases in young adults has not been completely delineated.We conducted a prospective study in which we followed 37,674 apparently healthy young men for incident angiography-proven coronary heart disease and diabetes through the Staff Periodic Examination Center of the Israeli Army Medical Corps. The height and weight of participants were measured at regular intervals, with the first measurements taken when they were 17 years of age.During approximately 650,000 person-years of follow-up (mean follow-up, 17.4 years), we documented 1173 incident cases of type 2 diabetes and 327 of coronary heart disease. In multivariate models adjusted for age, family history, blood pressure, lifestyle factors, and biomarkers in blood, elevated adolescent BMI (the weight in kilograms divided by the square of the height in meters; mean range for the first through last deciles, 17.3 to 27.6) was a significant predictor of both diabetes (hazard ratio for the highest vs. the lowest decile, 2.76; 95% confidence interval [CI], 2.11 to 3.58) and angiography-proven coronary heart disease (hazard ratio, 5.43; 95% CI, 2.77 to 10.62). Further adjustment for BMI at adulthood completely ablated the association of adolescent BMI with diabetes (hazard ratio, 1.01; 95% CI, 0.75 to 1.37) but not the association with coronary heart disease (hazard ratio, 6.85; 95% CI, 3.30 to 14.21). After adjustment of the BMI values as continuous variables in multivariate models, only elevated BMI in adulthood was significantly associated with diabetes (β=1.115, P=0.003; P=0.89 for interaction). In contrast, elevated BMI in both adolescence (β=1.355, P=0.004) and adulthood (β=1.207, P=0.03) were independently associated with angiography-proven coronary heart disease (P=0.048 for interaction).An elevated BMI in adolescence--one that is well within the range currently considered to be normal--constitutes a substantial risk factor for obesity-related disorders in midlife. Although the risk of diabetes is mainly associated with increased BMI close to the time of diagnosis, the risk of coronary heart disease is associated with an elevated BMI both in adolescence and in adulthood, supporting the hypothesis that the processes causing incident coronary heart disease, particularly atherosclerosis, are more gradual than those resulting in incident diabetes. (Funded by the Chaim Sheba Medical Center and the Israel Defense Forces Medical Corps.).

Preeclampsia and intrauterine growth restriction (IUGR) are pregnancy-specific disorders that share a common pathophysiology. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays an important role in placental development. HIF-1α is elevated in preeclamptic placentas and induces soluble vascular endothelial growth factor receptor-1 (sFLT-1), a central factor in preeclampsia and IUGR pathogenesis. Our objective was to investigate the effects of HIF-1α overexpression on pregnancy in mice. C57BL/6J pregnant mice were systemically administered either adenovirus expressing stabilized HIF-1α (cytomegalovirus [CMV]-HIF), luciferase control (CMV-Luc), or saline on gestational day 8. Pregnant mice overexpressing HIF-1α had significantly elevated blood pressure and proteinuria compared with pregnant controls. HIF-1α mice showed fetal IUGR, decreased placental weights, and histopathological placental abnormalities compared with control mice. Glomerular endotheliosis, the hallmark lesion of preeclampsia, was demonstrated in the kidneys of these mice relative to the normal histology in control mice. Moreover, liver enzyme levels were significantly elevated, whereas complete blood counts revealed significant anemia and thrombocytopenia in CMV-HIF mice compared with controls. Blood smears confirmed microangiopathic hemolytic anemia in CMV-HIF mice, consistent with HELLP (hemolysis, elevated liver enzymes, and low platelets)-like syndrome. CMV-HIF mice showed elevation in serum sFLT-1 and soluble endoglin, providing a mechanistic explanation for the observations. Collectively, our results suggest a possible role for HIF-1α in the pathogenesis of both preeclampsia and IUGR.

SummaryThe LIM-homeobox transcription factor islet-1 (Isl1) marks a cell population which gives rise to myocardial, pacemaker, endothelial and smooth muscle cells, which are derived from the secondary heart field during heart embryogenesis. Isl1+ precursors have the potential of self-renewal and differentiation into endothelial, cardiomyocyte and smooth muscle lineages. The primary objective of this study was to determine whether retroviral gene delivery of Isl1 to endothelial cells and mesenchymal stem cells (MSCs) could promote angiogenic and vasculogenic properties. To this end, endothelial cells and rat MSCs were retrovirally transduced to express Isl1. Isl1 expression in endothelial cells resulted in enhanced proliferation and adhesion to fibronectin. In addition, increased IL-1b and VEGF secretion was evident in Isl1 transduced endothelial cells, concomitant with increased migratory and tube formation properties of the endothelial cells. Isl1 expression in MSCs promoted their vasculogenic properties and resulted in enhanced in vitro tube formation. Finally, Isl1 expressing endothelial cells induced enhanced in vivo vascularisation in C57BL/6J mice. These data suggest, for the first time, that Isl1 promotes postnatal angiogenesis and vasculogenesis by improving the angiogenic properties of endothelial cells and MSCs.

