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1.
Clin Infect Dis ; 73(4): 672-679, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-33539531

RESUMO

BACKGROUND: Chagas disease is an infectious disease caused by the parasite Trypanosoma cruzi and is endemic from Latin American countries. The goal of our study was to identify novel genetic loci associated with chronic Chagas cardiomyopathy development in Chagas disease patients from different Latin American populations. METHODS: We performed a cross-sectional, nested case-control study including 3 sample collections from Colombia, Argentina, and Bolivia. Samples were genotyped to conduct a genome-wide association study (GWAS). These results were meta-analyzed with summary statistic data from Brazil, gathering a total of 3413 Chagas disease patients. To identify the functional impact of the associated variant and its proxies, we performed an in silico analysis of this region. RESULTS: The meta-analysis revealed a novel genome-wide statistically significant association with chronic Chagas cardiomyopathy development in rs2458298 (OR = 0.90, 95%CI = 0.87-0.94, P-value = 3.27 × 10-08), nearby the SAC3D1 gene. In addition, further in silico analyses displayed functional relationships between the associated variant and the SNX15, BAFT2, and FERMT3 genes, related to cardiovascular traits. CONCLUSIONS: Our findings support the role of the host genetic factors in the susceptibility to the development of the chronic cardiac form of this neglected disease.


Assuntos
Cardiomiopatia Chagásica , Doença de Chagas , Trypanosoma cruzi , Estudos de Casos e Controles , Cardiomiopatia Chagásica/genética , Estudos Transversais , Estudo de Associação Genômica Ampla , Humanos , Trypanosoma cruzi/genética
2.
Exp Parasitol ; 189: 19-27, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29726395

RESUMO

Combination therapies based on the available drugs have been proposed as promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been found to modify the evolution of the experimental infection. The objective of this study was to evaluate the combined effect of benznidazole (BZ) and clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro and their efficacy in a murine model. Life-stages of T. cruzi, BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and isobolograms and combination index (CI) were obtained. Swiss mice were infected with trypomastigotes and different treatment schedules were performed, each of which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated by comparing parasitemia, qPCR, survival and histological analysis. These results were analyzed using multivariate analysis to determine the combined effect of the drugs in vivo. CLO + BZ showed synergistic activity in vitro against the clinically relevant life-stages of T. cruzi. The most susceptible forms were the intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60), with no toxicity upon mammalian cells. The combination of both drugs CLO (1.25 mg/kg) and BZ (6.25 mg/kg), in vivo, significantly diminished the parasitic load in blood and the mortality rate. CLO + BZ presented a similar inflammatory response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ (6.25 mg/kg). Finally, the results from the principal component analysis reaffirmed that both drugs administered in combination presented higher activity compared with the individual administration in the acute experimental model.


Assuntos
Doença de Chagas/tratamento farmacológico , Clomipramina/farmacologia , Nitroimidazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Clomipramina/uso terapêutico , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Concentração Inibidora 50 , Masculino , Camundongos , Análise Multivariada , Músculo Esquelético/parasitologia , Músculo Esquelético/patologia , Miocárdio/patologia , Nitroimidazóis/uso terapêutico , Parasitemia/tratamento farmacológico , Análise de Componente Principal , Reação em Cadeia da Polimerase em Tempo Real , Tripanossomicidas/uso terapêutico
3.
Exp Mol Pathol ; 101(2): 274-280, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27677396

RESUMO

Clomipramine (CLO), a tricyclic antidepressant drug, has been used for the treatment of mice infected with Trypanosoma cruzi. In this work we evaluated the effectiveness of CLO treatment upon T. cruzi-infected mice in the chronic phase of the experimental infection using Quantitative polymerase chain reaction (qPCR) and recombinant ELISA. Sixty Swiss albino mice were inoculated with 50 trypomastigote forms of T. cruzi (Tulahuen strain). CLO treatment consisted of 5mg/kg/day during 60days by intraperitoneal injection, beginning on day 90 post infection (p.i) when the mice presented electrocardiographic (ECG) alterations compatible with the chronic phase of the disease. The evolution of experimental infection and the treatment efficacy were studied through survival, electrocardiography, serology using a mixture and individual (1, 2, 13, 30, 36 and SAPA) recombinant proteins from epimastigotes and trypomastigotes of T. cruzi; and qPCR on days 180 and 270 p.i. CLO treatment in the chronic phase decreased the parasite load, reduced the levels of antibodies against antigen 13 throughout 270days p.i and reversed the ECG abnormalities in the treated animals, from 100% of the mice with alterations at the beginning of the treatment to only 20% of the mice with alterations by day 270 p.i. This study shows that qPCR and the use of recombinant antigens are more sensitive to evaluate the effectiveness of the treatment and proves that clomipramine may be considered as a new chemotherapy for the chronic phase of the disease.


