Intestinal permeability evaluation in patients with chronic Chagas heart failure.

AIMS: We analysed intestinal permeability in patients with chronic Chagas cardiomyopathy (CCC) and evaluated its association with clinical manifestations, haemodynamic parameters measured by echocardiogram, and disease outcome. Intestinal permeability was compared between CCC patients and a group of healthy controls. BACKGROUND: Intestinal dysfunction may contribute to a more severe disease presentation with worse outcome in patients with CCC and heart failure. METHODS: Fifty patients with CCC and left ventricular ejection fraction (LVEF) of less than 55% were prospectively selected and followed for a mean period of 18 ± 8 months. A group of 27 healthy volunteers were also investigated. One patient was excluded from the analysis since he died before completing the intestinal permeability test. Intestinal permeability was evaluated with the sugar probe drink test. It consists in the urinary recovery of previously ingested sugar probes: mannitol, a monosaccharide, and lactulose, a disaccharide. RESULTS: Patient's mean age was 53.4 ± 10.4 years, and 31(63%) were male. Differential urinary excretion of lactulose/mannitol ratio did not differ significantly between healthy controls and CCC patients, regardless of clinical signs of venous congestion, haemodynamic parameters, and severity of presentation and outcome. CONCLUSIONS: The present study could not show a disturbance of the intestinal barrier in CCC patients with LVEF <55%, measured by lactulose/mannitol urinary excretion ratio. Further investigations are needed to verify if in patients with LVEF <40% intestinal permeability is increased.

Biomakers in Chronic Chagas Cardiomyopathy.

The primary objective was to observe the relationship between serum levels of BNP, Ca-125, C-reactive protein and uric acid as prognostic and functional markers in patients with chronic Chagas cardiomyopathy (CCC). Circulating levels of cytokines: IL-1ß, TNFα, IL-10, IL6, IL-8 and IL-12 were determined and investigated regarding their association with hemodynamic parameters, clinical signs of heart failure and outcome. Chagas is still a neglected disease that affects numerous individuals, many of them in their most productive years. CCC with left ventricular dysfunction is the most severe presentation of Chagas Disease. BNP is a well-recognized prognostic and clinical biomarker, not only in chronic heart failure patients but also in patients with CCC. Previous studies have shown Ca-125, C-reactive protein, and uric acid to be potentially good prognostic markers in heart failure (HF). Fifty patients with left ventricular fraction less (LVEF) than 55% were selected and followed for a mean period of 18 ± 8.3 months. Patient's mean age was 43.42 ± 10.3 years (32 male), their BNP was 293 (160-530) pg/mL, Ca-125 8.5 (5.5-16.75) U/mL, uric acid 6.2 ± 2 mg/dL, and C- reactive protein 4.5 (4.5-7.3) mg/L. Patients who had LVEF less than 35% had higher BNP (p = 0.0023), Ca-125 (p = 0.027) and uric acid (p = 0.01) serum levels. Patients who died also showed higher BNP (p = 0.01), uric acid (p = 0.05) and a trend towards higher Ca-125 serum levels (p = 0.056). All markers: BNP, Ca-125, uric acid and C-reactive had good predictability of death in Cox-regression univariate analysis, however, not on the final multivariate model. Of the inflammatory cytokines, IL-8 and IL-12 showed a relation to LVEF of less than 35%. IL-12 was related to adverse cardiovascular events and non-survival. IL-1ß was a good predictor of mortality in the final Cox regression model. Determination of Ca-125, uric acid levels and C-reactive protein may add useful clinical and prognostic information and may help clinical decision making for patients with CCC.

An overview about DNA methylation in childhood obesity: Characteristics of the studies and main findings.

Childhood obesity is a global burden affecting millions of children worldwide. It is well-known that the adiposity profile in children is critical for future occurrence of diseases. As a multifactorial disease, obesity is associated with genetic and environmental factors. Epigenetic mechanisms link the plethora of environmental clues to a given phenotype. DNA methylation is the most studied epigenetic mark and its importance in several diseases was acknowledged. In childhood obesity, specifically, the studies show a consistent association between adiposity and methylation at the gene and genome-wide scales. The relationship between DNA methylation and childhood obesity has been proved strong for some genes and pathways. However, the studies are heterogeneous in their design, methodologies, and results. The aim of this review is to discuss this heterogeneity and point out some aspects that should be considered in future studies to clarify the role of DNA methylation in childhood obesity.

