White Matter Hyperintensities as a Risk Factor for Ischemic Stroke in Patients With Systemic Lupus Erythematosus.

Objective: The occurrence of ischemic stroke in patients with systemic lupus erythematosus (SLE) can cause extended periods of reduced daily activities. However, the risk factors for ischemic stroke in SLE patients are not fully elucidated. Herein, we examined the effect of white matter hyperintensities (WMH) on the occurrence of ischemic stroke in SLE patients. Methods: We analyzed the relationship between WMH burden and ischemic stroke using follow-up brain magnetic resonance imaging (MRI) data of 79 patients with SLE. Of these patients, 16 developed stroke during the observation period. WMH on MRI were classified into periventricular hyperintensities and deep white matter hyperintensities (DWMH), while the lesion extent was graded using the Fazekas scale. Results: Kaplan-Meier curves showed that ischemic stroke events were significantly associated with age at initial brain MRI of ≥40 years (p = 0.015) and history of anti-phospholipid syndrome (p = 0.030). Additionally, ischemic stroke events were significantly associated with a one grade deterioration of periventricular hyperintensities (p = 0.003) and a one grade deterioration of DWMH (p = 0.002). Multivariate analysis using the logistic regression model showed that a one grade deterioration of DWMH was an independent risk factor for ischemic stroke (hazard ratio, 6.0; 95% confidence interval, 1.3-27.4). Conclusions: Although several factors affect the occurrence of ischemic stroke, SLE patients show increased risk of ischemic stroke via development of DWMH. An observation of DWMH deterioration on follow-up brain MRI may be useful for assessing the risk of ischemic stroke in SLE patients.

Clinical features of Guillain-Barré syndrome patients with elevated serum creatine kinase levels.

BACKGROUND: It is not well defined whether Guillain-Barré syndrome (GBS) patients with elevated serum creatine kinase (CK) levels have characteristic clinical features and are related to the subgroups of GBS. METHODS: We retrospectively studied 51 consecutive patients with GBS, who visited our hospital, and compared clinical, laboratory and electrophysiological findings between patients with and without elevated CK levels. RESULTS: Of 51 patients, 14 patients (27%) showed an elevation of serum CK levels. When compared with patients with the normal CK levels, the ratios of male, antecedent infections, and anti-GM1 antibody positivity were significantly higher in patients with elevated CK levels. The ratios of hypoesthesia, cranial nerve involvement, and urinary retention were significantly less in patients with elevated CK levels. There were no significant differences in disability at peak between two groups. In the electrophysiological examination, sensory nerve abnormalities were not observed. Although some patients with elevated CK levels showed prolongation of distal motor latencies (DMLs) and increase of durations in the initial examination, development of the prolongation of DMLs and increase of durations was not observed in the follow-up examinations. The findings were consistent with acute motor axonal neuropathy (AMAN) with reversible conduction failure (RCF) but not acute inflammatory demyelinating polyneuropathy (AIDP). CONCLUSIONS: The results suggest that the GBS patients with elevated CK levels represent not a group of AIDP but a group of AMAN with axonal degeneration or RCF even though the initial electrophysiological examination shows AIDP pattern.

[An autopsy case of nivolumab-induced myasthenia gravis and myositis].

An 84-year-old woman developed blepharoptosis, diplopia, weakness of extremities, and dysphagia with elevation of serum CK levels after treatment with nivolumab against renal cell carcinoma. 3 Hz repetitive stimulation showed waning in the trapezius muscle, leading to the diagnosis of myasthenia gravis. Laboratory examination showed that anti-acetylcholine receptor antibody was negative. We performed IVIg and steroid therapy. However, her symptoms did not improve, and she died of respiratory failure, although serum CK levels ameliorated to the normal range. The results of autopsy showed atrophy of muscle fibers and massive infiltration of inflammatory cells in the endomysium of the iliopsoas muscle and diaphragm, indicating occurrence of myositis. Immunohistochemical analysis showed that CD8-positive T cells mainly infiltrates in the endomysium with a small number of CD4-potive T cells. Here, we report an autopsy case of nivolumab-induced myasthenia gravis and myositis.

Clinical characteristics of long-term survival with noninvasive ventilation and factors affecting the transition to invasive ventilation in amyotrophic lateral sclerosis.

INTRODUCTION: We evaluated post-noninvasive ventilation survival and factors for the transition to tracheostomy in amyotrophic lateral sclerosis (ALS). METHODS: We analyzed 197 patients using a prospectively collected database with 114 patients since 2000. RESULTS: Among 114 patients, 59 patients underwent noninvasive ventilation (NIV), which prolonged the total median survival time to 43 months compared with 32 months without treatment. The best post-NIV survival was associated with a lack of bulbar symptoms, higher measured pulmonary function, and a slower rate of progression at diagnosis. The transition rate from NIV to tracheostomy gradually decreased over the years. Patients using NIV for more than 6 months were more likely to refuse tracheostomy and to be women. DISCUSSION: This study confirmed a positive survival effect with NIV, which was less effective in patients with bulbar dysfunction. Additional studies are required to determine the best timing for using NIV with ALS in patients with bulbar dysfunction. Muscle Nerve 58:770-776 2018.

Mechanism of the decrease in catalytic activity of human cytochrome P450 2C9 polymorphic variants investigated by computational analysis.

Cytochrome P450 (CYP) is deeply involved in the metabolism of chemicals including pharmaceuticals. Therefore, polymorphisms of this enzyme have been widely studied to avoid unfavorable side effects of drugs in chemotherapy. In this work, we performed computational analysis of the mechanism of the decrease in enzymatic activity for three typical polymorphisms in CYP 2C9 species: *2, *3, and *5. Based on the equilibrated structure obtained by molecular dynamics simulation, the volume of the binding pocket and the fluctuation of amino residues responsible for substrate holding were compared between the wild type and the three variants. Further docking simulation was carried out to evaluate the appropriateness of the binding pocket to accommodate substrate chemicals. Every polymorphic variant was suggested to be inferior to the wild type in enzymatic ability from the structural viewpoint. F-G helices were obviously displaced outward in CYP2C9*2. Expansion of the binding pocket, especially the space near F' helix, was remarkable in CYP2C9*3. Disappearance of the hydrogen bond between K helix and ß4 loop was observed in CYP2C9*5. The reduction of catalytic activity of those variants can be explained from the deformation of the binding pocket and the consequent change in binding mode of substrate chemicals. The computational approach is effective for predicting the enzymatic activity of polymorphic variants of CYP. This prediction will be helpful for advanced drug design because calculations forecast unexpected change in drug efficacy for individuals.