研究者業績

桑原 聡

クワバラ サトシ  (Satoshi Kuwabara)

基本情報

所属
千葉大学 大学院医学研究院脳神経内科学 教授 (教授)
学位
医学博士(1993年3月 千葉大学)

J-GLOBAL ID
200901033727459280
researchmap会員ID
1000200574

論文

 964
  • Antonino Uncini, Nortina Shahrizaila, Satoshi Kuwabara
    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 88(3) 266-271 2017年3月  査読有り
    In 2016, we have seen a rapid emergence of Zika virus-associated Guillain-Barre syndrome (GBS) since its first description in a French-Polynesian patient in 2014. Current evidence estimates the incidence of GBS at 24 cases per 100 000 persons infected by Zika virus. This will result in a sharp rise in the number of GBS cases worldwide with the anticipated global spread of Zika virus. A better understanding of the pathogenesis of Zika-associated GBS is crucial to prepare us for the current epidemic. In this review, we evaluate the existing literature on GBS in association with Zika and other flavivirus to better define its clinical subtypes and electrophysiological characteristics, demonstrating a demyelinating subtype of GBS in most cases. We also recommend measures that will help reduce the gaps in knowledge that currently exist.
  • Tomoya Muto, Chikako Ohwada, Koji Takaishi, Yusuke Isshiki, Yuhei Nagao, Nagisa Hasegawa, Chika Kawajiri-Manako, Emi Togasaki, Ryoh Shimizu, Shokichi Tsukamoto, Shio Sakai, Yusuke Takeda, Naoya Mimura, Masahiro Takeuchi, Emiko Sakaida, Sonoko Misawa, Naomi Shimizu, Tohru Iseki, Satoshi Kuwabara, Chiaki Nakaseko
    BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 23(2) 361-363 2017年2月  査読有り
    Although autologous stem cell transplantation can achieve excellent responses in patients with POEMS syndrome, the optimal regimen for peripheral blood stem cell (PBSC) collection is still controversial. We retrospectively investigated the safety and efficacy of 41 PBSC collecting procedures in 37 patients with POEMS syndrome. PBSC mobilization was performed using cyclophosphamide + granulocyte colony-stimulating factor (G-CSF) (CG, n = 14) or G-CSF alone (G, n = 27). Twelve (85.7%) patients in the CG group and all (100%) patients in the G group received induction chemotherapy before PBSC collection. The proportions of good mobilizers >= 2.0 x 10(6) CD34(+) cells/kg) were comparable between the 2 groups (CG versus G: 78.6% versus 70.4%, P=.71). Two (14.3%) patients in the CG group developed severe capillary leak symptoms during the PBSC mobilization period, whereas no patient in the G group experienced severe adverse events. Appropriate induction therapies followed by the G-CSF monotherapy compose an optimal strategy for PBSC collection. (C) 2017 American Society for Blood and Marrow Transplantation.
  • T. Kanai, A. Uzawa, N. Kawaguchi, K. Himuro, F. Oda, Y. Ozawa, S. Kuwabara
    EUROPEAN JOURNAL OF NEUROLOGY 24(2) 270-275 2017年2月  査読有り
    Background and purposeA single, oral dose of 3 mg/day tacrolimus, approved for myasthenia gravis (MG) treatment in Japan, was shown to reduce steroid dose and anti-acetylcholine receptor (AChR) antibody titers as well as to improve MG symptoms. However, no studies have investigated the association between tacrolimus concentration and its clinical efficacy in MG. In this study, we aimed to determine the optimal tacrolimus concentration for MG treatment. MethodsThe trough tacrolimus concentration in 51 patients with MG (positive for anti-AChR antibody, n = 48; negative for anti-AChR and anti-muscle-specific tyrosine kinase antibodies, n = 3) who received 3 mg/day tacrolimus for more than 1 year was measured using a chemiluminescent enzyme immunoassay. The clinical characteristics of patients with MG as well as the dose of prednisolone used before and after tacrolimus treatment were evaluated retrospectively. ResultsThe median trough tacrolimus concentration was 5.4 (range, 2.9-7.6) ng/mL, which was correlated with minimal manifestation or better status' (P = 0.0190, r = 0.3273) and the reduction in anti-AChR antibody 1 year after tacrolimus initiation (P = 0.0170, r = 0.3465). When the cut-off value for tacrolimus was defined as 4.8 ng/mL using a receiver operating characteristic curve, patients with adequate tacrolimus concentration (4.8 ng/mL) showed more reduction in anti-AChR antibody titers and more improvement in MG-related activities in daily life scores. More patients with adequate tacrolimus concentration achieved minimal manifestation or better status' compared with those with low tacrolimus concentration. ConclusionsAn adequate tacrolimus concentration is required for better MG prognosis.