Assuntos
Doença de Chagas/sangue , Doença de Chagas/tratamento farmacológico , Clomipramina/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Sorologia/métodos , Trypanosoma cruzi/fisiologia , Animais , Anticorpos Antiprotozoários/sangue , Doença de Chagas/diagnóstico por imagem , Doença de Chagas/parasitologia , DNA de Protozoário/sangue , Eletrocardiografia , Feminino , Masculino , Camundongos , Parasitemia/tratamento farmacológico , Padrões de Referência , Análise de Sobrevida , Resultado do Tratamento , Trypanosoma cruzi/imunologia
4.
Exp Mol Pathol ; 98(3): 467-75, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25835781

RESUMO

Trypanosoma cruzi invasion and replication in cardiomyocytes and other tissues induce cellular injuries and cytotoxic reactions, with the production of inflammatory cytokines and nitric oxide, both sources of reactive oxygen species. The myocyte response to oxidative stress involves the progression of cellular changes primarily targeting mitochondria. Similar alterations could be taking place in mitochondria from the skeletal muscle; if that is the case, a simple skeletal muscle biopsy would give information about the cardiac energetic production that could be used as a predictor of the chagasic cardiopathy evolution. Therefore, in the present paper we studied skeletal muscle mitochondrial structure and the enzymatic activity of citrate synthase and respiratory chain complexes I to IV (CI-CIV), in Albino Swiss mice infected with T. cruzi, Tulahuen strain and SGO Z12 and Lucky isolates, along the infection. Changes in the mitochondrial structure were detected in 100% of the mitochondria analyzed from the infected groups: they all presented at least 1 significant abnormality such as increase in their matrix or disorganization of their cristae, which are probably related to the enzymatic dysfunction. When we studied the Krebs cycle functionality through the measurement of the specific citrate synthase activity, we found it to be significantly diminished during the acute phase of the infection in Tulahuen and SGO Z12 infected groups with respect to the control one; citrate synthase activity from the Lucky group was significantly increased (p<0.05). The activity of this enzyme was reduced in all the infected groups during the chronic asymptomatic phase (p<0.001) and return to normal values (Tulahuen and SGO Z12) or increased its activity (Lucky) by day 365 post-infection (p.i.). When the mitochondrial respiratory chain was analyzed from the acute to the chronic phase of the infection through the measurement of the activity of complexes I to IV, the activity of CI remained similar to control in Tulahuen and Lucky groups, but was significantly augmented in the SGO Z12 one in the acute and chronic phases (p<0.05). CII increased its activity in Tulahuen and Lucky groups by day 75 p.i. and in SGO Z12 by day 365 p.i. (p<0.05). CIII showed a similar behavior in the 3 infected groups, remaining similar to control values in the first two stages of the infection and significantly increasing later on (p<0.0001). CIV showed an increase in its activity in Lucky throughout all stages of infection (p<0.0001) and an increase in Tulahuen by day 365days p.i. (p<0.0001); SGO Z12 on the other hand, showed a decreased CIV activity at the same time. The structural changes in skeletal muscle mitochondria and their altered enzyme activity began in the acute phase of infection, probably modifying the ability of mitochondria to generate energy; these changes were not compensated in the rest of the phases of the infection. Chagas is a systemic disease, which produces not only heart damage but also permanent skeletal muscle alterations.


Assuntos
Doença de Chagas/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Animais , Doença de Chagas/patologia , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Masculino , Camundongos , Mitocôndrias Musculares/ultraestrutura , Músculo Esquelético/ultraestrutura
5.
Parasitology ; 140(3): 414-21, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23137884

RESUMO

Chagasic cardiopathy has become one of the most frequent causes of heart failure and sudden death, as well as one of the most common causes of cardio-embolic stroke in Latin America. The myocyte response to oxidative stress involves the progression of cellular changes, primarily targeting the mitochondria and modifying therefore the energy supply. In this paper we analysed the effect of the infection of mice with 2 different strains of Trypanosoma cruzi (Tulahuen and SGO Z12) in the chronic indeterminate stage (75 days post-infection), upon the structure and function of cardiac mitochondria. The structural results showed that 83% of the mitochondria from the Tulahuen-infected mice presented an increase in their matrix and 91% of the mitochondria from the SGO Z12-infected group showed a reduction in their diameter (P < 0.05). When the Krebs cycle and mitochondrial respiratory chain functionality was analysed through the measurement of the citrate synthase and complexes I to IV activity, it showed that their activity was altered in all cases in a similar manner in both infected groups. In this paper we have demonstrated that the chronic indeterminate phase is not 'silent' and that cardiac mitochondria are clearly involved in the genesis and progression to the chronic chagasic cardiopathy when different factors alter the host-parasite equilibrium.


