Background Air pollution constitutes a significant stimulus of asthma exacerbations; however, the impacts of exposure to major air pollutants on asthma-related hospital admissions and emergency room visits (ERVs) have not been fully determined. Objective We sought to quantify the associations between short-term exposure to air pollutants [ozone (O3), carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), and particulate matter ≤10μm (PM10) and PM2.5] and the asthma-related emergency room visits (ERV) and hospitalizations. Methods Systematic computerized searches without language limitation were performed. Pooled relative risks (RRs) and 95% confidence intervals (95%CIs) were estimated using the random-effect models. Sensitivity analyses and subgroup analyses were also performed. Results After screening of 246 studies, 87 were included in our analyses. Air pollutants were associated with significantly increased risks of asthma ERVs and hospitalizations [O3: RR(95%CI), 1.009 (1.006, 1.011); I2 = 87.8%, population-attributable fraction (PAF) (95%CI): 0.8 (0.6, 1.1); CO: RR(95%CI), 1.045 (1.029, 1.061); I2 = 85.7%, PAF (95%CI): 4.3 (2.8, 5.7); NO2: RR(95%CI), 1.018 (1.014, 1.022); I2 = 87.6%, PAF (95%CI): 1.8 (1.4, 2.2); SO2: RR(95%CI), 1.011 (1.007, 1.015); I2 = 77.1%, PAF (95%CI): 1.1 (0.7, 1.5); PM10: RR(95%CI), 1.010 (1.008, 1.013); I2 = 69.1%, PAF (95%CI): 1.1 (0.8, 1.3); PM2.5: RR(95%CI), 1.023 (1.015, 1.031); I2 = 82.8%, PAF (95%CI): 2.3 (1.5, 3.1)]. Sensitivity analyses yielded compatible findings as compared with the overall analyses without publication bias. Stronger associations were found in hospitalized males, children and elderly patients in warm seasons with lag of 2 days or greater. Conclusion Short-term exposures to air pollutants account for increased risks of asthma-related ERVs and hospitalizations that constitute a considerable healthcare utilization and socioeconomic burden.
Background It is possible that cross-over studies included in current systematic reviews are being inadequately assessed, because the current risk of bias tools do not consider possible biases specific to cross-over design. We performed this study to evaluate whether this was being done in cross-over studies included in Cochrane Systematic Reviews (CSRs). Methods We searched the Cochrane Library (up to 2013 issue 5) for CSRs that included at least one cross-over trial. Two authors independently undertook the study selection and data extraction. A random sample of the CSRs was selected and we evaluated whether the cross-over trials in these CSRs were assessed according to criteria suggested by the Cochrane handbook. In addition we reassessed the risk of bias of these cross-over trials by a checklist developed form the Cochrane handbook. Results We identified 688 CSRs that included one or more cross-over studies. We chose a random sample of 60 CSRs and these included 139 cross-over studies. None of these CSRs undertook a risk of bias assessment specific for cross-over studies. In fact items specific for cross-over studies were seldom considered anywhere in quality assessment of these CSRs. When we reassessed the risk of bias, including the 3 items specific to cross-over trials, of these 139 studies, a low risk of bias was judged for appropriate cross-over design in 110(79%), carry-over effects in 48(34%) and for reporting data in all stages of the trial in 114(82%).Assessment of biases in cross-over trials could affect the GRADE assessment of a review’s findings. Conclusion The current Cochrane risk of bias tool is not adequate to assess cross-over studies. Items specific to cross-over trials leading to potential risk of bias are generally neglected in CSRs. A proposed check list for the evaluation of cross-over trials is provided.
KRAS mutations have been established as a major predictive biomarker for resistance to the treatment of metastatic colorectal cancer (mCRC) with anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MoAbs). However, many patients with KRAS wild-type tumors still do not respond to the treatment. We conducted a systematic review with meta-analysis to assess whether BRAF mutations, PIK3CA mutations and PTEN loss can predict the outcomes of patients with KRAS wild-type mCRC treated with anti-EGFR MoAbs. Studies that explored the association of one or more of the three biomarkers with progression-free survival (PFS), overall survival (OS) and/or objective response rate (ORR) were identified through August 2012. Summary hazard ratios (HRs) and rate differences (RDs) and corresponding 95% confidence intervals (CIs) were calculated by using the random-effects model. BRAF mutations, PIK3CA exon 20 mutations and PTEN loss were all associated with shorter PFS (HR = 2.59, 95% CI 1.67-4.03; HR = 2.52, 95% CI 1.33-4.78 and HR = 1.75, 95% CI 1.19-2.56, respectively), shorter OS (HR = 2.74, 95% CI 1.79-4.19; HR = 3.29, 95% CI 1.60-6.75 and HR = 1.85, 95% CI 1.30-2.64, respectively) and lower ORR (RD = -36%, 95% CI -44 to -28%; RD = -38%, 95% CI -51 to -24% and RD = -41%, 95% CI -68 to -14%, respectively). PIK3CA exon 9 mutations were associated with none of the outcomes. Studies with relevant data consistently demonstrated a stronger predictive power of combined multiple biomarkers as compared to one alteration alone. These results suggest that BRAF mutations, PIK3CA exon 20 mutations and PTEN loss are predictive of worseoutcomes in KRAS wild-type mCRC treated with anti-EGFR MoAbs [corrected]. However, the quality of included studies varied, and some of the meta-analyses were limited by significant between-study heterogeneity. In the future, well-designed large randomized controlled trials conducted in KRAS wild-type mCRC patients with subgroup analysis according to BRAF, PIK3CA exon 20 and PTEN status are essential to fully assess the clinical relevance of these biomarkers.
