Impact of Glucocorticoid Receptor Gene Polymorphisms on the Metabolic Profile of Adult Patients with the Classical Form of 21-Hydroxylase Deficiency

Background: CAH patients have an increased risk of cardiovascular disease, and it remains unknown if lifelong glucocorticoid (GC) treatment is a contributing factor. In the general population, glucocorticoid receptor gene (NR3C1) polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of CAH patients. Methodology: Sixty-eight adult patients (34SV/34SW) with a mean age of 28.4 +/- 9 years received dexamethasone (mean 0.27 +/- 0.11 mg/day) to obtain normal androgen levels. SW patients also received fludrocortisone (50 mu g/day). Metabolic syndrome (MetS) was defined by the NCEP ATPIII criteria and obesity by BMI >= 30 kg/m(2). NR3C1 alleles were genotyped, and association analyses with phenotype were carried out with Chi-square, t-test and regression analysis. Results: Obesity and MetS were observed in 23.5% and 7.3% of patients, respectively, and were not correlated with GC doses and treatment duration. BMI was positively correlated with blood pressure (BP), triglycerides (TG), LDL-c levels and HOMA-IR and inversely correlated with HDL-c levels. BclI and A3669G variants were found in 26.4% and 9.6% of alleles, respectively. Heterozygotes for the BclI polymorphism presented with higher BMI (29 kg/m(2) +/- 5.3 vs. 26 kg/m(2) +/- 5.3, respectively) and waist circumference (89 cm +/- 12.7 vs. 81 cm +/- 13, respectively) compared to wild-type subjects. Hypertension was found in 12% of patients and heterozygotes for the BclI polymorphism presented higher systolic BP than wild type subjects. Low HDL-c and high TG levels were identified in 30% and 10% of patients, respectively, and were not associated with the NR3C1 polymorphisms. A3669G carriers and non-carriers did not differ. Conclusion: In addition to GC therapy, the BclI GR variant might play an important role in obesity susceptibility in CAH patients. Genotyping of GR polymorphisms could result in the identification of a subgroup at risk patients, allowing for the establishment of personalized treatment and the avoidance of long-term adverse consequences.

Transcriptional response to GAA deficiency (Pompe disease) in infantile-onset patients

Pompe disease is a genetic disorder resulting from a deficiency of lysosomal acid alpha-glucosidase (GAA) that manifests as a clinical spectrum with regard to symptom severity and rate of progression. In this study, we used microarrays to examine gene expression from the muscle of two cohorts of infantile-onset Pompe patients to identify transcriptional differences that may contribute to the disease phenotype. We found strong similarities among the gene expression profiles generated from biceps and quadriceps, and identified a number of signaling pathways altered in both cohorts. We also found that infantile-onset Pompe patient muscle had a gene expression pattern characteristic of immature or regenerating muscle, and exhibited many transcriptional markers of inflammation, despite having few overt signs of inflammatory infiltrate. Further, we identified genes exhibiting correlation between expression at baseline and response to therapy. This combined dataset can serve as a foundation for biological discovery and biomarker development to improve the treatment of Pompe disease. (C) 2012 Elsevier Inc. All rights reserved.

EFFECTS OF VITAMIN C SUPPLEMENTATION ON ACUTE PHASE CHAGAS DISEASE IN EXPERIMENTALLY INFECTED MICE WITH Trypanosoma cruzi QM1 STRAIN

The tissue changes that occur in Chagas disease are related to the degree of oxidative stress and antioxidant capacity of affected tissue. Studies with vitamin C supplementation did not develop oxidative damage caused by Chagas disease in the host, but other studies cite the use of peroxiredoxins ascorbate - dependent on T. cruzi to offer protection against immune reaction. Based on these propositions, thirty "Swiss" mice were infected with T. cruzi QM1 strain and treated with two different vitamin C doses in order to study the parasitemia evolution, histopathological changes and lipid peroxidation biomarkers during the acute phase of Chagas disease. The results showed that the parasite clearance was greater in animals fed with vitamin C overdose. There were no significant differences regarding the biomarkers of lipid peroxidation and inflammatory process or the increase of myocardium in animals treated with the recommended dosage. The largest amount of parasite growth towards the end of the acute phase suggests the benefit of high doses of vitamin C for trypomastigotes. The supplementation doesn't influence the production of free radicals or the number of amastigote nests in the acute phase of Chagas disease.

