Determination of free 25(OH)D concentrations and their relationships to total 25(OH)D in multiple clinical populations

Context : The optimal measure of vitamin D(D) status is unknown. Objective : Directly measure circulating free 25(OH)D concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans. Design : Cross-sectional analysis Setting : Seven academic sites Patients : 1661 adults: (healthy(n=211), pre-diabetic(n=479), outpatients(n=783), cirrhotic(n=90), pregnant(n=20), nursing home(n=79)) Interventions : Merge research data on circulating free 25(OH)D (directly measured immunoassay), total 25(OH)D (LC/MS/MS), D binding protein (DBP by radial (polyclonal) immunodiffusion assay)), albumin, creatinine, iPTH and DBP haplotype Main outcome measures : Distribution of free 25(OH)D (ANOVA with Bonferroni correction for post hoc comparisons) and relationships between free and total 25(OH)D (mixed effects modeling incorporating clinical condition, DBP haplotype with sex, race, eGFR, BMI and other covariates). Results : Free 25(OH)D was 4.7±1.8 pg/mL (mean ±SD) in healthy and 4.3 ±1.9 pg/mL in outpatients with 0.5-8.1 pg/mL and 0.9-8.1 pg/mL encompassing 95% of healthy and outpatients, respectively. Free 25(OH)D was higher in cirrhotics (7.1 ±3.0 pg/mL, pnursing home>prediabetic > outpatient > pregnant), and BMI (lesser effect) as covariates affecting relationships but not eGFR, sex, race or DBP haplotype. Conclusions : Total 25(OH)D, health condition, race and DBP haplotype affected free 25(OH)D, but only health conditions and BMI affected relationships between total and free 25(OH) D. Clinical importance of free 25(OH)D needs to be established in studies assessing outcomes

To Sleep, to Strive, or Both: How Best to Optimize Memory

While numerous studies have shown that a night of sleep profits memory relative to wake, we still have little understanding about what factors mediate this effect of sleep. A clear understanding of the dynamics of this effect of sleep beyond the initial night of sleep is also lacking. Here, we examined the effect of extrinsic rewards on sleep-dependent declarative memory processing across 12 and 24 hr training-retest intervals. Subjects were either paid based on their performance at retest ($1 for each correct answer), or received a flat fee for participation. After a 12 hr interval we observed pronounced benefits of both sleep and reward on memory. Over an extended 24 hr interval we found 1) that an initial night of sleep partially protects memories from subsequent deterioration during wake, and 2) that sleep blocks further deterioration, and may even have a restorative effect on memory, when it follows a full day of wake. Interestingly, the benefit imparted to rewarded (relative to unrewarded) stimuli was equal for sleep and wake subjects, suggesting that the sleeping brain may not differentially process rewarded information, relative to wake. However, looking at the overall impact of sleep relative to reward in this protocol, it was apparent that sleep both imparted a stronger mnemonic boost than reward, and provided a benefit to memory regardless of whether it occurred in the first or the second 12 hrs following task training

Estimating Grizzly and Black Bear Population Abundance and Trend in Banff National Park Using Noninvasive Genetic Sampling

We evaluated the potential of two noninvasive genetic sampling methods, hair traps and bear rub surveys, to estimate population abundance and trend of grizzly (Ursus arctos) and black bear (U. americanus) populations in Banff National Park, Alberta, Canada. Using Huggins closed population mark-recapture models, we obtained the first precise abundance estimates for grizzly bears ( = 73.5, 95% CI = 64–94 in 2006;  = 50.4, 95% CI = 49–59 in 2008) and black bears ( = 62.6, 95% CI = 51–89 in 2006;  = 81.8, 95% CI = 72–102 in 2008) in the Bow Valley. Hair traps had high detection rates for female grizzlies, and male and female black bears, but extremely low detection rates for male grizzlies. Conversely, bear rubs had high detection rates for male and female grizzlies, but low rates for black bears. We estimated realized population growth rates, lambda, for grizzly bear males ( = 0.93, 95% CI = 0.74–1.17) and females ( = 0.90, 95% CI = 0.67–1.20) using Pradel open population models with three years of bear rub data. Lambda estimates are supported by abundance estimates from combined hair trap/bear rub closed population models and are consistent with a system that is likely driven by high levels of human-caused mortality. Our results suggest that bear rub surveys would provide an efficient and powerful means to inventory and monitor grizzly bear populations in the Central Canadian Rocky Mountains

