Cardiac disturbances and changes in tissue cytokine levels in mice fed with a high-refined carbohydrate diet.

AIMS: The consumption of highly refined carbohydrates increases systemic inflammatory markers, but its potential to exert direct myocardial inflammation is uncertain. Herein, we addressed the impact of a high-refined carbohydrate (HC) diet on mice heart and local inflammation over time. MAIN METHODS: BALB/c mice were fed with a standard chow (control) or an isocaloric HC diet for 2, 4, or 8 weeks (HC groups), in which the morphometry of heart sections and contractile analyses by invasive catheterization and Langendorff-perfused hearts were assessed. Cytokines levels by ELISA, matrix metalloproteinase (MMP) activity by zymography, in situ reactive oxygen species (ROS) staining and lipid peroxidation-induced TBARS levels, were also determined. KEY FINDINGS: HC diet fed mice displayed left ventricular hypertrophy and interstitial fibrosis in all times analyzed, which was confirmed by echocardiographic analyses of 8HC group. Impaired contractility indices of HC groups were observed by left ventricular catheterization, whereas ex vivo and in vitro indices of contraction under isoprenaline-stimulation were higher in HC-fed mice compared with controls. Peak levels of TNF-α, TGF-ß, ROS, TBARS, and MMP-2 occur independently of HC diet time. However, a long-lasting local reduction of the anti-inflammatory cytokine IL-10 was found, which was linearly correlated to the decline of systolic function in vivo. SIGNIFICANCE: Altogether, the results indicate that short-term consumption of HC diet negatively impacts the balance of anti-inflammatory defenses and proinflammatory/profibrotic mediators in the heart, which can contribute to HC diet-induced morphofunctional cardiac alterations.

Anthelmintic Drugs as Emerging Immune Modulators in Cancer.

Despite recent advances in treatment approaches, cancer is still one of the leading causes of death worldwide. Restoration of tumor immune surveillance represents a valid strategy to overcome the acquired resistance and cytotoxicity of conventional therapies in oncology and immunotherapeutic drugs, such as immune checkpoint inhibitors and immunogenic cell death inducers, and has substantially progressed the treatment of several malignancies and improved the clinical management of advanced disease. Unfortunately, because of tumor-intrinsic and/or -extrinsic mechanisms for escaping immune surveillance, only a fraction of patients clinically respond to and benefit from cancer immunotherapy. Accumulating evidence derived from studies of drug repositioning, that is, the strategy to identify new uses for approved or investigational drugs that are outside the scope of the original medical indication, has suggested that some anthelmintic drugs, in addition to their antineoplastic effects, exert important immunomodulatory actions on specific subsets of immune cell and related pathways. In this review, we report and discuss current knowledge on the impact of anthelmintic drugs on host immunity and their potential implication in cancer immunotherapy.

TRAIL-Sensitizing Effects of Flavonoids in Cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major hurdle, thus limiting the use of TRAIL as a single agent. Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated in resistant tumors by combined treatment with antitumor agents, ranging from synthetic molecules to natural products. Among the latter, flavonoids, the most prevalent polyphenols in plants, have shown remarkable competence in improving TRAIL-driven apoptosis in resistant cell lines as well as tumor-bearing mice with minimal side effects. Here, we summarize the molecular mechanisms, such as the upregulation of death receptor (DR)4 and DR5 and downregulation of key anti-apoptotic proteins [e.g., cellular FLICE-inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), survivin], underlying the TRAIL-sensitizing properties of different classes of flavonoids (e.g., flavones, flavonols, isoflavones, chalcones, prenylflavonoids). Finally, we discuss limitations, mainly related to bioavailability issues, and future perspectives regarding the clinical use of flavonoids as adjuvant agents in TRAIL-based therapies.

Altered heart cytokine profile and action potential modulation in cardiomyocytes from Mas-deficient mice.

The renin-angiotensin system (RAS) is a key hormonal system. In recent years, the functional analysis of the novel axis of the RAS (ACE2/Ang-(1-7)/Mas receptor) revealed that its activation can become protective against several pathologies, including cardiovascular diseases. Mas knockout mice (Mas-KO) represent an important tool for new investigations. Indeed, extensive biological research has focused on investigating the functional implications of Mas receptor deletion. However, although the Mas receptor was identified in neonatal cardiomyocytes and also in adult ventricular myocytes, only few reports have explored the Ang-(1-7)/Mas signaling directly in cardiomyocytes to date. This study investigated the implication of Mas receptor knockout to the cytokine profile, energy metabolism, and electrical properties of mice-isolated cardiomyocytes. Here, we demonstrated that Mas-KO mice have modulation in some cytokines, such as G-CSF, IL-6, IL-10, and VEGF in the left ventricle. This model also presents increased mitochondrial number in cardiomyocytes and a reduction in the myocyte diameter. Finally, Mas-KO cardiomyocytes have altered action potential modulation after diazoxide challenge. Such electrical finding was different from the data showed for the TGR(A1-7)3292 (TGR) model, which overexpresses Ang-(1-7) in the plasma by 4.5, used by us as a control. Collectively, our findings exemplify the importance of understanding the ACE2/Ang-(1-7)/Mas pathway in cardiomyocytes and heart tissue. The Mas-KO mice model can be considered an important tool for new RAS investigations.

