Neurochemical effects ofl-pyroglutamic acid

The effect ofl-pyroglutamic acid, a metabolite that accumulates in pyroglutamic aciduria, on different neurochemical parameters was investigated in adult male Wistar rats. Glutamate binding, adenylate cyclase activity and G protein coupling to adenylate cyclase were assayed in the presence of the acid.l-pyroglutamic acid decreased Na⁺-dependent and Na⁺-independent glutamate binding Basal and GMP-PNP stimulated adenylate cyclase activity were not affected by the acid. Furthermore, rats received unilateral intrastriatal injections of 10–300 nmol of bufferedl-pyroglutamic acid. Vehicle (0.25 M Tris-Cl, pH 7.35–7.4) was injected into the contralateral striatum. Neurotoxic damage was assessed seven days after the injection by histological examination and by weighing both cerebral hemispheres. No difference in histology or weight could be identified between hemispheres. These results suggest that, although capable of interfering with glutamate binding, pyroglutamate did not cause a major lesion in the present model of neurotoxicity.     

EFFECTS OF INGESTION OF A CARBOHYDRATE-FAT MEAL ON THE LEVELS AND SYNTHESIS OF 5-HYDROXYINDOLES IN VARIOUS REGIONS OF THE RAT CENTRAL NERVOUS SYSTEM

—The concentrations of tryptophan, serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in spinal cord and most brain regions increase 2 h after fasted rats begin to consume a carbohydrate-fat meal: indole levels rise in all portions of the brain studied, but the increase is not statistically significant in the hypothalamus and corpus striatum. The rate at which the brain synthesizes 5-hydroxy-indoles (as estimated in vivo by measuring 5-hydroxytryptophan accumulation following an injection of the decarboxylase inhibitor RO4-4602) is also accelerated in all of the regions in which the experimental diet elevates tryptophan, 5-HT and 5-HIAA levels. These observations indicate that the previously reported increase in brain 5-hydroxyindole levels following consumption of a protein-free meal reflects accelerated serotonin synthesis, and occurs within both the cell bodies and the terminals of serotonin-containing neurons. It is possible that diet-induced changes in neuronal serotonin levels influence the quantities of the neurotransmitter released into synapses, either spontaneously or in response to drugs.     

Early-Life Hepatitis E Infection in Pigs: The Importance of Maternally-Derived Antibodies

Passive immunity (PI), acquired through colostrum intake, is essential for piglet protection against pathogens. Maternally-derived antibodies (MDAs) can decrease the transmission of pathogens between individuals by reducing shedding from infected animals and/or susceptibility of naïve animals. Only a limited number of studies, however, have been carried out to quantify the level of protection conferred by PI in terms of transmission. In the present study, an original modeling framework was designed to estimate parameters governing the transmission of infectious agents in the presence and absence of PI. This epidemiological model accounts for the distribution of PI duration and two different forces of infection depending on the serological status of animals after colostrum intake. A Bayesian approach (Metropolis-Hastings algorithm) was used for parameter estimation. The impact of PI on hepatitis E virus transmission in piglets was investigated using longitudinal serological data from six pig farms. A strong impact of PI was highlighted, the efficiency of transmission being on average 13 times lower in piglets with maternally-derived antibodies than in fully susceptible animals (range: 5–21). Median infection-free survival ages, based on herd-specific estimates, ranged between 8.7 and 13.8 weeks in all but one herd. Indeed, this herd exhibited a different profile with a relatively low prevalence of infected pigs (50% at slaughter age) despite the similar proportions of passively immune individuals after colostrum intake. These results suggest that the age at HEV infection is not strictly dependent upon the proportion of piglets with PI but is also linked to farm-specific husbandry (mingling of piglets after weaning) and hygiene practices. The original methodology developed here, using population-based longitudinal serological data, was able to demonstrate the relative impact of MDAs on the transmission of infectious agents.     