  • Masayuki Homma, Akiyuki Uzawa, Hitoshi Tanaka, Naoki Kawaguchi, Tetsuya Kanai, Kenji Nakajima, Masakuni Narita, Yukio Hara, Hideya Maruyama, Yasumasa Ogawa, Keiichi Himuro, Satoshi Kuwabara
    NEUROTHERAPEUTICS 14(1) 191-198 2017年1月  査読有り
    Most patients with myasthenia gravis (MG) have elevated levels of autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction, which leads to muscle weakness. We developed a fusion protein, AChR-Fc, as a novel therapeutic biomolecule for patients with MG and examined its efficacy. AChR-Fc was expressed by Chinese hamster ovary cells and purified. We examined the neutralizing activity and cellular cytotoxicity of AChR-Fc using anti-AChR antibody-producing hybridoma cells and serum samples from 16 patients with MG. The effects of AChR-Fc in vivo were also examined using rat MG models. AChR-Fc bound to anti-AChR antibodies and exhibited cytotoxicity against patient-derived antibody-producing B cells. Additionally, a dose-dependent improvement in the clinical signs of disease was observed in a rat MG model. AChR-Fc can diminish signs of MG by neutralizing anti-AChR antibodies and enhancing cytotoxicity against autoantibody-producing B cells. Thus, AChR-Fc can be a novel therapeutic biomolecule for patients with MG.
  • Satoshi Kuwabara, Yukari Sekiguchi, Sonoko Misawa
    CLINICAL NEUROPHYSIOLOGY 128(1) 215-219 2017年1月  
    Fisher syndrome (FS), a variant of Guillain-Barre syndrome (GBS), is characterized by the clinical triad of ophthalmoplegia, ataxia, and areflexia. The lesion sites for these unique clinical features include the oculomotor nerves and group 1a neurons in the dorsal root ganglion, and the presence of FS is determined by the expression of ganglioside GQ1b in the human nervous system. Neurophysiological findings suggest that ataxia and areflexia are due to an impaired proprioceptive afferent system. Typically, the soleus H-reflex is absent and a body-sway analysis using posturography shows a 1-Hz peak, which indicates proprioception dysfunction. Sensory nerve action potentials and somatosensory-evoked potentials are abnormal in approximately 30% of FS patients, indicating the occasional involvement of cutaneous (group 2) afferents. During the disease course, approximately 15% of FS patients suffer an overlap of axonal GBS with nerve conduction abnormalities that reflect axonal dysfunction. This review summarizes electro-physiological abnormalities and their clinical significance in FS. (C) 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
  • Beppu M, Sawai S, Misawa S, Mori M, Ito S, Sogawa K, Nishimura M, Matsushita K, Nomura F, Kuwabara S
    Journal of neuroimmunology 302 20-22 2017年1月  査読有り
  • Shimada H, Kitamura S, Shinotoh H, Endo H, Niwa F, Hirano S, Kimura Y, Zhang MR, Kuwabara S, Suhara T, Higuchi M
    Alzheimer's & dementia (Amsterdam, Netherlands) 6 11-20 2017年  査読有り
  • Masuda H, Mori M, Iwai Y, Kuwabara S
    Internal medicine (Tokyo, Japan) 56(7) 879-880 2017年  査読有り
  • Atsuhiko Sugiyama, Makoto Kobayashi, Ayaka Daizo, Miyako Suzuki, Hirotoshi Kawashima, Shin-ichiro Kagami, Hiroaki Tanaka, Yoshio Suzuki, Takashi Matsunaga, Satoshi Kuwabara
    INTERNAL MEDICINE 56(13) 1715-1718 2017年  査読有り