Assuntos
Cardiomiopatia Chagásica/patologia , Cardiomiopatia Chagásica/fisiopatologia , Coração/parasitologia , Interações Hospedeiro-Parasita , Mitocôndrias/enzimologia , Mitocôndrias/parasitologia , Trypanosoma cruzi/patogenicidade , Animais , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Doença de Chagas/fisiopatologia , Doença Crônica , Citrato (si)-Sintase/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Eletrocardiografia , Feminino , Coração/fisiopatologia , Humanos , Masculino , Camundongos , Mitocôndrias/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Parasitemia/parasitologia , Parasitemia/fisiopatologia , Especificidade da Espécie , Trypanosoma cruzi/classificação
6.
Parasitol Int ; 80: 102213, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33137501

RESUMO

Host genetic factors have been proposed as determinants of the variable progression of Chagas disease (ChD). Two polymorphisms, H558R and A572D, of the voltage-gated sodium channel α-subunit SCN5A gene were studied in chagasic patients in order to determine their contribution to the susceptibility to the development and/or to the progression of the cardiovascular disease. A total of 104 patients were classified as seronegative or seropositive for Trypanosoma cruzi antibodies. Clinical evaluation, electrocardiograms (ECG) and echocardiograms (Echo) were performed to detect any conduction and/or structural alteration. Patients were classified into: G1: without ECG and/or Echo alterations, G2: with ECG alterations and G3: with ECG and Echo alterations. H558R and A572D polymorphisms were detected by PCR. Cardiac alterations were more frequent in G2 + G3 seropositive patients. For H558R polymorphism, the C allele was significantly increased in seropositive G2 + G3 patients (P = 0.049. OR = 2.08; 95% CI = 1.12-4.33). When comparing the disease cardiac progression (G2 vs G3), the genotypes from the H558R polymorphism were associated to more intense cardiac alterations (P = 0.018). For A572D polymorphism, no associations were found. The results suggest a possible involvement of SCN5A polymorphisms in the susceptibility to chronic ChD and the disease progression, contributing to the elucidation of the molecular mechanism underlying this complex myocardiopathy. In this regard, this is the first work that studies this gene in the context of chagasic cardiomyopathy.


Assuntos
Cardiomiopatia Chagásica/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Polimorfismo Genético , Adulto , Idoso , Argentina , Cardiomiopatia Chagásica/patologia , Feminino , Marcadores Genéticos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo
7.
Parasitol Res ; 107(5): 1279-83, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20680335

RESUMO

We have previously shown that clomipramine and allopurinol used separately are effective in preventing chronic chagasic cardiomyopathy. The aim of the present study was to evaluate the effect of the association of clomipramine (Clo--5 mg/kg/day/90 days) and allopurinol (Allo--5, 10, or 15 mg/kg/day/90 days) for the treatment of experimental Chagas disease in the acute stage. Treatment effectiveness was evaluated through parasitemia, survival, electrocardiography, serology, and cardiac histopathology. Groups treated showed no electrocardiographic abnormalities, in contrast to those untreated which presented 25% of mice with conduction alterations. The myocardium of treated mice (Clo, Allo10+Clo, and Allo15+Clo) presented no structural alterations. Cardiac b-receptor affinity was preserved in mice treated with Clo or Clo+Allo at the different doses; receptor density of the Clo and Allo15+Clo groups did not differ from the non-infected group. Anti-cruzipain antibody levels were similar in treated and untreated groups. Survival was significantly increased in the treated groups (p < 0.05), with Clo and all the Clo+Allo groups presenting the highest rates. These results show that the association of clomipramine + allopurinol is effective for Chagas disease treatment and has the same effect as clomipramine alone.


