Direct Deviations in Astrocyte Free Ca2+ Concentration Control Multiple Arteriole Tone States

Astrocytes elicit bidirectional control of microvascular diameter in acutely isolated brain slices through vasoconstriction and vasodilation pathways that can be differentially recruited via the free Ca2+ concentration in endfeet and/or the metabolic status of the tissue. However, the Ca2+-level hypothesis has not been tested using direct manipulation. To overcome this, we used Ca2+-clamp whole-cell patching of peri-arteriole astrocytes to change astrocyte-free Ca2+ to different concentrations and examined the vascular response. We discovered that clamping Ca2+ at the approximate resting value (100 nM) had no impact on arteriole diameter in a pre-constricted arteriole. However, a moderate elevation to 250 nM elicited sustained vasodilation that was blocked by the COX-1 antagonist SC-560 (500 nM). The vasodilation to 250 nM Ca2+ was sensitive to the metabolic state, as it converted to vasoconstriction when oxygen tension was dramatically elevated. In normal oxygen, clamping astrocyte Ca2+ well above the resting level (750 nM) produced sustained vasoconstriction, which converted to vasodilation in the 20-HETE blocker HET0016 (1 μM). This response was fully blocked by the addition of SC-560 (500 nM), showing that 20-HETE-induced vasoconstriction dominated the dilatory action of COX-1. These data demonstrate that direct changes in astrocyte free Ca2+ can control multiple arteriole tone states through different mediators.

Abnormal Liver Tests during Hospitalization Predict Mortality in Patients with COVID-19: A Multicenter Study from South America

Background. The role of liver function tests (LFT) as prognostic factors in patients admitted with COVID-19 has not been fully investigated, particularly outside resource-rich countries. We aimed at evaluating the prognostic value of abnormal LFT on admission and during hospitalization of patients with COVID-19. Methods. We performed a retrospective study that included 298 adult patients hospitalized for COVID-19, between 05/2020 and 02/2021, in 6 hospitals from 5 countries in South America. We analyzed demographic and comorbid variables and laboratory tests on admission and during hospitalization. LFT over twice the upper limit of normal (ALEx2) were also evaluated in relation to a variety of factors on admission and during hospitalization. De novo-ALEx2 was defined as the presence of ALEx2 at one week of hospitalization in patients without ALEx2 on admission. Patients were followed until hospital discharge or death. Multivariable analysis was used to evaluate the association between ALEx2 on admission and during hospitalization and mortality. Results. Of the total of 298 patients, 60% were male, with a mean age of 60 years, and 74% of patients had at least one comorbidity. Of those, 137 (46%) patients were transferred to the intensive care unit and 66 (22.1%) patients died during hospitalization. ALEx2 on admission was present in 87 (29.2%) patients and was found to be independently associated with 1-week mortality (odds ratio (OR) = 3.55; 95% confidence interval (95%CI) 1.05–12.05). Moreover, 84 (39.8%) out of 211 patients without ALEx2 at admission developed de novo-ALEx2, which was independently associated with mortality during second week of hospitalization (OR = 6.09; 95%CI 1.28–29) and overall mortality (OR = 2.93, 95%CI 1.05–8.19). Conclusions. A moderate elevation of LFT during admission was associated with a poor short-term prognosis in patients hospitalized with COVID-19. In addition, moderate elevation of LFT at one week of hospitalization was an independent risk factor for overall mortality in these patients.

Ketone Ester D‐β‐Hydroxybutyrate‐(R)‐1,3 Butanediol Prevents Decline in Cardiac Function in Type 2 Diabetic Mice

Background Heart failure is responsible for approximately 65% of deaths in patients with type 2 diabetes mellitus. However, existing therapeutics for type 2 diabetes mellitus have limited success on the prevention of diabetic cardiomyopathy. The aim of this study was to determine whether moderate elevation in D‐β‐hydroxybutyrate improves cardiac function in animals with type 2 diabetes mellitus. Methods and Results Type 2 diabetic (db/db) and their corresponding wild‐type mice were fed a control diet or a diet where carbohydrates were equicalorically replaced by D‐β‐hydroxybutyrate‐(R)‐1,3 butanediol monoester (ketone ester [KE]). After 4 weeks, echocardiography demonstrated that a KE diet improved systolic and diastolic function in db/db mice. A KE diet increased expression of mitochondrial succinyl‐CoA:3‐oxoacid‐CoA transferase and restored decreased expression of mitochondrial β‐hydroxybutyrate dehydrogenase, key enzymes in cardiac ketone metabolism. A KE diet significantly enhanced both basal and ADP‐mediated oxygen consumption in cardiac mitochondria from both wild‐type and db/db animals; however, it did not result in the increased mitochondrial respiratory control ratio. Additionally, db/db mice on a KE diet had increased resistance to oxidative and redox stress, with evidence of restoration of decreased expression of thioredoxin and glutathione peroxidase 4 and less permeability transition pore activity in mitochondria. Mitochondrial biogenesis, quality control, and elimination of dysfunctional mitochondria via mitophagy were significantly increased in cardiomyocytes from db/db mice on a KE diet. The increase in mitophagy was correlated with restoration of mitofusin 2 expression, which contributed to improved coupling between cytosolic E3 ubiquitin ligase translocation into mitochondria and microtubule‐associated protein 1 light chain 3–mediated autophagosome formation. Conclusions Moderate elevation in circulating D‐β‐hydroxybutyrate levels via KE supplementation enhances mitochondrial biogenesis, quality control, and oxygen consumption and increases resistance to oxidative/redox stress and mPTP opening, thus resulting in improvement of cardiac function in animals with type 2 diabetes mellitus.

