Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy

OBJECTIVES: To assess skeletal muscle weakness and progression as well as the cardiopulmonary involvement in oculopharyngeal muscular dystrophy (OPMD). MATERIALS AND METHODS: Cross-sectional study including symptomatic patients with genetically confirmed OPMD. Patients were assessed by medical history, ptosis, ophthalmoplegia, facial and limb strength, and swallowing capability. Cardiopulmonary function was evaluated using forced expiratory capacity in 1 s (FEV1), electrocardiogram (ECG), Holter monitoring, and echocardiography. RESULTS: We included 13 symptomatic patients (six males, mean age; 64 years (41-80) from 8 families. Ptosis was the first symptom in 8/13 patients followed by limb weakness in the remaining 5 patients Dysphagia was never the presenting symptom. At the time of examination, all affected patients had ptosis or had previously been operated for ptosis, while ophthalmoplegia was found in 9 patients. Dysphagia, tested by cold-water swallowing test, was abnormal in 9 patients (17-116 s, ref <8 s). Six patients could not climb stairs of whom two were wheelchair bound and one used a rollator. Six patients had reduced FEV1 (range 23%-59%). No cardiac involvement was identified. CONCLUSIONS: Limiting limb weakness is common in OPMD and can even be the presenting symptom of the disease. In contrast, dysphagia was not the initial symptom in any of our patients, although it was obligatory for diagnosing OPMD before genetic testing became available. Mild respiratory dysfunction, but no cardiac involvement, was detected

Efficacy and safety of rozanolixizumab in moderate to severe generalized myasthenia gravis : a phase 2 randomized control trial

OBJECTIVE: To explore the clinical efficacy and safety of subcutaneous (SC) rozanolixizumab, an anti-neonatal Fc receptor humanized monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: In this phase 2a, randomized, double-blind, placebo-controlled, 2-period, multicenter trial (NCT03052751), patients were randomized (1:1) in period 1 (days 1-29) to 3 once-weekly (Q1W) SC infusions of rozanolixizumab 7 mg/kg or placebo. In period 2 (days 29-43), patients were re-randomized to either rozanolixizumab 7 mg/kg or 4 mg/kg (3 Q1W SC infusions), followed by an observation period (days 44-99). Primary endpoint was change from baseline to day 29 in Quantitative Myasthenia Gravis (QMG) score. Secondary endpoints were change from baseline to day 29 in MG-Activities of Daily Living (MG-ADL) and MG-Composite (MGC) scores and safety. RESULTS: Forty-three patients were randomized (rozanolixizumab 21, placebo 22 [period 1]). Least squares (LS) mean change from baseline to day 29 for rozanolixizumab vs placebo was as follows: QMG (LS mean -1.8 vs -1.2, difference -0.7, 95% upper confidence limit [UCL] 0.8; p = 0.221; not statistically significant), MG-ADL (LS mean -1.8 vs -0.4, difference -1.4, 95% UCL -0.4), and MGC (LS mean -3.1 vs -1.2, difference -1.8, 95% UCL 0.4) scores. Efficacy measures continued to improve with rozanolixizumab 7 mg/kg in period 2. The most common adverse event in period 1 was headache (rozanolixizumab 57%, placebo 14%). CONCLUSION: Whereas change from baseline in QMG was not statistically significant, the data overall suggest rozanolixizumab may provide clinical benefit in patients with gMG and was generally well tolerated. Phase 3 evaluation is ongoing (NCT03971422). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, rozanolixizumab is well-tolerated, but did not significantly improve QMG score

A complementary method for detecting qi vacuity

<p>Abstract</p> <p>Background</p> <p>Qi vacuity (QV) is defined by traditional Chinese medicine as a loss of energy in the human body. An objective method for detecting QV was not available until recently, however. The automatic reflective diagnosis system (ARDK) is a device that detects human bioenergy through measuring skin conductance at 24 special acupoints on the wrists and ankles.</p> <p>Methods</p> <p>This study used the ARDK to measure skin conductance on 193 patients with QV and 89 sex- and age-matched healthy controls to investigate whether the device is useful in detecting QV. Patients diagnosed with QV have three or more of five symptoms or signs; symptom severity is measured on 5 levels and scored from 0 to 4 points. We compared the difference in the mean ARDK values between patients with QV and healthy controls, and further used linear regression analysis to investigate the correlation between the mean ARDK values and QV scores in patients diagnosed with QV.</p> <p>Results</p> <p>The mean ARDK values in patients with QV (30.2 ± 16.8 μA) are significantly lower than those of healthy controls (37.7 ± 10.8 μA; <it>P </it>< 0.001). A negative correlation was found between the mean ARDK values and QV scores (<it>r </it>coefficient = -0.61; <it>P </it>< 0.001). After adjusting for age, the decreased mean ARDK values in patients with QV showed a significant correlation with the QV scores.</p> <p>Conclusion</p> <p>These results suggest that the mean ARDK values reflect the severity of QV in patients diagnosed with the disorder. They also suggest that the bioenergy level of the human body can be measured by skin conductance. ARDK is a safe and effective complementary method for detecting and diagnosing QV.</p

Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy

Nemaline myopathy (NM) is a skeletal muscle disorder caused by mutations in genes that are generally involved in muscle contraction, in particular those related to the structure and/or regulation of the thin filament. Many pathogenic aspects of this disease remain largely unclear. Here, we report novel pathological defects in skeletal muscle fibres of mouse models and patients with NM: irregular spacing and morphology of nuclei; disrupted nuclear envelope; altered chromatin arrangement; and disorganisation of the cortical cytoskeleton. Impairments in contractility are the primary cause of these nuclear defects. We also establish the role of microtubule organisation in determining nuclear morphology, a phenomenon which is likely to contribute to nuclear alterations in this disease. Our results overlap with findings in diseases caused directly by mutations in nuclear envelope or cytoskeletal proteins. Given the important role of nuclear shape and envelope in regulating gene expression, and the cytoskeleton in maintaining muscle fibre integrity, our findings are likely to explain some of the hallmarks of NM, including contractile filament disarray, altered mechanical properties and broad transcriptional alterations

TOPCAT and Gaia

TOPCAT, and its command line counterpart STILTS, are powerful tools for working with large source catalogues. ESA's Gaia mission, most recently with its second data release, is producing source catalogues of unprecedented quality for more than a billion sources. This paper presents some examples of how TOPCAT and STILTS can be used for analysis of Gaia data.Comment: 4 pages, 2 figures; to appear in the Proceedings of ADASS 2018, Astronomical Society of the Pacific (ASP) Conference Serie

Long-term safety and efficacy of eculizumab in generalized myasthenia gravis

Introduction: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. Methods: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. Results: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001). Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 201

Age-Associated Salivary MicroRNA Biomarkers for Oculopharyngeal Muscular Dystrophy

Small non-coding microRNAs (miRNAs) are involved in the regulation of mRNA stability. Their features, including high stability and secretion to biofluids, make them attractive as potential biomarkers for diverse pathologies. This is the first study reporting miRNA as potential biomarkers for oculopharyngeal muscular dystrophy (OPMD), an adult-onset myopathy. We hypothesized that miRNA that is differentially expressed in affected muscles from OPMD patients is secreted to biofluids and those miRNAs could be used as biomarkers for OPMD. We first identified candidate miRNAs from OPMD-affected muscles and from muscles from an OPMD mouse model using RNA sequencing. We then compared the OPMD-deregulated miRNAs to the literature and, subsequently, we selected a few candidates for expression studies in serum and saliva biofluids using qRT-PCR. We identified 126 miRNAs OPMD-deregulated in human muscles, but 36 deregulated miRNAs in mice only (pFDR < 0.05). Only 15 OPMD-deregulated miRNAs overlapped between the in humans and mouse studies. The majority of the OPMD-deregulated miRNAs showed opposite deregulation direction compared with known muscular dystrophies miRNAs (myoMirs), which are associated. In contrast, similar dysregulation direction was found for 13 miRNAs that are common between OPMD and aging muscles. A significant age-association (p < 0.05) was found for 17 OPMD-deregulated miRNAs (13.4%), whereas in controls, only six miRNAs (1.4%) showed a significant age-association, suggesting that miRNA expression in OPMD is highly age-associated. miRNA expression in biofluids revealed that OPMD-associated deregulation in saliva was similar to that in muscles, but not in serum. The same as in muscle, miRNA expression levels in saliva were also found to be associated with age (p < 0.05). Moreover, the majority of OPMD-miRNAs were found to be associated with dysphagia as an initial symptom. We suggest that levels of specific miRNAs in saliva can mark muscle degeneration in general and dysphagia in OPMDFrench Muscular Dystrophy Association (AFM-Téléthon). Research grant to the eOPMD (European OPMD consortium, V.R. and B.G.M.v.E.)