Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially ...deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis.
Sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent a new class of oral hypoglycemic agents used in the treatment of type 2 diabetes mellitus. They have a positive effect on the progression ...of chronic kidney disease, but there is a concern that they might cause acute kidney injury (AKI).
We conducted a systematic review and meta-analysis of the effect of SGLT2is on renal adverse events (AEs) in randomized controlled trials and controlled observational studies. PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov were searched without date restriction until 27 September 2019. Data extraction was performed using a standardized data form, and any discrepancies were resolved by consensus. One hundred and twelve randomized trials (n = 96,722) and 4 observational studies with 5 cohorts (n = 83,934) with a minimum follow-up of 12 weeks that provided information on at least 1 adverse renal outcome (AKI, combined renal AE, or hypovolemia-related events) were included. In 30 trials, 410 serious AEs due to AKI were reported. SGLT2is reduced the odds of suffering AKI by 36% (odds ratio OR 0.64 95% confidence interval (CI) 0.53-0.78, p < 0.001). A total of 1,089 AKI events of any severity (AEs and serious AEs SAEs) were published in 41 trials (OR 0.75 95% CI 0.66-0.84, p < 0.001). Empagliflozin, dapagliflozin, and canagliflozin had a comparable benefit on the SAE and AE rate. AEs related to hypovolemia were more commonly reported in SGLT2i-treated patients (OR 1.20 95% CI 1.10-1.31, p < 0.001). In the observational studies, 777 AKI events were reported. The odds of suffering AKI were reduced in patients receiving SGLT2is (OR 0.40 95% CI 0.33-0.48, p < 0.001). Limitations of this study are the reliance on nonadjudicated safety endpoints, discrepant inclusion criteria and baseline hypoglycemic therapy between studies, inconsistent definitions of renal AEs and hypovolemia, varying follow-up times in different studies, and a lack of information on the severity of AKI (stages I-III).
SGLT2is reduced the odds of suffering AKI with and without hospitalization in randomized trials and the real-world setting, despite the fact that more AEs related to hypovolemia are reported.
The global systematics of primitive arc melts Schmidt, M. W.; Jagoutz, O.
Geochemistry, geophysics, geosystems : G3,
August 2017, 2017-08-00, 20170801, Letnik:
18, Številka:
8
Journal Article
Recenzirano
We extracted all volcanic arc rock analyses calculated to be in equilibrium with mantle olivine from the global georoc database. This results in 938 primitive melt compositions from 30 arcs. Based on ...geochemical criteria six principal types of primitive arc melts can be distinguished: calc‐alkaline basalts and andesites, tholeiitic basalts, highly depleted tholeiitic andesites, shoshonites and low‐Si basalts. Their major element systematics indicates that last mantle equilibration occurred mostly at 1.0–2.5 GPa, 1220–1350°C for tholeiitic and calc‐alkaline basalts, at 0.5–1.2 GPa and ∼1200°C for depleted tholeiitic andesites, and at 0.7–1.2 GPa, 1050–1150°C for calc‐alkaline andesites. Quantitative treatment of major and trace elements suggests that the different melt types can be explained by a combination of variable mantle wedge preconditioning (degree of depletion prior to slab component addition, metasomatism in the lithosphere), variation in the amount and nature of the slab component added, and ‐ for primitive calc‐alkaline andesites ‐ reactive fractionation in the lithospheric top of the mantle wedge. The different slab components are best characterized by high Na2O, TiO2, Zr and Th for slab melts; high K2O/Na2O and more pronounced Nb, Sr, and Pb anomalies for fluids; and high K2O at high K2O/Na2O for supercritical liquids. A slab component that is dominantly a slab melt is common in continental but rare in intra‐oceanic arcs, consistent with comparatively cooler slabs in intra‐oceanic subduction zones. A majority of the arcs has more than one melt type, testifying for heterogeneity in the mantle wedge and added slab component.
Key Points
We provide a complete data set of truly primitive arc melts
We identify six arc melt types as formed in the mantle and their major formation mechanisms
The nature of the slab component and the characteristics of the mantle wedge is deduced via major and trace elements
A dysbalanced coagulation system is part of the pathological host response to infection in sepsis. Activation of pro-coagulant pathways and attenuation of anti-coagulant activity ultimately lead to ...microvascular stasis and consequent organ failure. No treatment approaches specifically targeting this axis are available. We explored the effects of therapeutic plasma exchange (TPE) on microvascular coagulation dysbalance in septic shock.
We conducted a prospective single-center study enrolling 31 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4 μg/kg/min). Clinical and biochemical data, including measurement of protein C; a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13); and von Willebrand factor antigen (vWF:Ag), were obtained before and after TPE against fresh frozen plasma.
Antithrombotic acting proteins such as antithrombin-III (ATIII) and protein C were markedly reduced in septic patients, but their activity increased after TPE (ATIII, 51% (41-61) vs. 63% (48-70), p = 0.029; protein C, 47% (38-60) vs. 62% (54-69), p = 0.029). Median ADAMTS13 activity was increased by TPE from 27 (21-42) % before to 47 (38-62) % after TPE (p < 0.001). In contrast, vWF:Ag was elevated and could be reduced by TPE (353 (206-492) IU/dL vs. 170 (117-232) IU/dL, p < 0.001). Regression analysis yielded a correlation between ADAMTS13 activity and platelet count (p = 0.001, R
= 0.316).
Septic shock was associated with activation of pro-coagulant pathways and simultaneous depletion of anti-coagulant factors. TPE partially attenuated this dysbalance by removing pro- and by replacing anti-coagulant factors.
ClinicalTrials.gov, NCT03065751. Retrospectively registered on 28 February 2017.
