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Experimental studies have shown that urinary dipeptidyl peptidase 4 (uDPP4), unlike serum DPP4 (sDPP4) activity, correlates with proteinuria, serum creatinine, and left ventricular (LV) hypertrophy in chronic kidney disease (CKD) models, suggesting a potential role for uDPP4 in CKD progression. This study examined the relationship of uDPP4 and sDPP4 activities with renal, cardiovascular, and metabolic markers, along with mortality and initiation of kidney replacement therapy (KRT) events in individuals with CKD. DPP4 activity was measured in the urine and serum of 426 participants from the Brazilian CKD cohort, PROGREDIR. Participants were stratified into tertiles based on uDPP4 and sDPP4 activities. Multivariable linear regression, Kaplan–Meier analysis, Cox hazards, and competing risk models (cause-specific and Fine–Gray) were used. uDPP4 activity was positively associated with albuminuria, urinary retinol-binding protein 4, LV mass, and type 2 diabetes but inversely associated with body mass index and use of renin-angiotensin system blockers. In contrast, sDPP4 activity correlated only with age and biological sex. Higher uDPP4 activity was associated with a higher incidence rate of all-cause mortality (p < 0.0001). Participants in the second and third uDPP4 activity tertiles had greater mortality risk compared to the lowest tertile (HR 2.03, 95% CI 1.36–3.04 and HR 2.48, 95% CI 1.67–3.67, respectively), even after controlling for potential confounders. No independent association was found between sDPP4 activity and mortality or initiation of KRT. These findings support uDPP4’s involvement in CKD progression and its association with increased mortality risk in individuals with CKD.

Background Observational studies support a role for oral anticoagulation to reduce the risk of dementia in atrial fibrillation patients, but conclusive data are lacking. Since dabigatran offers a more stable anticoagulation, we hypothesized it would reduce cognitive decline when compared to warfarin in old patients with atrial fibrillation. Methods The GIRAF trial was a 24-month, randomized, parallel-group, controlled, open-label, hypothesis generating trial. The trial was done in six centers including a geriatric care unit, secondary and tertiary care cardiology hospitals in São Paulo, Brazil. We included patients aged ≥ 70 years and CHA2DS2-VASc score > 1. The primary endpoint was the absolute difference in cognitive performance at 2 years. Patients were assigned 1:1 to take dabigatran (110 or 150 mg twice daily) or warfarin, controlled by INR and followed for 24 months. Patients were evaluated at baseline and at 2 years with a comprehensive and thorough cognitive evaluation protocol of tests for different cognitive domains including the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), a composite neuropsychological test battery (NTB), and computer-generated tests (CGNT). Results Between 2014 and 2019, 5523 participants were screened and 200 were assigned to dabigatran ( N = 99) or warfarin ( N = 101) treatment. After adjustment for age, log of years of education, and raw baseline score, the difference between the mean change from baseline in the dabigatran group minus warfarin group was − 0.12 for MMSE (95% confidence interval [CI] − 0.88 to 0.63; P = 0.75), 0.05 (95% CI − 0.07 to 0.18; P = 0.40) for NTB, − 0.15 (95% CI − 0.30 to 0.01; P = 0.06) for CGNT, and − 0.96 (95% CI − 1.80 to 0.13; P = 0.02) for MoCA, with higher values suggesting less cognitive decline in the warfarin group. Conclusions For elderly patients with atrial fibrillation, and without cognitive compromise at baseline that did not have stroke and were adequately treated with warfarin (TTR of 70%) or dabigatran for 2 years, there was no statistical difference at 5% significance level in any of the cognitive outcomes after adjusting for multiple comparisons. Trial registration Cognitive Impairment Related to Atrial Fibrillation Prevention Trial (GIRAF), NCT01994265 .

Background Sodium-glucose cotransport-2 inhibitors (SGLT2i) have established benefits in diabetes mellitus, heart failure, and chronic kidney disease, but their physiological effects during critical illness remain unclear. We explored whether dapagliflozin affected urinary output, fluid balance, and other physiological parameters in critically ill patients with acute organ dysfunction. Methods This secondary analysis of the DEFENDER trial included 401 critically ill patients with acute organ dysfunction randomized to receive dapagliflozin 10 mg daily or standard care. We analyzed urinary output, fluid balance, electrolytes, acid–base status, glycemia, and vasopressor requirements over the first five days using Bayesian models. Results Dapagliflozin progressively increased urinary output (day 5: + 157 mL/day, 95% CrI -90 to 386, probability 90%) and decreased fluid balance (day 5: -290 mL/day, 95% CrI -564 to -27, probability 98%). Furosemide use was lower in the dapagliflozin group (overall -3%, 95% CrI -7% to 1%, probability 90%). Dapagliflozin had minimal effects on creatinine and electrolytes but was associated with progressive small decreases in pH (day 5: -0.02, probability 96%). Maximum glucose levels were consistently lower with dapagliflozin (-9 mg/dL overall, probability 83%). Norepinephrine requirements showed a time-dependent increase in the dapagliflozin group, with the expected dose difference reaching 0.034 mcg/kg/min by day 5 (probability 94%), and heterogeneity analysis revealed larger effects in patients with sepsis or on mechanical ventilation. Conclusion This exploratory analysis suggests dapagliflozin may enhance diuresis and reduce loop diuretic requirements in critically ill patients, potentially at the cost of increased vasopressor needs. Glucose levels were likely slightly lower with dapagliflozin. Given the study's limitations and heterogeneous treatment effects, these findings should be considered hypothesis-generating pending confirmation in prospective trials.

The angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II) and angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) (Ang-(1-7)) pathways are coexpressed in most tissues. The balance between these pathways determines, at least in part, whether tissue damage will occur in response to pathological stimuli. The present study tested the hypothesis that male sex and high blood pressure are associated with ACE/ACE2 imbalance in the lungs. Experiments were conducted in male and female Wistar rats and spontaneously hypertensive rats (SHRs). Lung ACE and ACE2 gene expression was also evaluated in normotensive and hypertensive humans using the Genotype-Tissue Expression (GTEx) project. Compared with Wistar rats and female SHRs, male SHRs displayed reduced lung ACE2 mRNA, ACE2 protein abundance and ACE2 activity, and increased Ang II concentration. Lung ACE mRNA levels were higher in male SHRs than in Wistar rats, whereas lung ACE protein abundance and activity were similar among the four groups of rats. Lung Ang-(1-7) concentration was higher in female than in male SHRs (89 ± 17 vs. 43 ± 2 pg/g, P<0.05). Lung ACE to ACE2 mRNA expression in hypertensive patients was significantly higher than that in normotensive subjects. Taken together, these results demonstrate that male hypertensive rats display imbalance between the ACE/Ang II and ACE2/Ang-(1-7) pathways in the lungs mainly attributable to ACE2 down-regulation. Further studies should be conducted to investigate whether this imbalance between ACE/ACE2 may promote and accelerate lung injury in respiratory infections, including coronavirus disease 2019 (COVID-19).

Droughts are predicted to increase in both frequency and intensity by the end of the 21st century, but ecosystem response is not expected to be uniform across landscapes. Here we assess the importance of the hill-to-valley hydrologic gradient in shaping vegetation embolism resistance under different rainfall regimes using hydraulic functional traits. We demonstrate that rainfall and hydrology modulate together the embolism resistance of tree species in different sites and topographic positions. Although buffered by stable access to groundwater, valley plants are intrinsically more vulnerable to drought-induced embolism than those on hills. In all study sites, the variability in resistance to embolism is higher on hills than on valleys, suggesting that the diversity of strategies to cope with drought is more important for tree communities on hills. When comparing our results with previously published data across the tropics, we show greater variability at the local scale than previously reported. Our results reinforce the urgent need to extend sampling efforts across rainfall regimes and topographic positions to improve the characterization of ecosystem resistance to drought at finer spatial scales.

Background Rhipicephalus ( Boophilus ) microplus is the most important tick species affecting cattle in the world. Under field conditions, the non-parasitic phase of R . ( B .) microplus is unknown in the Amazon biome, including Brazil. The present study aimed to evaluate the non-parasitic phase of R . ( B .) microplus in field (grass plots) and laboratory conditions. Methods The study was conducted from September 2020 to April 2022 in an Amazonian region (Maranhão State, Brazil). We evaluated the biological parameters of R. ( B. ) microplus under laboratory and field conditions. Engorged females were exposed to experimental conditions every 14 days, totaling 20 months of study. The following biological parameters were observed: pre-oviposition period, egg mass incubation period, and maximum larval survival period. Results Abiotic data (e.g., temperature and humidity) varied little throughout the year. Precipitation was the factor that varied the most throughout the year (dry ~ 30 mm 3 and rain 400 mm 3 ), and the parameters of pre-oviposition and pre-hatching are longer during the rainy season. A possible negative effect of the dry season on the percentage of hatched eggs was observed. Larval longevity in the plots of both control and free females was short (mean ~ 50–60 days), below that recorded for larvae under controlled conditions (mean ~ 95 days). Conclusions Rhipicephalus ( Boophilus ) microplus was able to complete its non-parasitic phase by producing host-seeking larvae in the pasture during all months of the study. The results indicate that R. ( B. ) microplus can complete up to six generations per year in biome Amazon. To our knowledge, this is the highest number of annual generations for R. ( B. ) microplus in Latin America. Graphical Abstract

Rheumatoid Arthritis (RA) is a chronic disease characterized by persistent inflammation and pain. Alternative therapies to reduce these symptoms are needed. Marine algae are valuable sources of diverse bioactive compounds. Lithothamnion muelleri (Hapalidiaceae) is a marine algae with anti-inflammatory, antitumor, and immunomodulatory properties. Here, we investigated the potential anti-inflammatory and analgesic activities of L. muelleri in a murine model of antigen-induced arthritis (AIA) in mice. Our results demonstrate that treatment with L. muelleri prevented inflammation and hypernociception in arthritic mice. Mechanistically, the crude extract and the polysaccharide-rich fractions of L. muelleri may act impairing the production of the chemokines CXCL1 and CXCL2, and consequently inhibit neutrophil influx to the knee joint by dampening the adhesion step of leukocyte recruitment in the knee microvessels. Altogether our results suggest that treatment with L.muelleri has a potential therapeutic application in arthritis treatment.

