Strategies for genetic model specification in the screening of genome-wide meta-analysis signals for further replication

Background Meta-analysis is increasingly being employed as a screening procedure in large-scale association studies to select promising variants for follow-up studies. However, standard methods for meta-analysis require the assumption of an underlying genetic model, which is typically unknown a priori. This drawback can introduce model misspecifications, causing power to be suboptimal, or the evaluation of multiple genetic models, which augments the number of false-positive associations, ultimately leading to waste of resources with fruitless replication studies. We used simulated meta-analyses of large genetic association studies to investigate naive strategies of genetic model specification to optimize screenings of genome-wide meta-analysis signals for further replication. Methods Different methods, meta-analytical models and strategies were compared in terms of power and type-I error. Simulations were carried out for a binary trait in a wide range of true genetic models, genome-wide thresholds, minor allele frequencies (MAFs), odds ratios and between-study heterogeneity (tau(2)). Results Among the investigated strategies, a simple Bonferroni-corrected approach that fits both multiplicative and recessive models was found to be optimal in most examined scenarios, reducing the likelihood of false discoveries and enhancing power in scenarios with small MAFs either in the presence or in absence of heterogeneity. Nonetheless, this strategy is sensitive to tau(2) whenever the susceptibility allele is common (MAF epsilon 30%), resulting in an increased number of false-positive associations compared with an analysis that considers only the multiplicative model. Conclusion Invoking a simple Bonferroni adjustment and testing for both multiplicative and recessive models is fast and an optimal strategy in large meta-analysis-based screenings. However, care must be taken when examined variants are common, where specification of a multiplicative model alone may be preferable.

Bazex-Dupre-Christol syndrome in a 1-year-old boy and his mother

Bazex - Dupre - Christol syndrome is a rare genodermatosis with cancer predisposition, characterized by follicular atrophoderma, multiple milia, congenital hypotrichosis, hypohidrosis and basal cell malformations that include nevoid basal cell carcinomas of early onset. We present two patients with this syndrome, a 1-year-old boy with diffuse scalp and eyebrows alopecia, milia papules on the face, ears, trunk, and limbs. Hypohidrosis was observed on his trunk and head. His 16-year-old mother had identical changes since childhood, with hair fragility, and multiple atrophic ""ice pick"" follicular depressions on the dorsa of her hands. She also had a basal cell carcinoma on her face. Microscopic examination of hairs from the mother revealed abnormalities such as diameter irregularities, broken shafts, trichorrexis nodosa and pili bifurcatti. Pili bifurcatti is an uncommon hair shaft dysplasia that has not before been observed in Bazex - Dupre - Christol syndrome.

Molecular epidemiology and genetic diversity of hepatitis B virus genotype E in an isolated Afro-Colombian community

Hepatitis B virus (HBV) infection is a significant public health concern with 350 million chronic carriers worldwide. Eight HBV genotypes (A-H) have been described so far. Genotype E (HBV/E) is widely distributed in West Africa and has rarely been found in other continents, except for a few cases in individuals with an African background. In this study, we characterized HBV genotypes in Quibdo, Colombia, by partial S/P gene sequencing, and found, for the first time, HBV/E circulating in nine Afro-Colombian patients who had no recent contact with Africa. The presence of HBV/E in this community as a monophyletic group suggests that it was a result of a recent introduction by some Afro-descendent contact or, alternatively, that the virus came with slaves brought to Colombia. By using sequences with sampling dates, we estimated the substitution rate to be about 3.2x10(-4) substitutions per site per year, which resulted in a time to the most recent common ancestor (TMRCA) of 29 years. In parallel, we also estimated the TMRCA for HBV/E by using two previously estimated substitution rates (7.7x10(-4) and 1.5x10(-5) substitutions per site per year). The TMRCA was around 35 years under the higher rate and 1500 years under the slower rate. In sum, this work reports for the first time the presence of an exclusively African HBV genotype circulating in South America. We also discuss the time of the entry of this virus into America based on different substitution rates estimated for HBV.

Frequency of concurrent autoimmune disorders in patients with autoimmune hepatitis - Effect of age, gender, and genetic background

Background: Concurrent autoimmune disorders (CAIDs) have been shown to occur in 22% to 34% of the patients with autoimmune hepatitis (AIH). Their presence has been linked to female gender, older age, and to certain HLA antigens, namely HLA-A11. DRB1*04, and DRB4*01. Aims: To assess the frequency and nature of CAID in Brazilian patients with AIH types 1 (AIH-1) and 2 (AIH-2) and to investigate the influence of age, gender, and genetic background in their occurrence. Patients and Methods: The presence and nature of CAID was studied in 143 patients [117 females, median age 11 (1.3 to 69)] with AIH-1 (n = 125) and AIH-2 (n = 28). HLA typing and tumor necrosis factor a gene promoter and exon I cytotoxic T lymphocyte associated antigen 4 (CTLA-4) gene polymorphisms were determined by polymerase chain reaction-based techniques. Results: The frequency of CAID was similar in patients with AIH-1 (14%) and AIH-2 (18%), but their nature was shown to vary. Arthritis was seen in half of the patients (n = 8) with CAID and AIH-1 and in none of those with AIH-2. Subjects with AIH-1 and CAID were shown to be older [24 (1.3 to 6 1) vs. 11 (1.3 to 69) y P = 0.02] and to have more often circulating antinuclear antibody (76% vs. 40%, P = 0.008) and less frequently antiactin antibodies (33% vs. 75%, P = 0.008) when compared with their counterparts without CAID. No particular HLA-DR and DQ alleles, as well as tumor necrosis factor a and CTLA-4 genotypes, were associated with CAID. Conclusions: The nature, but not the frequency, of CAID was shown to vary in AIH-1 and AIH-2. In subjects with AIH-1, CAID was linked to older subjects and to the presence of antinuclear antibody. No predisposition to CAID was associated to HLA-DRB1*04 or DDB4*01 alleles. The observed lower frequency of CAID could be attributed to the lower age of disease onset in Brazilians and to differences in HLA-encoded susceptibility to AIH-1 observed in South America.

The Genetic Landscape of the Childhood Cancer Medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

Hematological indices at birth in relation to arterial and venous Doppler in small-for-gestational-age fetuses

Objective. To correlate Doppler results with hematological indices at birth in small-for-gestational-age (SGA) fetuses. Design. Prospective study. Setting. Tertiary teaching hospital, Sao Paulo, Brazil. Population. One hundred singleton pregnancies with SGA fetuses of > 27 weeks gestational age. Methods. All women had Doppler velocimetry of the umbilical arteries, middle cerebral artery, and ductus venosus within < 72 hours prior to delivery. After birth, umbilical artery blood was collected for hematological analysis. Main outcome measures. The association between fetal Doppler velocimetry pulsatility index (PI) and some hematological indices. Results. Umbilical artery PI showed a positive correlation with nucleated red blood cell count in the umbilical cord (r = 0.46; p<0.01), and a negative correlation with platelet count (r = -0.53; p<0.01) and white blood cell count (r = -0.42; p<0.01). Middle cerebral artery PI was positively correlated with platelet count (r = 0.43; p<0.01) and white blood cell count (r = 0.38; p<0.01), and was negatively correlated with nucleated red blood cell count (r = -0.39; p<0.01). The ductus venosus pulsatility index showed a positive correlation with nucleated red blood cell count (r = 0.36; p<0.01), and a negative correlation with platelet count (r = -0.37; p<0.01) and white blood cell count (r = -0.26; p<0.01). Conclusion. A significant positive or negative correlation between nucleated red blood cell, platelet and white blood cell counts, and Doppler indices suggests an association between placental insufficiency and the fetal hematological response.

Aseptic Loosening of Total Hip Arthroplasty: Preliminary Genetic Investigation

Femoral and acetabular loosening call be attributed different factors, but the Causes and mechanism of early failure are still obscure, The objective of this Study was to investigate the relationship between gene polymorphisms and early implant failure. Fifty-eight patients older than 50 years was recruited for analysis of MMP-1 promoter polymorphisms in early osseointegrated implant failure. The results showed in control group a frequency of 20.97% of 2G allele and 67.74% the genotype 1G/1G whereas, in the test group, a frequency of 83.33% of 2G allele and 66.66% the genotype 2G/2G. These results indicate that the polymorphism ill the promoter of the MMP-1 gene could be it risk factor for early implant failure of total hip arthroplasty.

