Lipoprotein-associated phosphoplipase a2 (lp-pla2) as a therapeutic target to prevent retinal vasopermeability during diabetes

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA(2), darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA(2) and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood–retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA(2) inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA(2) inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA(2) may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents

Health disparities across the counties of Kenya and implications for policy makers, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.

BACKGROUND:The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 provided comprehensive estimates of health loss globally. Decision makers in Kenya can use GBD subnational data to target health interventions and address county-level variation in the burden of disease. METHODS:We used GBD 2016 estimates of life expectancy at birth, healthy life expectancy, all-cause and cause-specific mortality, years of life lost, years lived with disability, disability-adjusted life-years, and risk factors to analyse health by age and sex at the national and county levels in Kenya from 1990 to 2016. FINDINGS:The national all-cause mortality rate decreased from 850·3 (95% uncertainty interval [UI] 829·8-871·1) deaths per 100 000 in 1990 to 579·0 (562·1-596·0) deaths per 100 000 in 2016. Under-5 mortality declined from 95·4 (95% UI 90·1-101·3) deaths per 1000 livebirths in 1990 to 43·4 (36·9-51·2) deaths per 1000 livebirths in 2016, and maternal mortality fell from 315·7 (242·9-399·4) deaths per 100 000 in 1990 to 257·6 (195·1-335·3) deaths per 100 000 in 2016, with steeper declines after 2006 and heterogeneously across counties. Life expectancy at birth increased by 5·4 (95% UI 3·7-7·2) years, with higher gains in females than males in all but ten counties. Unsafe water, sanitation, and handwashing, unsafe sex, and malnutrition were the leading national risk factors in 2016. INTERPRETATION:Health outcomes have improved in Kenya since 2006. The burden of communicable diseases decreased but continues to predominate the total disease burden in 2016, whereas the non-communicable disease burden increased. Health gains varied strikingly across counties, indicating targeted approaches for health policy are necessary. FUNDING:Bill & Melinda Gates Foundation

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms