Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy

Contains fulltext : 88828.pdf (publisher's version ) (Open Access)BACKGROUND: A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms. METHODS AND RESULTS: Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r = 0.83, p = 0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented. SIGNIFICANCE: These data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk

High-velocity power training has similar effects to traditional resistance training for functional performance in older adults: a systematic review

Question: What is the effect of high-velocity power training (HVPT) compared with traditional resistance training (TRT) on functional performance in older adults? What is the quality of intervention reporting for the relevant literature? Design: Systematic review and meta-analysis of randomised controlled trials. Participants: Older adults (age > 60 years), regardless of health status, baseline functional capacity or residential status. Interventions: High-velocity power training with the intent to perform the concentric phase as quickly as possible compared with traditional moderate-velocity resistance training performed with a concentric phase of ≥ 2 seconds. Outcome measures: Short physical performance battery (SPPB), timed up-and-go-test (TUG), five times sit-to-stand test (5-STS), 30 second sit-to-stand test (30-STS), gait speed tests, static or dynamic balance tests, stair climb tests, and walking tests for distance. The quality of intervention reporting was assessed with the consensus on exercise reporting template (CERT) score. Results: Nineteen trials with 1,055 participants were included in the meta-analysis. Compared with TRT, HVPT had a weak-to-moderate effect on change from baseline scores for the SPPB (SMD 0.27, 95% CI 0.02 to 0.53; low quality evidence) and TUG (SMD 0.35, 95% CI 0.06 to 0.63; low quality evidence). The effect of HVPT relative to TRT for other outcomes remained very uncertain. The average CERT score across all trials was 53%, with two trials rated high quality and four rated moderate quality. Conclusion: HVPT has similar effects as TRT for functional performance in older adults, but there is considerable uncertainty in most estimates. HVPT had better effects on the SPPB and TUG, but it is unclear whether the benefit is large enough to be clinically worthwhile

Discrete seasonal hydroclimate reconstructions over northern Vietnam for the past three and a half centuries

We present a 350-year hydroclimatic year (HY) index for northern Vietnam derived from three discrete seasonal reconstructions from tree rings: an index of autumn rainfall from the earlywood widths of Chinese Douglas fir (Pseudotsuga sinensis), the first such record from this species, and two nearby published Palmer Drought Severity Index (PDSI) reconstructions from cypress (Fokienia hodginsii) tree rings for spring and summer, respectively. Autumn rainfall over the study region constitutes only around 9% of the annual total, but its variability is strongly linked to the strength of the atmospheric gradient over Asia during the transition from the boreal summer to winter monsoons. Deficit or surplus of autumn rainfall enhances or mitigates, respectively, the impact of the annual winter dry season on trees growing on porous karst hillsides. The most protracted HY drought (dry across all seasons) occurred at the turn of the twentieth century at a time of relative quiet, but a mid-to-late eighteenth century multi-year HY drought coincided with a period of great societal turmoil across mainland Southeast Asia and the Tay Son Rebellion in northern Vietnam. A mid-nineteenth century uprising accompanied by a smallpox epidemic, crop failure and famine, occurred during the worst autumn drought of the past two and a half centuries but only moderate drought in spring and summer. The “Great Vietnamese Famine” of the mid-twentieth century was dry only in autumn, with a wet spring and an average summer

Stringy origin of Tevatron Wjj anomaly

The invariant mass distribution of dijets produced in association with W bosons, recently observed by the CDF Collaboration at Tevatron, reveals an excess in the dijet mass range 120-160 GeV/c^2, 3\sigma beyond Standard Model expectations. We show that such an excess is a generic feature of low mass string theory, due to the production and decay of a leptophobic Z', a singlet partner of SU(3) gluons coupled primarily to the U(1) baryon number. In this framework, U(1) and SU(3) appear as subgroups of U(3) associated with open strings ending on a stack of 3 D-branes. In addition, a minimal model contains two other stacks to accommodate the electro-weak SU(2) \in U(2) and the hypercharge U(1). Of the three U(1) gauge bosons, the two heavy Z' and Z" receive masses through the Green-Schwarz mechanism. For a given Z' mass, the model is quite constrained. Fine tuning three of its free parameters is just sufficient to simultaneously ensure: a small Z-Z' mixing in accord with the stringent LEP data on the $Z$ mass; very small (less than 1%) branching ratio into leptons; and a large hierarchy between Z" and Z' masses. The heavier neutral gauge boson Z" is within the reach of LHC.Comment: v1 8 pages revtex; v2 better fit to the data (Z" within LHC reach), references added; v3 to appear in PL

Beyond synthesis: Augmenting systematic review procedures with practical principles to optimise impact and uptake in educational policy and practice

Whilst systematic reviews, meta-analyses and other forms of synthesis are often constructed as sitting proudly atop the hierarchy of research evidence, their limited impact on educational policy and practice has been criticised. In this article, we analyse why systematic reviews do not benefit users of evidence more consistently and suggest how review teams can optimise the impact of their work. We introduce the Beyond Synthesis Impact Chain (BSIC), an integrated framework of practical strategies for enhancing the impact of systematic reviews. Focusing upon examples from health professions education, we propose that review teams can optimise the impact of their work by employing strategies that 1) focus on practical problems and mindful planning in collaboration with users; 2) ensure reviews are relevant and syntheses reflexively account for users’ needs; and 3) couch reports in terms that resonate with users’ needs and increase access through targeted and strategic dissemination. We argue that combining practical principles with robust and transparent procedures can purposefully account for impact, and foster the uptake of review evidence in educational policy and practice. For systematic review teams, this paper offers strategies for enhancing the practical utility and potential impact of systematic reviews and other forms of synthesis

Global DNA methylation and cognitive and behavioral outcomes at 4 years of age: A cross‐sectional study

Background Accumulating evidence suggests that breastfeeding exclusivity and duration are positively associated with child cognition. This study investigated whether DNA methylation, an epigenetic mechanism modified by nutrient intake, may contribute to the link between breastfeeding and child cognition. The aim was to quantify the relationship between global DNA methylation and cognition and behavior at 4 years of age. Methods Child behavior and cognition were measured at age 4 years using the Wechsler Preschool and Primary Scale of Intelligence, third version (WPPSI‐III), and Child Behavior Checklist (CBC). Global DNA methylation (%5‐methylcytosines (%5mC)) was measured in buccal cells at age 4 years, using an enzyme‐linked immunosorbent assay (ELISA) commercial kit. Linear regression models were used to quantify the statistical relationships. Results Data were collected from 73 children recruited from the Women and Their Children's Health (WATCH) study. No statistically significant associations were found between global DNA methylation levels and child cognition or behavior (p > .05), though the estimates of effect were consistently negative. Global DNA methylation levels in males were significantly higher than in females (median %5mC: 1.82 vs. 1.03, males and females, respectively, (p < .05)). Conclusion No association was found between global DNA methylation and child cognition and behavior; however given the small sample, this study should be pooled with other cohorts in future meta‐analyses

Ursodeoxycholic acid as a novel disease-modifying treatment for Parkinson’s disease: protocol for a two-centre, randomised, double-blind, placebo-controlled trial, The 'UP' study

Introduction There are no disease-modifying treatments for Parkinson’s disease (PD). We undertook the first drug screen in PD patient tissue and idntified ursodeoxycholic acid (UDCA) as a promising mitochondrial rescue agent. The aims of this trial are to determine safety and tolerability of UDCA in PD at 30 mg/kg, confirm the target engagement of UDCA, apply a novel motion sensor-based approach to quantify disease progression objectively, and estimate the mean effect size and its variance on the change in motor severity. Methods and analysis This is a phase II, two-centre, double-blind, randomised, placebo-controlled trial of UDCA at a dose of 30 mg/kg in 30 participants with early PD. Treatment duration is 48 weeks, followed by an 8-week washout phase. Randomisation is 2:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48 and 56. The primary outcome is safety and tolerability. Secondary outcomes will compare the change between baseline and week 48 using the following three approaches: the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part 3 in the practically defined ‘OFF’ medication state; confirmation of target engagement, applying 31Phosphorus MR Spectroscopy to assess the levels of ATP and relevant metabolites in the brain; and objective quantification of motor impairment, using a validated, motion sensor-based approach. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups. For each secondary outcome, the change from baseline will be summarised within treatment groups using summary statistics and appropriate statistical tests assessing for significant differences. All outcomes will use an intention-to-treat analysis population. Ethics and dissemination This trial has been approved by the East of England – Cambridgeshire and Hertfordshire Research Ethics committee. Results will be disseminated in peer-reviewed journals, presentations at scientific meetings and to patients in a lay-summary format. Trial registration number NCT03840005

