Well‐characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one‐third of the variability in ...therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R2 of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R2 of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R2 was 26–43% with the clinical algorithm and 42–58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.
Clinical Pharmacology & Therapeutics (2010) 87 5, 572–578. doi: 10.1038/clpt.2010.13
An online survey of lesbian, gay, and bisexual (LGB) adults (
N
= 1,552) examined minority stress (I. H.
Meyer, 2003
) and psychological distress following the 2006 general election in which ...constitutional amendments to limit marriage to 1 man and 1 woman were on the ballot in 9 states. Following the November election, participants living in states that passed a marriage amendment reported significantly more minority stress (i.e., exposure to negative media messages and negative conversations, negative amendment-related affect, and LGB activism) and higher levels of psychological distress (negative affect, stress, and depressive symptoms) than participants living in the other states. Multiple hierarchical regression analyses revealed significant positive main effects of minority stress factors and state ballot status on psychological distress. In addition, the association between amendment-related affect and psychological distress was significantly higher in states that had passed a marriage amendment compared with other states. Discussion of these findings emphasizes that marriage amendments create an environment associated with negative psychological outcomes for LGB individuals.
The presence of cardiovascular (CV) risk factors and CV disease in patients with chronic obstructive pulmonary disease (COPD) leads to worse outcomes. A number of tools are currently available to ...stratify the risk of adverse outcomes in these patients with COPD. This post hoc analysis evaluated the Summit Lab Score for validation as a predictor of the first episode of moderate-to-severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and other outcomes, in patients with COPD and high arterial pulse wave velocity (aPWV).
Data from a multicenter, randomized, placebo-controlled, double-blind study were retrospectively analyzed to evaluate treatment effects of once-daily fluticasone furoate/vilanterol 100/25 μg in patients with COPD and an elevated CV risk (aPWV≥11m/s) over 24 weeks. The previously derived Summit Lab Score and, secondarily, the Intermountain Risk Score (IMRS) were computed for each patient, with patients then stratified into tertiles for each score. Risk of moderate-to-severe AECOPD was analyzed across tertiles using Kaplan-Meier survival curve and Cox regression analyses.
In 430 patients with COPD, Kaplan-Meier probabilities of no moderate-to-severe AECOPD for Summit Lab Score tertiles 1, 2, and 3 were 92.3%, 95.5%, and 85.1%, respectively (
trend = 0.015), over 24 weeks. Grouped by IMRS tertiles, the respective probabilities were 92.9%, 91.2%, and 88.3%, respectively (
trend = 0.141). Length of stay in the hospital (
= 0.034) and the hospital ward (
= 0.042) were also significantly different between Summit Lab Score tertiles but not for intensive care (
= 0.191).
The Summit Lab Score was associated with the 24-week risk of moderate-to-severe AECOPD in COPD patients with elevated CV risk. Secondarily, IMRS showed a trend towards differences in the risk of AECOPD, which was not statistically significant.
Legal recognition of same-sex couple relationships provides at least some material benefits to couple members; however, few studies have examined the associations between legal recognition and ...psychological distress or well-being. Using an online survey sample of 2,677 lesbian, gay, bisexual (LGB) individuals, participants were placed in 4 groups: single, dating, in a committed relationship, and in a legally recognized relationship. Analyses revealed that participants in committed or legally recognized relationships reported less psychological distress (i.e., internalized homophobia, depressive symptoms, and stress) and more well-being (i.e., the presence of meaning in life) than single participants. Significant group differences and multivariate analyses indicated that participants in a legally recognized relationship reported less internalized homophobia, fewer depressive symptoms, lower levels of stress, and more meaning in their lives than those in committed relationships, even after controlling for other factors. The need for further research on the psychological benefits of legal relationship recognition for same-sex couples is discussed.
