A genome-wide association study demonstrates significant genetic variation for fracture risk in Thoroughbred racehorses

Background: Thoroughbred racehorses are subject to non-traumatic distal limb bone fractures that occur during racing and exercise. Susceptibility to fracture may be due to underlying disturbances in bone metabolism which have a genetic cause. Fracture risk has been shown to be heritable in several species but this study is the first genetic analysis of fracture risk in the horse. Results: Fracture cases (n = 269) were horses that sustained catastrophic distal limb fractures while racing on UK racecourses, necessitating euthanasia. Control horses (n = 253) were over 4 years of age, were racing during the same time period as the cases, and had no history of fracture at the time the study was carried out. The horses sampled were bred for both flat and National Hunt (NH) jump racing. 43,417 SNPs were employed to perform a genome-wide association analysis and to estimate the proportion of genetic variance attributable to the SNPs on each chromosome using restricted maximum likelihood (REML). Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31. Three SNPs on chromosome 18 (62.05 Mb – 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p <0.05) in a genome-wide association study (GWAS). Two of the SNPs on ECA 18 were located in a haplotype block containing the gene zinc finger protein 804A (ZNF804A). One haplotype within this block has a protective effect (controls at 1.95 times less risk of fracture than cases, p = 1 × 10-4), while a second haplotype increases fracture risk (cases at 3.39 times higher risk of fracture than controls, p = 0.042). Conclusions: Fracture risk in the Thoroughbred horse is a complex condition with an underlying genetic basis. Multiple genomic regions contribute to susceptibility to fracture risk. This suggests there is the potential to develop SNP-based estimators for genetic risk of fracture in the Thoroughbred racehorse, using methods pioneered in livestock genetics such as genomic selection. This information would be useful to racehorse breeders and owners, enabling them to reduce the risk of injury in their horses

DO IT Trial: vitamin D Outcomes and Interventions in Toddlers - a TARGet Kids! randomized controlled trial.

BackgroundVitamin D levels are alarmingly low (<75 nmol/L) in 65-70% of North American children older than 1 year. An increased risk of viral upper respiratory tract infections (URTI), asthma-related hospitalizations and use of anti-inflammatory medication have all been linked with low vitamin D. No study has determined whether wintertime vitamin D supplementation can reduce the risk of URTI and asthma exacerbations, two of the most common and costly illnesses of early childhood. The objectives of this study are: 1) to compare the effect of 'high dose' (2000 IU/day) vs. 'standard dose' (400 IU/day) vitamin D supplementation in achieving reductions in laboratory confirmed URTI and asthma exacerbations during the winter in preschool-aged Canadian children; and 2) to assess the effect of 'high dose' vitamin D supplementation on vitamin D serum levels and specific viruses that cause URTI.Methods/designThis study is a pragmatic randomized controlled trial. Over 4 successive winters we will recruit 750 healthy children 1-5 years of age. Participating physicians are part of a primary healthcare research network called TARGet Kids!. Children will be randomized to the 'standard dose' or 'high dose' oral supplemental vitamin D for a minimum of 4 months (200 children per group). Parents will obtain a nasal swab from their child with each URTI, report the number of asthma exacerbations and complete symptom checklists. Unscheduled physician visits for URTIs and asthma exacerbations will be recorded. By May, a blood sample will be drawn to determine vitamin D serum levels. The primary analysis will be a comparison of URTI rate between study groups using a Poisson regression model. Secondary analyses will compare vitamin D serum levels, asthma exacerbations and the frequency of specific viral agents between groups.DiscussionIdentifying whether vitamin D supplementation of preschoolers can reduce wintertime viral URTIs and asthma exacerbations and what dose is optimal may reduce population wide morbidity and associated health care and societal costs. This information will assist in determining practice and health policy recommendations related to vitamin D supplementation in healthy Canadian preschoolers

Pharmacokinetics of Mephedrone Enantiomers in Whole Blood after a Controlled Intranasal Administration to Healthy Human Volunteers

