Collagen VI-Related Myopathies: Navigating through the Molecular Maze, Myomatrix and Clinical Manifestations on a Journey toward Clinical Trials

The congenital muscular dystrophies are a clinically and genetically heterogeneous group of disorders characterised by a congenital onset of weakness and hypotonia, typically associated with dystrophic-appearing muscle biopsy findings. The spectrum of clinical phenotypes associated with the congenital muscular dystrophy subgroup resulting from a deficiency of collagen VI in the extracellular matrix of muscle are collectively termed ‘collagen VI-related myopathies’ and include the early onset Ullrich congenital muscular dystrophy and the milder and later onset Bethlem myopathy as well as a phenotype of intermediate severity called ‘intermediate collagen VI-related myopathy.’ A major goal of this research has been to study the natural history of respiratory insufficiency in the collagen VI-related myopathies by analyzing longitudinal forced vital capacity data in a large, international cohort. A total of 486 forced vital capacity measurements obtained in 145 genetically and/or biochemically confirmed collagen VI-related myopathy patients from 10 neuromuscular centres [United States (2), United Kingdom (2), Australia (2), Italy (2), France (1) and Belgium (1)] were analysed and the resulting clarification of the phenotypic stratification of collagen VI-related myopathies reported. Another focus of this research has been the evaluation and the refining of the challenging diagnostic pathway for collagen VI-related myopathy patients, including evaluations of the diagnostic role of muscle histopathology, skin fibroblast immunocytochemistry and flow cytometry studies as well as muscle ultrasound and muscle magnetic resonance imaging studies. Finally, this research has studied the role of next generation genetic sequencing technologies including whole-genome and exome sequencing in the assessment of patients evaluated for collagen VI-related myopathies and related conditions

HTS step-edge Josephson junction terahertz harmonic mixer

© 2016 Federal Australian Crown copyright. A high-temperature superconducting (HTS) terahertz (THz) frequency down-converter or mixer based on a thin-film ring-slot antenna coupled YBa2Cu3O7-x (YBCO)/MgO step-edge Josephson junction is reported. The frequency down-conversion was achieved using higher order harmonics of an applied lower frequency (19-40 GHz) local oscillator signal in the Josephson junction mixing with a THz signal of over 600 GHz, producing a 1-3 GHz intermediate frequency signal. Up to 31st order of harmonic mixing was obtained and the mixer operated stably at temperatures up to 77 K. The design details of the antenna, HTS Josephson junction mixer, the matching and isolation circuits, and the DC and RF performance evaluation are described in this paper

Harmonic Mixing Using a HTS Step-Edge Josephson Junction at 0.6 THz Frequency

© 2002-2011 IEEE. A high-temperature superconducting (HTS) terahertz (THz) heterodyne mixer based on a thin-film antenna-coupled YBa 2Cu3O7-x step-edge Josephson junction is presented. The frequency down-conversion from 0.6 THz to an intermediate frequency (IF) of 2 GHz was achieved using high-order harmonic mixing of a local oscillator (LO), thus removing the need to use a second THz source as the LO pumping source. The DC and RF characteristics of the harmonic mixer as well as the relationship of the IF output power versus the harmonic number were experimentally studied and compared with simulated results. Most of our measurements were made at 40 K, but we also observed stable harmonic mixing at 77 K which we believe has not been reported previously in HTS junction mixers

Whole-genome sequencing and the clinician: a tale of two cities.

Clinicians are faced with unprecedented opportunities to identify the genetic aetiologies of hitherto molecularly uncharacterised conditions via the use of high-throughput sequencing. Access to genomic technology and resultant data is no longer limited to clinicians, geneticists and bioinformaticians, however; ongoing commercialisation gives patients themselves ever greater access to sequencing services. We report an increasingly common medical scenario by describing two neuromuscular patients-a mother and adult son-whose consumer access to whole-genome sequencing affected their diagnostic journey

Physical and mental health comorbidity is common in people with multiple sclerosis: nationally representative cross-sectional population database analysis

<b>Background</b> Comorbidity in Multiple Sclerosis (MS) is associated with worse health and higher mortality. This study aims to describe clinician recorded comorbidities in people with MS. <p></p> <b>Methods</b> 39 comorbidities in 3826 people with MS aged ≥25 years were compared against 1,268,859 controls. Results were analysed by age, gender, and socioeconomic status, with unadjusted and adjusted Odds Ratios (ORs) calculated using logistic regression. <p></p> <b>Results</b> People with MS were more likely to have one (OR 2.44; 95% CI 2.26-2.64), two (OR 1.49; 95% CI 1.38-1.62), three (OR 1.86; 95% CI 1.69-2.04), four or more (OR 1.61; 95% CI 1.47-1.77) non-MS chronic conditions than controls, and greater mental health comorbidity (OR 2.94; 95% CI 2.75-3.14), which increased as the number of physical comorbidities rose. Cardiovascular conditions, including atrial fibrillation (OR 0.49; 95% CI 0.36-0.67), chronic kidney disease (OR 0.51; 95% CI 0.40-0.65), heart failure (OR 0.62; 95% CI 0.45-0.85), coronary heart disease (OR 0.64; 95% CI 0.52-0.71), and hypertension (OR 0.65; 95% CI 0.59-0.72) were significantly less common in people with MS. <p></p> <b>Conclusion</b> People with MS have excess multiple chronic conditions, with associated increased mental health comorbidity. The low recorded cardiovascular comorbidity warrants further investigation