Influenza A virus causes annual epidemics which affect millions of people worldwide. A recent Influenza pandemic brought new awareness over the health impact of the disease. It is thought that a severe inflammatory response against the virus contributes to disease severity and death. Therefore, modulating the effects of inflammatory mediators may represent a new therapy against Influenza infection. Platelet activating factor (PAF) receptor (PAFR) deficient mice were used to evaluate the role of the gene in a model of experimental infection with Influenza A/WSN/33 H1N1 or a reassortant Influenza A H3N1 subtype. The following parameters were evaluated: lethality, cell recruitment to the airways, lung pathology, viral titers and cytokine levels in lungs. The PAFR antagonist PCA4248 was also used after the onset of flu symptoms. Absence or antagonism of PAFR caused significant protection against flu-associated lethality and lung injury. Protection was correlated with decreased neutrophil recruitment, lung edema, vascular permeability and injury. There was no increase of viral load and greater recruitment of NK1.1(+) cells. Antibody responses were similar in WT and PAFR-deficient mice and animals were protected from re-infection. Influenza infection induces the enzyme that synthesizes PAF, lyso-PAF acetyltransferase, an effect linked to activation of TLR7/8. Therefore, it is suggested that PAFR is a disease-associated gene and plays an important role in driving neutrophil influx and lung damage after infection of mice with two subtypes of Influenza A. Further studies should investigate whether targeting PAFR may be useful to reduce lung pathology associated with Influenza A virus infection in humans.

The plant species Libidibia ferrea (Mart. ex Tul.) LP Queiroz var. ferrea basionym of Caesalpinia ferrea (Mart. ex Tul.) is used in various regions of Brazil in folk medicine in the treatment of several health problems, especially in acute and chronic inflammatory processes. Most of the preparations employed are alcoholic. Therefore, this study aimed to evaluate the acute toxicity of the hydroethanolic extract of fruits of Libidibia ferrea (EHEFLf) in zebrafish, emphasizing the possible changes in the organic-cellular level of the gills, liver, kidneys, and intestine and on embryos. The result obtained by LC-M/MS from EHEFLf indicated a high concentration of possible polyhydroxylated substances. EHEFLf, at a dose of 2 g/kg orally, produced non-significant alterations of the analyzed organs. However, for embryos, the treatment with different concentrations demonstrated heart toxicity that was concentration-dependent. There is no evidence of a correlation of the observed effects with the phytochemical composition, and considering the species of animal used, it can be suggested that the oral use of L. ferrea hydroethanolic extract has an acceptable degree of safety for use as an oral medicinal product. and embryo results have shown significant affinity to the heart; however, it is perceived to be related to the concentrations used.

The inhabitants of the floodplain of the Mazagão River in the State of Amapá in the Brazilian Amazon have inherited from indigenous African and Cabocla cultures indications for the use and forms of preparation of medicinal plants to cure diseases of the body and spirit. This study aimed to perform an ethnopharmacological survey of medicinal plants used by the riparian community of the floodplains of the Mazagão River, in the State of Amapá. In this study, we chose semistructured interviews with socioeconomic, ethnopharmacological, and ethnobotanical aims. The collection of medicinal plants occurred during guided tours. The Use Value (UV), Informant Consensus Factor (ICF), Correction Factor (CF), and Fidelity level (FL) were calculated. There were 130 species of medicinal plants, distributed in 116 genera and 57 families; Fabaceae (16), Lamiaceae (14), Euphorbiaceae (7), and Arecaceae (6) include 33.33% of the total species sampled. All 95 native species of floodplain forests were previously described, and 35 are exotic species. The species with the highest UV (≥ 0.5) at the mouth of the Mazagão River were Carapa guianensis (0.91), Pentachlethra macroloba (0.83), Dalbergia subcymosa (0.77), Uncaria tomentosa (0.75), Otacanthus azureus (0.62), Virola surinamensis (0.62), Hura crepitans (0.58), Euterpe oleracea (0.56), and Arrabidaea chica (0.51). These species were also the ones that presented the highest ICF among the informants and 100% in FL for a specific therapeutic use. The study is comprised of 16 categories of therapeutic use, of which the majority of the plants used are related to diseases such as microbial infections (20.67%, 73 species), gastrointestinal disorders (13.31%), and inflammation (11.61%). The results showed that knowledge about the use of medicinal plants along the rivers and streams that form the mouth of the Mazagão River is evenly distributed. Most of the interviewees present diversified knowledge about the medicinal resources because they have a close relationship with the floodplain forest. Native species of this forest predominate among the most commonly used medicinal plants as subsidies for future pharmacological studies.