Prediction of susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factors

Major depressive disorder (MDD) is the most common psychiatric disorder and the second overall cause of disability. Even though a significant amount of the variance in the MDD phenotype is explained by inheritance, specific genetic variants conferring susceptibility to MDD explain only a minimal proportion of MDD causality. Moreover, genome-wide association studies have only identified two small-sized effect loci that reach genome-wide significance. In this study, a group of Mexican-American patients with MDD and controls recruited for a pharmacogenetic study were genotyped for nonsynonymous single-nucleotide polymorphisms (nsSNPs) and used to explore the interactions of multiple functional genetic variants with risk-classification tree analysis. The risk-classification tree analysis model and linkage disequilibrium blocks were used to replicate exploratory findings in the database of genotypes and phenotypes (dbGaP) for major depression, and pathway analysis was performed to explore potential biological mechanisms using the branching events. In exploratory analyses, we found that risk-classification tree analysis, using 15 nsSNPs that had a nominal association with MDD diagnosis, identified multiple increased-MDD genotype clusters and significant additive interactions in combinations of genotype variants that were significantly associated with MDD. The results in the dbGaP for major depression disclosed a multidimensional dependent phenotype constituted of MDD plus significant modifiers (smoking, marriage status, age, alcohol abuse/dependence and gender), which then was used for the association tree analysis. The reconstructed tree analysis for the dbGaP data showed robust reliability and replicated most of the genes involved in the branching process found in our exploratory analyses. Pathway analysis using all six major events of branching (PSMD9, HSD3B1, BDNF, GHRHR, PDE6C and PDLIM5) was significant for positive regulation of cellular and biological processes that are relevant to growth and organ development. Our findings not only provide important insights into the biological pathways underlying innate susceptibility to MDD but also offer a predictive framework based on interactions of multiple functional genetic variants and environmental factors. These findings identify novel targets for therapeutics and for translation into preventive, clinical and personalized health care

A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis

BACKGROUND: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). METHODS/PRINCIPAL FINDINGS: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. CONCLUSION/SIGNIFICANCE: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. TRIAL REGISTRATION: Clinicaltrials.gov NCT00690118

The Tell-Tale Heart: Population-Based Surveillance Reveals an Association of Rofecoxib and Celecoxib with Myocardial Infarction

Background. COX-2 selective inhibitors are associated with myocardial infarction (MI). We sought to determine whether population health monitoring would have revealed the effect of COX-2 inhibitors on population-level patterns of MI. Methodology/Principal Findings. We conducted a retrospective study of inpatients at two Boston hospitals, from January 1997 to March 2006. There was a population-level rise in the rate of MI that reached 52.0 MI-related hospitalizations per 100,000 (a two standard deviation exceedence) in January of 2000, eight months after the introduction of rofecoxib and one year after celecoxib. The exceedence vanished within one month of the withdrawal of rofecoxib. Trends in inpatient stay due to MI were tightly coupled to the rise and fall of prescriptions of COX-2 inhibitors, with an 18.5 % increase in inpatient stays for MI when both rofecoxib and celecoxib were on the market (P,0.001). For every million prescriptions of rofecoxib and celecoxib, there was a 0.5 % increase in MI (95%CI 0.1 to 0.9) explaining 50.3 % of the deviance in yearly variation of MI-related hospitalizations. There was a negative association between mean age at MI and volume of prescriptions for celecoxib and rofecoxib (Spearman correlation, 20.67, P,0.05). Conclusions/Significance. The strong relationship between prescribing and outcome time series supports a population-level impact of COX-2 inhibitors on MI incidence. Further, mean age at MI appears to have been lowered by use of these medications. Use of a population monitoring approach as an adjunct t

QUALIDADE DE GRÃOS DE SOJA ARMAZENADOS EM BAIXAS TEMPERATURAS / QUALITY OF SOYBEAN GRAINS STORED IN LOW TEMPERATURES

Objetivou-se com este estudo avaliar a qualidade de grãos de soja armazenada durante seis meses em ambiente com temperaturas baixas e em diferentes embalagens. O delineamento experimental utilizado foi inteiramente casualizado, fatorial (2x3x2), sendo dois tipos de embalagens (sacos de papel permeável e sacos de plástico de polietileno), três temperaturas de acondicionamento (3, 10 e 23 0C) e dois tempos de avaliação (zero e seis meses). O aumento do tempo de armazenamento reduziu à qualidade dos grãos de soja, independentemente das condições de armazenamento e embalagem. O armazenamento em embalagem permeável afetou mais a qualidade dos grãos de soja. A temperatura de armazenamento de 23 °C foi a que mais alterou negativamente a qualidade dos grãos de soja. O armazenamento na temperatura do ar de 3 °C foi mais favorável para a qualidade dos grãos de soja, embora alguns resultados de qualidade foram iguais, com o armazenamento na temperatura de 10 °C. Concluiu-se que, o resfriamento artificial do ambiente de armazenamento para temperaturas inferiores a 10 °C pode ser a melhor alternativa para preservar a qualidade dos grãos armazenados. As embalagens impermeabilizadas, para as mesmas condições médias de temperatura e umidade relativa do ar de armazenagem podem contribuir para minimizar perdas em grãos de soja, em comparação com embalagens permeáveis, considerando-se os atributos qualitativos analisados.</p

SECAGEM DE GRÃOS DE MILHO DO CERRADO EM UM SECADOR COMERCIAL DE FLUXOS MISTOS / DRYING CLOSED CORN GRAIN DRYER FLOW IN A COMMERCIAL MIXED

Objetivou-se avaliar os efeitos da temperatura do ar de secagem (80, 100 e 120 °C) e a redução dos teores de água na qualidade física e físico-química de grãos de milho (Zea mays L.) em um secador de fluxo mistos operando de forma continua. O delineamento experimental foi inteiramente casualizado, em esquema fatorial (7x3) (teores de água x temperaturas de secagem). A redução dos teores de água associados ao aumento da temperatura do ar de secagem reduziu o comprimento, a largura, a espessura, o volume, a esfericidade e a circularidade dos grãos de milho. Os índices de acidez e a porcentagem de cinzas aumentaram com a redução dos teores de água, não havendo diferenças entre as temperaturas do ar de secagem. A diminuição dos teores de água com o aumento da temperatura do ar de secagem aumentou a condutividade elétrica e reduziu a germinação dos grãos, não havendo diferença entre as temperaturas de 100 e 120 °C. Concluiu-se que, o processo de secagem contínua em secadores de fluxo misto de ar e produto na temperatura do ar de até 80 °C, não afetou negativamente a qualidade física e físico-química dos grãos de milho.</p

A Virtual Reality Based Simulator for Gynecologic Exam Training

Abstract—Training is an effective way to acquire knowledge. In the last years, realistic training has been proposed and offered by the use of virtual reality (VR) systems. This work presents a VR based simulator for gynecologic exam training- the SITEG. This system integrates stereoscopic view and touch to simulate a real exam in a virtual environment. In this environment the user can practice and learn different gynecological pathologies in several stages