Associations between ACTN3 and OPPERA pain-related genes in malocclusion

We have investigated an orthognathic surgery population to determine how variation in masticatory muscle gene expression and genotype plays a key role in development of both jaw-deformation malocclusion and temporomandibular joint disorders (TMD). A gene of particular interest is ACTN3 since the common R577X polymorphism results in α-actinin-3 protein loss, reduced myofiber Z-disc structural integrity in skeletal muscle and decreased osteoblast/osteoclast activity in bone formation. Secondly, since the prevalence of TMD in this population is quite high (30%) we sought to determine if genes related to pain processes─previously identified in the Orofacial Pain: Prospective Evaluation and Risk Assessment Study (OPPERA) were differentially expressed

Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis

Peer reviewedPublisher PD

Development and Evaluation of a Palliative Medicine Curriculum for Third-Year Medical Students

Abstract Objective: To assess the impact, retention, and magnitude of effect of a required didactic and experiential palliative care curriculum on third-year medical students' knowledge, confidence, and concerns about end-of-life care, over time and in comparison to benchmark data from a national study of internal medicine residents and faculty. Design: Prospective study of third-year medical students prior to and immediately after course completion, with a follow-up assessment in the fourth year, and in comparison to benchmark data from a large national study. Setting: Internal Medicine Clerkship in a public accredited medical school. Participants: Five hundred ninety-three third-year medical students, from July 2002 to December 2007. Main outcome measures: Pre- and postinstruction performance on: knowledge, confidence (self-assessed competence), and concerns (attitudes) about end-of-life care measures, validated in a national study of internal medicine residents and faculty. Medical student's reflective written comments were qualitatively assessed. Intervention: Required 32-hour didactic and experiential curriculum, including home hospice visits and inpatient hospice care, with content drawn from the AMA-sponsored Education for Physicians on End-of-life Care (EPEC) Project. Results: Analysis of 487 paired t tests shows significant improvements, with 23% improvement in knowledge (F1,486=881, p<0.001), 56% improvement in self-reported competence (F1,486=2,804, p<0.001), and 29% decrease in self-reported concern (F1,486=208, p<0.001). Retesting medical students in the fourth year showed a further 5% increase in confidence (p<0.0002), 13% increase in allaying concerns (p<0.0001), but a 6% drop in knowledge. The curriculum's effect size on M3 students' knowledge (0.56) exceeded that of a national cross-sectional study comparing residents at progressive training levels (0.18) Themes identified in students' reflective comments included perceived relevance, humanism, and effectiveness of methods used to teach and assess palliative care education. Conclusions: We conclude that required structured didactic and experiential palliative care during the clinical clerkship year of medical student education shows significant and largely sustained effects indicating students are better prepared than a national sample of residents and attending physicians.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98455/1/jpm%2E2010%2E0502.pd

Markedly Divergent Tree Assemblage Responses to Tropical Forest Loss and Fragmentation across a Strong Seasonality Gradient

We examine the effects of forest fragmentation on the structure and composition of tree assemblages within three seasonal and aseasonal forest types of southern Brazil, including evergreen, Araucaria, and deciduous forests. We sampled three southernmost Atlantic Forest landscapes, including the largest continuous forest protected areas within each forest type. Tree assemblages in each forest type were sampled within 10 plots of 0.1 ha in both continuous forests and 10 adjacent forest fragments. All trees within each plot were assigned to trait categories describing their regeneration strategy, vertical stratification, seed-dispersal mode, seed size, and wood density. We detected differences among both forest types and landscape contexts in terms of overall tree species richness, and the density and species richness of different functional groups in terms of regeneration strategy, seed dispersal mode and woody density. Overall, evergreen forest fragments exhibited the largest deviations from continuous forest plots in assemblage structure. Evergreen, Araucaria and deciduous forests diverge in the functional composition of tree floras, particularly in relation to regeneration strategy and stress tolerance. By supporting a more diversified light-demanding and stress-tolerant flora with reduced richness and abundance of shade-tolerant, old-growth species, both deciduous and Araucaria forest tree assemblages are more intrinsically resilient to contemporary human-disturbances, including fragmentation-induced edge effects, in terms of species erosion and functional shifts. We suggest that these intrinsic differences in the direction and magnitude of responses to changes in landscape structure between forest types should guide a wide range of conservation strategies in restoring fragmented tropical forest landscapes worldwide

Developing Global Maps of the Dominant Anopheles Vectors of Human Malaria

Simon Hay and colleagues describe how the Malaria Atlas Project has collated anopheline occurrence data to map the geographic distributions of the dominant mosquito vectors of human malaria