A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan

Cataloged from PDF version of article.The limb girdle muscular dystrophies are a heterogeneous group of conditions characterized by proximal muscle weakness and disease onset ranging from infancy to adulthood. We report here eight patients from seven unrelated families affected by a novel and relatively mild form of autosomal recessive limb girdle muscular dystrophy (LGMD2) with onset in the first decade of life and characterized by severe mental retardation but normal brain imaging. Immunocytochemical studies revealed a significant selective reduction of α-dystroglycan expression in the muscle biopsies. Linkage analysis excluded known loci for both limb girdle muscular dystrophy and congenital muscular dystrophies in the consanguineous families. We consider that this represents a novel form of muscular dystrophy with associated brain involvement. The biochemical studies suggest that it may belong to the growing number of muscular dystrophies with abnormal expression of α-dystroglycan. © 2003 Published by Elsevier B.V

Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding

Insights into surface chemistry down to nanoscale: an accessible colour hyperspectral imaging approach for scanning electron microscopy

Chemical imaging (CI) is the spatial identification of molecular chemical composition and is critical to characterising the (in-) homogeneity of functional material surfaces. Nanoscale CI on bulk functional material surfaces is a longstanding challenge in materials science and is addressed here. We demonstrate the feasibility of surface sensitive CI in the scanning electron microscope (SEM) using colour enriched secondary electron hyperspectral imaging (CSEHI). CSEHI is a new concept in the SEM, where secondary electron emissions in up to three energy ranges are assigned to RGB (red, green, blue) image colour channels. The energy ranges are applied to a hyperspectral image volume which is collected in as little as 50 s. The energy ranges can be defined manually or automatically. Manual application requires additional information from the user as first explained and demonstrated for a lithium metal anode (LMA) material, followed by manual CSEHI for a range of materials from art history to zoology. We introduce automated CSEHI, eliminating the need for additional user information, by finding energy ranges using a non-negative matrix factorization (NNMF) based method. Automated CSEHI is evaluated threefold: (1) benchmarking to manual CSEHI on LMA; (2) tracking controlled changes to LMA surfaces; (3) comparing automated CSEHI and manual CI results published in the past to reveal nanostructures in peacock feather and spider silk. Based on the evaluation, CSEHI is well placed to differentiate/track several lithium compounds formed through a solution reaction mechanism on a LMA surface (eg. lithium carbonate, lithium hydroxide and lithium nitride). CSEHI was used to provide insights into the surface chemical distribution on the surface of samples from art history (mineral phases) to zoology (di-sulphide bridge localisation) that are hidden from existing surface analysis techniques. Hence, the CSEHI approach has the potential to impact the way materials are analysed for scientific and industrial purposes

Evidence for 28 genetic disorders discovered by combining healthcare and research data

De novo mutations in protein-coding genes are a well-established cause of developmental disorders. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders

Th1 Disabled Function in Response to TLR4 Stimulation of Monocyte-Derived DC from Patients Chronically-Infected by Hepatitis C Virus

Background: Lack of protective antibodies and inefficient cytotoxic responses are characteristics of chronic hepatitis C infection. A defect in dendritic cell (DC) function has thus been suspected, but this remains a controversial issue. Methods and Findings: Here we show that monocyte-derived DC (MoDC) from chronically-infected patients can mature in response to TLR1/2, TLR2/6 or TLR3 ligands. In contrast, when stimulated with the TLR4 ligand LPS, MoDC from patients show a profound defect in inducing IFNc secretion by allogeneic T cells. This defect is not due to defective phenotypic maturation or to the presence of HCV-RNA in DC or monocytes but is correlated to reduced IL-12 secretion by DC. Restoration of DC ability to stimulate IFNc secretion can be obtained by blocking MEK activation in DC, indicating that MEK/ ERK pathway is involved in the Th1 defect of MoDC. Monocytes from HCV patients present increased spontaneous secretion of cytokines and chemokines, especially MIP-1b. Addition of MIP-1b on healthy monocytes during differentiation results in DC that have Th1 defect characteristic of MoDC from HCV patients, suggesting that MIP-1b secretion by HCV monocytes participates in the Th1 defect of DC. Conclusions: Our data indicate that monocytes from HCV patients are activated in vivo. This interferes with their differentiation into DC, leading to deficient TLR4 signaling in these cells that are enable to induce a Th1 response. Thi