Abstract Background and aims Routine, periodic fasting is associated with a lower prevalence of coronary artery disease (CAD). Animal studies show that fasting may increase longevity and alter ...biological parameters related to longevity. We evaluated whether fasting initiates acute changes in biomarker expression in humans that may impact short- and long-term health. Methods and results Apparently-healthy volunteers ( N = 30) without a recent history of fasting were enrolled in a randomized cross-over trial. A one-day water-only fast was the intervention and changes in biomarkers were the study endpoints. Bonferroni correction required p ≤ 0.00167 for significance ( p < 0.05 was a trend that was only suggestively significant). The one-day fasting intervention acutely increased human growth hormone ( p = 1.1 × 10−4 ), hemoglobin ( p = 4.8 × 10−7 ), red blood cell count ( p = 2.5 × 10−6 ), hematocrit ( p = 3.0 × 10−6 ), total cholesterol ( p = 5.8 × 10−5 ), and high-density lipoprotein cholesterol ( p = 0.0015), and decreased triglycerides ( p = 1.3 × 10−4 ), bicarbonate ( p = 3.9 × 10−4 ), and weight ( p = 1.0 × 10−7 ), compared to a day of usual eating. For those randomized to fast the first day ( n = 16), most factors including human growth hormone and cholesterol returned to baseline after the full 48 h, with the exception of weight ( p = 2.5 × 10−4 ) and (suggestively significant) triglycerides ( p = 0.028). Conclusion Fasting induced acute changes in biomarkers of metabolic, cardiovascular, and general health. The long-term consequences of these short-term changes are unknown but repeated episodes of periodic short-term fasting should be evaluated as a preventive treatment with the potential to reduce metabolic disease risk. Clinical trial registration ( ClinicalTrials.gov ): NCT01059760 (Expression of Longevity Genes in Response to Extended Fasting The F asting and E xpr e ssion of L ongevity G enes during F ood abstinence {FEELGOOD} Trial).
Purpose: This retrospective, observational cohort study investigated the association of blood eosinophil counts within 1 week of hospitalization for acute exacerbation of COPD (AECOPD) with ...subsequent risk of all-cause and COPD-related readmission from a large integrated health system. Patients and Methods: Electronic medical records were extracted for index hospitalization for AECOPD at all Intermountain Healthcare hospitals. The primary outcome was the relationship of blood eosinophil count to 30-day all-cause readmission; secondary outcomes were 60-day, 90-day, and 12-month all-cause readmission, COPD-related readmission, and empiric derivation of the eosinophil count with the highest area under the curve (AUC) for predicting 30-day all-cause readmission. Results: Of 2445 included patients, 1935 (79%) had a blood eosinophil count <300 cells/microL and 510 (21%) had a count greater than or equal to300 cells/microL. Using a 300-cells/microL threshold, there was no significant difference between high and low eosinophil groups in 30-day (odds ratio OR =1.05, 95% confidence interval CI=0.75-1.47) or 60-day (OR=1.15, 95% CI=0.88-1.51) all-cause readmissions. However, patients with greater (versus lesser) eosinophil counts had increased 90-day and 12-month all-cause readmissions (OR=1.35, 95% CI=1.06-1.72, and OR=1.32, 95% CI=1.07-1.62). COPD-related readmission rates were significantly greater for patients with greater (versus lesser) eosinophil counts at 30, 60, and 90 days and 12 months (OR range=1.52-1.97). A total of 70 cells/microL had the most discriminatory power to predict 30-day all-cause readmission (highest AUC). Conclusion: Eosinophil counts in patients with COPD were not associated with a difference in 30-day all-cause readmissions. However, greater eosinophil counts were associated with increased risk of all-cause readmission at 90 days and 12 months and COPD-related readmission at 30, 60, and 90 days and 12 months. Patients with eosinophils <70 cells/microL had the lowest risk for 30-day all-cause readmission. Blood eosinophils in patients hospitalized with AECOPD may be a useful biomarker for the risk of hospital readmission. Keywords: AECOPD, phenotype, biomarkers, eosinophils, electronic medical records
We combine all available information to constrain the nature of OGLE-2005-BLG-071Lb, the second planet discovered by microlensing and the first in a high-magnification event. These include ...photometric and astrometric measurements from the Hubble Space Telescope, as well as constraints from higher order effects extracted from the ground-based light curve, such as microlens parallax, planetary orbital motion, and finite-source effects. Our primary analysis leads to the conclusion that the host of Jovian planet OGLE-2005-BLG-071Lb is an M dwarf in the foreground disk with mass M = 0.46 ± 0.04 M, distance Dl = 3.2 ± 0.4 kpc, and thick-disk kinematics vLSR ~ 103 km s-1. From the best-fit model, the planet has mass Mp = 3.8 ± 0.4 MJupiter, lies at a projected separation r{up tack} = 3.6 ± 0.2AU from its host, and so has an equilibrium temperature of T ~ 55 K, that is, similar to Neptune. A degenerate model gives similar planetary mass Mp = 3.4 ± 0.4 MJupiter with a smaller projected separation, r{up tack} = 2.1 ± 0.1AU, and higher equilibrium temperature, T ~ 71 K. These results from the primary analysis suggest that OGLE-2005-BLG-071Lb is likely to be the most massive planet yet discovered that is hosted by an M dwarf. However, the formation of such high-mass planetary companions in the outer regions of M dwarf planetary systems is predicted to be unlikely within the core-accretion scenario. There are a number of caveats to this primary analysis, which assumes (based on real but limited evidence) that the unlensed light coincident with the source is actually due to the lens, that is, the planetary host. However, these caveats could mostly be resolved by a single astrometric measurement a few years after the event.
