Dietary Nitrate Acutely and Markedly Increased Exhaled Nitric Oxide in a Cystic Fibrosis Case

Airway nitric oxide (NO) is a ubiquitous signaling molecule with bronchoprotective, antiinflammatory and anti-infective roles. Cystic fibrosis (CF) is a chronic lung condition associated with deceased exhaled NO. Strategies to increase exhaled NO in CF have yielded inconsistent results. A potential new method of increasing systemic NO involves ingestion of dietary, inorganic nitrate which is reduced to nitrite and NO. We present the case of a 12 year-old, athletic male with CF who demonstrated acute but marked increases in exhaled NO following dietary nitrate consumption compared to placebo

Blunted serum 25(OH)D response to vitamin D3 supplementation in children with autism

Introduction: Data suggest a potential role for vitamin D in autism spectrum disorder (ASD) prevention and treatment. It is likely that the serum response to vitamin D supplementation contributes to its effectiveness. Multiple factors affect serum vitamin D 25(OH)D response to supplementation. Methods: We conducted post-hoc analysis of two double-blind, randomized, placebo-controlled trials (RCT) of vitamin D3 supplementation, one RCT involving children with ASD and another involving children with asthma. Both trials were conducted in the same geographic location (Dublin, Ireland, 53°N), conducted over Winter season and utilized the same vitamin D3 dose (2000 IU/day). Results: We included 18 children with ASD and 17 children with asthma. There was no significant difference in 25(OH)D or age at baseline, however, BMI was significantly lower in ASD (P = 0.03). Compliance with vitamin D supplementation was high in both trials. Despite a significantly longer intervention period (20w vs. 15w; P \u3c 0.0001), ASD children had a significantly lower absolute increase (+26 vs. +45 nmol/l) in 25(OH)D (P = 0.04). Conclusions: Despite similar demographics, children with ASD had a lower increase in 25(OH)D levels with supplementation. Potential mechanisms include altered absorption/metabolism as well as well genetic factors. Clinical and research work relating to vitamin D is ASD should measure 25(OHO)D response to supplementation to assess therapeutic doses

Vitamin D Receptor Variants and Uncontrolled Asthma

BACKGROUND: Asthma is a common childhood respiratory disease, affecting around 20% of Irish children. In other populations, vitamin D receptor (VDR) polymorphisms have been associated with asthma risk. We aimed to investigate the association between 2 VDR polymorphisms and uncontrolled paediatric asthma. METHODS: 44 asthmatic children and 57 healthy volunteers were studied. The VDR TaqI gene variant in exon 9 (T/C) (rs731236) and ApaI (rs7975232) in intron 8 (C/T) were determined, using TaqMan®Assays. The lung function, serum 25-hydroxyvitamin D (25OHD) levels and other biomarkers of allergy, immunity, airway and systemic inflammation were assessed. RESULTS: The distribution of T and C alleles and genotype frequencies differed significantly between asthmatics and controls for both polymorphisms (

Outcome in patients with cystic fibrosis liver disease

AbstractBackgroundLiver disease is an important complication in CF.AimsTo determine if CFLD is a risk factor for mortality in CF, and which baseline characteristics predict all-cause mortality.MethodsIrish children with CFLD, and their age and gender matched controls were enrolled at baseline and reviewed after 10years to determine which characteristics predict mortality.Results72/84 (85.71%) participants were followed, (mean age Cases 21.71yrs SD 6.5, CF controls 23.62 SD 5.6, 22 (61%) males), with no difference in duration of follow-up. Nineteen participants (26.4%) died, 38.9% (14/36) with CFLD and 13.89% (5/36) CF controls (Odds Ratio (OR) 3.94 95% CI:1.23–12.56 p=0.005). In logistic regression, liver disease (OR 4.28 95% CI 1.07–17.16) female gender (OR 12.25 95% CI 2.37–63.24), reduced pulmonary function, (OR 5.11 95% CI 1.09–23.81) were each independent risk factors for mortality in CF.ConclusionsLiver disease is an independent risk factor for mortality in CF

