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All Publications

  • Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Green, T., Flash, S., Reiss, A. L. 2018


    The study of sexual dimorphism in psychiatric and neurodevelopmental disorders is challenging due to the complex interplay of diverse biological, psychological, and social factors. Males are more susceptible to neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and attention-deficit activity disorder. Conversely, after puberty, females are more prone to major depressive disorder and anxiety disorders compared to males. One major biological factor contributing to sex differences is the sex chromosomes. First, the X and Y chromosomes have unique and specific genetic effects as well as downstream gonadal effects. Second, males have one X chromosome and one Y chromosome, while females have two X chromosomes. Thus, sex chromosome constitution also differs between the sexes. Due to this complexity, determining genetic and downstream biological influences on sexual dimorphism in humans is challenging. Sex chromosome aneuploidies, such as Turner syndrome (X0) and Klinefelter syndrome (XXY), are common genetic conditions in humans. The study of individuals with sex chromosome aneuploidies provides a promising framework for studying sexual dimorphism in neurodevelopmental and psychiatric disorders. Here we will review and contrast four syndromes caused by variation in the number of sex chromosomes: Turner syndrome, Klinefelter syndrome, XYY syndrome, and XXX syndrome. Overall we describe an increased rate of attention-deficit hyperactivity disorder and autism spectrum disorder, along with the increased rates of major depressive disorder and anxiety disorders in one or more of these conditions. In addition to contributing unique insights about sexual dimorphism in neuropsychiatric disorders, awareness of the increased risk of neurodevelopmental and psychiatric disorders in sex chromosome aneuploidies can inform appropriate management of these common genetic disorders.

    View details for PubMedID 30127341

  • Cutaneous malignant melanoma and Parkinson disease: Common pathways? Annals of neurology Inzelberg, R. n., Flash, S. n., Friedman, E. n., Azizi, E. n. 2016; 80 (6): 811?20


    The mechanisms underlying the high prevalence of cutaneous malignant melanoma (CMM) in Parkinson disease (PD) are unclear, but plausibly involve common pathways. 129Ser-phosphorylated ?-synuclein, a pathological PD hallmark, is abundantly expressed in CMM, but not in normal skin. In inherited PD, PARK genes harbor germline mutations; the same genes are somatically mutated in CMM, or their encoded proteins are involved in melanomagenesis. Conversely, genes associated with CMM affect PD risk. PD/CMM-targeted cells share neural crest origin and melanogenesis capability. Pigmentation gene variants may underlie their susceptibility. We review putative genetic intersections that may be suggestive of shared pathways in neurodegeneration/melanomagenesis. Ann Neurol 2016;80:811-820.

    View details for DOI 10.1002/ana.24802

    View details for PubMedID 27761938

  • Long-term secular trends in the age at menarche in Israel: a systematic literature review and pooled analysis. Hormone research in paediatrics Flash-Luzzatti, S. n., Weil, C. n., Shalev, V. n., Oron, T. n., Chodick, G. n. 2014; 81 (4): 266?71


    A worldwide decline in the age at menarche (AAM) has been reported in recent decades. This trend has been also clinically observed among Israeli women and was reported in our previous study.We reviewed the literature reporting the mean AAM in Israel during the past century. Studies were excluded if participants had been investigated due to illness or any condition which could affect sexual maturation. Mean AAM was analyzed using a simple linear regression weighted for number of participants in each birth cohort and stratified to birth cohorts before and after 1970, based on the outcome of our previous study.AAM varied little among women born between 1875 and 1970, but there was a clear downwards trend from 13.4 in 1970 to 12.8 two decades later. In a stratified analysis we found a significant negative association between birth year and AAM in the birth cohort after 1970 (standardized ? coefficient = -0.94 per year, R(2) = 0.87; p < 0.001).These results suggest a significant decline in mean AAM in Israeli women born in 1970 or later.

    View details for DOI 10.1159/000357444

    View details for PubMedID 24504328

  • The direct medical cost of cardiovascular diseases, hypertension, diabetes, cancer, pregnancy and female infertility in a large HMO in Israel. Health policy (Amsterdam, Netherlands) Chodick, G. n., Porath, A. n., Alapi, H. n., Sella, T. n., Flash, S. n., Wood, F. n., Shalev, V. n. 2010; 95 (2-3): 271?76


    The aim of this study was to assess the direct medical cost of treating major chronic illnesses in Maccabi Healthcare Services, a 1.8 million member health maintenance organization in Israel.Direct medical costs were calculated for each member in 2006. We used multiple linear regression models to evaluate the overall costs of chronic conditions (cardiovascular diseases, diabetes mellitus, hypertension, female infertility treatments, and cancer), pregnancy and treatments for female infertility.According to the study model, hypertension was associated with the largest direct medical costs in both sexes. Cardiovascular diseases accounted for 9.5% of the total direct medical costs in men, but only 5.9% in women. Diabetes mellitus accounted for 3.5% of the total medical costs both in men and women and is comparable to the total pregnancy-related costs in women.The findings indicate that hypertension, diabetes mellitus and female infertility treatments impose a considerable economic burden on public healthcare services in Israel which is comparable with the costs of cancer and cardiovascular diseases.

