RESUMO
BACKGROUND: A positive Trypanosoma cruzi polymerase chain reaction (PCR) is associated with a worse prognosis in patients with chronic Chagas disease (CD). OBJECTIVES: To study the association of clinical, electrocardiographic, and echocardiographic characteristics and biomarker blood levels with positive T. cruzi PCR in chronic CD. METHODS: This is a single-centre observational cross-sectional study. Positive T. cruzi PCR association with clinical, electrocardiographic, and echocardiographic characteristics, and biomarker blood levels were studied by logistic regression analysis. p values < 0.05 were considered significant. FINDINGS: Among 333 patients with chronic CD (56.4% men; 62 ± 10 years), T. cruzi PCR was positive in 41.1%. Stepwise multivariate logistic regression showed an independent association between positive T. cruzi PCR and diabetes mellitus {odds ratio (OR) 0.53 [95% confidence interval (CI) 0.30-0.93]; p = 0.03}, right bundle branch block [OR 1.78 (95% CI 1.09-2.89); p = 0.02], and history of trypanocidal treatment [OR 0.13 (95% CI 0.04-0.38); p = 0.0002]. Among patients with a history of trypanocidal treatment (n = 39), only four (10%) patients had a positive T. cruzi PCR. MAIN CONCLUSIONS: Among several studied parameters, only diabetes mellitus, right bundle branch block, and history of trypanocidal treatment showed an independent association with positive T. cruzi PCR. History of trypanocidal treatment was a strong protective factor against a positive T. cruzi PCR.
Assuntos
Doença de Chagas , Diabetes Mellitus , Tripanossomicidas , Trypanosoma cruzi , Feminino , Humanos , Masculino , Biomarcadores , Bloqueio de Ramo/complicações , Bloqueio de Ramo/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Doença Crônica , Estudos Transversais , Diabetes Mellitus/tratamento farmacológico , Reação em Cadeia da Polimerase , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/genética , Pessoa de Meia-Idade , IdosoRESUMO
Neurological commitment is a neglected manifestation of Chagas disease (CD). Meningoencephalitis mainly affects children and immunosuppressed patients, while stroke can occur with or without cardiac compromise. One of the possible causes of stroke development is microvascular commitment. Our group previously described that experimental Trypanossoma cruzi acute infection leads to cerebral microvasculopathy. This condition is characterized by decreased capillary density, increased leukocyte rolling and adhesion, and endothelial dysfunction. CD was discovered 114 years ago, and until today, only two drugs have been available for clinical treatment: benznidazole and nifurtimox. Both present a high cure rate for the acute phase (80%) and small cure rate for the chronic phase (20%). In addition, the high occurrence of side-effects, without proper medical follow-up, can result in treatment abandonment. Therefore, the search for new therapeutic schemes is necessary. Statins are drugs already used in the clinic that have several pleiotropic effects including endothelial function improvement, anti-inflammatory action, as well as trypanocidal effects, making them a potential alternative treatment for brain microvasculopathy in CD. Here, we investigate the effect of lovastatin (LOV) on brain microvasculopathy and inflammatory parameters. Swiss Webster mice were intraperitoneally inoculated with the Y strain of T. cruzi. Treatment with lovastatin (20 mg/kg/day) was initiated 24 h after the infection and continued for 14 consecutive days. We observed that LOV treatment did not affect parasitemia, brain microcirculation alterations, or the reduction in cerebral blood flow caused by T. cruzi infection. Also, LOV did not prevent the increased number of CD3+ cells and eNOS levels in the T. cruzi-infected brain. No alterations were observed on VCAM-1 and MCP-1 expressions, neither caused by infection nor LOV treatment. However, LOV prevented the increase in F4/80+ cells and ICAM-1 levels in the brain caused by acute infection with T. cruzi. These results suggest an anti-inflammatory activity of LOV, but more studies are needed to elucidate the role of LOV in CD acute infection.
RESUMO
Central nervous system alterations was described in Chagas disease in both human and experimental models, leading to meningoencephalitis, stroke and cognitive impairment. Recently, our group demonstrated that acute infection by Trypanossoma cruzi leads to cerebral microvasculophaty in mice with endothelial dysfunction, capillary rarefaction, increased rolling and leukocyte adhesion. Only benznidazole and nifurtimox are available for clinical treatment, they have an efficiency of 80% in the acute phase and less than 20% in chronic phase. However, the effect of these drugs on brain microcirculation has not yet been evaluated. We hypothesized that early treatment with benznidazole could protect brain microcirculation during acute experimental Chagas disease. Swiss Webster mice were inoculated with 104 trypomastigotes forms of T. cruzi, and after 24 h they were treated with 50 or 100 mg/kg/day of benznidazole for 14 consecutive days. In untreated infected mice, we observed cerebral microvascular rarefaction, increase in leukocyte rolling and adhesion, reduced cerebral blood flow, and increased CD3+ and F4-80+ cells in brain tissue. Early treatment with benznidazole at 100 mg/kg/day and 50 mg/kg/day prevented the occurrence of the alterations mentioned. Here, we show that BZ is able to protect the microcirculation and reduced brain inflammation in acute experimental Chagas disease.