Assuntos
Alopurinol/administração & dosagem , Antiprotozoários/administração & dosagem , Doença de Chagas/tratamento farmacológico , Clomipramina/administração & dosagem , Animais , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Cisteína Endopeptidases/imunologia , Modelos Animais de Doenças , Quimioterapia Combinada , Eletrocardiografia , Masculino , Camundongos , Miocárdio/patologia , Parasitemia/tratamento farmacológico , Proteínas de Protozoários , Análise de Sobrevida , Resultado do Tratamento , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/isolamento & purificação
8.
Artigo em Espanhol | MEDLINE | ID: mdl-21450143

RESUMO

Multiple factors, both dependent on the host and the parasite are involved in determining resistance or susceptibility to infection with T. cruzi, but the influence of the sex of the host is a factor that has not been clearly established. In this paper we analyzed the influence of this factor upon the infected individuals. We used Swiss albino mice infected with 50 trypomastigotes / mouse of T. cruzi, strain Tulahuen: males (n = 73) and females (n = 64). The highest parasitemia was detected on day 21 post-infection (pi) in both males and females and became negative on day 56 pi, and males exhibited significantly higher levels of parasitemia. The highest mortality occurred between day 21 and day 28 pi; by day 270 pi (chronic stage) one male (3%) survived every 7.6 females (23%). In skeletal muscle of male and female mice on days 90, 180 and 270 pi, lympho-monocitary infiltrates were found nests of amastigotes, whereas the myocardium of these animals showed inflammatory infiltrates only. We conclude that males showed greater susceptibility to infection and higher mortality than females in this mouse model infected with T. cruzi, Tulahuen strain, but the characteristics of the infection and cardiomyopathy development are similar in nature.


Assuntos
Doença de Chagas/parasitologia , Interações Hospedeiro-Parasita/fisiologia , Parasitemia/parasitologia , Fatores Sexuais , Trypanosoma cruzi/fisiologia , Animais , Doença de Chagas/mortalidade , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Masculino , Camundongos
9.
Rev Fac Cien Med Univ Nac Cordoba ; 77(4): 276-280, 2020 12 01.
Artigo em Espanhol | MEDLINE | ID: mdl-33351388

RESUMO

Introduction: Two different methods are used in goniometry of the ankle: the neutral zero method (N0M) and the bone reference method (BRM). In addition, the N0M has a subtype (N0I), with a different technique. Purpose: To determine the average of the amplitude of flexion-extension of the ankle, measured in different body positions, using N0M, N0I and BRM, in young adults of both sexes, with the objective of providing evidence so that the ankle goniometry is more reliable. Material and methods: 190 students from the School of Kinesiology and Physiotherapy were studied, using the three methods of joint measurement in 4 different body positions; the amplitude of flex-extension in an ankle per student was evaluated. Results: In most positions, the measurements were different in the three methods compared (P<0.05). The M0 and M0I methods yielded similar results in some comparisons. The patient's position also significantly influences the result obtained. Dorsal ankle flexion was similar between men and women in most of the methods and positions; the plantar flexion that was greater in women in all cases (P<0.0001). The full flex-extension value, in most cases, was higher in women than in men (P<0.001). Conclusions: Both the method and the patient's position significantly influence the results of the goniometric measurement. Gender influences the joint width of the plantar ankle flexion, regardless of the measurement method used.


Introducción: En la goniometría de tobillo se utilizan dos métodos diferentes, el método cero neutral (M0N) y el método de referencias óseas (MRO). Además, el M0N tiene un subtipo (M0I), con una técnica diferente. Objetivo: Determinar el promedio de la amplitud de flexo-extensión de tobillo, medida en diferentes posiciones corporales, utilizando M0N, M0I y MRO, en adultos jóvenes de ambos sexos, con el objetivo de aportar evidencia para que la goniometría de tobillo sea más fiable. Materiales y Métodos: Se estudiaron 190 alumnos de la Escuela de Kinesiología y Fisioterapia, utilizando los tres métodos de medición articular en 4 posiciones corporales diferentes; se evaluó la amplitud de flexo-extensión en un tobillo por alumno. Resultados: En la mayoría de las posiciones, las mediciones fueron diferentes en los tres métodos comparados (P<0,05). Los métodos M0 y M0I arrojaron resultados similares en algunas comparaciones puntuales. La posición del paciente también influye significativamente en el resultado obtenido. La flexión dorsal de tobillo fue similar entre hombres y mujeres en la mayoría de los métodos y posiciones del paciente, no así la flexión plantar que fue mayor en las mujeres en todos los casos (P<0,0001). El valor completo de flexo-extensión, en la mayoría de los casos fue mayor en las mujeres que en los varones (P<0,001). Conclusiones: Tanto el método como la posición del paciente influyen significativamente en los resultados de la medición goniométrica. El género influye en la amplitud articular de la flexión plantar de tobillo, independientemente del método de medición utilizado.