Family history of cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology consortium

Alcohol and tobacco consumption are well-recognized risk factors for head and neck cancer (HNC). Evidence suggests that genetic predisposition may also play a role. Only a few epidemiologic studies, however, have considered the relation between HNC risk and family history of HNC and other cancers. We pooled individual-level data across 12 case-control studies including 8,967 HNC cases and 13,627 controls. We obtained pooled odds ratios (OR) using fixed and random effect models and adjusting for potential confounding factors. All statistical tests were two-sided. A family history of HNC in first-degree relatives increased the risk of HNC (OR = 1.7, 95% confidence interval, CI, 1.2-2.3). The risk was higher when the affected relative was a sibling (OR = 2.2, 95% CI 1.6-3.1) rather than a parent (OR = 1.5, 95% CI 1.1-1.8) and for more distal HNC anatomic sites (hypopharynx and larynx). The risk was also higher, or limited to, in subjects exposed to tobacco. The OR rose to 7.2 (95% CI 5.5-9.5) among subjects with family history, who were alcohol and tobacco users. A weak but significant association (OR = 1.1, 95% CI 1.0-1.2) emerged for family history of other tobacco-related neoplasms, particularly with laryngeal cancer (OR = 1.3, 95% CI 1.1-1.5). No association was observed for family history of nontobacco-related neoplasms and the risk of HNC (OR = 1.0, 95% CI 0.9-1.1). Familial factors play a role in the etiology of HNC. In both subjects with and without family history of HNC, avoidance of tobacco and alcohol exposure may be the best way to avoid HNC. (C) 2008 Wiley-Liss, Inc,

Suicidality in Obsessive-Compulsive Disorder: Prevalence and Relation to Symptom Dimensions and Comorbid Conditions

Background: Suicidal thoughts and behaviors, also known as suicidality, are a fairly neglected area of study in patients with obsessive-compulsive disorder (OCD). Objective: To evaluate several aspects of suicidality in a large multicenter sample of OCD patients and to compare those with and without suicidal ideation, plans, and attempts according to demographic and clinical variables, including symptom dimensions and comorbid disorders. Method: This cross-sectional study included 582 outpatients with primary OCD (DSM-IV) recruited between August 2003 and March 2008 from 7 centers of the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders. The following assessment instruments were used: the Yale-Brown Obsessive Compulsive Scale, the Dimensional Yale-Brown Obsessive Compulsive Scale, the Beck Depression and Anxiety Inventories, the Structured Clinical Interview for DSM-IV Axis I Disorders, and 6 specific questions to investigate suicidality. After univariate analyses, logistic regression analyses were performed to adjust the associations between the dependent and explanatory variables for possible confounders. Results: Thirty-six percent of the patients reported lifetime suicidal thoughts, 20% had made suicidal plans, 11% had already attempted suicide, and 10% presented current suicidal thoughts. In the logistic regression, only lifetime major depressive disorder and posttraumatic stress disorder (PTSD) remained independently associated with all aspects of suicidal behaviors. The sexual/religious dimension and comorbid substance use disorders remained associated with suicidal thoughts and plans, while impulse-control disorders were associated with current suicidal thoughts and with suicide plans and attempts. Conclusions: The risk of suicidal behaviors must be carefully investigated in OCD patients, particularly those with symptoms of the sexual/religious dimension and comorbid major depressive disorder, PTSD, substance use disorders, and impulse-control disorders. J Clin Psychiatry 2011;72(1):17-26 (C) Copyright 2011 Physicians Postgraduate Press, Inc.

