Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I(2) measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2) measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI> or =32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI<25 kg/m(2)) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.

Plasma free fatty acids do not provide the link between obesity and insulin resistance or β-cell dysfunction: results of the Reading, Imperial, Surrey, Cambridge, Kings (RISCK) study

Aims To investigate the relationship between adiposity and plasma free fatty acid levels and the influence of total plasma free fatty acid level on insulin sensitivity and β-cell function. Methods An insulin sensitivity index, acute insulin response to glucose and a disposition index, derived from i.v. glucose tolerance minimal model analysis and total fasting plasma free fatty acid levels were available for 533 participants in the Reading, Imperial, Surrey, Cambridge, Kings study. Bivariate correlations were made between insulin sensitivity index, acute insulin response to glucose and disposition index and both adiposity measures (BMI, waist circumference and body fat mass) and total plasma free fatty acid levels. Multivariate linear regression analysis was performed, controlling for age, sex, ethnicity and adiposity. Results After adjustment, all adiposity measures were inversely associated with insulin sensitivity index (BMI: β = −0.357; waist circumference: β = −0.380; body fat mass: β = −0.375) and disposition index (BMI: β = −0.215; waist circumference: β = −0.248; body fat mass: β = −0.221) and positively associated with acute insulin response to glucose [BMI: β = 0.200; waist circumference: β = 0.195; body fat mass β = 0.209 (P values <0.001)]. Adiposity explained 13, 4 and 5% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. After adjustment, no adiposity measure was associated with free fatty acid level, but total plasma free fatty acid level was inversely associated with insulin sensitivity index (β = −0.133), acute insulin response to glucose (β = −0.148) and disposition index [β = −0.218 (P values <0.01)]. Plasma free fatty acid concentration accounted for 1.5, 2 and 4% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. Conclusions Plasma free fatty acid levels have a modest negative association with insulin sensitivity, β-cell secretion and disposition index but no association with adiposity measures. It is unlikely that plasma free fatty acids are the primary mediators of obesity-related insulin resistance or β-cell dysfunction.

Genetic variant rs17225178 in the ARNT2 gene is associated with Asperger Syndrome

Background Autism Spectrum Conditions (ASC) are neurodevelopmental conditions characterized by difficulties in communication and social interaction, alongside unusually repetitive behaviours and narrow interests. Asperger Syndrome (AS) is one subgroup of ASC and differs from classic autism in that in AS there is no language or general cognitive delay. Genetic, epigenetic and environmental factors are implicated in ASC and genes involved in neural connectivity and neurodevelopment are good candidates for studying the susceptibility to ASC. The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) gene encodes a transcription factor involved in neurodevelopmental processes, neuronal connectivity and cellular responses to hypoxia. A mutation in this gene has been identified in individuals with ASC and single nucleotide polymorphisms (SNPs) have been nominally associated with AS and autistic traits in previous studies. Methods In this study, we tested 34 SNPs in ARNT2 for association with AS in 118 cases and 412 controls of Caucasian origin. P values were adjusted for multiple comparisons, and linkage disequilibrium (LD) among the SNPs analysed was calculated in our sample. Finally, SNP annotation allowed functional and structural analyses of the genetic variants in ARNT2. We tested the replicability of our result using the genome-wide association studies (GWAS) database of the Psychiatric Genomics Consortium (PGC). Results We report statistically significant association of rs17225178 with AS. This SNP modifies transcription factor binding sites and regions that regulate the chromatin state in neural cell lines. It is also included in a LD block in our sample, alongside other genetic variants that alter chromatin regulatory regions in neural cells. Conclusions These findings demonstrate that rs17225178 in the ARNT2 gene is associated with AS and support previous studies that pointed out an involvement of this gene in the predisposition to ASC.

A comprehensive meta-analysis of common genetic variants in autism spectrum conditions

Background Autism spectrum conditions (ASC) are a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication alongside repetitive and stereotyped behaviours. ASC are heritable, and common genetic variants contribute substantial phenotypic variability. More than 600 genes have been implicated in ASC to date. However, a comprehensive investigation of candidate gene association studies in ASC is lacking. Methods In this study, we systematically reviewed the literature for association studies for 552 genes associated with ASC. We identified 58 common genetic variants in 27 genes that have been investigated in three or more independent cohorts and conducted a meta-analysis for 55 of these variants. We investigated publication bias and sensitivity and performed stratified analyses for a subset of these variants. Results We identified 15 variants nominally significant for the mean effect size, 8 of which had P values below a threshold of significance of 0.01. Of these 15 variants, 11 were re-investigated for effect sizes and significance in the larger Psychiatric Genomics Consortium dataset, and none of them were significant. Effect direction for 8 of the 11 variants were concordant between both the datasets, although the correlation between the effect sizes from the two datasets was poor and non-significant. Conclusions This is the first study to comprehensively examine common variants in candidate genes for ASC through meta-analysis. While for majority of the variants, the total sample size was above 500 cases and 500 controls, the total sample size was not large enough to accurately identify common variants that contribute to the aetiology of ASC.

Improved likelihood inference in Birnbaum-Saunders regressions

The Birnbaum-Saunders regression model is commonly used in reliability studies. We address the issue of performing inference in this class of models when the number of observations is small. Our simulation results suggest that the likelihood ratio test tends to be liberal when the sample size is small. We obtain a correction factor which reduces the size distortion of the test. Also, we consider a parametric bootstrap scheme to obtain improved critical values and improved p-values for the likelihood ratio test. The numerical results show that the modified tests are more reliable in finite samples than the usual likelihood ratio test. We also present an empirical application. (C) 2009 Elsevier B.V. All rights reserved.

Use of Metals and Anion Species with Chemometrics Tools for Classification of Unprocessed and Processed Coconut Waters

Coconut water is a natural isotonic, nutritive, and low-caloric drink. Preservation process is necessary to increase its shelf life outside the fruit and to improve commercialization. However, the influence of the conservation processes, antioxidant addition, maturation time, and soil where coconut is cultivated on the chemical composition of coconut water has had few arguments and studies. For these reasons, an evaluation of coconut waters (unprocessed and processed) was carried out using Ca, Cu, Fe, K, Mg, Mn, Na, Zn, chloride, sulfate, phosphate, malate, and ascorbate concentrations and chemometric tools. The quantitative determinations were performed by electrothermal atomic absorption spectrometry, inductively coupled plasma optical emission spectrometry, and capillary electrophoresis. The results showed that Ca, K, and Zn concentrations did not present significant alterations between the samples. The ranges of Cu, Fe, Mg, Mn, PO (4) (3-) , and SO (4) (2-) concentrations were as follows: Cu (3.1-120 A mu g L(-1)), Fe (60-330 A mu g L(-1)), Mg (48-123 mg L(-1)), Mn (0.4-4.0 mg L(-1)), PO (4) (3-) (55-212 mg L(-1)), and SO (4) (2-) (19-136 mg L(-1)). The principal component analysis (PCA) and hierarchical cluster analysis (HCA) were applied to differentiate unprocessed and processed samples. Multivariated analysis (PCA and HCA) were compared through one-way analysis of variance with Tukey-Kramer multiple comparisons test, and p values less than 0.05 were considered to be significant.

Ion pair stabilization effects on a series of procaine structural analogs

In this work, a series of 10 structural procaine analogs have been synthesized in order to investigate the structural features affecting the stability of ion pair formation and its influence on the lipophilicity of ionizable compounds. The structural variation within this series was focused on the terminal nitrogen substituents and on the intermediate chain linkage nature. The hydrophobic parameters log P(n) and log P(i) (partition coefficient of the neutral and ionic species, respectively), as well as the ionization constants pK(a) and pK(a)(oct), were obtained from log D-pH profiles measured at pH values ranging from 2 to 12. The difference between log P(i) and log P(n) values (i.e. difflog P) of each prepared compound was considered a measure of the stability of ion pair formation. In this set, the difflog P values varied nearly over one log unit, ranging from -2.40 to -3.37. It has been observed that the presence of hydrogen bonding groups (especially donor) and low steric hindrance around the terminal amine ionizable group increases the relative lipophilicity of the ionic species as compared to the corresponding neutral species. These results were interpreted as due to the increased stability of ion pairs of the compounds bearing these structural features. (C) 2010 Elsevier B.V. All rights reserved.

