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

Overzicht van Europese grenswaarden voor de blootstelling aan stoffen op de werkplek

Het RIVM heeft van 47 (groepen van) stoffen een overzicht gemaakt van de in de EU beschikbare grenswaarden voor beroepsmatige blootstelling en de classificatie die er op basis van mogelijke kankerverwekkende eigenschappen aan wordt gegeven. De overzichten maken het mogelijk om de bestaande grenswaarden en classificaties direct te vergelijken. Om een veilige en gezonde werkomgeving te creëren voor werknemers die met gevaarlijke stoffen werken, is het belangrijk dat de blootstelling zoveel mogelijk wordt beperkt. Hiervoor is het nodig te bepalen welke concentratie van een stof maximaal in de lucht mag zitten die nog veilig wordt geacht. Deze grenswaarden kunnen worden vastgelegd op Europees niveau, op nationaal niveau of door bedrijven. De regelgeving hiervoor kan echter verschillen, waardoor er voor één stof binnen Europa meerdere grenswaarden kunnen bestaan. Naast de grenswaarden kunnen stoffen worden ingedeeld in categorieën op basis van hun mogelijk kankerverwekkende eigenschappen. Ook voor deze zogeheten classificatie bestaan er binnen Europa verschillende systemen en verschillende criteria. De gegevens over grenswaarden zijn overgenomen van de beoordelingen van het Wetenschappelijk Comité inzake grenswaarden voor beroepsmatige blootstelling (SCOEL), de Europese wetgeving voor chemische stoffen (REACH)- registratiedossiers, en gepubliceerde grenswaarden in Nederland, Duitsland, Frankrijk, het Verenigd Koninkrijk en Finland. Daarnaast zijn gegevens over classificatie op basis van kankerverwekkende eigenschappen overgenomen van de Europese Commissie en het Internationaal Agentschap voor Kankeronderzoek (IARC).This report provides an overview of occupational exposure limit values and classifications for carcinogenicity within the EU for 47 (groups of) substances. The data presented allow a direct comparison of the available limit values and classifications. To assure a safe and healthy workplace for employees working with hazardous chemicals, it is important that the exposure to these substances is minimized. For this purpose, it is necessary to determine the maximum concentration of a chemical in air that may still be considered safe. These occupational exposure limits (OELs) can be set at European level, at national level or by companies themselves. However, regulations for setting OELs may vary, so that for one substance several different OELs may exist within Europe. In addition to OELs, substances can be classified based on their possible carcinogenic properties. Information on OELs was obtained from the Scientific Committee on Occupational Exposure Limits (SCOEL), the European chemicals legislation (REACH) -dossiers, and statutory OELs published by the Netherlands, Germany, France, the United Kingdom and Finland. Further, data on classification for carcinogenicity was obtained from the European Commission and the International Agency for Research on Cancer (IARC).Ministerie van Sociale Zaken en Werkgelegenhei

Novel Insights Into the Effects of Interleukin 6 Antagonism in Non–ST‐Segment–Elevation Myocardial Infarction Employing the SOMAscan Proteomics Platform

Background: Interleukin 6 concentration is associated with myocardial injury, heart failure, and mortality after myocardial infarction. In the Norwegian tocilizumab non–ST‐segment–elevation myocardial infarction trial, the first randomized trial of interleukin 6 blockade in myocardial infarction, concentration of both C‐reactive protein and troponin T were reduced in the active treatment arm. In this follow‐up study, an aptamer‐based proteomic approach was employed to discover additional plasma proteins modulated by tocilizumab treatment to gain novel insights into the effects of this therapeutic approach. / Methods and Results: Plasma from percutaneous coronary intervention–treated patients, 24 in the active intervention and 24 in the placebo‐control arm, drawn 48 hours postrandomization were randomly selected for analysis with the SOMAscan assay. Employing slow off‐rate aptamers, the relative abundance of 1074 circulating proteins was measured. Proteins identified as being significantly different between groups were subsequently measured by enzyme immunoassay in the whole trial cohort (117 patients) at all time points (days 1–3 [7 time points] and 3 and 6 months). Five proteins identified by the SOMAscan assay, and subsequently confirmed by enzyme immunoassay, were significantly altered by tocilizumab administration. The acute‐phase proteins lipopolysaccharide‐binding protein, hepcidin, and insulin‐like growth factor‐binding protein 4 were all reduced during the hospitalization phase, as was the monocyte chemoattractant C‐C motif chemokine ligand 23. Proteinase 3, released primarily from neutrophils, was significantly elevated. / Conclusions: Employing the SOMAscan aptamer‐based proteomics platform, 5 proteins were newly identified that are modulated by interleukin 6 antagonism and may mediate the therapeutic effects of tocilizumab in non–ST‐segment–elevation myocardial infarction