Objective: Patients with age-related macular degeneration (AMD) exhibit pathologic neovascularization under the retina, with choroidal neovascularization (CNV) suggestive of defective angiogenesis. The endothelial progenitor cells (EPCs) present in the peripheral blood contribute to angiogenesis and vasculogenesis, and their regulation is altered in several vascular disorders. We investigated whether the numbers and functional properties of EPCs may be disordered in newly diagnosed neovascular AMD. Methods Fifteen suitable AMD patients and 10 controls matched for age, risk factors for atherosclerosis and use of medi- cation that could influence the circulating pool of EPCs were studied. Circulating EPCs were assayed by the col- ony-forming unit (CFU) method. The EPCs' adhesive capacity was studied by evaluating their ability to attach to fi- bronectin and cultured endothelial cells. Serum levels of vascular endothelial growth factor (VEGF) were studied and cor- related with EPC numbers. Results: The patients had significantly fewer circulating EPCs(16.5±2.8) compared to their controls (31±4.6; p=0.0085). The functional properties of both groups' EPCs were similar. Conclusions: The peripheral circulating pool of endothelial stem cells is altered in patients with newly diagnosed neovas- cular AMD, suggesting that pathologic angiogenesis may result from or influence the regulation of endothelial precursor circulation.

Background: Oxidative stress appears to play a significant role in the pathogenesis of heart failure (HF). Antibodies to oxidized low-density lipoprotein (Ox LDL Abs) reflect an immune response to LDL over a prolonged period and may thus represent oxidative stress over an extended time. Ox LDL Abs have been shown to correlate with clinical control in HF patients. We evaluated the predictive power of Ox LDL Abs on the outcome in patients with HF. Methods and Results: BaselinelevelsofOxLDLAbsweredeterminedbyenzyme-linkedimmunosorbent assay in 284 consecutive outpatients with severe chronic HF who were being treated in the cardiology services of our medical center. Their mean New York Heart Association (NYHA) Class was 2.8. The mean follow-up for the group was 3.7 years, during which 107 (37%) died. The mean time from symptom onset to first hospital admission from HF was 25.8 months. Ox LDL Abs were found to predict morbidity and mortality as evaluated by a Cox multivariate regression analysis with a hazard ration of 1.013 (P ! .013), whereas N-terminal pro-B-type natriuretic peptide (NT pro-BNP) levels achieved a HR of 1.028 (P ! .099). Conclusions: Ox LDL Abs level maybe a useful parameter for monitoring and planning better management of patients with HF. It was superior to pro-BNP as a predictor of clinical course as expressed by time to hospitalization. (J Cardiac Fail 2009;15:770e774)

Background Short stature was suggested as a risk factor for diabetes onset among middle age individuals, but whether this is the case among young adults is unclear. Our goal was to assess the association between height and incident diabetes among young men. Methods and Findings Incident diabetes was assessed among 32,055 men with no history of diabetes, from the prospectively followed young adults of the MELANY cohort. Height was measured at two time points; at adolescence (mean age 17.4±0.3 years) and grouped according to the US-CDC percentiles and at young adulthood (mean age 31.0±5.6 years). Cox proportional hazards models were applied. There were 702 new cases of diabetes during a mean follow-up of 6.3±4.3 years. There was a significant increase in the crude diabetes incidence rate with decreasing adolescent height percentile, from 4.23 cases/104 person-years in the

Video surveillance is a tool for managing safety and security within public spaces. In mental health facilities, the major benefit of video surveillance is that it enables 24 hour monitoring of patients, which has the potential to reduce violent and aggressive behavior. The major disadvantage is that such observation is by nature intrusive. It diminishes privacy, a factor of huge importance for psychiatric inpatients. Thus, an ongoing debate has developed following the increasing use of cameras in this setting. This article presents the experience of a medium-large academic state hospital that uses video surveillance, and explores the various ethical and administrative aspects of video surveillance in mental health facilities.

The effect of early hypertension on midlife cardiovascular (CV) mortality remains controversial. We assessed the association of established hypertension in late adolescence with subsequent CV mortality. Of 2,298,130 Israeli adolescents (60 % males; age 17.4 ± 0.3 years) who underwent a compulsory medical examination prior to military service between 1967 and 2010, 8720 teenagers (0.4 %) were formally diagnosed with persistent hypertension. Using Cox proportional hazards modeling, we compared the hypertensive group to the large normotensive group with regard to time to event analysis of midlife mortality due to cerebrovascular accidents (CVA), coronary heart disease (CHD), sudden death (SD) and their summation as cardiovascular disease (CVD). During 45,729,521 person-years of follow-up, we identified 2918 CV deaths—2879 and 39 among the 2,289,410 normotensive and 8720 hypertensive adolescents, respectively. Hypertension at a young age was associated with a threefold elevation of stroke mortality compared to normotension when adjusted for sex, age at examination, birth year, country of origin, socioeconomic status, education, body mass index (BMI) and height [hazard ratio (HR) 3.12; 95 % confidence interval (CI) 1.76–5.54; p

Background Physicians in Israel are required to do an internship in an accredited hospital upon completion of the medical studies, and prior to receiving the medical license. For most students, the assignment is determined by a lottery, which takes into consideration the preferences of these students. Objectives We propose a novel way to perform this lottery, in which (on average) a larger number of students gets one of their top choices. We report about implementing this method in the 2014 Internship Lottery in Israel. Methods The new method is based on calculating a tentative lottery, in which each student has some probability of getting to each hospital. Then a computer program “trades” between the students, where trade is performed only if it is beneficial to both sides. This trade creates surplus, which translates to more students getting one of their top choices. Results The average student improved his place by 0.91 seats. Conclusions The new method can improve the welfare of medical graduates, by giving them more probability to get to one of their top choices. It can be applied in internship markets in other countries as well.