Assuntos
Tornozelo , Artrometria Articular , Articulação do Tornozelo , Feminino , Humanos , Masculino , Amplitude de Movimento Articular , Adulto Jovem
10.
Artigo em Inglês | MEDLINE | ID: mdl-32074218

RESUMO

Proinflammatory and inflammatory mediators induced by Trypanosoma cruzi infection increase the oxidative stress, generating toxicity for cells targeting mitochondria of different tissues. We studied the activity of citrate synthase and complexes I-IV of respiratory chain in mitochondria of blood lymphomonocyte fraction, from albino Swiss mice infected with different isolates of T. cruzi , during Chagas disease evolution. Complexes I-IV were modified in infected groups (p<0.05) in all the stages, and an inflammatory process of different magnitudes was detected in the heart and skeletal muscle according to the isolate. The citrate synthase activity presented modifications in the SGO Z12 and the Tulahuen group (p<0.05). Hearts showed fiber fragmentation and fibrosis; skeletal muscle presented inflammatory infiltrates and in the Tulahuen infected group, there were also amastigote nests. The inflammatory processes produced an oxidative stress that induced different alterations of mitochondrial enzymes activities in the lymphomonocyte fraction that can be detected by a simple blood extraction, suggesting that they could be used as disease markers, especially in the indeterminate phase of Chagas disease.


Assuntos
Doença de Chagas/enzimologia , Citrato (si)-Sintase/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/enzimologia , Animais , Doença de Chagas/metabolismo , Doença de Chagas/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Masculino , Mitocôndrias/parasitologia , Mitocôndrias/patologia , Parasitemia
11.
Acta Trop ; 210: 105546, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32492396

RESUMO

The aim of the present study was to analyze IL6 rs1800795 genetic variant in the susceptibility to Trypanosoma cruzi infection and in the development of chronic Chagas cardiomyopathy (CCC), in five independent Latin American cohorts. A total of 3,087 individuals from Latin American countries (Argentina, Bolivia, Peru, and two cohorts from Colombia) were studied. In all cohorts, patients were classified as seropositive for T. cruzi antigens (n= 1,963) and seronegative (n= 1,124). Based on clinical evaluation, the seropositive patients, were classified as CCC (n= 900) and asymptomatic (n= 1,063). No statistically significant differences in the frequency of IL6 rs1800795 between seropositive and seronegative, or between CCC and asymptomatic patients, were found. Furthermore, after the meta-analysis no statistically significant differences were observed. Our results do not support a contribution of IL6 rs1800795 genetic variant in the susceptibility to the infection and the development of chronic Chagas cardiomyopathy in the studied populations.


Assuntos
Cardiomiopatia Chagásica/genética , Predisposição Genética para Doença , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Cardiomiopatia Chagásica/etiologia , Doença Crônica , Feminino , Humanos , América Latina , Masculino , Pessoa de Meia-Idade
12.
Sci Rep ; 10(1): 5015, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193469

RESUMO

Genetic factors and the immunologic response have been suggested to determine the susceptibility against the infection and the outcome of Chagas disease. In the present study, we analysed three IL17A genetic variants (rs4711998, rs8193036 and rs2275913) regarding the predisposition to Trypanosoma cruzi infection and the development of chronic Chagas cardiomyopathy (CCC) in different Latin American populations. A total of 2,967 individuals from Colombia, Argentina, Bolivia and Brazil, were included in this study. The individuals were classified as seronegative and seropositive for T. cruzi antigens, and this last group were divided into asymptomatic and CCC. For T. cruzi infection susceptibility, the IL17A rs2275913*A showed a significant association in a fixed-effect meta-analysis after a Bonferroni correction (P = 0.016, OR = 1.21, 95%CI = 1.06-1.41). No evidence of association was detected when comparing CCC vs. asymptomatic patients. However, when CCC were compared with seronegative individuals, it showed a nominal association in the meta-analysis (P = 0.040, OR = 1.20, 95%CI = 1.01-1.45). For the IL17A rs4711998 and rs8193036, no association was observed. In conclusion, our results suggest that IL17A rs2275913 plays an important role in the susceptibility to T. cruzi infection and could also be implicated in the development of chronic cardiomyopathy in the studied Latin American population.


