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, Volume:
18, Issue:
8
Journal Article
Peer reviewed
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
Production of short-chain fatty acids (SCFAs), especially butyrate, in the gut microbiome is required for optimal health but is frequently limited by the lack of fermentable fiber in the diet. We ...attempted to increase butyrate production by supplementing the diets of 174 healthy young adults for 2 weeks with resistant starch from potatoes (RPS), resistant starch from maize (RMS), inulin from chicory root, or an accessible corn starch control. RPS resulted in the greatest increase in total SCFAs, including butyrate. Although the majority of microbiomes responded to RPS with increases in the relative abundance of bifidobacteria, those that responded with an increase in
or
were more likely to yield higher butyrate concentrations, especially when their microbiota were replete with populations of the butyrate-producing species
RMS and inulin induced different changes in fecal communities, but they did not generate significant increases in fecal butyrate levels.
These results reveal that not all fermentable fibers are equally capable of stimulating SCFA production, and they highlight the importance of the composition of an individual's microbiota in determining whether or not they respond to a specific dietary supplement. In particular,
or
may be required for enhanced butyrate production in response to RS. Bifidobacteria, though proficient at degrading RS and inulin, may not contribute to the butyrogenic effect of those fermentable fibers in the short term.
For decades, rods and cones were thought to be the only photoreceptors in the mammalian retina. However, a population of atypical photoreceptive retinal ganglion cells (RGCs) expresses the ...photopigment melanopsin and is intrinsically photosensitive (ipRGCs). These ipRGCs are crucial for relaying light information from the retina to the brain to control circadian photoentrainment, pupillary light reflex, and sleep. ipRGCs were initially described as a uniform population involved solely in signaling irradiance for non-image forming functions. Recent work, however, has uncovered that ipRGCs are unexpectedly diverse at the molecular, cellular and functional levels, and could even be involved in image formation. This review summarizes our current understanding of the diversity of ipRGCs and their various roles in modulating behavior.
Outer membrane vesicles (OMVs) are important tools in bacterial virulence but their role in the pathogenesis of infections caused by enterohemorrhagic Escherichia coli (EHEC) O157, the leading cause ...of life-threatening hemolytic uremic syndrome, is poorly understood. Using proteomics, electron and confocal laser scanning microscopy, immunoblotting, and bioassays, we investigated OMVs secreted by EHEC O157 clinical isolates for virulence factors cargoes, interactions with pathogenetically relevant human cells, and mechanisms of cell injury. We demonstrate that O157 OMVs carry a cocktail of key virulence factors of EHEC O157 including Shiga toxin 2a (Stx2a), cytolethal distending toxin V (CdtV), EHEC hemolysin, and flagellin. The toxins are internalized by cells via dynamin-dependent endocytosis of OMVs and differentially separate from vesicles during intracellular trafficking. Stx2a and CdtV-B, the DNase-like CdtV subunit, separate from OMVs in early endosomes. Stx2a is trafficked, in association with its receptor globotriaosylceramide within detergent-resistant membranes, to the Golgi complex and the endoplasmic reticulum from where the catalytic Stx2a A1 fragment is translocated to the cytosol. CdtV-B is, after its retrograde transport to the endoplasmic reticulum, translocated to the nucleus to reach DNA. CdtV-A and CdtV-C subunits remain OMV-associated and are sorted with OMVs to lysosomes. EHEC hemolysin separates from OMVs in lysosomes and targets mitochondria. The OMV-delivered CdtV-B causes cellular DNA damage, which activates DNA damage responses leading to G2 cell cycle arrest. The arrested cells ultimately die of apoptosis induced by Stx2a and CdtV via caspase-9 activation. By demonstrating that naturally secreted EHEC O157 OMVs carry and deliver into cells a cocktail of biologically active virulence factors, thereby causing cell death, and by performing first comprehensive analysis of intracellular trafficking of OMVs and OMV-delivered virulence factors, we provide new insights into the pathogenesis of EHEC O157 infections. Our data have implications for considering O157 OMVs as vaccine candidates.
Distinct subclasses of retinal ganglion cells (RGCs) mediate vision and nonimage-forming functions such as circadian photoentrainment. This distinction stems from studies that ablated ...melanopsin-expressing intrinsically photosensitive RGCs (ipRGCs) and showed deficits in nonimage-forming behaviors, but not image vision. However, we show that the ON alpha RGC, a conventional RGC type, is intrinsically photosensitive in mammals. In addition to their classical response to fast changes in contrast through rod/cone signaling, melanopsin expression allows ON alpha RGCs to signal prior light exposure and environmental luminance over long periods of time. Consistent with the high contrast sensitivity of ON alpha RGCs, mice lacking either melanopsin or ON alpha RGCs have behavioral deficits in contrast sensitivity. These findings indicate a surprising role for melanopsin and ipRGCs in vision.
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•All ON alpha RGCs, a conventional RGC type, are intrinsically photosensitive•ON alpha RGCs signal irradiance and light history via melanopsin phototransduction•Melanopsin phototransduction is required for contrast sensitivity•Non-M1 ipRGCs influence contrast sensitivity necessary for image formation
The behavioral roles of melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) have traditionally been attributed to nonimage functions. In this study, Schmidt et al. demonstrate a role for melanopsin and ipRGCs in setting the contrast detection threshold for vision.
The melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) are a relatively recently discovered class of atypical ganglion cell photoreceptor. These ipRGCs are a ...morphologically and physiologically heterogeneous population that project widely throughout the brain and mediate a wide array of visual functions ranging from photoentrainment of our circadian rhythms, to driving the pupillary light reflex to improve visual function, to modulating our mood, alertness, learning, sleep/wakefulness, regulation of body temperature, and even our visual perception. The presence of melanopsin as a unique molecular signature of ipRGCs has allowed for the development of a vast array of molecular and genetic tools to study ipRGC circuits. Given the emerging complexity of this system, this review will provide an overview of the genetic tools and methods used to study ipRGCs, how these tools have been used to dissect their role in a variety of visual circuits and behaviors in mice, and identify important directions for future study.
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.
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