VEGF-A165b protects against proteinuria in a mouse model with progressive depletion of all endogenous VEGF-A splice isoforms from the kidney

Chronic kidney disease (CKD) is strongly associated with a decrease in the expression of VEGF-A. However, little is known about the contribution of VEGF-A splice isoforms to kidney physiology and pathology. Previous studies suggest that the splice isoform VEGF-A165b (resulting from alternative usage of a 3’ splice site in the terminal exon) is protective for kidney function. We show here, in a quad-transgenic model, that over-expression of VEGF-A165b alone is sufficient to rescue the increase in proteinuria as well as glomerular water permeability in the context of progressive depletion of all VEGF-A isoforms from the podocytes. Ultrastructural studies show that the glomerular basement membrane is thickened, podocyte slit width is increased and sub-podocyte space coverage is reduced when VEGF-A is depleted, all of which are rescued in VEGF-A165b over-expressors. VEGF-A165b restores the expression of PECAM-1 in glomerular endothelial cells and glomerular capillary circumference. Mechanistically, it increases VEGFR2 expression both in vivo and in vitro and down-regulates genes involved in migration and proliferation of endothelial cells, otherwise up-regulated by the canonical isoform VEGF-A165. Our study indicates that manipulation of VEGF-A splice isoforms could be a novel therapeutic avenue in chronic glomerular disease

Genetic analysis of patients with Fuchs endothelial corneal dystrophy in India

<p>Abstract</p> <p>Background</p> <p>Mutations in <it>COL8A2 </it>gene which encodes the collagen alpha-2 (VIII) chain have been identified in both familial and sporadic cases of Fuchs endothelial corneal dystrophy (FECD). Heterozygous mutations in the <it>SLC4A11 </it>gene are also known to cause late-onset FECD. Therefore we screened for <it>COL8A2</it>, <it>SLC4A11 </it>gene variants in Indian FECD patients.</p> <p>Methods</p> <p>Eighty patients with clinically diagnosed FECD and 100 age matched normal individuals were recruited. Genomic DNA was isolated from peripheral blood leukocytes. Mutations in <it>COL8A2</it>, <it>SLC4A11 </it>coding regions were screened using bi-directional sequencing. Fischer's exact test or Pearson's chi squared test were used to predict the statistical association of genotypes with the phenotype.</p> <p>Results</p> <p>Screening of <it>COL8A2 </it>gene revealed 2 novel c.1610G>A, c.1643A>G and 3 reported variations c.112G>A, c.464G>A and c.1485G>A. In <it>SLC4A11 </it>gene, novel c.1659C>T, c.1974C>T and reported c.405G>A, c.481A>C and c.639G>A variants were identified. However all the variations in both the genes were also present in unaffected controls.</p> <p>Conclusions</p> <p>This is the first study analysing <it>COL8A2 </it>gene in Indian patients with FECD. No pathogenic mutations were identified in <it>COL8A2</it>. Merely silent changes, which showed statistically insignificant association with FECD, were identified in the screening of <it>SLC4A11 </it>gene. These results suggest that <it>COL8A2</it>, <it>SLC4A11 </it>genes may not be responsible for FECD in patients examined in this study.</p

Introduction:strategy in EU foreign policy

The point of departure for the special collection is provided by the observation that the growing complexity of the crises in the neighbourhood and the internal ones faced by the Union provides a sense of urgency to any type of strategic thinking that the EU might embrace. Against this backdrop, the recent shift towards geopolitics and strategic thinking is contextualized and the understanding of key aspects of ways in which the shift is translated into strategies by EU actors is put forward. The analysis recognizes the recent developments within the institutional dimension of EU’s foreign and security policy, yet it confirms the fundamental meaning of the member states’ willingness to invest resources and harmonize their foreign policy strategies at the EU level

Geographical information system and predictive risk maps of urinary schistosomiasis in Ogun State, Nigeria