    An 87-year-old woman presented with a 3-month history of fever, edema of the lower legs, and gait disturbance. A laboratory examination revealed high serum levels of myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA). Although microscopic polyangiitis was initially suspected and treated, the patient subsequently developed transient hemiparesis and disturbed consciousness. Brain magnetic resonance imaging/angiography revealed infarct-like lesions, pachymeningeal involvement, and diffuse cerebral vasoconstriction. A random skin biopsy confirmed the histological diagnosis of intravascular lymphoma. Diffuse cerebral vasoconstriction and a high serum MPO-ANCA level have rarely been reported in patients with intravascular lymphoma. Endothelial damage due to immune-mediated mechanisms, tumor derived factors, or the direct interaction of lymphoma cells with endothelial cells may commonly predispose patients to both cerebral vasoconstriction and the development of ANCAs.
  • Marie Murakawa, Kazumoto Shibuya, Yukari Sekiguchi, Satoshi Kuwabara
    INTERNAL MEDICINE 56(13) 1747-1748 2017年  査読有り
  • Akiyuki Hiraga, Satoshi Kuwabara
    INTERNAL MEDICINE 56(21) 2865-2869 2017年  査読有り
    Objective The differences in the frequency and clinical features of malignant syndrome (MS) and serotonin syndrome (SS) in same population have only rarely been reported. To report the frequency and clinical features of MS and SS in a general hospital setting. Methods The clinical and laboratory features of patients with MS and those with SS, who were consecutively admitted to Chiba Rosai Hospital, during the past 4.5 years were reviewed. Results Of the 2005 patients admitted, MS was observed in 16 patients (0.8%) and SS in 2 (0.1%). In the 16 patients with MS, the underlying disorder included depression (n = 5), and dementia or parkinsonism (n = 11). The underlying etiology of the 2 patients with SS was depression. In 5 patients, MS was difficult to distinguish from SS because of overlapping symptoms and signs and/or treatments with both neuroleptic and serotoninergic drugs. Of the 16 patients with MS, 1 died, 1 remained wheelchair-bound, 4 were able to walk with assistance, and 10 regained their ability to ambulate independently. The 2 patients with SS recovered after cyproheptadine therapy and were discharged on foot. Conclusion MS occurs more frequently than SS in the general hospital setting. Underlying aetiologies in patients with MS were more common due to dementia or parkinsonism than in patients with psychiatric disorders. The differential diagnosis of MS and SS is often difficult and the diagnostic sensitivities largely differ for each of the diagnostic criteria. As a result, the establishment of new diagnostic criteria that specifically focus on distinguishing MS from SS is therefore required.
  • Tatsuya Yamamoto, Masato Asahina, Yoshitaka Yamanaka, Tomoyuki Uchiyama, Shigeki Hirano, Miki Fuse, Yasuko Koga, Ryuji Sakakibara, Satoshi Kuwabara
    PLOS ONE 12(1) 2017年1月  査読有り
    Objective To determine the ability of sphincter electromyography (EMG) and post-void residual urine volume (PVR) during a free-flow study and a pressure-flow study (PFS) for distinguishing multiple system atrophy (MSA) from Parkinson's disease (PD). Methods We retrospectively reviewed 241 case records; both urodynamic study and sphincter EMG were performed in patients with MSA (n = 147) and PD (n = 94). Results There was a statistically significant difference (p < 0.01) in the mean PVR during the free-flow study (113.1 +/- 7.5 mL in MSA and 40.4 +/- 3.8 mL in PD), mean PVR during PFS (230.1 +/- 12.6 mL in MSA and 71.7 +/- 6.6 mL in PD), and mean duration of MUP for sphincter EMG (9.3 +/- 0.1 ms in MSA and 7.7 +/- 0.1 ms in PD). The area under the curve used for differentiating MSA from PD was 0.79 and 0.73 for PVR during PFS and the free-flow study, respectively. There was a mean duration of 0.69 ms for the sphincter EMG. Conclusions The present results suggested that PVR was more appropriate than sphincter EMG for differentiating MSA from PD.
