Exercise capacity in relation to autoantibodies in systemic sclerosis patients

Autoantibodies have been detected in systemic sclerosis patients, and typical clinical features regarding organ involvement by each autoantibody have been reported. To reveal differences in exercise intolerance in patients with either anti-topoisomerase-I or anti-centromere antibodies, 53 systemic sclerosis patients were investigated retrospectively. A 6-min walking distance showed no significant differences (P = 0.090) between autoantibodies, while exercise-induced hypoxia during the 6-min walking test was significant in subjects with the anti-topoisomerase-I antibody (P = 0.033). The percent predicted of vital capacity, the diffusion capacity of the lung for carbon monoxide, and the modified Rodnan skin score were affected more in subjects with the anti-topoisomerase-I antibody than the anti-centromere antibody. The main parameter affecting the 6-min walking distance was the percent predicted of vital capacity for each autoantibody, and there was a significant positive relationship for all subjects (R 2 = 0.30, P < 0.0001). Exercise-induced hypoxia was also shown in the more affected subjects in the percent predicted of vital capacity and the diffusion capacity of the lung for carbon monoxide. Lung parameters were suggested to be more important factors determining exercise intolerance and induced hypoxia than detected autoantibodies. © 2012 The Author(s)

Predictors of exercise-induced oxygen desaturation in systemic sclerosis patients with interstitial lung disease

金沢大学医薬保健研究域保健学系Background: The diffusion capacity of the lung for carbon monoxide (DLCO) is a good marker of disease severity in patients with idiopathic interstitial pneumonia, and is associated with oxygen saturation; however, little is known about DLCO in systemic sclerosis patients with interstitial lung disease. We studied potential predictors of exercise-induced oxygen desaturation in patients with systemic sclerosis. Methods: Data were collected prospectively from 80 of 110 consecutive systemic sclerosis patients with normal oxygen saturation (> 95%) at rest, who could perform the 6-min walk test without physical discomfort, including leg pain. Pulmonary function tests and echocardiography were collected from all subjects. Results: Thirty subjects showed a ≥ 4% decline in oxygen saturation during the 6-min walk test (desaturation group). The other subjects were assigned to the normoxic group. The percent-of-predicted values for FVC, FEV1, total lung capacity, DLCO, and DLCO/alveolar volume were lower, and FEV1/FVC was higher, in the desaturation group. Logistic regression analysis showed the percent-of-predicted DLCO as a highly accurate predictor of exercise-induced oxygen desaturation: the area under the receiver operating characteristic curve was 0.92 (cutoff point 56.3%, sensitivity 0.83, specificity 0.86). Five subjects over the cutoff point of the percent-of-predicted DLCO in the desaturation group could not be distinguished from the normoxic subjects with the lung-volume measurements or right-ventricular systolic pressure. Conclusions: The factor underlying exercise-induced oxygen desaturation appeared to be reduced percent-of-predicted DLCO, which was useful as a predictor in over 80% of the subjects. © 2014 Daedalus Enterprises

Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease

Background:Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ), which is produced from amyloid precursor protein by β- and γ-secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease. Methodology/Principal Findings:We differentiated human iPS (hiPS) cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, β-secretase, and γ-secretase components, and were capable of secreting Aβ into the conditioned media. Aβ production was inhibited by β-secretase inhibitor, γ-secretase inhibitor (GSI), and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (Aβ surge) and drastic decline of Aβ production. Conclusions/Significance:These results indicate that the hiPS cell-derived neuronal cells express functional β- and γ-secretases involved in Aβ production; however, anti-Aβ drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation

Oropharyngeal dysphagia in dermatomyositis: Associations with clinical and laboratory features including autoantibodies

金沢大学医薬保健研究域保健学系Objective: Dysphagia develops with low frequency in patients with dermatomyositis. Our objective was to determine the clinical and laboratory features that can estimate the development of dysphagia in dermatomyositis. Methods: This study included 92 Japanese patients with adult-onset dermatomyositis. The associations between dysphagia and clinical and laboratory features including disease-specific autoantibodies determined by immunoprecipitation assays were analyzed. Results: Videofluoroscopy swallow study (VFSS) was performed for all patients with clinical dysphagia (n = 13, 14.1%) but not for patients without clinical dysphagia. Typical findings of dysphagia (pharyngeal pooling, n = 11 and/or nasal regurgitation, n = 4) was detected by VFSS in all patients with clinical dysphagia. Eleven patients with dysphagia (84.6%) had anti-transcription intermediary factor 1γ (TIF-1γ) antibody. By univariate analysis, the average age and the male to female ratio, internal malignancy, and anti-TIF-1γ antibody were significantly higher and the frequency of interstitial lung diseases and manual muscle testing (MMT) scores of sternomastoid and dertoid muscles were significantly lower in patients with dysphagia than in patients without dysphagia. Among patients with anti-TIF-1γ antibody, the mean age, the ratios of male to female and internal malignancy were significantly higher and mean MMT scores of sternomastoid muscle were significantly lower in patients with dysphagia compared with patients without dysphagia. By multivariable analysis, the risk of dysphagia was strongly associated with the existence of internal malignancy and ant-TIF-1γ antibody and was also associated with reduced scores of manual muscle test of sternomastoid muscle. Dysphagia was markedly improved after the treatment against myositis in all 13 patients. Conclusion: These findings indicate that dysphagia can develop frequently in patients with internal malignancy, anti-TIF-1γ antibody, or severe muscle weakness of sternomastoid muscle. © 2016 Mugii et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited