Early-onset obesity and paternal 2pter deletion encompassing the ACP1, TMEM18, and MYT1L genes.

Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader-Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties. Among these patients, three had de novo pure 2pter deletions, one presented with a paternal derivative der(2)t(2;15)(p25.3;q26) with deletion in the 2pter region and the last patient presented with an interstitial 2p25 deletion. The size of the deletions was characterized by SNP array or array-CGH and was confirmed by fluorescence in situ hybridization (FISH) studies. Four patients shared a 2p25.3 deletion with a minimal critical region estimated at 1.97 Mb and encompassing seven genes, namely SH3HYL1, ACP1, TMEMI8, SNTG2, TPO, PXDN, and MYT1L genes. The fifth patient had a smaller interstitial deletion encompassing the TPO, PXDN, and MYT1L genes. Paternal origin of the deletion was determined by genotyping using microsatellite markers. Analysis of the genes encompassed in the deleted region led us to speculate that the ACP1, TMEM18, and/or MYT1L genes might be involved in early-onset obesity. In addition, intellectual deficiency and behavioural troubles can be explained by the heterozygous loss of the SNTG2 and MYT1L genes. Finally, we discuss the parent-of-origin of the deletion.

PARK2 mediates interleukin 6 and monocyte chemoattractant protein 1 production by human macrophages.

Leprosy is a persistent infectious disease caused by Mycobacterium leprae that still affects over 200,000 new patients annually. The host genetic background is an important risk factor for leprosy susceptibility and the PARK2 gene is a replicated leprosy susceptibility candidate gene. The protein product of PARK2, Parkin, is an E3 ubiquitin ligase that is involved in the development of various forms of Parkinsonism. The human macrophage is both a natural host cell of M. leprae as well as a primary mediator of natural immune defenses, in part by secreting important pro-inflammatory cytokines and chemokines. Here, we report that down-regulation of Parkin in THP-1 macrophages, human monocyte-derived macrophages and human Schwann cells resulted in a consistent and specific decrease in interleukin-6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1/CCL2) production in response to mycobacteria or LPS. Interestingly, production of IL-6 at 6 hours by THP-1 cells stimulated with live M. leprae and M. bovis BCG was dependent on pretreatment with 1,25-dihydroxyvitamin D(3) (VD). Parkin knockdown in VD-treated cells blocked IL-6 induction by mycobacteria. However, IκB-α phosphorylation and levels of IκB-ξ, a nuclear protein required for IL-6 expression, were not affected by Parkin silencing. Phosphorylation of MAPK ERK1/2 and p38 was unaffected by Parkin silencing while JNK activation was promoted but did not explain the altered cytokine production. In a final set of experiments we found that genetic risk factors of leprosy located in the PARK2 promoter region were significantly correlated with M. leprae sonicate triggered CCL2 and IL6 transcript levels in whole blood assays. These results associated genetically controlled changes in the production of MCP-1/CCL2 and IL-6 with known leprosy susceptibility factors.

Determinants of high birth weight by geographic region in Canada.

This study aims to analyze the determinants of high birth weight (> 4000 grams) by various geographic regions of Canada. Analyses were performed using the data from cycles 1 to 4 (1994-2001; N=20,002 children) of the Canadian National Longitudinal Survey of Children and Youth (NLSCY). Children were grouped into five geographic residential area categories: the Atlantic provinces, Quebec, Ontario, the Prairie provinces and British Columbia. Determinants analyzed in the study include sex, gestational age and birth rank of children; maternal age and education; maternal smoking during pregnancy; family type; family socioeconomic status (SES) and maternal health (postpartum depression; hypertension and prescription drug use during pregnancy). In comparison to Quebec, the odds of giving birth to a high-birth-weight child were 25 percent higher in Ontario, 41 percent higher in the Atlantic provinces and 53 percent higher in British Columbia. In Quebec, non-smoking mothers of higher SES had increased odds of delivering a baby weighing more than 4000 grams, while in British Columbia, the odds of having a birth weight greater than 4000 grams doubled for children of non-smoking mothers from the lowest SES quintiles. The relationship between social disparities and macrosomia was found to vary by geographic region.

Problem eating behaviors related to social factors and body weight in preschool children: A longitudinal study.