Novel anti-inflammatory agent 3-[(dodecylthiocarbonyl)-methyl]-glutarimide ameliorates murine models of inflammatory bowel disease

Objective and design: To examine the effect of 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G), a novel anti-inflammatory agent that inhibits lipopolysaccharide (LPS) activation of RAW264.7 macrophages, on murine models of colitis and RAW264.7 cells. Materials and methods: Colitis was induced by rectally infusing trinitrobenzenesulfonic acid (TNBS) (1.5 mg in 50 % ethanol) in BALB/c mice or orally administering 3 % dextran sulfate sodium (DSS) for 5 days in C57BL/6 mice. The severity of colitis was assessed after intraperitoneally injecting DTCM-G (40 mg/kg). The anti-inflammatory properties of DTCM-G and its mechanisms were investigated in LPS-stimulated RAW264.7 cells. Results: DTCM-G significantly ameliorated TNBS-induced colitis, according to the body weight loss, disease activity index, colonic obstruction, macroscopic colonic inflammation score, mucosal myeloperoxidase activity, and histopathology. Immunohistochemistry and isolated lamina propria mononuclear cells showed significantly reduced colonic F4/80+ and CD11b+ macrophage infiltration. DTCM-G significantly suppressed tumor necrosis factor (TNF)-α and interleukin (IL)-6 messenger RNA expression in the colon and attenuated DSS-induced colitis, according to the disease activity index and histopathology. In RAW264.7 cells, DTCM-G suppressed LPS-induced TNF-α/IL-6 production and enhanced glycogen synthase kinase-3β phosphorylation. Conclusions: DTCM-G attenuated murine experimental colitis by inhibiting macrophage infiltration and inflammatory cytokine expression. Thus, DTCM-G may be a promising treatment for inflammatory bowel disease

Location and severity of aortic valve calcium and implications for aortic regurgitation after transcatheter aortic valve implantation

Location of aortic valve calcium (AVC) can be better visualized on contrast-enhanced multidetector row computed tomography. The present evaluation examined whether AVC severity and its location could influence paravalvular aortic regurgitation (AR) after transcatheter aortic valve implantation. A total of 79 patients (age 80 ± 7 years, 49% men) with preprocedural multidetector row computed tomography were included. Volumetric AVC quantification and its location were assessed. Transesophageal echocardiography was performed to assess the presence and site of AR after transcatheter aortic valve implantation. Receiver operating characteristic curves were generated to evaluate the usefulness of AVC in determining paravalvular AR at a specific site. Postprocedural AR of grade 1 or more was observed in 63 patients. In most patients (n = 56, 71%), AR was of paravalvular origin. Calcium at the aortic wall of each valve cusp had the largest area under the curve (0.93, p <0.001) in predicting paravalvular AR at the aortic wall site compared to calcium at the valvular edge or body (area under the curve 0.58 and 0.67, respectively). Calcium at the valvular commissure was better than calcium at the valvular edge (area under the curve 0.94 vs 0.71) in predicting paravavular AR originating from the corresponding commissure. In conclusion, contrast-enhanced multidetector row computed tomography can be performed to quantify AVC. Both AVC severity and its exact location are important in determining paravalvular AR after transcatheter aortic valve implantation

Location and severity of aortic valve calcium and implications for aortic regurgitation after transcatheter aortic valve implantation.

Location of aortic valve calcium (AVC) can be better visualized on contrast-enhanced multidetector row computed tomography. The present evaluation examined whether AVC severity and its location could influence paravalvular aortic regurgitation (AR) after transcatheter aortic valve implantation. A total of 79 patients (age 80 \ub1 7 years, 49% men) with preprocedural multidetector row computed tomography were included. Volumetric AVC quantification and its location were assessed. Transesophageal echocardiography was performed to assess the presence and site of AR after transcatheter aortic valve implantation. Receiver operating characteristic curves were generated to evaluate the usefulness of AVC in determining paravalvular AR at a specific site. Postprocedural AR of grade 1 or more was observed in 63 patients. In most patients (n = 56, 71%), AR was of paravalvular origin. Calcium at the aortic wall of each valve cusp had the largest area under the curve (0.93, p <0.001) in predicting paravalvular AR at the aortic wall site compared to calcium at the valvular edge or body (area under the curve 0.58 and 0.67, respectively). Calcium at the valvular commissure was better than calcium at the valvular edge (area under the curve 0.94 vs 0.71) in predicting paravavular AR originating from the corresponding commissure. In conclusion, contrast-enhanced multidetector row computed tomography can be performed to quantify AVC. Both AVC severity and its exact location are important in determining paravalvular AR after transcatheter aortic valve implantation