TNF blockers alone and associated with Benznidazole impact in vitro cytokine dynamics in chronic Chagas disease.

Studies involving the immune response in Chagas disease suggest an imbalance in the immune response of symptomatic patients, with an inflammatory profile dominating in Chagas heart disease, mainly by tumour necrosis factor (TNF). TNF is considered a key cytokine in immunopathology in chronic carriers in several processes during the immune response. Our work aimed to evaluate regulatory (interleukin [IL]-4 and IL-10) and inflammatory (TNF, interferon-gamma [IFN-γ], IL-2 and IL-6) cytokines in peripheral blood mononuclear cells culture supernatants. of affected patients with undetermined clinical forms-IND (n = 13) mild heart form-CARD1 (n = 13) and severe cardiac form-CARD2 (n = 16), treated in vitro with two TNF blockers, Adalimumab (ADA) and Etanercept (ETA) alone or in association with Benznidazole (BZ). The results indicate that ADA was more competent in blocking TNF (compared to ETA) in all groups but with much lower levels in the CARD2 group. ETA statistically decreased TNF levels only in the CARD2 group. IFN-γ increased in the CARD2 group after treatment with ETA relative to ADA. IL-4 had its levels decreased when treated by both drugs. IL-2 was detected in cells from CARD2 carriers compared to the NEG group after treatment with both drugs. The association with BZ decreased levels of IL-2/TNF and increased IL-4. These data reinforce the participation of TNF in severe Chagas heart disease and bring perspectives on using these blockers in the immunological treatment of Chagas disease since the use of BZ is extremely limited in these patients.

Exploring the Chagas disease-Stroke 'Connection': Findings from a Large Multicenter Study.

INTRODUCTION: Strokes are traditionally attributed to risk factors like aging, hypertension, diabetes, and atherosclerosis. Chagas disease has emerged as an important risk factor for stroke in Latin American. Our study aims at describing the largest cohort of patients with Chagas disease and ischemic stroke and determining variables associated with stroke recurrence and cardioembolic cause. METHODS: This study is the result of a national multicenter cohort study conducted in Brazil. The study spanned from January 2009 to December 2016 and involved a comprehensive retrospective analysis of medical records of patients with both Chagas disease and stroke. This cohort comprised 499 individuals from diverse Brazilian regions, focusing on vascular risk factors and the epidemiological variables associated with Chagas disease and stroke. RESULTS: Our findings underscore the significant prevalence of traditional vascular risk factors among Chagas disease patients who had stroke. 81% of patients had hypertension, 56% dyslipidemia and 25% diabetes. We observed a 29.7% recurrence rate, especially within the cardioembolic subgroup. 56% of the patients had embolic stroke of undetermined source (ESUS). Specific EKG abnormalities were associated with an increased risk of cardioembolic etiology (with three altered results increasing 81fold the chance of the stroke being of cardioembolic nature). Age emerged as a protective factor (OR:0.98, CI 0.970 - 0.997) against cardioembolic etiology. Anticoagulation therapy was associated with reduced risk (OR:0.221 |CI 0.104 - 0.472), highlighting the importance of accurate etiological classification. Conversely, female gender(OR:1.83 CI 1.039 - 3.249) emerged as a significant risk factor for stroke recurrence. CONCLUSION: This study significantly advances our epidemiological understanding of the intersection between Chagas disease and stroke. It emphasizes the critical need for extensive epidemiological investigations, a deeper comprehension of stroke recurrence determinants, and accurate etiological classification to reduce the ESUS population. Our findings have substantial clinical implications, suggesting the need of control of vascular risk factors and comorbidities and hold promise for improving patient care and reducing the burden of Chagas disease and stroke worldwide.

