Granule Cell Dispersion in Human Temporal Lobe Epilepsy: Proteomics investigation of neurodevelopmental migratory pathways

Granule cell dispersion (GCD) is a common pathological feature observed in the hippocampus of patients with Mesial Temporal Lobe Epilepsy (MTLE). Pathomechanisms underlying GCD remain to be elucidated, but one hypothesis proposes aberrant reactivation of neurodevelopmental migratory pathways, possibly triggered by febrile seizures. This study aims to compare the proteomes of basal and dispersed granule cells in the hippocampus of eight MTLE patients with GCD to identify proteins that may mediate GCD in MTLE. Quantitative proteomics identified 1882 proteins, of which 29% were found in basal granule cells only, 17% in dispersed only and 54% in both samples. Bioinformatics analyses revealed upregulated proteins in dispersed samples were involved in developmental cellular migratory processes, including cytoskeletal remodelling, axon guidance and signalling by Ras homologous (Rho) family of GTPases (P<0.01). The expression of two Rho GTPases, RhoA and Rac1, was subsequently explored in immunohistochemical and in situ hybridisation studies involving eighteen MTLE cases with or without GCD, and three normal post mortem cases. In cases with GCD, most dispersed granule cells in the outer-granular and molecular layers have an elongated soma and bipolar processes, with intense RhoA immunolabelling at opposite poles of the cell soma, while most granule cells in the basal granule cell layer were devoid of RhoA. A higher density and percentage of cells expressing RhoA was observed in cases with GCD than without GCD (P<0.004). In GCD cases, the density and percentage of cells expressing RhoA was significantly higher in the inner molecular layer than granule cell layer (P<0.026), supporting proteomic findings. In situ hybridisation studies using probes against RHOA and RAC1 mRNAs revealed fine peri- and nuclear puncta in granule cells of all cases. The density of cells expressing RHOA mRNAs were significantly higher in the inner molecular layer of cases with GCD than without GCD(P=0.05). In summary, our study has found limited evidence for ongoing adult neurogenesis in the hippocampus of patients with MTLE, but evidence of differential dysmaturation between dispersed and basal granule cells has been demonstrated, and elevated expression of Rho GTPases in dispersed granule cells may contribute to the pathomechanisms underpinning GCD in MTLE

Down syndrome, paternal age and education: comparison of California and the Czech Republic

BACKGROUND: The association between maternal age and risk of Down syndrome has been repeatedly shown in various populations. However, the effect of paternal age and education of parents has not been frequently studied. Comparative studies on Down syndrome are also rare. This study evaluates the epidemiological characteristics of Down syndrome in two culturally and socially contrasting population settings, in California and the Czech Republic. METHODS: The observed live birth prevalence of Down syndrome was studied among all newborns in the California counties monitored by California Birth Defects Monitoring Program from 1996 to 1997, and in the whole Czech Republic from 1994 to 1998. Logistic regression was used to analyze the data. RESULTS: A total of 516,745 (California) and 475,834 (the Czech Republic) infants were included in the analysis. Among them, 593 and 251, respectively, had Down syndrome. The mean maternal age of children with Down syndrome was 32.1 years in California and 26.9 years in the Czech Republic. Children born to older mothers were at greater risk of Down syndrome in both populations. The association with paternal age was mostly explained by adjusting for maternal age, but remained significant in the Czech Republic. The association between maternal education and Down syndrome was much stronger in California than in the Czech Republic but parental age influences higher occurrence of Down syndrome both in California and in the Czech Republic. CONCLUSION: The educational gradient in California might reflect selective impact of prenatal diagnosis, elective termination, and acceptance of prenatal diagnostic measures in Californian population

Demographic and Social Correlates of Suicide in the Czech Republic

In this article the authors review the trends & differentials in mortality from self-inflicted injury & poisoning in the Czech Republic between the early 1970s & the present in terms of their socio-economic & demographic associations. They describe the sources of data on suicide & explore the possible extent of under-reporting of deaths from suicide, & they examine the differences in suicide incidence by age & sex. With the decline in mortality from suicide, the male/female ratio of suicide rates increased from about 2.6 in the early 1970s to around 4.0 in recent years. Suicide rates increase steadily with age, & this pattern did not noticeably change during the period reviewed. The age specific suicide rates of older men & women declined more than the rates for younger people. As in other societies, married men & women have the lowest suicide rates; in contrast, divorce puts both men & women at the greatest risk of suicide. The authors attempt to investigate the social correlates of suicide by analysing the variation in suicide rates among districts in the Czech Republic & selected socio-economic & demographic characteristics of the district populations. Stepwise regression analysis is used to identify three independent variables that explain 50% of the variation in suicide rates among districts: the abortion ratio, the percentage of locally born population, & the percentage of adults with limited education

