Ferritin heavy chain supports stability and function of the regulatory T cell lineage.

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

Vivência e trabalho: percepção de profissionais de Medicina e Enfermagem que atuaram durante a pandemia em uma universidade pública mineira / Experience and work: perceptions of medical and nursing professionals working in a public university in Minas Gerais during the pandemic / Vivencia y trabajo: percepción de profesionales de medicina y enfermería que actuaron durante la pandemia en una universidad pública del Estado de Minas Gerais

O artigo buscou compreender a percepção de servidores públicos de uma instituição federal de ensino superior acerca do trabalho realizado em colaboração com a prefeitura municipal, na atuação assistencial durante a pandemia de Covid-19. Trata-se de uma pesquisa com abordagem qualitativa que realizou entrevistas com 15 profissionais. Na análise dos dados, utilizou-se Análise de Conteúdo, apoiada pelo software Iramuteq, e deles emergiram duas categorias temáticas: "Sentimento em relação ao deslocamento momentâneo da função" e "Compreensão sobre postura institucional para que as atividades acontecessem", cada uma com suas subcategorias. O estudo aponta que, mesmo com fatores de proteção e motivação para o trabalho realizado, os momentos críticos que envolveram a saúde pública causaram danos emocionais nos profissionais que atuaram nessas circunstâncias e a busca por apoio psicológico deve ser sempre encorajada e disponibilizada em caso de necessidade.

This study sought to understand the perceptions of civil servants working in a federal higher education institution about working in collaboration with the city council in the development of care activities during the Covid-19 pandemic. We conducted a qualitative study based on interviews with 15 professionals. The data were analyzed using content analysis and the software Iramuteq. Two core thematic categories emerged from the analysis, each with their subcategories: feelings regarding the temporary displacement of the function; and understanding of institutional posture towards activities. The findings show that, despite protective factors and motivation for the work undertaken, critical moments involving public health caused emotional damage to the professionals and that seeking help for mental health problems should always be encouraged and support should be on hand as and when needed.

El artículo buscó comprender la percepción de servidores públicos de una institución federal de enseñanza superior sobre el trabajo realizado en colaboración con la municipalidad, en la actuación asistencial durante la pandemia de Covid-19. Investigación con abordaje cualitativo y entrevista a 15 profesionales. En el análisis de los datos se utilizó el Análisis de Contenido apoyado por el Software Iramuteq y de ellos surgieron dos categorías temáticas: Sentimiento con relación al desplazamiento momentáneo de la función y Comprensión sobre la postura institucional para que las actividades sucedieran, cada una con sus subcategorías. El estudio señala que incluso con factores de protección y motivación para el trabajo realizado, los momentos críticos que envolvieron la salud pública causaron daños emocionales en los profesionales que actuaron y la búsqueda de apoyo psicológico siempre debe incentivarse y ponerse a disposición en caso de necesidad.

Natural Coumarin Derivatives Targeting Melanoma.

In general, a cancerous process starts from uncontrolled cell growth, apoptosis, and rapid proliferation of cellular clones, as well as, reactive oxygen species (ROS) and imbalance of ROS-antioxidant production also could be involved in the genesis of the disease. Cancer has accounted for millions of deaths worldwide every year, representing a relevant threat to human lives. In this context, malignant melanoma represents the most aggressive and deadliest type of cancer, leading to increased rates of patient deaths. Natural active compounds have demonstrated their pharmacological benefits in several different studies. Among these compounds, coumarin analogs have demonstrated promising biological profiles, considering their efficacy and low toxicity. In this context, this phytochemical oxygenated core has been broadly investigated since it presents several biological properties of interest in the medicinal field. Herein, we reported a complete compilation of studies focused on natural coumarins against melanoma, as well as, tyrosinase since it is a cooper-catalyzed oxidase that performs an essential role during melanogenesis (Eu-melanins and Pheo-melanins), which is associated with melanoma. Thus, three different subclasses of natural coumarin were described in detail, such as simple coumarin core, furanocoumarins, pyranocoumarins, and pyrone-substituents. Additionally, insights on tyrosinase have been provided, allowing an overview of some structural/functional aspects of its enzyme, such as the presence of a binuclear type 3 cooper coordination at the binding site of this target, acting as cofactors. Posteriorly, several coumarin-based analogs with anti-tyrosinase activity also were reported and discussed. Finally, we believe that unprecedented review can be a valuable source of information, which can be used to design and develop novel coumarin-based analogs targeting melanoma and also tyrosinase enzyme, contributing to the advances in the field of natural products.

