Transforming growth factor-ß as a therapeutic target for the cardiac damage of Chagas disease

Transforming growth factor beta (TGF-β) is deeply involved on the pathogenesis of Chagas disease. Our group has been investigating the participation of this pleiotropic cytokine in different aspects of Chagas disease over the last 20 years. Important observations have been made, such as: (i) the ability of Trypanosoma cruzi in activating latent TGF-β; (ii) the potential involvement of TGF-β pathway on T. cruzi invasion of host cells; (iii) association of TGF-β with parasite intracellular replication; (iv) cardiac fibrosis development and maintenance; (v) disruption of Connexin-43 plaque structures and (vi) inflammation and immune response. In this perspective article we intend to discuss the advances of the potential use of new therapies targeting TGF-β to treat the cardiac alterations of Chagas disease-affected patients.

Translational research in Chagas disease: perspectives in nutritional therapy emerging from selenium supplementation studies as a complementary treatment

Translational research (TR) is an interdisciplinary branch of the biomedical field that seeks to connect its three supporting pillars: basic research on the bench, the hospital beds and other health system services, and the delivery of products for the well-being and health of the community. Here, we review the five transition stages of the TR spectrum, registering the lessons learned during > 20 years leading to the first clinical trial designed and performed in Brazil for testing a complementary treatment for Chagas disease (CD): the selenium trial (STCC). Lessons learned were: (1) to consider all the TR spectrum since the beginning of the project; (2) to start simultaneously animal studies and translation to humans; (3) to ensure a harmonious interaction between clinical and basic research teams; (4) to include MSc and PhD students only in pre-clinical and basic studies (TR0) or vertical clinical studies using retrospective samples and data (TR1); (5) to identify potential suppliers in the national commercial market for a future final treatment since the pre-clinical stage; (6) to keep an international network of experts as permanent advisers on the project. In the whole process, some perspectives were created: a complementary clinical trial for the opened questions and the construction of a Brazilian clinical CD platform.

The benefits of using selenium in the treatment of Chagas disease: prevention of right ventricle chamber dilatation and reversion of Trypanosoma cruzi-induced acute and chronic cardiomyopathy in mice

Cardiac damage is a frequent manifestation of Chagas disease, which is caused by the parasite Trypanosoma cruzi. Selenium (Se) is an essential micronutrient, the deficiency of which has been implicated in the development of cardiomyopathy. Our group has previously demonstrated that Se supplementation prevents myocardial damage during acute T. cruzi infection in mice. In this study, we analyzed the effect of Se treatment in cases of T. cruzi infection using prevention and reversion schemes. In the Se prevention scheme, mice were given Se supplements (2 ppm) starting two weeks prior to inoculation with T. cruzi(Brazil strain) and continuing until 120 days post-infection (dpi). In the Se reversion scheme, mice were treated with Se (4 ppm) for 100 days, starting at 160 dpi. Dilatation of the right ventricle was observed in the infected control group at both phases of T. cruzi infection, but it was not observed in the infected group that received Se treatment. Surviving infected mice that were submitted to the Se reversion scheme presented normal P wave values and reduced inflammation of the pericardium. These data indicate that Se treatment prevents right ventricular chamber increase and thus can be proposed as an adjuvant therapy for cardiac alterations already established by T. cruziinfection.

Absence of Fas-L aggravates renal injury in acute Trypanosoma cruzi infection

Trypanosoma cruzi infection induces diverse alterations in immunocompetent cells and organs, myocarditis and congestive heart failure. However, the physiological network of disturbances imposed by the infection has not been addressed thoroughly. Regarding myocarditis induced by the infection, we observed in our previous work that Fas-L-/- mice (gld/gld) have very mild inflammatory infiltration when compared to BALB/c mice. However, all mice from both lineages die in the early acute phase. Therefore, in this work we studied the physiological connection relating arterial pressure, renal function/damage and cardiac insufficiency as causes of death. Our results show that a broader set of dysfunctions that could be classified as a cardio/anaemic/renal syndrome is more likely responsible for cardiac failure and death in both lineages. However, gld/gld mice had very early glomerular deposition of IgM and a more intense renal inflammatory response with reduced renal filtration, which is probably responsible for the premature death in the absence of significant myocarditis in gld/gld.