    View details for DOI 10.1016/j.healthpol.2009.12.007

    View details for PubMedID 20061044

  • Seasonality in birth weight: review of global patterns and potential causes. Human biology Chodick, G. n., Flash, S. n., Deoitch, Y. n., Shalev, V. n. 2009; 81 (4): 463?77


    Birth weight is the single most significant determinant of infant mortality and the chances of a newborn to experience healthy development. Low birth weight also appears to be related to higher risks of several important chronic conditions, such as ischemic heart disease, non-insulin-dependent diabetes, and cancer in adults. Thus factors that influence in utero growth and birth weight may have a serious effect on health outcomes many years later in life. Analysis of seasonal variations in birth weights may enable us to suggest specific factors that influence this measure. In this review we summarize the literature on seasonal variations in birth weight. Although causes of seasonal variation in developing regions are more clearly understood, it is not yet clear which factors affect apparent seasonal variation in birth weight in developed countries. In our analysis we observed a pattern of seasonal variations in developed countries that differed between low-, middle-, and high-latitude countries, and we suggest several mechanisms that may be responsible for this diversity. Namely, we suggest that in middle-latitude climates, the large annual temperature range may cause low birth weights during summer, whereas in high- and low-latitude regions variations in sunlight exposure between seasons may contribute to low birth weights apparent during winter. Identification of the suggested causal environmental factors may have public health implications in the development of primary prevention programs for low birth weight and macrosomia in developed countries.

    View details for DOI 10.3378/027.081.0405

    View details for PubMedID 20067370

  • High frequency stimulation and pharmacological inactivation of the subthalamic nucleus reduces 'compulsive' lever-pressing in rats. Experimental neurology Klavir, O. n., Flash, S. n., Winter, C. n., Joel, D. n. 2009; 215 (1): 101?9


    In recent years there have been several attempts to establish high frequency stimulation (HFS) as an additional treatment strategy for obsessive-compulsive disorder (OCD). Two studies reported that bilateral HFS of the subthalamic nucleus (STN) dramatically alleviated compulsions and improved obsessions in three patients with co-morbid Parkinson's disease and OCD. A recent study reported that HFS as well as pharmacological inactivation of the STN alleviate compulsive checking in the quinpirole rat model of OCD. As the quinpirole model is based on a dopaminergic manipulation, the aim of the present study was to test whether HFS and pharmacological inactivation of the STN exert an anti-compulsive effect also in the drug-naive brain, using the signal attenuation rat model of OCD. The main finding of the present study is that both HFS and pharmacological inactivation of the STN exerted an anti-compulsive effect, although the two manipulations differed in their effects on other behavioral measures. These findings support the possibility that HFS of the STN may provide an additional therapeutic strategy for OCD.

    View details for DOI 10.1016/j.expneurol.2008.09.017

    View details for PubMedID 18951894

  • The role of the subthalamic nucleus in 'compulsive' behavior in rats. The European journal of neuroscience Winter, C. n., Flash, S. n., Klavir, O. n., Klein, J. n., Sohr, R. n., Joel, D. n. 2008; 27 (8): 1902?11


    Different lines of evidence point to dysfunction of basal ganglia-thalamocortical circuits in obsessive-compulsive disorder (OCD). It has been hypothesized that the circuits' dysfunction in OCD may be characterized by a relative under-activity of the indirect compared with the direct pathway within these circuits. The present study tested whether lesions of the subthalamic nucleus (STN), a major node of the indirect pathway, would affect compulsive behavior, using the signal attenuation rat model of OCD. In this model, compulsive lever-pressing is induced by the attenuation of an external signal of reward delivery; an attenuation that is hypothesized to simulate the deficient response feedback suggested to underlie obsessions and compulsions in patients with OCD. Rats sustaining lesions to the STN showed a selective increase in compulsive lever-pressing compared with sham-operated rats. A post mortem biochemical analysis revealed a decrease in serotonin content in the prelimbic and infralimbic cortices, caudate-putamen (but not nucleus accumbens), globus pallidus and substantia nigra-ventral tegmental area, as well as a decrease in dopamine content in the caudate-putamen in STN-lesioned compared with sham rats. A comparison to recent findings that lesions to the orbitofrontal cortex, which also result in a selective increase in compulsive lever-pressing, lead to a decrease in serotonin and dopamine content in the caudate-putamen suggests that there may be a final common pathway by which different brain pathologies may lead to a pro-compulsive state.