BACKGROUND: Despite the increasing prevalence of overweight/obesity and its association to eating patterns in adolescents and adults, little is known about the relationship between problematic eating behaviours and body weight in the preschool years within the context of various social factors. This research aims to analyze the relationship between social factors, mothers' perceptions of their child's eating behaviour (picky eating and overeating), and body weight in preschool years, in a population-based cohort of preschoolers from Québec (Canada). METHODS: Analyses were performed on 1498 children from the Longitudinal Study of Child Development in Québec, a representative sample of children born in 1998 in the Canadian province of Québec. Eating behaviours (picky eating and overeating) were derived from questionnaires at 2.5, 3.5, and 4.5 years of age. BMI was calculated from children's measured height and weight at 4.5 years. Children's sex and birth weight, mothers' age, immigrant status, smoking status during pregnancy, and education level, family type, annual household income and income sufficiency, the number of overweight/obese parents, children's day-care attendance, and food insufficiency were part of the analysis. Multivariate logistic regressions were used to determine odds ratios for different body weight profiles (underweight, normal weight, at risk of overweight, overweight), and one-way analysis-of-variances (ANOVA) allowed for group comparisons of means. RESULTS: The proportion of children reported for each eating behaviour category remained quite stable across the years studied. Picky eating and overeating related to body weight among 4.5-year-old children, even when social and parental factors were accounted for in multivariate analysis. Picky eaters were twice as likely to be underweight at 4.5 years as children who were never picky eaters. Adjusted odds ratios revealed overeaters were 6 times more likely to be overweight at 4.5 years than were children who were never overeaters. CONCLUSION: Given the association between eating behaviours and bodyweight among 4.5-year-old children, particularly among those from less educated, lower income families and younger mothers, health professionals should target parents of children at risk of overweight/obesity and underweight with focussed messages and strategies for the management of emerging problematic eating behaviours.

Computation of haplotypes on SNPs subsets: advantage of the "global method".

BACKGROUND: Genetic association studies aim at finding correlations between a disease state and genetic variations such as SNPs or combinations of SNPs, termed haplotypes. Some haplotypes have a particular biological meaning such as the ones derived from SNPs located in the promoters, or the ones derived from non synonymous SNPs. All these haplotypes are "subhaplotypes" because they refer only to a part of the SNPs found in the gene. Until now, subhaplotypes were directly computed from the very SNPs chosen to constitute them, without taking into account the rest of the information corresponding to the other SNPs located in the gene. In the present work, we describe an alternative approach, called the "global method", which takes into account all the SNPs known in the region and compare the efficacy of the two "direct" and "global" methods. RESULTS: We used empirical haplotypes data sets from the GH1 promoter and the APOE gene, and 10 simulated datasets, and randomly introduced in them missing information (from 0% up to 20%) to compare the 2 methods. For each method, we used the PHASE haplotyping software since it was described to be the best. We showed that the use of the "global method" for subhaplotyping leads always to a better error rate than the classical direct haplotyping. The advantage provided by this alternative method increases with the percentage of missing genotyping data (diminution of the average error rate from 25% to less than 10%). We applied the global method software on the GRIV cohort for AIDS genetic associations and some associations previously identified through direct subhaplotyping were found to be erroneous. CONCLUSION: The global method for subhaplotyping can reduce, sometimes dramatically, the error rate on patient resolutions and haplotypes frequencies. One should thus use this method in order to minimise the risk of a false interpretation in genetic studies involving subhaplotypes. In practice the global method is always more efficient than the direct method, but a combination method taking into account the level of missing information in each subject appears to be even more interesting when the level of missing information becomes larger (>10%).

Determinants of birthweight inequalities: population-based study.

BACKGROUND: The aim of this paper is to study the whole spectrum of birthweight in a population-based birth cohort in order to document the role played by social factors, which complement physiological and behavioural factors, in the development of birthweight inequalities at the population level. METHODS: The analyses were performed with data from the 'Quebec Longitudinal Study of Child Development 1998-2002 (QLSCD)'. The study follows a representative sample (n = 2103) of the children born in 1998 in the Canadian province of Québec. RESULTS: Multivariate analyses adjusted for gestational age and mother's age indicate that mean birthweight was higher for boys than girls; improved with birth rank, mother's body mass index (BMI), and family socioeconomic status; and was lower for children of smoking mothers. Compared with children born to non-smoking mothers of higher socioeconomic status, the odds of having a low birthweight were between 6 and 12 times higher for children born to smoking mothers of lower or middle socioeconomic status. When maternal smoking status and mother's BMI are combined, socioeconomic status could still be seen to have a positive effect on mean birthweight except for overweight or obese smoking mothers, among whom the relationship between socioeconomic status and mean birthweight was reversed. In families of lower socioeconomic status, maternal smoking was the most important factor in birthweight inequalities, and in families of higher socioeconomic status, mother's BMI was the most important factor in birthweight inequalities. CONCLUSION: This research is not only important for children in developed nations, but also for those in developing countries, where high birthweight and obesity are becoming more prevalent.

Breast-feeding, day-care attendance and the frequency of antibiotic treatments from 1.5 to 5 years: a population-based longitudinal study in Canada.