Assuntos
Doença de Chagas , Animais , Humanos , Camundongos , Doença de Chagas/tratamento farmacológicoRESUMO
BACKGROUND A positive Trypanosoma cruzi polymerase chain reaction (PCR) is associated with a worse prognosis in patients with chronic Chagas disease (CD). OBJECTIVES To study the association of clinical, electrocardiographic, and echocardiographic characteristics and biomarker blood levels with positive T. cruzi PCR in chronic CD. METHODS This is a single-centre observational cross-sectional study. Positive T. cruzi PCR association with clinical, electrocardiographic, and echocardiographic characteristics, and biomarker blood levels were studied by logistic regression analysis. p values < 0.05 were considered significant. FINDINGS Among 333 patients with chronic CD (56.4% men; 62 ± 10 years), T. cruzi PCR was positive in 41.1%. Stepwise multivariate logistic regression showed an independent association between positive T. cruzi PCR and diabetes mellitus {odds ratio (OR) 0.53 [95% confidence interval (CI) 0.30-0.93]; p = 0.03}, right bundle branch block [OR 1.78 (95% CI 1.09-2.89); p = 0.02], and history of trypanocidal treatment [OR 0.13 (95% CI 0.04-0.38); p = 0.0002]. Among patients with a history of trypanocidal treatment (n = 39), only four (10%) patients had a positive T. cruzi PCR. MAIN CONCLUSIONS Among several studied parameters, only diabetes mellitus, right bundle branch block, and history of trypanocidal treatment showed an independent association with positive T. cruzi PCR. History of trypanocidal treatment was a strong protective factor against a positive T. cruzi PCR.
RESUMO
A distrofia muscular de Duchenne (DMD) atinge 1 a cada 3600 a 600 meninos nascidos vivos e é uma doença genética ligada ao cromossomo X. Ela é causada por mutações no gene da distrofina, levando ao comprometimento na expressão da distrofina, proteína que estabiliza o sarcolema durante a contração. Na DMD, ocorre uma degeneração e fraqueza muscular pro-gressiva, resultando na perda da função muscular, complicações cardiorrespiratórias e a morte em torno aos 20 anos de idade. A laminina-111(LAM-111) foi proposta para DMD como uma efetiva terapia baseada em proteína, prevenindo a patologia em camundongos mdx, modelo animal da doença. Uma proteólise parcial de proteínas da matriz extracelular, como a lamini-na-111, produz peptídeos chamados matricinas e vários deles são capazes de modular ativida-des celulares. Nesse estudo avaliamos o efeito biológico dos peptídeos derivados da LAM-111 em mioblastos e do peptídeo SIKVAV ou da LAM-111 em músculos distróficos de mdx. Para avaliar a adesão de mioblastos, nós incubamos a linhagem celular C2C12 em placas pré-tratadas com 1\03BCg de LAM-111 ou seus peptídeos e bloqueada com BSA. O peptídeo AG73 foi capaz de promover a adesão assim como a LAM-111. Depois disso, avaliamos a migração de mioblastos com ensaio de Transwell, a LAM-111 e seus peptídeos foram incubados com 1, 50 ou 100 \03BCg na câmara inferior. Na parte superior colocamos as células em meio sem soro. Depois de 16 horas, contamos as células migrantes O AG73 e a LAM-111 promoveram a adesão como o controle positivo de migração com soro. Para avaliar a diferenciação, nós cul-tivamos mioblastos C2C12 em placas tratadas com 10 \03BCg de LAM-111 e seus peptídeos e induzimos a diferenciação por três dias. Interessantemente, o AG73 aumentou a hipertrofia dos miotubos, o que não foi observado em outras condições. Para avaliação de proliferação nos tempos de 24 e 48 horas, os mioblastos foram incubados em placas tratadas com 1 ou 10 \03BCg de LAM-111 ou peptídeos. Não foram observadas diferenças entre os grupos. Devido aos efeitos biológicos relevantes do peptídeo SIKVAV descritos na literatura, avaliamos o efeito protetor desse fragmento ou da LAM-111 in vivo no modelo animal da DMD com ou sem o dano induzido por CTX. Para isso, camundongos mdx de 3 a 4 semanas receberam 100\03BCL de peptídeo SIKVAV (0,1\03BCg/mL) ou LAM-111 (100 \03BCM) nas patas direitas e nas patas esquer-das, tampão fosfato (PBS). Depois de três dias, os músculos foram coletados para análise ou foram exacerbados em dano com 100\03BCL de cardiotoxina (CTX)(10\03BCM), e depois outras cole-tas foram realizadas, no quarto e no décimo dia após à injúria. Os tratamentos foram capazes de reduzir os linfócitos no quarto dia após a CTX. A fibrose é um importante evento patológi-co da doença, o tratamento com LAM-111 foi capaz de reduzir a fibrose no decimo dia após a CTX e o dano seguido de regeneração no quarto dia. Em suma, o peptídeo AG73 demostrou in vitro efeitos biológicos relevantes a fisiologia muscular. E o peptídeo SIKVAV não mos-trou efeito protetor em músculos distróficos danificados com CTX.