  • Yasufumi Hayano, Keiko Takasu, Yoshihisa Koyama, Moe Yamada, Koichi Ogawa, Kazuhisa Minami, Toshiyuki Asaki, Kazuhiro Kitada, Satoshi Kuwabara, Toshihide Yamashita
    JOURNAL OF EXPERIMENTAL MEDICINE 213(13) 2949-2966 2016年12月  査読有り
    Because of the incomplete understanding of the molecular mechanisms that underlie chronic pain, the currently available treatments for this type of pain remain inefficient. In this study, we show that Netrin-4, a member of the axon guidance molecule family, was expressed in dorsal horn inner lamina II excitatory interneurons in the rat spinal cord. A similar expression pattern for Netrin-4 was also observed in human spinal cord. Behavioral analysis revealed that tactile and heat hyperalgesia after peripheral nerve injury or inflammation were abolished in Netrin-4-mutant rats. Transient suppression of Netrin-4 or its receptor Unc5B after injury could also prevent allodynia. Conversely, intrathecal administration of Netrin-4 protein to naive rats enhanced excitatory synaptic transmission in the dorsal horn and induced allodynia, suggesting that Netrin-4 is involved in spinal sensitization. Furthermore, the Unc5B receptor and subsequent activation of the tyrosine phosphatase SHP2 mediated Netrin-4-induced pain signaling in the spinal cord. These results identify Netrin-4 as a novel protein regulating spinal sensitization leading to chronic pain. Our findings provide evidence for the function of Netrin in the adult nervous system, as well as a previously unknown function in inducing pain signals from dorsal horn interneurons.
  • Ryutaro Akiba, Hirotaka Yokouchi, Masahiro Mori, Toshiyuki Oshitari, Takayuki Baba, Setsu Sawai, Satoshi Kuwabara, Shuichi Yamamoto
    PLOS ONE 11(12) e0167473 2016年12月  査読有り
    Background Previous studies of neuromyelitis optica spectrum disorder (NMOSD) using spectral domain optical coherence tomography (SD-OCT) showed that the outer nuclear layer (ONL) in eyes without a history of optic neuritis (ON) was thinner than that of healthy controls. It remains unclear whether the ONL thinning is caused by a direct attack on the retina by an autoantibody or a retrograde degeneration. Objective To determine the mechanisms involved in the retinal damage in eyes with NMOSD without ON. Methods SD-OCT was used to determine the thicknesses of the different retinal layers of 21 eyes of 12 NMOSD patients without prior ON and 19 eyes of 10 healthy controls. Eyes with peripapillary retinal nerve fiber layer (RNFL) thinning were excluded to eliminate the confounding effects of retrograde degeneration. Microperimetry was used to determine the central retinal sensitivity. The data of the two groups were compared using generalized estimated equation models to account for inter-eye dependencies. Results The ganglion cell plus inner plexiform layer and the inner nuclear layer plus outer plexiform layer thicknesses of the NMOSD eyes were not significantly different from that of the control eyes (P = 0.28, P = 0.78). However, the ONL and average macular thickness (AMT) in the NMOSD eyes were significantly thinner than that of the control eyes (P = 0.022, P = 0.036). The retinal sensitivity in the central 10 degrees, 10 degrees to 2 degrees, and 2 degrees sectors were significantly lower in the NMOSD eyes than in the control eyes (P = 0.013, P = 0.022, P = 0.002). Conclusions The ONL thinning, AMT thinning, and reduced retinal sensitivity in eyes with NMOSD without significant peripapillary RNFL thinning are most likely due to direct retinal pathology.