Longevity of daily oral Vitamin D3 supplementation:Differences in 25OHD and 24,25(OH)2D observed 2 years after cessation of a 1-year randomized controlled trial (VICtORy RECALL)

Purpose To determine the longevity of vitamin D status following cessation of vitamin D3 supplementation, 2 and 3 years after a 1 year randomised double blind placebo controlled trial: (Vitamin D and Cardiovascular Risk (VICtORY)); and to investigate possible predictive factors. Method Of the 305 Caucasian non-smoking postmenopausal women randomised to ViCtORY (2009-2010), participants who had not taken vitamin D supplements since the trial ended were invited to attend follow up visits. Total 25-hydroxyvitamin D (25OHD) and 24,25-dihydroxyvitamin D (24,25OH2D) were measured by dual tandem mass spectrometry of serum samples following removal of protein and de-lipidation; the original RCT samples were re-analysed simultaneously. Vitamin D binding protein (VDBP) was measured by monoclonal immunoassay. Results In March 2012 and March 2013, 159 women (mean (SD) age 67.6 (2.1) years) re-attended, distributed between the original treatment groups: daily vitamin D3 400IU; 1000IU; and placebo. One month after the RCT ended (March 2010) the proportion of women in placebo, 400IU, and 1000IU vitamin D3 groups, respectively, with 25OHD0.001, n=46,44,54); 42%, 33%, 12% (2y, p=0.002,n=50,48,57) and 45%, 27%, 29% (3y, p=0.138, n=47,45,51,). VDBP was a predictor of circulating 25OHD longevity (beta for VDBP in µg/ml:0.736; 95% CI 0.216-1.255,p=0.006) but not 24,25OH2D

In Vivo Fluorescence Imaging of Bacteriogenic Cyanide in the Lungs of Live Mice Infected with Cystic Fibrosis Pathogens

10.1371/journal.pone.0021387PLoS ONE67

Epidemiology of HPV genotypes in Uganda and the role of the current preventive vaccines: A systematic review

<p>Abstract</p> <p>Background</p> <p>Limited data are available on the distribution of human papillomavirus (HPV) genotypes in the general population and in invasive cervical cancer (ICC) in Uganda. Yet, with the advent of preventive HPV vaccines that target HPV 16 and 18 responsible for causing about 70% of ICC cases in the world, such information is crucial to predict how vaccination and HPV-based screening will influence prevention of ICC.</p> <p>Methods</p> <p>To review the distribution of HPV infection and prevalent genotypes, electronic databases (e.g. PubMed/MEDLINE and HINARI) were searched for peer reviewed English articles on HPV infection up to November 30, 2010. Eligible studies were selected according to the following criteria: DNA-confirmed cervical or male genital HPV prevalence and genotypes, HPV incidence estimates and HPV seroprevalence among participants.</p> <p>Results</p> <p>Twenty studies were included in the review. Among HIV negative adult women, the prevalence of HR-HPV infections ranged from 10.2% -40.0% compared to 37.0% -100.0% among HIV positive women. Among HIV positive young women aged below 25 years, the prevalence of HR-HPV genotypes ranged from 41.6% -75.0% compared to 23.7% -67.1% among HIV negative women. Multiple infections with non vaccine HR-HPV genotypes were frequent in both HIV positive and HIV negative women. The main risk factors for prevalent HPV infections were age, lifetime number of sexual partners and HIV infection. Incident infections with HR-HPV genotypes were more frequent among adult HIV positive than HIV negative women estimated at 17.3 and 7.0 per 100 person-years, respectively. Similarly, incident HR-HPV among young women aged below 25 years were more frequent among HIV positive (40.0 per 100 person-years) than HIV negative women (20.3 per 100 person-years) women. The main risk factor for incident infection was HIV infection. HPV 16 and 18 were the most common genotypes in ICC with HPV 16/18 contributing up to 73.5% of cases with single infections.</p> <p>Among uncircumcised adult HIV positive males, HR-HPV prevalence ranged from 55.3% -76.6% compared to 38.6% -47.6% in HIV negative males. Incident and multiple HR-HPV infections were frequent in HIV positive males. Being uncircumcised was the main risk factor for both prevalent and incident HPV infection.</p> <p>Conclusion</p> <p>Infections with HR-HPV genotypes were very common particularly among HIV positive individuals and young women irrespective of HIV status. Given the high prevalence of HIV infection, HPV-associated conditions represent a major public health burden in Uganda. However, although the most common HPV genotypes in ICC cases in Uganda were those targeted by current preventive vaccines, there were a large number of individuals infected with other HR-HPV genotypes. Technology allowing, these other HR-HPV types should be considered in the development of the next generation of vaccines.</p

