Abstract Background Fibroblast-like synoviocytes (FLS) play a prominent role in rheumatoid synovitis and degradation of the extracellular matrix through the production of inflammatory cytokines and metalloproteinases (MMPs). Since animal models are frequently used for elucidating the disease mechanism and therapeutic development, it is relevant to study the ultrastructural characteristics and functional responses in human and mouse FLS. The objective of the study was to analyze ultrastructural characteristics, Interleukin-6 (IL-6) and Metalloproteinase-3 (MMP-3) production and the activation of intracellular pathways in Fibroblast like synoviocytes (FLS) cultures obtained from patients with rheumatoid arthritis (RA) and from mice with collagen-induced arthritis (CIA). Methods FLSs were obtained from RA patients (RA-FLSs) (n = 8) and mice with CIA (CIA-FLSs) (n = 4). Morphology was assessed by transmission and scanning electron microscopy. IL-6 and MMP-3 production was measured by ELISA, and activation of intracellular signaling pathways (NF-κB and MAPK: p-ERK1/2, p-P38 and p-JNK) was measured by Western blotting in cultures of RA-FLSs and CIA-FLSs stimulated with tumor necrosis factor-alpha (TNF-α) and IL-1β. Results RA-FLS and CIA-FLS cultures exhibited rich cytoplasm, rough endoplasmic reticula and prominent and well- developed Golgi complexes. Transmission electron microscopy demonstrated the presence of lamellar bodies, which are cytoplasmic structures related to surfactant production, in FLSs from both sources. Increased levels of pinocytosis and numbers of pinocytotic vesicles were observed in RA-FLSs (p < 0.05). Basal production of MMP-3 and IL-6 was present in RA-FLSs and CIA-FLSs. Regarding the production of MMP-3 and IL-6 and the activation of signaling pathways, the present study demonstrated a lower response to IL-1β by CIA-FLSs than by RA-FLSs. Conclusion This study provides a comprehensive understanding of the biology of RA-FLS and CIA-FLS. The differences and similarities in ultrastructural morphology and important inflammatory cytokines shown, contribute to future in vitro studies using RA-FLS and CIA-FLS, in addition, they indicate that the adoption of CIA-FLS for studies should take careful and be well designed, since they do not completely resemble human diseases. Fibroblastlike FLS (FLS MMPs. MMPs . (MMPs) development Interleukin6 Interleukin 6 Interleukin- IL6 IL (IL-6 Metalloproteinase3 Metalloproteinase 3 Metalloproteinase- MMP3 MMP (MMP-3 (RA collageninduced collagen induced CIA. (CIA) RAFLSs (RA-FLSs n 8 CIAFLSs (CIA-FLSs 4. 4 4) IL- MMP- ELISA NFκB NF κB MAPK pERK1/2, pERK12 pERK p ERK1/2, ERK1 2 ERK p-ERK1/2 pP38 pP P38 P p-P3 pJNK JNK p-JNK factoralpha factor alpha TNFα TNF α (TNF-α IL1β. IL1β ILβ 1β. 1β β RAFLS CIAFLS cytoplasm complexes bodies sources 0.05. 005 0.05 0 05 0.05) CIAFLSs. FLSs. RAFLSs. CIAFLS. shown CIAFLS, FLS, addition designed diseases (MMPs (IL- (MMP- (CIA pERK1 pERK1/2 ERK12 ERK1/2 p-ERK1/ pP3 P3 p-P 00 0.0 (IL (MMP pERK1/ ERK1/ p-ERK1 0. p-ERK

Resumo Fundamento A Sociedade Brasileira de Cardiologia promove anualmente a prova para obtenção do título de especialista em Cardiologia, sendo a Comissão Julgadora do Título de Especialista em Cardiologia responsável pela sua organização e aplicação. A análise psicométrica dos itens de uma prova, por meio da Teoria de Resposta ao Item (TRI) pode fornecer informações robustas e contribuir para o aprimoramento contínuo dessa avaliação. Objetivos Avaliar as propriedades psicométricas da prova do Título de Especialista em Cardiologia no ano de 2019, em relação aos parâmetros da TRI. Métodos Estudo observacional, com a análise psicométrica das 120 questões da prova realizada por 1120 (mil cento e vinte) candidatos para a obtenção do título de especialista em Cardiologia, no ano de 2019. Resultados A análise da prova pela TRI mostrou 32,2% dos itens com poder de discriminação “alto” ou “muito alto”, 49,2% dos itens categorizados como “fácil” ou “muito fácil” e 41,5% apresentavam alta probabilidade de acerto ao acaso . Foram identificados 69 itens com problemas em relação aos parâmetros da TRI e, portanto, com baixo poder de avaliar a proficiência do candidato. Conclusões A análise psicométrica da prova de título de Especialista em Cardiologia pela TRI demonstrou um alto percentual de questões fáceis, com cerca de dois terços dos itens com alta probabilidade de acerto ao acaso. Esses dados poderão desencadear uma série de discussões e propostas para a construção das futuras provas em cardiologia.