Association between micronuclei frequency in pollen mother cells of Tradescantia and mortality due to cancer and cardiovascular diseases: A preliminary study in Sao Jose dos Campos, Brazil

The present study was designed to explore the correlation between the frequency of micronuclei in Trad-MN, measured across 28 biomonitoring stations during the period comprised between 11 of May and 2 of October, 2006, and adjusted mortality rates due to cardiovascular, respiratory diseases and cancer in Sao Jose dos Campos, Brazil, an area with different sources of air pollution. For controlling purposes, mortality rate due to gastrointestinal diseases (an event less prone to be affected by air pollution) was also considered in the analysis. Spatial distribution of micronuclei frequency was determined using average interpolation. The association between health estimators and micronuclei frequency was determined by measures of Pearson`s correlation. Higher frequencies of micronuclei were detected in areas with high traffic and close to a petrochemical pole. Significant associations were detected between micronuclei frequency and adjusted mortality rate due to cardiovascular diseases (r = 0.841, p = 0.036) and cancer (r = 0.890, p = 0.018). The association between mortality due to chronic obstructive pulmonary diseases was positive but did not reach statistical significance (r = 0.640, p = 0.172), probably because of the small number of events. Gastrointestinal mortality did not exhibit significant association with micronuclei frequency. Because the small number of observations and the nature of an ecological study, the present findings must be considered with caution and considered as preliminary. Further studies, performed in different conditions of contamination and climate should be done before considering Trad-MN in the evaluation of human health risk imposed by air pollutants. (C) 2009 Elsevier Ltd. All rights reserved.

Expression of smooth muscle and extracellular matrix proteins in relation to airway function in asthma

Background: Smooth muscle content is increased within the airway wall in patients with asthma and is likely to play a role in airway hyperresponsiveness. However, smooth muscle cells express several contractile and structural proteins, and each of these proteins may influence airway function distinctly. Objective: We examined the expression of contractile and structural proteins of smooth muscle cells, as well as extracellular matrix proteins, in bronchial biopsies of patients with asthma, and related these to lung function, airway hyperresponsiveness, and responses to deep inspiration. Methods: Thirteen patients with asthma (mild persistent, atopic, nonsmoking) participated in this cross-sectional study. FEV1 % predicted, PC20 methacholine, and resistance of the respiratory system by the forced oscillation technique during tidal breathing and deep breath were measured. Within 1 week, a bronchoscopy was performed to obtain 6 bronchial biopsies that were immunuhistochemically stained for alpha-SM-actin, desmin, myosin light chain kinase (MLCK), myosin, calponin, vimentin, elastin, type III collagen, and fibronectin. The level of expression was determined by automated densitometry. Results: PC20 methacholine was inversely related to the expression of alpha-smooth muscle actin (r = -0.62), desmin (r = -0.56), and elastin (r = -0.78). In addition, FEV1% predicted was positively related and deep inspiration-induced bronchodilation inversely related to desmin (r = -0.60), MLCK (r = -0.60), and calponin (r = -0.54) expression. Conclusion: Airway hyperresponsiveness, FEV1% predicted, and airway responses to deep inspiration are associated with selective expression of airway smooth muscle proteins and components of the extracellular matrix.

Balance between early life tolerance and sensitization in allergy: dependence on the timing and intensity of prenatal and postnatal allergen exposure of the mother

P>Allergens can be maternally transferred to the fetus or neonate, though it is uncertain how this initial allergen exposure may impact the development of allergy responses. To evaluate the roles of timing and level of maternal allergen exposure in the early life sensitization of progeny, female BALB/c mice were given ovalbumin (OVA) orally during pregnancy, lactation or weekly at each stage to investigate the immunoglobulin E (IgE) antibody production and cellular responsiveness of their offspring. Exposure to OVA during pregnancy was also evaluated in OVA-specific T-cell receptor (TCR) transgenic (DO11.10) mice. The effect of prenatal antigen exposure on offspring sensitization was dependent on antigen intake, with low-dose OVA inducing tolerance followed by neonatal immunization that was sustained even when pups were immunized when 3 weeks old. These offspring received high levels of transforming growth factor-beta via breastfeeding. High-dose exposure during the first week of pregnancy or perinatal period induced transient inhibition of IgE production following neonatal immunization; although for later immunization IgE production was enhanced in these offspring. Postnatal maternal antigen exposure provided OVA transference via breastfeeding, which consequently induced increased offspring susceptibility to IgE antibody production according to week post-birth. The effect of low-dose maternal exposure during pregnancy was further evaluated using OVA transgenic TCR dams as a model. These progeny presented pronounced entry of CD4(+) T cells into the S phase of the cell cycle with a skewed T helper type 2 response early in life, revealing the occurrence of allergen priming in utero. The balance between tolerance and sensitization depended on the amount and timing of maternal allergen intake during pregnancy.

