Dietary vitamin A intake below the recommended daily intake during pregnancy and the risk of congenital diaphragmatic hernia in the offspring

BACKGROUND

Vitamin A has been related to the etiology of congenital diaphragmatic hernia (CDH). We performed a case‐control study to investigate whether maternal dietary vitamin A intake is related to CDH in the offspring.

METHODS

Thirty‐one pregnancies diagnosed with CDH and 46 control pregnancies were included during the study. After CDH diagnosis and inclusion of controls by risk set sampling, maternal vitamin A intake was investigated with a food frequency questionnaire. Serum retinol and retinol‐binding protein were determined. Univariable and multivariable logistic regression models were used to calculate risk estimates with adjustment for potential confounders.

RESULTS

We found no significant differences in the overall nutrient and vitamin A intake between case and control mothers. After stratification in body mass index (BMI) categories, case mothers with normal weight showed a lower energy adjusted vitamin A intake (685 vs. 843 μg retinol activity equivalents [RAEs] / day; p = 0.04) and a slightly lower serum retinol (1.58 vs. 1.67 μmol/L; p = 0.08) than control mothers. Vitamin A intake <800 μg retinol activity equivalents (recommended daily intake) in normal weight mothers was associated with a significantly increased CDH risk (odds ratio [OR], 7.2; 95% confidence interval [CI], 1.5–34.4; p = 0.01). Associations were not significantly different in underweight and overweight mothers.

CONCLUSIONS

In normal‐weight mothers, dietary vitamin A intake during pregnancy below the recommended daily intake is significantly associated with an increased risk of a child with CDH. This finding supports the retinoid hypothesis in human CDH, but warrants further investigation in larger study populations. Birth Defects Research (Part A), 2013. © 2013 Wiley Periodicals, Inc.     

Spatial Assessment of Amphibian Chytrid Fungus (Batrachochytrium dendrobatidis) in South Africa Confirms Endemic and Widespread Infection

Chytridiomycosis has been identified as a major cause of global amphibian declines. Despite widespread evidence of Batrachochytrium dendrobatidis infection in South African frogs, sampling for this disease has not focused on threatened species, or whether this pathogen poses a disease risk to these species. This study assessed the occurrence of Bd-infection in South African Red List species. In addition, all known records of infection from South Africa were used to model the ecological niche of Bd to provide a better understanding of spatial patterns and associated disease risk. Presence and prevalence of Bd was determined through quantitative real-time PCR of 360 skin swab samples from 17 threatened species from 38 sites across the country. Average prevalence was 14.8% for threatened species, with pathogen load varying considerably between species. MaxEnt was used to model the predicted distribution of Bd based on 683 positive records for South Africa. The resultant probability threshold map indicated that Bd is largely restricted to the wet eastern and coastal regions of South Africa. A lack of observed adverse impacts on wild threatened populations supports the endemic pathogen hypothesis for southern Africa. However, all threatened species occur within the limits of the predicted distribution for Bd, exposing them to potential Bd-associated risk factors. Predicting pathogen distribution patterns and potential impact is increasingly important for prioritising research and guiding management decisions.     

Effect of Natural and ARV-Induced Viral Suppression and Viral Breakthrough on Anti-HIV Antibody Proportion and Avidity in Patients with HIV-1 Subtype B Infection

Background

Viral suppression and viral breakthrough impact the humoral immune response to HIV infection. We evaluated the impact of viral suppression and viral breakthrough on results obtained with two cross-sectional HIV incidence assays.

Methods

All samples were collected from adults in the US who were HIV infected for >2 years. Samples were tested with the BED capture enzyme immunoassay (BED-CEIA) which measures the proportion of IgG that is HIV-specific, and with an antibody avidity assay based on the Genetic Systems 1/2+ O ELISA. We tested 281 samples: (1) 30 samples from 18 patients with natural control of HIV-1 infection known as elite controllers or suppressors (2) 72 samples from 18 adults on antiretroviral therapy (ART), with 1 sample before and 2–6 samples after ART initiation, and (3) 179 samples from 20 virally-suppressed adults who had evidence of viral breakthrough receiving ART (>400 copies/ml HIV RNA) and with subsequent viral suppression.

