Discovery of circulating miRNAs as biomarkers of chronic Chagas heart disease via a small RNA-Seq approach.

Chagas disease affects approximately 7 million people worldwide in Latin America and is a neglected tropical disease. Twenty to thirty percent of chronically infected patients develop chronic Chagas cardiomyopathy decades after acute infection. Identifying biomarkers of Chagas disease progression is necessary to develop better therapeutic and preventive strategies. Circulating microRNAs are increasingly reliable biomarkers of disease and therapeutic targets. To identify new circulating microRNAs for Chagas disease, we performed exploratory small RNA sequencing from the plasma of patients and performed de novo miRNA prediction, identifying potential new microRNAs. The levels of the new microRNAs temporarily named miR-Contig-1519 and miR-Contig-3244 and microRNAs that are biomarkers for nonchagasic cardiomyopathies, such as miR-148a-3p and miR-224-5p, were validated by quantitative reverse transcription. We found a specific circulating microRNA signature defined by low miR-Contig-3244, miR-Contig-1519, and miR-148a-3 levels but high miR-224-5p levels for patients with chronic Chagas disease. Finally, we predicted in silico that these altered circulating microRNAs could affect the expression of target genes involved in different cellular pathways and biological processes, which we will explore in the future.

Association between altered tryptophan metabolism, plasma aryl hydrocarbon receptor agonists, and inflammatory Chagas disease.

Introduction: Chagas disease causes a cardiac illness characterized by immunoinflammatory reactions leading to myocardial fibrosis and remodeling. The development of Chronic Chagas Cardiomyopathy (CCC) in some patients while others remain asymptomatic is not fully understood, but dysregulated inflammatory responses are implicated. The Aryl hydrocarbon receptor (AhR) plays a crucial role in regulating inflammation. Certain tryptophan (Trp) metabolites have been identified as AhR ligands with regulatory functions. Methods results and discussion: We investigated AhR expression, agonist response, ligand production, and AhR-dependent responses, such as IDO activation and regulatory T (Treg) cells induction, in two T. cruzi-infected mouse strains (B6 and Balb/c) showing different polymorphisms in AhR. Furthermore, we assessed the metabolic profile of Trp catabolites and AhR agonistic activity levels in plasma samples from patients with chronic Chagas disease (CCD) and healthy donors (HD) using a luciferase reporter assay and liquid chromatography-mass spectrophotometry (LC-MS) analysis. T. cruzi-infected B6 mice showed impaired AhR-dependent responses compared to Balb/c mice, including reduced IDO activity, kynurenine levels, Treg cell induction, CYP1A1 up-regulation, and AhR expression following agonist activation. Additionally, B6 mice exhibited no detectable AhR agonist activity in plasma and displayed lower CYP1A1 up-regulation and AhR expression upon agonist activation. Similarly, CCC patients had decreased AhR agonistic activity in plasma compared to HD patients and exhibited dysregulation in Trp metabolic pathways, resulting in altered plasma metabolite profiles. Notably, patients with severe CCC specifically showed increased N-acetylserotonin levels in their plasma. The methods and findings presented here contribute to a better understanding of CCC development mechanisms and may identify potential specific biomarkers for T. cruzi infection and the severity of associated heart disease. These insights could be valuable in designing new therapeutic strategies. Ultimately, this research aims to establish the AhR agonistic activity and Trp metabolic profile in plasma as an innovative, non-invasive predictor of prognosis for chronic Chagas disease.

Enhanced Migratory Capacity of T Lymphocytes in Severe Chagasic Patients Is Correlated With VLA-4 and TNF-α Expression.