Defibrotide inhibits donor leucocyte‐endothelial interactions and protects against acute graft‐versus‐host disease

Allogeneic hematopoietic stem cell transplantation (allo‐HCT) is an effective therapy for the treatment of high‐risk haematological malignant disorders and other life‐threatening haematological and genetic diseases. Acute graft‐versus‐host disease (aGvHD) remains the most frequent cause of non‐relapse mortality following allo‐HCT and limits its extensive clinical application. Current pharmacologic agents used for prophylaxis and treatment of aGvHD are not uniformly successful and have serious secondary side effects. Therefore, more effective and safe prophylaxis and therapy for aGvHD are an unmet clinical need. Defibrotide is a multi‐target drug successfully employed for prophylaxis and treatment of veno‐occlusive disease/sinusoidal obstruction syndrome. Recent preliminary clinical data have suggested some efficacy of defibrotide in the prevention of aGvHD after allo‐HCT. Using a fully MHC‐mismatched murine model of allo‐HCT, we report here that defibrotide, either in prophylaxis or treatment, is effective in preventing T cell and neutrophil infiltration and aGvHD‐associated tissue injury, thus reducing aGvHD incidence and severity, with significantly improved survival after allo‐HCT. Moreover, we performed in vitro mechanistic studies using human cells revealing that defibrotide inhibits leucocyte‐endothelial interactions by down‐regulating expression of key endothelial adhesion molecules involved in leucocyte trafficking. Together, these findings provide evidence that defibrotide may represent an effective and safe clinical alternative for both prophylaxis and treatment of aGvHD after allo‐HCT, paving the way for new therapeutic approaches.     

Monosialoganglioside Increases Catalase Activity in Cerebral Cortex of Rats

Monosialoganglioside (GM1) is a neuroprotective agent that has been reported to scavenge free radicals generated during reperfusion and to protect receptors and enzymes from oxidative damage. However, only a few studies have attempted to investigate the effects of GM1 on enzymatic antioxidant defenses of the brain. In the present study, we evaluate the effects of the systemic administration of GM1 on the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), and on spontaneous chemiluminescence and total radical-trapping potential (TRAP) in cerebral cortex of rats ex vivo. The effects of GM1 on CAT activity and spontaneous chemiluminescence in vitro were also determined.

Animals received two injections of GM1 (50?mg/kg, i.p.) or saline (0.85% NaCl, i.p.) spaced 24?h apart. Thirty minutes after the second injection the animals were sacrificed and enzyme activities and spontaneous chemiluminescence and TRAP were measured in cell-free homogenates. GM1 administration reduced spontaneous chemiluminescence and increased catalase activity ex vivo, but had no effect on TRAP, SOD or GSH-Px activities. GM1, at high concentrations, reduced CAT activity in vitro. We suggest that the antioxidant activity of GM1 ganglioside in the cerebral cortex may be due to an increased catalase activity.     

High prevalence of asthma symptoms in Warao Amerindian children in Venezuela is significantly associated with open-fire cooking: a cross-sectional observational study

Background

The International Study on Asthma and Allergies in Childhood (ISAAC) reported a prevalence of asthma symptoms in 17 centers in nine Latin American countries that was similar to prevalence rates reported in non-tropical countries. It has been proposed that the continuous exposure to infectious diseases in rural populations residing in tropical areas leads to a relatively low prevalence of asthma symptoms. As almost a quarter of Latin American people live in rural tropical areas, the encountered high prevalence of asthma symptoms is remarkable. Wood smoke exposure and environmental tobacco smoke have been identified as possible risk factors for having asthma symptoms.

Methods

We performed a cross-sectional observational study from June 1, 2012 to September 30, 2012 in which we interviewed parents and guardians of Warao Amerindian children from Venezuela. Asthma symptoms were defined according to the ISAAC definition as self-reported wheezing in the last 12 months. The associations between wood smoke exposure and environmental tobacco smoke and the prevalence of asthma symptoms were calculated by means of univariate and multivariable logistic regression analyses.

Results

We included 630 children between two and ten years of age. Asthma symptoms were recorded in 164 of these children (26%). The prevalence of asthma symptoms was associated with the cooking method. Children exposed to the smoke produced by cooking on open wood fires were at higher risk of having asthma symptoms compared to children exposed to cooking with gas (AOR 2.12, 95% CI 1.18 - 3.84). Four percent of the children lived in a household where more than ten cigarettes were smoked per day and they had a higher risk of having asthma symptoms compared to children who were not exposed to cigarette smoke (AOR 2.69, 95% CI 1.11 - 6.48).

Conclusion

Our findings suggest that children living in rural settings in a household where wood is used for cooking or where more than ten cigarettes are smoked daily have a higher risk of having asthma symptoms.