Results

For elite suppressors, 10/18 had BED-CEIA values <0.8 normalized optical density units (OD-n) and these values did not change significantly over time. For patients receiving ART, 14/18 had BED-CEIA values that decreased over time, with a median decrease of 0.42 OD-n (range 0.10 to 0.63)/time point receiving ART. Three patterns of BED-CEIA values were observed during viral breakthrough: (1) values that increased then returned to pre-breakthrough values when viral suppression was re-established, (2) values that increased after viral breakthrough, and (3) values that did not change with viral breakthrough.

Conclusions

Viral suppression and viral breakthrough were associated with changes in BED-CEIA values, reflecting changes in the proportion of HIV-specific IgG. These changes can result in misclassification of patients with long-term HIV infection as recently infected using the BED-CEIA, thereby influencing a falsely high value for cross-sectional incidence estimates.     

More Than Meets the Eye: Associations of Vaginal Bacteria with Gram Stain Morphotypes Using Molecular Phylogenetic Analysis

Bacterial vaginosis (BV) is a highly prevalent condition associated with adverse health outcomes. Gram stain analysis of vaginal fluid is the standard for confirming the diagnosis of BV, wherein abundances of key bacterial morphotypes are assessed. These Lactobacillus, Gardnerella, Bacteroides, and Mobiluncus morphotypes were originally linked to particular bacterial species through cultivation studies, but no studies have systematically investigated associations between uncultivated bacteria detected by molecular methods and Gram stain findings. In this study, 16S-rRNA PCR/pyrosequencing was used to examine associations between vaginal bacteria and bacterial morphotypes in 220 women with and without BV. Species-specific quantitative PCR (qPCR) and fluorescence in Situ hybridization (FISH) methods were used to document concentrations of two bacteria with curved rod morphologies: Mobiluncus and the fastidious BV-associated bacterium-1 (BVAB1). Rank abundance of vaginal bacteria in samples with evidence of curved gram-negative rods showed that BVAB1 was dominant (26.1%), while Mobiluncus was rare (0.2% of sequence reads). BVAB1 sequence reads were associated with Mobiluncus morphotypes (p<0.001). Among women with curved rods, mean concentration of BVAB1 DNA was 2 log units greater than Mobiluncus (p<0.001) using species-specific quantitative PCR. FISH analyses revealed that mean number of BVAB1 cells was 2 log units greater than Mobiluncus cells in women with highest Nugent score (p<0.001). Prevotella and Porphyromonas spp. were significantly associated with the “Bacteroides morphotype,” whereas Bacteroides species were rare. Gram-negative rods designated Mobiluncus morphotypes on Gram stain are more likely BVAB1. These findings provide a clearer picture of the bacteria associated with morphotypes on vaginal Gram stain.     

Characterization of seven novel mutations on the HEXB gene in French Sandhoff patients

Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by mutations in the HEXB gene encoding the beta subunit of hexosaminidases A and B, two enzymes involved in GM2 ganglioside degradation. Eleven French Sandhoff patients with infantile or juvenile forms of the disease were completely characterized using sequencing of the HEXB gene. A specific procedure was developed to facilitate the detection of the common 5′-end 16 kb deletion which was frequent (36% of the alleles) in our study. Eleven other disease-causing mutations were found, among which four have previously been reported (c.850C>T, c.793T>G, c.115del and c.800_817del). Seven mutations were completely novel and were analyzed using molecular modelling. Two deletions (c.176del and c.1058_1060del), a duplication (c.1485_1487dup) and a nonsense mutation (c.552T>G) were predicted to strongly alter the enzyme spatial organization. The splice mutation c.558+5G>A affecting the intron 4 consensus splice site led to a skipping of exon 4 and to a truncated protein (p.191X). Two missense mutations were found among the patients studied. The c.448A>C mutation was probably a severe mutation as it was present in association with the known c.793T>G in an infantile form of Sandhoff disease and as it significantly modified the N-terminal domain structure of the protein. The c.171G>C mutation resulting in a p.W57C amino acid substitution in the N-terminal region is probably less drastic than the other abnormalities as it was present in a juvenile patient in association with the c.176del. Finally, this study reports a rapid detection of the Sandhoff disease-causing alleles facilitating genetic counselling and prenatal diagnosis in at-risk families.     

