Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC. Radiolog

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

The pathogenesis of the hemolytic uremic syndrome in childhood

Contains fulltext : 146670.pdf (Publisher’s version ) (Open Access)207 p

Het hemolytisch-uremisch syndroom op de kinderleeftijd

Contains fulltext : 25967___.PDF (publisher's version ) (Open Access

The effect of verocytotoxin-1 on non-adherent human monocytes : binding characteristics, protein synthesis and induction of cytokine release

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[Persistent neonatal hypoglycaemia caused by arterial positioning of the umbilical venous catheter],Persisterende onverklaarde neonatale hypoglykemie door arteri̐ưele positie van een navelvenelijn.

Item does not contain fulltextTwo neonates, a girl born at 40 2/7 weeks weighing 4165 g and a boy born at 37 6/7 weeks weighing 4040 g, received umbilical venous catheters to help manage hypoglycaemia. The catheter was ineffective or only effective when high doses of glucose were used, due to what later appeared to be arterial positioning of the catheter. Both patients recovered without consequences. Persistent hypoglycaemia is a common problem in newborns and can cause severe neurological sequelae. A relatively uncommon cause is malpositioning of the umbilical catheter. Positioning in an artery leads to direct infusion of glucose into the pancreas, which causes hyperinsulinaemia and can lead to potentially dangerous nonketotic hypoglycaemia. Arterial positioning of the umbilical catheter should be ruled out at an early stage. Correct catheter positioning can be determined using careful inspection of the umbilical veins, radiological examination of the catheter position, blood gas analysis or vascular pulsation

[Acute caffeine intoxication after intake of 'herbal energy capsules']

Item does not contain fulltextTwo males, 15 and 17 years old respectively, presented at the Emergency Department complaining of cramping abdominal pain, nausea and vomiting after ingestion of energy capsules. Physical examination revealed sinus tachycardia and slight abdominal pain. Laboratory examination showed substantial hypokalaemia and mild hyperglycaemia. Questioning revealed that they had taken 5 and 3 'herbal energy capsules' respectively and that these capsules supposedly contained 200 mg of caffeine each. Toxicological analysis showed a greatly increased serum caffeine concentration in both patients. The peak concentrations calculated were in the highly toxic range and could have led to severe acute complications such as convulsions. Pharmaceutical analysis demonstrated that these 'Supercap Xtreme'-capsules contained 700 mg caffeine or more. All symptoms presented were compatible with caffeine intoxication. The content of these capsules is not reliable and could lead to life-threatening intoxication

Verocytotoxin inhibits mitogenesis and protein synthesis in purified human glomerular mesangial cells without affecting cell viability : evidence for two distinct mechanisms

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Effects of verocytotoxin-1 on nonadherent human monocytes: Binding characteristics, protein synthesis, and induction of cytokine release

The epidemic form of the hemolytic uremic syndrome (HUS) has been associated with a verocytotoxin producing Escherichia coli infection. Endothelial cell damage of glomeruli and arterioles of the kidney plays a central role in the pathogenesis of HUS. A number of observations in vivo and in vitro indicate that inflammatory mediators contribute to this process. In this study we investigated the binding of 125I-verocytotoxin-1 (VT-1) to freshly isolated human nonadherent monocytes as well as the nature of the ligand to which VT-1 binds on monocytes. On the average, freshly isolated monocytes have 0.07 x 105 specific binding sites for 125I-VT-1 per cell. Preincubation of nonadherent monocytes with bacterial lipopolysaccharide (LPS) caused a 23- to 30-fold increase of specific binding sites for VT-1 as shown by Scatchard plot analysis. Thin-layer chromatography of extracted neutral glycolipids of the cells and subsequent binding of 125I-VT-1 showed that human monocytes bind VT-1 to a globotriaosylceramide (Gb3) species that is different from that found on endothelial cells, probably a short-chain fattyacyl Gb3 or an α-OH-Gb3. In addition, we evaluated the functional consequences of VT-1 binding to human monocytes by investigating the effects of VT-1 on the total protein synthesis and, specifically, the production of the cytokines interleukin-1β (IL-1β), tumor necrosis factor- α (TNF-α), IL-6, and IL-8. We observed that VT-1 did not inhibit overall protein synthesis, nor under basal conditions, neither after stimulation with LPS, in contrast to previous observations with endothelial cells. Furthermore, we found that VT-1 induces the synthesis of the cytokines IL- 1β, TNF-α, IL-6, and IL-8 in nonstimulated monocytes by a LPS-independent cell activation. The increase in the production of cytokines was parallelled by an increase in mRNA, as was demonstrated for IL-6 by reverse transcription-polymerase chain reaction. These data suggest that inflammatory mediators locally produced by VT-1-stimulated monocytes may contribute to the pathogenic mechanism of the HUS. Chemicals/CAS: Bacterial Toxins; globotriaosylceramide, 71965-57-6; Interleukin-1; Interleukin-6; Interleukin-8; Interleukins; Ligands; Lipopolysaccharides; Polytetrafluoroethylene, 9002-84-0; Shiga-Like Toxin I; Trihexosylceramides; Tumor Necrosis Factor-alph

Foreign adopted children are a source of methicillin-resistant Staphylococcus aureus transmission to countries with low prevalence

Item does not contain fulltextWe report a 13.0% prevalence rate of methicillin-resistant Staphylococcus aureus (MRSA) carriers in foreign adopted children, who are frequently hospitalized within the first year after arrival. Hospitalization in the country of origin and special need status are no significant risk factors for MRSA colonization. Healthcare workers are overrepresented among their adoptive parents. These children represent a potential source of MRSA transmission into the healthcare system