Stability of Carotenoids, Total Phenolics and In Vitro Antioxidant Capacity in the Thermal Processing of Orange-Fleshed Sweet Potato (Ipomoea batatas Lam.) Cultivars Grown in Brazil

Intervention strategies regarding the biofortification of orange-fleshed sweet potato, which is a rich source of carotenoids for combating vitamin A deficiency, are being developed in Brazil. This study was conducted to evaluate the concentrations of individual carotenoids, total phenolic compounds and antioxidant capacity in the roots of four biofortified sweet potato cultivars that were raw or processed by four common heat treatments. HPLC, Folin-Ciocalteu, DPPH and ABTS assays were used. All cultivars showed high levels of carotenoids in raw roots, predominantly all-trans-beta-carotene (79.1-128.5 mg.100 g(-1) DW), suggesting a high estimated vitamin A activity. The CNPH 1194 cultivar reported carotenoids values highest than those of other cultivars (p < 0.05). The total phenolic compounds varied among cultivars and heat treatments (0.96-2.05 mg.g(-1) DW). In most cases, the heat treatments resulted in a significant decrease in the carotenoids and phenolic compounds contents as well as antioxidant capacity. Processing of flour presented the greatest losses of major carotenoids and phenolics. The phenolic compounds showed more stability than carotenoids after processing. There were significant correlations between the carotenoids and phenolic compounds and the antioxidant capacity.

Interaction of dietary vitamin D-3 and sunlight exposure on B. indicus cattle: Animal performance, carcass traits, and meat quality

Attempts to improve beef tenderness through supplementation with dietary vitamin D-3 have been challenged by null results and negative impacts on animal performance and carcass traits. Because vitamin D-3 is also synthesised by the animal via ultraviolet radiation from sunlight, the effectiveness of supplementation with dietary vitamin D-3 may be modulated by the degree of exposure of the animal to sunlight. Hence, this work aimed to verify whether dietary vitamin D-3 modifies meat quality without negatively affecting animal performance and carcass traits in B. indicus beef cattle that were either exposed to or protected from natural sunlight. Forty-two (411 +/- 38 kg) Nellore-type castrated males were fed a high-concentrate diet for 45 days after assignment to a treatment group. The treatments comprised combinations of three levels of vitamin D3 [ViTD - none (V0) or 2 x 10(6) IU of vitamin D-3 administered for either 2 (V2) or 8 (V8) consecutive days pre-slaughter] and two shading conditions (SHADE - unshaded or shaded). The post-mortem (pm) measurements were taken in the Longissimus thoracis et lumborum muscle. The animal performance and carcass traits were unaffected by ViTD or SHADE The V2 treatment increased the Myofibrillar Fragmentation Index in shaded animals compared to unshaded ones. Animals under shade had higher muscle calcium concentration. There was no effect of either ViTD or SHADE on the shear force. The L* values were higher at 24 h pm than at 0 and 1 h pm, with no differences among the animals in the ViTD or SHADE groups. Higher a* values were observed among animals in the V8 group than in the V0 group, and higher b* values were observed among animals in the V8 group than in the V2 or V0 groups, which were not different. In conclusion, ViTD and SHADE did not affect animal performance, carcass traits or shear force, whereas animals receiving a lower ViTD dosage and SHADE exhibited altered myofibrillar fragmentation. ViTD affected the colour parameters, and changes in the lightness of the beef related to the time pm were found in meat from animals under SHADE. (c) 2012 Elsevier B.V. All rights reserved.

IL-12p40 Deficiency Leads to Uncontrolled Trypanosoma cruzi Dissemination in the Spinal Cord Resulting in Neuronal Death and Motor Dysfunction

Chagas' disease is a protozoosis caused by Trypanosoma cruzi that frequently shows severe chronic clinical complications of the heart or digestive system. Neurological disorders due to T. cruzi infection are also described in children and immunosuppressed hosts. We have previously reported that IL-12p40 knockout (KO) mice infected with the T. cruzi strain Sylvio X10/4 develop spinal cord neurodegenerative disease. Here, we further characterized neuropathology, parasite burden and inflammatory component associated to the fatal neurological disorder occurring in this mouse model. Forelimb paralysis in infected IL-12p40KO mice was associated with 60% (p<0.05) decrease in spinal cord neuronal density, glutamate accumulation (153%, p<0.05) and strong demyelization in lesion areas, mostly in those showing heavy protein nitrosylation, all denoting a neurotoxic degenerative profile. Quantification of T. cruzi 18S rRNA showed that parasite burden was controlled in the spinal cord of WT mice, decreasing from the fifth week after infection, but progressive parasite dissemination was observed in IL-12p40KO cords concurrent with significant accumulation of the astrocytic marker GFAP (317.0%, p<0.01) and 8-fold increase in macrophages/microglia (p<0.01), 36.3% (p<0.01) of which were infected. Similarly, mRNA levels for CD3, TNF-alpha, IFN-gamma, iNOS, IL-10 and arginase I declined in WT spinal cords about the fourth or fifth week after infection, but kept increasing in IL-12p40KO mice. Interestingly, compared to WT tissue, lower mRNA levels for IFN-gamma were observed in the IL-12p40KO spinal cords up to the fourth week of infection. Together the data suggest that impairments of parasite clearance mechanisms in IL-12p40KO mice elicit prolonged spinal cord inflammation that in turn leads to irreversible neurodegenerative lesions.

