925 research outputs found
Prevalence and incidence of COPD in smokers and non-smokers: the Rotterdam Study
COPD is the third leading cause of death in the world and its global burden is predicted to increase further. Even though the prevalence of COPD is well studied, only few studies examined the incidence of COPD in a prospective and standardized manner. In a prospective population-based cohort study (Rotterdam Study) enrolling subjects aged ≥45, COPD was diagnosed based on a pre-bronchodilator obstructive spirometry (FEV1/FVC < 0.70). In absence of an interpretable spirometry within the Rotterdam Study, cases were defined as having COPD diagnosed by a physician on the basis of clinical presentation and obstructive lung function measured by the general practitioner or respiratory physician. Incidence rates were calculated by dividing the number of incident cases by the total number of person years of subjects at risk. In this cohort of 14,619 participants, 1993 subjects with COPD were identified of whom 689 as prevalent ones and 1304 cases as incident ones. The overall incidence rate (IR) of COPD was 8.9/1000 person-years (PY); 95 % Confidence Interval (CI) 8.4–9.4. The IR was higher in males and in smokers. The proportion of female COPD participants without a history of smoking was 27.2 %, while this proportion was 7.3 % in males. The prevalence of COPD in the Rotterdam Study i
Utilisation of cardiac pacemakers over a 20-year period: Results from a nationwide pacemaker registry
The implantation of cardiac pacemakers has become a well-established therapy for conduction disorders and sinus node dysfunction. In many countries pacemaker registries have been initiated in order to collect information on patient characteristics, trends in numbers and the types of pacemakers used, to identify problematic devices, and for safety monitoring. For this utilisation study the Central Pacemaker Patients Registration (CPPR) from the Netherlands Pacemaker Registry Foundation (CPPR-SPRN) containing data collected for more than 20 years was used. During this period nearly 97,000 first pacemakers were implanted. Analyses show an increase in the rate of implanted devices. The change in pacemaker type from VVI to DDD, followed by biventricular stimulation, is reflected by the number of simultaneously implanted leads, which is partly a consequence of cardiac resynchronisation therapy. Our data demonstrate that indications for implantation and type of pacemaker are comparable with other European countries
The role of plasma concentrations and drug characteristics of beta-blockers in fall risk of older persons
Beta-blocker usage is inconsistently associated with increased fall risk in the literature. However, due to age-related changes and interindividual heterogeneity in pharmacokinetics and dynamics, it is difficult to predict which older adults are more at risk for falls. Therefore, we wanted to explore whether elevated plasma concentrations of selective and nonselective beta-blockers are associated with an increased risk of falls in older beta-blocker users. To answer our research question, we analyzed samples of selective (metoprolol, n = 316) and nonselective beta-blockers (sotalol, timolol, propranolol, and carvedilol, n = 179) users from the B-PROOF cohort. The associations between the beta-blocker concentration and time to first fall were assessed using Cox proportional hazard models. Change of concentration over time in relation to fall risk was assessed with logistic regression models. Models were adjusted for potential confounders. Our results showed that above the median concentration of metoprolol was associated with an increased fall risk (HR 1.55 [1.11–2.16], p =.01). No association was found for nonselective beta-blocker concentrations. Also, changes in concentration over time were not associated with increased fall risk. To conclude, metoprolol plasma concentrations were associated with an increased risk of falls in metoprolol users while no associations were found for nonselective beta-blockers users. This might be caused by a decreased β1-selectivity in high plasma concentrations. In the future, beta-blocker concentrations could potentially help clinicians estimate fall risk in older beta-blockers users and personalize treatment.</p
The PDZ domain of the SpoIVB serine peptidase facilitates multiple functions