This paper aims to study, at the population level, the protective role of breast-feeding on child health and its relation to day-care attendance during the first 5 years of life. The analysis, done on a national sample of children, uses antibiotic treatments as a general measure of health. It takes into account mother's education level, family poverty level, mother's smoking status during pregnancy and after birth, mother's age, sex, gestation duration, and birth rank. The analyses were performed using data from the Longitudinal Study of Child Development in Quebec (LSCDQ), conducted by Santé Québec, a division of the Institut de la Statistique du Québec (ISQ). The study was based on face-to-face interviews and included a set of questionnaires addressed to the children's mothers and fathers. A total of 1841 were included in the sample analyzed. Detailed information on breast-feeding and complementary feeding was collected at 5 and 17 months through face-to-face interviews with the most knowledgeable person, generally the mother. From this information, it has been possible to estimate breast-feeding duration and exclusivity. Our results indicate that the positive effects of breast-feeding on health persist up to the second year of life, even in the presence of day-care attendance. The analyses indicate that breast-feeding reduced the number of antibiotic treatments given to children entering day care before 2.5 years of age. The study also indicates that the more-at-risk children could be protected by breast-feeding and by being taken care of in a familial setting, especially before 2.5 years of age. Mother's education, family poverty level, and other social inequality indicators did not play a role in the frequency of antibiotic treatments. Over the long term, it will be important to continue to monitor the health of children and to implement public health interventions aimed at reducing health problems among children of preschool age.

Comparison of the expression patterns of five neural RNA binding proteins in the Xenopus retina.

An increasing body of evidence indicates that gene expression can be modulated by posttranscriptional mechanisms. RNA binding proteins, for instance, control gene expression at many regulatory levels including RNA splicing, transport, stability, and translation. Although numerous RNA binding proteins have been identified, very few have been studied extensively in the context of developmental processes. We focused our study on five neural RNA binding proteins: one Musashi homolog, Nrp-1, one member of the Bruno gene family, BruL-1 (also known as Etr-1), and three members of the ELAV/Hu family, ElrB, ElrC, and ElrD. As an initial step in addressing their function during Xenopus neurogenesis, we used in situ hybridization to determine their expression patterns during retinal development. We found that RNA binding proteins belonging to different families have distinct spatio-temporal expression. These combinatorial expression patterns are reminiscent of previously described cell type-specific expression patterns of transcription factors during retinal development. The distribution of RNA binding proteins within the retina suggests that these regulators of posttranscriptional events may play important roles in multiple steps of retinogenesis.

Impact of methoxymycolic acid production by Mycobacterium bovis BCG vaccines.

BCG vaccines are a family of closely related daughter strains of an attenuated isolate of Mycobacterium bovis derived by in vitro passage from 1908 to 1921. During subsequent laboratory propagation of the vaccine strain until its lyophilization in 1961, BCG Pasteur underwent at least seven further genomic mutations. The impact of these mutations on the properties of the vaccine is currently unknown. One mutation, a glycine-to-aspartic acid substitution in the mmaA3 gene, occurred between 1927 and 1931 and impairs methoxymycolic acid synthesis in BCG strains obtained from the Pasteur Institute after this period. Mycolic acids of the cell wall are classified into three functional groups (alpha-, methoxy-, and ketomycolic acids), and together these lipids form a highly specialized permeability barrier around the bacterium. To explore the impact of methoxymycolic acid production by BCG strains, we complemented the functional gene of mmaA3 into BCG Denmark and tested a number of in vitro and in vivo phenotypes. Surprisingly, restoration of methoxymycolic acids alone had no effect on cell wall permeability, resistance to antibiotics, or growth in cultured macrophages and C57BL/6 mice. Our results demonstrate that the loss of methoxymycolic acid production did not apparently affect the virulence of BCG strains.

Increased proteolytic activity and matrix metalloprotease expression in lungs during infection by porcine reproductive and respiratory syndrome virus.

The local increase in the secretion of extracellular proteases, allowing cleavage of the extracellular matrix and thereby facilitating the infiltration of T cells, monocytes and neutrophils, is a hallmark of chronic inflammation and autoimmunity. In pulmonary genetic diseases, such as emphysema and cystic fibrosis, proteases can also favour the development of local immunodeficiency by degrading key regulators of the immune response, such as CD4, CD8, IgG, ICAM-1 and C3b receptors. Since several infectious agents can give rise to severe pulmonary disorders associated with opportunistic infections, we sought to determine whether an increase in proteolytic activity occurred during infection with porcine reproductive and respiratory syndrome virus (PRRSV), the causative agent of a new disease in swine characterized by severe respiratory problems in young pigs. Piglets were infected with the virus and bronchoalveolar lavages were collected at various times post-infection to measure the net proteolytic activity. It was shown that PRRSV infection leads to a significant increase in proteolytic activity in pulmonary fluids. Maximal activity was found at 7 and 14 days post-infection, with a return towards normal levels at day 42. Zymographic analyses showed a significant increase in the secretion of matrix metalloproteases (MMPs) 2 and 9, two enzymes involved in tissue remodelling. Histological analyses showed a correlation between the increase in proteolytic activity and the appearance of lesions that were characterized by massive lymphomononuclear cell infiltration. These results suggest that virus infection of the lungs can lead to a transient increase in proteolytic activity that could favour opportunistic infection.