Weathering on volcanic edifices under semi-arid climates. Insights from a regional assessment of the composition of Fogo Island regoliths (Cape Verde)

In this study, the geochemistry and mineralogy of regoliths formed on Fogo Island (Cape Verde), a polygenic stratovolcano built during the Quaternary, are used to assess the geomorphological factors that control the early stages of basalt weathering. Fogo Island soils are mainly derived from relatively homogenous silica-undersaturated basaltic rocks. However, a discernible exotic component is recognised in areas most exposed to prevailing winds by ratios on non-mobile elements that are hosted in different amounts by basaltic rocks (e.g., Th, Sc and Ti). Weathering extent is evidenced by a relative depletion in mobile elements (e.g., Na, Ca, Mg) and an enrichment in non-mobile elements (e.g., Ti, Fe, Sc, Al), the decomposition of the most labile minerals (olivines), and the enrichment in secondary components (phyllosilicates and some Fe-oxides, such as hematite-goethite), along with quartz supplied from non-volcanic areas. It depends on bedrock age and type (pyroclastic deposits vs. lava-flows). In particular, soils covering older volcanic units tend to be more affected by chemical alteration than those overlying younger units. In addition, more intense weathering is observed in locations characterised by a combination of moderate elevation, slopes with low gradient and relatively high rainfall. The present investigation shows that even in low humidity environments recently formed basalt are affected by weathering, with the extent of chemical decomposition being mainly determined by the age of surface exposure and local orographic/climatic features.

Acute icteric hepatitis as the first isolated symptom of COVID-19

Patients with COVID-19 may be asymptomatic or present with extrarespiratory symptoms, such as liver injury. It has been reported that 22.5%–46.2% of patients have moderate elevation of liver enzymes. To our knowledge, acute hepatitis has never been described as an isolated symptom of COVID-19 in a previously healthy patient. We report the case of a 53-year-old patient with COVID-19 whose first clinical presentation was acute icteric hepatitis, several days before the development of others symptoms. During the pandemic, we suggest that patients with acute hepatitis be considered as COVID-19 suspects, tested and isolated.

Prostate-Specific Antigen: From Promising to Disappointment Tool for Diagnosis of Chronic Renal Failure in Predialysis Patients

Introduction Prostate-specific antigen (PSA) is a biomarker commonly used for detection of prostate cancer. Its viability as a marker for diagnosis of chronic renal failure (CRF) in predialysis patients was investigated. Methods Sera from 230 patients with CRF were analyzed by enzyme-linked immunosorbent assay (ELISA) for determining total PSA (tPSA) levels before hemodialysis. Results Of the patients investigated, 98.69% had a normal PSA level with a value less than 4 ng/mL. Three elderly men with both kidney failure showed a moderate elevation of PSA level. Conclusion PSA is considered a nonsignificant indicator for diagnosis of CRF.

Contrasting exhumation histories and relief development within the Three Rivers Region (south-east Tibet)

The Three Rivers Region in south-east Tibet represents a transition between the strongly deformed zone around the Eastern Himalayan Syntaxis (EHS) and the less deformed south-east Tibetan Plateau margin in Yunnan and Sichuan. In this study, we compile and model published thermochronometric ages for two massifs facing each other across the Mekong River in the core of the Three Rivers Region (TRR), using the thermo-kinematic code Pecube to constrain their exhumation and relief history. Modelling results for the low-relief (< 600 m), moderate-elevation (∼ 4500 m) Baima Xueshan massif, east of the Mekong River, suggest regional rock uplift at a rate of 0.25 km/Myr since ∼ 10 Ma, following slow exhumation at a rate of 0.01 km/Myr since at least 22 Ma. Estimated Mekong River incision accounts for 30 % of the total exhumation since 10 Ma. We interpret exhumation of the massif as a response to regional uplift around the EHS and conclude that the low relief of the massif was acquired at high elevation (> 4500 m), probably in part due to glacial “buzzsaw-like” processes active at such high elevation and particularly efficient during Quaternary glaciations. Exhumation of the Baima Xueshan is significantly higher (2.5 km since ∼ 10 Ma) than that estimated for the most emblematic low-relief “relict” surfaces of eastern Tibet, where apatite (U–Th) / He (AHe) ages > 50 Ma imply only a few hundreds of metres of exhumation since the onset of the India–Asia collision. The low-relief Baima Xueshan massif, with its younger AHe ages (< 50 Ma) that record significant rock uplift and exhumation, thus cannot be classified as a relict surface. Modelling results for the high-relief, high-elevation Kawagebo massif, to the west of the Mekong, imply a similar contribution of Mekong River incision (25 %) to exhumation but much stronger local rock uplift at a rate of 0.45 km/Myr since at least 10 Ma, accelerating to 1.86 km/Myr since 1.6 Ma. We show that the thermochronometric ages are best reproduced by a model of rock uplift on a kinked westward-dipping thrust striking roughly parallel to the Mekong River, with a steep shallow segment flattening out at depth. Thus, the strong differences in elevation and relief of two massifs are linked to variable exhumation histories due to strongly differing tectonic imprint.