Trypanosoma cruzi infection in humans leads to progression to chronic chagasic myocarditis (CCM) in 30% of infected individuals, paralleling T cell inflammatory infiltrates in the heart tissue. T-cell trafficking into the hearts of CCM patients may be modulated by in situ expression of chemotactic or haptotactic molecules, as the chemokine CXCL12, the cytokine tumor necrosis factor-alpha (TNF-α), and extracellular matrix proteins (ECM), such as fibronectin. Herein we evaluated the expression of fibronectin, CXCL12, and TNF-α in the myocardial tissue of T. cruzi seropositive (asymptomatic or with CCM), as well as seronegative individuals as healthy controls. Hearts from CCM patients exhibited enhanced expression of these three molecules. CXCL12 and TNF-α serum levels were also increased in CCM individuals. We then evaluated T lymphocytes from chronic chagasic patients by cytofluorometry, in terms of membrane expression levels of molecules involved in cell activation and cell migration, respectively, HLA-DR and the VLA-4 (very late antigen-4, being one integrin-type fibronectin receptor). Indeed, the expression of HLA-DR and VLA-4 was enhanced on T lymphocytes from chagasic patients, especially in the CCM group. To further approach the dynamics of T cell migratory events, we performed fibronectin-, TNF-α-, and CXCL12-driven migration. Peripheral blood mononuclear cells (PBMCs) and T cells from CCM patients presented an ex vivo enhanced migratory capacity driven by fibronectin alone when this ECM protein was placed in the membrane of transwell migration chambers. When TNF-α was previously placed upon fibronectin, we observed a further and significant increase in the migratory response of both PBMCs and T lymphocytes. Overall, these data suggest the existence in patients with chronic Chagas disease of a cardiac inflammatory infiltrate vector that promotes the recruitment and accumulation of activated T cells, driven in part by enhanced tissue expression of fibronectin and TNF-α, as well as the respective corresponding VLA-4 and TNF receptors.

Diminished Prolinemia in Chronic Chagasic Patients: A New Clue for Disease Pathology?

Trypanosoma cruzi, the etiological agent of Chagas disease, is dependent on proline for a variety of processes, such as energy metabolism, host cell invasion, differentiation, and resistance to osmotic, metabolic, and oxidative stress. On this basis, we investigated a possible relationship between prolinemia and severity of T. cruzi infection in chronic patients, as reported here. The study population consisted of 112 subjects, separated into 83 chronically T. cruzi-infected patients and 29 age-matched healthy volunteers (control) of both sexes, recruited at the Chagas Disease Service from the Department of Cardiology, Hospital Provincial del Centenario de Rosario (Rosario, Argentina). Chagasic patients were separated into three groups: chronic asymptomatic, mild/moderate, and severe chronic chagasic cardiomyopathy (CCC) subjects. We observed a significant decrease of 11.7% in prolinemia in chagasic patients when compared to controls. Further analysis within the three groups of chagasic patients also revealed a statistically significant decrease of prolinemia in severe CCC patients compared to controls, showing a relative difference of 13.6% in proline concentrations. These data point to the possibility that collagen-which participates in the healing process of cardiac tissue-and proline metabolism in the myocardium could constitute new factors affecting the evolution of Chagas disease.

Dysregulated Network of Immune, Endocrine and Metabolic Markers is Associated to More Severe Human Chronic Chagas Cardiomyopathy.

Individuals who are infected with Trypanosoma cruzi develop chronic Chagas cardiomyopathy (CCC), which is a complication involving a series of immune pathogenetic mechanisms, although an association between immune and metabolic alterations was more recently proposed. Accordingly, we investigated the immuno-metabolic response in chagasic patients and their possible influence on CCC pathogenesis. To this end, T. cruzi-seropositive (asymptomatic or with CCC) and sero-negative individuals were studied. Serum tumour necrosis factor (TNF)-α, interleukin (IL)-6, adipocytokines and the expression of their receptors in peripheral blood mononuclear cell (PBMC) were evaluated, together with other factors influencing the immune response. CCC patients showed major metabolic and hormonal abnormalities, in parallel with increased IL-6 and leptin serum levels. TNF-α receptor s, leptin and adiponectin receptors (ObR and Adipo-Rs respectively), as well as PPAR-γ expression in PBMCs from CCC patients were compatible with a counteracting response leading to an unfavourable immune-metabolic profile. These results suggest that persistently increased levels of immune-metabolic pro-inflammatory mediators along with the adverse endocrine anti-inflammatory response of CCC individuals, may contribute to the underlying mechanisms dealing with myocardial tissue damage.

Benznidazole and Posaconazole in Eliminating Parasites in Asymptomatic T. Cruzi Carriers: The STOP-CHAGAS Trial.

