Research cardiac magnetic resonance imaging in end stage renal disease - incidence, significance and implications of unexpected incidental findings

Objectives: Left ventricular mass (LVM) at cardiac magnetic resonance imaging (CMR) is a frequent end point in clinical trials in nephrology. Trial participants with end stage renal disease (ESRD) may have a greater frequency of incidental findings (IF). We retrospectively investigated prevalence of IF in previous research CMR and reviewed their subsequent impact on participants. Methods: Between 2002 and 2006, 161 ESRD patients underwent CMR in a transplant assessment study. Images were used to assess LV mass and function. In the current study a radiologist reviewed the scans for IF. Review of patient records determined the subsequent clinical significance of IF. Results: There were 150 IF in 95 study participants. Eighty-four (56 %) were new diagnoses. One hundred and two were non-cardiac. Fifteen were suspicious of malignancy. There was a clinically significant IF for 14.9 % of the participants. In six cases earlier identification of an IF may have improved quality of life or survival. Conclusions: Without radiology support clinically important IF may be missed on CMR. Patients undergoing CMR in trials should be counselled about the frequency and implications of IF. Patients with ESRD have a higher prevalence of IF than reported in other populations. Nephrology studies require mechanisms for radiologist reporting and strategies for dealing with IF

Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

SNP selection for genes of iron metabolism in a study of genetic modifiers of hemochromatosis

<p>Abstract</p> <p>Background</p> <p>We report our experience of selecting tag SNPs in 35 genes involved in iron metabolism in a cohort study seeking to discover genetic modifiers of hereditary hemochromatosis.</p> <p>Methods</p> <p>We combined our own and publicly available resequencing data with HapMap to maximise our coverage to select 384 SNPs in candidate genes suitable for typing on the Illumina platform.</p> <p>Results</p> <p>Validation/design scores above 0.6 were not strongly correlated with SNP performance as estimated by Gentrain score. We contrasted results from two tag SNP selection algorithms, LDselect and Tagger. Varying r²from 0.5 to 1.0 produced a near linear correlation with the number of tag SNPs required. We examined the pattern of linkage disequilibrium of three levels of resequencing coverage for the transferrin gene and found HapMap phase 1 tag SNPs capture 45% of the ≥ 3% MAF SNPs found in SeattleSNPs where there is nearly complete resequencing. Resequencing can reveal adjacent SNPs (within 60 bp) which may affect assay performance. We report the number of SNPs present within the region of six of our larger candidate genes, for different versions of stock genotyping assays.</p> <p>Conclusion</p> <p>A candidate gene approach should seek to maximise coverage, and this can be improved by adding to HapMap data any available sequencing data. Tag SNP software must be fast and flexible to data changes, since tag SNP selection involves iteration as investigators seek to satisfy the competing demands of coverage within and between populations, and typability on the technology platform chosen.</p

Longevity and relationships with children: the importance of the parental role

<p>Abstract</p> <p>Background</p> <p>Social networks predict longevity across societies but specific mechanisms are largely unknown. The aim of this work was to examine the role of children in the longevity of elderly men and women in a cohort of community dwelling elderly people in Spain.</p> <p>Methods</p> <p>The data were taken from the "Aging in Leganes" cohort study with 15 years of follow-up. The baseline population was an age- and sex-stratified random sample of community dwelling people over 65 living in Leganés (Madrid) in 1993. Poor relationship with at least one child, emotional support and the perceived roles elders play in the lives of their children, extended family, spouse and friends were assessed at baseline. Cox proportional hazards models were fit to investigate the effects of social roles variables on longevity, adjusting for a wide range of socioeconomic, behavioural and health covariates.</p> <p>Results</p> <p>In the fully adjusted model, having a poor relationship with at least one child increased mortality by 30%. Elderly persons who felt their role in their children's lives was important (HR = 0.70; 95% CI 0.54; 0.91) had a lower mortality risk than those who felt they played a small role. Feeling loved and listened to by one's children did not have an effect on survival. Maintaining an important role in the extended family was also significantly associated with survival.</p> <p>Conclusion</p> <p>In this Mediterranean population, maintaining an important role in the lives of one's children is associated with survival. Functions of social networks related to meaning of life and different forms of social support may have important effects on mortality, and these functions may vary across cultures according to family norms and values.</p