Temporal trends and spatial clusters of gastric cancer mortality in Brazil.

Objective: To identify nationwide temporal trends and spatial patterns of gastric cancer-related mortality in Brazil. Methods: An ecological study was performed using death certificates registered from 2000 to 2019 in which gastric cancer was recorded as any cause of death (an underlying or associated cause). Trends over time were assessed using joinpoint regression models. Spatial and spatiotemporal clusters were identified by Kulldorff's space-time scan statistics to identify high-risk areas. Results: In 276 897/22 663 091 (1.22%) death certificates gastric cancer was recorded as any cause of death. Age-adjusted gastric cancer-related mortality increased significantly over time (annual percentage change [APC]: 0.7, 95% confidence interval [CI]: 0.5 to 0.8). The increase in mortality was more pronounced in the less-developed North and Northeast Regions (North Region, APC: 3.1, 95% CI: 2.7 to 3.5; Northeast Region, APC: 3.1, 95% CI: 2.5 to 3.7). Eight spatiotemporally associated high-risk clusters of gastric cancer-related mortality were identified in the North, South, Northeast and Central-West Regions, as well as a major cluster covering a wide geographical range in the South and Southeast Regions of Brazil during the first years of the study period (2000 to 2009). Conclusions: More recently, during 2010 to 2019, clusters of gastric cancer have been identified in the Northeast Region. The nationwide increase in mortality in this analysis of 20 years of data highlights the persistently high burden of gastric cancer in Brazil, especially in socioeconomically disadvantaged regions. The identification of these areas where the population is at high risk for gastric cancer-related mortality emphasizes the need to develop effective and intersectoral control measures.

Hemodynamic phenotyping of transgenic rats with ubiquitous expression of an angiotensin-(1-7)-producing fusion protein.

Activation of the angiotensin (Ang)-converting enzyme (ACE) 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system (RAS) induces protective mechanisms in different diseases. Herein, we describe the cardiovascular phenotype of a new transgenic rat line (TG7371) that expresses an Ang-(1-7)-producing fusion protein. The transgene-specific mRNA and the corresponding protein were shown to be present in all evaluated tissues of TG7371 with the highest expression in aorta and brain. Plasma Ang-(1-7) levels, measured by radioimmunoassay (RIA) were similar to control Sprague-Dawley (SD) rats, however high Ang-(1-7) levels were found in the hypothalamus. TG7371 showed lower baseline mean arterial pressure (MAP), assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma atrial natriuretic peptide (ANP) and higher urinary sodium concentration. Moreover, evaluation of regional blood flow and hemodynamic parameters with fluorescent microspheres showed a significant increase in blood flow in different tissues (kidneys, mesentery, muscle, spleen, brown fat, heart and skin), with a resulting decrease in total peripheral resistance (TPR). TG7371 rats, on the other hand, also presented increased cardiac and global sympathetic tone, increased plasma vasopressin (AVP) levels and decreased free water clearance. Altogether, our data show that expression of an Ang-(1-7)-producing fusion protein induced a hypotensive phenotype due to widespread vasodilation and consequent fall in peripheral resistance. This phenotype was associated with an increase in ANP together with an increase in AVP and sympathetic drive, which did not fully compensate the lower blood pressure (BP). Here we present the hemodynamic impact of long-term increase in tissue expression of an Ang-(1-7)-fusion protein and provide a new tool to investigate this peptide in different pathophysiological conditions.

ACE2 activator diminazene aceturate exerts renoprotective effects in gentamicin-induced acute renal injury in rats.

Acute Kidney Injury (AKI) comprises a rapidly developed renal failure and is associated with high mortality rates. The Renin-Angiotensin System (RAS) plays a pivotal role in AKI, as the over-active RAS axis exerts major deleterious effects in disease progression. In this sense, the conversion of Angiotensin II (Ang II) into Angiotensin-(1-7) (Ang-(1-7)) by the Angiotensin-converting enzyme 2 (ACE2) is of utmost importance to prevent worse clinical outcomes. Previous studies reported the beneficial effects of oral diminazene aceturate (DIZE) administration, an ACE2 activator, in renal diseases models. In the present study, we aimed to evaluate the therapeutic effects of DIZE administration in experimental AKI induced by gentamicin (GM) in rats. Our findings showed that treatment with DIZE improved renal function and tissue damage by increasing Ang-(1-7) and ACE2 activity, and reducing TNF-α. These results corroborate with a raising potential of ACE2 activation as a strategy for treating AKI.