Gap junction reduction in cardiomyocytes following transforming growth factor-â treatment and Trypanosoma cruzi infection

Gap junction connexin-43 (Cx43) molecules are responsible for electrical impulse conduction in the heart and are affected by transforming growth factor-â (TGF-â). This cytokine increases during Trypanosoma cruzi infection, modulating fibrosis and the parasite cell cycle. We studied Cx43 expression in cardiomyocytes exposed or not to TGF-â T. cruzi, or SB-431542, an inhibitor of TGF-â receptor type I (ALK-5). Cx43 expression was also examined in hearts with dilated cardiopathy from chronic Chagas disease patients, in which TGF-â signalling had been shown previously to be highly activated. We demonstrated that TGF-â treatment induced disorganised gap junctions in non-infected cardiomyocytes, leading to a punctate, diffuse and non-uniform Cx43 staining. A similar pattern was detected in T. cruzi-infected cardiomyocytes concomitant with high TGF-â secretion. Both results were reversed if the cells were incubated with SB-431542. Similar tests were performed using human chronic chagasic patients and we confirmed a down-regulation of Cx43 expression, an altered distribution of plaques in the heart and a significant reduction in the number and length of Cx43 plaques, which correlated negatively with cardiomegaly. We conclude that elevated TGF-â levels during T. cruzi infection promote heart fibrosis and disorganise gap junctions, possibly contributing to abnormal impulse conduction and arrhythmia that characterise severe cardiopathy in Chagas disease.

O design e a promoção da saúde nos laboratórios de pesquisa da Fiocruz / The design and promotion of health in the Fiocruz research laboratories

Discute a relação entre os objetos e os ambientes físicos destinados à pesquisa e à promoção da saúde. Analisa o ambiente físico dos laboratórios de pesquisa do Instituto Oswaldo Cruz (IOC/Fiocruz) à luz de princípios da promoção da saúde como ampliação do conceito de saúde, e também a participação dos atores no processo decisório relativo aos espaços de saúde e envolvimento de diferentes disciplinas no planejamento desses ambientes. Encontra a estreita relação entre design, arquitetura e promoção da saúde ao longo da história da Fiocruz e apresenta depoimentos colhidos na oficina de trabalho denominada Espaço, Criação e Alegria, instrumento de sensibilização, participação e escuta dos usuários de ambientes laboratoriais, desenvolvido e aperfeiçoado no IOC/Fiocruz.

The article discusses the relationship between the objects and the physical environments devoted to research and health promotion. It analyzes the physical environment of the Instituto Oswaldo Cruz (IOC/Fiocruz) research laboratories in light of such health promotion principles as expanding the concept of health, participation by the players in the decision making process regarding health areas and the involvement of different disciplines in the planning of these environments. It finds a close relationship between design, architecture and health promotion throughout the history of Fiocruz and presents interviews obtained in the workshop denominated Space, Creation and Happiness, an instrument for sensitization, participation and listening utilized by users of the laboratory environments, developed and perfected in the IOC/Fiocruz.

Clássicos em doença de Chagas: histórias e perspectivas / Classics in Chagas disease: histories and perspectives

Em 1909, Carlos Chagas anunciou a descoberta de uma nova doença: a tripanossomíase humana, doença de Chagas. A descoberta representou não apenas uma contribuição inovadora para o campo da medicina tropical, em particular os estudos sobre as doenças parasitárias, mas também mostrou a realidade sanitária e social do interior do país, assolado pelas endemias rurais. Cem anos depois nos deparamos com uma valiosa oportunidade de reflexão sobre os múltiplos sentidos e implicações da comemoração do grande feito de Carlos Chagas, que, tal como a biografia do cientista, associam ciência, saúde pública e projetos para a nação. Comemorar, lembrar junto, significa, assim, refletir sobre as várias temporalidades imbricadas nesta data: a memória de um passado que engendou o presente e convida a pensar os desafios do futuro. A história, tecendo os fios de um tempo construído por tantos indivíduos e gerações ao longo destes cem anos, apresenta-se como caminho para congregar todos aqueles que se associam a este legado e pretendem compartilhá-lo entre as novas gerações. Diante deste cenário e do atual quadro epidemiológico de uma enfermidade que ainda afeta milhões de pessoas em toda a América Latina, evidencia-se a importância de se articular ações que permitam suprir as lacunas relacionadas ao conhecimento da doença de Chagas e às medidas efetivas para tratamento e controle. Os textos reunidos neste livro constituem um importante marco nesse sentido. Clássicos em Doença de Chagas: história e perspectivas no cenário da descoberta lança nova luz sobre os estudos da doença a partir da reunião de 15 artigos científicos comentados por renomados pesquisadores, especialmente convidados para esta homenagem. Estamos diante de um valioso acervo documental que esperamos possa estimular o avanço do conhecimento e, assim, contribuir para a busca de soluções dos problemas sociais e de saúde relacionados á enfermidade de Chagas.