Modelagem matemática para o transporte de partículas sujeitas a múltiplos mecanismos de retenção

Discrepancies between classical model predictions and experimental data for deep bed filtration have been reported by various authors. In order to understand these discrepancies, an analytic continuum model for deep bed filtration is proposed. In this model, a filter coefficient is attributed to each distinct retention mechanism (straining, diffusion, gravity interception, etc.). It was shown that these coefficients generally cannot be merged into an effective filter coefficient, as considered in the classical model. Furthermore, the derived analytic solutions for the proposed model were applied for fitting experimental data, and a very good agreement between experimental data and proposed model predictions were obtained. Comparison of the obtained results with empirical correlations allowed identifying the dominant retention mechanisms. In addition, it was shown that the larger the ratio of particle to pore sizes, the more intensive the straining mechanism and the larger the discrepancies between experimental data and classical model predictions. The classical model and proposed model were compared via statistical analysis. The obtained p values allow concluding that the proposed model should be preferred especially when straining plays an important role. In addition, deep bed filtration with finite retention capacity was studied. This work also involves the study of filtration of particles through porous media with a finite capacity of filtration. It was observed, in this case, that is necessary to consider changes in the boundary conditions through time evolution. It was obtained a solution for such a model using different functions of filtration coefficients. Besides that, it was shown how to build a solution for any filtration coefficient. It was seen that, even considering the same filtration coefficient, the classic model and the one here propposed, show different predictions for the concentration of particles retained in the porous media and for the suspended particles at the exit of the media

Análise da efetividade do transplante renal na qualidade de vida dos receptores no estado do Rio Grande do Norte

This study was developed with the aim of analyzing the effectiveness of renal transplantation on quality of life of kidney recipients in the Rio Grande do Norte State. This is a descriptive study with longitudinal design, panel type with quantitative approach to data analysis. The Quality of Life (QoL) of chronic disease kidney patients before and after kidney transplantation was assessed by the WHOQOL-bref, The population consisted of patients in pre and post-renal transplantation, the sample had 63 patients older than 18 years. The study was conducted after approval by the Research Ethics Committee of the Onofre Lopes University Hospital, Federal University of Rio Grande do Norte, No. CAAE 0008.0.294.000-10. Data collection was performed at a referral center for renal transplantation in Rio Grande do Norte, from May 2010 to May 2013. Data were analyzed using descriptive statistics and presented in tables and graphs. For statistical analyzes, Microsoft Excel XP and SPSS 15.0 software were used. The tests used were simple variance (ANOVA), t-test, Mann-Whitney and Wilcoxon test to compare means, and Spearman correlations. P values <0.05 were considered significant. The demographic data showed a predominance of people between 18 and 45 years (68.2%) with a mean age of 39.9 years (SD 12.2), male (63.5%), married (58.7%), with children (51.0%). Regarding the education level was observed that 49.2% of participants had completed primary school, and most did not engage in any work activity (90.4%) during the study period. Hemodialysis was the predominant renal replacement therapy (96.8%) and the average waiting time for execution of transplantation was 1.9 years (SD 1.9). Comparison of QoL before and after transplantation showed significant differences in all areas analyzed, demonstrating that kidney transplantation had a positive impact on QoL in chronic renal patients undergoing kidney transplantation. Sociodemographic factors did not influence the quality of life in this group of patients, indicating that transplantation was the main factor to explain the improvement in quality of life. Thus, the alternative hypothesis of the study was accept, that there is a significant difference in quality of life before and after kidney transplant. It is expected that the results of this study may contribute to the development of strategies to encourage organ donation and kidney transplantation process

Accuracy of six minute walk test, stair test and spirometry using maximal oxygen uptake as gold standard

OBJETIVO: Determinar a acurácia das variáveis: tempo de escada (tTE), potência de escada (PTE), teste de caminhada (TC6) e volume expiratório forçado (VEF1) utilizando o consumo máximo de oxigênio (VO2máx) como padrão-ouro. MÉTODOS: Os testes foram realizados em 51 pacientes. O VEF1 foi obtido através da espirometria. O TC6 foi realizado em corredor plano de 120m. O TE foi realizado em escada de 6 lances obtendo-se tTE e PTE. O VO2máx foi obtido por ergoespirometria, utilizando o protocolo de Balke. Foram calculados a correlação linear de Pearson (r) e os valores de p, entre VO2máx e variáveis. Para o cálculo da acurácia, foram obtidos os pontos de corte, através da curva característica operacional (ROC). A estatística Kappa (k) foi utilizada para cálculo da concordância. RESULTADOS: Obteve-se as acurácias: tTE - 86%, TC6 - 80%, PTE - 71%, VEF1(L) - 67%, VEF1% - 63%. Para o tTE e TC6 combinados em paralelo, obteve-se sensibilidade de 93,5% e em série, especificidade de 96,4%. CONCLUSÃO: O tTE foi a variável que apresentou a melhor acurácia. Quando combinados o tTE e TC6 podem ter especificidade e sensibilidade próxima de 100%. Estes testes deveriam ser mais usados rotineiramente, especialmente quando a ergoespirometria para a medida de VO2máx não é disponível.