Abstract Background The Cardiology Certification Exam is issued annually by the Brazilian Cardiology Society and set and applied by the Judging Committee for the Cardiologist Title (CJTEC). The psychometric analysis of the exam items using the Item Response Theory (IRT) may provide robust data that can help in the continuous improvement of this instrument. Objectives To evaluate the psychometric properties of the 2019 Cardiology Certification Exam in relation to the IR parameters. Methods This was an observational study, with psychometric analysis of the 120 questions of the exam taken by 1,120 candidates for the title of Cardiologist in 2019. Results The IRT analysis revealed that 32.2% of the items had a “high” or “very high” discriminating power, 49.2% were categorized as “easy” or “very easy”, and 41.5% showed a high probability of a correct guessing. Sixty-nine deficient items in terms of the IRT parameters were identified, which were then considered poorly effective in evaluating the candidate’s ability. Conclusions The psychometric analysis of the 2019 Cardiology Certification Exam by the IRT revealed a high percentage of easy questions, with nearly two thirds of the items with a high probability of correct guessing. These data may serve as a basis for a series of discussions and proposals for the elaboration of future certificate exams in Cardiology.

Abstract The EPAs approach has had a great impact on medical education since it emerged in 2005. Its dissemination has required translation into several languages, sometimes generating terminological and meaning confusion. This paper is the result of an expert consensus procedure regarding the translation of key terms for understanding the EPA approach in Spanish and Portuguese. It was carried out through a process of meaning analysis of each term in its idiomatic context and of the practice of health professionals training in Latin America. Participated on this consensus by twelve professionals, teachers and scholars involved in the implementation and training with EPAs in eight countries, who participated as coordinator, facilitators or participants in the International Course Ins and Outs of EPAs for Latin America.

Resumen El enfoque de EPAs ha tenido un gran impacto en la educación médica desde que surgió en 2005. Su difusión a través de diferentes regiones del mundo ha requerido traducción a varios idiomas, y en algunas ocasiones ha generado confusiones terminológicas y de significado. Este artículo es el resultado de un consenso respecto de la traducción de términos clave para la comprensión del enfoque en español y portugués. Se llevó a cabo a través de un proceso de análisis de significado de cada término en el contexto idiomático y de la realidad de la formación de profesionales de la salud en Latinoamérica. Estuvo a cargo de doce profesionales, docentes y académicos involucrados en la implementación y formación con EPAs en ocho países, que formaron parte como responsables, facilitadores o participantes del International Course Ins and Outs of EPAs 2021 para Latinoamérica.

Abstract Background: Rheumatoid arthritis is a risk factor for early mortality due to cardiovascular disease. Interleukin-33 appears to protect against the development of atherosclerosis. The purpose of this study was to investigate the relationship between serum levels of interleukin-33 and its soluble receptor with the presence of subclinical carotid atherosclerosis in rheumatoid arthritis patients. Methods: Rheumatoid arthritis patients without atherosclerotic disease were subjected to clinical and laboratory assessments, including carotid ultrasound. Interleukin-33 and its soluble receptor serum levels were measured by ELISA. Results: 102 patients were included. The prevalence of carotid plaques was 23.5% and the median intima-media thickness was 0.7 mm. The median interleukin-33 and its soluble receptor concentration was 69.1 and 469.8 pg/ml. No association was found between serum interleukin-33 or its soluble receptor and intima-media thickness or plaque occurrence. Each 0.1 mm increase of intima-media thickness raised the odds of plaque occurrence by 5.3-fold, and each additional year of rheumatoid arthritis duration increased the odds of plaque occurrence by 6%. Each additional year in patients age and each one-point increase in the Framingham Risk Score were associated with a 0.004 mm and 0.012 mm increase in intima-media thickness. Methotrexate use was associated with a 0.07 mm reduction in intima-media thickness. Conclusions: Interleukin-33 and its soluble receptor were not associated with subclinical atherosclerosis. Traditional risk factors for atherosclerosis and rheumatoid arthritis duration were associated with intima-media thickness and plaque occurrence; methotrexate use was associated with a lower intima-media thickness.