Guideline of the Brazilian Society of Cardiology on Diagnosis and Treatment of Patients with Chagas Disease Cardiomyopathy / Diretriz da Sociedade Brasileira de Cardiologia sobre Diagnóstico e Tratamento de Pacientes com Cardiomiopatia da Doença de Chagas

This guideline aimed to update the concepts and formulate the standards of conduct and scientific evidence that support them, regarding the diagnosis and treatment of the Cardiomyopathy of Chagas disease, with special emphasis on the rationality base that supported it.  Chagas disease in the 21st century maintains an epidemiological pattern of endemicity in 21 Latin American countries. Researchers and managers from endemic and non-endemic countries point to the need to adopt comprehensive public health policies to effectively control the interhuman transmission of T. cruzi infection, and to obtain an optimized level of care for already infected individuals, focusing on diagnostic and therapeutic opportunistic opportunities.   Pathogenic and pathophysiological mechanisms of the Cardiomyopathy of Chagas disease were revisited after in-depth updating and the notion that necrosis and fibrosis are stimulated by tissue parasitic persistence and adverse immune reaction, as fundamental mechanisms, assisted by autonomic and microvascular disorders, was well established. Some of them have recently formed potential targets of therapies.  The natural history of the acute and chronic phases was reviewed, with enhancement for oral transmission, indeterminate form and chronic syndromes. Recent meta-analyses of observational studies have estimated the risk of evolution from acute and indeterminate forms and mortality after chronic cardiomyopathy. Therapeutic approaches applicable to individuals with Indeterminate form of Chagas disease were specifically addressed. All methods to detect structural and/or functional alterations with various cardiac imaging techniques were also reviewed, with recommendations for use in various clinical scenarios. Mortality risk stratification based on the Rassi score, with recent studies of its application, was complemented by methods that detect myocardial fibrosis.  The current methodology for etiological diagnosis and the consequent implications of trypanonomic treatment deserved a comprehensive and in-depth approach. Also the treatment of patients at risk or with heart failure, arrhythmias and thromboembolic events, based on pharmacological and complementary resources, received special attention. Additional chapters supported the conducts applicable to several special contexts, including t. cruzi/HIV co-infection, risk during surgeries, in pregnant women, in the reactivation of infection after heart transplantation, and others.     Finally, two chapters of great social significance, addressing the structuring of specialized services to care for individuals with the Cardiomyopathy of Chagas disease, and reviewing the concepts of severe heart disease and its medical-labor implications completed this guideline.

Esta diretriz teve como objetivo principal atualizar os conceitos e formular as normas de conduta e evidências científicas que as suportam, quanto ao diagnóstico e tratamento da CDC, com especial ênfase na base de racionalidade que a embasou. A DC no século XXI mantém padrão epidemiológico de endemicidade em 21 países da América Latina. Investigadores e gestores de países endêmicos e não endêmicos indigitam a necessidade de se adotarem políticas abrangentes, de saúde pública, para controle eficaz da transmissão inter-humanos da infecção pelo T. cruzi, e obter-se nível otimizado de atendimento aos indivíduos já infectados, com foco em oportunização diagnóstica e terapêutica. Mecanismos patogênicos e fisiopatológicos da CDC foram revisitados após atualização aprofundada e ficou bem consolidada a noção de que necrose e fibrose sejam estimuladas pela persistência parasitária tissular e reação imune adversa, como mecanismos fundamentais, coadjuvados por distúrbios autonômicos e microvasculares. Alguns deles recentemente constituíram alvos potenciais de terapêuticas. A história natural das fases aguda e crônica foi revista, com realce para a transmissão oral, a forma indeterminada e as síndromes crônicas. Metanálises recentes de estudos observacionais estimaram o risco de evolução a partir das formas aguda e indeterminada e de mortalidade após instalação da cardiomiopatia crônica. Condutas terapêuticas aplicáveis aos indivíduos com a FIDC foram abordadas especificamente. Todos os métodos para detectar alterações estruturais e/ou funcionais com variadas técnicas de imageamento cardíaco também foram revisados, com recomendações de uso nos vários cenários clínicos. Estratificação de risco de mortalidade fundamentada no escore de Rassi, com estudos recentes de sua aplicação, foi complementada por métodos que detectam fibrose miocárdica. A metodologia atual para diagnóstico etiológico e as consequentes implicações do tratamento tripanossomicida mereceram enfoque abrangente e aprofundado. Também o tratamento de pacientes em risco ou com insuficiência cardíaca, arritmias e eventos tromboembólicos, baseado em recursos farmacológicos e complementares, recebeu especial atenção. Capítulos suplementares subsidiaram as condutas aplicáveis a diversos contextos especiais, entre eles o da co-infecção por T. cruzi/HIV, risco durante cirurgias, em grávidas, na reativação da infecção após transplante cardíacos, e outros.    Por fim, dois capítulos de grande significado social, abordando a estruturação de serviços especializados para atendimento aos indivíduos com a CDC, e revisando os conceitos de cardiopatia grave e suas implicações médico-trabalhistas completaram esta diretriz. 

