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  • 1
    Keywords: DISEASE ; kidney ; TRIAL ; HEALTH ; OUTCOMES ; METAANALYSIS ; RENIN-ANGIOTENSIN SYSTEM ; GENOME-WIDE ASSOCIATION ; GENETIC-VARIANTS ; D SUPPLEMENTATION
    Abstract: Background Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. Methods In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. Findings In phenotypic analyses (up to n=49 363), increased 25(OH) D concentration was associated with decreased systolic blood pressure (beta per 10% increase, -0.12 mm Hg, 95% CI -0.20.to -0.04; p=0.003) and reduced odds of hypertension (odds ratio [OR] 0.98, 95% CI 0.97-0.99; p=0.0003), but not with decreased diastolic blood pressure (beta per 10% increase, -0.02 mm Hg, -0.08 to 0.03; p=0.37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0.10 mm Hg in systolic blood pressure (-0.21 to -0.0001; p=0.0498) and a change of -0.08 mm Hg in diastolic blood pressure (-0.15 to -0.02; p=0.01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0.98, 0.96-0.99; p=0.001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH) D concentration was associated with a change of -0.29 mm Hg in diastolic blood pressure (-0.52 to -0.07; p=0.01), a change of -0.37 mm Hg in systolic blood pressure (-0.73 to 0.003; p=0.052), and an 8 1% decreased odds of hypertension (OR 0.92, 0.87-0.97; p=0.002). Interpretation Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
    Type of Publication: Journal article published
    PubMed ID: 24974252
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  • 2
    Abstract: Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74〈rg〈-0.55) and blood pressure (-0.35〈rg〈-0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.
    Type of Publication: Journal article published
    PubMed ID: 28613276
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  • 3
    Keywords: INHIBITOR ; RISK ; TRIAL ; EVENTS ; SERUM-LEVELS ; ARTERY-DISEASE ; MENDELIAN RANDOMIZATION ; HEALTHY-MEN ; EPIC-NORFOLK ; ACUTE CORONARY SYNDROMES
    Abstract: OBJECTIVES: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. BACKGROUND: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. METHODS: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. RESULTS: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. CONCLUSIONS: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
    Type of Publication: Journal article published
    PubMed ID: 23916927
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  • 4
  • 5
    Keywords: EXPRESSION ; COHORT ; GENE ; GENES ; HEART ; ASSOCIATION ; IDENTIFICATION ; LINKAGE ANALYSIS ; genetics ; BLOOD-PRESSURE ; HYPERTENSION ; SINGLE NUCLEOTIDE POLYMORPHISMS ; METAANALYSIS ; duration ; CARDIOMYOPATHY ; GENOME-WIDE ASSOCIATION ; association study ; genetic variation ; COMMON VARIANTS ; Left ventricular hypertrophy ; electrocardiography
    Abstract: BACKGROUND: Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH. METHODS AND RESULTS: We calculated the Sokolow-Lyon index, Cornell product, 12-lead QRS voltage sum, and 12-lead QRS voltage product in 10 256 individuals from 3 population-based cohorts and typed their DNA using a customized gene array (the Illumina HumanCVD BeadChip 50K array), containing 49 094 genetic variants in approximately 2100 genes of cardiovascular relevance. We followed-up promising associations in 11 777 additional individuals. We identified and replicated 4 loci associated with ECG-LVH indices: 3p22.2 (SCN5A, rs6797133, P=1.22 x 10(-7)) with Cornell product and 12q13.3 (PTGES3, rs2290893, P=3.74 x 10(-8)), 15q25.2 (NMB, rs2292462, P=3.23 x 10(-9)), and 15q26.3 (IGF1R, rs4966014, P=1.26 x 10(-7)) with the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 12-lead QRS voltage sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2, and 15q26.3 loci versus those carrying 0 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci effects in monocytes. CONCLUSIONS: These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait.