BACKGROUND: Benznidazole is recommended for treatment of Chagas infection. Effects of combination therapy with benznidazole and posaconazole have not been tested in Trypanosoma cruzi carriers. OBJECTIVES: The purpose of this study was to determine whether posaconazole alone or combined with benznidazole were superior to benznidazole monotherapy in eliminating T. cruzi parasites measured by real time polymerase chain reaction (RT-PCR) in asymptomatic Chagas carriers. METHODS: A prospective, multicenter randomized placebo-controlled study was conducted in 120 subjects from Latin America and Spain who were randomized to 4 groups: posaconazole 400 mg twice a day (b.i.d.); benznidazole 200 mg + placebo b.i.d.; benznidazole 200 mg b.i.d. + posaconazole 400 mg b.i.d.; or placebo 10 mg b.i.d. T. cruzi deoxyribonucleic acid was detected by RT-PCR at 30, 60, 90, 120, 150, 180, and 360 days. The primary efficacy outcome is the proportion of subjects with persistent negative RT-PCR by day 180; the secondary outcome was negative RT-PCR at 360 days. RESULTS: Only 13.3% of those receiving posaconazole and 10% receiving placebo achieved the primary outcome, compared with 80% receiving benznidazole + posaconazole and 86.7% receiving benznidazole monotherapy (p < 0.0001 vs. posaconazole/placebo). Posaconazole monotherapy or posaconazole combined with benznidazole achieved high RT-PCR conversion rates during treatment (30 days; 93.3% and 88.9% and 60 days; 90%, and 92.3%) that were similar to benznidazole (89.7% and 89.3%); all were superior to placebo or posaconazole (10% and 16.7%, p < 0.0001). This was not observed at 360 days; benznidazole + posaconazole and benznidazole monotherapy (both 96%) versus placebo (17%) and posaconazole (16%, p < 0.0001). Serious adverse events were rare (6 patients) and were observed in the benznidazole-treated patients. Permanent discontinuation was reported in 19 patients (31.7%) receiving either benznidazole monotherapy or combined with posaconazole. CONCLUSIONS: Posaconazole demonstrated trypanostatic activity during treatment, but it is ineffective long-term in asymptomatic T. cruzi carriers. Benznidazole monotherapy is superior to posaconazole, with high RT-PCR conversion rates sustained at 1 year. Side effects lead to therapy discontinuation in 32%. No advantages were observed with combined therapy versus benznidazole monotherapy. (A Study of the Use of Oral Posaconazole [POS] in the Treatment of Asymptomatic Chronic Chagas Disease [P05267] [STOP CHAGAS]: NCT01377480).

Ingesta alimentaria y estado nutricional de pacientes con enfermedad de chagas / Dietary intake and nutritional status of patients with Chagas disease

La enfermedad de Chagas es una infección parasitaria que afecta a 17 millones de personas en Latinoamérica. Es aún desconocida la real influencia del efecto del estado nutricional y la ingesta alimentaria sobre la evolución de la enfermedad hacia la miocardiopatía chagásica crónica, así como los factores de riesgo cardiovascular que pueden influir en la evolución de la patología. Con el objetivo de caracterizar la ingesta alimentaria y determinar el estado nutricional de las personas con enfermedad de Chagas, se llevó a cabo un estudio descriptivo transversal de una muestra de pacientes atendidos en el servicio de cardiología del Hospital Centenario de Rosario. Se recolectaron datos sobre las características generales de la muestra, se realizaron mediciones antropométricas y se entrevistó sobre el consumo de alimentos a través de un cuestionario de frecuencia de consumo y un atlas fotográfico. Se reclutaron 113 paciente, de los cuales el 70% de los hombres y el 90 % de las mujeres presentaban sobrepeso u obesidad. Además el 78.9% de las mujeres y el 27% de los hombres, presento un Índice cintura/cadera de riesgo cardiovascular. En el análisis de la ingesta de macronutrientes se observa que se superan las recomendaciones del aporte de lípidos. Al analizar la ingesta de alimentos por grupos se encontró que los hombres consumen más carne vacuna magra, fiambres y embutidos, carne de cerdo y bebidas alcohólicas, en cambio las mujeres ingieren más lácteos enteros y bebidas azucaradas. Esta muestra urbana de pacientes con enfermedad de Chagas, presenta un perfil nutricional similar al de la población general, y el consumo alimentario se encuentra influenciado por la vida en las grandes ciudades(AU)

Chagas disease is a parasitic infection that affects 17 million people in Latin America. The real influence of nutritional status and food intake effect over the course of the disease to chronic Chagas Cardiomyopathy is still unknown. Furthermore, some cardiovascular risk factors might influence the evolution of the disease. A cross-sectional study of a sample of patients with Chagas disease attending the Cardiology Section of the Hospital Centenario of Rosario was carried out in order to characterize their food intake and nutritional status. Data on the general characteristics of the sample was collected; anthropometric measurements were performed and food consumption was investigated using a food frequency questionnaire and a n photographic atlas. One hundred and thirteen patients were enrolled; 70% of men and 90% of women were overweight or obese. In addition 78.9% of women and 27% of men presented a waist-hip ratio according to cardiovascular risk. When analyzing macronutrient intake, it was observed that lipid intake recommendations were exceeded. When the food intake groups were analyzed separately, it was found that men consume more lean beef, cold cuts, pork and alcoholic drinks, while women eat more whole dairy products and sugary drinks. This patients´ urban sample with Chagas disease, he presents a nutritional profile similar to that of the general population, and the food consumption is influenced by life in big cities(AU)

Dietary intake and nutritional status of patients with Chagas disease.

