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Mutations in tRNA ligases, essential components of the translational machinery, are associated with Charcot-Marie-Tooth peripheral neuropathy, but the mechanistic details are not known. The authors report that the tyrosyl-tRNA synthetase is an evolutionary-conserved F-actin organizer, and dysregulation of this function is associated with the disorder.

Abstract Aims The outpatient diuretic dose is a marker of diuretic resistance and prognosis in chronic heart failure (HF). Still, the impact of the preadmission dose on diuretic efficiency (DE) and prognosis in acute HF is not fully known. Methods and results We conducted an observational and prospective study. All patients admitted for acute HF treated with intravenous diuretic and at least one criterion of congestion on admission were evaluated. Decongestion [physical examination, hemoconcentration, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) change, and lung ultrasound], DE (weight loss and urine output per unit of 40 mg furosemide), and urinary sodium were monitored on the fifth day of admission. DE was dichotomized into high–low based on the median value. A multivariate Cox regression analysis was conducted to find predictors of HF readmission or mortality. A total of 105 patients were included between July 2017 and July 2019. Mean age was 74.5 ± 12.0 years, 64.8% were male, 33.3% had de novo HF, and mean left ventricular ejection fraction was 46 ± 17%. Median follow‐up was 26 [15–35] months. Low DE based on weight loss was associated with a higher previous dose of furosemide (odds ratio [OR] 1.01 [1.00–1.02]), thiazide treatment before admission (OR 9.37 [2.19–40.14]), and lower diastolic blood pressure (OR 0.95 [0.91–0.98]) in the multivariate regression model. Only previous dose of furosemide (OR 1.01 [1.00–1.02]) and haemoglobin at admission (OR 0.76 [0.58–0.99]) were associated with low DE based on urine output in the multivariate analysis. The correlation between the previous dose of furosemide and DE based on weight loss was poor (r = −0.12; P = 0.209) and with DE based on urine output was weak to moderate (r = −0.33; P 80 mg in ADHF identified patients with particularly poor prognosis (log‐rank

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol‐associated and metabolic‐associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol‐associated liver disease plus metabolic‐associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA‐sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.

Binge drinking, i.e., heavy episodic drinking in a short time, has recently become an alarming societal problem with negative health impact. However, the harmful effects of acute alcohol injury in the gut-liver axis remain elusive. Hence, we focused on the physiological and pathological changes and the underlying mechanisms of experimental binge drinking in the context of the gut-liver axis. Eight-week-old mice with a C57BL/6 background received a single dose (p.o.) of ethanol (EtOH) [6 g/kg b.w.] as a preclinical model of acute alcohol injury. Controls received a single dose of PBS. Mice were sacrificed 8 h later. In parallel, HepaRGs and Caco-2 cells, human cell lines of differentiated hepatocytes and intestinal epithelial cells intestinal epithelial cells (IECs), respectively, were challenged in the presence or absence of EtOH [0–100 mM]. Extracellular vesicles (EVs) isolated by ultracentrifugation from culture media of IECs were added to hepatocyte cell cultures. Increased intestinal permeability, loss of zonula occludens-1 (ZO-1) and MUCIN-2 expression, and alterations in microbiota—increased Lactobacillus and decreased Lachnospiraceae species—were found in the large intestine of mice exposed to EtOH. Increased TUNEL-positive cells, infiltration of CD11b-positive immune cells, pro-inflammatory cytokines (e.g., tlr4, tnf, il1β), and markers of lipid accumulation (Oil Red O, srbep1) were evident in livers of mice exposed to EtOH, particularly in females. In vitro experiments indicated that EVs released by IECs in response to ethanol exerted a deleterious effect on hepatocyte viability and lipid accumulation. Overall, our data identified a novel mechanism responsible for driving hepatic injury in the gut-liver axis, opening novel avenues for therapy.

Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response.

