Clinical and epidemiological aspects of chronic Chagas disease from Southern Brazil.

INTRODUCTION: Patients with Chagas disease (CD), caused by Trypanosoma cruzi, present a higher risk of developing other chronic diseases, which may contribute to CD severity. Since CD is underreported in the southern state of Paraná, Brazil, we aimed to characterize clinical and epidemiological aspects of individuals chronically infected with T. cruzi in Southern Brazil. METHODS: A community hospital-based study was performed, recording clinical/demographic characteristics of 237 patients with CD from Southern Brazil. To estimate the association between different forms of CD and sociodemographic and clinical variables, multiple logistic regression models were built using the Akaike information criterion. RESULTS: Mean age was 57.5 years and 59% were females. Most patients' (60%) place of origin/birth was within Paraná and they were admitted to the CD outpatient clinic after presenting with cardiac/digestive symptoms (64%). The predominant form of CD was cardiac (53%), followed by indeterminate (36%), and digestive (11%). The main electrocardiographic changes were in the right bundle branch block (39%) and left anterior fascicular block (32%). The average number of comorbidities per patient was 3.9±2.3; systemic arterial hypertension was most common (64%), followed by dyslipidemia (34%) and diabetes (19%); overlapping comorbidities were counted separately. Male sex was associated with symptomatic cardiac CD (OR=2.92; 95%CI: 1.05-8.12; p=0.040). CONCLUSIONS: This study provided greater understanding of the distribution and clinical profile of CD patients in Southern Brazil, indicating a high prevalence of comorbidities among these patients who are a vulnerable group due to advanced age and substantial risk of morbidity.

Association of caspase-1 polymorphisms with Chagas cardiomyopathy among individuals in Santa Cruz, Bolivia.

INTRODUCTION:: Trypanosoma cruzi (Tc) infection is usually acquired in childhood in endemic areas, leading to Chagas disease, which progresses to Chagas cardiomyopathy in 20-30% of infected individuals over decades. The pathogenesis of Chagas cardiomyopathy involves the host inflammatory response to T. cruzi, in which upstream caspase-1 activation prompts the cascade of inflammatory chemokines/cytokines, cardiac remodeling, and myocardial dysfunction. The aim of the present study was to examine the association of two caspase-1 single nucleotide polymorphisms (SNPs) with cardiomyopathy. METHODS:: We recruited infected (Tc+, n = 149) and uninfected (Tc-, n = 87) participants in a hospital in Santa Cruz, Bolivia. Cardiac status was classified (I, II, III, IV) based on Chagas cardiomyopathy-associated electrocardiogram findings and ejection fractions on echocardiogram. Genotypes were determined using Taqman probes via reverse transcription-polymerase chain reaction of peripheral blood DNA. Genotype frequencies were analyzed according to three inheritance patterns (dominant, recessive, additive) using logistic regression adjusted for age and sex. RESULTS:: The AA allele for the caspase-1 SNP rs501192 was more frequent in Tc+ cardiomyopathy (classes II, III, IV) patients compared to those with a normal cardiac status (class I) [odds ratio (OR) = -2.18, p = 0.117]. This trend approached statistical significant considering only Tc+ patients in class I and II (OR = -2.64, p = 0.064). CONCLUSIONS:: Caspase-1 polymorphisms may play a role in Chagas cardiomyopathy development and could serve as markers to identify individuals at higher risk for priority treatment.

