Browsing by Author "Carr, Jonathan A"

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    Mechanisms underlying the development of weakness in idiopathic inflammatory myopathies: an in vitro single muscle fibre contractility study
    (2018) Henning, Franclo; Kohn, Tertius A; Carr, Jonathan A
    Introduction: Polymyositis (PM), dermatomyositis (DM) and necrotising autoimmune myopathy (NAM) form part of the spectrum of idiopathic inflammatory myopathies (IIMs). Although the pathogenic mechanisms are different, the unifying feature is that of weakness caused, in some way or another, by an inflammatory attack on muscle. The mechanism by which weakness develops is still unclear, but experimental animal data suggest that dysfunction of the contractile apparatus might contribute to muscle weakness in these conditions. This study investigated the contractile function of single muscle fibres from patients with IIMs in vitro. Methods: Muscle biopsies obtained from patients with IIMs and healthy controls were dissected and chemically permeabilised. Single muscle fibres were dissected out and subjected to contractility measurement based on standard protocols utilising a permeabilised single fibre system. Specific force (SF; maximum force normalised to cross-sectional area), was calculated for each fibre and compared between the two groups. In addition, maximum shortening velocity and power output were assessed in some of the fibres, and calcium sensitivity in the rest. The myosin heavy chain composition of each fibre was determined by means of gel electrophoresis. Results: A total of 178 fibres from IIM cases and 174 fibres from controls were studied. Specific (normalised) force was 23%, 24% and 29% lower in the IIM group for all fibre types combined, type I fibres, and type IIa fibres, respectively. Shortening velocity and maximum power output were significantly higher in the IIM group for both type I and IIa fibres, compared to controls, while calcium sensitivity was higher in type IIa fibres from IIM cases than controls. Discussion: The findings from this study suggest that weakness in IIMs may, at least in part, be caused by dysfunction of the contractile apparatus leading to impaired contractile force. The higher shortening velocity, power output and calcium sensitivity in fibres from IIM cases probably represents compensatory mechanisms. Although the mechanism by which contractile function is affected has not been investigated, animal studies suggest a role for TNF-α. The findings of this study provide a basis for further investigation into the mechanisms underlying weakness in IIMs.
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    Reliability and diagnostic performance of CT imaging criteria in the diagnosis of tuberculous meningitis
    (Public Library of Science, 2012) Botha, Hugo; Ackerman, Christelle; Candy, Sally; Carr, Jonathan A; Griffith-Richards, Stephanie; Bateman, Kathleen J
    Introduction Abnormalities on CT imaging may contribute to the diagnosis of tuberculous meningitis (TBM). Recently, an expert consensus case definition (CCD) and set of imaging criteria for diagnosing basal meningeal enhancement (BME) have been proposed. This study aimed to evaluate the sensitivity, specificity and reliability of these in a prospective cohort of adult meningitis patients. METHODS: Initial diagnoses were based on the CCD, classifying patients into: ‘Definite TBM’ (microbiological confirmation), ‘Probable TBM’ (diagnostic score ≥10), ‘Possible TBM’ (diagnostic score 6-9), ‘Not TBM’ (confirmation of an alternative diagnosis) or ‘Uncertain’ (diagnostic score of <6). CT images were evaluated independently on two occasions by four experienced reviewers. Intra-rater and inter-rater agreement were calculated using the kappa statistic. Sensitivities and specificities were calculated using both ‘Definite TBM’ and either ‘Definite TBM’ or ‘Probable TBM’ as gold standards. RESULTS: CT scan criteria for BME had good intra-rater agreement (κ range 0.35-0.78) and fair to moderate inter-rater agreement (κ range 0.20-0.52). Intra- and inter-rater agreement on the CCD components were good to fair (κ  =  ranges 0.47-0.81 and 0.21-0.63). Using ‘Definite TBM’ as a gold standard, the criteria for BME were very specific (61.5%-100%), but insensitive (5.9%-29.4%). Similarly, the imaging components of the CCD were highly specific (69.2-100%) but lacked sensitivity (0-56.7%). Similar values were found when using ‘Definite TBM’ or ‘Probable TBM’ as a gold standard. DISCUSSION: The fair to moderate inter-rater agreement and poor sensitivities of the criteria for BME suggest that little reliance should be placed in these features in isolation. While the presence of the CCD criteria of acute infarction or tuberculoma(s) appears useful as rule-in criteria, their absence is of little help in excluding TBM. The CCD and criteria for BME, as well as any new criteria, need to be standardized and validated in prospective cohort studies.