Mephedrone, which is one of the most popular synthetic cathinones, has one chiral centre and thus exists as two enantiomers: R-(+)-mephedrone and S-(−)-mephedrone. There are some preliminary data suggesting that the enantiomers of mephedrone may display enantioselective pharmacokinetics and exhibit different neurological effects. In this study, enantiomers of mephedrone were resolved via chromatographic chiral recognition and the absolute configuration was unambiguously determined by a combination of elution order and chiroptical analysis (i.e., circular dichroism). A chiral liquid chromatography tandem mass spectrometry method was fully validated and was applied to the analysis of whole blood samples collected from a controlled intranasal administration of racemic mephedrone hydrochloride to healthy male volunteers. Both enantiomers showed similar kinetics, however, R-(+)-mephedrone had a greater mean Cmax of 48.5 ± 11.9 ng/mL and a longer mean half-life of 1.92 ± 0.27 h compared with 44.6 ± 11.8 ng/mL and 1.63 ± 0.23 h for S-(−)-mephedrone, respectively. Moreover, R-(+)-mephedrone had a lower mean clearance and roughly 1.3 times greater mean area under the curve than S-(−)-mephedrone. Significant changes in the enantiomeric ratio over time were observed, which suggest that the analytes exhibit enantioselective pharmacokinetics. Even though the clinical significance of this finding is not yet fully understood, the study confirms that the chiral nature, and consequently the enantiomeric purity of mephedrone, can be a crucial consideration when interpreting toxicological results

Chemically treated 3D printed polymer scaffolds for biomineral formation

We present the synthesis of nylon-12 scaffolds by 3D printing and demonstrate their versatility as matrices for cell growth, differentiation, and biomineral formation. We demonstrate that the porous nature of the printed parts makes them ideal for the direct incorporation of preformed nanomaterials or material precursors, leading to nanocomposites with very different properties and environments for cell growth. Additives such as those derived from sources such as tetraethyl orthosilicate applied at a low temperature promote successful cell growth, due partly to the high surface area of the porous matrix. The incorporation of presynthesized iron oxide nanoparticles led to a material that showed rapid heating in response to an applied ac magnetic field, an excellent property for use in gene expression and, with further improvement, chemical-free sterilization. These methods also avoid changing polymer feedstocks and contaminating or even damaging commonly used selective laser sintering printers. The chemically treated 3D printed matrices presented herein have great potential for use in addressing current issues surrounding bone grafting, implants, and skeletal repair, and a wide variety of possible incorporated material combinations could impact many other areas

Submillimetre line spectrum of the Seyfert galaxy NGC1068 from the Herschel-SPIRE Fourier Transform Spectrometer

The first complete submillimetre spectrum (190-670um) of the Seyfert 2 galaxy NGC1068 has been observed with the SPIRE Fourier Transform Spectrometer onboard the {\it Herschel} Space Observatory. The sequence of CO lines (Jup=4-13), lines from water, the fundamental rotational transition of HF, two o-H_2O+ lines and one line each from CH+ and OH+ have been detected, together with the two [CI] lines and the [NII]205um line. The observations in both single pointing mode with sparse image sampling and in mapping mode with full image sampling allow us to disentangle two molecular emission components, one due to the compact circum-nuclear disk (CND) and one from the extended region encompassing the star forming ring (SF-ring). Radiative transfer models show that the two CO components are characterized by density of n(H_2)=10^4.5 and 10^2.9 cm^-3 and temperature of T=100K and 127K, respectively. The comparison of the CO line intensities with photodissociation region (PDR) and X-ray dominated region (XDR) models, together with other observational constraints, such as the observed CO surface brightness and the radiation field, indicate that the best explanation for the CO excitation of the CND is an XDR with density of n(H_2) 10^4 cm^-3 and X-ray flux of 9 erg s^-1 cm^-2, consistent with illumination by the active galactic nucleus, while the CO lines in the SF-ring are better modeled by a PDR. The detected water transitions, together with those observed with the \her \sim PACS Spectrometer, can be modeled by an LVG model with low temperature (T_kin \sim 40K) and high density (n(H_2) in the range 10^6.7-10^7.9 cm^-3).Comment: Accepted for publication on the Astrophysical Journal, 30 August 201

A population-based cross-sectional study of age-specific risk factors for high risk human papillomavirus prevalence in rural Nigeria

