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Hyperhomocysteinemia (HHcy) is a risk factor for vascular disease, but the underlying mechanisms remain incompletely defined. Reduced bioavailability of nitric oxide (NO) is a principal manifestation of underlying endothelial dysfunction, which is an initial event in vascular disease. Inhibition of cellular methylation reactions by S-adenosylhomocysteine (AdoHcy), which accumulates during HHcy, has been suggested to contribute to vascular dysfunction. However, thus far, the effect of intracellular AdoHcy accumulation on NO bioavailability has not yet been fully substantiated by experimental evidence. The present study was carried out to evaluate whether disturbances in cellular methylation status affect NO production by cultured human endothelial cells. Here, we show that a hypomethylating environment, induced by the accumulation of AdoHcy, impairs NO production. Consistent with this finding, we observed decreased eNOS expression and activity, but, by contrast, enhanced NOS3 transcription. Taken together, our data support the existence of regulatory post-transcriptional mechanisms modulated by cellular methylation potential leading to impaired NO production by cultured human endothelial cells. As such, our conclusions may have implications for the HHcy-mediated reductions in NO bioavailability and endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Copyright of Revista Española de Cirugía Ortopédica y Traumatologia (English Edition) is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Inhaled corticosteroids (ICS) and long-acting β(2)-agonists (LABAs) are recommended in patients with asthma that is not well-controlled; however, many patients continue to have inadequately controlled asthma despite this therapy.Objective: To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy.Design: Prospective, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00314575).Setting: 193 investigational sites in the United States and 4 sites in Canada.Patients: 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs, with or without other controllers.Intervention: Omalizumab (n = 427) or placebo (n = 423) was added to existing medication regimens for 48 weeks.Measurements: The primary end point was the rate of protocol-defined exacerbations over the study period. Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol, mean total asthma symptom score, and mean overall score on the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Safety end points included the frequency and severity of treatment-emergent adverse events.Results: During 48 weeks, the rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (0.66 vs. 0.88 per patient; P = 0.006), representing a 25% relative reduction (incidence rate ratio, 0.75 [95% CI, 0.61 to 0.92]). Omalizumab improved mean AQLQ(S) scores (0.29 point [CI, 0.15 to 0.43]), reduced mean daily albuterol puffs (-0.27 puff/d [CI, -0.49 to -0.04 puff/d]), and decreased mean asthma symptom score (-0.26 [CI, -0.42 to -0.10]) compared with placebo during the 48-week study period. The incidence of adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%) were similar in the omalizumab and placebo groups, respectively.Limitations: The results are limited by early patient discontinuation (20.8%). The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup.Conclusion: In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy.Primary Funding Source: Genentech and Novartis Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Objective The Honduran HIV/AIDS Program began to scale up access to HIV therapy in 2002. Up to May 2008, more than 6000 patients received combination antiretroviral therapy (cART). As HIV drug resistance is the major obstacle for effective treatment, the purpose of this study was to assess the prevalence of antiretroviral drug resistance in Honduran HIV-1-infected individuals. Methods We collected samples from 138 individuals (97 adults and 41 children) on cART with virological, immunological or clinical signs of treatment failure. HIV-1 pol sequences were obtained using an in-house method. Resistance mutations were identified according to the 2007 International AIDS Society (IAS)-USA list and predicted susceptibility to cART was scored using theanrs algorithm. Results Resistance mutations were detected in 112 patients (81%), 74% in adults and 98% in children. Triple-, dual- and single-class drug resistance was documented in 27%, 43% and 11% of the study subjects, respectively. Multiple logistic regression showed that resistance was independently associated with type of treatment failure [virological failure (odds ratio (OR)=1) vs. immunological failure (OR=0.11; 95% confidence interval (CI) 0.030–0.43) vs. clinical failure (OR=0.037; 95% CI 0.0063–0.22)], route of transmission (OR=42.8; 95% CI 3.73–491), and years on therapy (OR=1.81; 95% CI 1.11–2.93). Conclusion The prevalence of antiretroviral resistance was high in Honduran HIV-infected patients with signs of treatment failure. A majority of study subjects showed dual- or triple-class resistance to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors and protease inhibitors. Virologically defined treatment failure was a strong predictor of resistance, indicating that viral load testing is needed to correctly identify patients with treatment failure attributable to resistance. [ABSTRACT FROM AUTHOR]