  • Yuhei Nagao, Naoya Mimura, June Takeda, Motohiko Oshima, Kenichi Yoshida, Yusuke Shiozawa, Kazumasa Aoyama, Atsunori Saraya, Shuhei Koide, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Chika Kawajiri-Manako, Nagisa Hasegawa, Shio Sakai, Yusuke Takeda, Chikako Ohwada, Masahiro Takeuchi, Emiko Sakaida, Tohru Iseki, Sonoko Misawa, Koutaro Yokote, Satoru Miyano, Osamu Ohara, Satoshi Kuwabara, Masashi Sanada, Atsushi Iwama, Seishi Ogawa, Chiaki Nakaseko
    BLOOD 128(22) 2016年12月  
    0
  • Satoshi Kuwabara
    Brain and Nerve 68(12) 1411-1414 2016年12月1日  査読有り
    Fisher syndrome is regarded as a peculiar inflammatory neuropathy associated with ophthalmoplegia, ataxia, and areflexia. The disorder is associated with preceding infection, cerebrospinal fluid albumino-cytological dissociation, and spontaneous recovery, and regarded as a variant of Guillain-Barré syndrome. The discovery of anti-GQ1b IgG antibodies led to dramatic advances in understanding the pathophysiology of Fisher syndrome. The lesions in Fisher syndrome are determined by expression of ganglioside GQ1 b in the human nervous system. This review article focuses on the pathophysiology of ataxia in Fisher syndrome. Current evidence suggests that antibody attack on Group la neurons in the dorsal root ganglia is mainly responsible for the sensory ataxia. Involvement of the muscle spindles might also contribute to the development of ataxia.
  • Chika Kawajiri-Manako, Naoya Mimura, Masaki Fukuyo, Hiroe Namba-Fukuyo, Bahityar Rahmutulla, Yuhei Nagao, Emi Togasaki, Ryoh Shimizu, Nagisa Hasegawa, Shio Sakai, Yusuke Takeda, Chikako Ohwada, Masahiro Takeuchi, Emiko Sakaida, Tohru Iseki, Sonoko Misawa, Koutaro Yokote, Makoto Tsuiji, Satoshi Kuwabara, Atsushi Kaneda, Chiaki Nakaseko
    BLOOD 128(22) 2016年12月  
    0
  • Atsuhiko Sugiyama, Makoto Kobayashi, Kumiko Agatsuma, Takeshi Bo, Toshiaki Shiojiri, Hidetoshi Mochida, Yoshio Suzuki, Takashi Matsunaga, Satoshi Kuwabara
    Brain and Nerve 68(12) 1477-1482 2016年12月1日  査読有り
    A 61-year-old woman presented with a 10-month history of gait disturbance and a 7-month history of urinary incontinence. The Hasegawa dementia scale-revised score indicated cognitive impairment. Brain magnetic resonance imaging (MRI) indicated hydrocephalus with disproportionately enlarged subarachnoid space. This is usually considered a characteristic finding in idiopathic normal pressure hydrocephalus (iNPH). Ventriculo-peritoneal shunting improved the patient's symptoms. Neurosarcoidosis was suspected as a cause of the hydrocephalus because of the abnormalities in the cerebrospinal fluid and the abnormal enhancement of the cauda equina, the leptomeninges of the brainstem, and the spinal cord, as seen on MRI with gadolinium enhancement. A biopsy from the mediastinum lymph nodes confirmed the histological diagnosis of sarcoidosis. Physicians should consider the possibility of neurosarcoidosis in patients presenting with hydrocephalus, even in cases where clinical and radiological data are characteristic of iNPH.