    Type of Publication: Journal article published
    PubMed ID: 21965548
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  • 6
    Keywords: MODEL ; LOCI ; GENOME-WIDE ASSOCIATION ; COMMON VARIANTS ; CHRONIC HEART-FAILURE ; CARDIAC REPOLARIZATION ; SARCOPLASMIC-RETICULUM ; QRS DURATION ; PR INTERVAL ; TRPM7
    Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain similar to 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
    Type of Publication: Journal article published
    PubMed ID: 24952745
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  • 7
    ISSN: 1432-1181
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Description / Table of Contents: Zusammenfassung Es wurde “non-darcy” Mischkonvektion an beheizten vertikalen und horizontalen Platten in gesättigten porösen Medien unter Benutzung von angenä herten Grenzschichten betrachtet. Es wurde angenommen, daß die Strömung durch Auftriebskräfte hervorgerufen werden. Für vertikale und horizontale Platten wurden einanderä hnliche Lösungen erzielt. Die beschreibenden Gleichungen wurden numerisch mit einer Shooting-Methode gelöst. Die Wä rme- und Stoffübertragung und die Oberflä chenreibung wurden infolge von Trä gheitskrä ften reduziert. Mit den Auftriebsparametern steigen sie für Gleichstrom an und fallen für Gegenstrom ab. Es wurde festgestellt, daß sich die Wärme- und Stoffübertragungskoeffizienten für Gleichstrom asymptotisch den Werten der erzwungenen oder freien Konvektion annä hern, wenn der Auftriebsparameter gegen null oder unendlich geht.
    Notes: Abstract The non-darcy mixed convection flows from heated vertical and horizontal plates in saturated porous media have been considered using boundary layer approximations. The flows are considered to be driven by multiple buoyancy forces. The similarity solutions for both vertical and horizontal plates have been obtained. The governing equations have been solved numerically using a shooting method. The heat transfer, mass transfer and skin friction are reduced due to inertial forces. Also, they increase with the buoyancy parameter for aiding flow and decrease for the opposing flow. For aiding flow, the heat and mass transfer coefficients are found to approach asymptotically the forced or free convection values as the buoyancy parameter approaches zero or infinity.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1181
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Description / Table of Contents: Zusammenfassung Es wurden Grenzschichteffekte zweiter Ordnung bei instationärer laminarer inkompressibler Strömung am Staupunkt eines dreidimensionalen Körpers, sowohl für knotenartige als auch für sattelförmige Bereiche studiert. Dabei wurde angenommen, daß die Freistrahlgeschwindigkeit, die Wandtemperatur und der Stoffübergang beliebig mit der Zeit variieren. Der Einfluß Prandtlzahl wurde mit in Betracht gezogen. Die partiellen Differentialgleichungen welche die Strömung beschreiben, wurden zum ersten Mal abgeleitet und dann numerisch gelöst, wobei ein implizites finites Differenzverfahren verwendet wurde. Es wurde gefunden, daß die Verteilung der instationären Freistrahlgeschwindigkeit die Natur des Staupunktes und der Stofftransport die Wandreibung und den Wärmeübergang stark beeinflussen, während die Prandtl-Zahl und zeitlich veränderliche Wandtemperaturen sich nur auf den Wärmeübergang auswirken. Die Wandreibung infolge der kombinierten Einflüsse von Grenzschichten erster und zweiter Ordnung ist kleiner als diejenige infolge der Grenzschichten erster Ordnung, während der Wärmetransport umgekehrtes Verhalten zeigt. Eine Absaugung erhöht die Wandreibung und den Wärmeübergang Zublasen hat umgekehrte Wirkung.