How people affected by Chagas disease have struggled with their negligence: history, associative movement and World Chagas Disease Day.

It is well documented that Chagas disease (CD) can pose a public health problem to countries. As one of the World Health Organization Neglected Tropical Diseases undoubtedly calls for comprehensive healthcare, transcending a restricted biomedical approach. After more than a century since their discovery, in 1909, people affected by CD are still frequently marginalised and/or neglected. The aim of this article is to tell the story of their activism, highlighting key historical experiences and successful initiatives, from 1909 to 2019. The first association was created in 1987, in the city of Recife, Brazil. So far, thirty associations have been reported on five continents. They were created as independent non-profit civil society organisations and run democratically by affected people. Among the common associations' objectives, we notably find: increase the visibility of the affected; make their voice heard; build bridges between patients, health system professionals, public health officials, policy makers and the academic and scientific communities. The International Federation of Associations of People Affected by CD - FINDECHAGAS, created in 2010 with the input of the Americas, Europe and the Western Pacific, counts as one of the main responses to the globalisation of CD. Despite all the obstacles and difficulties encountered, the Federation has thrived, grown, and matured. As a result of this mobilisation along with the support of many national and international partners, in May 2019 the 72nd World Health Assembly decided to establish World Chagas Disease Day, on 14 April. The associative movement has increased the understanding of the challenges related to the disease and breaks the silence around Chagas disease, improving surveillance, and sustaining engagement towards the United Nations 2030 agenda.

Prognosis of chronic Chagas heart disease and other pending clinical challenges.

In this chapter, the main prognostic markers of Chagas heart disease are addressed, with an emphasis on the most recent findings and questions, establishing the basis for a broad discussion of recommendations and new approaches to managing Chagas cardiopathy. The main biological and genetic markers and the contribution of the electrocardiogram, echocardiogram and cardiac magnetic resonance are presented. We also discuss the most recent therapeutic proposals for heart failure, thromboembolism and arrhythmias, as well as current experience in heart transplantation in patients suffering from severe Chagas cardiomyopathy. The clinical and epidemiological challenges introduced by acute Chagas disease due to oral contamination are discussed. In addition, we highlight the importance of ageing and comorbidities in influencing the outcome of chronic Chagas heart disease. Finally, we discuss the importance of public policies, the vital role of funding agencies, universities, the scientific community and health professionals, and the application of new technologies in finding solutions for better management of Chagas heart disease.

How people affected by Chagas disease have struggled with their negligence: history, associative movement and World Chagas Disease Day

