Effect of mangiferin, a naturally occurring glucoxylxanthone, on fear memory in rats

Mangiferin (1,3,6,7-tetrahydroxy-2-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] -xanthen-9-one, CAS 4773-96-0), a naturally occurring glucosylxanthone, is widely distributed in higher plants and a constituent of folk medicine. In the present study the effect of systemic administration of mangiferin on behavioural outcomes of neurological function in normal rats was investigated. A single intraperitoneal injection of mangiferin (10, 50 and 100 mg/kg body weight) immediately post-training produced an impairment of long-term memory for aversive training and a reduced freezing in a dose independent manner, when given immediately post-training. The administration of mangiferin 6 h post-training did not affect fear memory. The results indicate that mangiferin might induce deficits of emotionally motivated memory.     

Synthesis and purification of the aflatoxin B1-lysine adduct

This work reports the chemical synthesis of aflatoxin B₁ (AFB₁)-lysine based on procedures available in the literature, but using lysine without a protection group in the α-amine group. AFB₁-exo-8,9-epoxide was obtained by epoxidation of AFB₁ with chloroperoxybenzoic acid in dichloromethane and phosphate buffer. Purification and identification of the AFB₁-lysine were conducted by liquid chromatography (LC), and its structure was confirmed by LC with mass spectrometer and diode-array detection. The preparation of AFB₁-lysine using lysine without a protection group in the α-amine group was completed in 24?h, being a practical modification of available methods that can be reproduced in analytical laboratories.     

【In Press】Clinical outcomes of patterned laser trabeculoplasty as adjuvant therapy in open-angle glaucoma and ocular hypertension

AIM: To assess the efficacy and safety of patterned laser trabeculoplasty (PLT) as an adjunctive treatment in open-angle glaucoma (OAG) or ocular hypertension (OHT) patients who were under antiglaucoma medical treatment. METHODS: This study was a retrospective review of primary or secondary OAG patients and OHT patients with medically uncontrolled (≥18 mm Hg) intraocular pressure (IOP) who underwent 360º PLT from June 2016 to August 2016. Follow-up visits at week 1, and 1, 3 and 6mo were performed. IOP, best corrected visual acuity (BCVA), complications and eye drop glaucoma medication were recorded at each follow-up visit. Success was defined as IOP reduction ≥20% from baseline. RESULTS: Forty one eyes of 25 patients were included in this study. Pre-treatment mean IOP was 20.2±1.6 mm Hg. After PLT, IOP was 19.3±5.2, 16.1±2.7, 17.1±3.7 and 16.3±3.5 mm Hg, at 1wk, 1, 3 and 6mo, respectively. IOP reduction from baseline was statistically significant from the first month, remaining stable at 6mo (P<0.001). PLT success at 6mo of follow-up was 48.7%. The number of glaucoma medication per eye (P=0.10) and the mean BCVA both remained constant (P=0.37). Complications included transient IOP spikes in 4 eyes (9.7%) and peripheral anterior synechiae in 7 eyes (17.1%). CONCLUSION: PLT is an effective and safe method for the management of patients with OHT or OAG as an adjunctive therapy. Additional larger studies should be designed to verify the long-term stability of IOP reduction with this laser technology.     

In Vitro Diagnostic Assay to Detect SARS-CoV-2-Neutralizing Antibody in Patient Sera Using Engineered ACE-2 Mini-Protein

The recent development and mass administration of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines allowed for disease control, reducing hospitalizations and mortality. Most of these vaccines target the SARS-CoV-2 Spike (S) protein antigens, culminating with the production of neutralizing antibodies (NAbs) that disrupt the attachment of the virus to ACE2 receptors on the host cells. However, several studies demonstrated that the NAbs typically rise within a few weeks after vaccination but quickly reduce months later. Thus, multiple booster administration is recommended, leading to vaccination hesitancy in many populations. Detecting serum anti-SARS-CoV-2 NAbs can instruct patients and healthcare providers on correct booster strategies. Several in vitro diagnostics kits are available; however, their high cost impairs the mass NAbs diagnostic testing. Recently, we engineered an ACE2 mimetic that interacts with the Receptor Binding Domain (RBD) of the SARS-2 S protein. Here we present the use of this engineered mini-protein (p-deface2 mut) to develop a detection assay to measure NAbs in patient sera using a competitive ELISA assay. Serum samples from twenty-one patients were tested. Nine samples (42.8%) tested positive, and twelve (57.1%) tested negative for neutralizing sera. The data correlated with the result from the standard commercial assay that uses human ACE2 protein. This confirmed that p-deface2 mut could replace human ACE2 in ELISA assays. Using bacterially expressed p-deface2 mut protein is cost-effective and may allow mass SARS-CoV-2 NAbs detection, especially in low-income countries where economical diagnostic testing is crucial. Such information will help providers decide when a booster is required, reducing risks of reinfection and preventing the administration before it is medically necessary.     