Time has always had a special status in physics because of its fundamental role in specifying the regularities of nature and because of the extraordinary precision with which it can be measured. This ...precision enables tests of fundamental physics and cosmology, as well as practical applications such as satellite navigation. Recently, a regime of operation for atomic clocks based on optical transitions has become possible, promising even higher performance. We report the frequency ratio of two optical atomic clocks with a fractional uncertainty of 5.2 x 10⁻¹⁷. The ratio of aluminum and mercury single-ion optical clock frequencies νAl⁺/νHg⁺ is 1.052871833148990438(55), where the uncertainty comprises a statistical measurement uncertainty of 4.3 x 10⁻¹⁷, and systematic uncertainties of 1.9 x 10⁻¹⁷ and 2.3 x 10⁻¹⁷ in the mercury and aluminum frequency standards, respectively. Repeated measurements during the past year yield a preliminary constraint on the temporal variation of the fine-structure constant α of Formula: see text.
Cytokine adsorption using the CytoSorb® adsorber has been proposed in various clinical settings including sepsis, ARDS, hyperinflammatory syndromes, cardiac surgery or recovery after cardiac arrest. ...The aim of this analysis is to provide evidence for the efficacy of the CytoSorb® adsorber with regard to mortality in various settings.
We searched PubMed, Cochrane Library database and the database provided by Cytosorbents™ (01.1.2010-29.5.2022). We considered randomized controlled trials and observational studies with control groups. The longest reported mortality was defined as the primary endpoint. We computed risk ratios and 95%-confidence intervals and used DerSimonian and Lairds random effects model. We analysed all studies combined and divided them into the subgroups: sepsis, cardiopulmonary bypass surgery (CPB), other severe illness, SARS-CoV-2 infection and recovery from cardiac arrest. The meta-analysis was registered in advance (PROSPERO: CRD42022290334).
Of an initial 1295 publications, 34 studies were found eligible, including 1297 patients treated with CytoSorb® and 1314 controls. Cytosorb® intervention did not lower mortality (RR 95%-CI: all studies 1.07 0.88; 1.31, sepsis 0.98 0.74; 1.31, CPB surgery 0.91 0.64; 1.29, severe illness 0.95 0.59; 1.55, SARS-CoV-2 1.58 0.50; 4.94). In patients with cardiac arrest, we found a significant survival advantage of the untreated controls (1.22 1.02; 1.46). We did not find significant differences in ICU length of stay, lactate levels, or IL-6 levels after treatment. Of the eligible 34 studies only 12 were randomized controlled trials. All observational studies showed moderate to serious risk of bias.
To date, there is no evidence for a positive effect of the CytoSorb® adsorber on mortality across a variety of diagnoses that justifies its widespread use in intensive care medicine.
Diabetic kidney disease (DKD) is a health burden of rising importance. Slowing progression to end stage kidney disease is the main goal of drug treatment. The aim of this analysis is to compare drug ...treatments of DKD by means of a systemic review and a network meta-analysis. We searched Medline, CENTRAL and clinicaltrials.gov for randomized, controlled studies including adults with DKD treated with the following drugs of interest: single angiotensin-converting-enzyme-inhibitor or angiotensin-receptor-blocker (single ACEi/ARB), angiotensin-converting-enzyme-inhibitor and angiotensin-receptor-blocker combination (ACEi+ARB combination), aldosterone antagonists, direct renin inhibitors, non-steroidal mineralocorticoid-receptor-antagonists (nsMRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). As primary endpoints, we defined: overall mortality and end-stage kidney disease, as secondary endpoints: renal composite outcome and albuminuria and as safety endpoints: acute kidney injury, hyperkalemia and hypotension. Under the use of a random effects model, we computed the overall effect estimates using the statistic program R4.1 and the corresponding package "netmeta". Risk of bias was assessed using the RoB 2 tool and the quality of evidence of each pairwise comparison was rated according to GRADE (Grading of Recommendations Assessment, Development and Evaluation). Of initial 3489 publications, 38 clinical trials were found eligible, in total including 42346 patients. Concerning the primary endpoints overall mortality and end stage kidney disease, SGLT2i on top of single ACEi/ARB compared to single ACEi/ARB was the only intervention significantly reducing the odds of mortality (OR 0.81, 95%CI 0.70-0.95) and end-stage kidney disease (OR 0.69, 95%CI 0.54-0.88). The indirect comparison of nsMRA vs SGLT2i in our composite endpoint suggests a superiority of SGLT2i (OR 0.60, 95%CI 0.47-0.76). Concerning safety endpoints, nsMRA and SGLT2i showed benefits compared to the others. As the only drug class, SGLT2i showed in our analysis beneficial effects on top of ACEi/ARB treatment regarding mortality and end stage kidney disease and by that reconfirmed its position as treatment option for diabetic kidney disease. nsMRA reduced the odds for a combined renal endpoint and did not raise any safety concerns, justifying its application.
Pyrogenic carbon (PyC), the residue of an incomplete combustion of biomass, is considered as a carbon (C) sink due to its assumed stability in soil. PyC turnover time estimated using two modelling ...approaches, based on data from 16 published studies (n = 54) on PyC degradation, ranged from a decadal to centennial time scale, varying with initial biomass type, pyrolysis temperature, and incubation or field study. The average turnover time using a one-pool approach was 88 y, and the best estimate using a two-pool approach was 3 y for a fast-cycling pool and 870 y for a slow-cycling pool. Based on this meta-analysis, PyC cannot be assumed to persist in soils for thousands of years, and its use as a strategy for offsetting carbon emissions requires prudence and further research.
PDF