Assuntos
Doença de Chagas/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Interleucina-17/genética , Polimorfismo Genético/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Chagas/etiologia , Feminino , Humanos , América Latina , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade
13.
PLoS Negl Trop Dis ; 13(11): e0007859, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31751351

RESUMO

Host genetic factors have been suggested to play an important role in the susceptibility to Chagas disease. Given the influence of interleukin 18 (IL-18) in the development of the disease, in the present study, we analyzed three IL18 genetic variants (rs2043055, rs1946518, rs360719) regarding the predisposition to Trypanosoma cruzi infection and the development of chronic Chagas cardiomyopathy (CCC), in different Latin America populations. Genetic data of 3,608 patients from Colombia, Bolivia, Argentina, and Brazil were meta-analyzed to validate previous findings with increased statistical power. Seropositive and seronegative individuals were compared for T. cruzi infection susceptibility. In the Colombian cohort, the allelic frequencies of the three variants showed a significant association, with adjustment for sex and age, and also after applying multiple testing adjustments. Among the Colombian and Argentinean cohorts, rs360719 showed a significant genetic effect in a fixed-effects meta-analysis after a Bonferroni correction (OR: 0.76, CI: 0.66-0.89, P = 0.001). For CCC, the rs2043055 showed an association with protection from cardiomyopathy in the Colombian cohort (OR: 0.79, CI: 0.64-0.99, P = 0.037), with adjustment for sex and age, and after applying multiple testing adjustments. The meta-analysis of the CCC vs. asymptomatic patients from the four cohorts showed no evidence of association. In conclusion, our results validated the association found previously in the Colombian cohort suggesting that IL18 rs360719 plays an important role in the susceptibility to T. cruzi infection and no evidence of association was found between the IL18 genetic variants and CCC in the Latin American population studied.


Assuntos
Doença de Chagas/genética , Interleucina-18/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Argentina , Bolívia , Brasil , Doença de Chagas/parasitologia , Estudos de Coortes , Colômbia , Feminino , Predisposição Genética para Doença , Hispânico ou Latino/genética , Humanos , América Latina , Masculino , Pessoa de Meia-Idade , Trypanosoma cruzi/fisiologia , Adulto Jovem
14.
World J Gastroenterol ; 14(28): 4454-61, 2008 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-18680223

RESUMO

AIM: To evaluate the role of genetic factors in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC), we investigated the single nucleotide polymorphisms (SNPs) of NOD2/CARD15 (R702W, G908R and L1007finsC), and Toll-like receptor 4 (TLR4) genes (D299G and T399I) in a selected inflammatory bowel disease (IBD) population coming from Southern Italy. METHODS: Allele and genotype frequencies of NOD2/CARD15 (R702W, G908R and L1007finsC) and TLR4 (D299G and T399I) SNPs were examined in 133 CD patients, in 45 UC patients, and in 103 healthy controls. A genotype-phenotype correlation was performed. RESULTS: NOD2/CARD15 R702W mutation was significantly more frequent in CD (9.8%) than in controls (2.4%, P = 0.001) and in UC (2.3%, P = 0.03). No significant difference was found between UC patients and control group (P > 0.05). In CD and UC patients, no significant association with G908R variant was found. L1007finsC SNP showed an association with CD (9.8%) compared with controls (2.9%, P = 0.002) and UC patients (2.3%, P = 0.01). Moreover, in CD patients, G908R and L1007finsC mutations were significantly associated with different phenotypes compared to CD wild-type patients. No association of IBD with the TLR4 SNPs was found in either cohort (allele frequencies: D299G-controls 3.9%, CD 3.7%, UC 3.4%, P > 0.05; T399I-controls 2.9%, CD 3.0%, UC 3.4%, P > 0.05). CONCLUSION: These findings confirm that, in our IBD patients selected from Southern Italy, the NOD2/CARD15, but not TLR4 SNPs, are associated with increased risk of CD.


Assuntos
Doenças Inflamatórias Intestinais/genética , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor 4 Toll-Like/genética , Adulto , Estudos de Casos e Controles , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/etnologia , Colite Ulcerativa/genética , Doença de Crohn/epidemiologia , Doença de Crohn/etnologia , Doença de Crohn/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/etnologia , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco
15.
Life Sci ; 74(22): 2749-56, 2004 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-15043989