Coumarin-Based Compounds as Inhibitors of Tyrosinase/Tyrosine Hydroxylase: Synthesis, Kinetic Studies, and In Silico Approaches.

Cancer represents the main cause of morbidity and mortality worldwide, constituting a serious health problem. In this context, melanoma represents the most aggressive and fatal type of skin cancer, with death rates increasing every year. Scientific efforts have been addressed to the development of inhibitors targeting the tyrosinase enzyme as potential anti-melanoma agents due to the importance of this enzyme in melanogenesis biosynthesis. Coumarin-based compounds have shown potential activity as anti-melanoma agents and tyrosinase inhibitors. In this study, coumarin-based derivatives were designed, synthesized, and experimentally evaluated upon tyrosinase. Compound FN-19, a coumarin-thiosemicarbazone analog, exhibited potent anti-tyrosinase activity, with an IC50 value of 42.16 ± 5.16 µM, being more active than ascorbic acid and kojic acid, both reference inhibitors. The kinetic study showed that FN-19 acts as a mixed inhibitor. Still, for this compound, molecular dynamics (MD) simulations were performed to determine the stability of the complex with tyrosinase, generating RMSD, RMSF, and interaction plots. Additionally, docking studies were performed to elucidate the binding pose at the tyrosinase, suggesting that the hydroxyl group of coumarin derivative performs coordinate bonds (bidentate) with the copper(II) ions at distances ranging from 2.09 to 2.61 Å. Then, MM/PBSA calculations revealed that van der Waals interactions are the most relevant intermolecular forces for complex stabilization. Furthermore, it was observed that FN-19 has a binding energy (ΔEMM) value similar to tropolone, a tyrosinase inhibitor. Therefore, the data obtained in this study will be useful for designing and developing novel coumarin-based analogs targeting the tyrosinase enzyme.

Changes in lifestyle behaviors during the COVID-19 pandemic in children and adolescents with congenital heart disease / Mudanças nos comportamentos de estilo de vida durante a pandemia COVID-19 em crianças e adolescentes com cardiopatia congênita

Abstract Objective: To describe the changes in lifestyle behaviors during the COVID-19 pandemic in children and adolescents with congenital heart disease and to investigate the association of congenital heart disease complexity with lifestyle behavior changes. Methods: Cross-sectional study with 127 children and adolescents with congenital heart disease, who underwent cardiac procedure (mean postoperative time: 10.11±3.13 years), conducted between December 2020 and January 2021. Lifestyle behaviors, such as dietary intake, physical activity, sedentary behavior, and sleep, were assessed through telephone interview based on validated questionnaires. Dietary patterns were identified using principal component analysis. Frequency of general and specific combinations of healthy and unhealthy lifestyle behavior changes was evaluated. Multinomial logistic regressions were used to test the association between congenital heart disease complexity and changes in lifestyle behavior. Results: The main lifestyle behaviors acquired during pandemic were: 83.5% decreased physical activity; 37.0% increased sedentary behavior; 26.0% slept more than usual; and 23.6% adopted a less-healthy dietary pattern. Almost half of the participants (41.8%) had at least one unhealthy change in lifestyle behavior. Complex congenital heart diseases were associated with increased sedentary behavior (OR 3.49, 95%CI 1.23-9.90). Conclusions: Children and adolescents with congenital heart disease had unhealthy lifestyle behavior during the pandemic, mainly in the form of reduced physical activity and increased sedentary behavior.

Resumo Objetivo: Descrever as mudanças nos estilos de vida durante a pandemia em crianças e adolescentes com cardiopatia congênita e investigar a associação da complexidade da cardiopatia congênita com as mudanças de estilo de vida. Métodos: Estudo transversal com 127 crianças e adolescentes com cardiopatia congênita, que realizaram procedimento cardíaco (tempo médio de pós-operatório: 10,11 (3,13) anos), realizado entre dezembro de 2020 e janeiro de 2021. O estilo de vida (alimentação, atividade física, comportamento sedentário e sono) foi avaliado por entrevista telefônica, com base em questionários validados. Padrões alimentares foram identificados por meio da análise de componentes principais. Frequência de combinações gerais e específicas de mudanças de estilo de vida saudável e não saudável foram avaliadas. Regressões logísticas multinominais foram utilizadas para testar associações. Resultados: Os principais comportamentos de estilo de vida adquiridos durante a pandemia foram: 83,5% reduziram a atividade física, 37,0% aumentaram o comportamento sedentário, 26,0% dormiram mais e 23,6% mudaram para um padrão alimentar menos saudável. Quase metade (41,8%) dos participantes teve pelo menos uma mudança não saudável no estilo de vida. Cardiopatias congênitas complexas foram associadas ao aumento do comportamento sedentário durante a pandemia (odds ratio 3,49, IC95% 1,23-9,90). Conclusões: Crianças e adolescentes com cardiopatia congênita apresentaram estilo de vida não saudável durante a pandemia, principalmente na forma de redução da atividade física e aumento do comportamento sedentário.

Effects of Calendula officinalis extract on liver histopathology, lipid profile, and oxidative stress in rats submitted to a diet rich in cholesterol and carbohydrates

ABSTRACT Purpose: To evaluate the modulatory properties of Calendula officinalis L. (Asteraceae) (C. officinalis) extract on cafeteria diet-fed rats. Methods: A cafeteria diet was administered ad libitum for 45 days to induce dyslipidemia. Then, the rats were treated with the formulations containing C. officinalis in the doses of 50, 100, and 150 mg/kg or only with the vehicle formulation; the control group received a commercial ration. Results: The cafeteria diet decreased glutathione S-transferase activity and high-density lipoprotein plasmatic levels and damaged the hepatic architecture. The C. officinalis extract was able to reduce lipid infiltration in liver tissue and to modulate oxidative stress and lipid profile markers. Conclusions: The correlations between the variables suggest a pathological connection between oxidative stress markers and serum lipid profile.

HDL-Cholesterol in Children and Adolescents with Congenital Heart Disease

Abstract Background Children and adolescents with congenital heart disease may be more likely to develop atherogenic cardiovascular diseases in adulthood. Therefore, the early identification of risk factors and intervention in childhood may be crucial for a good quality of life and longevity. Objectives To describe the distribution of high-density lipoprotein-cholesterol (HDL-c) levels and its association with socioeconomic, clinical and cardiovascular risk factors in children and adolescents with congenital heart disease. Methods Cross-sectional study with children and adolescents aged between 5 and 18 years, with congenital heart disease. Socioeconomic, clinical and cardiovascular risk factors were evaluated. HDL-c concentrations were evaluated by the direct method and categorized as desirable (>45 mg/dL), borderline (40-45 mg/dL) and low (<40 mg/dL). We also assessed the "undesirable" levels, consisting of the sum of "borderline" and "low" values for comparative purposes. The multivariate logistic regression analysis was used to evaluate the factor associated with undesirable HDL-c levels. A p<0.05 value was adopted as statistically significant. Results Mean HDL-c was 51.2 mg/dL (SD 12.6), with a prevalence of 33.2% of undesirable HDL-c. In the multivariate analysis, C-reactive protein levels ≥ 3mg/dL (OR 3.26; 95% CI 1.32-8.04), age ≥ 10 years old (OR: 2.11; 95% CI 1.12-3.99) and undesirable levels of triglycerides (OR 2.21; 95% CI 1.13-4.75) were associated with undesirable HDL-c. Conclusion In this sample of children and adolescents with congenital heart disease, almost one third presented low or borderline HDL-c levels. Age ≥10 years, C-reactive protein and triglycerides were associated with undesirable HDL-c levels. These factors should be considered in the prevention of cerebrovascular diseases in adulthood in this population.

Inserção de médicas na formação de especialidades da comissão de residência médica do Hospital Geral Roberto Santos / Inclusion of female physicians in the HGRS medical residency committee's medical specialties / Inserción de médicas en la formación de la especialidad del comité de residencia médica del Hospital General Roberto Santos

A inserção das mulheres na medicina tem sido progressiva, com média de 5,2% de aumento a cada década nos últimos trinta anos. As mulheres já são maioria entre as faixas etárias até 34 anos (55,3%) e até 29 anos, representando 58,5% dos graduandos, segundo o Conselho Federal de Medicina. A abordagem do tipo quantiqualitativa e exploratória, com levantamento e análise de dados secundários, buscou evidenciar uma amostra temporal sobre a inserção das mulheres na formação de especialidades médicas da Comissão de Residência Médica (Coreme) do Hospital Geral Roberto Santos (HGRS). Apesar da formação da graduação ser equânime e da entrada das médicas na residência no HGRS permanecer com média de 69,2%, os quantitativos de preceptoras, supervisoras e coordenadoras de serviço relacionados aos programas de residência médica na instituição são bem inferiores (40,5%; 17,4% e 26,1%, respectivamente), não oportunizando a progressão das médicas para os espaços de decisão e gestão. Quanto à coordenação da Coreme, não há registro de mulheres médicas na função da instituição. Trabalhar as questões de gênero em unidade hospitalar no contexto da medicina, profissão surgida da hegemonia masculina e patriarcal, enquanto cultura, não é simples, mas necessário. O estudo traz uma reflexão para o diálogo sobre a construção de políticas de desenvolvimento na gestão do trabalho, que envolva equidade e justiça social quanto ao gênero no ensino da residência médica, com equiparação de direitos e valores que possam beneficiar a igualdade no desenvolvimento social nos dias atuais.