  • Yamaguchi N, Misawa S, Sato Y, Nagashima K, Katayama K, Sekiguchi Y, Iwai Y, Amino H, Suichi T, Yokota T, Nishida Y, Kohara N, Hirata K, Nishiyama K, Yabe I, Kaida KI, Suzuki N, Nodera H, Tsuji S, Koike H, Kira JI, Hanaoka H, Kusunoki S, Kuwabara S, JET-GBS Group
    JMIR research protocols 5(4) e210 2016年11月7日  査読有り
  • Satoshi Kuwabara, Sonoko Misawa
    Clinical and Experimental Neuroimmunology 7(4) 320-323 2016年11月1日  
    Plasma exchange and intravenous immunoglobulin were established to be effective treatments for Guillain–Barré syndrome (GBS) in the 1980s and 1990s, respectively. However, even when treated with the currently best therapy available, the mortality rate is still approximately 5%, and approximately 20% of patients cannot walk unaided 6 months after onset. Therefore, many GBS patients still develop severe weakness and have a long disease course, often with pain and fatigue as a result of persistent axonal loss. A better treatment is required. A clinical trial of a second immunoglobulin is ongoing. Eculizumab, a humanized monoclonal antibody against complement C5, is a promising novel agent, and phase 1/2 trials are ongoing in Japan (Japanese Eculizumab Trial for GBS) and Scotland (Inhibition of Compliment Activation for GBS). Immunoglobulin G-degrading enzyme of Streptococcus pyogenes is another promising agent, and a phase 2 trial is planned. Prevention of severe axonal injury with new treatments early in the course of this disease remains a major focus, because axonal degeneration is an important limiting factor in achieving a good outcome.
  • Akiyuki Uzawa, Tetsuya Kanai, Naoki Kawaguchi, Fumiko Oda, Yukiko Ozawa, Keiichi Himuro, Satoshi Kuwabara
    Clinical and Experimental Neuroimmunology 7(4) 357-360 2016年11月1日  査読有り
    Objective: Damage-associated molecular patterns (DAMP) and cytokines can play a crucial role in inflammation at neuromuscular junctions in myasthenia gravis (MG). However, the relationship between DAMP and cytokine levels in MG pathogenesis remains unknown. To clarify this, we examined the relationship between serum levels of DAMP and cytokines in MG patients. Methods: Using serum data from 26 patients with anti-acetylcholine receptor antibody-positive MG, we investigated the relationship between the levels of DAMP (high-mobility group box 1 [HMGB1] and peroxiredoxin 5) and cytokines (interleukin [IL]-4, IL-15, IL-19, IL-20, IL-28A, IL-35, a proliferation-inducing ligand [APRIL] and vascular endothelial growth factor), which were reported to be significantly elevated in MG. Results: Serum levels of APRIL (r = 0.4789, P = 0.0133), IL-19 (r = 0.5496, P = 0.0036) and IL-35 (r = 0.5396, P = 0.0044) were correlated with those of HMGB1, but no cytokine levels were correlated with peroxiredoxin 5 levels. When we carried out multivariate analyses, only APRIL (P = 0.0244) and IL-19 (P = 0.0009) levels were correlated with HMGB1 levels. Conclusions: HMGB1 might be related with upregulation of IL-19 and APRIL levels in MG immunopathogenesis. These molecules could play a key role in controlling autoimmune inflammatory response, and represent a potent therapeutic target in MG.
  • Kenya Nishioka, Yasunobu Hoshino, Kauzuaki Kanai, Shinichi Ueno, Tomoko Nakazato, Masashi Takanashi, Ryota Tanaka, Kazumasa Yokoyama, Kimiyoshi Arimura, Satoshi Kuwabara, Nobutaka Hattori
    Clinical and Experimental Neuroimmunology 7(4) 369-372 2016年11月1日  査読有り
    The anti-paraneoplastic (Ma2/Ta) antibody is related to testicular, lung and ovarian cancers, and might cause paraneoplastic neurological disorders. We present a 25-year-old woman presenting various neurological symptoms of myokymia, chronic widespread pain, tremor, excessive daytime sleepiness, impaired eye of movements, and seizures and autonomic symptoms related to anti-Ma2/Ta antibodies. Needle electromyography showed spontaneous multiplet and myokymic discharges in the left vestus lateralis. Thus, we diagnosed her as Morvan syndrome. After initiation of steroids, plasma exchange and dantrolene, her symptoms partially improved with decreasing intensity of the antigen of anti-Ma2/Ta antibodies, from moderate strong to borderline. The present case expands the clinical spectrum of anti-Ma2/Ta antibodies-related disorders to include the existence of neuroimmune activation and Morvan syndrome.
