RESUMO
For over 60 years, selenium (Se) has been known as an essential microelement to many biological functions, including cardiovascular homeostasis. This review presents a compilation of studies conducted in the past 20 years related to chronic Chagas disease cardiomyopathy (CCC), caused by Trypanosoma cruzi infection, a neglected disease that represents a global burden, especially in Latin America. Experimental and clinical data indicate that Se may be used as a complementary therapy to prevent heart failure and improve heart function. Starting from the main questions "Is Se deficiency related to heart inflammation and arrhythmogenesis in CCC?" and "Could Se be recommended as a therapeutic strategy for CCC?", we show evidence implicating the complex and multidetermined CCC physiopathology, discussing its possible interplays with the multifunctional cytokine TGF-ß as regulators of immune response and fibrosis. We present two new proposals to face this global public health challenge in vulnerable populations affected by this parasitic disease: fibrosis modulation mediated by TGF-ß pathways and the possible use of selenoproteins as antioxidants regulating the increased reactive oxygen stress present in CCC inflammatory environments. We assess the opportunity to consider the beneficial effects of Se in preventing heart failure as a concept to be applied for CCC patients.
Assuntos
Doença de Chagas , Doenças Transmissíveis , Insuficiência Cardíaca , Selênio , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Fibrose , Humanos , Selênio/uso terapêutico , Fator de Crescimento Transformador beta , Trypanosoma cruzi/fisiologiaRESUMO
BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH AND RESULTS: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10-5 ) and Europeans (P = 9 × 10-5 ). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10-6 ). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. CONCLUSIONS: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.
Assuntos
Índice de Massa Corporal , Proteína C-Reativa/análise , Neoplasias da Vesícula Biliar/etiologia , Cálculos Biliares/complicações , Adulto , Fatores Etários , Chile/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Neoplasias da Vesícula Biliar/epidemiologia , Neoplasias da Vesícula Biliar/genética , Cálculos Biliares/epidemiologia , Predisposição Genética para Doença/genética , Variação Genética , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence. METHODS: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication. RESULTS: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low. CONCLUSION: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Neoplasias da Vesícula Biliar/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Chile/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Neoplasias da Vesícula Biliar/epidemiologia , Estudos de Associação Genética , Humanos , Indígenas Sul-Americanos/genética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , População Branca/genéticaRESUMO
BACKGROUND: Gallbladder cancer (GBC), although infrequent in industrialized countries, has high incidence rates in certain world regions, being a leading cause of death among elderly Chilean women. Surgery is the only effective treatment, and a five-year survival rate of advanced-stage patients is less than 10%. Hence, exploring immunotherapy is relevant, although GBC immunogenicity is poorly understood. This study examined the relationship between the host immune response and GBC patient survival based on the presence of tumor-infiltrating lymphocytes at different disease stages. METHODS: Tumor tissues from 80 GBC patients were analyzed by immunohistochemistry for the presence of CD3+, CD4+, CD8+, and Foxp3+ T cell populations, and the results were associated with clinical stage and patient survival. RESULTS: The majority of tumor samples showed CD3+ T cell infiltration, which correlated with better prognosis, particularly in advanced disease stages. CD8+, but not CD4+, T cell infiltration correlated with improved survival, particularly in advanced disease stages. Interestingly, a < 1 CD4+/CD8+ T cell ratio was related with increased survival. Additionally, the presence of Foxp3+ T cells correlated with decreased patient survival, whereas a ≤ 1 Foxp3+/CD8+ T cell ratio was associated with improved patient survival. CONCLUSIONS: Depending on the disease stage, the presence of CD8+ and absence of Foxp3+ T cell populations in tumor tissues correlated with improved GBC patient survival, and thus represent potential markers for prognosis and management of advanced disease, and supports testing of immunotherapy.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiorradioterapia Adjuvante/mortalidade , Fatores de Transcrição Forkhead/metabolismo , Neoplasias da Vesícula Biliar/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Adulto , Idoso , Feminino , Seguimentos , Neoplasias da Vesícula Biliar/imunologia , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
Pathogens may impair reproduction in association or not with congenital infections. We have investigated the effect of acute infection with Trypanosoma cruzi, the protozoan agent of Chagas disease, on reproduction of female mice. In the acute, parasitemic, phase of the infection, female mice were totally unable to reproduce. Most of them (80%) were infertiles and did not develop any gestation. In the few gravid infected mice, implantation numbers were as in uninfected control mice. However, their fetuses presented a weight meanly reduced by 40% as compared to those of uninfected females, and all of them died during the gestation or whithin 48 h after birth. Such massive mortality did not result from congenital infection, which did not occur. The infertility and the fetal mortality occuring early in gestation (resorptions) were significantly correlated with a high maternal parasitemia, whereas later fetal mortality was associated with the presence of intracellular parasites in the utero-placental unit. The decidua was particularly receptive to T. cruzi multiplication, since this tissue harboured 125 fold more amastigotes than the maternal heart or other placental tissues. In addition, placentas of dead fetuses presented histopathological lesions (inflammatory infiltrates, fibrine deposits and ischemic necrosis). Such harmfull effects of acute infection were not observed when female mice were in the chronic phase of the infection, since these reproduce normally. Their fetuses only suffered from moderate and reversible growth retardation. These results indicate that, following the maternal parasite burden, T. cruzi infection may induce very deleterious effects on gestation.