Burden of schistosomiasis-related mortality in Brazil: epidemiological patterns and spatial-temporal distribution, 2003-2018.

OBJECTIVE: To characterise the epidemiological patterns and the spatial-temporal distribution of schistosomiasis-related mortality in Brazil from 2003 to 2018. METHODS: A national population-based ecological study that used official data from the Mortality Information System. The data included all deaths recorded in Brazil from 2003 to 2018 in which schistosomiasis was mentioned in the death certificate as an underlying or associated cause of death (multiple causes). The municipalities of residence were used as units of geographic analysis, and standardised and smoothed mortality rates (per 100 000 inhabitants) were calculated using the local empirical Bayes method. Spatial autocorrelation was evaluated using global and local Moran indexes. To analyse the spatial dependence, the Getis-Ord G and Gi* statistics were used. RESULTS: During the study period, 18 421 113 deaths were recorded in Brazil. Schistosomiasis was mentioned in 11 487 deaths (proportional mortality: 0.06%); for 8141 deaths (70.87%), it was listed as the underlying cause, and for 3346 deaths (29.13%), it was listed as an associated cause. The mean mortality rate was 0.38 deaths/100 000 inhabitants. Individuals ≥ 70 years of age (RR: 115.34, 95% CI: 68.56-194.03) and residents in the Northeast region (RR: 10.81, 95% CI: 5.95-19.66) presented higher risks related to schistosomiasis. Municipalities with high mortality rates were identified in all regions, and high-risk clusters were found in municipalities located in the Northeast and Southeast regions of the country. CONCLUSIONS: Schistosomiasis remains an important cause of death in persistently endemic areas in Brazil, particularly in those with a high prevalence of the disease and a marked parasite load.

OBJECTIF: Caractériser les profils épidémiologiques et la distribution spatio-temporelle de la mortalité liée à la schistosomiase au Brésil de 2003 à 2018. MÉTHODES: Une étude écologique nationale basée sur la population qui a utilisé les données officielles du système d'information sur la mortalité. Les données incluaient tous les décès enregistrés au Brésil de 2003 à 2018 dans lesquels la schistosomiase était mentionnée dans le certificat de décès comme cause sous-jacente ou associée (causes multiples) de décès. Les municipalités de résidence ont été utilisées comme unités d'analyse géographique et les taux de mortalité normalisés et lissés (pour 100.000 habitants) ont été calculés à l'aide de la méthode empirique locale de Bayes. L'autocorrélation spatiale a été évaluée à l'aide d'indices de Moran globaux et locaux. Pour analyser la dépendance spatiale, les statistiques de Getis-Ord G et Gi* ont été utilisées. RÉSULTATS: Au cours de la période d'étude, 18.421.113 décès ont été enregistrés au Brésil. La schistosomiase a été mentionnée dans 11.487 décès (mortalité proportionnelle: 0,06%); pour 8.141 décès (70,87%), elle a été répertoriée comme la cause sous-jacente et pour 3.346 décès (29,13%), comme cause associée. Le taux de mortalité moyen était de 0,38 décès/100.000 habitants. Les personnes âgées de ≥70 ans (RR: 115,34 ; IC95%: 68,56 à 194,03) et les résidents de la région du Nord-Est (RR: 10,81 ; IC95%: 5,95 à 19,66) présentaient des risques plus élevés liés à la schistosomiase. Des municipalités présentant des taux de mortalité élevés ont été identifiées dans toutes les régions et des grappes à haut risque ont été trouvées dans des municipalités situées dans les régions du nord-est et du sud-est du pays. CONCLUSIONS: La schistosomiase reste une cause importante de mortalité dans les zones d'endémie persistante du Brésil, en particulier dans celles à forte prévalence de la maladie et à forte charge parasitaire.

Leprosy in the North and Northeast regions of Brazil: an integrated spatiotemporal approach.