Aim: The present investigation was designed to determine the in vivo antidiabetic effect of naringenin (NG) in normoglycaemic and diabetic rat models through blood glucose (GLU) measurements following acute and subchronic time periods. Possible modes of action of NG were investigated and its acute toxicity determined. Methods: Normoglycaemic and non-insulin-dependent diabetes mellitus (NIDDM) rat models were treated for acute and subchronic (5 days) time periods with 50 mg/kg/day of NG. Blood biochemical profiles were determined after 5 days of the treatment in normoglycaemic and NIDDM rats using commercial kits for GLU, triglycerides (TG), total cholesterol (CHOL) and high-density lipoprotein (HDL). In order to elucidate its antidiabetic mode of action, NG was administered intragastrically and an oral glucose tolerance test performed using GLU and sucrose (2 g/kg) as substrates. The inhibitory effect of a single concentration of NG (10 μM) on 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity in vitro was determined. Finally, the preclinical safety and tolerability of NG was determined by toxicological evaluation in mice and rats using Organization for Economic Cooperation and Development (OECD) protocols. Results: Intragastrically administered NG (50 mg/kg) induced a significant decrease in plasma GLU in normoglycaemic and NIDDM rat models (p < 0.05) following acute and subchronic time periods. After 5 days of administration, NG produced significant diminished blood GLU and TG levels in streptozotocin–nicotinamide–induced diabetic rats. The administration of NG to normal rats significantly increased the levels of TG, CHOL and HDL (p < 0.05). NG (5 and 50 mg/kg) induced a total suppression in the increase of plasma GLU levels after administration of substrates (p < 0.01), but NG did not produce inhibition of α-glucosidase activity in vitro. However, NG (10 μM) was shown to inhibit 11β-HSD1 activity by 39.49% in a cellular enzyme assay. Finally, NG showed a Medium Lethal Dose LD50 > 5000 mg/kg and ranking at level five based on OECD protocols. Conclusion: Our findings suggest that NG may exert its antidiabetic effect by extra-pancreatic action and by suppressing carbohydrate absorption from intestine, thereby reducing the postprandial increase in blood GLU levels. [ABSTRACT FROM AUTHOR]

Copyright of Revista Española de Cirugía Oral y Maxilofacial is the property of Sociedad Espanola de Cirugia Oral y Maxilofacial (SECOM) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: This paper discusses a study of silver precipitation in elemental form in the S2O3 2−–S2O4 2− system. The nature and kinetics of this process were determined. Using the method described here, silver precipitation is characterized by an induction period, followed by a conversion (precipitation) period, until almost all the silver is precipitated, leaving in solution a metal amount less than 1 ppm. Aggregates of individual crystals with a size less than 0.5 μm were obtained. In thiosulfate medium 1 mol dithionite precipitated 2 mol silver, whereas without thiosulfate in the reaction system, 1 mol dithionite precipitated 6 mol silver. In the kinetic study and in the induction period, the inverse of this parameter was proportional to [S2O4 2−]0.4 and an apparent activation energy of 108 kJ mol−1 was obtained. During the conversion period, the reaction order with respect to [S2O3 2−] was n =−3, and with respect to the initial [S2O4 2−] it was a 0.9. An activation energy of 52 kJ mol−1 was obtained. On the basis of the behavior described, an empirical mathematical model, including the induction and conversion periods, was established, which fits well with the experimental results. The precipitation process was applied to an industrial effluent (a fixing bath); metallic silver was obtained with a recovery of more than 99%. [Copyright &y& Elsevier]

Genetic predisposition, environmental toxins and aging contribute to Parkinson's disease (PD) multifactorial etiology. Weak environmental neurotoxic factors may accumulate over time increasing the disease risk in genetically predisposed subjects. Polymorphic genes encoding drug-metabolizing-enzymes (DMEs) are considered to account for PD susceptibility by determining individual toxic response variability. In this work, the allelic distributions and genotype associations of three major brain-expressed DMEs were characterized, in sporadic PD cases and controls. No significant association was found between CYP2D6 genotype and PD, but subjects with extensive metabolizer (EM) CYP2D6 phenotype, and the variant GSTP1*B genotype were at significantly higher PD risk than the corresponding poor or intermediary metabolizers ( CYP2D6 poor metabolizer phenotype+intermediary metabolizers). A significant association was observed between the GSTP1*B allele and zygosity with PD ( GSTP1*A/*B– 51.58%/34.37%, odds ratio (OR) = 2.29; 95% confidence interval (95% CI) = 1.25–4.18; * B/* B– 6.32%/1.05%, OR = 10.67; 95% CI = 1.19–94.79). This association was particularly strong in the elder patients group (≥69 year) who showed double PD risk for GSTP1*B heterozygous, whilst GSTP1*B/*B homozygous were exclusively found amongst patients. An interaction between GSTM1 and GSTP1 was observed in this late onset PD group. The present results suggest that native GSTP1 encoding the fully active transferase variant should play a relevant role in dopaminergic neuroprotection. [ABSTRACT FROM AUTHOR]

