Intravenous delivery of adeno-associated virus 9-encoded IGF-1Ea propeptide improves post-infarct cardiac remodelling

The insulin-like growth factor Ea propeptide (IGF-1Ea) is a powerful enhancer of cardiac muscle growth and regeneration, also blocking age-related atrophy and beneficial in multiple skeletal muscle diseases. The therapeutic potential of IGF-1Ea compared with mature IGF-1 derives from its local action in the area of synthesis. We have developed an adeno-associated virus (AAV) vector for IGF-1Ea delivery to the heart to treat mice after myocardial infarction and examine the reparative effects of local IGF-1Ea production on left ventricular remodelling. A cardiotropic AAV9 vector carrying a cardiomyocyte-specific IGF-1Ea-luciferase bi-cistronic gene expression cassette (AAV9.IGF-1Ea) was administered intravenously to infarcted mice, 5 h after ischemia followed by reperfusion (I/R), as a model of myocardial infarction. Virally encoded IGF-1Ea in the heart improved global left ventricular function and remodelling, as measured by wall motion and thickness, 28 days after delivery, with higher viral titers yielding better improvement. The present study demonstrates that single intravenous AAV9-mediated IGF-1Ea Gene Therapy represents a tissue-targeted therapeutic approach to prevent the adverse remodelling after myocardial infarct

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

The provision of non-needle/syringe drug injecting paraphernalia in the primary prevention of HCV among IDU: a systematic review

BACKGROUND: Sharing drug injecting paraphernalia other than needles and syringes (N/S) has been implicated in the transmission of Hepatitis C virus (HCV) among injecting drug users (IDU). We aimed to determine whether the provision of sterile non-N/S injecting paraphernalia reduces injecting risk behaviours or HCV transmission among IDU. METHODS: A systematic search of seven databases and the grey literature for articles published January 1989-February 2010 was undertaken. Thirteen studies (twelve observational and one non-randomized uncontrolled pilot intervention) were identified and appraised for study design and quality by two investigators. RESULTS: No studies examined the association between the provision of non-N/S injecting paraphernalia and incident HCV infection. One cross-sectional study found that individuals who frequently, compared to those who infrequently, used sterile cookers and water, were less likely to report prevalent HCV infection. Another found no association between the uptake of sterile non-N/S injecting paraphernalia and self-reported sharing of this paraphernalia. The remaining observational studies used attendance at needle and syringe exchange programmes (NSP) or safer injection facilities (SIF) that provided non-N/S injecting paraphernalia as a proxy measure. Eight studies presented adjusted odds ratios, ranging from 0.3 to 0.9, suggesting a reduced likelihood of self-reported sharing of non-N/S injecting paraphernalia associated with use of NSP or SIF. There was substantial uncertainty associated with these estimates however. Three unadjusted studies reported a reduction in the prevalence of sharing of non-N/S injecting paraphernalia over time among NSP users. Only one study reported an adjusted temporal trend in the prevalence of sharing non-N/S injecting paraphernalia, finding higher rates among non-NSP users than NSP users at each time point, and a greater reduction in sharing among non-NSP than NSP users over time. Study limitations included the use of convenience samples, self-reported exposure and outcome measures, flawed classification of the exposed and unexposed groups, and inadequate adjustment for potential confounding variables. CONCLUSIONS: The evidence to demonstrate that the provision of sterile non-N/S injecting paraphernalia reduces HCV transmission or modifies injecting risk behaviours is currently limited by an insufficient volume and quality of studies. Further research is required to inform practice and policy in this area

Habitat and Host Indicate Lineage Identity in Colletotrichum gloeosporioides s.l. from Wild and Agricultural Landscapes in North America

Understanding the factors that drive the evolution of pathogenic fungi is central to revealing the mechanisms of virulence and host preference, as well as developing effective disease control measures. Prerequisite to these pursuits is the accurate delimitation of species boundaries. Colletotrichum gloeosporioides s.l. is a species complex of plant pathogens and endophytic fungi for which reliable species recognition has only recently become possible through a multi-locus phylogenetic approach. By adopting an intensive regional sampling strategy encompassing multiple hosts within and beyond agricultural zones associated with cranberry (Vaccinium macrocarpon Aiton), we have integrated North America strains of Colletotrichum gloeosporioides s.l. from these habitats into a broader phylogenetic framework. We delimit species on the basis of genealogical concordance phylogenetic species recognition (GCPSR) and quantitatively assess the monophyly of delimited species at each of four nuclear loci and in the combined data set with the genealogical sorting index (gsi). Our analysis resolved two principal lineages within the species complex. Strains isolated from cranberry and sympatric host plants are distributed across both of these lineages and belong to seven distinct species or terminal clades. Strains isolated from V. macrocarpon in commercial cranberry beds belong to four species, three of which are described here as new. Another species, C. rhexiae Ellis & Everh., is epitypified. Intensive regional sampling has revealed a combination of factors, including the host species from which a strain has been isolated, the host organ of origin, and the habitat of the host species, as useful indicators of species identity in the sampled regions. We have identified three broadly distributed temperate species, C. fructivorum, C. rhexiae, and C. nupharicola, that could be useful for understanding the microevolutionary forces that may lead to species divergence in this important complex of endophytes and plant pathogens

Osteoporosis-related fracture case definitions for population-based administrative data

<p>Abstract</p> <p>Background</p> <p>Population-based administrative data have been used to study osteoporosis-related fracture risk factors and outcomes, but there has been limited research about the validity of these data for ascertaining fracture cases. The objectives of this study were to: (a) compare fracture incidence estimates from administrative data with estimates from population-based clinically-validated data, and (b) test for differences in incidence estimates from multiple administrative data case definitions.</p> <p>Methods</p> <p>Thirty-five case definitions for incident fractures of the hip, wrist, humerus, and clinical vertebrae were constructed using diagnosis codes in hospital data and diagnosis and service codes in physician billing data from Manitoba, Canada. Clinically-validated fractures were identified from the Canadian Multicentre Osteoporosis Study (CaMos). Generalized linear models were used to test for differences in incidence estimates.</p> <p>Results</p> <p>For hip fracture, sex-specific differences were observed in the magnitude of under- and over-ascertainment of administrative data case definitions when compared with CaMos data. The length of the fracture-free period to ascertain incident cases had a variable effect on over-ascertainment across fracture sites, as did the use of imaging, fixation, or repair service codes. Case definitions based on hospital data resulted in under-ascertainment of incident clinical vertebral fractures. There were no significant differences in trend estimates for wrist, humerus, and clinical vertebral case definitions.</p> <p>Conclusions</p> <p>The validity of administrative data for estimating fracture incidence depends on the site and features of the case definition.</p

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

Search for high-mass resonances decaying to dilepton final states in pp collisions at s√=7 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z * bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb−1 in the e + e − channel and 5.0 fb−1 in the μ + μ −channel. A Z ′ boson with Standard Model-like couplings is excluded at 95 % confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/MPl=0.1 is excluded at 95 % confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models