Eficacia de dos formulaciones de oxfendazol producidas localmente para el tratamiento de la cisticercosis en cerdos infectados naturalmente / Efficacy of two locally produced oxfendazole formulations for the treatment of cysticercosis in naturally infected pigs

Se evaluó la eficacia de dos formulaciones de oxfendazol (OFZ) contra cisticercosis producidas localmente, al 22,5% y 10% en comparación con una formulación comercial (Synanthic 9,06%) en 22 cerdos naturalmente infectados, que recibieron una dosis oral de 30 mg/kg. Los cerdos fueron sacrificados a las ocho semanas postratamiento para evaluar quistes en en sus carcasas, y se determinó la eficacia cisticida a través de la proporción de quistes degenerados sobre el total. Solo se encontraron quistes degenerados en la musculatura, corazón y lengua de los cerdos tratados con OFZ en todos los grupos, lo cual muestra una eficacia del 100%. En los cerebros se encontraron quistes viables y degenerados, con una eficacia menor en todos los grupos (65% [OFZ comercial], 47% [OFZ local 22,5%] y 31% [OFZ local 10%], p = 0,355. Las formulaciones de OFZ producidas localmente fueron igual de efectivas que la formulación comercial y pueden proporcionar una alternativa para el tratamiento de la cisticercosis porcina.

The efficacy of two locally produced oxfendazole (OFZ) formulations against cysticercosis at 22,5% and 10%, versus a commercial formulation (Synanthic 9,06%) was evaluated in twenty-two naturally infected pigs that received a single oral dose of 30 mg/kg. Pigs were sacrificed at eight weeks post-treatment to evaluate the cysts found in their carcasses, and to determine the cysticidal efficacy, which was defined as the proportion of degenerated cysts over total cysts. Only degenerated cysts were found in muscle, heart, and tongue of pigs treated with OFZ in all groups, which shows an efficacy of 100%. Viable and degenerated cysts were found in brains, being the efficacy lower in all groups (65% [commercial OFZ], 47% [local OFZ 22.5%] and 31% [local OFZ 10%], p = 0.355). Locally produced OFZ formulations were similarly effective to the commercial formulation and may provide a practical alternative for the treatment of porcine cysticercosis.

Clinical and epidemiological aspects of chronic Chagas disease from Southern Brazil

Abstract INTRODUCTION: Patients with Chagas disease (CD), caused by Trypanosoma cruzi, present a higher risk of developing other chronic diseases, which may contribute to CD severity. Since CD is underreported in the southern state of Paraná, Brazil, we aimed to characterize clinical and epidemiological aspects of individuals chronically infected with T. cruzi in Southern Brazil. METHODS: A community hospital-based study was performed, recording clinical/demographic characteristics of 237 patients with CD from Southern Brazil. To estimate the association between different forms of CD and sociodemographic and clinical variables, multiple logistic regression models were built using the Akaike information criterion. RESULTS: Mean age was 57.5 years and 59% were females. Most patients' (60%) place of origin/birth was within Paraná and they were admitted to the CD outpatient clinic after presenting with cardiac/digestive symptoms (64%). The predominant form of CD was cardiac (53%), followed by indeterminate (36%), and digestive (11%). The main electrocardiographic changes were in the right bundle branch block (39%) and left anterior fascicular block (32%). The average number of comorbidities per patient was 3.9±2.3; systemic arterial hypertension was most common (64%), followed by dyslipidemia (34%) and diabetes (19%); overlapping comorbidities were counted separately. Male sex was associated with symptomatic cardiac CD (OR=2.92; 95%CI: 1.05-8.12; p=0.040). CONCLUSIONS: This study provided greater understanding of the distribution and clinical profile of CD patients in Southern Brazil, indicating a high prevalence of comorbidities among these patients who are a vulnerable group due to advanced age and substantial risk of morbidity.

Association of caspase-1 polymorphisms with Chagas cardiomyopathy among individuals in Santa Cruz, Bolivia