Clusters of Nucleotide Substitutions and Insertion/Deletion Mutations Are Associated with Repeat Sequences

The authors propose that short repeat sequences may play an important role in causing the pervasive clustering of mutations across diverse genomes from prokaryotes to humans

Understanding the political motivations that shape Rwanda’s emergent developmental state

Twenty years after its horrific genocide, Rwanda has become a model for economic development. At the same time, its government has been criticized for its authoritarian tactics and use of violence. Missing from the often-polarized debate are the connections between these two perspectives. Synthesizing existing literature on Rwanda in light of a combined year of fieldwork, we argue that the GoR is using the developmental infrastructure to deepen state power and expand political control. We first identify the historical pressures that have motivated the Rwanda Patriotic Front (RPF) to re-imagine the political landscape. Sectarian unrest, political rivalry, wider regional insecurity, and aid withdrawal have all pressured the RPF to identify growth as strategic. However, the country’s political transformation extends beyond a prioritisation of growth and encompasses the reordering of the social and physical layout of the territory, the articulation of new ideologies and mindsets, and the provision of social services and surveillance infrastructure. Growth and social control go hand in hand. As such, the paper’s main contribution is to bring together the two sides of the Rwandan debate and place the country in a broader sociological literature about the parallel development of capitalist relations and transformations in state power

A Novel Role for the SMG-1 Kinase in Lifespan and Oxidative Stress Resistance in Caenorhabditis elegans

The PTEN tumour suppressor encodes a phosphatase, and its daf-18 orthologue in Caenorhabditis elegans negatively regulates the insulin/IGF-1 DAF-2 receptor pathway that influences lifespan in worms and other species. In order to identify new DAF-18 regulated pathways involved in aging, we initiated a candidate RNAi feeding screen for clones that lengthen lifespan. Here, we report that smg-1 inactivation increases average lifespan in a daf-18 dependent manner. Genetic analysis is consistent with SMG-1 acting at least in part in parallel to the canonical DAF-2 receptor pathway, but converging on the transcription factor DAF-16/FOXO. SMG-1 is a serine-threonine kinase which plays a conserved role in nonsense-mediated mRNA decay (NMD) in worms and mammals. In addition, human SMG-1 has also been implicated in the p53-mediated response to genotoxic stress. The effect of smg-1 inactivation on lifespan appears to be unrelated to its NMD function, but requires the p53 tumour suppressor orthologue cep-1. Furthermore, smg-1 inactivation confers a resistance to oxidative stress in a daf-18-, daf-16- and cep-1-dependent manner. We propose that the role of SMG-1 in lifespan regulation is at least partly dependent on its function in oxidative stress resistance. Taken together, our results unveil a novel role for SMG-1 in lifespan regulation

Diagnoses, problems and healthcare interventions amongst older people with an unscheduled hospital admission who have concurrent mental health problems: a prevalence study

Background Frail older people with mental health problems including delirium, dementia and depression are often admitted to general hospitals. However, hospital admission may cause distress, and can be associated with complications. Some commentators suggest that their healthcare needs could be better met elsewhere. Methods We studied consecutive patients aged 70 or older admitted for emergency medical or trauma care to an 1800 bed general hospital which provided sole emergency medical and trauma services for its local population. Patients were screened for mental health problems, and those screening positive were invited to take part. 250 participants were recruited and a sub-sample of 53 patients was assessed by a geriatrician for diagnoses, impairments and disabilities, healthcare interventions and outstanding needs. Results Median age was 86 years, median Mini-Mental State Examination score at admission was 16/30, and 45% had delirium. 19% lived in a care home prior to admission. All the patients were complex. A wide range of main admission diagnoses was recorded, and these were usually complicated by falls, immobility, pain, delirium, dehydration or incontinence. There was a median of six active diagnoses, and eight active problems. One quarter of problems was unexplained. A median of 13 interventions was recorded, and a median of a further four interventions suggested by the geriatrician. Those with more severe cognitive impairment had no less medical need. Conclusions This patient group, admitted to hospital in the United Kingdom, had numerous healthcare problems, and by implication, extensive healthcare needs. Patients with simpler conditions were not identified, but may have already been rapidly discharged or redirected to non-hospital services by the time assessments were made. To meet the needs of this group outside the hospital would need considerable investment in medical, nursing, therapy and diagnostic facilities. In the meantime, acute hospitals should adapt to deliver comprehensive geriatric assessment, and provide for their mental health needs