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  • A swollen calf.

    2 July 2018

  • In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype.

    3 July 2018

    The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1-0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes.

  • Biochemical investigation of human tumours in vivo with phosphorus-31 magnetic resonance spectroscopy.

    2 July 2018

    The bioenergetic state of 15 human tumours was examined with phosphorus-31 magnetic resonance spectroscopy. A striking diversity in metabolic patterns was observed, and significant differences from normal tissue were seen in all cases. A common feature was an elevation of intracellular pH, which may be related to an increase in Na+/H+ exchange during cell activation. It is unlikely that the patterns observed directly correlate with malignancy, but characterisation of the energetic state of a given tumour in a given physiological environment may help in the design and evaluation of interventions for that specific case.

  • EFNS guidelines on the diagnostic approach to pauci- or asymptomatic hyperCKemia.

    2 July 2018

    OBJECTIVE: To provide evidence-based guidelines to general neurologists for the assessment of patients with pauci- or asymptomatic hyperCKemia. BACKGROUND: Recent epidemiologic studies show that up to 20% of 'normal' individuals have an elevated creatine kinase activity in the serum (sCK). The possibility of a subclinical myopathy is often raised, and patients may be unnecessarily denied treatment with statins. SEARCH STRATEGY: Electronic databases including Medline, the Cochrane Library and the American Academy of Neurology were searched for existing guidelines. Articles dealing with series of patients investigated for asymptomatic/pauci-symptomatic hyperCKemia and articles dealing with myopathies that can present with asymptomatic hyperCKemia were identified and reviewed. RESULTS: The only guidelines found were those approved by the Italian Association of Myology Committee, and the only relevant articles identified describe class IV studies. RECOMMENDATIONS: HyperCKemia needs to be redefined as values beyond 1.5 times the upper limit of normal (which itself needs to be appropriately defined). Pauci- or asymptomatic hyperCKemia with no apparent medical explanation may be investigated with a muscle biopsy if one or more of the following are present; the sCK is >or=3x normal, the electromyogram is myopathic or the patient is <25 years of age. In addition, women with sCK<3 times normal may be offered DNA testing because of the possibility of carrying a dystrophin mutation.

  • Combinatorial glycoarray.

    3 July 2018

    Glycolipid-protein interactions are increasingly recognised as critical to numerous and diverse biological processes, including immune recognition, cell-cell signalling, pathogen adherence, and virulence factor binding. Previously, such carbohydrate-lectin interactions have been assessed in vitro largely by assaying protein binding against purified preparations of single glycolipids. Recent observations show that certain disease-associated autoantibodies and other lectins bind only to complexes formed by two different gangliosides. However, investigating such 1:1 glycolipid complexes can prove technically arduous. To address this problem, we have developed a semi-automated system for assaying lectin binding to large numbers of glycolipid complexes simultaneously. This employs an automated thin-layer chromatography sampler. Single glycolipids and their heterodimeric complexes are prepared in microvials. The autosampler is then used to print reproducible arrays of glycolipid complexes onto polyvinylidene difluoride membranes affixed to glass slides. A printing density of 300 antigen spots per slide is achievable. Following overnight drying, these arrays can then be probed with the lectin(s) of interest. Detection of binding is by way of a horseradish peroxidase-linked secondary antibody driving a chemiluminescent reaction rendered on radiographic film. Image analysis software can then be used to measure signal intensity for quantification.

  • Ganglioside antibodies and neuropathies.

    3 July 2018

    PURPOSE OF REVIEW: Continuing progress in the field of antiganglioside antibodies is expanding our comprehension of the pathogenesis of the inflammatory neuropathies. Recent studies have helped unravel all aspects of this process, addressing a range of subjects from the bacterial and host factors involved in antibody induction through to their pathogenic effects. RECENT FINDINGS: This review focuses on developments in the field over the past 18 months. Advances in our understanding of antibody induction, host risk factors, and pathogenic end effects are described systematically, and particular attention is given to the novel concept of ganglioside complexes. SUMMARY: The wealth of scientific data is now driving the design of novel, targeted therapies. This preclinical research is outlined and suggestions made as to how this might be translated into clinical practice.

  • Analysis of lectin binding to glycolipid complexes using combinatorial glycoarrays.

    3 July 2018

    Glycolipids are major components of the plasma membrane, interacting with themselves, other lipids, and proteins to form an array of heterogeneous domains with diverse biological properties. Considerable effort has been focused on identifying protein binding partners for glycolipids and the glycan specificity for these interactions, largely achieved through assessing interactions between proteins and homogenous, single species glycolipid preparations. This approach risks overlooking both the enhancing and attenuating roles of heterogeneous glycolipid complexes in modulating lectin binding. Here we report a simple method for assessing lectin-glycolipid interactions. An automatic thin-layer chromatography sampler is employed to create easily reproducible arrays of glycolipids and their heterodimeric complexes immobilized on a synthetic polyvinyl-difluoride membrane. This array can then be probed with much smaller quantities of reagents than would be required using existing techniques such as ELISA and thin-layer chromatography with immuno-overlay. Using this protocol, we have established that the binding of bacterial toxins, lectins, and antibodies can each be attenuated, enhanced, or unaffected in the presence of glycolipid complexes, as compared with individual, isolated glycolipids. These findings underpin the wide-ranging influence and importance of glycolipid-glycolipid cis interactions when the nature of protein-carbohydrate recognition events is being assessed.