Fig 3 is incorrect. The label on the y-axis of Fig 3 is missing. The label should read ‘Incidence Diabetes Rate (per 1,000 person-years).’ The authors have provided a corrected version here. Fig 3 Diabetes incidence rate by height categories at adulthood.

Asthma is one of the most common chronic diseases globally. Atopy, and especially allergic rhinitis (AR), was found as an important risk factor for asthma. The purpose of this study was to examine the association between different atopic parameters and military professions to the incidence of asthma.In a retrospective study, we included 128 591 Israel Defense Forces soldiers drafted between the mid-nineties to the early-2000s. We examined the incidence rates of asthma in relation to atopic background and to military profession.The relative risk (RR) for the development of asthma in persons with a history of AR and the RR for asthma in atopics vs. nonatopics was 1.86 (95% CI: 1.57-2.21) and 1.73 (95% CI: 1.47-2.04), respectively. The RR for the development of asthma in persons with a history of AR was higher in Combat Units (CU) and Administrative and Driving units (ADU) (RR = 2.80; 95% CI: 2.09-3.76 and RR = 1.58; 95% CI: 1.19-2.12, respectively) than in Maintenance Units (MU) (RR = 1.27; 95% CI: 0.93-1.74). When comparing the risk for asthma amongst persons with AR, we found it lower in MU compared to ADU (RR = 0.65; 95% CI: 0.43-0.97). In atopics vs. non-atopics, the risk for asthma was higher in ADU as compared to other occupations.Atopy, particularly AR, is a risk factor for the development of new-onset asthma in young adults. Atopy has the highest significant effect in CU where the physical demands are higher.

Background: Lymphocytes appear to influence atherosclerosis by altering cytokine production. Whereas primary lymphocyte activation requires T cell receptor ligation, costimulatory signals also appear requisite for generation of a functional T cell response. Inducible costimulator (ICOS) is a newly discovered T cell molecule with a dual role in immune mediated disorders. Herein, we tested the importance of ICOS in atherosclerosis. Methods and results: Atherosclerotic plaques from ApoE-KO mice were studied immunohistochemically for the presence and localization of ICOS and its receptors and its expression in splenocytes. ApoE-KO mice were immunized with human ICOS/Fc-chimera or non-fused Fc and either provided a chow diet for 6 weeks, or a high fat diet for 8 weeks. ICOS and its ligand were abundantly expressed within plaques from ApoE-KO mice: Spleen cells from atherosclerotic mice exhibited lowered constitutive expression of ICOS yet priming with oxLDL enhanced ICOS expression dose-dependently. In mice induced to develop fatty streaks and to generate ICOS blocking antibodies, early atherosclerosis was increased by ∼77% whereas upon inducing more advanced lesions, the increase in plaque area upon ICOS blockade group was ∼36%. IFN-gamma secretion by oxLDL-primed splenocytes in ICOS-immunized mice increased whereas IL-10 secretion diminished as compared to control animals. A similar trend in cytokine production was evident in the lesion by immunohistochemistry. Conclusion: ICOS appears as an influential costimulatory pathway in atherosclerosis that may play a protective rather that a proatherogenic role.

OBJECTIVES Herein, we determined the significance of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in atherosclerotic vascular disease. BACKGROUND Inflammation is associated with the pathogenesis of atherosclerosis. The TNF-related apoptosis-inducing ligand/APO-2L, a member of the TNF superfamily, has a role in apoptosis induction and is recognized for its immunomodulatory properties. METHODS Stable and vulnerable atherosclerotic human plaques and aortas from atherosclerotic mice were assayed for the presence of TRAIL, and its inducibility was assayed by immunoblot and real-time polymerase chain reaction on peripheral mononuclear cells incubated with oxidized low-density lipoprotein (oxLDL). Enzyme-linked immunosorbent assay was used for the determination of soluble TRAIL levels in atherosclerotic patients. RESULTS Tumor necrosis factor-related apoptosis-inducing ligand is present in stable atherosclerotic lesions, is increased in vulnerable plaques, and is found to colocalize with CD3 cells and oxLDL. The TNF-related apoptosis-inducing ligand messenger ribonucleic acid (mRNA) and protein expression was up-regulated in peripheral blood mononuclear cells after incubation with oxLDL. Serum levels of soluble TRAIL but not TNF-alpha or Fas-ligand were reduced significantly in patients with unstable angina as compared with patients with stable atherosclerotic disease and healthy subjects. A negative correlation was demonstrated between soluble TRAIL and C-reactive protein levels but not with levels of mRNA of TRAIL in peripheral blood mononuclear cells. CONCLUSIONS Tumor necrosis factor-related apoptosis-inducing ligand is expressed in plaque-infiltrating CD3 cells and induced by oxLDL, whereas levels of soluble TRAIL are reduced in patients with acute coronary syndromes and negatively correlate with C-reactive protein levels. These results support a possible role for TRAIL in atherosclerosis.