RESUMO

Biologic therapies, namely antibodies against tumor necrosis factor-alpha (TNF- alpha) or its receptors, have been recently introduced for the treatment of patients with inflammatory bowel disease (IBD). In the present study the effects of cloricromene, an agent with known antithrombotic actions and with demonstrated anti-TNF- alpha activity were investigated in a rat model of experimental colitis induced with dinitrobenzenesulphonic acid (DNB)/ethanol. We investigated three experimental groups: (i) sham-colitis with vehicle-treatment (controls, n = 6), (ii) colitis with vehicle-treatment (saline, 0.1 ml s.c., daily) (DNB-V, n = 7), (iii) colitis with cloricromene-treatment (10 mg/kg/day s.c.; DNB-C, n = 8). After 7 days, the weight gain, colon wet weight, macroscopic damage score, coagulation parameters, colon mucosal myeloperoxidase activity (MPO), and tissue concentrations of TNF- alpha and of macrophage inhibitory peptide-2 (MIP-2) were assessed. The macroscopic damage scores, colon wet weights, and tissue MIP-2 levels were significantly increased in untreated and in cloricromene-treated rats compared with controls. Cloricromene treatment was associated with a minor body weight loss (p < 0.025) and significantly reduced tissue concentrations of MPO and TNF-alpha (p < 0.02, both). Blood coagulation parameters were not affected by treatment. In the DNB-model treatment with cloricromene effectively reduces tissue levels of TNF- alpha and of myeloperoxidase, whereas MIP-2 concentrations were not influenced. Blood coagulation parameters remained unchanged indicating safety of treatment. Since biological therapies frequently fail to improve disease course of IBD, other therapies with similar targets should be further investigated.


Assuntos
Cromonar/análogos & derivados , Cromonar/uso terapêutico , Colite/prevenção & controle , Colo/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Animais , Benzenossulfonatos , Peso Corporal/efeitos dos fármacos , Quimiocina CXCL2 , Cromonar/administração & dosagem , Colite/induzido quimicamente , Colite/patologia , Colo/enzimologia , Colo/patologia , Injeções Subcutâneas , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Monocinas/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Peroxidase/metabolismo , Inibidores da Agregação Plaquetária/administração & dosagem , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
16.
Arch Med Res ; 45(3): 237-46, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24657595

RESUMO

BACKGROUND AND AIMS: The fundamental mechanisms involved in the genesis and progression of heart failure are not clearly understood. The present study was conducted to analyze the cardiac mitochondrial involvement in heart failure, the possible parallelism between cardiac and skeletal muscle and if there is a link between clinical symptoms and mitochondrial damage. METHODS: Left ventricle and pectoral biopsies were obtained from patients with heart failure (n: 21) and patients with inter-auricular communication as the unique diagnosis for surgery (n: 6). Mitochondria were isolated from these tissues and studied through electron microscopy, spectrophotometry to measure the activity of respiratory complex III and immunohistochemistry to determine the presence of reactive oxygen species. RESULTS: More than 90% of cardiac and skeletal muscle mitochondria presented structural and functional alterations in relation to an increment in the reactive oxygen species production, even in patients without the presence of any clinical Framingham criteria. CONCLUSIONS: We demonstrated some parallelism between cardiac and skeletal muscle mitochondrial alterations in patients with heart failure and that these alterations begin before the major clinical Framingham criteria are installed, pointing to mitochondria as one of the possibly responsible factors for the evolution of cardiac disease.


Assuntos
Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/ultraestrutura , Músculo Esquelético/ultraestrutura , Miocárdio/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo
17.
Trans R Soc Trop Med Hyg ; 105(5): 239-46, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21470646

RESUMO

The pathogenesis of chronic chagasic cardiopathy is still under discussion; there is considerable evidence that inflammatory infiltrates and their mediators have a direct effect on cardiac cells. Here we studied the structure and function of cardiac mitochondria in chronic chagasic myocardiopathy. Cardiac mitochondrial structure and enzyme activity of citrate synthase and complexes I to IV of the respiratory chain were studied in albino Swiss mice infected with Trypanosoma cruzi (Tulahuen strain or SGO Z12 isolate) on 365 days post-infection (dpi). The presence of parasites in cardiac and skeletal muscle was also investigated. The activity of complexes I to IV was altered in different ways, according to the strain employed (P<0.0001), in relation to the cristae disorganisation and the parasite persistence found in the Tulahuen group, and the chronic inflammatory process described in both groups; citrate synthase activity also increased in both infected groups. Changes in mitochondrial structure were detected in 89% of Tulahuen- and 58% of SGO Z12-infected mice. In this paper we demonstrate that parasite persistence and inflammation are likely to be involved in the structural and functional alterations in cardiac mitochondria from chronically T. cruzi-infected mice, demonstrating that the parasite strain determines different mitochondrial changes in chagasic cardiopathy.