Abstract Along with the aging of the world population, the incidence rate of Alzheimer's disease (AD) has been increasing. At present, AD has become one of the most serious problems faced by modern medicine. Studies have shown that estrogen has a positive effect on AD, but estrogen has the side effect of leading to tumors. Recent in vivo studies have shown that genistein, one of the selective estrogen receptor modulators (SERMs), can improve brain function through the blood–brain barrier (BBB), antagonize the toxicity of amyloid β‐protein (Aβ), that is, to inhibit neurotoxicity due to aggregation of beta amyloid protein, and have neuroprotective effects. In addition, the use of Gen can avoid the risk of endometrial cancer and breast cancer caused by estrogen therapy while exerting an estrogen‐like effect, which has some potential for the delay and treatment of AD.
Abstract Diabetes Mellitus is a chronic disease characterized by metabolic defects, including insulin deficiency and resistance. Individuals with diabetes are at increased risk of developing cardiovascular complications, such as atherosclerosis, coronary artery disease, and hypertension. Conventional treatment methods, though effective, are often challenging, costly, and may lead to systemic side effects. This study explores the potential of nanomedicine applications, specifically Metal-Organic Frameworks (MOFs), as drug carriers to overcome these limitations. The Materials Institute Lavoisier-89 nanoparticles (nanoMIL-89) have previously demonstrated promise as a drug delivery vehicle for chronic diseases due to their anti-oxidant and cardio-protective properties. In this investigation, nanoMIL-89 was loaded with the anti-diabetic drug metformin (MET), creating MET@nanoMIL-89 formulation. We examined the drug release kinetics of MET@nanoMIL-89 over 96 hours and assessed its impact on the viability of various endothelial cells. Furthermore, we investigated the nanoformulation effect on inflammatory markers in these cells and explored its influence on phosphorylated eNOS, total eNOS, and AKT levels. Our findings indicate that nanoMIL-89 effectively released metformin over 96 hours and caused a concentration-dependent reduction in CXCL-8 release from endothelial cells. Notably, MET@nanoMIL-89 reduced dihydroethidium levels and increased phosphorylated eNOS, total eNOS, and AKT levels. Our results underscore the potential of nanoMIL-89 as a versatile potential drug delivery platform for anti-diabetic drugs, offering a prospective therapeutic approach for diabetic patients with associated cardiovascular complications.
Metformin, the first choice of drug to treat diabetes, confers protection against cardiovascular disease (CVD) & also suppress tumor growth albeit at high concentrations. Since scientific evidence suggest a strong association between diabetes & CVD & more recently between concurrent diabetes & cancer, it is important to evaluate how the microvascular endothelial cells (MECs), which receive the initial impact of reduced oxygen & nutrient/glucose starvation (GS) during a myocardial infarction or in a tumor microenvironment, respond to metformin treatment. In the present study we investigated the effect of varying concentrations of metformin on GS induced endoplasmic reticulum (ER) stress & autophagy in MECs. Mouse Microvasuclar Endothelial Cells (MMECs) were subjected to GS for 24h in the presence & absence metformin (50μM & 2mM) & western blot analysis was performed to assess the induction of ER stress & autophagy. Immunofluorescence staining followed by confocal microscopy was also done to assess LC3B punctae staining in cells, indicating autophagy. ER stress activation & autophagic induction was observed in MMECs subjected to GS as evidenced by significant increase in the levels of ER stress markers (GRP78, ATF4 & CHOP) & autophagic markers (LC3A/B‐II), respectively. Accumulation of LC3B stained punctae in glucose‐starved cells also confirmed autophagic activation. Metformin treatment (2mM), independent of AMPK, significantly reversed GS induced ER stress & autophagy in MECs while lower concentrations had no effect. Our study demonstrates for the first time that metformin reverses GS induced ER stress & autophagy in the microvascular endothelium.
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