Study objective: To explore the causes of sudden and unexpected death in a young and healthy military population, to examine the various patterns of diseases associated with these tragic events, and to investigate the factors found to be associated with this grave outcome. Design: We retrospectively investigated 151 cases of Israeli military personnel who died unexpectedly over a 30-year period. We collected all the available medical records, autopsy results, and investigation committee reports. Results: A total of 151 cases of sudden and unexpected death occurred among enlisted military personnel during the period. Cardiac disorders caused 47% of deaths, followed by neurologic causes (17%) and pulmonary causes (11%). In 30 events (20%), the cause of death remained undetermined. Symptoms (eg, syncope, chest pain, palpitations, and others) occurred prior to death in 52 cases (34%). Asthma was the most common risk factor in our study population having been previously recognized in 10 cases (6.7%). Eight of the 13 subjects with asthma died following an acute asthmatic attack. Conclusion: Cardiac events are the leading cause of unexpected death in young healthy people. The frequency of subjects with asthma was found to be higher than that in the general age-adjusted population. (CHEST 2004; 126:528 –533)

To analyze patient satisfaction in Israeli Defense Forces primary care clinics (PCCs), and to compare different satisfaction indices that best correlate with general satisfaction index.Large-scale patient satisfaction survey throughout all PCCs, classified as active front clinics, training schools clinics, and home front clinics.Participants (5,103) filled out standardized questionnaires. Patients in active front clinics were more satisfied with their PCCs than in the other two settings. Patients showed the highest satisfaction level in the environment questions and the lowest satisfaction level in the accessibility questions. In training school clinics and home front clinics, accessibility questions were most important, whereas in active front clinics, health outcome questions prevailed.Overall patient satisfaction is the highest in active front clinics, lower in training school clinics, and lowest in home front clinics. Accessibility is the most important factor in patient satisfaction in training school and home front units, and is less important in active front units.

The aim of this work was to study the pathological processes underlying neurological dysfunctions displayed by BALB/C mice induced with experimental antiphospholipid syndrome (APS), as we have previously reported. Experimental APS was induced in female BALB/C mice by immunization with a pathogenic monoclonal anticardiolipin (aCL) antibody, H-3 (n=10), or an irrelevant immunoglobulin in controls (n=10). Mice immunized with H-3 developed clinical and neurological manifestations of APS, including: embryo resorption, thrombocytopenia neurological defects and behavioral disturbances. In mouse sera, the titer of various autoantibodies were elevated, including: anti-phospholipids (aPLs), anti-2 glycoprotein-I (β2GPI), anti-endothelial cell antibodies (AECA) and low titer of anti-dsDNA antibodies. Five months after APS induction, mice were sacrificed and brain tissue specimens were processed for hematoxylin and eosin (H&E), immunofluorescence staining and transmission electron microscopy (TEM). H&E staining of cortical tissue derived from all APS mice revealed mild inflammation, localized mainly in the meninges. Prominent IgG deposits in the large vessel walls and perivascular IgG leakage were observed by immunofluorescence. No large thrombi were observed in large vessels. However, EM evaluation of cerebral tissue revealed pathological changes in the microvessels. Thrombotic occlusion of capillaries in combination with mild inflammation was the main finding and may underlie the neurological defects displayed by mice with APS.

Background: 15-Lipoxygenase (15-LO) is a nonheme iron-containing enzyme that catalyzes the peroxidation of fatty acids. Herein, we studied the effect of 15-LO overexpression in the vascular endothelium on thymocyte apoptosis by evaluating thymuses from low-density lipoprotein receptor-deficient (LDL-RD) mice and LDL-RD/15-LO mice. Thymuses were evaluated by immunhistochemistry and by TUNEL whereas in vitro studies were carried out by employing freshly isolated thymocytes from the respective mice and evaluation of apoptosis by propidium iodide and annexin V cytometry. Methods and Results: The apoptotic index in LDL-RD/15-LO mice was significantly higher than in the LDL-RD mice. In the thymic medulla the difference was smaller, although still significant. Freshly isolated thymus cells from LDL-RD/15-LO mice exhibited a higher rate of spontaneous cell death than controls. Incubation of thymus cells in the presence of the cell-permeable caspase-3 inhibitor DEVD-CMK resulted in a decrease in the frequency of apoptotic cells in LDL-RD/15-LO thymocytes, whereas no effect was evident in control thymocytes. The antioxidant N-acetylcysteine causes the increase in apoptosis in both groups. Conclusion: LDL-RD/15-LO mice exhibit increased thymocyte apoptosis both in vivo and in vitro. These findings may suggest a role for 15-LO in the natural selection of thymocytes.

