Association Between Uric Acid Levels and Obstructive Sleep Apnea Syndrome in a Large Epidemiological Sample

Introduction: Recurrent hypoxia, which is associated with obstructive sleep apnea syndrome (OSAS), leads to an increase in the degradation of adenosine triphosphatase into xanthine, which in turn increases uric acid concentrations.Objective: the current study aimed to determine whether an association exists between OSAS and uric acid levels in the peripheral blood from a representative population of São Paulo (Brazil).Methods: A population-based survey adopting a probabilistic 3-stage cluster sample of São Paulo was used to represent the population according to gender, age, and socioeconomic class. A total of 1,042 volunteers underwent polysomnography recordings for OSAS diagnosis, blood pressure assessment, and biochemical blood analysis, and answered questionnaires.Results: Uric acid levels were correlated with most important risk factors for OSAS, such as AHI, desaturation time and index, minimum oxyhemoglobin saturation (SpO(2)), blood pressure, cholesterol, BMI, triglycerides and arousal, and with OSAS itself. Also, uric acid was increased in OSAS volunteers even after controlling for all confounders. Hyperuricemic volunteers presented lower mean and minimum SpO(2) and increased desaturation index. Importantly, minimum SpO(2) was a significant predictor of uric acid levels, which in turn was considered an independent predictor for OSAS in the binary logistic model. However, a ROC curve analysis for establishing cut-off points for uric acid levels as a biomarker of OSAS revealed moderate sensitivity and specificity.Conclusion: A strong association was found between uric acid levels and OSAS in a representative sample of the population of São Paulo. Although they do not qualify for a biomarker alone, uric acid levels may be involved in OSAS severity and should be considered in sleep apnea management in the future.Associacao Fundo de Incentivo a Pesquisa (AFIP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilFAPESP: CEPID 98/14303-3FAPESP: 10/50129-1Web of Scienc

Qualidade por concepção: uma nova abordagem para acelerar o desenvolvimento tecnológico e inovação na área da saúde

This article seeks to present a systematic and proactive quality management model based on scientific rigor, as well as on analysis and risk management, known as Quality by Design (QbD). Since 2012, regulatory agencies from the United States and the European Union have pressed the manufactures to speed the adoption of QbD principles for processes and products development. In Brazil, the new approach has received increasing attention from the pharmaceutical∕biotechnological community, as well as from Anvisa, and it is now seen as a global regulatory initiative to assure the rational development of products, reducing the lead and launch time to market, incrementing the elaboration of clinical protocols, controlling costs and increasing success chances of the pharmaceutical sector. In this context, the adoption of the QbD concepts aims to add value to existing quality policies in organizations, providing not only more agility and assertiveness, but also more confidence in the new developed products.O presente artigo pretende apresentar um modelo de gestão de qualidade sistemático e proativo, baseado no rigor científico e em análise e gerenciamento de risco, conhecido como Quality by Design (QbD) ou Qualidade por Concepção (QpC). Desde 2012, as agências reguladoras dos Estados Unidos e União Europeia têm sugerido a aplicação das diretrizes da QpC para o desenvolvimento de processos e produtos. No Brasil, a nova abordagem tem recebido atenção crescente da comunidade farmacêutica/biotecnológica, assim como da Anvisa, e é vista hoje como uma inciativa regulatória global que visa garantir o desenvolvimento racional dos produtos, reduzindo o tempo de disponibilização ao mercado, incrementando a elaboração de protocolos clínicos, controlando os custos e aumentando as chances de sucesso do setor farmacêutico. Nesse contexto, a adoção dos princípios da QpC pretende agregar valor à política de qualidade já existente nas organizações, propiciando não apenas mais agilidade e assertividade, como também mais confiança nos novos produtos desenvolvidos

Dopamine-beta hydroxylase polymorphism and cocaine addiction

Cocaine addiction involves a number of medical, psychological and social problems. Understanding the genetic aetiology of this disorder will be essential for design of effective treatments. Dopamine-beta hydroxylase (DbH) catalyzes the conversion of dopamine to norepinephrine and could, therefore, have an influence on both cocaine action and the basal sensitivity of neurotransmitter systems to cocaine. Recently, the -1021C>T polymorphism have been found to strongly correlated with individual variation in plasma DbH activity. To test the influence of this polymorphism on the susceptibility of cocaine addiction, we decided to genotype it in a sample of 689 cocaine addicts and 832 healthy individuals. Genotypic and allelic analyses did not show any evidence of association with cocaine addiction, even after correcting for the effect of population stratification and other possible confounders. Our results do not support a major role of the -1021C>T polymorphism or the gene itself in the development of cocaine addiction but further examination of other variants within this gene will be necessary to completely rule out an effect