Invasive species control: incorporating demographic data and seed dispersal into a management model for Rhododendron ponticum

Rhododendron ponticum is a serious invasive alien plant in the British Isles and is of significant conservation and economic concern. Here, we integrate information on both the life-history and spatial dynamics of this species within an individual-based, spatially-explicit model and investigate the effectiveness of different control strategies. Importantly, we simulate seed movement and dispersal using a mechanistic seed dispersal model. We investigate the effectiveness of initiating control at the edge versus the core of the infestation, with and without returning each year to remove seedlings. We compare these results to an age-dependent strategy whereby the oldest plants are removed each year. Age-dependent control, in which the oldest plants were removed first, was the most effective strategy investigated, both in terms of the probability of successful eradication and the number of years taken to control. We demonstrate that this is because the older (and taller) plants towards the core produce more seeds that, on average, travel further. Indeed, our results suggest that the expansion of the invading front is actually driven as much by seeds that disperse long distances from these larger plants as by the seed rain from recently matured plants located much closer to the front. Finally, we investigate the potential use of ‘quarantine lines’ - corridors of unsuitable habitat that are sufficiently wide to contain an infestation, preventing spread to vulnerable areas. This study has provided generic insights into best practice for management based on the current understanding of the biology and ecology of this pernicious, invasive plant

Is a posthumanist bildung possible? Reclaiming the promise of bildung for contemporary higher education

My central argument in this article is that the notion of Bildung may offer conceptual sustenance to those who wish to develop educative practices to supplement or contest the prevalence and privileging of market and economic imperatives in higher education, which configure teaching and learning as an object available to measurement. I pursue this argument by making the case for an ethical posthuman Bildung which recognises the inseparability of knowing and being, the materiality of educative relations, and the need to install an ecology of ethical relations at the centre of educational practice in higher education. Such a re-conceptualisation situates Bildung not purely as an individual goal but as a process of ecologies and relationships. The article explores Bildung as a flexible concept, via three theoretical lenses, and notes that it has always been subject to continuing revision in response to changing social and educational contexts. In proposing the possibility of, and need for, a posthuman Bildung, the articles offers a critical review of the promise of Bildung and outlines some of the radical ways that a posthuman Bildung might reinvigorate conceptualisations of contemporary higher education. Keywords : Bildung; posthumanism; higher education; ethics; ecology

The spin periods and magnetic moments of white dwarfs in magnetic cataclysmic variables

We have used a model of magnetic accretion to investigate the rotational equilibria of magnetic cataclysmic variables (mCVs). The results of our numerical simulations demonstrate that there is a range of parameter space in the P_spin / P_orb versus mu_1 plane at which rotational equilibrium occurs. This has allowed us to calculate the theoretical histogram describing the distribution of magnetic CVs as a function of P_spin / P_orb. We show that this agrees with the observed distribution assuming that the number of systems as a function of white dwarf magnetic moment is distributed approximately according to N(mu_1) d mu_1 proportional to 1/mu_1 d mu_1. The rotational equilibria also allow us to infer approximate values for the magnetic moments of all known intermediate polars. We predict that intermediate polars with mu_1 > 5 x 10^33 G cm^3 and P_orb > 3h will evolve into polars, whilst those with mu_1 < 5 x 10^33 G cm^3 and P_orb > 3h will either evolve into low field strength polars which are (presumably) unobservable, and possibly EUV emitters, or, if their fields are buried by high accretion rates, evolve into conventional polars once their magnetic fields re-surface when the mass accretion rate reduces. We speculate that EX Hya-like systems may have low magnetic field strength secondaries and so avoid synchronisation. Finally we note that the equilibria we have investigated correspond to a variety of different types of accretion flow, including disc-like accretion at small P_spin / P_orb values, stream-like accretion at intermediate P_spin / P_orb values, and accretion fed from a ring at the outer edge of the white dwarf Roche lobe at higher P_spin / P_orb values.Comment: Accepted for publication in ApJ. Figre 3 included here as a low resolution gif onl