A Randomized Trial of Noninvasive Positive End Expiratory Pressure in Patients With Acquired Immune Deficiency Syndrome and Hypoxemic Respiratory Failure

BACKGROUND: Acquired immunodeficiency syndrome (AIDS) is a pandemic disease commonly associated with respiratory infections, hypoxemia, and death. Noninvasive PEEP has been shown to improve hypoxemia. In this study, we evaluated the physiologic effects of different levels of noninvasive PEEP in hypoxemic AIDS patients. METHODS: Thirty AIDS patients with acute hypoxemic respiratory failure received a randomized sequence of noninvasive PEEP (5, 10, or 15 cm H2O) for 20 min. PEEP was provided through a facial mask with pressure-support ventilation (PSV) of 5 cm H2O and an F-IO2, of 1. Patients were allowed to breathe spontaneously for a 20-min washout period in between each PEEP trial. Arterial blood gases and clinical variables were recorded after each PEEP treatment. RESULTS: The results indicate that oxygenation improves linearly with increasing levels of PEEP. However, oxygenation levels were similar regardless of the first PEEP level administered (5, 10, or 15 cm H2O), and only the subgroup that received an initial treatment of the lowest level of PEEP (ie, 5 cm H2O) showed further improvements in oxygenation when higher PEEP levels were subsequently applied. The P-aCO2, also increased in response to PEEP elevation, especially with the highest level of PEEP (ie, 15 cm H2O). PSV of 5 cm H2O use was associated with significant and consistent improvements in the subjective sensations of dyspnea and respiratory rate reported by patients treated with any level of PEEP (from 0 to 15 cm H2O). CONCLUSIONS: AIDS patients with hypoxemic respiratory failure improve oxygenation in response to a progressive sequential elevation of PEEP (up to 15 cm H2O). However, corresponding elevations in P-aCO2, limit the recommended level of PEEP to 10 cm H2O. At a level of 5 cm H2O, PSV promotes an improvement in the subjective sensation of dyspnea regardless of the PEEP level employed.

Underlying Factors Associated with Anemia in Amazonian Children: A Population-Based, Cross-Sectional Study

Background: Although iron deficiency is considered to be the main cause of anemia in children worldwide, other contributors to childhood anemia remain little studied in developing countries. We estimated the relative contributions of different factors to anemia in a population-based, cross-sectional survey. Methodology: We obtained venous blood samples from 1111 children aged 6 months to 10 years living in the frontier town of Acrelandia, northwest Brazil, to estimate the prevalence of anemia and iron deficiency by measuring hemoglobin, erythrocyte indices, ferritin, soluble transferrin receptor, and C-reactive protein concentrations. Children were simultaneously screened for vitamin A, vitamin B-12, and folate deficiencies; intestinal parasite infections; glucose-6-phosphate dehydrogenase deficiency; and sickle cell trait carriage. Multiple Poisson regression and adjusted prevalence ratios (aPR) were used to describe associations between anemia and the independent variables. Principal Findings: The prevalence of anemia, iron deficiency, and iron-deficiency anemia were 13.6%, 45.4%, and 10.3%, respectively. Children whose families were in the highest income quartile, compared with the lowest, had a lower risk of anemia (aPR, 0.60; 95% CI, 0.37-0.98). Child age (<24 months, 2.90; 2.01-4.20) and maternal parity (>2 pregnancies, 2.01; 1.40-2.87) were positively associated with anemia. Other associated correlates were iron deficiency (2.1; 1.4-3.0), vitamin B-12 (1.4; 1.0-2.2), and folate (2.0; 1.3-3.1) deficiencies, and C-reactive protein concentrations (>5 mg/L, 1.5; 1.1-2.2). Conclusions: Addressing morbidities and multiple nutritional deficiencies in children and mothers and improving the purchasing power of poorer families are potentially important interventions to reduce the burden of anemia.

The Use of Nanotechnology in Cosmetic Formulations: The Influence of Vehicle in the Vitamin A Skin Penetration

Despite the efficacy of topical retinoic acid, skin reactions have limited its acceptance by patients. Other retinoids, like Retinyl Palmitate (RP), are considerably less irritating, but they are also less effective. In order to enhance the performance of retinoids, in this work RP has been added to cosmetic formulations such as nanoemulsions, which can provide better penetration of this active substance. Because the vehicle can directly influence the skin penetration and the effectiveness of RP, two skin care products containing 5000 UI RP have been developed and investigated, namely a nanoemulsifying system and a classic gel cream. In vitro penetration tests were conducted by using Franz diffusion cells and placing porcine ear skin and iso-propanol in the receptor compartment. The RP concentration in the skin layers was analyzed by high performance liquid chromatography, and a Zeta-Sizer system was employed for measurement of the the particle size distribution. The penetration tests revealed a large difference between the vehicles in terms of the RP concentrations in each skin layer. The classic gel cream furnished better RP penetration in both the stratum corneum and the epidermis without stratum corneum + dermis, as compared to the self-nanoemulsifying system. The two vehicles displayed the same particle size (between 100 and 200 nm). Better understanding of RP skin delivery using different vehicles has been acquired, and the importance of evaluating the efficacy of nanocosmetics. Results from the present study should also contribute to the assessment of commercial self-nanoemulsifying systems with potential application in the facile production of nanoemulsions.