Clássicos em doença de Chagas: história e perspectivas no centenário da descoberta / Classics in Chagas disease: history and perspectives on the centenary of the discovery

Revisões históricas aos avanços científicos para o controle da doença, o Simpósio Internacional Comemorativo do Centenário da Descoberta da Doença de Chagas (1909-2009).

Contribuição dos artigos de Muniz e Freitas (1944) para o diagnóstico sorológico da doença de chagas / Contribution of articles Muniz and Freitas (1944) for the serological diagnosis of Chagas disease

Revisões históricas aos avanços científicos para o controle da doença, o Simpósio Internacional Comemorativo do Centenário da Descoberta da Doença de Chagas (1909-2009).

O futuro da pesquisa em doença de chagas e o legado de Carlos Chagas / The future of research on Chagas disease and the legacy of Carlos Chagas

Revisões históricas aos avanços científicos para o controle da doença, o Simpósio Internacional Comemorativo do Centenário da Descoberta da Doença de Chagas (1909-2009).

Urban transmission of Chagas disease in Cochabamba, Bolivia

Chagas disease is a major public health problem in Bolivia. In the city of Cochabamba, 58 percent of the population lives in peripheral urban districts ("popular zones") where the infection prevalence is extremely high. From 1995 to 1999, we studied the demographics of Chagas infections in children from five to 13 years old (n = 2218) from the South zone (SZ) and North zone (NZ) districts, which differ in social, environmental, and agricultural conditions. Information gathered from these districts demonstrates qualitative and quantitative evidence for the active transmission of Trypanosoma cruzi in urban Cochabamba. Seropositivity was high in both zones (25 percent in SZ and 19 percent in NZ). We observed a high risk of infection in children from five to nine years old in SZ, but in NZ, a higher risk occurred in children aged 10-13, with odds ratio for infection three times higher in NZ than in SZ. This difference was not due to triatomine density, since more than 1,000 Triatoma infestans were captured in both zones, but was possibly secondary to the vector infection rate (79 percent in SZ and 37 percent in NZ). Electrocardiogram abnormalities were found to be prevalent in children and pre-adolescents (SZ = 40 percent, NZ = 17 percent), indicating that under continuous exposure to infection and re-infection, a severe form of the disease may develop early in life. This work demonstrates that T. cruzi infection should also be considered an urban health problem and is not restricted to the rural areas and small villages of Bolivia.

A escuta sensível: um estudo sobre o relacionamento entre pessoas e ambientes voltados para a saúde / La escucha sensible: un estudio sobre la relación entre personas y ambientes dedicados a la salud / Sensitive listening: a study on the relationship between people and health environments

O artigo apresenta resultados de estudos sobre o relacionamento entre as pessoas e os ambientes voltados para a saúde. Expõe o que se fala sobre os aspectos psicofisiológicos ou psicofísicos relativos a esses ambientes, pesquisando as vozes dos dirigentes e legisladores, por meio das leis e portarias ligadas ao tema na esfera federal, estadual e municipal e, por outro lado, escutando as vozes dos usuários por meio de uma oficina de trabalho intitulada "Espaço, Criação e Alegria", aplicada em laboratórios de pesquisa da Fiocruz. Os resultados são os dados provenientes da percepção dos participantes das oficinas sobre seus ambientes de trabalho, colhidos por meio de depoimentos e desenhos. Tais resultados demonstram que a oficina pode ser um instrumento de escuta sensível para designers e arquitetos envolvidos em projetos de obras e reformas de espaços destinados à saúde.

This article presents results of studies on the relationship between people and health environments. It explicits what is said about the psychophysical aspects of those ambiances by directors and legislators by examining the laws and norms linked to the theme. On the other hand, client's perspectives are contemplated by listening to their voices in the workshop "Environment, Creativity and Joy", applied at Fiocruz's research laboratories. The results are data proceeding from workshop participants' perceptions on their work environments, gathered by testimonies and drawings. Such results demonstrate that the workshop can be an instrument of sensitive listening for designers and architects involved in projects involving construction and renovation of health ambiances.

El artículo presenta resultados de estudios sobre la relación entre las personas y los ambientes dedicados a la salud. Expone lo que se dice sobre los aspectos psicofisiológicos o psicofísicos relativos a tales ambientes, pesquisando las voces de los dirigentes y de los legisladores, por medio de las leyes y decretos ligados al tema en la esfera federal, estatal y municipal y, por otro lado, oyendo las voces de los usuarios por medio de un taller de trabajo titulado "Espacio, Creación y Alegría", aplicado en laboratorios de pesquisa de la Fiocruz. Los resultados son los talleres sobre sus ambientes de trabajo, recogidos por medio de declaraciones y dibujos. Tales resultados demuestran que el taller puede ser un instrumento de escucha sensible para diseñadores y arquitectos envueltos en proyectos de obras y reformas de espacios destinados a la salud.