Summary Kawasaki disease (KD) is a systemic vasculitis with cardiac and noncardiac complications. Anti-­endothelial cell antibodies (AECA) are found among many patients with KD. The aim of this study was to investigate the pathogenic role of AECA in KD using in vitro and in vivo experimental models. F(ab)2 fragments of IgG-AECA and IgM-AECA were affinity purified from a patient with active KD. Their endothelial binding and ability to induce a pro-adhesive and a pro-inflammatory phenotype were evaluated in vitro. Twenty Balb/C mice were immunized with KD-AECA or with control Ig (N-Ig) to induce AECA in a murine model by the idiotypic manipulation method. Both KD-AECA isotypes bind significantly to human umbilical vein endothelial cell (HUVEC) compared to N-Ig. The in vitro activity was demonstrated by the antibodies ability to activate endothelial cells resulting in increased IL-6 secretion, adhesion molecule expression and monocytic cell line (U937) adherence to HUVEC. Five of the mice that received KD-AECA developed murine AECA after 3 months. None of the mice that received N-Ig produced AECA. The murine AECA increased monocyte adhesion to EC in vitro, similarly to the AECA used for immunization. Furthermore, all the mice that developed AECA had proteinuria and IgG deposition in the renal mesangium. No histological or immunofluorescence evidence of cardiac vasculitis could be detected. AECA might play a role in the emergence of some of KD manifestations.

Background — Atherosclerosis is a multifactorial disorder involving inflammatory processes. These responses are associated with robust activation of signaling cascades by diverse cell surface receptors in a variety of cell types. The processes that are involved in atherosclerosis would likely require intact Ras pathways, which play a key role in the control of cell growth, differentiation, and apoptosis. Methods and Results — We examined whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) can suppress atherogenesis in the apolipoprotein E–deficient mouse model. Mice were treated with FTS or a control regimen 3 times weekly for 6 weeks and fed a normal chow diet. Two additional groups included FTS-treated and control-treated mice that were fed a high-fat diet for 10 weeks. FTS reduced both fatty streaks and advanced lesions compared with the control treatment. Ras inhibition in vivo was evidenced by the reduced content of the active form of Ras (Ras-GTP) in aortas of FTS-treated mice. Splenocytes from the FTS-treated versus control mice exhibited reduced proliferation to oxidized LDL (OxLDL) but not to concanavalin A. IgG anti-OxLDL antibody levels were reduced in FTS-treated mice compared with controls. Whereas no effect of FTS was evident on plaque T lymphocyte and macrophage content, lesional vascular cell adhesion molecule-1 and nuclear factor-κB expression were considerably reduced compared with controls. Conclusions — FTS suppressed atherosclerotic plaques in apolipoprotein E–deficient mice, providing a useful tool for research in atherosclerosis.

This article presents findings from professional and scientific articles written on the subject of direct access to physical therapy services. Direct access is sometimes referred to as "self-referral"--the patient does not require a physician's referral prior to receiving physiotherapy treatment. The article provides insight from the experience of countries where direct access is accepted practice, which will serve as a theoretical and scientific basis for the use of direct access in Israel. Findings include the influence of direct access on the health care system: cost-benefit analysis, advantages and challenges, as well as the perspective of main stakeholders: physicians, physical therapists and patient-clients. .

OBJECTIVE Diabetes is a risk factor for an accelerated rate of cognitive decline and dementia. However, the relationship between cognitive function and the subsequent development of diabetes is unclear. RESEARCH DESIGN AND METHODS We conducted a historical-prospective cohort study merging data collected at premilitary recruitment assessment with information collected at the Staff Periodic Examination Center of the Israeli Army Medical Corps. Included were men aged 25 years or older without a history of diabetes at the beginning of follow-up with available data regarding their general intelligence score (GIS), a comprehensive measure of cognitive function, at age 17 years. RESULTS Among 35,500 men followed for a median of 5.5 years, 770 new cases of diabetes were diagnosed. After adjustment for age, participants in the lowest GIS category had a 2.6-fold greater risk for developing diabetes compared with those in the highest GIS category. In multivariable analysis adjusted for age, BMI, fasting plasma glucose, sociogenetic variables, and lifestyle risk factors, those in the lowest GIS category had a twofold greater risk for incident diabetes when compared with the highest GIS category (hazard ratio 2.1 [95% CI 1.5–3.1]; P < 0.001). Additionally, participants in the lowest GIS category developed diabetes at a mean age of 39.5 ± 4.7 years and those in the highest GIS group at a mean age of 41.5 ± 5.1 years (P for comparison 0.042). CONCLUSIONS This study demonstrates that in addition to a potential causal link between diabetes and enhanced cognitive decline, lower cognitive function at late adolescence is independently associated with an elevated risk for future diabetes.

Atherosclerosis is a complex vascular inflammatory disease. In the last decade it was suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) and in particular inhibition of cyclooxygenase (COX)-2 are associated with an increase in cardiovascular morbidity and mortality. Aspirin is known to reduce the incidence and mortality from ischemic heart disease and is a mainstay in the prevention of vascular complications of atherosclerosis.To examine the effect of meloxicam, a selective COX-2 inhibitor, or low dose aspirin on the development of experimental atherosclerosis in apoE knockout (KO) compared to wild-type (WT) mice. We aimed to test the hypothesis that meloxicam, a potential vasculitis inducer, would exacerbate atherosclerotic lesions while aspirin, which is known to reduce the incidence of thrombosis occlusive events, would increase protection in this model.We randomly divided 36 male apoE KO and 36 WT mice, 8 weeks old. Mice were treated for 10 weeks with 0.1 mg/ml aspirin, or 0.05 mg/ml meloxicam, dissolved in their drinking water. Control groups received regular drinking water. At sacrifice, the hearts were removed for histochemical staining and plaque size and composition were examined.Aspirin-treated animals displayed a decreased atherosclerotic lesion area compared to the untreated control mice, while meloxicam had a null effect on the extent of atherosclerosis in Apo E KO mice.These results suggest that low dose aspirin reduces early atherosclerosis, while inhibition of COX-2 by meloxicam is not associated with an increase in atherosclerotic plaque size in this mouse model.