Resumo Fundamento: Distúrbios trombóticos permanecem como uma das principais causas de morte no mundo ocidental. A dabigatrana surgiu como alternativa à varfarina para a anticoagulação no tratamento da fibrilação atrial (FA). O risco associado a eventos hemorrágicos com a sua utilização foi documentado em vários ensaios clínicos randomizados, mas nenhum grande estudo analisou detalhadamente o risco de hemorragia durante a extração dentária e em outros procedimentos odontológicos que envolvam sangramentos. Objetivo: Em indivíduos submetidos a procedimentos odontológicos, avaliar a intensidade de sangramento com o uso de dabigatrana em comparação ao uso de anticoagulante oral antagonista da vitamina K (varfarina). Métodos: Estudo prospectivo, controlado, unicêntrico, observador único. Pacientes com diagnóstico de FA não valvar atendidos em um centro de referência em cardiologia e com indicação de anticoagulação que necessitavam de tratamento odontológico para exodontia única ou múltipla, estando em uso de varfarina ou dabigatrana e avaliados até sete dias pós-exodontia. Foram avaliados os efeitos sobre: tempo de sangramento entre o início e o fim da sutura e hemostasia completa; sangramento antes do procedimento, após 24 e 48 horas, 7 dias, durante e após a remoção da sutura (tardio), sendo considerado como estatisticamente significativo valor de p < 0,05. Resultados: Foram avaliados 37 indivíduos, sendo 25 no grupo varfarina e 12 no dabigatrana. Idade, sexo, peso, altura, pressão arterial, cor, escolaridade, renda familiar e comorbidades foram semelhantes nos dois grupos. Em relação ao sangramento 24 horas após o procedimento, ninguém do grupo dabigatrana apresentou sangramento, que esteve presente em 32% do grupo varfarina (p = 0,028). Não houve diferenças entre os grupos em relação às outras variáveis analisadas. Conclusões: Os dados deste estudo permitem sugerir que, em indivíduos submetidos a procedimento odontológico de exodontia, não há diferença estatisticamente significante na intensidade de sangramento em uso de dabigatrana em comparação ao uso de varfarina. Há uma menor frequência de sangramento 24 horas após o procedimento nos indivíduos em uso de dabigatrana.

Abstract Background: Thrombotic disorders remain one of the leading causes of death in the Western world. Dabigatran appeared as an alternative to warfarin for anticoagulation in the treatment of atrial fibrillation (AF). The risk associated with bleeding due to its use has been documented in several randomized clinical trials, but no large study has examined in detail the risk of bleeding during dental extraction and other dental procedures involving bleeding. Objective: To compare the intensity of bleeding in individuals taking dabigatran or vitamin K antagonist (warfarin) and undergoing dental procedures. Methods: Prospective, single-center, controlled study with one single observer. Patients diagnosed with nonvalvular AF, on warfarin or dabigatran, cared for at a cardiology referral center, and requiring single or multiple dental extractions, were evaluated up to seven days post-extraction. The following outcomes were assessed: bleeding time between the beginning and the end of suture and complete hemostasis; bleeding before the procedure, after 24 hours, 48 hours, 7 days, during and after suture removal (late); p<0.05 was defined as of statistical relevance. Results: We evaluated 37 individuals, 25 in the warfarin group and 12 in the dabigatran group. Age, sex, weight, height, blood pressure, color, schooling, family income and comorbidities were similar between the two groups. Regarding bleeding after 24 hours of the procedure, no one in the dabigatran group had bleeding, whereas 32% in the warfarin group had documented bleeding (p = 0.028). The other variables analyzed did not differ between the groups. Conclusions: This study suggests that, regarding dental extraction, there is no statistically significant difference in the intensity of bleeding of patients taking dabigatran as compared to those taking warfarin. Bleeding 24 hours after the procedure was less frequent among patients on dabigatran.

RESUMO A melhor compreensão dos mecanismos inflamatórios da artrite reumatoide e o desenvolvimento da terapia biológica revolucionaram o tratamento da doença, permitindo uma interferência no ciclo sinovite–dano estrutural–incapacidade funcional. A interleucina 33 foi recentemente descrita como um novo membro da família da interleucina 1, cuja característica comum é a atividade pró-inflamatória. Por estar envolvida na patogênese de uma grande variedade de doenças, incluindo doenças autoimunes, a interleucina 33 começa a ser estudada na doença reumatoide. Ela tem sido avaliada em modelos experimentais de artrite, no soro, no líquido e membrana sinoviais de pacientes com artrite reumatoide. Demonstrou-se que a administração da interleucina 33 exacerba a artrite induzida por colágeno em modelos experimentais, e concentrações dessa citocina no soro e no líquido sinovial de pacientes com artrite reumatoide correlacionaram-se positivamente com a atividade da doença. Esse manuscrito apresenta a interleucina 33 e discute as evidências do seu papel em diferentes doenças, com ênfase na artrite reumatoide.

