Polimorfizmy genu receptora witaminy D (TaqI oraz ApaI) oraz cyrkulacja osteokalcyny u pacjentów chorujących na cukrzycę typu 2 i osób zdrowych

  Introduction: Vitamin D receptor (VDR) is encoded by the VDR gene. Several studies have supported that this gene is associated with diabetes. Heterodimer VDR/RXR functions as an enhancer of the BGLAP gene and increases the basal transcription rate of osteocalcin (OC) during osteoblast differentiation. OC is a regulator of glucose metabolism in mice. Moreover, OC level is decreased in patients with type 2 diabetes (T2D). Although inversely correlated with serum glucose insulin and glycated haemoglobin, it is unclear whether OC reduction is caused by diabetes or plays a role in the pathogenesis and/or progression of the disease. In this study we analysed the association between TaqI and ApaI VDR gene polymorphisms and OC serum concentration in T2D subjects. Material and methods: Patients underwent clinical and nutritional assessment. Genomic DNA was extracted from leucocytes using a standard salting-out procedure. The polymorphisms were genotyped by PCR-RFLP method. ELISA was used to measure OC and insulin concentrations. Results: Association between TT genotype of TaqI polymorphism and low levels of OC was observed only in the population with overweight and obesity. No association between TaqI and ApaI polymorphisms and T2D was observed (p > 0.05). Furthermore, in T2D subjects, no correlation between ApaI and TaqI genotypes and age, sex, Body Mass Index (BMI), glucose, or OC was observed. Conclusions: The TT genotype of TaqI VDR gene polymorphism was correlated with low levels of OC in overweight and obese subjects. However, TaqI and ApaI VDR gene polymorphisms were not associated with T2D. (Endokrynol Pol 2015; 66 (4): 329–333)    Wstęp: Receptor witaminy D (VDR) kodowany jest przez gen VDR. Kilka badań potwierdziło, że gen ten jest związany z cukrzycą. Heterodimer VDR/RXR funkcjonuje jako stymulator genu BGLAP i zwiększa podstawowy wskaźnik transkrypcji osteokalcyny (OC) podczas różnicowania osteoblastów. Osteokalcyna jest regulatorem metabolizmu glukozy u myszy. Ponadto, stężenie OC jest obniżone u pacjentów z cukrzycą typu 2 (T2D). Pomimo odwrotnej korelacji między stężeniem OC a stężeniem glukozy i insuliny w surowicy, a także hemoglobiną glikowaną, nie jest wiadome czy obniżenie stężenia OC jest wywołane przez cukrzycę lub odgrywa rolę w patogenezie i/lub progresji choroby. W niniejszym badaniu autorzy przeanalizowali związek pomiędzy polimorfizmami genów VDR TaqI oraz ApaI, a także stężenie OC w surowicy u pacjentów z T2D. Materiał i metody: Pacjentów poddano ocenie klinicznej i żywieniowej. Genomowe DNA pobrano z leukocytów dzięki standardowej procedurze wysalania. Polimorfizmy genotypowano metodą PCR-RFLP. Testem ELISA zmierzono stężenia OC oraz insuliny. Wyniki: Związek pomiędzy genotypem TT polimorfizmu TaqI a niskim stężeniem OC zaobserwowano jedynie u populacji z nadwagą i otyłością. Nie wykazano związku pomiędzy polimorfizmami TaqI i ApaI oraz T2D (p > 0,05). Co więcej, u pacjentów z T2D nie wykazano korelacji pomiędzy genotypami ApaI i TaqI oraz wiekiem, płcią, wskaźnikiem masy ciała (BMI), glukozą lub OC. Wnioski: Genotyp TT polimorfizmu genu VDR TaqI jest skorelowany z niskim stężeniem OC u pacjentów z nadwagą i otyłością. Jednakże, polimorfizmy genu VDR TaqI i ApaI nie są związane z T2D. (Endokrynol Pol 2015; 66 (4): 329–333)

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Funder: laura and john arnold foundationBACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Fewer clouds in the Mediterranean: Consistency of observations and climate simulations

Clouds play a major role in the climate system, but large uncertainties remain about their decadal variations. Here we report a widespread decrease in cloud cover since the 1970 s over the Mediterranean region, in particular during the 1970 s–1980 s, especially in the central and eastern areas and during springtime. Confidence in these findings is high due to the good agreement between the interannual variations of cloud cover provided by surface observations and several satellite-derived and reanalysis products, although some discrepancies exist in their trends. Climate model simulations of the historical experiment from the Coupled Model Intercomparison Project Phase 5 (CMIP5) also exhibit a decrease in cloud cover over the Mediterranean since the 1970 s, in agreement with surface observations, although the rate of decrease is slightly lower. The observed northward expansion of the Hadley cell is discussed as a possible cause of detected trends.ISSN:2045-232

Cas Ilgly Induces Apoptosis in Glioma C6 Cells In Vitro and In Vivo through Caspase-Dependent and Caspase-Independent Mechanisms

In this work, we investigated the effects of Casiopeina Il-gly (Cas ILgly)—a new copper compound exhibiting antineoplastic activity—on glioma C6 cells under both in vitro and in vivo conditions, as an approach to identify potential therapeutic agents against malignant glioma. The exposure of C6 cells to Cas Ilgly significantly inhibited cell proliferation, increased reactive oxygen species (ROS) formation, and induced apoptosis in a dose-dependent manner. In cultured C6 cells, Cas Ilgly caused mitochondrio-nuclear translocation of apoptosis induction factor (AIF) and endonuclease G at all concentrations tested; in contrast, fragmentation of nucleosomal DNA, cytochrome c release, and caspase-3 activation were observed at high concentrations. Administration of N-acetyl-l-cystein, an antioxidant, resulted in significant inhibition of AIF translocation, nucleosomal DNA fragmentation, and caspase-3 activation induced by Cas Ilgly. These results suggest that caspase-dependent and caspase-independent pathways both participate in apoptotic events elicited by Cas Ilgly. ROS formation induced by Cas Ilgly might also be involved in the mitochondrio-nuclear translocation of AIF and apoptosis. In addition, treatment of glioma C6-positive rats with Cas Ilgly reduced tumor volume and mitotic and cell proliferation indexes, and increased apoptotic index. Our findings support the use of Cas Ilgly for the treatment of malignant gliomas

Additional file 2 of Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

Additional file 2. Email invitation

Additional file 7 of Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

Additional file 7. Sensitivity analyses: various meta-analytic approaches