On the threshold of dispersal: hitchhiking on a giant fly favours exaggerated male traits in a male‐dimorphic pseudoscorpion

The evolution of exaggerated male traits is frequently driven by competition between males to control resources critical for female survival and/or reproductive success. For flightless arthropods specializing on patchy habitats, dispersal agents may represent one such critical resource. The Neotropical pseudoscorpion, Semeiochernes armiger, disperses to new habitats by attaching to the giant timber fly, Pantophthalmus tabaninus, as it ecloses from pupal boreholes within decaying Ficus trees. In a study that combined field observations of mating with experimental removal of individuals from a large, pre‐dispersal population, our morphometric analyses revealed that S. armiger is among the most highly sexually dimorphic pseudoscorpions known, with males possessing unusual, triangular‐shaped pedipalpal chelae (hands) and a male‐specific, dimorphic chela peg that exhibits threshold trait expression. Several lines of evidence indicate that extreme sexual dimorphism in S. armiger results from male competition to monopolize pantophthalmid bores as strategic sites for inseminating females on the verge of dispersal. Sexually dimorphic pedipalpal characters were significantly larger in males located in and around pantophthalmid boreholes, compared with males collected at the periphery of the pantophthalmid emergence zone. Removal of pseudoscorpions resulted in a significant decline in pedipalpal size of males associated with pantophthalmid bores, followed by a rebound in size after collected individuals were returned to the tree. Most significantly, field observations of mating indicate that this competition translates into intense selection for exaggerated male traits, with all traits of the sexually dimorphic chelae exhibiting highly significant sexual selection differentials in males. © 2013 The Linnean Society of London     

Extending ecological niche models to the past 120 000 years corroborates the lack of strong phylogeographic structure in the Crested Drongo (Dicrurus forficatus forficatus) on Madagascar

We conduct a phylogeographic study of the Crested Drongo (Dicrurus forficatus forficatus), a broadly distributed bird species on Madagascar. We first determined the demographic and spatial pattern inferred from mitochondrial and nuclear data, and then compared these results with predictions from a present to 0.120‐Myr‐old reconstruction of the spatial dynamics of the range of D. f. forficatus on Madagascar, enabling putative areas of stability (lineage persistence) to be detected. Weak genetic structure along an east–west pattern and comparatively low genetic diversity were recovered, with strong evidence of population expansion found at all ten loci sampled. The palaeoclimatic distribution models over the past 0.120 Myr suggest the presence of extensive areas of suitable climate in the east and west for the species since its colonization of Madagascar, a result in strong concordance with the spatial and genetic signal derived from our multilocus data set. © 2013 The Linnean Society of London     

PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy

Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.     

Omi, a recessive mutation on chromosome 10, is a novel allele of Ostm1

Large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis has provided many rodent models for human disease. Here we describe the initial characterization and mapping of a recessive mutation that leads to degeneration of the incisors, failure of molars to erupt, a grey coat colour, and mild osteopetrosis. We mapped the omi mutation to chromosome 10 between D10Mit214 and D10Mit194. The Ostm1 gene is a likely candidate gene in this region and the grey-lethal allele, Ostm1 ^gl , and omi mutations fail to complement each other. We show that om/om mice have reduced levels of Ostm1 protein. To date we have not been able to identify the causative mutation. We propose that omi is a novel hypomorphic mutation affecting Ostm1 expression, potentially in a regulatory element.