Chagas disease is a parasitic infection that affects 17 million people in Latin America. The real influence of nutritional status and food intake effect over the course of the disease to chronic Chagas Cardiomyopathy is still unknown. Furthermore, some cardiovascular risk factors might influence the evolution of the disease. A cross-sectional study of a sample of patients with Chagas disease attending the Cardiology Section of the Hospital Centenario of Rosario was carried out in order to characterize their food intake and nutritional status. Data on the general characteristics of the sample was collected; anthropometric measurements were performed and food consumption was investigated using a food frequency questionnaire and a n photographic atlas. One hundred and thirteen patients were enrolled; 70% of men and 90% of women were overweight or obese. In addition 78.9% of women and 27% of men presented a waist-hip ratio according to cardiovascular risk. When analyzing macronutrient intake, it was observed that lipid intake recommendations were exceeded. When the food intake groups were analyzed separately, it was found that men consume more lean beef, cold cuts, pork and alcoholic drinks, while women eat more whole dairy products and sugary drinks. This patients´ urban sample with Chagas disease, he presents a nutritional profile similar to that of the general population, and the food consumption is influenced by life in big cities.

Early double-negative thymocyte export in Trypanosoma cruzi infection is restricted by sphingosine receptors and associated with human chagas disease.

The protozoan parasite Trypanosoma cruzi is able to target the thymus and induce alterations of the thymic microenvironmental and lymphoid compartments. Acute infection results in severe atrophy of the organ and early release of immature thymocytes into the periphery. To date, the pathophysiological effects of thymic changes promoted by parasite-inducing premature release of thymocytes to the periphery has remained elusive. Herein, we show that sphingosine-1-phosphate (S1P), a potent mediator of T cell chemotaxis, plays a role in the exit of immature double-negative thymocytes in experimental Chagas disease. In thymuses from T. cruzi-infected mice we detected reduced transcription of the S1P kinase 1 and 2 genes related to S1P biosynthesis, together with increased transcription of the SGPL1 sphingosine-1-lyase gene, whose product inactivates S1P. These changes were associated with reduced intrathymic levels of S1P kinase activity. Interestingly, double-negative thymocytes from infected animals expressed high levels of the S1P receptor during infection, and migrated to lower levels of S1P. Moreover, during T. cruzi infection, this thymocyte subset expresses high levels of IL-17 and TNF-α cytokines upon polyclonal stimulation. In vivo treatment with the S1P receptor antagonist FTY720 resulted in recovery the numbers of double-negative thymocytes in infected thymuses to physiological levels. Finally, we showed increased numbers of double-negative T cells in the peripheral blood in severe cardiac forms of human Chagas disease.

Valoración de anticuerpos con reactividad cruzada patógeno-huésped en pacientes con diferentes estadios de cardiopatía chagásica crónica / Assessment of cross-reactive host-pathogen antibodies in patients with different stages of chronic Chagas disease

Introducción y objetivos. La infección por Trypanosoma cruzi induce una respuesta autoinmunitaria humoral contra diferentes antígenos del huésped. En especial, los anticuerpos que presentan reactividad cruzada con antígenos del miocardio tienen un papel importante en el desarrollo de las formas graves de la cardiopatía chagásica crónica. En este trabajo se analiza la asociación del estadio clínico de la enfermedad con la presencia de autoanticuerpos en pacientes con cardiopatía chagásica crónica. Métodos. Estudio transversal con pacientes con serología positiva para enfermedad de Chagas, categorizados en tres grupos según la clasificación de cardiopatía chagásica de Storino et al. Se realizó a todas las personas incluidas un examen clínico completo y se usaron las muestras de suero para cuantificar los autoanticuerpos. Resultados. Todos los pacientes presentaron cantidades detectables de anti-p2Beta y anti B13; el anti-Na-K-ATPasa fue negativo en todos los casos. No se halló asociación significativa entre las alteraciones electrocardiográficas y los valores de autoanticuerpos. Los pacientes con cardiopatía chagásica en estadio III presentaron mayor concentración de anti-B13 y riesgo de mortalidad alto, lo que muestra una clara asociación entre el estadio de la enfermedad y la puntuación de mortalidad. Conclusiones. La concentración del autoanticuerpo anti-B13 fue significativamente mayor en los pacientes con cardiopatía chagásica en estadio III , lo que indica que este anticuerpo puede estar involucrado en la progresión de la enfermedad y podría usarse como marcador de mal pronóstico respecto a la afección cardiaca. Los resultados revelan también una importante correlación entre el anti-B13 y la insuficiencia cardiaca sintomática y la cardiomiopatía dilatada (AU)