Trypanosoma cruzi-cardiomyocytes: new contributions regarding a better understanding of this interaction

The present paper summarizes new approaches regarding the progress done to the understanding of the interaction of Trypanosoma cruzi-cardiomyocytes. Mannose receptors localized at the surface of heart muscle cell are involved in binding and uptake of the parasite. One of the most striking events in the parasite-heart muscle cells interaction is the disruption of the actin cytoskeleton. We have investigated the regulation of the actin mRNA during the cytopathology induced in myocardial cells by the parasite. T. cruzi invasion increases calcium resting levels in cardiomyocytes. We have previously shown that Ca2+ ATPase of the sarcoplasmic reticulum (SERCA) is involved in the invasion of T. cruzi in cardiomyocytes. Treating the cells with thapsigargin, a drug that binds to all SERCA ATPases and causes depletion of intracellular calcium stores, we found a 75 per cent inhibition in the T. cruzi-cardiomyocytes invasion.

Sulphate-reducing bacteria associated with biocorrosion: a review

Biocorrosion means any process of corrosion in wich microorganisms are somehow involved. As far as the petroleum industry is concerned, the anaerobic type is the more important, with Sulphate-Reducing Bacteria (SRB) accouting for half of the described processes. SRB are obligate anaerobs that use sulphur, sulphate or other oxidized sulphur compounds as oxidizing agents when decomposing organic material. A typical product of SRB metabolism, hydrogen sulphide -H2S-, is extremely toxic. In the present work we review the literature on mechanisms underlying biocorrosive process in wich SRB are involved and summarize some of the ultrastructural and eletrochemical work developed using SRB obtained from water injection flow in wells located on PETROBRAS offshore marine plataforms, sampled directly in the field over metallic probes, or cultured under laboratory conditions. Biofilms develop when SRB adhere to inert surfaces. A high diversity of morphological types is found inside these biofilms. Their extracellular matrix is highly hydrated and mainly anionic, as shown by its avid reaction with cationic compounds like ruthenium red. We have noted that variations in iron contet lead to interesting changes in the ultrastructure of the bacterial cell coat and also in the rate of corrosion induced in metallic test cupons. Since routine methods to prevent and treat SRB contamination and biodeterioration involve the use of biocides that are toxic and always have some environmental impact, an accurate diagnosis of biocorrosion is always required prior to a treatment decision. We developed a method that detects and semi-quantifies the presence of living or dead SRB by using free silver potentials as an indicator of corrosive action by SRB-associated sulphides. We found a correlation between sulphide levels (determined either by spectrophotometry, or using a silver electrode -E(Ag)- that measured changes in free potentials induced by the presence of exogeneously added sulphide) and SRB concentration (enumerated by a culturing method). E(Ag) was characterized under a variety of conditions and was found to be relatively immune to possible interference resulting from aeration of media or from the presence of iron corrosion products. The method offers a simple, rapid, and effective means of diagnosing biocorrosive process prior to their control

Trypanosoma cruzi recognition by macrophages and muscle cells: perspectives after a 15-year study

Macrophages and muscle cells are the main targets for invasion of Trypanosoma cruzi. Ultrastructural studies of this phenomenon in vitro showed that invasion occurs by endocytosis, with attachment and internalization being mediated by different components capable of recognizing epi-or trypomastigotes (TRY). A parasitophorus vacuole was formed in both cell types, thereafter fusing with lysosomes. Then, the mechanism of T. cruzi invasion of host cells (HC) is essentially similar (during a primary infection in the abscence of a specific immune response), regardless of wether the target cell is a professional or a non-professional phagocytic cell. Using sugars, lectins, glycosidases, proteinases and proteinase inhibitors, we observed that the relative balance between exposed sialic acid and galactose/N-acetyl galactosamine (GAL) residues on the TRY surface, determines the parasite's capacity to invade HC, and that lectin-mediated phagocytosis with GAL specificity is important for internalization of T. cruzi into macrophages. On the other hand, GAL on the surface to heart muscle cells participate on TRY adhesion. TRY need to process proteolytically both the HC and their own surface, to expose the necessary ligands and receptors that allow binding to, and internalization in the host cell. The diverse range of molecular mechanisms which the parasite could use to invade the host cell may correspond to differences in the available "receptors"on the surface of each specific cell type. Acute phase components, with lectin or proteinase inhibitory activities (a-macroglobulins), may also be involved in T. cruzi-host cell interaction