Influence of genetic ancestry on the risk of obstructive sleep apnoea syndrome

The aim of the present study was to evaluate the influence of ethnicity on the risk of developing obstructive sleep apnoea syndrome (OSAS) using genomic analysis methods to estimate ancestry.DNA samples were obtained from 1,010 individuals participating in the São Paulo Epidemiologic Sleep Study, who underwent full-night polysomnography. A total of 31 genetic ancestry-informative markers were selected in order to estimate individual admixture proportions.Of patients with a diagnosis of OSAS, a higher number self-reporting Caucasian ethnicity (65.3%), as well as an increased percentage of European ancestry (78.2 +/- 16.7%) and lower percentage of West African ancestry (16.1 +/- 15.3%), than among individuals without OSAS (53.6, 73.5 +/- 18.1 and 20.1 +/- 16.8%, respectively) (p < 0.001) was observed. Moreover, after correcting for sex, age, body mass index and socioeconomic status, logistic regression demonstrated that European ancestry was significantly associated with an increased risk of manifesting OSAS (OR 2.80, 95% CI 1.11-7.09). Conversely, West African ancestry was associated with a reduced risk of the OSAS phenotype (OR 0.26, 95% CI 0.09-0.72).This is the first study to incorporate genomic analysis methods to measure the influence of ethnicity on the risk of OSAS. Since genetically determined ancestry may not capture unmeasured cultural and lifestyle differences, the contribution of environmental factors to the current findings should not be disregarded.Psychopharmacology Incentive FundFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Psychobiol, Escola Paulista Med, BR-04024002 São Paulo, BrazilInst Pesquisas Tecnol & Inovacao, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, Escola Paulista Med, BR-04024002 São Paulo, BrazilFAPESP: CEPID 98/14303-3Web of Scienc

Validation of commonly used reference genes for sleep-related gene expression studies

<p>Abstract</p> <p>Background</p> <p>Sleep is a restorative process and is essential for maintenance of mental and physical health. In an attempt to understand the complexity of sleep, multidisciplinary strategies, including genetic approaches, have been applied to sleep research. Although quantitative real time PCR has been used in previous sleep-related gene expression studies, proper validation of reference genes is currently lacking. Thus, we examined the effect of total or paradoxical sleep deprivation (TSD or PSD) on the expression stability of the following frequently used reference genes in brain and blood: <it>beta-actin (b-actin), beta-2-microglobulin (B2M), glyceraldehyde-3-phosphate dehydrogenase (GAPDH)</it>, and <it>hypoxanthine guanine phosphoribosyl transferase (HPRT)</it>.</p> <p>Results</p> <p>Neither TSD nor PSD affected the expression stability of all tested genes in both tissues indicating that <it>b-actin, B2M, GAPDH </it>and <it>HPRT </it>are appropriate reference genes for the sleep-related gene expression studies. In order to further verify these results, the relative expression of <it>brain derived neurotrophic factor (BDNF) </it>and <it>glycerol-3-phosphate dehydrogenase1 (GPD1) </it>was evaluated in brain and blood, respectively. The normalization with each of four reference genes produced similar pattern of expression in control and sleep deprived rats, but subtle differences in the magnitude of expression fold change were observed which might affect the statistical significance.</p> <p>Conclusion</p> <p>This study demonstrated that sleep deprivation does not alter the expression stability of commonly used reference genes in brain and blood. Nonetheless, the use of multiple reference genes in quantitative RT-PCR is required for the accurate results.</p

Apolipoprotein E polymorphisms and sleep quality in Obstructive Sleep Apnea Syndrome

Background: the purpose of this study was to evaluate the influence of polymorphism on sleep parameters of Obstructive Sleep Apnea Syndrome (OSAS) patients.Methods: Patients were genotyped after a full-night polysomnography using the large Epidemiologic Sleep Study of São Paulo population-based sample.Results: Individuals who carry the APOE epsilon 2 allele showed longer sleep latency, lower sleep efficiency and higher numbers of arousals/hour, when compared to epsilon 3 allele homozygous and carriers of epsilon 4 allele (p<0.05). These findings remained significant even after correction for potential confounders, such as sex, age and African genetic ancestry.Conclusion: the APOE polymorphisms may modulate the effects of intermittent hypoxia and sleep fragmentation in the sleep architecture of OSAS patients, and that the presence of the epsilon 2 allele may serve as a biological marker for the identification of a subgroup of patients who are more likely to suffer with OSAS detrimental effects on sleep, impacting not only the daily functioning, but also their quality of life. (C) 2011 Elsevier B.V. All rights reserved.Associacao Fundo de Incentivo a Psicofarmacologia (AFIP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilFAPESP: 07/50525-1FAPESP: 98/14303-3Web of Scienc

Estratificação populacional em sul-americanos de origem européia e sua importância para a pesquisa genética psiquiátrica no Brasil