Women have been progressively integrating medicine programs, with an average increase of 5.2% each decade in the past 30 years. Female physicians are already the majority among the age groups of up to 34 years (55.3%) and up to 29 years, representing 58.5% of undergraduates, according to the Federal Council of Medicine. This quantitative, qualitative and exploratory research, based on survey and analysis of secondary data, sought to highlight a temporal sample on the inclusion of women in the medical specialties of the Geral Roberto Santos Hospital's (HGRS) Medical Residency Committee (Coreme). Despite an equanimous graduation education and a fixed average entry of female physicians (69.2%) into the HGRS residency, the number of female preceptors, supervisors and service coordinators related to the residency programs are much lower (40.5%,17.4% and 26.1%, respectively), hindering their carrier progression to decision and management roles. As for the Coreme coordination, there is no record of female physicians exercising this role. Discussing gender issues in medicine­ a profession that emerged from male and patriarchal hegemony­within a hospital setting as a cultural phenomenon is complex and necessary. The study reflects on the development of management policies to include gender-based equity and social justice in medical residency, fostering equal rights and values in today's society.

La creciente inserción de la mujer en la medicina ha sido progresiva, con un aumento promedio del 5,2% cada década en los últimos 30 años. Las mujeres predominan entre los grupos de edad de los 34 años (55,3%) y de los 29 años, y representa el 58,5% de los estudiantes de grado según el Consejo Federal de Medicina. El enfoque cuantitativo-cualitativo, exploratorio, con encuesta y análisis de datos secundarios, buscó destacar una muestra temporal sobre la inclusión de mujeres en la formación de especialidades médicas de la Comisión de Residencia Médica (Coreme) del Hospital General Roberto Santos (HGRS). A pesar de que la formación de graduación es ecuánime y de que el ingreso de médicas a la residencia en el HGRS se mantiene en un promedio del 69,2%, el número de preceptoras, supervisoras y coordinadoras de servicios relacionado con los programas de residencia en la institución es muy inferior (el 40,5%; el 17,4% y el 26,1%, respectivamente), lo que no permite la progresión de las médicas a los espacios de decisión y gestión. En cuanto a la coordinación del Coreme, no existe registro de mujeres médicas en el rol de la institución. No es sencillo sino necesario trabajar temas de género en una unidad del hospital en el contexto de la medicina, una profesión que surgió de la hegemonía masculina patriarcal como cultura. Este estudio permite reflexionar sobre el diálogo de la formación de políticas de desarrollo en la gestión del trabajo, que incluya la equidad y la justicia social respecto al género en la enseñanza de residencia médica, con igualdad de derechos y valores que pueden favorecer la igualdad al desarrollo social en la actualidad.

Protective immunity triggered by ectonucleoside triphosphate diphosphohydrolase-based biopharmaceuticals attenuates cardiac parasitism and prevents mortality in Trypanosoma cruzi infection.

