Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

ENDOGLIN is dispensable for vasculogenesis, but required for vascular endothelial growth factor-induced angiogenesis

ENDOGLIN (ENG) is a co-receptor for transforming growth factor-β (TGF-β) family members that is highly expressed in endothelial cells and has a critical function in the development of the vascular system. Mutations in Eng are associated with the vascular disease known as hereditary hemorrhagic telangiectasia type l. Using mouse embryonic stem cells we observed that angiogenic factors, including vascular endothelial growth factor (VEGF), induce vasculogenesis in embryoid bodies even when Eng deficient cells or cells depleted of Eng using shRNA are used. However, ENG is required for the stem cell-derived endothelial cells to organize effectively into tubular structures. Consistent with this finding, fetal metatarsals isolated from E17.5 Eng heterozygous mouse embryos showed reduced VEGF-induced vascular network formation. Moreover, shRNA-mediated depletion and pharmacological inhibition of ENG in human umbilical vein cells mitigated VEGF-induced angiogenesis. In summary, we demonstrate that ENG is required for efficient VEGF-induced angiogenesis

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Monotherapy versus polytherapy in epilepsy : experimental and clinical studies

Contains fulltext : 18916.pdf (publisher's version ) (Open Access)Antiepiletic drugs are about equally efficacious in suppressing epileptic seizures,however they do differ in type and severity of their adverse effects. The main hypothesis of this was that, contrary to what is commonly assumed, giving more than one antiepileptic drug does not lead to more adverse effects and may even offer advantages. In a unique collaboration with neurologists from Northern Limburg, Noord-Brabant, Utrecht and Gelderland a multicentre trial was carried out, in which patients who were to receive antiepileptic drugs for the first time, were given either one drug at its normal dosage or two drugs both at half of their normal dosage. No differences were found concerning seizure control or adverse effects in patients who completed the trial, however more patients on only one drug than on two drugs tended to withdraw from treatment due to adverse effects. Similarly, in experiments with rats who spontaneously develop epilepsy, the animals who received combination therapy were less passive (which can be seen as a measure for sedation) than the animals on one drug. These encouraging findings open the way for more extensive evaluation of combination therapy, and especially into which of these combinations offer advantagesXIII, 192 p

Dialogues de la fiscalité – Anno 2011

Ce deuxième volume des Dialogues de la fiscalité rassemble les actes des quatre séminaires organisés entre janvier et avril 2011 dans la cadre de la Chaire PwC de droit fiscal de l’Université Catholique de Louvain. Il représente le signe tangible d’une collaboration fructueuse entre le monde académique et le monde de l’entreprise, qui repose avant toute chose sur la confiance et le respect de l’indépendance des partenaires. La Chaire PwC de droit fiscal a comme objectif de stimuler l’étude et le débat autour de thématiques fiscales actuelles. Sa spécificité réside dans la recherche d’un équilibre entre les positions de tous les acteurs de la fiscalité : personnes chargées de l’application des règles fiscale à tous les niveaux de pouvoir, professionnels du conseil juridique et/ou fiscal et experts issus de l’université ou d’autres centres de recherches reconnus. Par ailleurs, par le contenu des thèmes choisis, la Chaire tend également à faire une balance entre les préoccupations des praticiens et des réflexions – plus générales – de politique fiscale. Nous laissons le soin au lecteur d’apprécier si ces objectifs ont été atteints. Les thèmes choisis cette année reflètent l’actualité fiscale nationale et internationale. Le premier séminaire, plus prospectif, brosse à grands traits, une esquisse des grandes mutations que les actuelles crises économiques et politiques pourraient faire subir à notre système fiscal : mutations portant tant sur la transformation radicale du policy mix entre les différents impôts, voire de la nature de ceux-ci que sur leur répartition institutionnelle entre les différents niveaux de pouvoirs. Le second séminaire explore quelques thématiques à l’intersection entre le droit pénal et le droit fiscal, ayant de délicates conséquences sur les libertés individuelles des contribuables. Le troisième séminaire aborde de manière transversale l’actualité d’un secteur important de notre société, aux contours parfois indéfinis, qualifié – parfois de manière trop réductrice – de “non-marchand”. Enfin, dans le quatrième séminaire, l’on revient sur un thème “indémodable”, celui de la fiscalité immobilière, en adoptant le point de vue de l’investisseur, tant dans un cadre national (et régional) que dans sa dimension transfrontalière