Satisfactory results have not yet been obtained in therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome (APS). We therefore compared single antiplatelet therapy and a combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with APS. The subjects were 20 ischemic stroke patients with antiphospholipid antibody, 13 with primary antiphospholipid syndrome and 7 with SLE-related antiphospholipid syndrome. Diagnosis of APS was based on the 2006 Sydney criteria. Eligible patients were randomly assigned to either single antiplatelet therapy (aspirin 100 mg) or a combination of antiplatelet and anticoagulation therapy (target INR: 2.0-3.0; mean 2.4±0.3) for the secondary prevention of stroke according to a double-blind protocol. There was no significant difference between the two groups in age, gender, NIH Stroke Scale on admission, mRS at discharge, or rate of hypertension, diabetes mellitus, hyperlipidemia, or cardiac disease. We obtained Kaplan-Meier survival curves for each treatment. The primary outcome was the occurrence of stroke. The mean follow-up time was 3.9±2.0 years. The cumulative incidence of stroke in patients with single antiplatelet treatment was statistically significantly higher than that in patients receiving the combination of antiplatelet and anticoagulation therapy (log-rank test, p-value=0.026). The incidence of hemorrhagic complications was similar in the two groups. The recent APASS study did not show any difference in effectiveness for secondary prevention between single antiplatelet (aspirin) and single anticoagulant (warfarin) therapy. Our results indicate that combination therapy may be more effective in APS-related ischemic stroke.

Objective:To identify the gene mutation of tubular aggregate myopathy (TAM) and gain mechanistic insight into the pathogenesis of the disorder.Methods:We described a family affected by autosomal dominant TAM and performed exome and Sanger sequencing to identify mutations. We further analyzed the functional significance of the identified mutation by expression studies and intracellular Ca2+ measurements.Results:A 42-year-old man presented with slowly progressive muscle weakness and atrophy in all 4 limbs and the trunk. Muscle biopsy and microscopic examination revealed tubular aggregates in his skeletal muscle. Genetic analysis of this family identified a novel heterozygous mutation, c.1450_1451insGA (p.Ile484ArgfsX21), in stromal interaction molecule 1 (STIM1), a Ca2+ sensor in sarcoplasmic reticulum. We transfected cultured cells with STIM1 and demonstrated that the mutant STIM1 exhibited aggregation-like appearance in shrunk cytoplasm. Furthermore, we revealed that the intracellular Ca2+ influx is decreased by the mutant STIM1.Conclusions:The novel mutation p.Ile484ArgfsX21 is located in the cytoplasmic C-terminal inhibitory domain (CTID) of STIM1. However, all mutations reported so far in TAM reside in the luminal N-terminal EF hand region. The aggregation-like appearance of STIM1 and the decreased intracellular Ca2+ influx in cells transfected with CTID mutant are in sharp contrast to these previous reports. Taken together, these findings indicate that mutations of STIM1 cause TAM through the dysregulation of Ca2+ homeostasis.

Matriglycan [-GlcA-β1,3-Xyl-α1,3-]n serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. Like-acetylglucosaminyltransferase-1 (LARGE1) synthesizes and extends matriglycan on α-dystroglycan (α-DG) during skeletal muscle differentiation and regeneration; however, the mechanisms which regulate matriglycan elongation are unknown. Here, we show that Protein O-Mannose Kinase (POMK), which phosphorylates mannose of core M3 (GalNac-β1,3-GlcNac-β1,4-Man) preceding matriglycan synthesis, is required for LARGE1-mediated generation of full-length matriglycan on α-DG (~150 kDa). In the absence of Pomk gene expression in mouse skeletal muscle, LARGE1 synthesizes a very short matriglycan resulting in a ~90 kDa α-DG which binds laminin but cannot prevent eccentric contraction-induced force loss or muscle pathology. Solution NMR spectroscopy studies demonstrate that LARGE1 directly interacts with core M3 and binds preferentially to the phosphorylated form. Collectively, our study demonstrates that phosphorylation of core M3 by POMK enables LARGE1 to elongate matriglycan on α-DG, thereby preventing muscular dystrophy.

BackgroundJapan has four seasons and many chances of low atmospheric pressure or approaches of typhoon, therefore it has been empirically known that the fluctuation of weather induces migraine in people. Generally, its mechanism has been interpreted as follows: physical loading, attributed by atmospheric pressure to human bodies, compresses or dilates human blood vessels, which leads to abnormality in blood flow and induces migraine. We report our examination of the stage in which migraine tends to be induced focusing on the variation of atmospheric pressure.FindingsSubjects were 34 patients with migraine, who were treated in our hospital. The patients included 31 females and three males, whose mean age was 32 ± 6.7. 22 patients had migraine with aura and 12 patients had migraine without aura. All of patients with migraine maintained a headache diary to record atmospheric pressures when they developed a migraine. The standard atmospheric pressure was defined as 1013 hPa, and with this value as the criterion, we investigated slight fluctuations in the atmospheric pressure when they developed a migraine. It was found that the atmospheric pressure when the patients developed a migraine was within 1003–1007 hPa in the approach of low atmospheric pressure and that the patients developed a migraine when the atmospheric pressure decreased by 6–10 hPa, slightly less than the standard atmospheric pressure.ConclusionSmall decreases of 6–10 hPa relative to the standard atmospheric pressure of 1013 hPa induced migraine attacks most frequently in patients with migraine.