Dust grains are nucleation centers and catalysts for the growth of icy mantles in quiescent interstellar clouds, the products of which may accumulate into preplanetary matter when new stars and solar ...systems form within the clouds. In this paper, we present the first spectroscopic detections of silicate dust and the molecular ices H sub(2)O, CO, and CO sub(2) in the vicinity of the prestellar core L183 (L134N). An infrared photometric survey of the cloud was used to identify reddened background stars, and we present spectra covering solid-state absorption features in the wavelength range 2-20 mu m for nine of them. The mean composition of the ices in the best-studied line of sight (toward J15542044-0254073) is H sub(2)O:CO:CO sub(2) approx = 100:40:24. The ices are amorphous in structure, indicating that they have been maintained at low temperature (<, ~ 15 K) since formation. The ice column density N(H sub(2)O) correlates with reddening by dust, exhibiting a threshold effect that corresponds to the transition from unmantled grains in the outer layers of the cloud to ice-mantled grains within, analogous to that observed in other dark clouds. A comparison of results for L183 and the Taurus and IC 5146 dark clouds suggests common behavior, with mantles first appearing in each case at a dust column corresponding to a peak optical depth tau sub(9.7) = 0.15 + or - 0.03 in the silicate feature. Our results support a previous conclusion that the color excess EJ - K does not obey a simple linear correlation with the total dust column in lines of sight that intercept dense clouds. The most likely explanation is a systematic change in the optical properties of the dust as the density increases.
Sensing the osmolarity of the environment is a critical response for all organisms. Whereas bacteria will migrate away from high osmotic conditions, most eukaryotic cells are not motile and use ...adaptive metabolic responses for survival. The p38 MAPK pathway is a crucial mediator of survival during cellular stress. We have discovered a novel scaffold protein that binds to actin, the GTPase Rac, and the upstream kinases MEKK3 and MKK3 in the p38 MAPK phospho-relay module. RNA interference (RNAi) demonstrates that MEKK3 and the scaffold protein are required for p38 activation in response to sorbitol-induced hyperosmolarity. FRET identifies a cytoplasmic complex of the MEKK3 scaffold protein that is recruited to dynamic actin structures in response to sorbitol treatment. Through its ability to bind actin, relocalize to Rac-containing membrane ruffles and its obligate requirement for p38 activation in response to sorbitol, we have termed this protein osmosensing scaffold for MEKK3 (OSM). The Rac-OSM-MEKK3-MKK3 complex is the mammalian counterpart of the CDC42-STE50-STE11-Pbs2 complex in Saccharomyces cerevisiae that is required for the regulation of p38 activity.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A systematic review and a meta‐analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism ...on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC‐homozygotes, T‐allele carriers required an 8.3% (95% confidence interval (CI): 5.6–11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.
Clinical Pharmacology & Therapeutics (2012); 92 6, 746–756. doi:10.1038/clpt.2012.184
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