Assuntos
Doença de Chagas/complicações , Morte Fetal/parasitologia , Infertilidade/parasitologia , Complicações Parasitárias na Gravidez , Trypanosoma cruzi , Doença Aguda , Animais , Doença Crônica , Feminino , Morte Fetal/patologia , Camundongos , Camundongos Endogâmicos BALB C , Necrose , Placenta/parasitologia , Gravidez , Trypanosoma cruzi/patogenicidadeRESUMO
Objetivo: Describir las características clínicas y epidemiológicas de la epilepsia-ausencias en niños en el Hospital Nacional Cayetano Heredia (HNCH). Materiales y Métodos: Estudio descriptivo-retrospectivo. Se identificaron los pacientes con diagnóstico de ausencias del Servicio de Neuropediatría atendidos desde enero de 1998 hasta diciembre del 2002. Criterios de inclusión: manifestaciones clínicas de ausencias y electroencefalograma característico. Exclusión: pacientes con lesiones cerebrales. Resultados: Se incluyeron 33 pacientes (6.4 por ciento del total). La edad promedio al inicio de enfermedad fue 6.6 años, sexo femenino: 54.5 por ciento y tiempo de enfermedad antes del diagnóstico: 12.5 meses. Presentaron antecedente familiar de convulsiones 30.3 por ciento y antecedente de eventos perinatales adversos 18.2 por ciento. El 39.4 por ciento de pacientes presentó ausencias simples y 60.6 por ciento ausencias complejas. El 36.4 por ciento tuvo inicialmente un patrón electroencefalográfico bilateral asimétrico que posteriormente se tornó simétrico. Todos recibieron ácido valproico pero en 6 por ciento se tuvo que cambiar de medicación debido a efectos adversos y 12 por ciento tuvieron que recibir terapia combinada por falta de control. Edad, sexo, tipo de crisis, EEG, antecedentes familiares o perinatales no influyeron en las características clínicas, electroencefalográficas o respuesta terapéutica. Conclusión: Las ausencias complejas con automatismos son las más frecuentes y el ácido valproico es un tratamiento efectivo. El tiempo de enfermedad antes del diagnóstico fue 12.5 meses por lo cual se recomienda mayor difusión a nivel de padres, educadores y personal de salud para diagnósitco y control oportunos.
Assuntos
Humanos , Masculino , Pré-Escolar , Feminino , Criança , Epilepsia Tipo Ausência , Estudos Retrospectivos , Epidemiologia DescritivaRESUMO
Micronutrient deficiencies and infectious disease often coexist and show complex interactions leading to mutually reinforced detrimental clinical effects. Such a combination is predominantly observed in underprivileged people of developing countries, particularly in rural regions. Several micronutrients such as trace elements (zinc, iron, selenium) modulate immune function and influence the susceptibility of the host to infection. Nevertheless, the effect of individual micronutrients on components of innate immunity is difficult to design and interpret. Micronutrient deficiency, in general, has a widespread effect on nearly all components of the innate immune response. Chagas' disease is a pertinent model to study interaction of nutrition, immunity and infection, as it implies many components of innate immunity. An important question is whether alterations on micronutrient intake modify the course of infection. Some interactions of trace elements with innate immunity and acute inflammatory response are reviewed in this article with a special focus on selenium deficiency and Trypanosoma cruzi infection.
Assuntos
Imunidade Inata/fisiologia , Parasitos/imunologia , Oligoelementos/fisiologia , Reação de Fase Aguda/imunologia , Animais , Humanos , Deficiências de Ferro , Modelos Biológicos , Nematoides/imunologia , Selênio/deficiência , Trypanosoma cruzi/imunologia , Zinco/deficiênciaRESUMO
Chagasic patients with cardiomyopathy have low levels of selenium (Se), a fundamental trace element. We evaluated the effect of supplementing infected mice with Se (0.25-16 ppm). Supplementation with 0.25 or 1 ppm Se led to parasitaemia and survival curves similar to those of the control group. Mice treated with 4-16 ppm showed a dose-dependent decrease of parasitaemia, significant for the highest concentration. This was probably due to a direct effect on the parasites, which were lysed after in vitro incubation with Se. Survival rates did not change significantly; however, heart damage was reduced in infected mice supplemented with 4 ppm Se, as indicated by a lower cardiac isoform of creatine kinase levels. Our results imply that Se supplementation does not lead to a general protection during infection, but may help protect the heart from inflammatory damage. The effect of Se supplementation in the course of T. cruzi infection depends on the host-parasite pair employed.
