Revertant fibres and dystrophin traces in Duchenne muscular dystrophy: Implication for clinical trials

Duchenne muscular dystrophy (DMD) is characterised by the absence of dystrophin in muscle biopsies, although residual dystrophin can be present, either as dystrophin-positive (revertant) fibres or traces. As restoration of dystrophin expression is the end point of clinical trials, such residual dystrophin is a key factor in recruitment of patients and may also confound the analysis of dystrophin restoration in treated patients, if, as previously observed in the mdx mouse, revertant fibres increase with age. In 62% of the diagnostic biopsies reports of 65 DMD patients studied, traces or revertants were recorded with no correlation between traces or revertants, the patients' performance, or corticosteroids response. In nine of these patients, there was no increase in traces or revertants in biopsies taken a mean of 8.23 years (5.8-10.4 years) after the original diagnostic biopsy. This information should help in the design and execution of clinical trials focused on dystrophin restoration strategies. (C) 2010 Elsevier B.V. All rights reserved

Scaffolding Discourse in Asynchronous Learning Networks

Discourse, a form of collaborative learning, is fundamentally a communications process. This in-progress study adapts Clark and Brennan’s grounding in communications principles to investigate how to “scaffold” asynchronous discourse. Scaffolding is defined as providing support for the learner at his or her level until the support is no longer needed. This paper presents early results from an experimental study measuring learning effectiveness. In the experiment, content and process scaffolding are manipulated based on pedagogic principles. A major contribution of the study is building and testing a technologymediated, discourse-centered, teaching and learning model called the Asynchronous Learning Networks Cognitive Discourse Model (ALNCDM). As discourse is one of the most widely used online methods of teaching and learning, the results of the study are expected to add to the body of knowledge on how to structure asynchronous online discourse assignments for more effective student learning

Interactions between magnetohydrodynamic shear instabilities and convective flows in the solar interior

Motivated by the interface model for the solar dynamo, this paper explores the complex magnetohydrodynamic interactions between convective flows and shear-driven instabilities. Initially, we consider the dynamics of a forced shear flow across a convectively-stable polytropic layer, in the presence of a vertical magnetic field. When the imposed magnetic field is weak, the dynamics are dominated by a shear flow (Kelvin-Helmholtz type) instability. For stronger fields, a magnetic buoyancy instability is preferred. If this stably stratified shear layer lies below a convectively unstable region, these two regions can interact. Once again, when the imposed field is very weak, the dynamical effects of the magnetic field are negligible and the interactions between the shear layer and the convective layer are relatively minor. However, if the magnetic field is strong enough to favour magnetic buoyancy instabilities in the shear layer, extended magnetic flux concentrations form and rise into the convective layer. These magnetic structures have a highly disruptive effect upon the convective motions in the upper layer.Comment: 11 pages, 10 figures, accepted for publication in MNRA

Translational and Regulatory Challenges for Exon Skipping Therapies

Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and interpretation of appropriate clinical outcome measures. Others are inherent to the antisense oligonucleotide (AON)-mediated exon skipping approach, which employs small modified DNA or RNA molecules to manipulate the splicing process. This is a new approach and only limited information is available on long-term safety and toxicity for most AON chemistries. Furthermore, AONs often act in a mutation-specific manner, in which case multiple AONs have to be developed for a single disease. A workshop focusing on preclinical development, trial design, outcome measures, and different forms of marketing authorization was organized by the regulatory models and biochemical outcome measures working groups of Cooperation of Science and Technology Action: "Networking towards clinical application of antisense-mediated exon skipping for rare diseases." The workshop included participants from patient organizations, academia, and members of staff from the European Medicine Agency and Medicine Evaluation Board (the Netherlands). This statement article contains the key outcomes of this meeting.status: publishe

Fluctuation dynamo and turbulent induction at low magnetic Prandtl numbers

This paper is a detailed report on a programme of simulations used to settle a long-standing issue in the dynamo theory and demonstrate that the fluctuation dynamo exists in the limit of large magnetic Reynolds number Rm>>1 and small magnetic Prandtl number Pm<<1. The dependence of the critical Rm_c vs. the hydrodynamic Reynolds number Re is obtained for 1<Re<6700. In the limit Pm<<1, Rm_c is ~3 times larger than for Pm>1. The stability curve Rm_c(Re) (and, it is argued, the nature of the dynamo) is substantially different from the case of the simulations and liquid-metal experiments with a mean flow. It is not as yet possible to determine numerically whether the growth rate is ~Rm^{1/2} in the limit Re>>Rm>>1, as should be the case if the dynamo is driven by the inertial-range motions. The magnetic-energy spectrum in the low-Pm regime is qualitatively different from the Pm>1 case and appears to develop a negative spectral slope, although current resolutions are insufficient to determine its asymptotic form. At 1<Rm<Rm_c, the magnetic fluctuations induced via the tangling by turbulence of a weak mean field are investigated and the possibility of a k^{-1} spectrum above the resistive scale is examined. At low Rm<1, the induced fluctuations are well described by the quasistatic approximation; the k^{-11/3} spectrum is confirmed for the first time in direct numerical simulations.Comment: IoP latex, 27 pages, 25 figures, 3 tables. Accepted by New J. Physic