Assuntos
Cardiomiopatia Chagásica/parasitologia , Mitocôndrias Cardíacas/parasitologia , Trypanosoma cruzi , Animais , Respiração Celular/fisiologia , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/fisiopatologia , Doença Crônica , Progressão da Doença , Feminino , Coração/parasitologia , Masculino , Camundongos , Mitocôndrias Cardíacas/fisiologia , Músculo Esquelético/parasitologia , Taxa de Sobrevida
18.
Parasitol Res ; 103(3): 663-9, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18512075

RESUMO

Treatment of Chagas disease is a controversial issue because the available drugs are highly toxic. Clomipramine is a tricyclic antidepressant drug that inhibits Trypanosoma cruzi's trypanothione reductase, provoking the death of the parasite and preventing the cardiac damage when used for the treatment of acutely infected mice. Here, we studied the effectiveness of clomipramine (5 mg/kg/day for one month) as chemotherapy for T. cruzi-infected mice in the chronic indeterminate stage of the infection. The animals were analyzed in the cardiac chronic phase. Survival of treated animals was 84% while for the untreated ones was 40%; most of the animals presented electrocardiographic abnormalities. Affinity and density of cardiac beta receptors from infected and treated mice were similar to those in the indeterminate phase, showing that clomipramine treatment stopped the increment of functional alterations provoked by the infection, while untreated mice presented affinity and density significantly diminished. Hearts from infected and untreated mice in the chronic stage presented mononuclear cells, necrosis and fiber dissolution while hearts from treated animals showed only isolated inflammatory infiltrates. Present results demonstrate that clomipramine used in the chronic indeterminate phase of the T. cruzi infection modified the natural evolution of the chagasic cardiopathy.


Assuntos
Antiprotozoários/uso terapêutico , Doença de Chagas/tratamento farmacológico , Clomipramina/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Animais , Doença de Chagas/fisiopatologia , Eletrocardiografia , Coração/fisiopatologia , Camundongos , Miocárdio/patologia , Receptores Adrenérgicos/fisiologia , Análise de Sobrevida
19.
Anal Bioanal Chem ; 389(6): 1755-63, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17589835

RESUMO

The present research is focused on the development of a comprehensive two-dimensional gas chromatography-rapid scanning quadrupole mass spectrometric (GC x GC-qMS) methodology for the analysis of trace-amount pesticides contained in a complex real-world sample. Reliable peak assignment was carried out by using a recently developed, dedicated pesticide MS library (for comprehensive GC analysis), characterized by a twin-filter search procedure, the first based on a minimum degree of spectral similarity and the second on the interactive use of linear retention indices (LRI). The library was constructed by subjecting mixtures of commonly used pesticides to GC x GC-qMS analysis and then deriving their pure mass spectra and LRI values. In order to verify the effectiveness of the approach, a pesticide-contaminated red grapefruit extract was analysed. The certainty of peak assignment was attained by exploiting both the enhanced separation power of dual-oven GC x GC and the highly effective search procedure.


Assuntos
Citrus paradisi/química , Análise de Alimentos/métodos , Contaminação de Alimentos/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Resíduos de Praguicidas/isolamento & purificação , Resíduos de Praguicidas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
20.
Parasitol Res ; 101(5): 1459-62, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17619906

RESUMO

There is a real need for new and less toxic drugs for the treatment of Chagas disease, as nifurtimox and benznidazole are effective but toxic and provoke unpleasant side effects, especially in adult patients. Allopurinol, commonly used to treat the hiperuricemia, is also used by the Trypanosoma cruzi's hypoxantine guanine fosforyltransferase as an alternative substrate incorporating it into the parasite's ribonucleic acid, provoking the death of the parasite. However, the results of using allopurinol as chemotherapy for Chagas disease are not clear. For that, we investigated the evolution of the T. cruzi infection in mice treated with allopurinol (5, 10 or 15 mg/kg for 90 days) obtaining a reduction in the parasitaemia (p<0.05), no electrocardiographic alterations (p<0.05) and a conserved myocardial and cardiac beta-receptors' affinity values with the highest dose of the drug, compared to those of the uninfected mice. Cruzipain immunoglobulin G levels remained high in all the groups as well as the survival (70%, 90 days post-infection). Allopurinol prevented the acute phase evolving into the chronic cardiac disease.


Assuntos
Alopurinol/uso terapêutico , Doença de Chagas/tratamento farmacológico , Trypanosoma cruzi/efeitos dos fármacos , Alopurinol/administração & dosagem , Animais , Anticorpos Antiprotozoários/sangue , Doença de Chagas/parasitologia , Doença de Chagas/fisiopatologia , Cisteína Endopeptidases/imunologia , Eletrocardiografia , Masculino , Camundongos , Miocárdio/patologia , Parasitemia , Proteínas de Protozoários , Análise de Sobrevida , Trypanosoma cruzi/crescimento & desenvolvimento
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