Classical galactosaemia is an autosomal recessive inherited metabolic disorder due to deficient galactose-1-phosphate uridyltransferase (GALT). Over 180 different base changes and disease-causing mutations have been reported in the GALT gene. Mutation p.Q188R was found to be the most common molecular defect among caucasian classical galactosaemia patients. We have characterized the spectrum of GALT mutations in a group of 51 Spanish families and 32 Portuguese families with this disease. p.Q188R is also the most prevalent mutation in the Spanish and Portuguese population, accounting for 50% and 57.8% of galactosaemic alleles, respectively. An additional 15 mutations were also identified in Spanish patients, four of which were novel: p.D28H, p.S181A, c.658dupG and c.377+53_1059+87del. In the Portuguese population, 11 different mutations were found, three of which were novel: p.R33H, p.P185S, and p.S192G. The differences observed between the genotypes identified in Portuguese and Spanish galactosaemic populations are notable. Only mutations p.Q188R, p.R148Q and c.820+13g>a were identified in both populations. In spite of the geographical proximity of Spain and Portugal, it seems that they have received genetic influences from different populations. The repeated migrations that occurred in the Iberian Peninsula throughout centuries may explain such variability. [ABSTRACT FROM AUTHOR]

Hyperhomocysteinaemia has been regarded as a new modifiable risk factor for atherosclerosis and vascular disease. Homocysteine is a branch-point intermediate of methionine metabolism, which can be further metabolised via two alternative pathways: degraded irreversibly through the transsulphuration pathway or remethylated to methionine by the remethylation pathway. Both pathways are B-vitamin-dependent. Plasma homocysteine concentrations are determined by nongenetic and genetic factors. The metabolism of homocysteine, the role of B vitamins and the contribution of nongenetic and genetic determinants of homocysteine concentrations are reviewed. The mechanisms whereby homocysteine causes endothelial damage and vascular disease are not fully understood. Recently, a link has been postulated between homocysteine, or its intermediates, and an alterated DNA methylation pattern. The involvement of epigenetic mechanisms in the context of homocysteine and atherosclerosis, due to inhibition of transmethylation reactions, is briefly overviewed. [ABSTRACT FROM AUTHOR]

Explains that medical genetics researchers investigated the effect of the common 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298A→C mutations on leukocyte genomic DNA methylation status. DNA methylation patterns are maintained by DNA methyltransferases using S-adenosylmethionine; Regulatory enzyme of Hcy metabolism.

Abstract Aims: The study was undertaken with the objective of understanding the virulence-associated genes of the CTX and TCP gene clusters in environmental isolates of Vibrio cholerae , an important human pathogen, isolated from the aquaculture environment. The involvement of the omp U gene in conferring bile resistance in these isolates was also evaluated. Methods and Results: The V. cholerae isolates were tested by PCR and fluorescent antibody test for O1 (Ogawa and Inaba) and O139 serotypes. All isolates were found to be non-toxigenic V. cholerae confirmed by their positive PCR reaction for tox R but negative for ctx , zot and tcp gene. The hly A gene was detected in 85% of the strains and omp U in 77%. The results on the bactericidal effect of bile salts suggest that omp U may play a role in conferring bile resistance in non-O1/non-O139 strains. Conclusion: The results of the study indicate that most environmental strains lacked the CTX and TCP gene clusters. However, most isolates had the hly A gene indicating the potential of these environmental strains to cause mild gastroenteritis. It was also observed that strains lacking omp U showed less tolerance to bile salts. Significance and Impact of the Study: Information on virulence factors of V. cholerae associated with aquaculture environment and products would be of value in risk assessment for human health. [ABSTRACT FROM AUTHOR]

• A dual-wavelength passive mode-locked in a spectral filter free cavity with NPR is presented. • The dual-wavelength is obtained by decreasing linear and circular birefringence in the cavity by twisting the fiber. • The double-twist fiber allows to eliminate the spectral dependence of the saturable absorber. We present the experimental investigation of a dual-wavelength passively mode-locked Er-doped fiber laser with strict polarization control. The configuration includes a double-pass amplifier with a Faraday mirror and twisted fiber. We observe that including double-twist fiber cancels circular and linear birefringence and allows obtaining dual-wavelength emission varying the losses in the cavity. In contrast, results including single-twist fiber which only emits single-wavelength due to large circular birefringence. [ABSTRACT FROM AUTHOR]