Chagas disease is a potentially fatal infection in 21 endemic Latin America countries for which the effectiveness of reference antiparasitic chemotherapy is limited. Thus, we developed three biopharmaceuticals and evaluated the effectiveness of different immunization strategies (recombinant protein NTPDase-1 [rNTPDase-1], DNA plasmid encoding Trypanosoma cruzi NTPDase-1 [TcNTPDase-1] and DNA-NTPDase-1 prime/rNTPDase-1 boost [Prime-boost]) based on the surface ecto-nucleoside triphosphate diphosphohydrolase (ecto-NTPDase) enzyme of T. cruzi in animals challenged with a virulent strain (Y) of this parasite. BALB/c mice were immunized three times at 30 days intervals, challenged with T. cruzi 15 days after the last immunization, and euthanized 30 days after T. cruzi challenge. Our results showed limited polarization of specific anti-ecto-NTPDase immunoglobulins in mice receiving both immunization protocols. Conversely, the Prime-boost strategy stimulated the Th1 protective phenotype, upregulating TNF-α and downregulating IL-10 production while increasing the activation/distribution of CD3+/CD8+, CD4+/CD44hi and CD8+/CD44hi/CD62L cells in immunized and infected mice. Furthermore, IL-6 and IL10 levels were reduced, while the distribution of CD4+/CD44hi and CD3+/CD8+ cells was increased from rNTPDase-1 and DNA-NTPDase1-based immunization strategies. Animals receiving DNA-NTPDase1 and Prime-boost protocols before T. cruzi challenged exhibited an enhanced immunological response associated with IL-17 upregulation and remarkable downregulation of heart parasitism (T. cruzi DNA) and mortality. These findings indicated that NTPDase-1 with Prime-boost strategy induced a protective and sustained Th17 response, enhancing host resistance against T. cruzi. Thus, ecto-NTPDase is a potentially relevant and applicable in the development of biopharmaceuticals with greater immunoprophylactic potential for Chagas disease.

Acute upper gastrointestinal bleeding due to portal hypertension in children: What is the best timing of endoscopy?

OBJECTIVE: To compare initial clinical/laboratory parameters and outcomes of mortality/rebleeding of endoscopy performed <12 h(early UGIE) versus endoscopy performed after 12-24h(late UGIE) of ED admission in children with acute upper gastrointestinal bleeding(AUGIB) due to portal hypertension. METHODS: This is a retrospective cohort study. From January 2010 to July 2017, medical records of all children admitted to a tertiary care hospital with AUGIB due to portal hypertension were reviewed until 60 days after ED admission. RESULTS: A total of 98 ED admissions occurred from 73 patients. Rebleeding was identified in 8/98(8%) episodes, and 9 deaths were observed. UGIE was performed in 92(94%) episodes, and 53(58%) of them occurred within 12 h of ED admission. Episodes with early UGIE and late UGIE were similar in terms of history/complaints/laboratory data at admission, chronic liver disease associated, AUGIB duration, and initial management. No statistically significant associations were found between early UGIE and the outcomes of death/rebleeding and prevalence of endoscopic hemostatic treatment (band ligation or sclerotherapy) compared to late UGIE. In the multivariable logistic regression model, the endoscopic hemostatic treatment showed a negative association with early UGIE(OR=0.33;95%CI=0.1-0.9;p = 0.04). CONCLUSIONS: This study suggests that in pediatric patients with AUGIB and portal hypertension, UGIE may be performed after 12-24 h without harm to the patient, facilitating better initial clinical stabilization/treatment and optimization of resources.

Aspectos acadêmicos da coreme no HGRS: ampliando a qualidade do ensino na residência médica / Academic aspects of coreme at HGRS: improving teaching quality in medical residency / Aspectos académicos de coreme en HGRS: aumentar la calidad de la enseñanza en la residencia médica

Aprimorar o serviço acadêmico da residência médica é fundamental para a credibilidade do ensino de uma instituição que tem credenciamento de programas para a formação de médicos especialistas. O objetivo deste trabalho é descrever a experiência dos últimos dois anos com a implementação de ações da secretaria acadêmica da Comissão de Residência Médica (Coreme) em um hospital público e promover novas reflexões e conhecimentos sobre a estrutura acadêmica do ensino na residência médica e suas dimensões técnicas, políticas, administrativas e éticas. Com o desenvolvimento organizativo da Coreme do Hospital Geral Roberto Santos (HGRS), foi possível aumentar a satisfação dos profissionais médicos residentes na instituição com a qualidade da formação. A adesão aos programas foi ampliada e a transferência, a desistência e a evasão dos residentes diminuíram, principalmente durante o período da pandemia da covid-19. Além disso, a interação e a integração entre os supervisores e preceptores dos programas melhorou, favorecendo a troca de informações e experiências e formando um grupo mais coeso em prol da qualidade da residência médica. A Coreme do HGRS, incluindo todos os seus representantes, incorpora incessantemente seu papel nas práticas educacionais promovidas na residência médica do Hospital Geral Roberto Santos a fim de fomentar iniciativas exitosas e inovadoras na instituição.