Introduction and objectives. Trypanosoma cruzi infection has been shown to induce humoral autoimmune responses against host antigens tissues. Particularly, antibodies cross-reacting with myocardial antigens may play a role in the development of the severe forms of chronic Chagas disease. The aim of this study was to determine the association between clinical stage of the disease and the presence of autoantibodies in patients with chronic Chagasic disease. Methods. We performed a cross-sectional study in T. cruzi-seropositive patients divided into 3 groups according to the classic classification of chronic Chagas heart of Storino et al. All participants underwent complete clinical examination and their sera were used to measure autoantibody levels. Results. All patients had detectable levels of anti-p2Beta and anti-B13 autoantibodies but none had anti-Na-K-ATPase antibodies. No association was observed between electrocardiographic conduction disturbances and autoantibody levels. Patients with chronic Chagas disease stage III had the highest levels of anti-B13 antibodies and a high risk of mortality score, showing a clear association between disease stage and this score. Conclusions. Anti-B13 antibodies were significantly higher in chronic Chagas disease stage III patients, suggesting that these antibodies may be involved in disease progression and that they might be a useful marker of poor prognosis in terms of heart compromise. Our results also reveal an important correlation between the level of anti-B13 autoantibodies and symptomatic heart failure and/or dilated cardiomyopathy (AU)

Assessment of cross-reactive host-pathogen antibodies in patients with different stages of chronic Chagas disease.

INTRODUCTION AND OBJECTIVES: Trypanosoma cruzi infection has been shown to induce humoral autoimmune responses against host antigens tissues. Particularly, antibodies cross-reacting with myocardial antigens may play a role in the development of the severe forms of chronic Chagas disease. The aim of this study was to determine the association between clinical stage of the disease and the presence of autoantibodies in patients with chronic Chagasic disease. METHODS: We performed a cross-sectional study in T. cruzi-seropositive patients divided into 3 groups according to the classic classification of chronic Chagas heart of Storino et al. All participants underwent complete clinical examination and their sera were used to measure autoantibody levels. RESULTS: All patients had detectable levels of anti-p2ß and anti-B13 autoantibodies but none had anti-Na-K-ATPase antibodies. No association was observed between electrocardiographic conduction disturbances and autoantibody levels. Patients with chronic Chagas disease stage III had the highest levels of anti-B13 antibodies and a high risk of mortality score, showing a clear association between disease stage and this score. CONCLUSIONS: Anti-B13 antibodies were significantly higher in chronic Chagas disease stage III patients, suggesting that these antibodies may be involved in disease progression and that they might be a useful marker of poor prognosis in terms of heart compromise. Our results also reveal an important correlation between the level of anti-B13 autoantibodies and symptomatic heart failure and/or dilated cardiomyopathy.

Chagasic thymic atrophy does not affect negative selection but results in the export of activated CD4+CD8+ T cells in severe forms of human disease.

