Pancreatic β-cells can secrete insulin via 2 pathways characterized as KATP channel -dependent and -independent. The KATP channel-independent pathway is characterized by a rise in several potential ...metabolic signaling molecules, including the NADPH/NADP+ ratio and α-ketoglutarate (αKG). Prolyl hydroxylases (PHDs), which belong to the αKG-dependent dioxygenase superfamily, are known to regulate the stability of hypoxia-inducible factor α. In the current study, we assess the role of PHDs in vivo using the pharmacological inhibitor dimethyloxalylglycine (DMOG) and generated β-cell-specific knockout (KO) mice for all 3 isoforms of PHD (β-PHD1 KO, β-PHD2 KO, and β-PHD3 KO mice). DMOG inhibited in vivo insulin secretion in response to glucose challenge and inhibited the first phase of insulin secretion but enhanced the second phase of insulin secretion in isolated islets. None of the β-PHD KO mice showed any significant in vivo defects associated with glucose tolerance and insulin resistance except for β-PHD2 KO mice which had significantly increased plasma insulin during a glucose challenge. Islets from both β-PHD1 KO and β-PHD3 KO had elevated β-cell apoptosis and reduced β-cell mass. Isolated islets from β-PHD1 KO and β-PHD3 KO had impaired glucose-stimulated insulin secretion and glucose-stimulated increases in the ATP/ADP and NADPH/NADP+ ratio. All 3 PHD isoforms are expressed in β-cells, with PHD3 showing the most distinct expression pattern. The lack of each PHD protein did not significantly impair in vivo glucose homeostasis. However, β-PHD1 KO and β-PHD3 KO mice had defective β-cell mass and islet insulin secretion, suggesting that these mice may be predisposed to developing diabetes.
More than one billion people depend upon glaciers for water, yet this exploitation is seldom underpinned by science‐led water management practice. Previous work has detected that glaciers store and ...then subsequently release contaminants to downstream ecosystems, revealing a potentially harmful legacy that needs to be managed in conjunction with contemporary atmospheric pollution and climate change. Remarkably, while several classes of harmful organic pollutants have been considered in this context, almost no attention has been given to black carbon, a dark aerosol that is host to several adsorbed contaminants and that greatly increases glacier melt by enhancing the absorption of solar radiation. The future impact of black carbon upon glacier melt and contaminant release cannot be managed until we know how much historical black carbon is stored in Earth's glaciers. Further, as the residence time of ice within many mountain glaciers is between 100 and 1000 years, major changes in these impacts can be anticipated in the near future. A case is therefore made for using glacier dynamic models to understand the distribution of postindustrial, contaminated ice within glaciers, so that their impacts upon melt water quantity and quality can be forecast. A research framework is proposed that ranges from high flux, dynamic glaciers which are replete with postindustrial ice, to low flux, polar glaciers which are unlikely to become replete before they disappear. Research into the processing of contaminants following their melt‐out is also required, because microbial processes will lead to their bioflocculation and biodegradation on glacier surfaces.
This article is categorized under:
Water and Life > Nature of Freshwater Ecosystems
The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis with the aim of preventing the clinical syndrome associated with CMV ...infection.
To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause mortality in solid organ transplant recipients.
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, reference lists and abstracts from conference proceedings without language restriction. Date of last search: February 2007
Randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications and comparing different regimens of the same antiviral medications in recipients of any solid organ transplant.
Statistical analyses were performed using the random effects model and results expressed as relative risk (RR) for dichotomous outcomes with 95% confidence intervals (CI). Subgroup analysis and univariate meta-regression were performed using restricted maximum-likelihood to estimate the between study variance. Multivariate meta-regression was performed to investigate whether the results were altered after allowing for differences in drugs used, organ transplanted and recipient CMV serostatus at the time of transplantation.
Thirty four studies (3850 participants) were identified. Prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment significantly reduced the risk for CMV disease (19 studies; RR 0.42, 95% CI 0.34 to 0.52), CMV infection (17 studies; RR 0.61, 95% CI 0.48 to 0.77), and all-cause mortality (17 studies; RR 0.63, 95% CI 0.43 to 0.92) primarily due to reduced mortality from CMV disease (7 studies; RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduced the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but not fungal infection, acute rejection or graft loss. Meta-regression showed no significant difference in the relative benefit of treatment (risk of CMV disease or all-cause mortality) by organ transplanted or CMV serostatus; no conclusions were possible for CMV negative recipients of negative organs. In direct comparison studies, ganciclovir was more effective than aciclovir in preventing CMV disease (7 studies; RR 0.37, 95% CI 0.23 to 0.60). Valganciclovir and IV ganciclovir were as effective as oral ganciclovir.
Prophylaxis with antiviral medications reduces CMV disease and CMV-associated mortality in solid organ transplant recipients. They should be used routinely in CMV positive recipients and in CMV negative recipients of CMV positive organ transplants.
Microorganisms have a crucial role to play in the cycling of nutrients within glacial environments. These systems are often nutrient-limited, and so biogeochemical reactions, which ensure the ...availability of nutrients for microbial communities, are critical for the maintenance of these systems. This study uses molecular biology to characterise the supraglacial cryoconite microbial communities that are capable of cycling carbon and nitrogen in a range of glacial environments. Organisms with the potential to photosynthesise were identified, including Cyanobacteria, Actinobacteria, Betaproteobacteria, Stramenopiles and Haptophyceae. Organisms with the potential to perform nitrification and denitrification processes were also identified and featured Betaproteobacteria, Alphaproteobacteria, Thaumarchaeota and Cyanobacteria. While it is unlikely that the chemical and physical parameters of the supraglacial environment will facilitate optimal rates of all of the nitrogen-related biogeochemical processes, the transport of these cryoconite communities to downstream locations, where more favourable conditions may prevail, will perhaps provide a valuable inoculation of microorganisms with the genetic potential to catalyse these reactions elsewhere.