Improving medical residency academic service is essential for teaching credibility in institutions with accredited training programs for specialist physicians. This work aims to describe the past two-year experience of the academic secretariat of the Medical Residency Committee (COREME) in implementing actions aimed at promoting new reflections and knowledge about the academic structure of teaching in medical residency in a public hospital, considering its technical, political, administrative, and ethical dimensions. The organizational development of COREME in the Hospital Geral Roberto Santos (HGRS) improved satisfaction of medical professionals undertaking residency in the institution with training quality, increasing adherence to the programs while reducing transfer, withdrawal, and evasion ­ especially considering the COVID-19 pandemic period. Moreover, COREME improved interaction and integration among supervisors and preceptors, favoring the exchange of information and experiences and forming a more cohesive group in favor of the quality of medical residency. In the context of HGRS, COREME and all its representatives play a key role in the teaching promoted in medical residency, seeking to offer and incorporate innovative and successful teaching and research practices for improving teaching quality in the institution.

Mejorar el servicio académico de la residencia médica es fundamental para la credibilidad de la docencia en una institución que cuenta con programas acreditados para la formación de médicos especialistas. El objetivo de este trabajo es describir la experiencia de los últimos dos años sobre la implementación de acciones de la secretaría académica del Comité de Residencia Médica en un hospital público y promover nuevas reflexiones y conocimientos sobre la estructura académica de la docencia en la residencia médica, en sus dimensiones técnicas, políticas, administrativas y éticas. Con el desarrollo organizacional del Coreme del hospital HGRS, se logró promover una mejor satisfacción de los profesionales médicos residentes en la institución con la calidad de la capacitación, ampliando la adherencia a los programas, al tiempo que se redujo el traslado, retiro y evasión del residente, especialmente considerando el período de pandemia de Covid-19. Se mejoró la interacción e integración entre supervisores y preceptores del programa, favoreciendo el intercambio de información y experiencias, con un grupo más cohesionado a favor de la calidad de la residencia médica. El Coreme de HGRS, incluyendo todo lo que representa, incorpora su rol en las prácticas docentes impulsadas en la residencia médica del Hospital Geral Roberto Santos en una búsqueda incesante por promover, incorporar e innovar con prácticas docentes e investigadoras exitosas en beneficio de la calidad docente desarrollada en la institución.

Optimal Cutoff of the TG/HDL-c ratio for Cardiovascular Risk in Hypertensive and Diabetic Patients Monitored by Primary Health Care in a city in Minas Gerais

Abstract Background The analysis of the atherogenic potential of the lipid profile for biomarkers, such as the TG/HDL-c ratio, predicts cardiovascular risk better than isolated lipids. Objective To identify the TG/HDL-c cutoff points for multiple risks (hypertension, Diabetes Mellitus, obesity) and to evaluate the association between sociodemographic, clinical, laboratory, anthropometric, and life habit variables and the TG/HDL-c ratio in hypertensive and/or diabetic individuals in the context of Primary Health Care. Methods This was a cross-sectional study with 833 hypertensive and/or diabetic patients, conducted between August 2017 and April 2018. The cutoff point of the TG/HDL-c were obtained by the ROC curve. Cardiovascular risk was discriminated by TG/HDL-c, categorized by the cutoff and evaluated in relation to multiple risks. The magnitude of the association between TG/HDL-c and independent variables was estimated by logistic regression. The significance level of p<0.05 was adopted for all tests. Results The cutoff values of TG/HDL-c (3.26 for men and 2.72 for women) were more sensitive and less specific than those in the literature. Women (OR=1.90 and 95% CI 1.13-3.20) and men (OR=4.58 and 95% CI 1.78-11.76) with multiple risks, and white men, alcohol users, with a history of stroke, had a higher chance of altered GT/HDL-c. Increases in glycosylated hemoglobin, glycemia, and phosphorus in women, and cholesterol, glycemia, and microalbuminuria in men increased the chances of altered TG/HDL-c. Being a former smoker and black reduced the chance of altered TG/HDL-c in women. Conclusions TG/HDL-c proved to be a good indicator for habitual use in Primary Care.

Computer-aided design of 1,4-naphthoquinone-based inhibitors targeting cruzain and rhodesain cysteine proteases.