ABSTRACT A better understanding of the inflammatory mechanisms of rheumatoid arthritis and the development of biological therapy revolutionized its treatment, enabling an interference in the synovitis – structural damage – functional disability cycle. Interleukin 33 was recently described as a new member of the interleukin-1 family, whose common feature is its pro-inflammatory activity. Its involvement in the pathogenesis of a variety of diseases, including autoimmune diseases, raises the interest in the possible relationship with rheumatoid arthritis. Its action has been evaluated in experimental models of arthritis as well as in serum, synovial fluid and membrane of patients with rheumatoid arthritis. It has been shown that the administration of interleukin-33 exacerbates collagen-induced arthritis in experimental models, and a positive correlation between cytokine concentrations in serum and synovial fluid of patients with rheumatoid arthritis and disease activity was found. This review discusses evidence for the role of interleukin-33 with a focus on rheumatoid arthritis.

PURPOSE: To investigate hemostatic effects of supplementary factor XIII and desmopressin (DDAVP) in resuscitation of uncontrolled bleeding.METHODS:Fifty-four rabbits were randomized in nine groups: G1: Sham; G2: FXIII and normotensive resuscitation (NBP); G3: FXIII and permissive hypotension (PH) (MAP 60% baseline); G4: FXIII/DDAVP/NBP; G5: FXIII/DDAVP/PH; G6: NBP only; G7: FXIII no hemorrhage; G8: FXIII/DDAVP no hemorrhage; G9: PH only. Thromboelastometry and intra-abdominal blood loss were assessed. Scanning electron microscopy (EM) of the clots was performed.RESULTS: Compared to Sham, only G8 (FXIII/DDAVP w/o hemorrhage) showed clotting time (CT) significantly lower (p<0.05). NBP alone (G6) resulted in significantly prolonged CT compared to G2, G3 and G5 (p<0.05). Similarly, median alpha angle was significantly larger in G3,4,5, and 9 compared to G6 (p<0.05). Area under the curve was significantly greater in G5 than G2. Intra-abdominal blood loss was lower in G5 and G9 compared to G2 and G6. FXIII/DDAVP and PH resulted in more robust fibrin mesh by EM.CONCLUSIONS: Normotensive resuscitation provokes more bleeding and worsens coagulation compared to pH, that is partially reversed by factor XIII and desmopressin. FXIII and DDAVP can synergistically improve coagulation. Permissive hypotension reduces bleeding regardless of those agents.

This work sought to evaluate the ability of fungi Phanerochaete chryosporium to degrade congo red azo dye in batch reactor, evaluate the influence of glucose and wheat bran as co-substrates on the removal of the dye in the medium and investigate the influence of ammonium chloride, ammonium nitrate and ammonium sulfate as the inorganic nitrogen source for the process. Wheat bran was not effective satisfactorily for the removal of dye and organic matter had no desired effect for the removal of color and organic matter and showed the lowest values of k2, 0.008 M-1.d-1and 0.0004 M-1.d-1, respectively. Glucose presented the best response with the highest final percentage of dye removal (97%) and rate of dye removal (0.017 M-1.d-1), without adding an external source of nitrogen.

OBJETIVO: Avaliar efeitos precoces do transplante de células de medula óssea para o miocárdio de pacientes com insuficiência cardíaca (IC) de etiologia chagásica. MÉTODOS: A amostra consistiu de 28 pacientes, idade média 52,2±9,9 anos, 24 masculinos, 25 em classe NYHA III e 3 em NYHA IV, apesar de tratamento otimizado. O procedimento consistiu na aspiração de 50ml de medula óssea, separação da fração mononuclear e injeção intracoronariana. Foram avaliados os efeitos sobre a fração de ejeção ventricular esquerda (FEVE), distância no teste de 6 minutos, qualidade de vida, classe NYHA, efeitos arritmogênicos e bioquímicos. RESULTADOS: Não houve complicações relacionadas diretamente ao procedimento. A fração de ejeção ventricular esquerda em repouso antes do transplante era 20,1±6,8% e, após 60 dias, aumentou para 23,0±9,0%, p = 0,02. Houve melhora da classe NYHA (3,1±0,3 para 1,8±0,5; p<0.0001); qualidade de vida (50,9±11,7 para 21,8±13,4; p<0.0001); distância caminhada (355±136 m para 443±110 m; p = 0,003). O número de extrassístoles ventriculares em 24h apresentou tendência à elevação (5.322±4.977 para 7.441±7.955; p = 0,062), porém sem incremento dos episódios de taquicardia ventricular (61±127 para 54±127; p = 0,27). CONCLUSÃO: Nossos dados demonstram que a injeção intracoronariana de células mononucleares da medula óssea é exeqüível e sugere ser potencialmente segura e eficaz em pacientes com IC de etiologia chagásica.