Matrix metalloproteinase-2 polymorphism is associated with prognosis in prostate cancer

Objective: Prostate cancer (PCa) is the most frequent tumor in males in Brazil. Single nucleotide polymorphisms (SNP) have been demonstrated in the promoter region of matrix metalloproteinases (MMPs) genes and have been associated with development and progression of some cancers. In this study, our aim was to investigate a possible relation between polymorphism of the promoter region of the MMP2 gene and classical prognostic parameters in prostate cancer. Materials and methods: Genomic DNA was extracted using conventional protocols. The DNA sequence containing the polymorphic site was amplified by real-time polymerase chain reaction, using fluorescent probes (TaqMan). Results: In patients with tumors of a higher stage (pT3), a polymorphic allele in the MMP2 gene was more frequent (P = 0.026) than in patients with lower tumor stage. A polymorphic allele in the MMP2 gene was more frequent in Gleason >= 7 than in Gleason <= 6 (P = 0.042). Conclusions: We conclude that MMP2 polymorphism can be used together with pathological stage and Gleason score to identify patients with worse prognosis. Our results illustrate the potential use of MMP2 SNP as a molecular marker for prostate cancer. (C) 2010 Elsevier Inc. All rights reserved.

Reticular angiomatoid ""malignant"" fibrous histiocytoma-a case report with cytogenetics and molecular genetic analyses

Angiomatoid ""malignant"" fibrous histiocytoma is a rare sarcoma of low malignant potential that occurs most commonly in the extremities of children and young adults. Herein, we present a case of angiomatoid malignant fibrous histiocytoma with unusual histologic features arising in the mediastinum of an 80-year-old man. The tumor exhibited a reticular growth pattern and myxoid stroma. The tumor cells expressed epithelial membrane antigen and desmin. Cytogenetic analysis revealed the translocation t(2;22)(q33;q12). Molecular genetic analysis confirmed the rearrangement of the EWSR1 locus and the presence of the EWSR1/CREB1 fusion. This report expands the clinicopathologic spectrum of angiomatoid malignant fibrous histiocytoma and underscores the value of integrating morphologic, immunophenotypic, and molecular findings in the identification of its unusual morphologic variants. (C) 2011 Elsevier Inc. All rights reserved.

The relation of triceps surae surgical lengthening and crouch gait in patients with cerebral palsy

To investigate the effect of earlier triceps surae (TS) surgical lengthening at knee kinematics in the stance phase in patients with cerebral palsy (CP). One thousand and thirty-nine participants from an eligible total of 1750 children with CP were referred to gait analysis laboratory from January 2000 to April 2007. Inclusion criteria were the diagnosis of diparetic spastic CP levels I to III (GMFCS) and complete kinematics documentation. Patients with an asymmetrical knee pattern at kinematics and with different types of TS management among sides were excluded. The patients were divided into two groups according to the mean minimum knee flexion (MMKF) in stance phase: group A (n = 253) MMKF >= 30 degrees and group B (n = 786) MMKF less than 30 degrees. For each group, the occurrence of following procedures for TS in the past: (i) earlier surgery, (ii) gastrocnemius lengthening (zone I), (iii) gastrocnemius and soleus lengthening (zone II), and (iv) calcaneous tendon lengthening (zone III), was investigated. A chi(2) test was applied to check if the number of procedures performed was different between groups. The level of significance was defined as P value of less than 0.05. The number of patients with no earlier surgeries at TS was higher in group B (51.8%) than in group A (39.1%), and this difference was significant (P<0.01). In addition, the number of procedures at the calcaneous tendon was more elevated in group A (36.8%) than in group B (27%), and this finding was statistically significant as well (P<0.02). The percentage of surgical lengthening at zones I and II was very similar between the groups A and B. This study has shown that patients without earlier surgical procedures at TS are more susceptible to reach better extension of the knees in the stance phase. Patients in a crouch gait had a higher number of calcaneous tendon lengthening performed in the past than patients with a more normal knee extension in the stance phase. J Pediatr Orthop B 19:226-230 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.