Workers, particularly outdoor workers, are among the populations most disproportionately affected by climate-related hazards. However, scientific research and control actions to comprehensively ...address these hazards are notably absent. To assess this absence, a seven-category framework was developed in 2009 to characterize the scientific literature published from 1988-2008. Using this framework, a second assessment examined the literature published through 2014, and the current one examines literature from 2014-2021. The objectives were to present literature that updates the framework and related topics and increases awareness of the role of climate change in occupational safety and health. In general, there is substantial literature on worker hazards related to ambient temperatures, biological hazards, and extreme weather but less on air pollution, ultraviolet radiation, industrial transitions, and the built environment. There is growing literature on mental health and health equity issues related to climate change, but much more research is needed. The socioeconomic impacts of climate change also require more research. This study illustrates that workers are experiencing increased morbidity and mortality related to climate change. In all areas of climate-related worker risk, including geoengineering, research is needed on the causality and prevalence of hazards, along with surveillance to identify, and interventions for hazard prevention and control.
Abstract Aims Early diagnosis of cystic fibrosis (CF) related diabetes (CFRD) is important to improve outcomes. International guidelines recommend an oral glucose tolerance test (OGTT) for all CF ...patients aged ≥ 10 years — this approach is controversial. The aim of this study was to develop an effective screening tool and reduce the need for a universal OGTT. Methods Adult CF patients (without CFRD) attending an annual review assessment were recruited prospectively (March 2009–July 2012) into two sequential studies — a primary investigative study followed by validation study. All patients underwent an OGTT and were simultaneously screened by predetermined biochemical/clinical criteria to identify their risk of CFRD. A sensitivity/specificity analysis was performed using the World Health Organisation diabetes criteria as gold standard; modifications were made to improve the screening tool's accuracy and determine the optimal screening thresholds. This was tested in the validation study. Results 429 patients (primary, n = 94; validation, n = 335: mean age = 31.7 ± 10.4(SD), 43% female, 77% on pancreatic supplements). Primary study: in predicting a positive OGTT, the test sensitivity was 66.7% and specificity 60%. HbA1c was carried over to the validation study as it was the most discriminative (optimal threshold ≥ 5.8% (40 mmol/mol); receiver operating curve, ROC, score 0.60). Validation study: the number of patients with a normal, impaired and diabetic OGTT was 268(80%), 51(15.2%) and 16(4.8%), respectively. HbA1c provided a test sensitivity, specificity and ROC score of 93.8%, 53.0% and 0.73, respectively. Conclusions The use of HbA1c ≥ 5.8%(40 mmol/mol) is an effective tool for CFRD screening and reduced the need for an OGTT by 50.7%.
Streamflow is one of the most important variables in hydrology, but it is difficult to measure continuously. As a result, nearly all streamflow time series are estimated from rating curves that ...define a mathematical relationship between streamflow and some easy-to-measure proxy like water surface elevation (stage). Despite the existence of automated methods, most rating curves are still fit manually, which can be time-consuming and subjective. Although several automated methods exist, they vary greatly in performance because of the non-convex nature of the problem. In this work, we develop a parameterization of the segmented power law that works reliably with minimal data, which could serve operationally or as a benchmark for evaluating other methods. The model, along with test data and tutorials, is available as an open-source Python package called ratingcurve. The implementation uses a modern probabilistic machine-learning framework, which is relatively easy to modify so that others can improve upon it.
The purpose of this study was to evaluate the test performance of duplex sonographic parameters in screening for hemodynamically significant renal artery stenosis, which occurs in approximately 5% of ...persons with hypertension.
A comprehensive literature search was conducted to find studies on the diagnosis of renal artery stenosis in which duplex sonography and intraarterial angiography were compared and in which sensitivity and specificity were calculated. MEDLINE (1966-2005), EMBASE (1988-2005), and reference lists were searched and the authors contacted. Data were subjected to meta-analysis according to the hierarchical summary receiver operating characteristic curve model. Heterogeneity in test performance relating to population and design features was investigated.
From 1,357 titles, 88 studies involving 9,974 arteries in 8,147 patients were included. The following four parameters were evaluated: peak systolic velocity (21 studies), acceleration time (13 studies), acceleration index (13 studies), and renal-aortic ratio (13 studies). The corresponding diagnostic odds ratios (ORs) were 60.9 (95% CI, 28.3-131.2), 28.9 (95% CI, 7.1-117.2), 16.0 (95% CI, 5.1-50.6), and 29.3 (95% CI, 12.7-67.7). Results based on studies in which parameters were directly compared showed that peak systolic velocity had greater accuracy than renal-aortic ratio (relative diagnostic OR, 1.8; p = 0.03; nine studies) and acceleration index (relative diagnostic OR, 5.3; p < 0.001; five studies). Acceleration time versus acceleration index showed no evidence of a difference in accuracy (relative diagnostic OR, 1.1; p = 0.65; nine studies). Analysis of peak systolic velocity used in combination with other parameters compared with peak systolic velocity alone (seven studies) showed evidence of a shift in test positivity (p < 0.001) but only weak evidence of improvement in accuracy (relative diagnostic OR, 1.6; p = 0.09).
Sonography is a moderately accurate screening test for renal artery stenosis. The single measurement, peak systolic velocity, has the highest performance characteristics, an expected sensitivity of 85% and specificity of 92%. Additional measurements do not increase accuracy.
As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors ...(HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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