It is well documented that Chagas disease (CD) can pose a public health problem to countries. As one of the World Health Organization Neglected Tropical Diseases undoubtedly calls for comprehensive healthcare, transcending a restricted biomedical approach. After more than a century since their discovery, in 1909, people affected by CD are still frequently marginalised and/or neglected. The aim of this article is to tell the story of their activism, highlighting key historical experiences and successful initiatives, from 1909 to 2019. The first association was created in 1987, in the city of Recife, Brazil. So far, thirty associations have been reported on five continents. They were created as independent non-profit civil society organisations and run democratically by affected people. Among the common associations' objectives, we notably find: increase the visibility of the affected; make their voice heard; build bridges between patients, health system professionals, public health officials, policy makers and the academic and scientific communities. The International Federation of Associations of People Affected by CD - FINDECHAGAS, created in 2010 with the input of the Americas, Europe and the Western Pacific, counts as one of the main responses to the globalisation of CD. Despite all the obstacles and difficulties encountered, the Federation has thrived, grown, and matured. As a result of this mobilisation along with the support of many national and international partners, in May 2019 the 72nd World Health Assembly decided to establish World Chagas Disease Day, on 14 April. The associative movement has increased the understanding of the challenges related to the disease and breaks the silence around Chagas disease, improving surveillance, and sustaining engagement towards the United Nations 2030 agenda.

Prognosis of chronic Chagas heart disease and other pending clinical challenges

In this chapter, the main prognostic markers of Chagas heart disease are addressed, with an emphasis on the most recent findings and questions, establishing the basis for a broad discussion of recommendations and new approaches to managing Chagas cardiopathy. The main biological and genetic markers and the contribution of the electrocardiogram, echocardiogram and cardiac magnetic resonance are presented. We also discuss the most recent therapeutic proposals for heart failure, thromboembolism and arrhythmias, as well as current experience in heart transplantation in patients suffering from severe Chagas cardiomyopathy. The clinical and epidemiological challenges introduced by acute Chagas disease due to oral contamination are discussed. In addition, we highlight the importance of ageing and comorbidities in influencing the outcome of chronic Chagas heart disease. Finally, we discuss the importance of public policies, the vital role of funding agencies, universities, the scientific community and health professionals, and the application of new technologies in finding solutions for better management of Chagas heart disease.

Rectal Biopsy Technique for the Diagnosis of Hirschsprung Disease in Children: A Systematic Review and Meta-Analysis.

ABSTRACT: The diagnosis of Hirschsprung disease (HD) depends on the histopathological analysis of rectal biopsies. This review aims to define the best rectal biopsy technique. A systematic literature review and proportional meta-analysis of the available case series studies of rectal biopsies were performed in this study. All case series with more than five rectal biopsies in children younger than 18 years of age suspected of HD that described at least one type of rectal biopsy were included. The studies that did not specify the rate of conclusive results and the rate of complications of the biopsy procedures were excluded. According to the literature review, there were four different techniques of rectal biopsy: open, suction, punch, and endoscopic. In the title and abstract screening process, we assessed 496 articles, 159 fulfilled the eligibility criteria, and 71 studies reported our outcomes of interest and were included in the meta-analysis. The pooled proportion of conclusive results was 94% in open biopsies (95% CI 0.89-0.98), 95% in punch (95% CI 0.90-0.98), and 88% in suction group (95% CI 0.85-0.92). The pooled proportion of complication rates was 2% in open biopsies (95% CI 0.00031-0.04), 0.039% in suction (95% CI 0.00023-0.0006), and 2% in punch biopsies (95% CI 0.00075-0.04). Suction, punch, and open techniques presented comparable rates of conclusive results. In the suction group, the association between different methods of histopathological analysis increased conclusive results rates; however, the punch biopsy was associated with significantly higher complication rates than the suction technique.

Are biopsies always necessary in upper and lower gastrointestinal endoscopy in children? A retrospective 10-year analysis.