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

HABITAT: A longitudinal multilevel study of physical activity change in mid-aged adults

Purpose. To explore the role of the neighborhood environment in supporting walking Design. Cross sectional study of 10,286 residents of 200 neighborhoods. Participants were selected using a stratified two-stage cluster design. Data were collected by mail survey (68.5% response rate). Setting. The Brisbane City Local Government Area, Australia, 2007. Subjects. Brisbane residents aged 40 to 65 years. Measures. Environmental: street connectivity, residential density, hilliness, tree coverage, bikeways, and street lights within a one kilometer circular buffer from each resident’s home; and network distance to nearest river or coast, public transport, shop, and park. Walking: minutes in the previous week categorized as < 30 minutes, ≥ 30 < 90 minutes, ≥ 90 < 150 minutes, ≥ 150 < 300 minutes, and ≥ 300 minutes. Analysis. The association between each neighborhood characteristic and walking was examined using multilevel multinomial logistic regression and the model parameters were estimated using Markov chain Monte Carlo simulation. Results. After adjustment for individual factors, the likelihood of walking for more than 300 minutes (relative to <30 minutes) was highest in areas with the most connectivity (OR=1.93, 99% CI 1.32-2.80), the greatest residential density (OR=1.47, 99% CI 1.02-2.12), the least tree coverage (OR=1.69, 99% CI 1.13-2.51), the most bikeways (OR=1.60, 99% CI 1.16-2.21), and the most street lights (OR=1.50, 99% CI 1.07-2.11). The likelihood of walking for more than 300 minutes was also higher among those who lived closest to a river or the coast (OR=2.06, 99% CI 1.41-3.02). Conclusion. The likelihood of meeting (and exceeding) physical activity recommendations on the basis of walking was higher in neighborhoods with greater street connectivity and residential density, more street lights and bikeways, closer proximity to waterways, and less tree coverage. Interventions targeting these neighborhood characteristics may lead to improved environmental quality as well as lower rates of overweight and obesity and associated chromic disease

Symptomatic reactions, clinical outcomes and patient satisfaction associated with upper cervical chiropractic care: A prospective, multicenter, cohort study

<p>Abstract</p> <p>Background</p> <p>Observational studies have previously shown that adverse events following manipulation to the neck and/or back are relatively common, although these reactions tend to be mild in intensity and self-limiting. However, no prospective study has examined the incidence of adverse reactions following spinal adjustments using upper cervical techniques, and the impact of this care on clinical outcomes.</p> <p>Methods</p> <p>Consecutive new patients from the offices of 83 chiropractors were recruited for this practice-based study. Clinical outcome measures included 1) Neck pain disability index (100-point scale), 2) Oswestry back pain index (100-point scale), 3) 11-point numerical rating scale (NRS) for neck, headache, midback, and low back pain, 4) treatment satisfaction, and 5) Symptomatic Reactions (SR). Data were collected at baseline, and after approximately 2 weeks of care. A patient reaching sub-clinical status for pain and disability was defined as a follow-up score <3 NRS and <10%, respectively. A SR is defined as a new complaint not present at baseline or a worsening of the presenting complaint by >30% based on an 11-point numeric rating scale occurring <24 hours after any upper cervical procedure.</p> <p>Results</p> <p>A total of 1,090 patients completed the study having 4,920 (4.5 per patient) office visits requiring 2,653 (2.4 per patient) upper cervical adjustments over 17 days. Three hundred thirty- eight (31.0%) patients had SRs meeting the accepted definition. Intense SR (NRS ≥8) occurred in 56 patients (5.1%). Outcome assessments were significantly improved for neck pain and disability, headache, mid-back pain, as well as lower back pain and disability (<it>p </it><0.001) following care with a high level (mean = 9.1/10) of patient satisfaction. The 83 chiropractors administered >5 million career upper cervical adjustments without a reported incidence of serious adverse event.</p> <p>Conclusions</p> <p>Upper cervical chiropractic care may have a fairly common occurrence of mild intensity SRs short in duration (<24 hours), and rarely severe in intensity; however, outcome assessments were significantly improved with less than 3 weeks of care with a high level of patient satisfaction. Although our findings need to be confirmed in subsequent randomized studies for definitive risk-benefit assessment, the preliminary data shows that the benefits of upper cervical chiropractic care may outweigh the potential risks.</p