Poloxomer 188 Has a Deleterious Effect on Dystrophic Skeletal Muscle Function

Duchenne muscular dystrophy (DMD) is an X-linked, fatal muscle wasting disease for which there is currently no cure and limited palliative treatments. Poloxomer 188 (P188) is a tri-block copolymer that has been proposed as a potential treatment for cardiomyopathy in DMD patients. Despite the reported beneficial effects of P188 on dystrophic cardiac muscle function, the effects of P188 on dystrophic skeletal muscle function are relatively unknown. Mdx mice were injected intraperitoneally with 460 mg/kg or 30 mg/kg P188 dissolved in saline, or saline alone (control). The effect of single-dose and 2-week daily treatment was assessed using a muscle function test on the Tibialis Anterior (TA) muscle in situ in anaesthetised mice. The test comprises a warm up, measurement of the force-frequency relationship and a series of eccentric contractions with a 10% stretch that have previously been shown to cause a drop in maximum force in mdx mice. After 2 weeks of P188 treatment at either 30 or 460 mg/kg/day the drop in maximum force produced following eccentric contractions was significantly greater than that seen in saline treated control mice (P = 0.0001). Two week P188 treatment at either dose did not significantly change the force-frequency relationship or maximum isometric specific force produced by the TA muscle. In conclusion P188 treatment increases susceptibility to contraction-induced injury following eccentric contractions in dystrophic skeletal muscle and hence its suitability as a potential therapeutic for DMD should be reconsidered

Identification of novel pathogenic variants and features in patients with pseudohypoparathyroidism and acrodysostosis, subtypes of the newly classified inactivating PTH/PTHrP signaling disorders.

Albright hereditary osteodystrophy (AHO) is a complex disorder defined by the presence of a short adult stature relative to the height of an unaffected parent and brachydactyly type E, as well as a stocky build, round face, and ectopic calcifications. AHO and pseudohypoparathyroidism (PHP) have been used interchangeably in the past. The term PHP describes end-organ resistance to parathyroid hormone (PTH), occurring with or without the physical features of AHO. Conversely, pseudopseudohypoparathyroidism (PPHP) describes individuals with AHO features in the absence of PTH resistance. PHP and PPHP are etiologically linked and caused by genetic and/or epigenetic alterations in the guanine nucleotide-binding protein alpha-stimulating (Gs α) locus (GNAS) in chromosome 20q13. Another less-recognized group of skeletal dysplasias, termed acrodysostosis, partially overlap with skeletal, endocrine, and neurodevelopmental features of AHO/PHP and can be overlooked in clinical practice, causing confusion in the literature. Acrodysostosis is caused by defects in two genes, PRKAR1A and PDE4D, both encoding important components of the Gs α-cyclic adenosine monophosphate-protein kinase A signaling pathway. We describe the clinical course and genotype of two adult patients with overlapping AHO features who harbored novel pathogenic variants in GNAS (c.2273C > G, p.Pro758Arg, NM_080425.2) and PRKAR1A (c.803C > T, p.Ala268Val, NM_002734.4), respectively. We highlight the value of expert radiological opinion and molecular testing in establishing correct diagnoses and discuss phenotypic features of our patients, including the first description of subcutaneous ossification and spina bifida occulta in PRKAR1A-related acrodysostosis, in the context of the novel inactivating PTH/PTH related peptide signaling disorder classification system.Cambridge NIHR Biomedical Research Centr

Emotional impact of genetic trials in progressive paediatric disorders: a dose-ranging exon-skipping trial in Duchenne muscular dystrophy.

Gene-modifying trials offer hope for improvement in chronic paediatric disorders, but they may also lead to disappointment and have an adverse emotional effect on families. This study aimed to examine emotional impact on participants in a paediatric exon-skipping trial

A π-Extended Donor-Acceptor-Donor Triphenylene Twin linked via a Pyrazine-bridge

Beta-amino triphenylenes can be accessed via palladium catalyzed amination of the corresponding triflate using benzophe-none imine. Transformation of amine 6 to benzoyl amide 18 is also straightforward and its wide mesophase range demon-strates that the new linkage supports columnar liquid crystal formation. Amine 6 also undergoes clean aerobic oxidation to give a new twinned structure linked through an electron-poor pyrazine ring. The new discotic liquid crystal motif contains donor and acceptor fragments, and is more oval in shape rather than disk-like. It forms a wide range columnar mesophase. Absorption spectra are strong and broad; emission is also broad and occurs with a Stokes shift of ca. 0.7 eV, indicative of charge-transfer characte