Assuntos
Cardiomiopatia Chagásica/tratamento farmacológico , Suplementos Nutricionais , Miocárdio/patologia , Selênio/uso terapêutico , Doença Aguda , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Doença Crônica , Relação Dose-Resposta a Droga , Feminino , Camundongos , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Parasitemia/patologia , Selênio/administração & dosagem , Resultado do Tratamento , Trypanosoma cruzi/patogenicidadeRESUMO
Selenium (Se) deficiency is linked with some cardiomyopathies. Its status was determined in 170 patients with chronic Chagas' disease from 2 Brazilian regions (Rio de Janeiro and Belo Horizonte), clinically stratified into groups as follows: indeterminate or asymptomatic (IND); cardiac asymptomatic (CARDa); cardiac symptomatic with moderate to severe heart dysfunction (CARDb); and healthy adults (HA), used for comparison. In most HA, Se levels were normal, excluding an overall Se deficiency. Se was significantly lower in CARDb than in HA, IND, or CARDa patients. This was not associated with a concomitant decrease in activity of glutathione peroxidase. Thyrotropin was normal, excluding iodine deficiency. Se correlated positive and significantly with ventricular ejection fraction (assessed via echocardiography). Asymptomatic children with acute Chagas' disease had normal Se as well as 5 noninfectious cases of cardiomyopathy. Low Se was found in 6 of 10 chagasic patients with digestive megasyndromes. Thus, the decrease in Se in chagasic patients seems to be a biological marker for Trypanosoma cruzi infection and related to the progression of pathology.
Assuntos
Cardiomiopatia Chagásica/fisiopatologia , Glutationa Peroxidase/sangue , Selênio/deficiência , Animais , Anticorpos Antiprotozoários/sangue , Brasil , Cardiomiopatia Chagásica/imunologia , Doença de Chagas/imunologia , Doença de Chagas/fisiopatologia , Criança , Progressão da Doença , Humanos , Imunoglobulina G/sangue , Pessoa de Meia-Idade , Análise de Regressão , Selênio/sangue , Tireotropina/sangue , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/isolamento & purificaçãoRESUMO
Selenium is an essential trace element and its deficiency was implicated in heart diseases. We recently showed low Se levels in chronic chagasic patients with cardiomyopathy. Herein, mice were depleted in Se by feeding the mothers with chow containing only 0.005 mg Se/kg and maintaining this diet for offspring, that were further infected with Trypanosoma cruzi. Survival rate was significantly lower in Se deficient than in control mice. Parasitemia was similar in all groups. Necrotic heart lesions were found after infection (high CK-MB levels). No outbreaks of parasite growth were detected in chronic survivors submitted or not to a second Se depletion. The present results confirm our hypothesis that a nutritional deficiency in Se is associated to a higher mortality during T. cruzi infection. The potential beneficial effect of Se supplementation is a perspective. Hypothesis to explain the higher susceptibility of Se-depleted mice to T. cruzi infection are discussed.
Assuntos
Doença de Chagas/mortalidade , Parasitemia/mortalidade , Selênio/deficiência , Animais , Cardiomiopatia Chagásica/patologia , Doença de Chagas/complicações , Doença de Chagas/imunologia , Doença Crônica , Creatina Quinase/sangue , Creatina Quinase Forma MB , Suscetibilidade a Doenças , Feminino , Isoenzimas/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Necrose , Parasitemia/complicações , Parasitemia/imunologia , Gravidez , Taxa de SobrevidaRESUMO
Las formas limítrofes de alteración de la conciencia pueden ser tanto un fenómeno patológico como un conflicto que expresa las contradicciones psicológicas que propician o entorpecen la adaptación a las condiciones del entorno. Cualquier fenómeno que actúe sobre algún sistema de la actividad del organismo puede convertirse en factor traumatizante y la respuesta tendrá determinadas características dependiendo de la intensidad y duración de la acción de aquel. La exploración clínica de 100 personas de la región de Tepito en el Distrito Federal de México, que fueron afectadas en sus bienes materiales por los movimientos telúricos de septiembre de 1985 permitío detectar algunos síntomas psíquicos a nivel de primer registro, respuesta que pareciera estar vinculada a particulares neuro-psíquicas, psico-sociales y afectivo-personales de las mismas, siendo importante no sólo el momento mismo del impacto sino también la historia de las vivencias significativas y el grado de tensión emocional previo en cada una de ellas