OBJECTIVE: To evaluate early effects of bone marrow cell transplantation to the myocardium of patients with heart failure (CHF) due to Chagas disease. METHODS: We studied 28 patients (mean age 52.2 ± 9.9), of whom 24 were male. Despite optimized treatment, 25 patients were in NYHA class III and three patients, in NYHA class IV. The procedure consisted of aspiration of 50 mL of bone marrow, separation of the mononuclear fraction, and intracoronary injection. Effects on left ventricle ejection fraction (LVEF), distance walked in the six-minute walking test, quality-of-life, NYHA class, arrhythmogenic and biochemical parameters, were all evaluated. RESULTS: There were no complications directly related to the procedure. Baseline left ventricular ejection fraction was 20.1 ± 6.8%, and 60 days after transplantation it increased to 23.0 ± 9.0%, p = 0.02. Significant improvements were observed in the NYHA class (3.1 ± 0.3 to 1.8 ± 0.5; p < 0.0001); quality-of-life (50.9 ± 11.7 to 21.8 ± 13.4; p < 0.0001); and distance walked in six minutes (355 ± 136 m to 443 ± 110 m; p = 0,003). The number of ventricular premature beats in 24 hours tended to increase (5,322 ± 4,977 to 7,441 ± 7,955; p = 0,062), but without increase in ventricular tachycardia episodes (61 ± 127 to 54 ± 127; p = 0.27). CONCLUSION: Our data demonstrate for the first time that intracoronary injection of bone marrow mononuclear cells is feasible and suggest that it may be potentially safe and effective in patients with CHF due to Chagas disease.

OBJETIVO: A toxina de escorpião purificada do veneno do escorpião Tityus serrulatus (Tx) induz um aumento no volume, acidez e secreção de pepsina no suco gástrico de ratos. A ligadura do esôfago diminui a secreção ácida do estômago em ratos. O objetivo deste trabalho foi determinar a influência da ligadura do esôfago sobre a secreção gástrica induzida pela Tx em ratos. MÉTODOS: 44 ratos machos, brancos foram administrados água ad libitum, mas não alimentados por 20 a 24 horas, anestesiados com uretana e canulados a traquéia e a veia jugular. Foram realizadas as ligaduras do esôfago cervical ou abdominal ou operações simuladas antes e após a administração na veia jugular de 0,25 mg/kg de toxina de escorpião (fração T1). Uma hora após foram determinados o volume, acidez, pH e atividade péptica do suco gástrico. RESULTADOS: A toxina de escorpião induziu um aumento do volume do suco gástrico, da acidez gástrica e da produção de pepsina e uma diminuição do pH quando injetada na veia de animais não operados ou com operação simulada. A ligadura do esôfago cervical não interferiu nos efeitos da toxina, enquanto a ligadura do esôfago abdominal diminuiu os efeitos da toxina no estômago do rato. CONCLUSÃO: A ligadura do esôfago abdominal diminui a secreção gástrica estimulada pela toxina de escorpião.

PURPOSE: Scorpion toxin purified from Tityus serrulatus venom (Tx) induces an increase in volume, acidity and pepsin secretion in the gastric juice of rats. Ligation of oesophagus has been shown to reduce the acid gastric secretion in rats. The aim of this paper was to determine the influence of the esophageal ligation on gastric secretion induced by Tx in rats METHODS: Forty-four male albino rats were given water ad libitum, but no food for 20 to 24 hours, anesthetized with urethane and the trachea and jugular vein cannulated. Cervical or abdominal esophageal ligation or sham-operations were performed before and after the injection of 0.25 mg/kg of scorpion toxin (fraction T1) into the jugular vein. One hour later, the volume, acidity, pH and peptic activity of gastric juice were determined. RESULTS: The scorpion toxin induced an increase in gastric juice volume, acidity and pepsin output and a decrease in pH when injected into the vein of intact animals or in sham-operated animals. Cervical esophagus ligation did not interfere with the effects of toxin, however, ligation of the abdominal esophageal decreased the toxin effect on the rat stomach. CONCLUSION: Ligation of the abdominal esophagus decreases the gastric secretion induced by scorpion toxin.