<p>Abstract</p> <p>Background</p> <p>The control of urinary schistosomiasis in Ogun State, Nigeria remains inert due to lack of reliable data on the geographical distribution of the disease and the population at risk. To help in developing a control programme, delineating areas of risk, geographical information system and remotely sensed environmental images were used to developed predictive risk maps of the probability of occurrence of the disease and quantify the risk for infection in Ogun State, Nigeria.</p> <p>Methods</p> <p>Infection data used were derived from carefully validated morbidity questionnaires among primary school children in 2001–2002, in which school children were asked among other questions if they have experienced "blood in urine" or urinary schistosomiasis. The infection data from 1,092 schools together with remotely sensed environmental data such as rainfall, vegetation, temperature, soil-types, altitude and land cover were analysis using binary logistic regression models to identify environmental features that influence the spatial distribution of the disease. The final regression equations were then used in Arc View 3.2a GIS software to generate predictive risk maps of the distribution of the disease and population at risk in the state.</p> <p>Results</p> <p>Logistic regression analysis shows that the only significant environmental variable in predicting the presence and absence of urinary schistosomiasis in any area of the State was Land Surface Temperature (LST) (B = 0.308, p = 0.013). While LST (B = -0.478, p = 0.035), rainfall (B = -0.006, p = 0.0005), ferric luvisols (B = 0.539, p = 0.274), dystric nitosols (B = 0.133, p = 0.769) and pellic vertisols (B = 1.386, p = 0.008) soils types were the final variables in the model for predicting the probability of an area having an infection prevalence equivalent to or more than 50%. The two predictive risk maps suggest that urinary schistosomiasis is widely distributed and occurring in all the Local Government Areas (LGAs) in State. The high-risk areas (≥ 50% prevalence) however, are confined to scatter foci in the north western part of the State. The model also estimated that 98.99% of schools aged children (5–14 years) are living in areas suitable for urinary schistosomiasis transmission and are at risk of infection.</p> <p>Conclusion</p> <p>The risk maps developed will hopefully be useful to the state health officials, by providing them with detailed distribution of urinary schistosomiasis, help to delineate areas for intervention, assesses population at risk thereby helping in optimizing scarce resources.</p

NADPH oxidases: key modulators in aging and age-related cardiovascular diseases?

Reactive oxygen species (ROS) and oxidative stress have long been linked to aging and diseases prominent in the elderly such as hypertension, atherosclerosis, diabetes and atrial fibrillation (AF). NADPH oxidases (Nox) are a major source of ROS in the vasculature and are key players in mediating redox signalling under physiological and pathophysiological conditions. In this review, we focus on the Nox-mediated ROS signalling pathways involved in the regulation of 'longevity genes' and recapitulate their role in age-associated vascular changes and in the development of age-related cardiovascular diseases (CVDs). This review is predicated on burgeoning knowledge that Nox-derived ROS propagate tightly regulated yet varied signalling pathways, which, at the cellular level, may lead to diminished repair, the aging process and predisposition to CVDs. In addition, we briefly describe emerging Nox therapies and their potential in improving the health of the elderly population

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

The significance of faith for Black men's educational aspirations

It is uncontested that British African Caribbean men are minimally represented in elite UK higher education institutions. Even as data demonstrates that African Caribbean males are more likely to study further education than White males and that the proportion of UK-domiciled Black students pursuing higher education has increased since the 2003/04 academic year (ECU, 2014), the representation of Black students throughout the Russell Group remains low. Less than 3% of the entire Russell Group's student population comprised British African Caribbean students in 2011/12 and 2012/2013 (ECU, 2013, p. 203; ECU, 2014, p. 358). However, according to the 2011 Census, ‘Black’ people represent 5.5% (3.1 million) of the total UK population (ONS, 2015). For the few Black men who are successful in attaining acceptance at these exclusive universities, to what assets or capitals do these young men attribute their ability to get to and successful graduate from these institutions? Interviews with 15 Black male students who attended Russell Group universities in England and Wales were analysed and several ‘capitals’ or resources were identified as beneficial to their ability to succeed. Drawing on Bourdieu's work on cultural and social capital, this paper advances the concept of ‘faith capital’ as a unique recognised asset that six of the participants described and reflected upon as being influential on their academic trajectories. Based on findings from the ESRC-funded research Exploring the narratives of the few: British African Caribbean male graduates of elite universities in England and Wales, this paper discusses these six participants’ accounts of their higher education journeys in relation to how they identified faith as a resource that was influential to their academic success