VARIATION IN METATARSAL MORPHOLOGY AMONG SUBGROUPS OF NORTH AMERICAN MOOSE (Alces alces)

The objectives of this study were to characterize variation in dimensional data from the metatarsus of 4 different subpopulations of North American moose (Alces alces) that are known to differ in stature, and to determine if specific metatarsal width measurements (proximal, middle, distal) can be used to accurately predict metatarsal length in these subpopulations. We found that subpopulations differ in the dimensions of their metatarsal bones. Alaskan moose (A. a. gigas) are significantly larger in the length and width of the metatarsus than non-Alaskan moose. Moose from Isle Royale have significantly shorter metatarsal bones than the other groups which is associated with a proportional reduction in the middle metatarsal width; the ratio of middle width:length was similar across groups in contrast to the proximal: and distal width:length ratios. These dimensions were not reduced proportionally in Isle Royale specimens as these ratios were greater in the Isle Royale moose than in other groups. Predictive equations for estimating metatarsal length from each of the 3 width measurements were developed. The length could be predicted accurately from each of the width measurements if separate predictive equations were developed for specimens collected from Isle Royale versus the other subgroups. These data indicate that considerable variation exists in the dimensions of a single bone, the metatarsus, in subgroups of the same species. Valid predictive equations developed using data sets from one subgroup may not provide accurate predictions when applied to other subgroups of the same species

Prevalence of alcohol and drugs in urine of patients involved in road accidents

Objective. Road injuries are the leading injury-related cause of death among people aged 15-44. A clear dose-effect relationship has been demonstrated for drug and alcohol use and road traffic accidents. The objective of our study was to estimate the prevalence of drug and/or alcohol use in subjects admitted for road traffic accidents to an Emergency Department. Methods. In this study, conducted between January and April 2006, 100 patients of both sexes (age 18-65) examined after road traffic accidents were consecutively enrolled. A commercial rapid urine test was used to detect drugs by the Emergency Department staff. The alcohol concentration was determined from a blood sample at the central laboratory. Results. Most of the patients were drivers under 35 years of age. 67/100 road traffic accidents occurred at the weekend (Friday- Sunday), nearly 60% between 24:00-09:00 hrs; on non-weekend days about 80% of road traffic accidents were recorded between 14:00-24:00 hrs (p inf. 0.0001). With the alcoholemia test and urine test for drugs detection 43/100 patients showed a single or multiple positivity. Alcohol and drug presence is relevant during the weekend (37/43 cases), in contrast with non weekend (6/43 cases) [OR 3.04 (95% CI 1.43; 6.46)]. Alcohol was the most frequently detected abuse substance (72%), followed by benzodiazepines (42%), tetrahydrocannabinol (21%) and cocaine (14%). Discussion. 43% of patients examined were under the influence of psychotropic substances (alcohol, drugs or both). The greater part of road traffic accidents in positive test patients occurred during the week-end, in particular during the late night/early morning hours, probably after recreational time. The high incidence of alcohol and/or drug abuse may have caused physical and/or psychological problems, therefore the high number of road traffic accidents, especially if taken in combination. Conclusion. The rapid urine test used cannot represent a diagnosis, and requires a confirmation test. It can be used for medical purposes as an easy and fast preliminary response which enables a faster diagnostic and therapeutic guideline, but it cannot be used for sanctions. Further studies are advisable with an increase of number of patients, in a wider temporal range, including control subjects, and using confirmation tests

Genome-wide screening for DNA variants associated with reading and language traits

This research was funded by: Max Planck Society, the University of St Andrews - Grant Number: 018696, US National Institutes of Health - Grant Number: P50 HD027802, Wellcome Trust - Grant Number: 090532/Z/09/Z, and Medical Research Council Hub Grant Grant Number: G0900747 91070Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills.Publisher PDFPeer reviewe

Deletion of the Virion Host Shut-off Gene Enhances Neuronal-Selective Transgene Expression from an HSV Vector Lacking Functional IE Genes