During spore formation in Bacillus subtilis, the SpoIVB protein is a critical component of the sigma (K) regulatory checkpoint. SpoIVB has been shown to be a serine peptidase that is synthesized in the spore chamber and which self-cleaves, releasing active forms. These forms can signal proteolytic processing of the transcription factor sigma (K) in the outer mother cell chamber of the sporulating cell. This forms the basis of the sigma (K) checkpoint and ensures accurate sigma (K)-controlled gene expression. SpoIVB has also been shown to activate a second distinct process, termed the second function, which is essential for the formation of heat-resistant spores. In addition to the serine peptidase domain, SpoIVB contains a PDZ domain. We have altered a number of conserved residues in the PDZ domain by site-directed mutagenesis and assayed the sporulation phenotype and signaling properties of mutant SpoIVB proteins. Our work has revealed that the SpoIVB PDZ domain could be used for up to four distinct processes, (i) targeting of itself for trans proteolysis, (11) binding to the protease inhibitor BofC, (iii) signaling of pro-sigma (K) processing, and (iv) signaling of the second function of SpoIVB
Anomalies and the chiral magnetic effect in the Sakai-Sugimoto model
In the chiral magnetic effect an imbalance in the number of left- and
right-handed quarks gives rise to an electromagnetic current parallel to the
magnetic field produced in noncentral heavy-ion collisions. The chiral
imbalance may be induced by topologically nontrivial gluon configurations via
the QCD axial anomaly, while the resulting electromagnetic current itself is a
consequence of the QED anomaly. In the Sakai-Sugimoto model, which in a certain
limit is dual to large-N_c QCD, we discuss the proper implementation of the QED
axial anomaly, the (ambiguous) definition of chiral currents, and the
calculation of the chiral magnetic effect. We show that this model correctly
contains the so-called consistent anomaly, but requires the introduction of a
(holographic) finite counterterm to yield the correct covariant anomaly.
Introducing net chirality through an axial chemical potential, we find a
nonvanishing vector current only before including this counterterm. This seems
to imply the absence of the chiral magnetic effect in this model. On the other
hand, for a conventional quark chemical potential and large magnetic field,
which is of interest in the physics of compact stars, we obtain a nontrivial
result for the axial current that is in agreement with previous calculations
and known exact results for QCD.Comment: 35 pages, 4 figures, v2: added comments about frequency-dependent
conductivity at the end of section 4; references added; version to appear in
JHE
Quantifying impacts of short-term plasticity on neuronal information transfer
Short-term changes in efficacy have been postulated to enhance the ability of
synapses to transmit information between neurons, and within neuronal networks.
Even at the level of connections between single neurons, direct confirmation of
this simple conjecture has proven elusive. By combining paired-cell recordings,
realistic synaptic modelling and information theory, we provide evidence that
short-term plasticity can not only improve, but also reduce information
transfer between neurons. We focus on a concrete example in rat neocortex, but
our results may generalise to other systems. When information is contained in
the timings of individual spikes, we find that facilitation, depression and
recovery affect information transmission in proportion to their impacts upon
the probability of neurotransmitter release. When information is instead
conveyed by mean spike rate only, the influences of short-term plasticity
critically depend on the range of spike frequencies that the target network can
distinguish (its effective dynamic range). Our results suggest that to
efficiently transmit information, the brain must match synaptic type, coding
strategy and network connectivity during development and behaviour.Comment: Accepted for publication in Phys Rev E. 42 pages in referee format, 9
figure
OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users
Substrates for the Organic Cation Transporter 1, encoded by the SLC22A1 gene, are metformin, amantadine, pramipexole, and, possibly, levodopa. Recently, we identified that the rs622342 A > C polymorphism is associated with the HbA1c lowering effect in metformin users. In the Rotterdam Study, we associated this polymorphism with higher prescribed doses of all anti-Parkinsonian drugs. Between the first and fifth prescriptions for levodopa, for each minor rs622342 C allele, the prescribed doses were 0.34 defined daily dose higher (95% CI 0.064, 0.62; p = 0.017). The mortality ratio after start of levodopa therapy was 1.47 times higher (95% CI 1.01, 2.13; p = 0.045)
Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group
Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis
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