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      Cellular and genetic mechanisms involved in the generation of protective and pathogenic immune responses in human Chagas disease

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          Abstract

          Perhaps one of the most intriguing aspects of human Chagas disease is the complex network of events that underlie the generation of protective versus pathogenic immune responses during the chronic phase of the disease. While most individuals do not develop patent disease, a large percentage may develop severe forms that eventually lead to death. Although many efforts have been devoted to deciphering these mechanisms, there is still much to be learned before we can fully understand the pathogenesis of Chagas disease. It is clear that the host's immune response is decisive in this process. While characteristics of the parasite influence the immune response, it is becoming evident that the host genetic background plays a fundamental role in the establishment of pathogenic versus protective responses. The involvement of three complex organisms, host, parasite and vector, is certainly one of the key aspects that calls for multidisciplinary approaches towards the understanding of Chagas disease. We believe that now, one hundred years after the discovery of Chagas disease, it is imperative to continue with highly interactive research in order to elucidate the immune response associated with disease evolution, which will be essential in designing prophylactic or therapeutic interventions.

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          Most cited references75

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          Types of neurons in the enteric nervous system.

          This paper, written for the symposium in honour of more than 40 years' contribution to autonomic research by Professor Geoffrey Burnstock, highlights the progress made in understanding the organisation of the enteric nervous system over this time. Forty years ago, the prevailing view was that the neurons within the gut wall were post-ganglionic neurons of parasympathetic pathways. This view was replaced as evidence accrued that the neurons are part of the enteric nervous system and are involved in reflex and integrative activities that can occur even in the absence of neuronal influence from extrinsic sources. Work in Burnstock's laboratory led to the discovery of intrinsic inhibitory neurons with then novel pharmacology of transmission, and precipitated investigation of neuron types in the enteric nervous system. All the types of neurons in the enteric nervous system of the small intestine of the guinea-pig have now been identified in terms of their morphologies, projections, primary neurotransmitters and physiological identification. In this region there are 14 functionally defined neuron types, each with a characteristic combination of morphological, neurochemical and biophysical properties. The nerve circuits underlying effects on motility, blood flow and secretion that are mediated through the enteric nervous system are constructed from these neurons. The circuits for simple motility reflexes are now known, and progress has been made in analysing those involved in local control of blood flow and transmucosal fluid movement in the small intestine.
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            Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial.

            Benznidazole is effective for treating acute-stage Chagas disease, but its effectiveness for treating indeterminate and chronic stages remains uncertain. To compare long-term outcomes of patients with nonacute Chagas disease treated with benznidazole versus outcomes of those who did not receive treatment. Clinical trial with unblinded, nonrandom assignment of patients to intervention or control groups. Chagas disease center in Buenos Aires, Argentina. 566 patients 30 to 50 years of age with 3 positive results on serologic tests and without heart failure. The primary outcome was disease progression, defined as a change to a more advanced Kuschnir group or death. Secondary outcomes included new abnormalities on electrocardiography and serologic reactivity. Oral benznidazole, 5 mg/kg of body weight per day for 30 days (283 patients), or no treatment (283 patients). Fewer treated patients had progression of disease (12 of 283 [4%] vs. 40 of 283 [14%]; adjusted hazard ratio, 0.24 [95% CI, 0.10 to 0.59]; P = 0.002) or developed abnormalities on electrocardiography (15 of 283 [5%] vs. 45 of 283 [16%]; adjusted hazard ratio, 0.27 [CI, 0.13 to 0.57]; P = 0.001) compared with untreated patients. Left ventricular ejection fraction (hazard ratio, 0.97 [CI, 0.94 to 0.99]; P < 0.002) and left ventricular diastolic diameter (hazard ratio, 2.45 [CI, 1.53 to 3.95]; P < 0.001) were also associated with disease progression. Conversion to negative results on serologic testing was more frequent in treated patients than in untreated patients (32 of 218 [15%] vs. 12 of 212 [6%]; adjusted hazard ratio, 2.1 [CI, 1.06 to 4.06]; P = 0.034). Nonrandom, unblinded treatment assignment was used, and follow-up data were missing for 20% of patients. Loss to follow-up was more common among patients who were less sick. Two uncontrolled interim analyses were conducted. Compared with no treatment, benznidazole treatment was associated with reduced progression of Chagas disease and increased negative seroconversion for patients presenting with nonacute disease and no heart failure. These observations indicate that a randomized, controlled trial should now be conducted.
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              Predictors of mortality in chronic Chagas disease: a systematic review of observational studies.

              Chagas disease is a major cause of morbidity and mortality in Latin America. Knowledge of the predictors of prognosis can help clinical decision making by identifying patients' level of risk. We reviewed the published literature on prognostic factors in patients with Chagas disease by performing a PubMed search for articles published in any language between 1985 and February 2006 and hand searches of the reference lists of retrieved articles. Studies were selected if they included patients in the chronic phase of Chagas disease, analyzed a clearly defined outcome (all-cause mortality, sudden cardiac deaths, and/or cardiovascular deaths), and used multivariable regression models of prognosis. From 606 potentially relevant studies, 12 met the inclusion criteria: 8 clinic-based studies including 3928 patients and 4 hospital-based studies including 349 patients. Impaired left ventricular function by echocardiogram or cineventriculogram was found to be the most common and consistent independent predictor of death. New York Heart Association functional class III/IV and cardiomegaly on the chest radiography also were independently associated with higher mortality. More recently, strong evidence was found that nonsustained ventricular tachycardia on 24-hour Holter monitoring indicated an adverse prognosis. The typical ECG abnormalities showed limited additional prognostic value. Other often-mentioned risk factors, advanced age and male sex, showed inconsistent results. A formal meta-analysis was not feasible because of the heterogeneity of published studies and the lack of minimal standards in reporting results. A systematic review of published studies indicates that impaired left ventricular function, New York Heart Association class III/IV, cardiomegaly, and nonsustained ventricular tachycardia indicate a poor prognosis in patients with chronic Chagas disease.
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                Author and article information

                Journal
                mioc
                Memórias do Instituto Oswaldo Cruz
                Mem. Inst. Oswaldo Cruz
                Instituto Oswaldo Cruz, Ministério da Saúde (Rio de Janeiro, RJ, Brazil )
                0074-0276
                1678-8060
                July 2009
                : 104
                : suppl 1
                : 208-218
                Affiliations
                [01] orgnameDepartamento de Morfologia
                [02] London orgnameUniversity of Western Ontario orgdiv1Robarts Research Institute Canadá
                [03] Uberlândia MG orgnameUniversidade Federal de Uberlândia orgdiv1Instituto de Ciências Biomédicas orgdiv2Departamento de Morfologia Brasil
                [04] Belo Horizonte MG orgnameUniversidade Federal de Minas Gerais orgdiv1Instituto de Ciências Biológicas orgdiv2Departamento de Bioquímica-Imunologia Brasil
                Article
                S0074-02762009000900027 S0074-0276(09)10400027
                10.1590/S0074-02762009000900027
                c554cdb6-75f6-428e-ae17-35e6af3d2791

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 14 May 2009
                : 06 April 2009
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 75, Pages: 11
                Product

                SciELO Brazil


                pathology,protection,T-cells,immunoregulation,Chagas disease

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