OBJECTIVE: To analyse the spatiotemporal patterns of leprosy occurrence in the North and Northeast regions of Brazil from 2001 to 2017. METHODS: Mixed population-based ecological study with spatial and temporal trend analysis of epidemiological indicators based on new cases reported to the Information System for Notifiable Diseases of the Ministry of Health occurring in individuals residing in North and Northeast states of Brazil. RESULTS: A total of 396 987 new cases were analysed; 9.2% of these involved children <15 years of age, and 5.4% involved individuals with grade 2 disability (G2D). The Northeast region recorded 66.4% of the new cases. Most cases involved males between 15 and 59 years of age and of brown race/colour. The temporal trend showed a reduction in most of the indicators and study variables. The G2D rate did not have trends over time in the Northeast Region, in individuals 0-14 years of age, or in municipalities with 'very high' social vulnerability indexes. The spatial and spatiotemporal analysis showed the presence of hyperendemic foci with high detection risk involving municipalities in the states of Tocantins, Pará and Maranhão. CONCLUSION: Leprosy in the North and Northeast regions of Brazil persists as a critical public health problem. Temporal and spatiotemporal patterns identified in this study confirm that leprosy remains epidemiologically relevant in vulnerable areas. Surveillance and control interventions are needed in municipalities with low detection in the general population, in children and in individuals with G2D, to reduce late diagnosis.

OBJECTIF: Analyser les profils spatiotemporels de l'apparition des cas de lèpre dans les régions du nord et du nord-est du Brésil de 2001 à 2017. MÉTHODES: Etude écologique mixte basée sur la population avec analyse des tendances spatiales et temporelles des indicateurs épidémiologiques sur la base des nouveaux cas rapportés dans le Système d'Information sur les Maladies à Déclaration Obligatoire du Ministère de la Santé, survenant chez des individus résidant dans les Etats du nord et du nord-est du Brésil. RÉSULTATS: 396.987 nouveaux cas ont été analysés; 9,2% d'entre eux concernaient des enfants de moins de 15 ans et 5,4% concernaient des personnes avec un handicap de grade 2 (G2D). La région du nord-est a enregistré 66,4% des nouveaux cas. La plupart des cas concernaient des hommes âgés de 15 à 59 ans et de race/couleur noire. La tendance temporelle a montré une réduction dans la plupart des indicateurs et des variables de l'étude. Le taux de G2D n'a pas évolué au cours du temps dans la région du nord-est, chez les individus de 0 à 14 ans ou dans les municipalités avec des indices de vulnérabilité sociale "très élevés". L'analyse spatiale et spatiotemporelle a montré la présence de foyers hyper endémiques à risque élevé de détection impliquant des municipalités dans les Etats de Tocantins, Pará et Maranhão. CONCLUSION: La lèpre dans les régions du nord et du nord-est du Brésil persiste comme problème critique de santé publique. Les schémas temporels et spatiotemporels identifiés dans cette étude confirment que la lèpre reste épidémiologiquement importante dans les zones vulnérables. Des interventions de surveillance et de contrôle sont nécessaires dans les municipalités à faible détection dans la population générale et chez les enfants, ainsi que chez les personnes atteintes de G2D, afin de réduire le diagnostic tardif.

Diminazene aceturate (DIZE) has cellular and in vivo antiarrhythmic effects.

Diminazene aceturate (DIZE) is an anti-protozoan compound that has been previously reported to increase the activity of the angiotensin-converting enzyme 2 (ACE2) and thus increase Angiotensin-(1-7) production, leading to cardioprotection against post-myocardial infarction dysfunction and structural remodelling. Moreover, DIZE is able to ameliorate morpho-functional changes after myocardial infarction by enhancing ACE2 activity, thus increasing Angiotensin-(1-7) production (a benefic peptide of the renin-angiotensin system). However, despite the improvement in cardiac function/structure, little is known about DIZE effects on arrhythmia suppression, contraction/excitable aspects of the heart and importantly its mechanisms of action. Thus, our aim was to test the acute effect of DIZE cardioprotection at the specific level of potential antiarrhythmic effects and modulation in excitation-contraction coupling. For this, we performed in vitro and in vivo techniques for arrhythmia induction followed by an acute administration of DIZE. For the first time, we described that DIZE can reduce arrhythmias which is explained by modulation of cardiomyocyte contraction and excitability. Such effects were independent of Mas receptor and nitric oxide release. Development of a new DIZE-based approach to ameliorate myocardial contractile and electrophysiological dysfunction requires further investigation; however, DIZE may provide the basis for a future beneficial therapy to post-myocardial infarction patients.

Propensity for COVID-19 severe epidemic among the populations of the neighborhoods of Fortaleza, Brazil, in 2020.