Cardiovascular health among the Czech population at the beginning of the 21st century: a 12-year follow-up study

BACKGROUND: In the late 1980s, Czechia was among the countries which had the highest cardiovascular mortality in the world. In spite of enormous improvements since that time, there are still large opportunities in further improving cardiovascular health. METHODS: Based on the Czech Health, Alcohol and Psychosocial Factors in Eastern Europe sample (n=8449 at baseline, 12 years of follow-up, 494 cardiovascular disease (CVD) deaths up to 2015-events), the impact of selected covariates such as education, smoking habits, high blood pressure, blood cholesterol level, diabetes, obesity, physical activity and binge drinking and their multifactorial effects on cardiovascular mortality was evaluated by Cox regression. In addition, population attributable fractions (PAFs) were used to quantify the impact of these factors on CVD mortality in the population. RESULTS: Education was found as the strongest determinant of CVD mortality (primary vs university, HR 2.77, P<0.001; PAF=50.5%). CVD risk was two times higher for persons with diabetes compared with those without (HR 2.02, P<0.001, PAF=23.2%). Furthermore, significant factors found were smoking (smoker vs non-smoker, HR 1.91, P<0.001; PAF=26.5%), high blood pressure (HR 1.73, P<0.001; PAF=35.3%) and physical inactivity (none vs sufficient, HR 1.60, P<0.001; PAF=22.9%). Conversely, the effect of obesity was low (HR 1.29, P value =0.020), and binge drinking and high blood cholesterol level were not significant at all. CONCLUSIONS: Education had the largest impact on cardiovascular mortality among the Czech population. More than 50% of CVD death would be prevented if the whole population had the same risk values as the highest educated population. Reducing disparities in health related to education should benefit from attention to cardiovascular health literacy

Granule Cell Dispersion in Human Temporal Lobe Epilepsy: Proteomics Investigation of Neurodevelopmental Migratory Pathways

Granule cell dispersion (GCD) is a common pathological feature observed in the hippocampus of patients with Mesial Temporal Lobe Epilepsy (MTLE). Pathomechanisms underlying GCD remain to be elucidated, but one hypothesis proposes aberrant reactivation of neurodevelopmental migratory pathways, possibly triggered by febrile seizures. This study aims to compare the proteomes of basal and dispersed granule cells in the hippocampus of eight MTLE patients with GCD to identify proteins that may mediate GCD in MTLE. Quantitative proteomics identified 1,882 proteins, of which 29% were found in basal granule cells only, 17% in dispersed only and 54% in both samples. Bioinformatics analyses revealed upregulated proteins in dispersed samples were involved in developmental cellular migratory processes, including cytoskeletal remodeling, axon guidance and signaling by Ras homologous (Rho) family of GTPases (P < 0.01). The expression of two Rho GTPases, RhoA and Rac1, was subsequently explored in immunohistochemical and in situ hybridization studies involving eighteen MTLE cases with or without GCD, and three normal post mortem cases. In cases with GCD, most dispersed granule cells in the outer-granular and molecular layers have an elongated soma and bipolar processes, with intense RhoA immunolabeling at opposite poles of the cell soma, while most granule cells in the basal granule cell layer were devoid of RhoA. A higher percentage of cells expressing RhoA was observed in cases with GCD than without GCD (P < 0.004). In GCD cases, the percentage of cells expressing RhoA was significantly higher in the inner molecular layer than the granule cell layer (P < 0.026), supporting proteomic findings. In situ hybridization studies using probes against RHOA and RAC1 mRNAs revealed fine peri- and nuclear puncta in granule cells of all cases. The density of cells expressing RHOA mRNAs was significantly higher in the inner molecular layer of cases with GCD than without GCD (P = 0.05). In summary, our study has found limited evidence for ongoing adult neurogenesis in the hippocampus of patients with MTLE, but evidence of differential dysmaturation between dispersed and basal granule cells has been demonstrated, and elevated expression of Rho GTPases in dispersed granule cells may contribute to the pathomechanisms underpinning GCD in MTLE

socioeconomic inequalities in suicide mortality in european urban areas before and during the economic recession