    Notes: Abstract All the second-order boundary-layer effects on the unsteady laminar incompressible flow at the stagnation-point of a three-dimensional body for both nodal and saddle point regions have been studied. It has been assumed that the free-stream velocity, wall temperature and mass transfer vary arbitrarily with time. The effect of the Prandtl number has been taken into account. The partial differential equations governing the flow have been derived for the first time and then solved numerically unsteady free-stream velocity distributions, the nature of the using an implicit finite-difference scheme. It is found that the stagnation point and the mass transfer strongly affect the skin friction and heat transfer whereas the effects of the Prandtl number and the variation of the wall temperature with time are only on the heat transfer. The skin friction due to the combined effects of first- and second-order boundary layers is less than the skin friction due to, the first-order boundary layers whereas the heat transfer has the opposite behaviour. Suction increases the skin friction and heat transfer but injection does the opposite.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1181
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Description / Table of Contents: Zusammenfassung Die instationäre laminare Strömung und die Wärme- und Stoffübertragung am Staupunkt eines dreidimensionalen Körpers in kompressiblen Fluiden mit variablen Stoffwerten wurden unter Benutzung einer Grenzschicht-Theorie zweiter Ordnung untersucht für den Fall, daß die Grundpotentialströmung Modellunabhängigkeit zuläßt. Sowohl Knoten- als auch Sattelpunktbereiche wurden betrachtet. Die Gleichungen, welche die Strömung beschreiben, wurden unter Benutzung eines impliziten Finite-Differenzen-Schemas numerisch gelöst. Es wird beobachtet, daß die Verstärkung oder Reduzierung der Oberflächenreibung und der Wärmeübertragung infolge der Grenzschicht zweiter Ordnung von der Größe der Parameter abhängt, welche die Unstetigkeit in der Freistromgeschwindigkeit, die Natur des Staupunktes, die Variation des Produktes aus Dichte und Viskosität über der Grenzschicht, die Stoffübertragung und Wandtemperatur charakterisieren. Der Sog läßt die Oberflächenreibung und die Wärmeübertragung ansteigen, wogegen Einspritzung das Gegenteil bewirkt.
    Notes: Abstract The flow, heat and mass transfer at the stagnation point of a three-dimensional body in unsteady laminar compressible fluid with variable properties have been studied using a second-order boundary-layer theory when the basic potential flow admits selfsimilarity. Both nodal and saddle point regions have been considered. The equations governing the flow have been solved numerically using an implicit finite-difference scheme. It is observed that the enhancement or reduction in the skin friction and heat transfer due to the second-order boundary layers depends upon the values of the parameter characterizing the unsteadiness in the free-stream velocity, the nature of the stagnation point, the variation of the density-viscosity product across the boundary layer, mass transfer and the wall temperature. The suction increases the skin friction and heat transfer whereas injection does the opposite.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1181
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Description / Table of Contents: Zusammenfassung In dieser Studie ist die Strömung und Wärmeübertragung über eine gedehnte Fläche mit magnetischem Feld in einem elektrisch leitenden Fluid untersucht worden. Der Einfluß des induzierten magnetischen Feldes und der Quellen oder Senken sind in die Untersuchung einbezogen. Die beiden Fälle, nicht-isotherme Wand und konstanter Wandwärmestrom, sind betrachtet worden. Mit dem Eliminationsverfahren sind bestehende Gleichungen numerisch gelöst worden. Es ist beobachtet worden, daß für eine vorgeschriebene Wandtemperatur die Oberflächenreibung, das induzierte magnetische Feld und die Wärmeübertragung aufgrund des magnetischen Feldes verbessert sind. Aber im allgemeinen reduzieren sie sich im umgekehrten Maß wie die magnetische Prandtlzahl ansteigt. Für den Fall des konstanten Wärmestromes sinkt die Wandtemperatur, wenn das magnetische Feld stärker wird. Die Temperatur steigt jedoch reziprok zur magnetischen Prandtlzahl an. Die Wärmeübertragung ist sehr stark von der Prandtlzahl, Wandtemperatur und der Senke beeinflußt. Bei Werten vonm〈−2 undPr≥2.5 sind unrealistische Temperaturverteilungen eingetreten. Die gezeigte Analyse ist allgemeiner als jede vorhergehende Untersuchung.
    Notes: Abstract The flow and heat transfer over a stretching sheet with a magnetic field in an electrically conducting ambient fluid have been studied. The effects of the induced magnetic field and sources or sinks have been included in the analysis. Both non-isothermal wall and constant heat flux conditions have been considered. The governing equations have been solved numerically using a shooting method. It is observed that for the prescribed wall temperature the skin friction, induced magnetic field at the wall and heat transfer are enhanced due to the magnetic field, but in general, they reduce as the reciprocal of the magnetic Prandtl number increases. For constant heat flux case, the temperature at the wall reduces as the magnetic field increases, but it increases with the reciprocal of the magnetic Prandtl number. The heat transfer is strongly affected by the Prandtl number, wall temperature and sink. Whenm〈−2 andPr〉2.5 the unrealistic temperature distributions are encountered. The present analysis is more general than any previous investigation.
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