BACKGROUND: The state of Ceará (Northeast Brazil) has shown a high incidence of coronavirus disease (COVID-19), and most of the cases that were diagnosed during the epidemic originated from the capital Fortaleza. Monitoring the dynamics of the COVID-19 epidemic is of strategic importance and requires the use of sensitive tools for epidemiological surveillance, including consistent analyses that allow the recognition of areas with a greater propensity for increased severity throughout the cycle of the epidemic. This study aims to classify neighborhoods in the city of Fortaleza according to their propensity for a severe epidemic of COVID-19 in 2020. METHODS: We conducted an ecological study within the geographical area of the 119 neighborhoods located in the city of Fortaleza. To define the main transmission networks (infection chains), we assumed that the spatial diffusion of the COVID-19 epidemic was influenced by population mobility. To measure the propensity for a severe epidemic, we calculated the infectivity burden (ItyB), infection burden (IonB), and population epidemic vulnerability index (PEVI). The propensity score for a severe epidemic in the neighborhoods of the city of Fortaleza was estimated by combining the IonB and PEVI. RESULTS: The neighborhoods with the highest propensity for a severe COVID-19 epidemic were Aldeota, Cais do Porto, Centro, Edson Queiroz, Vicente Pinzon, Jose de Alencar, Presidente Kennedy, Papicu, Vila Velha, Antonio Bezerra, and Cambeba. Importantly, we found that the propensity for a COVID-19 epidemic was high in areas with differing socioeconomic profiles. These areas include a very poor neighborhood situated on the western border of the city (Vila Velha), neighborhoods characterized by a large number of subnormal agglomerates in the Cais do Porto region (Vicente Pinzon), and those located in the oldest central area of the city, where despite the wealth, low-income groups have remained (Aldeota and the adjacent Edson Queiroz). CONCLUSION: Although measures against COVID-19 should be applied to the entire municipality of Fortaleza, the classification of neighborhoods generated through this study can help improve the specificity and efficiency of these measures.

Pollutants and nutrition: Are methylmercury effects on blood pressure and lipoprotein profile comparable to high-fat diet in mice?

Human exposure to methylmercury (MeHg) due to contaminated fish intake as part of a high-fat (HFD), high-carbohydrate diets is a reality today for many populations. HFD is associated with hypertension and hyperlipidemia, primary cardiovascular disease (CVD) risk factors. Some studies suggest that MeHg induces those risk factors. We evaluated the effect of MeHg exposure in mice fed with HFD or control diet for eight weeks. In the last experimental 15 days, the half group received a MeHg solution (20 mg/L) replacing water. Blood pressure (BP), heart rate, lipoprotein concentrations, and paraoxonase activity were evaluated. Liver cholesterol, triacylglycerol, and IBA-1+ cells, as well as transcriptional levels of genes related to lipid metabolism and inflammatory response, were also assessed. HFD and both MeHg groups presented increased BP and total cholesterol (TC). In the liver, HFD but not MeHg was related to an increase in TC. Also, MeHg intoxication reduced paraoxonase activity regardless of diet. MeHg intoxication and HFD increased steatosis and the number of IBA-1+ cells and modified some gene transcripts associated with lipid metabolism. In conclusion, we demonstrated that MeHg effects on CVD risk factors resemble those caused by HFD.

Unequal burden of mortality from gastric cancer in Brazil and its regions, 2000-2015.

BACKGROUND: Gastric cancer (GC) is an important cause of morbidity and mortality worldwide. However, population-based data on GC mortality dynamics in low and middle income countries are scarce. METHODS: We analyzed GC mortality in Brazil based on all GC-related deaths registered 2000-2015. RESULTS: A total of 17,374,134 deaths were recorded, with GC identified in 214,808 (1.24%) cases-203,941 (94.9%) as underlying cause, and 10,867 (5.1%) as associated cause of death. Adjusted rates for age and sex was 6.85 deaths/100,000 inhabitants [95% confidence interval (CI) 6.73-6.97]. The highest mortality rates were found in males [10.00; rate ratio (RR) 1.85; 95% CI 1.78-1.91; p < 0.0001] and patients ≥ 45 years of age (24.98; RR 3.79; 95% CI 3.55-4.05; p < 0.0001). The South (7.56; RR 1.62; 95% CI 1.50-1.76; p < 0.0001) and Southeast (7.36; RR 1.59; 95% CI 1.48-1.71; p < 0.0001) regions had the highest regional rates. Spatial and spatiotemporal high-risk mortality areas in 2004-2007 were located mainly in the South, Southeast, and Central-West regions. After 2008, the Northeast region became a high-risk area, especially Ceará State. CONCLUSION: GC remains a significant public health problem with high mortality burden and unequal distribution in Brazilian states. The new patterns in poorer regions and the high risk in some specific populations show a clear process of epidemiological transition over time. There is a need to strengthen nationwide epidemiological monitoring, surveillance, prevention, and control for GC in the country.