Data on adolescent precursors of thyroid cancer in adulthood are scant.In order to evaluate potential risk factors for thyroid cancer, we linked two national data sources: the military recruitment health examinations and the Israel National Cancer Register. The study population (1,624,310 participants) included 1,145,865 Jewish males aged 16-19 years when examined between 1967 and 2005, and 478,445 Jewish females aged 16-19 years when examined between 1989 and 2005. The cancer follow-up extended up to 2006. Multivariable Cox proportional hazards modeling was used.During 24,389,502 person years of follow-up, 760 incidence cases of thyroid cancer were identified. The mean age at diagnosis was 25.2±4.2 years for women and 37.2±10.0 years for men. Women had a substantially higher incidence (birth cohort-adjusted hazard ratio (HR)=5.70 [95% CI 4.45-7.31]; p0.001). Height predicted incidence in both sexes, with birth cohort-adjusted HRs of 1.03 (p0.001) in males and 1.04 (p0.001) in females, per 1 cm increment in height. In males, but not in females, there was a graded association between education, as measured by years of schooling, and incidence of thyroid cancer. Body mass index was not associated with incidence. In a multivariable analysis of 617,613 males and 469,185 females examined from 1989 onwards, which included sex, birth year, height, and education, the excess risk in females persisted strongly (HR=5.67 [CI 4.30-7.13]), as did the association with height.Female sex, measured height in adolescence, and later birth cohorts were independent predictors of thyroid cancer in young and middle-aged adults in Israel. Further study is needed to unravel the mechanisms whereby height is associated with thyroid cancer.

Gene therapy directed specifically to the vascular wall, particularly to angiogenic endothelial cells is a prerequisite in vascular disease treatment. Angiogenesis is a major feature in many pathological conditions including wound healing, solid tumors, developing metastases, ischemic heart diseases and diabetic retinopathy. In the present study we developed a tissue-specific gene therapy to the angiogenic blood vessels of tumor metastasis using an adeno-based vector containing the murine preproendothelin-1 (PPE-1) promoter. Genes activated by the PPE-1 promoter were highly expressed in bovine aortic endothelial cells in vitro. Systemic injection of the adenoviral vectors AdPPE-1-luciferase and AdCMV-luciferase to normal C57BL/6 mice, resulted in higher activity of PPE-1 promoter compared with CMV promoter in the aorta and vascularized tissues such as heart, kidney, lung and pancreas. Systemic administration of the adenoviral vector, in mice bearing Lewis lung carcinoma, resulted in high and specific activity of PPE-1 in the new vasculature of primary tumors and lung metastasis. Cellular distribution of the delivered gene revealed highest expression of GFP in angiogenic endothelial cells of the metastasis. We expect that this approach of 'vascular-directed' gene therapy will be applicable to both vascular diseases and cancer.

Background —It has been proposed that autoimmune factors can influence the progression of atherosclerosis. We have previously shown that immunization of LDL receptor–deficient (LDL-RD mice) with β 2 -glycoprotein I (β2GPI; a principal target of “autoimmune” antiphospholipid antibodies) enhances early atherosclerosis. In the present study, we tested the hypothesis that adoptive transfer of β2GPI-reactive T cells can accelerate fatty streak formation in LDL-RD mice. Methods and Results —LDL-RD mice were immunized with human β2GPI. An additional group of mice were immunized with β2GPI and boosted with the same antigen 3 weeks later. Control mice with immunized with human serum albumin. Lymphocytes obtained from the draining lymph node cells or from splenocytes of β2GPI- or human serum albumin–immunized mice were stimulated in vitro with β2GPI or with the mitogen concavalin A, respectively. The cultured lymphocytes were transferred intraperitoneally to syngenic LDL-RD mice, and the mice were fed a high-fat “Western” diet for 5 weeks until death. Mice injected with lymphocytes from draining lymph nodes or spleens of β2GPI-immunized animals displayed larger fatty streaks than those induced by control treated animals. T-cell–depleted splenocytes from β2GPI were unable to promote lesion formation in the mice. Conclusions —The present study provides the first direct evidence for a role of antigen (β2GPI)-reactive T cells in the promotion of fatty streaks in mice.

