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Drugs that act on α-adrenoceptors may contain morpholine and pyrimidinone heterocycles. The aim of this study was to synthesize a series of pyrimidinones (S6a-e and S8) and characterize their α-adrenoceptor activity. Cytotoxicity assays (MTT and LDH) were performed in A7r5 and HUVECs. Concentration-effect curves to phenylephrine (Phe) were performed in rat aortic rings in the presence of compounds S6a-e and S8 or vehicle. Nitric oxide (NO) production and NO stable metabolic products, nitrite and nitrate, expressed as total nitrogen oxides (NOx) were assessed in HUVECs by confocal microscopy with the DAF-2DA probe and by the Griess reaction, respectively. Molecular docking simulations were performed using the 6a compound and α2A-adrenoceptor. In the evaluated conditions, the percentage of viable cells and the release of LDH were similar between control cells and cells exposed to the tested pyrimidinones. S6d, S6e, S8, and the positive control prazosin (but not S6a, S6b, and S6c) decreased Phe-induced contractions in endothelium-denuded aortic rings. S6a, S6b, and S6c decreased Phe-induced contractions in endothelium-intact aortic rings. The effect of S6a was abolished by L-NAME. NO production and NOx levels were inhibited in the presence of the α2 receptor antagonist yohimbine and the NOS inhibitor L-NAME. The 6a docking simulation estimated that the mean binding free energy of the compound was lower than the estimated value for yohimbine. These data suggest that S6d, S6e, and S8 may be α1-adrenoceptor antagonists while S6a acts as an agonist of α2-adrenoceptors.

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This study aimed to analyze the spatial pattern of natural infection index (NII) for triatomines and the risk of Chagas disease transmission in an endemic area of Northeastern Brazil. An ecological study was conducted, based on 184 municipalities in five mesoregions. The NII for triatomines was evaluated in the Pernambuco State, Brazil, from 2016 to 2018. Spatial autocorrelations were evaluated using Global Moran Index (I) and Local Moran Index (II) and were considered positive when I > 0 and p < 0.05, respectively. In total, 7,302 triatomines belonging to seven different species were detected. Triatoma brasiliensis had the highest frequency (53%; n = 3,844), followed by Triatoma pseudomaculata (25%; n = 1,828) and Panstrongylus lutzi (18.5%; n=1,366). The overall NII was 12%, and the higher NII values were P. lutzi (21%) and Panstrongylus megistus (18%). In the mesoregions of Zona da Mata, Agreste, Sertao, and Sertao do Sao Francisco, 93% of triatomines were detected indoors. The global spatial autocorrelation of I to NII was positive (0.2; p = 0.01), and II values calculated using BoxMap, MoranMap, Lisa Cluster Map were statistically significant for natural infections. With regard to the risk areas for the presence of triatomines, Zone 2 (the Agreste and Sertao regions) presented a relative risk of 3.65 compared to other areas in the state. Our study shows the potential areas of vector transmission of Chagas disease. In this study, the application of different methods of spatial analysis made it possible to locate these areas, which would not have been identified by only applying epidemiological indicators.

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ABSTRACT This study aimed to analyze the spatial pattern of natural infection index (NII) for triatomines and the risk of Chagas disease transmission in an endemic area of Northeastern Brazil. An ecological study was conducted, based on 184 municipalities in five mesoregions. The NII for triatomines was evaluated in the Pernambuco State, Brazil, from 2016 to 2018. Spatial autocorrelations were evaluated using Global Moran Index (I) and Local Moran Index (II) and were considered positive when I > 0 and p < 0.05, respectively. In total, 7,302 triatomines belonging to seven different species were detected. Triatoma brasiliensis had the highest frequency (53%; n = 3,844), followed by Triatoma pseudomaculata (25%; n = 1,828) and Panstrongylus lutzi (18.5%; n=1,366). The overall NII was 12%, and the higher NII values were P. lutzi (21%) and Panstrongylus megistus (18%). In the mesoregions of Zona da Mata, Agreste, Sertao, and Sertao do Sao Francisco, 93% of triatomines were detected indoors. The global spatial autocorrelation of I to NII was positive (0.2; p = 0.01), and II values calculated using BoxMap, MoranMap, Lisa Cluster Map were statistically significant for natural infections. With regard to the risk areas for the presence of triatomines, Zone 2 (the Agreste and Sertao regions) presented a relative risk of 3.65 compared to other areas in the state. Our study shows the potential areas of vector transmission of Chagas disease. In this study, the application of different methods of spatial analysis made it possible to locate these areas, which would not have been identified by only applying epidemiological indicators.