Avaliação do Impacto da Implantação de um Sistema de Ambulância Pré-Hospitalar sobre Mortalidade por Infarto Agudo do Miocárdio em um País em Desenvolvimento

BackgroundThe effective management of patients with acute myocardial infarction (AMI) is time-dependent.ObjectivesTo assess the impacts of the implementation of prehospital care on admission rates and mortality associated with AMI.MethodsRetrospective, ecological study, which assessed data from the Brazilian Universal Health System, from all 853 municipalities of Minas Gerais, from 2008 to 2016. Excessive skewness of general and in-hospital mortality rates was smoothed using the empirical Bayes method. This study assessed the relationship between Mobile Emergency Care Service (SAMU) in each municipality and the following 3 outcomes: mortality rate due to AMI, AMI in-hospital mortality, and AMI hospitalization rate, using the Poisson hierarchical model. Rates were corrected by age structure and detrended by seasonality and temporal influences. A confidence interval of 95% was adopted.ResultsAMI mortality rates decreased throughout the study, on average 2% per year, with seasonal variation. AMI in-hospital mortality also showed a decreasing trend, from 13.81% in 2008 to 11.43% in 2016. SAMU implementation was associated with decreased AMI mortality (odds ratio [OR] = 0.967, 95% confidence interval [CI] 0.936 to 0.998) and AMI in-hospital mortality (OR = 0.914, 95% CI 0.845 to 0.986), with no relation with hospitalizations (OR = 1.003, 95% CI 0.927 to 1.083).ConclusionSAMU implementation was associated with a modest but significant decrease in AMI in-hospital mortality. This finding reinforces the key role of prehospital care in AMI care and the need for investments on this service to improve clinical outcomes in low- and middle-income countries.     

Multi-population generalizability of a deep learning-based chest radiograph severity score for COVID-19

To tune and test the generalizability of a deep learning-based model for assessment of COVID-19 lung disease severity on chest radiographs (CXRs) from different patient populations.A published convolutional Siamese neural network-based model previously trained on hospitalized patients with COVID-19 was tuned using 250 outpatient CXRs. This model produces a quantitative measure of COVID-19 lung disease severity (pulmonary x-ray severity (PXS) score). The model was evaluated on CXRs from 4 test sets, including 3 from the United States (patients hospitalized at an academic medical center (N = 154), patients hospitalized at a community hospital (N = 113), and outpatients (N = 108)) and 1 from Brazil (patients at an academic medical center emergency department (N = 303)). Radiologists from both countries independently assigned reference standard CXR severity scores, which were correlated with the PXS scores as a measure of model performance (Pearson R). The Uniform Manifold Approximation and Projection (UMAP) technique was used to visualize the neural network results.Tuning the deep learning model with outpatient data showed high model performance in 2 United States hospitalized patient datasets (R = 0.88 and R = 0.90, compared to baseline R = 0.86). Model performance was similar, though slightly lower, when tested on the United States outpatient and Brazil emergency department datasets (R = 0.86 and R = 0.85, respectively). UMAP showed that the model learned disease severity information that generalized across test sets.A deep learning model that extracts a COVID-19 severity score on CXRs showed generalizable performance across multiple populations from 2 continents, including outpatients and hospitalized patients.     

Ablação por Cateter é Superior a Drogas Antiarrítmicas como Tratamento de primeira linha para Fibrilação Atrial: uma Revisão Sistemática e Metanálise

BackgroundCatheter ablation is a well-established therapy for rhythm control in patients who are refractory or intolerant to anti-arrhythmic drugs (AAD). Less is known about the efficacy of catheter ablation compared with AAD as a first-line strategy for rhythm control in atrial fibrillation (AF).ObjectivesWe aimed to perform a systematic review and meta-analysis of catheter ablation vs. AAD in patients naïve to prior rhythm control therapies.MethodsPubMed, EMBASE, and Cochrane databases were searched for randomized controlled trials that compared catheter ablation to AAD for initial rhythm control in symptomatic AF and reported the outcomes of (1) recurrent atrial tachyarrhythmias (ATs); (2) symptomatic AF; (3) hospitalizations; and (4) symptomatic bradycardia. Heterogeneity was examined with I²statistics. P values of < 0.05 were considered statistically significant.ResultsWe included five trials with 994 patients, of whom 502 (50.5%) underwent catheter ablation. Mean follow-up ranged from one to five years. Recurrences of AT (OR 0.36; 95% CI 0.25-0.52; p<0.001) and symptomatic AF (OR 0.32; 95% CI 0.18-0.57; p<0.001), and hospitalizations (OR 0.25; 95% CI 0.15-0.42; p<0.001) were significantly less frequent in patients treated with catheter ablation compared with AAD. Symptomatic bradycardia was not significantly different between groups (OR 0.55; 95% CI 0.18-1.65; p=0.28). Significant pericardial effusions or tamponade occurred in eight of 464 (1.7%) patients in the catheter ablation group.ConclusionThese findings suggest that catheter ablation has superior efficacy to AAD as an initial rhythm control strategy in patients with symptomatic AF.     