De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in Blue Cone Monochromacy

X-linked cone dysfunction disorders such as Blue Cone Monochromacy and X-linked Cone Dystrophy are characterized by complete loss (of) or reduced L- and M- cone function due to defects in the OPN1LW/OPN1MW gene cluster. Here we investigated 24 affected males from 16 families with either a structurally intact gene cluster or at least one intact single (hybrid) gene but harbouring rare combinations of common SNPs in exon 3 in single or multiple OPN1LW and OPN1MW gene copies. We assessed twelve different OPN1LW/MW exon 3 haplotypes by semi-quantitative minigene splicing assay. Nine haplotypes resulted in aberrant splicing of ≥20% of transcripts including the known pathogenic haplotypes (i.e. ‘LIAVA’, ‘LVAVA’) with absent or minute amounts of correctly spliced transcripts, respectively. De novo formation of the ‘LIAVA’ haplotype derived from an ancestral less deleterious ‘LIAVS’ haplotype was observed in one family with strikingly different phenotypes among affected family members. We could establish intrachromosomal gene conversion in the male germline as underlying mechanism. Gene conversion in the OPN1LW/OPN1MW genes has been postulated, however, we are first to demonstrate a de novo gene conversion within the lineage of a pedigree

DNA Methylation Signatures Identify Biologically Distinct Subtypes in Acute Myeloid Leukemia

Abstract: We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates)

An Integrative Genomic and Epigenomic Approach for the Study of Transcriptional Regulation

The molecular heterogeneity of acute leukemias and other tumors constitutes a major obstacle towards understanding disease pathogenesis and developing new targeted-therapies. Aberrant gene regulation is a hallmark of cancer and plays a central role in determining tumor phenotype. We predicted that integration of different genome-wide epigenetic regulatory marks along with gene expression levels would provide greater power in capturing biological differences between leukemia subtypes. Gene expression, cytosine methylation and histone H3 lysine 9 (H3K9) acetylation were measured using high-density oligonucleotide microarrays in primary human acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) specimens. We found that DNA methylation and H3K9 acetylation distinguished these leukemias of distinct cell lineage, as expected, but that an integrative analysis combining the information from each platform revealed hundreds of additional differentially expressed genes that were missed by gene expression arrays alone. This integrated analysis also enhanced the detection and statistical significance of biological pathways dysregulated in AML and ALL. Integrative epigenomic studies are thus feasible using clinical samples and provide superior detection of aberrant transcriptional programming than single-platform microarray studies

Physical activity and cardiovascular risk factors in urban school children

Although the clinical signs of cardiovascular disease (CVD) are not evident until adulthood, many of the risk factors have their roots in early childhood. The aim of this study was to examine physical activity levels (PA) and the incidence of CVD risk factors in a small population (n=102) of primary school children in Dublin. Risk factors measured included overweight/obesity, blood lipids, blood pressure (BP), physical fitness and PA levels. Over a quarter of the group were overweight/obese (n = 29, 28%). Despite relatively good fitness levels, PA levels were low with less than half the group (n = 44, 46%) participating in the recommended 1 hour/day. Fewer girls reported spending > 1 hour/day at PA compared to boys (n = 14 v n = 30). Six children had elevated cholesterol levels and five children had higher than normal BP values. Sixteen children demonstrated clustering of CVD risk factors and in those who were inactive the risk was greater. Our data suggest that in children as young as 10 years significant risk factors already exist. Furthermore, the low level of PA in girls provides a target for health promotion programmes

Active video games as an exercise tool for children with cystic fibrosis.

Background: Active video games are used in many hospitals as exercise tools for children with cystic fibrosis. However, the exercise intensity associated with playing these games has not been examined in this population. Methods: Children with cystic fibrosis [n = 30, aged 12.3 (2.6) years, 17 boys, BMI 17.7 (2.8) kg/m2] were recruited from outpatient clinics in Dublin hospitals. Age and gender matched control children were recruited from local schools. Oxygen consumption, metabolic equivalents (METs) calculated from resting O2, and heart rate were measured while playing Nintendo Wii? (Nintendo Co. Ltd., Tokyo, Japan) Sports Boxing and Nintendo Wii Fit Free Jogging using a portable indirect calorimeter (Oxycon Mobile). Results: Playing Wii Boxing resulted in light intensity activity (2.46 METs) while playing Wii Fit Free Jogging resulted in moderate intensity physical activity (4.44 METs). No significant difference was seen between groups in the energy cost of playing active video games. Conclusion: Active video games are a useful source of light to moderate intensity physical activity in children with cystic fibrosis