Swimming reduces fatty acids-associated hypothalamic damage in mice.

The arcuate and the paraventricular and lateral hypothalamic nuclei, related to hunger and satiety control, are generally compromised by excess fatty acids. In this situation, fatty acids cause inflammation via TLR4 (toll like receptor 4) and the nuclei become less responsive to the hormones leptin and insulin, contributing to the development of obesity. In this work, these nuclei were analyzed in animals fed with high-fat diet and submitted to swimming without and with load for two months. For this, frontal sections of the hypothalamus were immunolabelled with GFAP (glial fibrillary acidic protein), synaptophysin, IL-6 (interleukin 6) and TLR4. Also, proteins extracted from the hypothalamus were analyzed using Western blotting (GFAP and synaptophysin), fluorometric analysis for caspases 3 and 7, and CBA (cytometric bead array) for Th1, Th2, and Th17 profiles. The high-fat diet significantly caused overweight and, in the hypothalamus, decreased synapses and increased astrocytic reactivity. The swimming with load, especially 80 % of the maximum load, reduced those consequences. The high-fat diet increased TLR4 in the arcuate nucleus and the swimming exercise with 80 % of the maximum load showed a tendency of reducing this expression. Swimming did not significantly influence the inflammatory or anti-inflammatory cytokines in the hypothalamus or in plasma. The high-fat diet in sedentary animals increased the expression of caspases 3 and 7 and swimming practice reduced this increment to levels compatible with animals fed on a normal diet. The set of results conclude that the impact of swimming on the damage caused in the hypothalamus by a high-fat diet is positive. The different aspects analyzed in here point to better cellular viability and conservation of the synapses in the hypothalamic nuclei of overweight animals that practiced swimming with a load.

Nitric oxide synthase expression correlates with death in an experimental mouse model of dengue with CNS involvement.

BACKGROUND: The clinical presentation of dengue is classified by the World Health Organization into dengue without warning signs, dengue with warning signs and severe dengue. Reports of neurological disease caused by Dengue virus (DENV) are becoming frequent, with symptoms that include reduced consciousness, severe headache, neck stiffness, focal neurological signs, tense fontanelle and convulsions. However, the immune mechanisms involved in neurovirulence remain poorly understood. Here we present a mouse model in which one genotype of DENV is inoculated by the intracranial route and infects C57/BL6 mice and replicates in the brain, causing death of mice. METHODS: Mice were infected with different serotypes/genotypes of DENV by the intracranial route to evaluate viral replication, host cytokine and nitric oxide synthase 2 (Nos2) expression in the brain via real-time PCR. Histological analysis of the brain tissues was also performed. An analysis of which cells were responsible for the expression of cytokines and Nos2 was performed using flow cytometry. Survival curves of infected animals were also generated RESULTS: DENV 3 genotype I infected mice and replicated in the brain, causing death in our murine model. The increased levels of NOS2 could be the cause of the death of infected mice, as viral replication correlates with increased Nos2 and cytokine expression in the brain of C57BL/6 mice. In Nos2-/- mice that were infected with DENV, no clinical signs of infection were observed and cytokines were expressed at low levels, with the exception of interferon gamma (Ifng). Additionally, the Ifng-/- mice infected with DENV exhibited a severe and lethal disease, similar to the disease observed in C57BL/6 mice, while the DENV- infected Nos2-/- mice did not display increased mortality. Analyses of the brains from infected C57BL/6 mice revealed neuronal degeneration and necrosis during histopathologic examination. IFNg and NOS2 were produced in the brains of infected mice by CD4+ T cells and macrophages, respectively. CONCLUSION: The neurovirulence of DENV 3 genotype I is associated with a deleterious role of NOS2 in the brain, confirming this murine model as an appropriate tool to study DENV neurovirulence.