[Mortality from leprosy in highly endemic contexts: integrated temporal-spatial analysis in BrazilMortalidad por lepra en zonas de alta endemicidad: análisis espacio-temporal integrado en Brasil]. / Mortalidade por hanseníase em contextos de alta endemicidade: análise espaço-temporal integrada no Brasil.

OBJECTIVE: To describe temporal trends and spatial patterns of leprosy-related mortality in the North and Northeast of Brazil from 2001 to 2017. METHODS: This population-based, mixed ecological study employed secondary data obtained from the Health Ministry's Mortality Information System. Death certificates were examined for extraction of information on leprosy as underlying or contributing cause of death. RESULTS: In the period of interest, 4 907 leprosy-related deaths were recorded. In 59.3%, leprosy was a contributing cause. "Leprosy, unspecified" (ICD-10 A30.9) was the most common cause recorded (72.7% as underlying cause; 76.1% as contributing cause). Increased risk of mortality by leprosy was observed in males, age ≥ 60 years and brown or black race/color. Joinpoint regression analysis of time trends revealed an increased overall mortality trend in the Northeast and in the states of Tocantins, Maranhão, Alagoas, and Bahia, as well as in the male sex. Regarding the spatial distribution of mortality rates adjusted by age and sex, as well as the analysis of moving spatial means and standardized mortality ratio, patterns that were above the mean for the area under study were identified for the states of Acre and Rondônia, the southern part of Pará, Tocantins, Maranhão, Piauí, south of Ceará, and north and south of Bahia. CONCLUSIONS: Leprosy mortality in the Brazilian North and Northeast is expressive and persistent, with a focal pattern of distribution in more vulnerable territories and populations. Comprehensive leprosy care must be strengthened in the Unified Health System in these regions.

OBJETIVO: Describir las tendencias temporales y los patrones espaciales de la mortalidad relacionada con la lepra en las regiones norte y nordeste de Brasil del 2001 al 2017. MÉTODOS: Estudio ecológico mixto basado en la población, con análisis de las tendencias temporal y espacial, hecho a partir de datos secundarios tomados de las declaraciones de defunción del Sistema de Información de Mortalidad (SIM) del Ministerio de Salud. Dichas declaraciones se examinaron para extraer los registros de lepra como causa básica y asociada de defunción. RESULTADOS: Se registraron 4 907 defunciones relacionadas con la lepra en el período de interés, en 59,3% de las cuales se la citó como causa asociada. La "lepra no especificada" (A30.9) fue la causa más citada en las declaraciones de defunción (causa básica: 72,7%; causa asociada: 76,1%). Se verificó un mayor riesgo de mortalidad por lepra en personas de sexo masculino, mayores de 60 años y de raza o de piel negra o morena. La tendencia temporal por análisis de puntos de inflexión (joinpoints) mostró un incremento en la tendencia general de la mortalidad en la región nordeste y en los estados de Tocantins, Maranhão, Alagoas y Bahía, así como en personas de sexo masculino. En lo referente a la distribución espacial de las tasas de mortalidad ajustadas por edad y sexo, así como a los análisis de las medias móviles espaciales y de la razón de mortalidad normalizada, se identificaron patrones superiores a la media de la zona de estudio en Acre, Rondônia, el Sur del estado de Pará, Tocantins, Maranhão, Piauí, el Sur de Ceará y las regiones del Norte y Sur de Bahía. CONCLUSIONES: La mortalidad por lepra en las regiones norte y nordeste es significativa y persistente, con un patrón focal de incidencia en los territorios y poblaciones con mayor vulnerabilidad. Se hace hincapié en la necesidad de fortalecer la atención integral a esta enfermedad en la red de atención del Sistema Único de Salud de esas regiones.

Enhancement of Bone Healing by Local Administration of Carbon Nanotubes Functionalized with Sodium Hyaluronate in Rat Tibiae.

It has been reported that carbon nanotubes (CNTs) serve as nucleation sites for the deposition of bone matrix and cell proliferation. Here, we evaluated the effects of multi-walled CNTs (MWCNTs) on bone repair of rat tibiae. Furthermore, because sodium hyaluronate (HY) accelerates bone restoration, we associated CNTs with HY (HY-MWCNTs) in an attempt to boost bone repair. The bone defect was created by a 1.6-mm-diameter drill. After 7 and 14 days, tibiae were processed for histological and morphometric analyses. Immunohistochemistry was used to evaluate the expression of vascular endothelial growth factor (VEGF) in bone defects. Expression of osteocalcin (OCN), bone morphogenetic protein-2 (BMP-2), and collagen I (Col I) was assessed by real-time PCR. Histomorphometric analysis showed a similar increase in the percentage of bone trabeculae in tibia bone defects treated with HY and HY-MWCNTs, and both groups presented more organized and thicker bone trabeculae than nontreated defects. Tibiae treated with MWCNTs or HY- MWCNTs showed a higher expression of VEGF. Treatment with MWCNTs or HY-MWCNTs increased the expression of molecules involved in the bone repair process, such as OCN and BMP-2. Also, HY- and MWCNT-treated tibiae had an increased expression of Col I. Thus, it is tempting to conclude that CNTs associated or not with other materials such as HY emerged as a promising biomaterial for bone tissue engineering.