Troponina I por Percentil 99 da Definição Universal de Infarto do Miocárdio versus Ponto de Corte de Melhor Acurácia em Síndromes Coronárias Agudas

Background Contemporary diagnosis of ACS and risk stratification are essential for appropriate management and reduction of mortality and recurrent ischemic events, in the acute phase of disease and after hospitalization. The Universal Definition of Myocardial Infarction recommends the detection of troponin levels above the 99^th percentile.Objectives To evaluate the occurrence of early death and acute myocardial infarction (AMI) in patients without elevation of troponin (<0.034 ng/mL), patients with mild elevation (above the 99^th percentile [>0.034 ng/mL and <0.12 ng/mL)], and patients with significant elevation of troponin (above the diagnostic cutoff for AMI defined by the troponin kit (≥0.12 ng/mL)]; and to analyze the impact of troponin on the indication for invasive strategy and myocardial revascularization.Methods Cross-sectional cohort study of patients with ACS with assessment of peak troponin I, risk score, prospective analysis of 30-day clinical outcomes and two-sided statistical tests, with statistical significance set at p<0.05.Results A total of 494 patients with ACS were evaluated. Troponin > 99^th percentile and below the cutoff point, as well as values above the cutoff, were associated with higher incidence of composite endpoint (p<0.01) and higher rates of percutaneous or surgical revascularization procedures (p<0.01), without significative difference in 30-day mortality.Conclusions Troponin levels above the 99^th percentile defined by the universal definition of AMI play a prognostic role and add useful information to the clinical diagnosis and risk scores by identifying those patients who would most benefit from invasive risk stratification and coronary revascularization procedures.     

Baixa Concordância entre a Classificação da NYHA e as Variáveis do Teste de Exercício Cardiopulmonar em Pacientes com Insuficiência Cardíaca e Fração de Ejeção Reduzida

BackgroundThe New York Heart Association (NYHA) functional classification is the most commonly used classification system for heart failure (HF), whereas cardiopulmonary exercise testing (CPET) is the gold standard for functional status evaluation in HF.ObjectiveThis study aimed to analyze correlation and concordance between NYHA classes and CPET variables.MethodsHF patients with clinical indication for CPET and ejection fraction (EF) < 50% were selected. Correlation (Spearman coefficient) and concordance (kappa) between NYHA classification and CPET-based classifications were analyzed. A p < 0.05 was accepted as significant.ResultsIn total, 244 patients were included. Mean age was 56 ± 14 years, and mean EF was 35.5% ± 10%. Distribution of patients according to NYHA classification was 31.2%% class I, 48.3% class II, 19.2% class III, and 1.3% class IV. Correlation (r) between NYHA and Weber classes was 0.489 (p < 0.001), and concordance was 0.231 (p < 0.001). Correlation (r) between NYHA and ventilatory classes (minute ventilation/carbon dioxide production [VE/VCO₂] slope) was 0.218 (p < 0.001), and concordance was 0.002 (p = 0.959). Spearman correlation between NYHA and CPET score classes was 0.223 (p = 0.004), and kappa concordance was 0.027 (p = 0.606).ConclusionThere was a moderate association between NYHA and Weber classes, although concordance was low. Ventilatory (VE/VCO₂slope) and CPET score classes had a weak association and a low concordance with NYHA classes.     

Multimodal investigation of dopamine D2/D3 receptors,default mode network suppression,and cognitive control in cocaine-use disorder

Stimulant-use disorders have been associated with lower availability of dopamine type-2 receptors (D2R) and greater availability of type-3 receptors (D3R). Links between D2R levels, cognitive performance, and suppression of the default mode network (DMN) during executive functioning have been observed in healthy and addicted populations; however, there is limited evidence regarding a potential role of elevated D3R in influencing cognitive control processes in groups with and without addictions. Sixteen individuals with cocaine-use disorder (CUD) and 16 healthy comparison (HC) participants completed [¹¹C]-(+)-PHNO PET imaging of D2R and D3R availability and fMRI during a Stroop task of cognitive control. Independent component analysis was performed on fMRI data to assess DMN suppression during Stroop performance. In HC individuals, lower D2R-related binding in the dorsal putamen was associated with improved task performance and greater DMN suppression. By comparison, in individuals with CUD, greater D3R-related binding in the substantia nigra was associated with improved performance and greater DMN suppression. Exploratory moderated-mediation analyses indicated that DMN suppression was associated with Stroop performance indirectly through D2R in HC and D3R in CUD participants, and these indirect effects were different between groups. To our knowledge, this is the first evidence of a dissociative and potentially beneficial role of elevated D3R availability in executive functioning in cocaine-use disorder.Subject terms: Addiction, Cognitive control