Extrathymic CD4+CD8+ double-positive (DP) T cells are increased in some pathophysiological conditions, including infectious diseases. In the murine model of Chagas disease, it has been shown that the protozoan parasite Trypanosoma cruzi is able to target the thymus and induce alterations of the thymic microenvironment and the lymphoid compartment. In the acute phase, this results in a severe atrophy of the organ and early release of DP cells into the periphery. To date, the effect of the changes promoted by the parasite infection on thymic central tolerance has remained elusive. Herein we show that the intrathymic key elements that are necessary to promote the negative selection of thymocytes undergoing maturation during the thymopoiesis remains functional during the acute chagasic thymic atrophy. Intrathymic expression of the autoimmune regulator factor (Aire) and tissue-restricted antigen (TRA) genes is normal. In addition, the expression of the proapoptotic Bim protein in thymocytes was not changed, revealing that the parasite infection-induced thymus atrophy has no effect on these marker genes necessary to promote clonal deletion of T cells. In a chicken egg ovalbumin (OVA)-specific T-cell receptor (TCR) transgenic system, the administration of OVA peptide into infected mice with thymic atrophy promoted OVA-specific thymocyte apoptosis, further indicating normal negative selection process during the infection. Yet, although the intrathymic checkpoints necessary for thymic negative selection are present in the acute phase of Chagas disease, we found that the DP cells released into the periphery acquire an activated phenotype similar to what is described for activated effector or memory single-positive T cells. Most interestingly, we also demonstrate that increased percentages of peripheral blood subset of DP cells exhibiting an activated HLA-DR+ phenotype are associated with severe cardiac forms of human chronic Chagas disease. These cells may contribute to the immunopathological events seen in the Chagas disease.

Alelos HLA-DRB1 en pacientes infectados con patógenos intracelulares en Rosario, Santa Fe / HLA-DRB1 alleles in patients infected with intracellular pathogens in Rosario, Santa Fe

En el desarrollo de la respuesta inmune a patógenos intracelulares participa el elevado polimorfismo de las moléculas HLA de clase II. El objetivo de este trabajo fue establecer la participación de los alelos HLA-DRB1 en personas con infección con Trypanosoma cruzi (T. cruzi) o con Mycobacterium leprae (M. leprae). Se estudiaron 252 individuos de la ciudad de Rosario, divididos en: 86 personas seropositivas para T cruzi (sin compromiso cardiológico de relevancia), 85 pacientes con diagnóstico de Lepra y 81 individuos controles, sin evidencia de patologías. El ADN genómico fue extraído de sangre periférica utilizando el método de salting out y empleado como templado para amplificar por PCR el segundo exón polimórfico de HLA-DRB1. Los alelos fueron tipificados mediante la técnica de PCR­-SSOP. La comparación de frecuencias mostró prevalencia de los alelos DRB1 *0409 y DRB1 *1503 en los individuos seropositivos para T. cruzi con respecto al grupo control. Por otra parte, el análisis estadístico indicó una disminución significativa del alelo DRB1 *1103 en pacientes con esta tripanosomiasis. Al examinar las frecuencias observamos en el grupo de pacientes con Lepra un aumento significativo de los alelos DRB1 *1401 y DRB1 *1406. Además observamos que las proporciones de los alelos DRB1 *0808 y DRB1 *1103 en los enfermos son significativamente inferiores con respecto al grupo control. Los alelos HLA DRB1 podrían actuar solos o en combinación con otros genes para conferir susceptibilidad o resistencia a estas infecciones en la población de Rosario, Argentina.

In the development of the immune response to intracellular pathogens implicated the high polymorphism of HLA class II molecules. The aim of this study was to establish the involvement of the HLA-DRB1 alleles in infected subjects with T. cruzi or leprosy patients in Rosario, Argentina. We studied 252 individuals who divided into: 86 positive people for T. cruzi without cardiac damage, 85 patients diagnosed with leprosy and controls 81 individuals without evidence of disease. Genomic DNA was extracted from peripheral blood using the standard salting out method and used as a template to amplify by the PCR the polymorphic second exon of the HLA­-DRB1. PCR products were hybridized separately with sequence-specifics oligonucleotides (SSOP). Statistical analysis indicated that of increased frequencies of DRB1 *0409, and DRB1 *1503 in individuals with Chagas' disease. DRB1 *1103 allele was prevalence in the group control and could be associated with resistance to the presence of trypanosomiasis. DRB1 *1401 and DRB1 *1406 alleles were significantly more prevalent in leprosy patients, whereas a decreased frequency of DRB1 *0808 and DRB1 *1103 alleles was found, by comparison with the group control. The HLA-DRB1 alleles could act alone or in combination with other genes to confer differential susceptibility and also protection to these diseases in Rosario, Argentina.

Distribution of HLA-DRB1 alleles in Argentinean patients with Chagas' disease cardiomyopathy.