Technological Device for Manufacturing Transdermal Films: Possible Applications to the Individualized Treatment for Erectile Dysfunction.

Pharmacological advances in erectile dysfunction (ED) treatment have aroused growing interest among health professionals towards sexual dysfunction, generating an increasing demand for dosage forms and drug delivery systems, including tadalafil. This study aimed to develop a device to generate patches that would enable drug dosage individualization and transdermal administration. To create such a mechanical device, technical drawings were made using the CAD software. A functional prototype was built, and a pharmaceutical formulation containing tadalafil (10 mg cm-2) was prepared. An analytical method (HPLC) was developed and validated. The average weight of adhesives (n = 10) was 241.01 mg; the content uniformity for preparations in unit doses (n = 10) was 108.93%, and a CV <2% for intraadhesive tadalafil content (n = 40) was observed. The ex vivo permeation of patches containing tadalafil was determined in Franz cells (n = 6), equipped with human skin and kept for 12 h in contact with the patch, by using the tape stripping method. The optimized method showed acceptable confidence limits within the range recommended by regulatory agencies, being validated for use in this ex vivo permeation study. Tadalafil could permeate to the viable epidermis and dermis (5.7%). The created device produced homogeneous patches of tadalafil, showing such technological innovation as to be feasible in individualized therapy for the treatment of ED.

Mefenamic acid decreases inflammation but not joint lesions in experimental osteoarthritis.

Mefenamic acid is a non-steroidal anti-inflammatory drug able to control the symptoms of osteoarthritis (OA), but its effects on protection of cartilage and bone are still unclear. This study aimed to investigate whether the control of inflammation by mefenamic acid translates into decreased joint lesions in experimental OA in rats. OA was induced by injecting 1 mg of monosodium iodoacetate (MIA) into the joints of rats. The animals were treated with mefenamic acid (50 mg/kg, daily, oral gavage) either pre-MIA injection (preventive) or post-MIA injection (therapeutic). Joint swelling and hyperalgesia were evaluated at baseline and 1, 3, 14 and 28 days after induction of OA. Intra-articular lavage and kinetics of cell migration into the synovium were measured 3 and 28 days after OA induction. Histopathological analysis, Osteoarthritis Research Society International (OARSI) score, total synovium cells count, cartilage area and levels of proteoglycans in joints were also evaluated. Mefenamic acid prevented joint oedema and hyperalgesia induced by MIA in the acute phase (3 days) of the disease. In the chronic phase (28 days), preventive and therapeutic regimens decreased the number of mononuclear cells in the joint cavity. In contrast, thickening of the synovium, bone resorption, loss of cartilage and levels of proteoglycans were unaffected by mefenamic acid when it was administered either preventively or therapeutically. Thus, mefenamic acid had anti-inflammatory effects but did not reduce the progression of OA lesions, thereby indicating that it is only effective for symptomatic control of OA.

New insights into the elucidation of angiotensin-(1-7) in vivo antiarrhythmic effects and its related cellular mechanisms.

NEW FINDINGS: What is the central question of this study? Recently, there have been many studies exploring the biological effects of angiotensin-(1-7), which has been proved to have cardioprotective actions. However, the effects of this peptide on cardiac arrhythmias in vivo and details regarding its mechanism of action are still undetermined. What is the main finding and its importance? We investigated protective effects of angiotensin-(1-7) on cardiac arrhythmias in vivo, which were not properly explored in terms of cellular mechanisms. To verify effects of angiotensin-(1-7), we used different but complementary experimental approaches. Our data provide new evidence on the cellular mechanism and an in vivo demonstration of the acute antiarrhythmic effect of angiotensin-(1-7). Angiotensin-(1-7) [Ang-(1-7)] has been proved to have cardioprotective effects. However, the effects of this peptide on cardiac arrhythmias in vivo and details regarding its mechanism of action are still undetermined. The aim of this study was to investigate the protective effects of Ang-(1-7) against cardiac arrhythmias, its in vivo effects and cellular mechanism of action. We analysed the ECG upon inducement of arrhythmias in vivo in rats using a combination of halothane and adrenaline. To analyse the effects of Ang-(1-7) on cells, fresh mouse ventricular cardiomyocytes were isolated. The cardiomyocytes were superfused with a solution containing halothane and isoprenaline as a model to induce arrhythmias and used in three different approaches, namely a contractility assay, patch-clamp technique and confocal microscopy. The in vivo ECG showed that the injection of Ang-(1-7) (4 nm i.v.) significantly reduced cardiac arrhythmias [before, 49 ± 43 arrhythmic events versus after Ang-(1-7), 16 ± 14 arrhythmic events]. This effect was blocked by injection of A-779 and l-NAME, without changes in haemodynamic parameters. In addition, contractility experiments showed that Ang-(1-7) significantly decreased the number of arrhythmic events without changing the fractional shortening. This protection was associated with a reduction of the action potential repolarization and membrane hyperpolarization. Moreover, Ang-(1-7) decreased the number of calcium waves without any changes in the amplitude of the calcium transient, despite a significant reduction in the decay rate. Our data provide new evidence on the cellular mechanism together with an in vivo demonstration of the antiarrhythmic effects of Ang-(1-7).