Abstract —Atherosclerotic lesions can be induced in rabbits and mice immunized with heat shock protein 65 (HSP65). In the current study, we investigated the role of interleukin (IL)-4 in the HSP65- and Mycobacterium tuberculosis (MT)–induced models that exhibit an inflammatory phenotype. Fatty streak formation in IL-4–knockout (IL-4 KO) mice immunized with HSP65 or MT was significantly reduced when compared with lesions in wild-type C57BL/6 mice. However, when injected with control (HSP-free) adjuvant, no differences were evident in the lesion size between wild-type and the IL-4 KO mice. Next, we studied comparatively the extent of humoral and cellular immune responses to HSP65 in the IL-4 KO and wild-type mice, as those are thought to be influential in murine atherosclerosis. Anti-HSP65 antibody levels were reduced in the HSP65-immunized IL-4 KO mice as compared with their wild-type littermates, whereas no differences were evident between the groups with respect to the primary cellular immune response to HSP65. Other than the absence of IL-4 in the knockout mice, the pattern of secreting cytokines interferon-γ and IL-10 in concanavalin A–primed splenocytes was similar between the groups. HSP65-primed inguinal lymphocytes from IL-4 KO mice immunized with HSP65 secreted higher levels of interferon-γ (previously shown to be proatherogenic in vivo) as compared with their wild-type controls. 12-/15-Lipoxygenase expression, known to be regulated by IL-4 and to contribute to murine atherosclerosis, in the lesions was not influenced by the immunization protocol used or by IL-4 disruption. Thus, IL-4 may prove a principal cytokine in the progression of early “inflammatory” atherosclerotic lesions and may serve as a target for immunomodulation.

Diabetes and atherosclerosis have been proposed to be influenced by immune and autoimmune mechanisms. A common incriminated antigen in both disorders is the heat shock protein (HSP)-60/65. In the current study, we established a model combining hyperglycemia with hyperlipidemia in LDL receptor-deficient (LDL-RD) mice and assessed its possible influences on lipid profile, HSP60/65, and atherogenesis. LDL-RD mice were injected either with streptozotocin to induce hyperglycemia or with citrate buffer (control). When hyperglycemia was induced, both study groups were challenged with a high-fat (Western) diet for 6 weeks. Plasma fasting glucose, lipid profile, and antibody levels to HSP65 and oxidized LDL were assessed. At death, the spleens from both groups were evaluated for their proliferative response to HSP65 and the consequent cytokine production. The extent of atherosclerosis was assessed at the aortic sinus. Plasma glucose, cholesterol, and triglyceride levels were elevated in mice injected with streptozotocin compared with control mice. Atherosclerotic lesions were significantly larger in the streptozotocin-injected hyperglycemic LDL-RD mice (132 +/- 23 x 10(5) microm2) in comparison to their normoglycemic litter-mates (20 +/- 6.6 x 10(5) microm2; P < 0.0001). Both humoral and cellular immune response to HSP65 was more pronounced in streptozotocin-injected mice. When challenged with HSP65 in vitro, splenocytes from streptozotocin-injected mice favored the production of the T-helper (TH)-1 cytokine gamma-interferon. In conclusion, we have established a mouse model that combines hyperglycemia with diet-induced hyperlipidemia in LDL-RD mice and studied its effect on atherosclerosis progression. The accelerated atherosclerotic process is associated with heightened immune response to HSP65 and a shift to a TH1 cytokine profile.

The modern view of atherosclerosis is of a chronic inflammatory disorder. In accord with this paradigm, the process of uninhibited influx of fat to the vessel wall results from an ‘adequate’ response to various forms of injury (i.e. turbulence, infections, modified lipoproteins). This idea has been further extended by several groups, to assume that the atherosclerotic lesion can be the target of an autoimmune mediated attack. According to this hypothesis, the site of initiation of the plaque should bear/express the target autoantigen, whereas concomitantly a respective immune response is generated in the periphery. The examples illuminating this notion are β2GPI as a target autoantigen, HSP60/65 an oxidized-LDL. Herein we present evidence to support the involvement of autoimmune mechanisms in atherogenesis based on the experience from experimental models and human studies.

Measurements at the end of puberty of neonates short for gestational age (SGA-L) are scant.To determine the correlation between birth length and weight in neonates, with height and weight at age 17 years.385 full-term neonates, measuring less than 48 cm (SGA-L) and 585 full-term neonates, measuring 48 cm or greater (adequate birth length for gestational age; AGA-L) were included. 234 SGA-L and 359 AGA-L were identified at age 17 years.Comparison of the two groups revealed that both sexes born SGA-L were also shorter at age 17 years than those born AGA-L (girls 158.9 cm (SD 7.6) vs 164.2 cm (SD 64) (p0.001) and boys 167.3 cm (SD 8.7) vs 173.8 cm (SD 7.1) (p0.001)). The subjects born SGA-L also weighed significantly less than those born AGA-L (p0.001) both at birth and at age 17 years.Children born SGA-L become short adults and weigh less at age 17 years than children with a normal birth length.

The objective of this work was to determine markers of endothelial cell activation in valves from patients with antiphospholipid syndrome (APS) and heart valve involvement, in order to establish a role for endothelial cells in the pathogenesis of the valvular disease. Sixteen valves from ten patients with APS, obtained from autopsies or removed during valve replacement, were studied. Two groups of valves were used as controls. One group included seven normal valves from patients who died from non-cardiac diseases. The other group of valves were obtained from patients with bacterial endocarditis during autopsies or valve replacement operations. Immunoperoxidase and immunofluorescence stainings with antibodies to human immunoglobulins, endothelial cells, a3β1 integrin, collagen IV, laminin and fibronectin were employed. Three histopathological patterns were apparent: normal valves, valves with verrucous endocarditis and valves with fibrocalcific changes. In all the valves with verrucous endocarditis the following findings were observed: (1) increased expression of the a3β1 integrin on the endothelial cells, (2) increased amount of collagen IV, laminin and fibronectin, (3) proliferation of blood vessels and (4) linear subendothelial deposition of immunoglobulins and complement. The valves with fibrocalcific changes were deformed and showed a thick layer of collagen IV, laminin and fibronectin, yet in two valves the indothelial cells showed an expression of the a3β1 integrin. The control valves did not express the integrin and had only a thin subendothelial band of collagen IV. In valves from patients with APS,1 markers of endothelial cell activation are upregulated while the inflammatory exudate is scant. There is also a prominent deposition of immunoglobulins in the valves from patients with APS, suggesting a possible association between the deposition of the antibodies and the activation of the endothelial cells in APS.