Abstract INTRODUCTION: Trypanosoma cruzi (Tc) infection is usually acquired in childhood in endemic areas, leading to Chagas disease, which progresses to Chagas cardiomyopathy in 20-30% of infected individuals over decades. The pathogenesis of Chagas cardiomyopathy involves the host inflammatory response to T. cruzi, in which upstream caspase-1 activation prompts the cascade of inflammatory chemokines/cytokines, cardiac remodeling, and myocardial dysfunction. The aim of the present study was to examine the association of two caspase-1 single nucleotide polymorphisms (SNPs) with cardiomyopathy. METHODS: We recruited infected (Tc+, n = 149) and uninfected (Tc−, n = 87) participants in a hospital in Santa Cruz, Bolivia. Cardiac status was classified (I, II, III, IV) based on Chagas cardiomyopathy-associated electrocardiogram findings and ejection fractions on echocardiogram. Genotypes were determined using Taqman probes via reverse transcription-polymerase chain reaction of peripheral blood DNA. Genotype frequencies were analyzed according to three inheritance patterns (dominant, recessive, additive) using logistic regression adjusted for age and sex. RESULTS: The AA allele for the caspase-1 SNP rs501192 was more frequent in Tc+ cardiomyopathy (classes II, III, IV) patients compared to those with a normal cardiac status (class I) [odds ratio (OR) = −2.18, p = 0.117]. This trend approached statistical significant considering only Tc+ patients in class I and II (OR = −2.64, p = 0.064). CONCLUSIONS: Caspase-1 polymorphisms may play a role in Chagas cardiomyopathy development and could serve as markers to identify individuals at higher risk for priority treatment.

Immunoinformatics prediction of linear epitopes from Taenia solium TSOL18.

Cysticercosis is a public health problem in several developing countries. The oncosphere protein TSOL18 is the most immunogenic and protective antigen ever reported against porcine cysticercosis, although no specific epitope has been identified to account for these properties. Recent evidence suggests that protection might be associated with conformational epitopes. Linear epitopes from TSOL18 were computationally predicted and evaluated for immunogenicity and protection against porcine cysticercosis. A synthetic peptide was designed based on predicted linear B cell and T cell epitopes that are exposed on the surface of the theoretically modeled structure of TSOL18. Three surface epitopes from TSOL18 were predicted as immunogenic. A peptide comprising a linear arrangement of these epitopes was chemically synthesized. The capacity of the synthetic peptide to protect pigs against an oral challenge with Taenia solium proglottids was tested in a vaccine trial. The synthetic peptide was able to produce IgG antibodies in pigs and was associated to a reduction of the number of cysts, although was not able to provide complete protection, defined as the complete absence of cysts in necropsy. This study demonstrated that B cell and T cell predicted epitopes from TSOL18 were not able to completely protect pigs against an oral challenge with Taenia solium proglottids. Therefore, other linear epitopes or eventually conformational epitopes may be responsible for the protection conferred by TSOL18.

Structure-Activity relationship in mutated pyrazinamidases from Mycobacterium tuberculosis.

The pncA gene codes the pyrazinamidase of Mycobacterium tuberculosis, which converts pyrazinamide to ammonia and pyrazinoic-acid, the active antituberculous compound. Pyrazinamidase mutations are associated to pyrazinamide-resistant phenotype, however how mutations affect the structure of the pyrazinamidase, and how structural changes affect the enzymatic function and the level of pyrazinamide-resistance is unknown. The structures of mutated pyrazinamidases from twelve Mycobacterium tuberculosis strains and the pyrazinamide-susceptible H37Rv reference strain were modelled using homology modelling and single amino acid replacement. Physical-chemical and structural parameters of each pyrazinamidase were calculated. These parameters were: The change of electrical charge of the mutated amino acid, the change of volume of the mutated amino acid, the change of a special amino acid, the distance of the mutated amino acid to the active site, the distance of the mutated amino acid to the metal-coordination site, and the orientation of the side-chain of the mutated amino acid. The variability of the enzymatic activity of the recombinant pyrazinamidases, and the microbiological susceptibility to pyrazinamide determined by BACTEC 460TB, were modelled in multiple linear regressions. Physical-chemical and structural parameters of the mutated pyrazinamidases were tested as predictors. Structural and physical-chemical variations of the pyrazinamidase explained 75% of the variability of the enzymatic activity, 87% of the variability of the kinetic constant and 40% of the variability of the pyrazinamide-resistance level. Based on computer models of mutated pyrazinamidases, the structural parameters explained a high variability of the enzymatic function, and to a lesser extent the resistance level.