Chagas disease and Human African Trypanosomiasis (HAT) are caused by Trypanosoma cruzi and T. brucei parasites, respectively. Cruzain (CRZ) and Rhodesain (RhD) are cysteine proteases that share 70% of identity and play vital functions in these parasites. These macromolecules represent promising targets for designing new inhibitors. In this context, 26 CRZ and 5 RhD 3D-structures were evaluated by molecular redocking to identify the most accurate one to be utilized as a target. Posteriorly, a virtual screening of a library containing 120 small natural and nature-based compounds was performed on both of them. In total, 14 naphthoquinone-based analogs were identified, synthesized, and biologically evaluated. In total, five compounds were active against RhD, being three of them also active on CRZ. A derivative of 1,4-naphthoquinonepyridin-2-ylsulfonamide was found to be the most active molecule, exhibiting IC50 values of 6.3 and 1.8 µM for CRZ and RhD, respectively. Dynamic simulations at 100 ns demonstrated good stability and do not alter the targets' structures. MM-PBSA calculations revealed that it presents a higher affinity for RhD (-25.3 Kcal mol-1) than CRZ, in which van der Waals interactions were more relevant. A mechanistic hypothesis (via C3-Michael-addition reaction) involving a covalent mode of inhibition for this compound towards RhD was investigated by covalent molecular docking and DFT B3LYP/6-31 + G* calculations, exhibiting a low activation energy (ΔG‡) and providing a stable product (ΔG), with values of 7.78 and - 39.72 Kcal mol-1, respectively; similar to data found in the literature. Nevertheless, a reversibility assay by dilution revealed that JN-11 is a time-dependent and reversible inhibitor. Finally, this study applies modern computer-aided techniques to identify promising inhibitors from a well-known chemical class of natural products. Then, this work could inspire other future studies in the field, being useful for designing potent naphthoquinones as RhD inhibitors.

Conhecimento geral, atitude psicológica e sua associação com a concentração de HbA1C em pacientes portadores de Diabetes Mellitus tipo 2 / General knowledge, psychological attitude and its association with the concentration of HbA1C in patients with Type 2 Diabetes Mellitus

Objetivo: Diabetes mellitus (DM) é uma doença relacionada a várias complicações e alta morbimortalidade, com comprometimento significativo da qualidade de vida do paciente, afetando sua saúde física e mental, bem como sua motivação ao autocuidado. Este estudo objetivou avaliar o conhecimento geral e a atitude psicológica para o DM, correlacionando a concentração de hemoglobina glicada (HbA1C) com escores do DKN-A e ATT-19 de pacientes portadores de DM tipo 2 (DM2). Métodos: Estudo observacional transversal com amostra de 65 participantes, 24,6% homens e 75,4% mulheres, com idade média de 57±12, avaliados entre novembro/2016 e fevereiro/2017. A avaliação do conhecimento geral e da atitude psicológica para o DM foi realizada pela aplicação do Diabetes Knowledge Questionnaire (DKN-A) e do Diabetes Attitude Questionnaire (ATT-19). O SPSS 20.0 foi utilizado para as análises estatísticas. Resultados: Para os escores de conhecimento (r=0,005; p=0,966) e de atitude (r=0,034; p=0,790) não houve correlação significante com a HbA1C, sendo que (94%) dos pacientes não atingiram o ponto de corte do ATT-19. Considerando o grupo com pontuação >8 para o escore de conhecimento, foi observada diferença negativa e significativa entre este escore e o de atitude (r=-0,444; p=0,0018). Conclusão: O conhecimento em relação à doença não traduziu em melhor controle da glicemia na população estudada, sugerindo que o controle eficiente da HbA1C não depende exclusivamente do conhecimento sobre a doença, mas sim de diversos outros fatores, que também precisam ser considerados na conduta do DM2.

Objective: Diabetes mellitus (DM) is a disease related to several complications and high morbidity and mortality, with significant impairment of the patient's quality of life, affecting his physical and mental health, as well as his motivation to self-care. The aim of this study was to evaluate the knowledge and attitude about type 2 DM (DM2) in its patients, correlating Diabetes Knowledge Questionnaire (DKN-A) and Diabetes Attitudes Questionnaire (ATT-19) scores with the concentration of glycated hemoglobin (HbA1c). Methods: Cross-sectional observational study with a sample of 65 participants, 24.6% male and 75.4% female, with a mean age of 57 ± 12, with low schooling, between November / 2016 and February / 2017. The evaluation of the knowledge and attitude about DM was carried out by the application of the DKN-A and ATT-19. SPSS 20.0 was used for statistical analysis. Results: There were no statistically significant correlations with HbA1c (r = 0.005, p = 0.966) and attitude (r = 0.034, p = 0.790), and 61 patients (94%) did not reach the cutoff point of ATT-19. Considering the group with scores higher than 8 points for the knowledge score, a negative and significant correlation was observed between this score and the attitude score (r = -0.444; p = 0.0018). Conclusion: Knowledge and attitude towards the disease did not translate into better glycemic control in the study population. The efficient control of HbA1c is multifactorial, involving genetic, comorbid, behavioral, drugs, health services, among others, that should be considered in the conduct.

