Rationale, design, methodology and sample characteristics for the family partners for health study: a cluster randomized controlled study

<p>Abstract</p> <p>Background</p> <p>Young children who are overweight are at increased risk of becoming obese and developing type 2 diabetes and cardiovascular disease later in life. Therefore, early intervention is critical. This paper describes the rationale, design, methodology, and sample characteristics of a 5-year cluster randomized controlled trial being conducted in eight elementary schools in rural North Carolina, United States.</p> <p>Methods/Design</p> <p>The first aim of the trial is to examine the effects of a two-phased intervention on weight status, adiposity, nutrition and exercise health behaviors, and self-efficacy in overweight or obese 2nd, 3 rd, and 4th grade children and their overweight or obese parents. The primary outcome in children is stabilization of BMI percentile trajectory from baseline to 18 months. The primary outcome in parents is a decrease in BMI from baseline to 18 months. Secondary outcomes for both children and parents include adiposity, nutrition and exercise health behaviors, and self-efficacy from baseline to 18 months. A secondary aim of the trial is to examine in the experimental group, the relationships between parents and children's changes in weight status, adiposity, nutrition and exercise health behaviors, and self-efficacy. An exploratory aim is to determine whether African American, Hispanic, and non-Hispanic white children and parents in the experimental group benefit differently from the intervention in weight status, adiposity, health behaviors, and self-efficacy.</p> <p>A total of 358 African American, non-Hispanic white, and bilingual Hispanic children with a BMI ≥ 85th percentile and 358 parents with a BMI ≥ 25 kg/m²have been inducted over 3 1/2 years and randomized by cohort to either an experimental or a wait-listed control group. The experimental group receives a 12-week intensive intervention of nutrition and exercise education, coping skills training and exercise (Phase I), 9 months of continued monthly contact (Phase II) and then 6 months (follow-up) on their own. Safety endpoints include adverse event reporting. Intention-to-treat analysis will be applied to all data.</p> <p>Discussion</p> <p>Findings from this trial may lead to an effective intervention to assist children and parents to work together to improve nutrition and exercise patterns by making small lifestyle pattern changes.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01378806">NCT01378806</a>.</p

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Pulmonary interstitial glycogenosis within a discrete pulmonary lesion mimicking congenital pulmonary airway malformation

Interstitial lung diseases (ILD) are a heterogeneous group of pulmonary disorders that are relatively rare in the pediatric population. These diseases are characterized by impaired gas exchange and typically manifest with diffuse infiltrates on radiographs. Pulmonary interstitial glycogenosis (PIG) has recently been identified as an ILD affecting neonates and infants that manifests diffusely throughout the lungs by imaging, has non-specific clinical features, and usually has a favorable outcome in the absence of significant comorbid conditions. We report two cases of PIG that presented with focal radiographic abnormalities, leading to erroneous diagnoses of congenital pulmonary airway malformations and pulmonary resection

Susceptibility of Hermansky-Pudlak Mice to Bleomycin-Induced Type II Cell Apoptosis and Fibrosis

Pulmonary inflammation, abnormalities in type II cell and macrophage morphology, and pulmonary fibrosis are features of Hermansky-Pudlak Syndrome (HPS), a recessive disorder associated with intracellular trafficking defects. We have previously reported that “Pearl” (HPS2) and “Pale Ear” (HPS1) mouse models have pulmonary inflammatory dysregulation and constitutive alveolar macrophage (AM) activation (Young LR et al., J Immunol 2006;176:4361–4368). In the current study, we used these HPS models to investigate mechanisms of lung fibrosis. Unchallenged HPS1 and HPS2 mice have subtle airspace enlargement and foamy AMs, but little or no histologic evidence of lung fibrosis. Seven days after intratracheal bleomycin (0.025 units), HPS1 and HPS2 mice exhibited increased mortality and diffuse pulmonary fibrosis compared to strain-matched C57BL/6J wild-type (WT) mice. HPS mice had significantly increased collagen deposition, and reduced quasi-static and static compliance consistent with a restrictive defect. The early airway and parenchymal cellular inflammatory responses to bleomycin were similar in HPS2 and WT mice. Greater elevations in levels of TGF-β and IL-12p40 were produced in the lungs and AMs from bleomycin-challenged HPS mice than in WT mice. TUNEL staining revealed apoptosis of type II cells as early as 5 h after low-dose bleomycin challenge in HPS mice, suggesting that type II cell susceptibility to apoptosis may play a role in the fibrotic response. We conclude that the trafficking abnormalities in HPS promote alveolar apoptosis and pulmonary fibrosis in response to bleomycin challenge

Tyrosine kinase-altered spindle cell neoplasms with EGFR internal tandem duplications.

In this study, we present two extra-renal pediatric spindle cell neoplasms with epidermal growth factor receptor (EGFR) internal tandem duplications (ITD). Histologically, these tumors demonstrated the same histologic features seen in other tyrosine kinase-altered spindle cell neoplasms, with one case showing abundant adipose tissue with cellular fibrous septae resembling lipofibromatosis and the other case showing fascicles of spindled cells resembling infantile fibrosarcoma. There was variable expression of CD34, S100, and SMA, and all cases were negative for panTRK. This case series adds to our molecular understanding of the spectrum of tyrosine kinase-altered spindle cell neoplasms and represents the first reported examples of EGFR ITDs in extra-renal tumors. The presence of EGFR alterations in the absence of gene fusions represents a potential therapeutic target and necessitates a broader testing panel for this group of tumors

Islet Interleukin-1β Immunoreactivity Is an Early Feature of Cystic Fibrosis That May Contribute to β-Cell Failure

OBJECTIVE:Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), increasing patient morbidity and mortality. Poor understanding of CFRD pathogenesis limits the development of targeted therapies to treat and/or prevent the disease. The aim of this study was to evaluate islet pathology, specifically, inflammation, amyloid deposition, and endocrine cell composition in subjects with CF with diabetes and with CF without diabetes. RESEARCH DESIGN AND METHODS:A retrospective analysis of archived pancreas tissue collected at autopsy was conducted using pancreas tissue from subjects with CF and diabetes (CFRD) (n = 18) and CF without diabetes (CF-no DM) (n = 17). Two cohorts of control non-CF subjects were identified, each matched to CFRD and CF-no DM subjects for age, sex, and BMI (non-CF older, n = 20, and non-CF younger, n = 20), respectively. Immunohistochemistry was performed to assess interleukin-1β (IL-1β) and islet hormone (insulin, glucagon, somatostatin, and pancreatic polypeptide) immunoreactivity; histochemistry was performed to quantify amyloid deposition. RESULTS:Islet IL-1β immunoreactivity was substantially increased in both CFRD and CF-no DM subjects compared with non-CF subjects and was common in young subjects with CF (≤10 years of age). In contrast, islet amyloid deposition was increased only in CFRD subjects. We also observe abnormal islet hormone immunoreactivity, characterized by increased glucagon immunoreactivity, in CF-no DM and CFRD subjects compared with non-CF subjects. CONCLUSIONS:These findings reveal novel molecular pathways and therapeutic targets underlying islet pathology in CF subjects and may be important in developing new approaches to treat CFRD