The ability of herpes simplex virus (HSV) to establish lifelong latency in neurons suggests that HSV-derived vectors hold promise for gene delivery to the nervous system. However, vector toxicity and transgene silencing have created significant barriers to vector applications to the brain. Recently, we described a vector defective for all immediate-early gene expression and deleted for the joint region between the two unique genome segments that proved capable of extended transgene expression in non-neuronal cells. Sustained expression required the proximity of boundary elements from the latency locus. As confirmed here, we have also found that a transgene cassette introduced into the ICP4 locus is highly active in neurons but silent in primary fibroblasts. Remarkably, we observed that removal of the virion host shutoff (vhs) gene further improved transgene expression in neurons without inducing expression of viral genes. In rat hippocampus, the vhs-deleted vector showed robust transgene expression exclusively in neurons for at least 1 month without evidence of toxicity or inflammation. This HSV vector design holds promise for gene delivery to the brain, including durable expression of large or complex transgene cassettes

Does the Mutation Type Affect the Response to Cranial Vault Expansion in Children With Apert Syndrome?

Most cases of Apert syndrome are caused by mutations in the FGFR2 gene, either Ser252Trp or Pro253Arg. In these patients, over the last decades, spring-assisted posterior vault expansion (SA-PVE) has been the technique of choice for cranial vault expansion in the Craniofacial Unit of Great Ormond Street Hospital for Children (GOSH), London. The aim of this study was to investigate if there is a difference in preoperative intracranial volume (ICV) in patients with Apert syndrome with Ser252Trp or Pro253Arg mutation and whether these mutations affect the change in ICV achieved by SA-PVE. The GOSH craniofacial SA-PVE database was used to select patients with complete genetic testing and preoperative and postoperative computed tomography scans. ICV was calculated using FSL (FMRIB Analysis Group, Oxford) and adjusted based on Apert-specific growth curves. Sixteen patients were included with 8 having Ser252Trp mutation and 8 having Pro253Arg mutation. The mean preoperative adjusted computed tomography volume for patients in the Ser252Trp group was 1137.7 cm3 and in the Pro253Arg group was 1115.8 cm3 (P=1.00). There was a significant increase in ICV following SA-PVE in all patients (P<0.001) with no difference in mean change in ICV between the groups (P=0.51). Four (50%) patients with Ser252Trp mutation and 3 (37.5%) with Pro253Arg mutations required a second operation after primary SA-PVE. The results demonstrate that regardless of the mutation present, SA-PVE was successful in increasing ICV in patients with Apert syndrome and that a repeat volume expanding procedure was required by a similar number of patients in the 2 groups

The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts

We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation

Genetic architecture of white matter hyperintensities differs in hypertensive and nonhypertensive ischemic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies suggest that white matter hyperintensities (WMH) are extremely heritable, but the underlying genetic variants are largely unknown. Pathophysiological heterogeneity is known to reduce the power of genome-wide association studies (GWAS). Hypertensive and nonhypertensive individuals with WMH might have different underlying pathologies. We used GWAS data to calculate the variance in WMH volume (WMHV) explained by common single nucleotide polymorphisms (SNPs) as a measure of heritability (SNP heritability [HSNP]) and tested the hypothesis that WMH heritability differs between hypertensive and nonhypertensive individuals. METHODS: WMHV was measured on MRI in the stroke-free cerebral hemisphere of 2336 ischemic stroke cases with GWAS data. After adjustment for age and intracranial volume, we determined which cardiovascular risk factors were independent predictors of WMHV. Using the genome-wide complex trait analysis tool to estimate HSNP for WMHV overall and within subgroups stratified by risk factors found to be significant in multivariate analyses. RESULTS: A significant proportion of the variance of WMHV was attributable to common SNPs after adjustment for significant risk factors (HSNP=0.23; P=0.0026). HSNP estimates were higher among hypertensive individuals (HSNP=0.45; P=7.99×10(-5)); this increase was greater than expected by chance (P=0.012). In contrast, estimates were lower, and nonsignificant, in nonhypertensive individuals (HSNP=0.13; P=0.13). CONCLUSIONS: A quarter of variance is attributable to common SNPs, but this estimate was greater in hypertensive individuals. These findings suggest that the genetic architecture of WMH in ischemic stroke differs between hypertensives and nonhypertensives. Future WMHV GWAS studies may gain power by accounting for this interaction