Chronic Chagas' disease occurs in a variable number of infected individuals and mainly manifests as an inflammatory cardiomyopathy that may lead to a fatal course. The factors underlying the establishment of chronic myocardial lesions are not fully understood. The study included 71 unrelated individuals serologically positive for T. cruzi. A group of 81 no related healthy individuals with neither symptoms nor previous diagnosis of Chagas' disease was studied as control group. Genomic DNA was extracted from peripheral blood using the standard salting out method and used as a template to amplify by the PCR the polymorphic second exon of the HLA-DRB1. PCR products were hybridized separately with sequence-specifics oligonucleotides (SSOP). DRB1*0409 and DRB1*1503 alleles were significantly more prevalent in seropositives (pC = 0.002, OR: 26.17 and 24.87 respectively). The prevalence of DRB1*1103 allele was statistically significant in the group control and could be associated with resistance Chagas' disease (pC = 0.026, OR: 0.19). Increased significance frequency of DRB1*1503 allele was found among cardiomyopathy patients suggesting that this antigen might be related with the genetic susceptibility to cardiac damage in these patients (pC = 0.014, OR: 9.22).

Chagas: atención primaria

Contenido: Nociones básicas. El paciente infectado en la zona endémica: chagas agudo vectorial. El paciente chagásico en zona urbana (1): chagas agudo. El paciente chagásico en zona urbana (2): chagas indeterminado. Patogenia de la enfermedad. El paciente con miocardiopatía chagßsica crónica (1): sospecha y estudio básico. El paciente con miocardiopatía chagásica crónica (2): intervención del cardiólogo. Prevención y tratamiento. Aspectos sociales y laborales del paciente chagásico...

Cardiovascular risk factors in chronic Chagas' disease are associated with a different profile of putative heart-pathogenic antibodies.

Given that cardiovascular risk factors (CRF), such as smoking, alcoholism and hypertension, may contribute to the development of heart lesions, chronically Trypanosoma cruzi-infected individuals were studied to explore the relationship between the presence of such CRF, cardiomyopathy and antibodies that have been proposed to play a pathogenetic role in Chagas' disease. The targets of these antibodies were T. cruzi antigens such as cruzipain (Cz), a P ribosomal antigen (P2), and a component of myelin sheaths also present in T. cruzi (sulphatide). Individuals were classified into four groups on the basis of specific serology and presence of CRF: subjects with T. cruzi infection and CRF; those with positive serology and no CRF; seronegatives with CRF; and seronegatives without CRF, were analysed. Seronegatives or seropositives with CRF showed a greater occurrence of heart involvement (chest X-ray and/or electrocardiogram abnormalities). Seropositives with CRF displayed significantly higher levels of antisulphatide antibodies than the three remaining groups and higher levels of antibodies against Cz and P2 compared to the seropositives without CRF. Increased amounts of anti-P2 and antisulphatide antibodies were also found in seropositives with marked heart involvement. The presence of CRF is associated with a different profile of antibody responses and degree of cardiac effects.

HLA class II DRB1 polymorphism in Argentinians undergoing chronic Trypanosoma cruzi infection.

DNA typing of human lymphocyte antigen (HLA)-dicloro-1-[beta]-D-ribofuranosyl-benzimidazole 1 (DRB1) alleles in 35 individuals serologically positive for T. cruzi and in 41 healthy controls was performed. DRB1*0409 allele was significantly more prevalent in seropositive individuals, with a trend being also observed for the DRB1*0701 and DRB1*1503 alleles. Although statistically insignificant, the latter was found more frequent in cases with cardiomyopathy.

Perfil lipídico en niños y adolescentes de una población escolar / Lipid profile in a school population of children and adolescents

Introducción. La relación existente entre las alteraciones del metabolismo lipídico y el riesgo de enfermedades cardiovasculares, unida a otras condiciones como la obesidad, lleva a considerar la importancia del estudio del perfil lipídico desde edades tempranas. El objetivo de este trabajo fue estudiar el perfil lipídico de niños y adolescentes para aportar datos según edad y sexo comparándolos con los obtenidos por otros autores.Población, material y métodos. Se realizó un estudio descriptivo transversal de una muestra de 960 niños y adolescentes escolarizados, en distintas escuelas públicas de Rosario y alrededores, pertenecientes a una situación socioeconómica media o baja. Se incluyeron varones y mujeres de 5 a 18 años, sin antecedentes patológicos conocidos; se excluyeron aquellos con sobrepeso (6,6 por ciento).Resultados. Se determinaron parámetros antropométricos y bioquímicos. Los valores obtenidos fueron:colesterol: 164,9 más o menos 23,6 mg/dl; triglicéridos: 72,3 más menos 31,7 mg/dl; colesterol LDL: 96,1 más menos 23,6 mg/dl; colesterol HDL: 55,1 más menos 5,6 mg/dl; colesterol no HDL: 110,1 más menos 25,4mg/dl; colesterol/colesterol HDL: 3,03 más menos 0,59; colesterol LDL/colesterol HDL: 1,77 más menos 0,59. En la muestra estudiada, no se observaron diferencias estadísticamente significativas en los parámetros entre varones y mujeres ni entre los distintos grupos etarios, a excepción de los triglicéridos (significativamente mayores en mujeres de 5 a 11 años, p mayor 0,001).Conclusión. La comparación de nuestros resultados con los de otros autores nos permitió establecer diferencias con distinto grado de significación. El aporte del estudio del perfil lipídico en una población de niños y adolescentes podría ser de utilidad como referente para identificar factores de riesgo modificables y la necesidad de intervenciones conducentes a adoptar medidas de prevención desde edades tempranas.