Objectives: Lately, many countries have restricted or even banned transfat, and palm oil has become a preferred replacement for food manufacturers. Whether palm oil is potentially an unhealthy food mainly due to its high content of saturated Palmitic Acid (PA) is a matter of debate. The aim of this study was to test whether qualitative aspects of diet such as levels of PA and the fat source are risk factors for Metabolic Syndrome (MS) and Metabolic Associated Fatty Liver Disease (MAFLD). Methods: C57BL/6 male mice were fed for 14 weeks with three types of Western diet (WD): 1. LP-WD—low concentration of PA (main fat source—corn and soybean oils); 2. HP-WD—high concentration of PA (main fat source—palm oil); 3. HP-Trans-WD—high concentration of PA (mainly transfat). Results: All types of WD caused weight gain, adipocyte enlargement, hepatomegaly, lipid metabolism alterations, and steatohepatitis. Feeding with HP diets led to more prominent obesity, hypercholesterolemia, stronger hepatic injury, and fibrosis. Only the feeding with HP-Trans-WD resulted in glucose intolerance and elevation of serum transaminases. Brief withdrawal of WDs reversed MS and signs of MAFLD. However, mild hepatic inflammation was still detectable in HP groups. Conclusions: HP and HP-Trans-WD play a crucial role in the genesis of MS and MAFLD.

IntroductionDiuretic resistance (DR) is a common condition during a heart failure (HF) hospitalization, and is related to worse prognosis. Although the risk factors for DR during a HF hospitalization are widely described, we do not know whether the risk of chronic DR could be predicted during admission.Material and methodsWe conducted a multicenter, prospective observational study between July 2017 and July 2019. All patients admitted for acute HF with intravenous diuretic treatment and at least one criterion of congestion on admission were invited to participate. Patients on renal replacement therapy, under intravenous diuretic treatment for >72 hours before screening and those who were unable to sign the informed consent were excluded. We monitored decongestion (physical exam, hemoconcentration, NTproBNP change and lung ultrasound) and DR (diuresis and weight loss per unit of 40mg furosemide and fractional excretion of sodium) on the fifth day of admission. Chronic DR was evaluate two months after hospitalization and was defined as persistent signs of congestion despite ≥80 mg furosemide per day. We compared variables from the hospitalization between patients with and without chronic DR. A multivariate logistic regression analysis was conducted to find predictors of chronic DR.ResultsA total of 105 patients were included in the study. Mean age was 74.5±12.0 years, 64.8% were male and mean LVEF was 46±17%. In the two months follow-up, five patients have died and one patient has had a heart transplant. Of the 99 remaining patients, 21 patients (21.2%) had chronic DR. The dose of furosemide before admission and the decrease in NT-proBNP ≤30% during admission were predictors of chronic DR in the multivariate analysis.ConclusionsWe can predict during a HF hospitalization which patients will develop chronic DR. The dose of furosemide before admission and the change in NT-proBNP are independent predictors of chronic DR.

Background: The presence of anti-Beta 2 glycoprotein antibodies (aB2GP1) of IgA isotype is common in patients with functional impairment of the organs in which B2GP1 is elaborated. Pretransplant IgA aB2GP1 has been associated with increased risk of thrombosis in kidney and heart transplanted patients and has also been related with early mortality after heart transplantation. Circulating immune complexes between IgA and B2GP1 (B2A-CIC) have been described in the blood of patients positive for IgA aB2GP1 with thrombotic clinical symptoms. In kidney transplanted patients, B2A-CIC is a biomarker that predicts which patients IgA aB2GP1 positive are at risk of thrombosis events following kidney transplantation and may lead to early prophylactic treatment. The prevalence of B2A-CIC and its relation with outcomes after heart transplantation is not known.Methods: Follow-up study based on 151 consecutive patients who received a heart transplant. Autoantibodies and B2A-CIC were quantified in pre-transplant serum samples. Three groups of patients were followed-up for 2 years: Group-1, positive for IgA aB2GP1 and B2A-CIC (N = 19). Group-2, only positive for IgA aB2GP1 (N = 28). Group-0 (control group): IgA aB2GP1 negative (N = 104).Results: Kaplan-Meir survival analysis showed that mortality in B2A-CIC positive was higher than group-0 at 3 months (HR:5.08; 95%CI: 1.36–19.01) and at 2 years (HR:3.82; 95%CI: 1.54–12.66). No significant differences were observed between group-2 and group-0. Multivariate analysis identified B2A-CIC as the most important independent risk factor for early mortality (OR = 6.12; 95% CI: 1.93–19.4). Post-transplant incidence of thrombosis was significantly higher in B2A-CIC positive patients than in the control group (OR: 6.42; 95%CI: 2.1–19.63). Multivariate analysis identified the presence of B2A-CIC (OR: 6.13; 95%CI: 2.1–19.63) and the pre-transplant habit of smoking actively (OR: 4.18; 95%CI: 1.35–12.94) as independent risk factor for thrombosis. The proportion of patients who had thrombotic events or died in the first trimester was significantly higher in group-1 (73.7%) than in group-0 (16.3%; p < 0.001) and in group-2 (39.3%; p = 0.02). Multivariate analysis identified B2A-CIC as the main independent risk factor for early outcomes (mortality or thrombosis) in the first 3 months after heart transplant (OR = 11.42, 95% CI: 1.69–9.68).Conclusion: B2A-CIC are a predictor of early mortality and thrombosis after heart transplant.

Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratory abnormalities to acute liver failure (ALF) and death. The cellular and molecular mechanisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts—neoantigens—that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanistic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.

Objective.This work sought to evaluate the effect of an educational intervention centered on the analysis of clinical cases to inquire on conceptual learning in students on the theme of nursing care of women with complicated puerperium. Methodology. This was a quasi-experimental study with before and after evaluation. Two groups of students participated from the eighth semester of the nursing program, which professionalized individuals who were already nursing technicians: the study group (n = 33) was taught the theme of nursing care to women with complicated puerperium with the case analysis technique and the control group (n = 27) received traditional teaching. A self-applied question here was used related to the thematic unit, which included three clinical cases and the resolution of a total of 37 questions related to set cases. This questionnaire was the same applied before and after the intervention. Results. The pre-intervention mean score was similar in both groups (26 during the study and 27 during the intervention). Upon completing the educational intervention, the post-intervention scores were equal in both groups (27 points). The intra-group analysis showed that in the study group the intervention produced a slight change in conceptual learning, which was statistically significant. During the post-hoc analysis differences in scores were found in students who worked in hospitals with tier three level of care. Conclusion. Educational intervention favored conceptual learning slightly in the study group. It is necessary to explore other intervening variables that propitiate this learning in the program.

Abstract Understanding the role of lipids in synapses and the aberrant molecular mechanisms causing the cognitive deficits that characterize most lipidosis is necessary to develop therapies for these diseases. Here we describe sphingomyelin (SM) as a key modulator of the dendritic spine actin cytoskeleton. We show that increased SM levels in neurons of acid sphingomyelinase knock out mice (ASMko), which mimic Niemann Pick disease type A (NPA), result in reduced spine number and size and low levels of filamentous actin. Mechanistically, SM accumulation decreases the levels of metabotropic glutamate receptors type I (mGluR1/5) at the synaptic membrane impairing membrane attachment and activity of RhoA and its effectors ROCK and ProfilinIIa. Pharmacological enhancement of the neutral sphingomyelinase rescues the aberrant molecular and morphological phenotypes in vitro and in vivo and improves motor and memory deficits in ASMko mice. Altogether, these data demonstrate the influence of SM and its catabolic enzymes in dendritic spine physiology and contribute to our understanding of the cognitive deficits of NPA patients, opening new perspectives for therapeutic interventions.

Data is growing at an unprecedented pace. With the variety, speed and volume of data flowing through networks and databases, newer approaches based on machine learning are required. But what is really big in Big Data? Should it depend on the numerical representation of the machine? Since portable embedded systems have been growing in importance, there is also increased interest in implementing machine learning algorithms with a limited number of bits. Not only learning, also feature selection, most of the times a mandatory preprocessing step in machine learning, is often constrained by the available computational resources. In this work, we consider mutual information—one of the most common measures of dependence used in feature selection algorithms—with reduced precision parameters.