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Adrenoceptors are the receptors for catecholamines, adrenaline, and noradrenaline. They are divided in α (α1 and α2) and ß (ß1, ß2 and ß3). α1-adrenoceptors are subdivided in α1A, α1B and α1D. Most tissues express mixtures of α1-adrenoceptors subtypes, which appear to coexist in different densities and ratios, and in most cases, their responses are probably due to the activation of more than one type. The three subtypes of α1-adrenoceptors are G-protein-coupled receptors (GPCR), specifically coupled to Gq/11. Additionally, the activation of these receptors may activate other signaling pathways or different components of these pathways, which leads to a great variety of possible cellular effects. The first clinically used α1 antagonist was Prazosin for Systemic Arterial Hypertension (SAH). It was followed by its congeners, Terazosin and Doxazosin. Nowadays, there are many classes of α-adrenergic antagonists with different selectivity profiles. In addition to SAH, the α1-adrenoceptors are used to treat Benign Prostatic Hyperplasia (BPH) and urolithiasis. This antagonism may be part of the mechanism of action of tricyclic antidepressants. Moreover, the activation of these receptors may lead to adverse effects such as orthostatic hypotension, similar to what happens with antidepressants and with some antipsychotics. Structure-activity relationships can explain, in part, how antagonists work and how selective they can be for each one of the subtypes. However, it is necessary to develop new molecules which antagonize the α1- adrenoceptors or make chemical modifications in these molecules to improve the selectivity and pharmacokinetic profile and/or reduce the adverse effects of known drugs.

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Chagas disease is among the 21 neglected diseases according to the World Health Organization. This study aimed to investigate the morbidity and mortality distribution of Chagas disease for identifying areas with greater prevalences and deaths of the disease in Northeast Brazil. A population-based ecological study was performed from 2016 to 2018 using data on acute Chagas disease patients from the Disease Notification Information System, chronic cases from the Chagas Disease and the referral Heart Failure Outpatient Clinic in Pernambuco, and Chagas disease-related mortality from the Mortality Information System. The unit of analysis were Pernambuco State mesoregions. The indicators were spatialized into thematic maps on the occurrence and mortality of the disease per 100,000 inhabitants. No cases of acute disease were reported in the period analyzed. Data on 801 chronic Chagas disease patients were analyzed. The population showed an average age of 62 years, with female predominance. The most prevalent comorbidity was systemic arterial hypertension and cardiologic involvement without ventricular dysfunction. The average chronic disease occurrence rate was 3.2/ 100,000 people/ year. As for deaths in the mortality system; in total, 350 deaths were recorded, showing male predominance, age ≥ 60 years, and chronic disease with cardiac involvement as the main mortality cause. The annual average mortality proportion was 1.6/100,000 people. The chronic case distribution showed spatial heterogeneity, with the highest rates of chronic disease and deaths observed in two mesoregions, with the main cause of death being heart-related. This highlights the need for more specialized services in areas with higher burden of the disease to avoid delay in the patients' care.