Perfil lipídico en niños y adolescentes de una población escolar / Lipid profile in a school population of children and adolescents

Introducción. La relación existente entre las alteraciones del metabolismo lipídico y el riesgo de enfermedades cardiovasculares, unida a otras condiciones como la obesidad, lleva a considerar la importancia del estudio del perfil lipídico desde edades tempranas. El objetivo de este trabajo fue estudiar el perfil lipídico de niños y adolescentes para aportar datos según edad y sexo comparándolos con los obtenidos por otros autores.Población, material y métodos. Se realizó un estudio descriptivo transversal de una muestra de 960 niños y adolescentes escolarizados, en distintas escuelas públicas de Rosario y alrededores, pertenecientes a una situación socioeconómica media o baja. Se incluyeron varones y mujeres de 5 a 18 años, sin antecedentes patológicos conocidos; se excluyeron aquellos con sobrepeso (6,6 por ciento).Resultados. Se determinaron parámetros antropométricos y bioquímicos. Los valores obtenidos fueron:colesterol: 164,9 más o menos 23,6 mg/dl; triglicéridos: 72,3 más menos 31,7 mg/dl; colesterol LDL: 96,1 más menos 23,6 mg/dl; colesterol HDL: 55,1 más menos 5,6 mg/dl; colesterol no HDL: 110,1 más menos 25,4mg/dl; colesterol/colesterol HDL: 3,03 más menos 0,59; colesterol LDL/colesterol HDL: 1,77 más menos 0,59. En la muestra estudiada, no se observaron diferencias estadísticamente significativas en los parámetros entre varones y mujeres ni entre los distintos grupos etarios, a excepción de los triglicéridos (significativamente mayores en mujeres de 5 a 11 años, p mayor 0,001).Conclusión. La comparación de nuestros resultados con los de otros autores nos permitió establecer diferencias con distinto grado de significación. El aporte del estudio del perfil lipídico en una población de niños y adolescentes podría ser de utilidad como referente para identificar factores de riesgo modificables y la necesidad de intervenciones conducentes a adoptar medidas de prevención desde edades tempranas.(AU)

Adrenergic nervous system influences on the induction of ventricular tachycardia.

BACKGROUND: Sudden cardiac death is a major cause of mortality in western countries and the ventricular tachyarrhythmias are mainly involved in this regard. The adrenergic autonomic nervous system has influences in provoking life-threatening arrhythmias, and the prevention of such arrhythmias with beta-blockers supports this viewpoint. To evaluate the effect of the adrenergic nervous system and some catecholamine-releasing stimuli on the induction of ventricular tachycardia, we decided to explore the occurrence of ventricular tachycardia in patients subjected to three consecutive tests, exercise testing, isoproterenol infusion, and mental stress. METHODS: Nineteen subjects who experienced exercise test-induced ventricular tachycardia were subjected to an isoproterenol infusion and mental stress. All but one patient had cardiac disease, with 70% due to Chagas' disease. Seventeen of the 19 study subjects had normal ventricular function. RESULTS: Exercise test-induced ventricular tachycardia was nonsustained in 17 patients and sustained in 2 cases. Isoproterenol infusion induced nonsustained ventricular tachycardia in 9 of 19 patients. Mental stress, on its own, was able to induce nonsustained ventricular tachycardia in 2 of 19 patients. CONCLUSIONS: Among patients preselected for exercise-induced ventricular tachycardia, almost half could be induced into ventricular tachycardia by isoproterenol infusion. Mental stress was a less powerful inducer of ventricular arrhythmias in this study group.