Universidade de São Paulo Medical School Department and Institute of PsychiatryUniversidade Federal de Minas Gerais Medical School Department of Mental HealthUniversidade Federal de São Paulo (UNIFESP) Department of Psychiatry Interdisciplinary Laboratory of Clinical NeuroscienceUniversidade Federal do Rio Grande do Sul Department of GeneticsUNIFESP, Department of Psychiatry Interdisciplinary Laboratory of Clinical NeuroscienceSciEL

Butyrylcholinesterase Genetic Variants: Association with Cocaine Dependence and Related Phenotypes

Objective: the search for genetic vulnerability factors in cocaine dependence has focused on the role that neuroplasticity plays in addiction. However, like many other drugs, the ability of an individual to metabolize cocaine can also influence susceptibility to dependence. Butyrylcholinesterase (BChE) metabolizes cocaine, and genetic variants of the BChE gene (BCHE) alter its catalytic activity. Therefore, we hypothesize that cocaine users with polymorphisms in BCHE can show diverse addictive behaviors due to differences in effective plasma concentrations of cocaine. Those polymorphisms might also influence users to prefer one of the two main preparations (crack or powder cocaine), despite having equal access to both. the present work investigates polymorphisms in BCHE and if those genetic variants constitute risk factors for cocaine dependence and for crack cocaine use.Methods: A total of 1,436 individuals (698 cocaine-dependent patients and 738 controls) were genotyped for three single nucleotide polymorphisms (SNPs) in BCHE: rs1803274, rs4263329, and rs4680662.Results: for rs4263329, a nominal difference was found between cases and controls. for rs1803274 (the functional SNP), a statistically significant difference was found between patients who used crack cocaine exclusively and those who used only powder cocaine (P = 0.027; OR = 4.36; 95% CI = 1.18-16.04). Allele frequencies and genotypes related to other markers did not differ between cases and controls or between the two cocaine subgroups.Conclusions: Our findings suggest that the AA genotype of rs1803274 is a risk factor for crack cocaine use, which is more addictive than powder cocaine use. Further studies are needed in order to confirm this preliminary result and clarify the role of BCHE and its variants in cocaine dependence.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ São Paulo, Sch Med, Dept & Inst Psychiat LIM 23, São Paulo, BrazilUniv São Paulo, Sch Med, Lab Genet & Mol Cardiol LIM 13, Heart Inst InCor, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Clin Neurosci Lab, São Paulo, BrazilUniv São Paulo, Sch Publ Hlth, São Paulo, BrazilUniversidade Federal de São Paulo, Natl Inst Alcohol & Drug Policies, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Clin Neurosci Lab, São Paulo, BrazilUniversidade Federal de São Paulo, Natl Inst Alcohol & Drug Policies, São Paulo, BrazilCNPq: 141762/2008-0Web of Scienc

Uma revisão sobre a pesquisa genética psiquiátrica na população brasileira

OBJECTIVE AND METHOD: A large increase in the number of Brazilian studies on psychiatric genetics has been observed in the 1970's since the first publications conducted by a group of researchers in Brazil. Here we reviewed the literature and evaluated the advantages and difficulties of psychiatric genetic studies in the Brazilian population. CONCLUSION: The Brazilian population is one of the most heterogeneous populations in the world, formed mainly by the admixture between European, African and Native American populations. Although the admixture process is not a particularity of the Brazilian population, much of the history and social development in Brazil underlies the ethnic melting pot we observe nowadays. Such ethnical heterogeneity of the Brazilian population obviously brings some problems when performing genetic studies. However, the Brazilian population offers a number of particular characteristics that are of major interest when genetic studies are carried out, such as the presence of isolated populations. Thus, differences in the genetic profile and in the exposure to environmental risks may result in different interactions and pathways to psychopathology.OBJETIVO E MÉTODO: Desde a década de 70, quando os primeiros estudos em genética psiquiátrica conduzidos por um grupo de brasileiros foram publicados, o número de trabalhos realizados no Brasil vem aumentando consideravelmente. Através desta revisão, avaliamos as vantagens e as dificuldades da realização de pesquisas em psiquiatria genética na população brasileira. CONCLUSÃO: A população brasileira é uma das mais heterogêneas do mundo, formada principalmente pela combinação entre populações européia, africana e nativa americana. Apesar de a mistura entre raças não ser uma particularidade da população brasileira, a história e o desenvolvimento social no Brasil ocasionou uma grande miscigenação étnica, a qual é observada atualmente. Devido à heterogeneidade de suas origens, diversos problemas são levantados em estudos genéticos realizados no Brasil. Porém, a população brasileira oferece características particulares para desenvolvimento de pesquisas genéticas, como a presença de populações isoladas. Portanto, diferenças genéticas e exposição a riscos ambientais podem resultar em diferentes interações e caminhos para alterações psicopatológicas