<p>Abstract</p> <p>Background</p> <p>Cervical cancer, caused by persistent infection with carcinogenic human papillomavirus (HR-HPV), is particularly prevalent in Sub-Saharan Africa and is associated with a high mortality rate. Some studies in West Africa, including our own, have found unusually high HR-HPV across all ages with a slight peak in older women. This increased prevalence at older ages may complicate screen-and-treat programs, which are implemented in regions where HPV prevalence declines with age and typically target women between 30-49 years. A better understanding of the determinants of high HR-HPV prevalence at older ages is needed. The goal of this study is to explore risk factors for HR-HPV prevalence by age among women in our population-based study in Irun, a rural town in southwestern Nigeria.</p> <p>Methods</p> <p>1,420 women were administered a clinic-based questionnaire regarding sexual and reproductive behavior, marital status (including co-wives), and malaria exposure. Logistic regression compared questionnaire responses and PCR positivity for a set of 13 carcinogenic HR-HPV types. Results were stratified by age (15-29, 30-45, 46-55, and 56+ years).</p> <p>Results</p> <p>Birth control use and age at first pregnancy were associated with HR-HPV (<it>p-value </it>= 0.03 and 0.05, respectively). Early age at sexual debut and multiple sex partners were risks for HR-HPV, but did not reach significance (<it>p-value </it>= 0.1 and 0.07, respectively). Neither self-reported malaria nor presence of co-wives in the household was associated with HR-HPV (<it>p-value </it>= 0.85 and 0.24, respectively). In age sub-categories, early age at sexual debut was a significant risk factor for HR-HPV among women 35-45 years (<it>p-value = 0.02</it>). Early age at first pregnancy remained a significant risk factor for women aged 56+ years (<it>p-value </it>= 0.04). Greater than 2 sex partners and use of birth control were associated (though not significantly) with HR-HPV in women aged 30-45 (<it>p-value </it>= 0.08, respectively).</p> <p>Conclusions</p> <p>In this high-risk region with elevated HR-HPV prevalence at older ages, we confirmed previously described, behavioral determinants of HR-HPV. There was no association with self-reported malaria or co-wives, which we had hypothesized might correlate with HR-HPV at older ages.</p

The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits

PMCID: PMC3410907This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The Electronic Influence of Ring Substituents and Ansa Bridges in Zirconocene Complexes as Probed by Infrared Spectroscopic, Electrochemical, and Computational Studies

The electronic influence of unbridged and ansa-bridged ring substituents on a zirconocene center has been studied by means of IR spectroscopic, electrochemical, and computational methods. With respect to IR spectroscopy, the average of the symmetric and asymmetric stretches (ν_(CO(av))) of a large series of dicarbonyl complexes (Cp^R)_2Zr(CO)_2 has been used as a probe of the electronic influence of a cyclopentadienyl ring substituent. For unbridged substituents (Me, Et, Pri, But, SiMe_3), ν_(CO(av)) on a per substituent basis correlates well with Hammett σ_(meta) parameters, thereby indicating that the influence of these substituents is via a simple inductive effect. In contrast, the reduction potentials (E°) of the corresponding dichloride complexes (Cp^R)_2ZrCl_2 do not correlate well with Hammett σ_(meta) parameters, thereby suggesting that factors other than the substituent inductive effect also influence E°. Ansa bridges with single-atom linkers, for example [Me_2C] and [Me_2Si], exert a net electron-withdrawing effect, but the effect is diminished upon increasing the length of the bridge. Indeed, with a linker comprising a three-carbon chain, the [CH_2CH_2CH_2] ansa bridge becomes electron-donating. In contrast to the electron-withdrawing effect observed for a single [Me_2Si] ansa bridge, a pair of vicinal [Me_2Si] ansa bridges exerts an electron-donating effect relative to that from the single bridge. DFT calculations demonstrate that the electron-withdrawing effect of the [Me_2C] and [Me_2Si] ansa-bridges is due to stabilization of the cyclopentadienyl ligand acceptor orbital, which subsequently enhances back-donation from the metal. The calculations also indicate that the electron-donating effect of two vicinal [Me_2Si] ansa bridges, relative to that of a single bridge, is a result of it enforcing a ligand conformation that reduces back-donation from the metal