    View details for DOI 10.1111/j.1460-9568.2008.06148.x

    View details for PubMedID 18412611

  • The achievement of target cholesterol level differs between coronary heart disease and diabetic patients. European journal of internal medicine Elis, A. n., Chodick, G. n., Heymann, A. D., Kokia, E. n., Flash, S. n., Lishner, M. n., Shalev, V. n. 2011; 22 (3): 262?65


    Guidelines recommend that LDL-C level should be <100mg/dl among diabetes mellitus (DM) and coronary heart disease (CHD) patients.To evaluate how patients with DM and CHD differ in attaining the target level and to examine the association between goal achievement, demographic and clinical parameters.The study was conducted in Maccabi Healthcare Services, the second largest health maintenance organization in Israel. All patients with DM (n=54,261), CHD (n=24,083) or DM and CHD (n=15,370) who were listed in the computerized database and had at least one LDL-C level measurement between January 1, 2007 and July 15, 2008 were eligible. The percentage of patients who attained LDL-C level <100mg/dl and its association with demographic and clinical parameters were analyzed.The rate of reaching the LDL-C target level was higher among the CHD and CHD and DM patients than DM ones (67% vs. 57% vs. 50%, p<0.001, respectively). Male gender; 5th socioeconomic status quintile; underlying disease i.e. CHD, CHD and DM; high statins compliance; and revascularization by percutaneous coronary intervention predicted for reaching target level. DM; absence of renal function evaluation; hospitalizations; HbA1C>7% or missing its measurements had a negative predictive value.The rate of reaching LDL-C target level should be increased in all high risk patients, mainly diabetic ones. Efforts should include educational programs to physicians and patients regarding the importance, the need to adhere and to intensify the cholesterol lowering treatment.

    View details for DOI 10.1016/j.ejim.2011.02.020

    View details for PubMedID 21570645

  • Diabetes and risk of incident cancer: a large population-based cohort study in Israel. Cancer causes & control : CCC Chodick, G. n., Heymann, A. D., Rosenmann, L. n., Green, M. S., Flash, S. n., Porath, A. n., Kokia, E. n., Shalev, V. n. 2010; 21 (6): 879?87


    Type 2 diabetes mellitus has been associated with an increased risk of a variety of cancers in observational studies, but few have reported the relationship between diabetes and cancer risk in men and women separately. The main goal of this retrospective cohort study was to evaluate the sex-specific risk of incident overall and site-specific cancer among people with DM compared with those without, who had no reported history of cancer at the start of the follow-up in January 2000. During an average of 8 years of follow-up (SD = 2.5), we documented 1,639 and 7,945 incident cases of cancer among 16,721 people with DM and 83,874 free of DM, respectively. In women, DM was associated with an adjusted hazard ratio of 1.96 (95% CI: 1.53-2.50) and 1.41 (95% CI: 1.20-1.66) for cancers of genital organs and digestive organs, respectively. A significantly reduced HR was observed for skin cancer (0.38; 95% CI: 0.22-0.66). In men with DM, there was no significant increase in overall risk of cancer. DM was related with a 47% reduction in the risk of prostate cancer. These findings suggest that the nature of the association between DM and cancer depends on sex and specific cancer site.

    View details for DOI 10.1007/s10552-010-9515-8

    View details for PubMedID 20148361

  • Persistence with statins and incident cataract: a population-based historical cohort study. Annals of epidemiology Chodick, G. n., Heymann, A. D., Flash, S. n., Kokia, E. n., Shalev, V. n. 2010; 20 (2): 136?42


    In recent years, there is a growing body of evidence suggesting that statins may have anti-inflammatory effects; consequently, it was hypothesized that statins may have a preventive effect against cataract.The study was carried out on a retrospective cohort of 180,291 new statin users in a large health organization in Israel. Study participants were followed between 1998 and 2007 for incident cataract or cataract extraction.During the study period 27,301 cataracts were diagnosed and 6,976 cataract extractions were performed among study participants. Persistence with statins was associated significantly (P < 0.001) with a reduced risk of cataract in men and women aged 45 to 74. Men aged 45-54 with a high (>80%) proportion of follow-up days covered with statins had an adjusted hazard ratio of 0.62 (95% confidence interval: 0.54-0.72), compared with patients with low persistence with statins. In elderly patients, no relationship or a positive relationship was observed.Persistent statin use was significantly protective for the incidence of cataract in men and women under 75 years of age.

    View details for DOI 10.1016/j.annepidem.2009.10.007

    View details for PubMedID 20123164

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