Little attention has been given to the efficiency and validity of performing routine endoscopic biopsies in normal areas in children. This study aimed to investigate the need to perform routine biopsies in upper gastrointestinal endoscopy (UDE) and colonoscopy in normal areas by comparing macroscopy and histology. It was a 10-year retrospective analysis with the inclusion of 761 UDEs and 177 colonoscopies. Considering all segments, UDEs showed false-positive result rates of 73.11% and false-negative result rates of 14.34%. The histological results modified the initial management in 53.95% of patients. Considering all segments, colonoscopies showed false-positive result rates of 63.64% and false-negative result rates of 30.97%. The histological results modified the initial management in 34.45% of patients.Conclusion: If biopsies were obtained only in abnormal areas, the diagnosis would be lost in 53.95% of the patients in upper endoscopies and 85.7% of the colonoscopies, which justifies routine maintenance of biopsies in macroscopically normal areas in children. What is Known: • Little attention has been given to the efficiency and validity of endoscopic biopsies of normal areas during pediatric exams. • Only a few pediatric studies have correlated macroscopic and histological findings from endoscopic biopsies, and low sensitivity and specificity, as well as poor agreement, were reported. What is New: • Our study confirms the evidence that routine biopsies from macroscopically normal areas during upper and lower digestive endoscopies can lead to histopathological diagnoses and different medical management. • This is the first research on this topic in a Latin population, from a developing country, reassuring the results obtained in previous papers from other countries.

MicroRNA expression profiles in the esophagus of children with caustic stenosis: A pathway towards esophageal cancer?

BACKGROUND: Eighty percent of caustic ingestions occur in children and esophageal neoplasms may develop as a late complication of such injury. The identification of biomarkers is a promising strategy to improve early diagnosis of esophageal cancer or caustic lesions that are at an increased risk of progression. STUDY DESIGN/AIMS: This study aimed at identifying global microRNA (miRNA) expression changes in esophageal mucosa from children with caustic stenosis. The study included 27 biopsy samples from 15 patients. Samples were divided into two groups, according to the time elapsed after injury (N = 15 in Group A, with less than five years of follow-up and N = 12 in Group B, with more than five years of follow-up). miRNA expression profiles were determined in each lesion, compared with normal esophageal tissues from control group. We used the TaqMan Human MicroRNA Arrays (Thermo Fisher) platform. Furthermore, bioinformatic algorithms were used to identify miRNA target genes and biological pathways including miRNAs and their target genes potentially associated with esophageal disease. RESULTS: Thirteen miRNAs were significantly deregulated (9 over- and 4 underexpressed) in patients from Group A. In patients from Group B, two miRNAs were over- and two were underexpressed. Of note, miR-374 and miR-574 were deregulated in Group B patients and have been linked to esophageal tumorigenesis. We identified signal transduction and transcription factor networks with genes strongly related to development and progression of esophageal cancer. CONCLUSION: miRNAs identified here contribute to a better understanding of pathways associated with malignant transformation from caustic stenosis to neoplastic lesions. This study may serve as a basis for validation of miRNAs, including miR-374 and miR-574, as potential biomarkers of early cancer detection.

Data on antigen recognition hindrance by antibodies covalently immobilized to Protein G magnetic beads by dimethyl pimelimidate (DMP) cross-linking.

The data presented herein is related to the article entitled "Trypanosoma cruzi immunoproteome: calpain-like CAP5.5 differentially detected throughout distinct stages of human Chagas disease cardiomyopathy" [1]. Electrophoretic analyses under denaturing and reducing conditions indicate that covalent immobilization of human IgG to Protein G magnetic beads by cross-linking with 50 mM dimethyl pimelimidate hinders the recognition of T. cruzi antigens in immunoprecipitation assays.

Trypanosoma cruzi immunoproteome: Calpain-like CAP5.5 differentially detected throughout distinct stages of human Chagas disease cardiomyopathy.