Subclinical atherosclerosis in children and adolescents with congenital heart disease.

BACKGROUND: Subclinical atherosclerosis in childhood can be evaluated by carotid intima-media thickness, which is considered a surrogate marker for atherosclerotic disease in adulthood. The aims of this study were to evaluate carotid intima-media thickness and, to investigate associated factors. METHODS: Cross-sectional study with children and adolescents with congenital heart disease (CHD). Socio-demographic and clinical characteristics were assessed. Subclinical atherosclerosis was evaluated by carotid intima-media thickness. Cardiovascular risk factors, such as physical activity, screen time, passive smoke, systolic and diastolic blood pressure, waist circumference, dietary intake, lipid parameters, glycaemia, and C-reactive protein, were also assessed. Factors associated with carotid intima-media thickness were analysed using multiple logistic regression. RESULTS: The mean carotid intima-media thickness was 0.518 mm and 46.7% had subclinical atherosclerosis (carotid intima-media thickness ≥ 97th percentile). After adjusting for confounding factors, cyanotic CHD (odds ratio: 0.40; 95% confidence interval: 0.20; 0.78), cardiac surgery (odds ratio: 3.17; 95% confidence interval: 1.35; 7.48), and be hospitalised to treat infections (odds ratio: 1.92; 95% confidence interval: 1.04; 3.54) were associated with subclinical atherosclerosis. CONCLUSION: Clinical characteristics related to CHD were associated with subclinical atherosclerosis. This finding suggests that the presence of CHD itself is a risk factor for subclinical atherosclerosis. Therefore, the screen and control of modifiable cardiovascular risk factors should be made early and intensively to prevent atherosclerosis.

M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity.

A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or ß-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or ß-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.

Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD) remains a major clinical drawback of allogeneic hematopoietic stem cell transplantation (HSCT). Here, we investigated how the stress responsive heme catabolizing enzyme heme oxygenase-1 (HO-1, encoded by HMOX1) regulates GVHD in response to allogeneic hematopoietic stem cell transplantation in mice and humans. We found that deletion of the Hmox1 allele, specifically in the myeloid compartment of mouse donor bone marrow, promotes the development of aggressive GVHD after allogeneic transplantation. The mechanism driving GVHD in mice transplanted with allogeneic bone marrow lacking HO-1 expression in the myeloid compartment involves enhanced T cell alloreactivity. The clinical relevance of these observations was validated in two independent cohorts of HSCT patients. Individuals transplanted with hematopoietic stem cells from donors carrying a long homozygous (GT)n repeat polymorphism (L/L) in the HMOX1 promoter, which is associated with lower HO-1 expression, were at higher risk of developing severe acute GVHD as compared to donors carrying a short (GT)n repeat (S/L or S/S) polymorphism associated with higher HO-1 expression. In this study, we showed the unique importance of donor-derived myeloid HO-1 in the prevention of lethal experimental GVHD and we corroborated this observation by demonstrating the association between human HMOX1 (GT)n microsatellite polymorphisms and the incidence of severe acute GVHD in two independent HSCT patient cohorts. Donor-derived myeloid HO-1 constitutes a potential therapeutic target for HSCT patients and large-scale prospective studies in HSCT patients are necessary to validate the HO-1 L/L genotype as an independent risk factor for developing severe acute GVHD.

Renal control of disease tolerance to malaria.

Malaria, the disease caused by Plasmodium spp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that kill Plasmodium However, these mechanisms are not sufficient per se to avoid the development of severe forms of disease. This is accomplished instead via the establishment of disease tolerance to malaria, a defense strategy that does not target Plasmodium directly. Here we demonstrate that the establishment of disease tolerance to malaria relies on a tissue damage-control mechanism that operates specifically in renal proximal tubule epithelial cells (RPTEC). This protective response relies on the induction of heme oxygenase-1 (HMOX1; HO-1) and ferritin H chain (FTH) via a mechanism that involves the transcription-factor nuclear-factor E2-related factor-2 (NRF2). As it accumulates in plasma and urine during the blood stage of Plasmodium infection, labile heme is detoxified in RPTEC by HO-1 and FTH, preventing the development of acute kidney injury, a clinical hallmark of severe malaria.