Interleukin 18 messenger RNA and proIL-18 protein expression in chorioamniotic membranes from pregnant women with preterm prelabor rupture of membranes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Influence of thermal and mechanical stresses on the strength of intact and relined denture bases

Statement of problem. Denture bases may become increasingly weaker as a result of thermal stress and flexural cyclic loading. Information regarding this potential problem and its relationship to the denture base reline is limited.Purpose. This study evaluated the influence of thermal and mechanical stresses on the strength of intact and relined denture bases.Material and methods. Twenty-eight microwave-polymerized (Acron MC) intact denture bases were prepared in the shape of a 3-mm-thick maxillary denture. Additionally, fifty-six 2-mm-thick denture bases were relined with 1 mm of autopolymerizing resin (Tokuyama Rebase Fast II or New Truliner) (n = 28). Intact and relined specimens were divided into 4 groups (n = 7) as follows: without stress (control); a mechanical stress at 0.8 Hz for 10,000 cycles; 5000 thermal cycles between 5 degrees C and 55 degrees C; or a combination thermo-mechanical stress. The specimens were vertically loaded in compression with a rounded rod at 5 mm/min until failure, using a universal testing machine. Data on maximum fracture load (N), deflection at fracture (%), and fracture energy (N-mm) were analyzed by 2-way analysis of variance and Student-Newman-Keuls tests (alpha = .05).Results. The strength of the denture bases relined with New Truliner was not significantly affected by any of the experimental conditions, but comparing the control groups, New Truliner exhibited the lowest maximum fracture load values. The maximum fracture load of intact denture bases (P = .002) and those relined with Tokuyama Rebase Fast II (P = .01) showed a significant decrease after thermal stress. Additionally, cyclic loading significantly decreased the maximum fracture load (P < .001), deflection at fracture (P = .025), and fracture energy (P < .001) of intact denture bases and those relined with Tokuyama Rebase (P values of .002, .039, and .001, respectively).Conclusion. Thermal and mechanical stresses exert deleterious effects on the strength of intact and/or relined denture bases, which vary according to the relining material used.

Radioautographic study of the seasonal distribution of leukocytes in turtles Phrynops hilarii (Chelonia Chelidae)

The aim of this study was to present a morphological description of the leukocytes of Phrynops hilarii turtles according to the seasonal distribution of these cells and to show their replacement in the blood circulation using a radioautographic method. Five animals of both sexes weighing 600-1200 g were used. The animal's blood was aspirated, smeared on glass slides, and stained with the Romanowsky stain, and 500 cells of each animal were counted during each season. The results obtained were analyzed statistically by analysis of variance followed by the Bonferrom test (NCSS), with the level of significance set at p < 0.05. The radioautographic analysis of turtle blood exposed to 1000 mu Ci of H-3-thymidine and developed after 30 days showed a large number of silver grains incorporated into the cells, except for basophils, with cell renewal occurring every seven days. Quantitative data demonstrated a seasonal influence on the distribution of some leukocyte types, with the following p values: heterophils (p = 0.0007), basophils (p = 0.0002), monocytes (p = 0.0016), eosinophils (p = 0.0073). However, using this statistical method, it was not possible to detect a significant difference related to seasonal influence on lymphocytes (p = 0. 16295) or thrombocytes (p = 0. 1046). Using this experimental animal model, a seasonal influence on the distribution of some leukocyte types was observed, and the radioautographic method revealed a cell renewal system occurring every seven days, except for basophils. (C) 2008 Elsevier Ltd. All rights reserved.

Depressive symptoms and level of physical activity in patients with Alzheimer's disease

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The Venomics of Bothrops alternatus is a Pool of Acidic Proteins with Predominant Hemorrhagic and Coagulopathic Activities

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)