Evaluation of carbon nanotubes functionalized with sodium hyaluronate in the inflammatory processes for oral regenerative medicine applications.

OBJECTIVES: The objectives of this study were to assess the effects of hyaluronic acid (HY), multi-walled carbon nanotubes (MWCNT), and MWCNT functionalized with HY (HY-MWCNT) on the resolution of neutrophilic inflammation in the pleural cavity of LPS-challenged mice and to assess the influence of these materials in the inflammatory process of bone repair of tooth sockets of rats. MATERIALS AND METHODS: C57Bl/6 mice were intra-pleurally injected with HY, MWCNT, HY-MWCNT, phosphate-buffered saline (PBS), or LPS. The animals were euthanized after 8 and 24 h, and cells were harvested for total and differential cell counting. The tooth sockets of Wistar rats were filled with HY, MWCNT, HY-MWCNT, or blood clot (control). After 1, 3, and 7 days, histological and morphometric analyses evaluated the number of cell nuclei and blood vessels, and bone trabeculae formation in the sockets. Myeloperoxidase (MPO) activity quantified neutrophil accumulation in the sockets. RESULTS: HY, MWCNT, and HY-MWCNT increased neutrophilic recruitment at 8 h and reduced the inflammatory process at 24 h in the pleural cavity. Histological and morphometric analyses and MPO activity showed no significant differences in the recruitment of inflammatory cells in the tooth sockets. HY increased the number of blood vessels, and HY and HY-MWCNT increased bone trabeculae formation at 7 days of tooth extraction. CONCLUSIONS: HY, MWCNT, and HY-MWCNT resolved the neutrophilic inflammation in the pleural cavity of the mice. However, these materials did not modulate the inflammatory process in the early stages of bone repair of the tooth sockets, thereby excluding this action as a possible mechanism by which these biomaterials accelerate bone repair. CLINICAL RELEVANCE: HY-MWCNT is capable of accelerating bone repair/regeneration without affecting the inflammatory phase during the bone healing process.

Effects of angiotensin II type I receptor blocker losartan on orthodontic tooth movement.

INTRODUCTION: Drugs that block the renin-angiotensin system (RAS) are widely used for treating hypertension, heart and kidney failure, and the harmful effects of diabetes. Components of the RAS have been identified in various organs, but little is known of their effects on bone remodeling. The aim of this study was to evaluate whether the blockage of the RAS influences strain-induced bone remodeling in a model of orthodontic tooth movement. METHODS: An orthodontic appliance was placed in C57BL6/J mice that were randomly divided into 2 groups: vehicle-treated mice (VH) and mice treated with losartan (an angiotensin II receptor blocker). Orthodontic tooth movement and the number of tartrate-resistant acid phosphatase-positive cells were determined by histopathologic analysis. The expression of mediators involved in bone remodeling was evaluated by quantitative real-time polymerase chain reaction. Blood pressure was measured before and during the experimental period. RESULTS: Orthodontic tooth movement and tartrate-resistant acid phosphatase-positive cells were significantly reduced in the losartan group compared with the VH group. mRNA levels of osteoclast markers (RANK, RANKL, cathepsin K, and metalloproteinase 13) were lower in the losartan mice than in the VH group, whereas the expressions of osteoblast markers and negative regulators of bone resorption (periostin, dentin matrix protein, alkaline phosphatase, collagen 1A1, semaphorin 3A3, metalloproteinase 2, and osteoprotegerin) were higher in the VH group. CONCLUSIONS: Blockage of the RAS system decreases osteoclast differentiation and activity and, consequently, results in decreased strain-induced bone remodeling in orthodontic tooth movement.