Airway Microbiota and Pathogen Abundance in Age-Stratified Cystic Fibrosis Patients

Bacterial communities in the airways of cystic fibrosis (CF) patients are, as in other ecological niches, influenced by autogenic and allogenic factors. However, our understanding of microbial colonization in younger versus older CF airways and the association with pulmonary function is rudimentary at best. Using a phylogenetic microarray, we examine the airway microbiota in age stratified CF patients ranging from neonates (9 months) to adults (72 years). From a cohort of clinically stable patients, we demonstrate that older CF patients who exhibit poorer pulmonary function possess more uneven, phylogenetically-clustered airway communities, compared to younger patients. Using longitudinal samples collected form a subset of these patients a pattern of initial bacterial community diversification was observed in younger patients compared with a progressive loss of diversity over time in older patients. We describe in detail the distinct bacterial community profiles associated with young and old CF patients with a particular focus on the differences between respective “early” and “late” colonizing organisms. Finally we assess the influence of Cystic Fibrosis Transmembrane Regulator (CFTR) mutation on bacterial abundance and identify genotype-specific communities involving members of the Pseudomonadaceae, Xanthomonadaceae, Moraxellaceae and Enterobacteriaceae amongst others. Data presented here provides insights into the CF airway microbiota, including initial diversification events in younger patients and establishment of specialized communities of pathogens associated with poor pulmonary function in older patient populations

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of ch

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10−8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.This research has been conducted using the UK Biobank Resource. The Fenland Study is supported by the UK Medical Research Council (MRC) (MC_UU_12015/1; MC_UU_12015/2; MC_UU_12015/3). EPIC-Norfolk is supported by the MRC (G401527, G1000143) and Cancer Research UK (A8257). The HCS is gratefully supported by the University of Newcastle (Australia) and the Fairfax Family Foundation. Sydney MAS is supported by the Australian National Health and Medical Research Council (NHMRC), grants ID568969, ID350833 and ID109308. Sydney MAS DNA was extracted by Genetic Repositories Australia, funded by NHMRC Enabling Grant 401184. The GEFOS Study, used as controls for the US and Jamaican athletes, was supported in part by NIH grants U01 HG004436 and P30 DK072488, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). TwinsUK was funded by the Wellcome Trust (WT), MRC, and European Union. The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. SNP Genotyping was performed by The WT Sanger Institute and National Eye Institute via NIH/CIDR. M.McC is a WT Senior Investigator and receives support from WT 090532 and 098381. TW is the recipient of a studentship from MedImmune. Research by A. Lucia is supported by Fondo de Investigaciones Sanitarias and Fondos Feder (grant # PI15/0558). EM-M. was a recipient of a Grant-in-Aid for JSPS Fellow from the Japan Society for the Promotion of Science. This work was supported in part by grants from the Grant-in-Aid for Scientific Research (B) (15H03081 to NF) of the Japanese Ministry of Education, Culture, Sports, Science and Technology and by a grant-in-aid for scientific research (to M. Miyachi) from the Japanese Ministry of Health, Labor, and Welfare. This work was further supported by NIH grants R01 AR41398 and U24 AG051129