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects millions of people worldwide, especially in Latin America. Approximately 30% of the cases evolve to the chronic symptomatic stage due to cardiac and/or digestive damage, generally accompanied by nervous system impairment. Given the higher frequency and severity of clinical manifestations related to cardiac tissue lesion, the goal of this study was the identification of proteins associated with the disease progression towards its cardiac form. Thus, T. cruzi bloodstream trypomastigotes proteins were submitted to immunoprecipitation using antibodies from patients with the asymptomatic or cardiac (stages B1 and C) forms of the disease and from healthy donors as control. Immunoreactive proteins were identified and quantified based on mass spectrometry analysis and shifts in the recognition profile were further evaluated. Compared to asymptomatic samples, IgG from stage C patients predominantly detected the I/6 autoantigen, whereas IgG from B1 patients resulted in higher yield of dihydrolipoamide acetyltransferase precursor, calpain cysteine peptidase, and two variants of CAP5.5. In this work, CAP5.5 recognition by serum immunoglobulin from patients with early cardiomyopathy generated a 23-fold abundance variation when compared to samples from asymptomatic patients, highlighting the participation of this protein in cardiac form progression of the disease. SIGNIFICANCE: While T. cruzi has become the major cause of infectious cardiomyopathy in Latin America, research groups have been struggling to find alternative treatment, vaccine candidates, and improved diagnostic tests. In addition, the absence of adequate biomarkers to assess cure and progression of disease is a major setback for clinical trials and patients monitoring. Therefore, our findings may contribute to a better understanding of T. cruzi pathogenesis and evaluation of suitable candidates for vaccine and diagnostic tests, besides the clinical applicability of the potential biomarkers for patient follow-up and prognosis. Finally, the identification of T. cruzi proteins recognized by IgG from healthy donors may contribute for the understanding and discovery of epitope conservation among a broad range of pathogens.

Observation time and spontaneous resolution of primary phimosis in children / Tempo de observação e resolução espontânea de fimose primária em crianças

ABSTRACT Objective: to investigate spontaneous resolution rate of a series of patients with physiologic phimosis in relation to observation time and presence of symptoms. Methods: retrospective and longitudinal follow-up study of patients with physiologic phimosis, that did not apply topic treatment. These patients were invited for a new visit for reevaluation, or recent data were obtained by chart analysis. Spontaneous resolution rate was determined and statistically compared to age, presence of symptoms at first medical visit and time until reevaluation. Results: seventy one patients were included. Medium time of observation from first visit to reevaluation was 37.4 months. There was spontaneous resolution of phimosis in 32 (45%) patients. Children with spontaneous resolution were younger at initial diagnosis and were observed during a longer period of time. Most asymptomatic patients at first visit presented spontaneous resolution. However, it was not possible to stablish a significant relationship between presence of symptoms and evolution of physiologic phimosis. Conclusions: time of observation was the main determinant of spontaneous resolution of patients with physiologic phimosis, reinforcing the current more conservative approach regarding circumcision of those patients.

RESUMO Objetivo: investigar a taxa de resolução espontânea de uma série de pacientes com diagnóstico de fimose fisiológica e sua relação com o tempo de observação e com a presença de sintomas. Métodos: estudo retrospectivo e de seguimento longitudinal e observacional de pacientes em acompanhamento por fimose fisiológica, que não haviam realizado tratamento tópico. Estes pacientes foram convocados para uma consulta médica de reavaliação ou tiveram dados recentes obtidos a partir da análise dos prontuários. A taxa de resolução espontânea foi determinada e comparada estatisticamente de acordo com a idade, com a presença de sintomas no momento da primeira consulta e com o tempo transcorrido entre a primeira consulta e a reavaliação. Resultados: setenta e um pacientes foram incluídos no estudo. O tempo médio de observação, entre a primeira consulta e a reavaliação foi de 37,4 meses. Houve resolução espontânea da fimose em 32 (45%) pacientes. As crianças que apresentaram resolução espontânea eram mais jovens no momento do diagnóstico inicial e foram observadas por um maior intervalo de tempo. A maior parte dos pacientes assintomáticos na primeira consulta apresentou resolução espontânea. No entanto, não foi possível estabelecer uma relação significativa entre a presença de sintomas e a evolução da fimose fisiológica. Conclusões: o tempo de observação foi o maior determinante para a resolução espontânea de pacientes com fimose fisiológica, o que reforça a tendência atual mais conservadora em relação às indicações de circuncisão para estes pacientes.