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ABSTRACT Chagas disease is among the 21 neglected diseases according to the World Health Organization. This study aimed to investigate the morbidity and mortality distribution of Chagas disease for identifying areas with greater prevalences and deaths of the disease in Northeast Brazil. A population-based ecological study was performed from 2016 to 2018 using data on acute Chagas disease patients from the Disease Notification Information System, chronic cases from the Chagas Disease and the referral Heart Failure Outpatient Clinic in Pernambuco, and Chagas disease-related mortality from the Mortality Information System. The unit of analysis were Pernambuco State mesoregions. The indicators were spatialized into thematic maps on the occurrence and mortality of the disease per 100,000 inhabitants. No cases of acute disease were reported in the period analyzed. Data on 801 chronic Chagas disease patients were analyzed. The population showed an average age of 62 years, with female predominance. The most prevalent comorbidity was systemic arterial hypertension and cardiologic involvement without ventricular dysfunction. The average chronic disease occurrence rate was 3.2/ 100,000 people/ year. As for deaths in the mortality system; in total, 350 deaths were recorded, showing male predominance, age ≥ 60 years, and chronic disease with cardiac involvement as the main mortality cause. The annual average mortality proportion was 1.6/100,000 people. The chronic case distribution showed spatial heterogeneity, with the highest rates of chronic disease and deaths observed in two mesoregions, with the main cause of death being heart-related. This highlights the need for more specialized services in areas with higher burden of the disease to avoid delay in the patients' care.

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OBJECTIVE: The aim of this study was to investigate whether different types of visuoconstructional abilities are useful to distinguish individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) from healthy controls (HCs). METHOD: We selected 20 patients with MCI and 14 with AD diagnosis based on standard criteria. The neuropsychological performance of MCI and AD groups were compared with that of a group of 11 HCs using a standard neuropsychological battery and visuoconstructional tasks that differed difficulty and type of implicated skills (graphomotor vs. non-graphomotor): two-dimensional (Clock Drawing Test, CDT; Block Design, BD; and Visual Puzzles, VP) and three-dimensional Block Construction (TBC). RESULTS: AD group scored significantly lower than HCs in BD, VP and TBC tasks, but no significant differences were found between HCs and MCI. CDT (copy condition) scores did not differ significantly among the groups. The receiver operating characteristic analysis showed that BD [sensitivity (se) = .85, specificity (sp) = .90, Youden index (J) = .76], VP (se = .78 and sp = .72, J = .51) and TBC (se = .71, sp = 100, J = .71) were accurate tasks to discriminate between AD and HCs. Moreover, BD tasks (se = .85, sp = .70, J = .55) and TBC (se = .71, sp = .80, J = .51) showed fair accuracy to differentiate between MCI and AD groups. CONCLUSIONS: These findings indicate that non-graphomotor visuoconstructional tasks are already impaired in the early stages of AD, but are preserved in MCI individuals when compared with HCs.

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Recent evidence suggests cardiac amyloidosis (CA) is a mostly underdiagnosed condition, particularly in the transthyretin-mediated form, and is a frequent cause of heart failure with preserved ejection fraction (HFpEF) in the elderly. New paradigms about CA also involve the development of disease-modifying specific therapies. This article summarizes these new concepts.

Evidências recentes sugerem que a amiloidose cardíaca é uma doença amplamente subdiagnosticada, particularmente na sua forma ligada à transtirretina, podendo ser uma causa comum de insuficiência cardíaca com fração de ejeção preservada (ICFEP) no idoso. Os novos paradigmas sobre a doença incluem o desenvolvimento de novas terapias específicas que modificam a história natural da doença. Este artigo traz uma síntese destes novos conceitos.

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Resumo Evidências recentes sugerem que a amiloidose cardíaca é uma doença amplamente subdiagnosticada, particularmente na sua forma ligada à transtirretina, podendo ser uma causa comum de insuficiência cardíaca com fração de ejeção preservada (ICFEP) no idoso. Os novos paradigmas sobre a doença incluem o desenvolvimento de novas terapias específicas que modificam a história natural da doença. Este artigo traz uma síntese destes novos conceitos.

Abstract Recent evidence suggests cardiac amyloidosis (CA) is a mostly underdiagnosed condition, particularly in the transthyretin-mediated form, and is a frequent cause of heart failure with preserved ejection fraction (HFpEF) in the elderly. New paradigms about CA also involve the development of disease-modifying specific therapies. This article summarizes these new concepts.

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