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

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

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

Determinants of cardiovascular disease and other non-communicable diseases in Central and Eastern Europe: Rationale and design of the HAPIEE study

BACKGROUND: Over the last five decades, a wide gap in mortality opened between western and eastern Europe; this gap increased further after the dramatic fluctuations in mortality in the former Soviet Union (FSU) in the 1990s. Recent rapid increases in mortality among lower socioeconomic groups in eastern Europe suggests that socioeconomic factors are powerful determinants of mortality in these populations but the more proximal factors linking the social conditions with health remain unclear. The HAPIEE (Health, Alcohol and Psychosocial factors In Eastern Europe) study is a prospective cohort study designed to investigate the effect of classical and non-conventional risk factors and social and psychosocial factors on cardiovascular and other non-communicable diseases in eastern Europe and the FSU. The main hypotheses of the HAPIEE study relate to the role of alcohol, nutrition and psychosocial factors. METHODS AND DESIGN: The HAPIEE study comprises four cohorts in Russia, Poland, the Czech Republic and Lithuania; each consists of a random sample of men and women aged 45–69 years old at baseline, stratified by gender and 5 year age groups, and selected from population registers. The total planned sample size is 36,500 individuals. Baseline information from the Czech Republic, Russia and Poland was collected in 2002–2005 and includes data on health, lifestyle, diet (food frequency), socioeconomic circumstances and psychosocial factors. A short examination included measurement of anthropometric parameters, blood pressure, lung function and cognitive function, and a fasting venous blood sample. Re-examination of the cohorts in 2006–2008 focuses on healthy ageing and economic well-being using face-to-face computer assisted personal interviews. Recruitment of the Lithuanian cohort is ongoing, with baseline and re-examination data being collected simultaneously. All cohorts are being followed up for mortality and non-fatal cardiovascular events. DISCUSSION: The HAPIEE study will provide important new insights into social, behavioural and biological factors influencing mortality and cardiovascular risk in the region

Structural basis for cytokinin production by LOG from Corynebacterium glutamicum

&quot;Lonely guy&quot; (LOG) has been identified as a cytokinin-producing enzyme in plants and plant-interacting fungi. The gene product of Cg2612 from the soil-dwelling bacterium Corynebacterium glutamicum was annotated as an LDC. However, the facts that C. glutamicum lacks an LDC and Cg2612 has high amino acid similarity with LOG proteins suggest that Cg2612 is possibly an LOG protein. To investigate the function of Cg2612, we determined its crystal structure at a resolution of 2.3 angstrom. Cg2612 functions as a dimer and shows an overall structure similar to other known LOGs, such as LOGs from Arabidopsis thaliana (AtLOG), Claviceps purpurea (CpLOG), and Mycobacterium marinum (MmLOG). Cg2612 also contains a &quot;PGG(X)GT(XX)E&quot; motif that contributes to the formation of an active site similar to other LOGs. Moreover, biochemical studies on Cg2612 revealed that the protein has phosphoribohydrolase activity but not LDC activity. Based on these structural and biochemical studies, we propose that Cg2612 is not an LDC family enzyme, but instead belongs to the LOG family. In addition, the prenyl-binding site of Cg2612 (CgLOG) comprised residues identical to those seen in AtLOG and CpLOG, albeit dissimilar to those in MmLOG. The work provides structural and functional implications for LOG-like proteins from other microorganisms.clos

Mortality in the Visegrad countries from the perspective of socioeconomic inequalities

OBJECTIVES: Large socioeconomic inequalities in health are still present in the Central Europe. The aim was to explore socioeconomic inequalities in mortality in Visegrad countries-the Czech Republic, Hungary, Poland and Slovakia (V4), by three different socioeconomic indicators (unemployment, risk of poverty/social exclusion, education). The study was conducted within the H2020 Euro-Healthy project. METHODS: The associations between selected socioeconomic indicators and the standardised mortality rates by four main causes (mortality related to cancer, circulatory, respiratory and digestive system) in the economically active population aged 20-64 years in the 35 NUTS 2 level regions of the V4 in the period 2011-2013 were explored, using linear regression models. RESULTS: Lower education level was the most significant predictor of mortality in the V4. The lowest mortality rates by all causes of death were found in the regions of the Czech Republic, the highest in regions of Hungary. CONCLUSIONS: Despite the common origin, the pathways of the V4 countries in employment, poverty and education seem to be different, also having impact on health equity. Therefore, where you live in the V4 can significantly influence your health