Objectives: To determine whether malignant thymoma is associated with high rates of concomitantly occurring autoimmune diseases. Methods: Sheba Medical Center computer records from 1966 to 1995 werereviewed to identify patients with malignant thymoma, either type I (invasive thymoma) or type II (thymic carcinoma). All patients who had malignant thymoma and autoimmune phenomena were analyzed. The diagnosis of thymic neoplasm was confirmed by two independent pathologists. The diagnosis of autoimmune diseases was based on both clinical and serological findings. Results: Six of 22 (27%) cases of malignant thymoma had an autoimmunedisease. Five patients had type I malignant thymoma and either myasthenia gravis (four patients) or Graves' disease (one patient). Only one patient had type II malignant thymoma with Sjbgren's syndrome. The diagnosis of autoimmune disease preceded the diagnosis of thymic neoplasm in four cases, and was diagnosed simultaneously in two. Conclusions: Malignant thymomas are highly associated with autoimmunediseases, as are benign thymomas. To our knowledge, we report the first documented cases of a patient with thymic carcinoma and Sjogren's syndrome, and another with invasive thymoma and Graves' disease.

Background —Immunization with β 2 -glycoprotein I (β2GPI), the probable target of autoimmune anticardiolipin antibodies, results in experimental antiphospholipid syndrome in different mouse strains. The present study was undertaken to evaluate the effect of β2GPI immunization on the progression of atherosclerosis. Methods and Results —In the first experiment, 3 groups of LDL receptor–deficient (LDL-RD) mice (n=15 per group) were immunized with either β2GPI or ovalbumin or were not immunized and were fed a chow diet for 12 weeks. In a second experiment, 3 groups of LDL-RD mice (n=10 per group) were immunized similarly and fed an atherogenic diet for 6 weeks. All β2GPI-immunized mice developed high titers of anti-β2GPI antibodies as well as a specific lymph node proliferation to β2GPI. The average cholesterol levels did not differ between the mice fed similar diets, regardless of the immunization protocol. Atherosclerosis was enhanced in the β2GPI-immunized mice (mean aortic lesion, 26 000±5700 μm 2 ) in comparison with their ovalbumin-immunized (mean, 3000±1099 μm 2 ; P 2 ; P 2 ) was larger than the ovalbumin-immunized mice (mean, 81 250±12 933 μm 2 ; P =NS) or the nonimmunized controls (mean, 75 625±7281 μm 2 ; P =NS). The atherosclerotic plaques in the β2GPI-immunized mice appeared to be more mature, and denser infiltration of CD4 lymphocytes was present in the subendothelium of the aortic sinuses from this group of mice. Conclusions —The results of the present study provide the first direct evidence for the proatherogenic effect of β2GPI immunization and establish a new model for immune-mediated atherosclerosis.

SUMMARY Heparin-induced thrombocytopenia/thrombosis (HIT) is a severe thrombotic disorder that occurs in ≈1% of patients treated with heparin. Affected patients commonly develop antibodies that recognize PF4/heparin complexes that may form on the surface of activated platelets and on the endothelium. However, it has not been established that anti-PF4/heparin antibodies are responsible for the clinical manifestations of HIT. To address this issue, we employed a recently developed model of active immunity to study the effect of IgG anti-PF4/heparin antibody in vivo. In previous studies we have shown that it is possible to induce autoimmune diseases such as systemic lupus erythematosus (SLE), anti-phospholipid syndrome (APS) or vasculitis in naive mice by active immunization with anti-DNA, anti-cardiolipin and anti-neutrophil cytoplasmic antibodies, respectively. Immunized animals develop anti-idiotypic antibodies (Ab2) and, after 2–4 months, anti-anti-idiotypic antibodies (Ab3). Ab3s generated in this manner often simulate the binding activity of Ab1 and their expression correlates with the development of specific clinical manifestations typical of the respective human disease. Based on this experience, naive BALB/c mice were immunized with IgG anti-PF4/heparin antibodies isolated from two patients with HIT. The actively immunized mice developed mouse anti-PF4/heparin antibody (Ab3). Administration of unfractionated heparin, but not low molecular weight heparin (LMWH), to the actively immunized animals induced thrombocytopenia by day 4 of drug exposure. There was no evidence of thrombosis. The results of this study support the importance of anti-PF4/heparin antibodies in the pathogenesis of HIT. Further, this model may help to elucidate the factors responsible for thrombosis as well as providing means to assess new treatment options for patients with this disorder.