Abstract Background Few studies have assessed the impact of the financial crisis on inequalities in suicide mortality in European urban areas. The objective of the study was to analyse the trend in area socioeconomic inequalities in suicide mortality in nine European urban areas before and after the beginning of the financial crisis. Methods This ecological study of trends was based on three periods, two before the economic crisis (2000–2003, 2004–2008) and one during the crisis (2009–2014). The units of analysis were the small areas of nine European cities or metropolitan areas, with a median population ranging from 271 (Turin) to 193 630 (Berlin). For each small area and sex, we analysed smoothed standardized mortality ratios of suicide mortality and their relationship with a socioeconomic deprivation index using a hierarchical Bayesian model. Results Among men, the relative risk (RR) comparing suicide mortality of the 95th percentile value of socioeconomic deprivation (severe deprivation) to its 5th percentile value (low deprivation) were higher than 1 in Stockholm and Lisbon in the three periods. In Barcelona, the RR was 2.06 (95% credible interval: 1.24–3.21) in the first period, decreasing in the other periods. No significant changes were observed across the periods. Among women, a positive significant association was identified only in Stockholm (RR around 2 in the three periods). There were no significant changes across the periods except in London with a RR of 0.49 (95% CI: 0.35–0.68) in the third period. Conclusions Area socioeconomic inequalities in suicide mortality did not change significantly after the onset of the crisis in the areas studied

Socioeconomic inequalities in suicide mortality in European urban areas before and during the economic recession

Few studies have assessed the impact of the financial crisis on inequalities in suicide mortality in European urban areas. The objective of the study was to analyse the trend in area socioeconomic inequalities in suicide mortality in nine European urban areas before and after the beginning of the financial crisis. This ecological study of trends was based on three periods, two before the economic crisis (2000-2003, 2004-2008) and one during the crisis (2009-2014). The units of analysis were the small areas of nine European cities or metropolitan areas, with a median population ranging from 271 (Turin) to 193 630 (Berlin). For each small area and sex, we analysed smoothed standardized mortality ratios of suicide mortality and their relationship with a socioeconomic deprivation index using a hierarchical Bayesian model. Among men, the relative risk (RR) comparing suicide mortality of the 95th percentile value of socioeconomic deprivation (severe deprivation) to its 5th percentile value (low deprivation) were higher than 1 in Stockholm and Lisbon in the three periods. In Barcelona, the RR was 2.06 (95% credible interval: 1.24-3.21) in the first period, decreasing in the other periods. No significant changes were observed across the periods. Among women, a positive significant association was identified only in Stockholm (RR around 2 in the three periods). There were no significant changes across the periods except in London with a RR of 0.49 (95% CI: 0.35-0.68) in the third period. Area socioeconomic inequalities in suicide mortality did not change significantly after the onset of the crisis in the areas studied

Social differences in avoidable mortality between small areas of 15 European cities : an ecological study

Peer reviewe

Health inequalities in European cities: perceptions and beliefs among local policymakers

Objective: To describe the knowledge and beliefs of public policymakers on social inequalities in health and policies to reduce them in cities from different parts of Europe during 2010 and 2011. Design: Phenomenological qualitative study. Setting: 13 European cities. Participants: 19 elected politicians and officers with a directive status from 13 European cities. Main outcome: Policymaker’s knowledge and beliefs. Results: Three emerging discourses were identified among the interviewees, depending on the city of the interviewee. Health inequalities were perceived by most policymakers as differences in life-expectancy between population with economic, social and geographical differences. Reducing health inequalities was a priority for the majority of cities which use surveys as sources of information to analyse these. Bureaucracy, funding and population beliefs were the main barriers. Conclusions: The majority of the interviewed policymakers gave an account of interventions focusing on the immediate determinants and aimed at modifying lifestyles and behaviours in the more disadvantaged classes. More funding should be put towards academic research on effective universal policies, evaluation of their impact and training policymakers and officers on health inequalities in city government