A 51-year-old woman presented with a one-year history of progressive dyspnea, WHO functional class III-IV and exercise-related syncope. Transthoracic echocardiography and computed tomography pulmonary angiography were performed, leading to a diagnosis of pulmonary arterial hypertension. She was referred to our pulmonary hypertension unit, where a complete study was performed, including ventilation/perfusion scan, which was consistent with chronic thromboembolic pulmonary hypertension. Risk factors for this condition were excluded and therapeutic options were evaluated. Imaging studies showed distal pulmonary disease so pulmonary endarterectomy was rejected. Further therapeutic options were evaluated and the patient was subsequently enrolled in an open-label uncontrolled trial with riociguat. After one year of treatment, significant improvement in functional class, 6-minute walk test and NT-proBNP were seen, without significant secondary effects. Resumo: Uma mulher de 51 anos de idade apresentou-se com história de um ano de dispneia progressiva com classe funcional III-IV e síncope relacionada com exercício. A ecocardiografia transtorácica e a angiotomografia pulmonar computadorizada foram realizadas, tendo sido diagnosticada hipertensão arterial pulmonar. A doente foi encaminhada para a Unidade de Hipertensão Pulmonar, onde foi repetido o estudo completo, incluindo verificação de ventilação/perfusão, compatível com hipertensão pulmonar tromboembólica crónica. Os fatores de risco para essa situação foram excluídos e foram avaliadas as opções terapêuticas. Estudos de imagem mostraram doença pulmonar distal pelo que a endarterectomia pulmonar foi rejeitada. Foram avaliadas novas opções terapêuticas e a doente foi posteriormente inscrita num estudo aberto, não controlado, com ensaio com riociguat. Após um ano de tratamento, uma melhoria significativa na classe funcional, um teste de caminhada de 6 minutos e NT-proBNP foram alcançados sem efeitos secundários significativos. Keywords: Chronic thromboembolic pulmonary hypertension, Treatment with riociguat, Safety profile of riociguat, Palavras-chave: Hipertensão pulmonar tromboembólica crónica, Tratamento com riociguat, Perfil de segurança do riociguat

Consensus exists that lipids must play key functions in synaptic activity but precise mechanistic information is limited. Acid sphingomyelinase knockout mice (ASMko) are a suitable model to address the role of sphingolipids in synaptic regulation as they recapitulate a mental retardation syndrome, Niemann Pick disease type A (NPA), and their neurons have altered levels of sphingomyelin (SM) and its derivatives. Electrophysiological recordings showed that ASMko hippocampi have increased paired-pulse facilitation and post-tetanic potentiation. Consistently, electron microscopy revealed reduced number of docked vesicles. Biochemical analysis of ASMko synaptic membranes unveiled higher amounts of SM and sphingosine (Se) and enhanced interaction of the docking molecules Munc18 and syntaxin1. In vitro reconstitution assays demonstrated that Se changes syntaxin1 conformation enhancing its interaction with Munc18. Moreover, Se reduces vesicle docking in primary neurons and increases paired-pulse facilitation when added to wt hippocampal slices. These data provide with a novel mechanism for synaptic vesicle control by sphingolipids and could explain cognitive deficits of NPA patients.

ABSTRACT Objective: to examine advanced practice nursing (APN) roles internationally to inform role development in Latin America and the Caribbean to support universal health coverage and universal access to health. Method: we examined literature related to APN roles, their global deployment, and APN effectiveness in relation to universal health coverage and access to health. Results: given evidence of their effectiveness in many countries, APN roles are ideally suited as part of a primary health care workforce strategy in Latin America to enhance universal health coverage and access to health. Brazil, Chile, Colombia, and Mexico are well positioned to build this workforce. Role implementation barriers include lack of role clarity, legislation/regulation, education, funding, and physician resistance. Strong nursing leadership to align APN roles with policy priorities, and to work in partnership with primary care providers and policy makers is needed for successful role implementation. Conclusions: given the diversity of contexts across nations, it is important to systematically assess country and population health needs to introduce the most appropriate complement and mix of APN roles and inform implementation. Successful APN role introduction in Latin America and the Caribbean could provide a roadmap for similar roles in other low/middle income countries.

Objective: to assess the situation of nursing education and to analyze the extent to which baccalaureate level nursing education programs in Latin America and the Caribbean are preparing graduates to contribute to the achievement of Universal Health. Method: quantitative, descriptive/exploratory, cross-sectional study carried out in 25 countries. Results: a total of 246 nursing schools participated in the study. Faculty with doctoral level degrees totaled 31.3%, without Brazil this is reduced to 8.3%. The ratio of clinical experiences in primary health care services to hospital-based services was 0.63, indicating that students receive more clinical experiences in hospital settings. The results suggested a need for improvement in internet access; information technology; accessibility for the disabled; program, faculty and student evaluation; and teaching/learning methods. Conclusion: there is heterogeneity in nursing education in Latin America and the Caribbean. The nursing curricula generally includes the principles and values of Universal Health and primary health care, as well as those principles underpinning transformative education modalities such as critical and complex thinking development, problem-solving, evidence-based clinical decision-making, and lifelong learning. However, there is a need to promote a paradigm shift in nursing education to include more training in primary health care.