  • Sonoko Misawa, Yasunori Sato, Kanako Katayama, Kengo Nagashima, Reiko Aoyagi, Yukari Sekiguchi, Gen Sobue, Haruki Koike, Ichiro Yabe, Hidenao Sasaki, Osamu Watanabe, Hiroshi Takashima, Masatoyo Nishizawa, Izumi Kawachi, Susumu Kusunoki, Yoshiyuki Mitsui, Seiji Kikuchi, Ichiro Nakashima, Shu-ichi Ikeda, Nobuo Kohara, Takashi Kanda, Jun-ichi Kira, Hideki Hanaoka, Satoshi Kuwabara
    LANCET NEUROLOGY 15(11) 1129-1137 2016年10月  査読有り
    Background Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare cause of demyelinating neuropathy, with multi-organ involvement characterised by plasma cell dyscrasia and VEGF overproduction. No treatments have been established for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide suppresses VEGF and plasma cell proliferation. We aimed to assess the safety and efficacy of thalidomide for the treatment of POEMS syndrome. Methods We did a randomised, double-blind, placebo-controlled, phase 2/3 trial at 12 hospitals in Japan. Adults (age >= 20 years) with POEMS syndrome who were ineligible for autotransplantation were randomly assigned (1:1) by a minimisation method to treatment with oral dexamethasone (12 mg/m(2) per day on the first 4 days of every 28-day cycle) plus either oral thalidomide (200 mg daily) or placebo for six cycles. All study personnel and patients were masked to treatment allocation. The primary endpoint was the reduction rate of serum VEGF concentrations at 24 weeks. Analysis was by intention to treat. This study is registered with the UMIN Clinical Trials Registry, UMIN000004179. Findings Between Nov 11, 2010, and July 3, 2014, we randomly assigned 25 patients to receive either thalidomide (n=13) or placebo (n=12); one patient in the placebo group was excluded from analyses because of a protocol violation. The adjusted mean VEGF concentration reduction rate at 24 weeks was 0.39 (SD 0.34) in the thalidomide group compared with -0.02 (0.54) in the placebo group (adjusted mean difference 0.41, 95% CI 0.02-0.80; p=0.04). Mild sinus bradycardia was more frequent in the thalidomide group than in the placebo group (seven [54%] vs zero; p=0.006). Five patients had serious adverse events: three in the thalidomide group (transient cardiac arrest, heart failure, and dehydration) and two in the placebo group (ileus and fever). No deaths occurred during the randomised study. In the 48-week open-label study period (n=22), newly developed adverse events were sinus bradycardia (n=4), constipation (n=5), and mild sensory neuropathy (n=5). Two patients died in the open-label study; both patients were initially in the placebo group, and the cause of death was progression of the disease. Interpretation Thalidomide reduces serum VEGF concentrations and represents a new treatment for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide treatment poses a risk of bradycardia; however, the benefits are likely to exceed the risk.
  • Akiyuki Uzawa, Masahiro Mori, Tomohiko Uchida, Hiroki Masuda, Ryohei Ohtani, Satoshi Kuwabara
    MULTIPLE SCLEROSIS JOURNAL 22(10) 1371-1375 2016年9月  査読有り
    Background: Recently, new diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD) were published. Objective: Our primary aim was to evaluate the usefulness of the new diagnostic criteria in anti-aquaporin 4 (AQP4) antibody-negative cases. Methods: Consecutive 471 patients whose anti-AQP4 antibody was measured at Chiba University were reviewed. Results: Four anti-AQP4 antibody negative-patients, who fulfilled the new diagnostic criteria for NMOSD but not 2006 diagnostic criteria for neuromyelitis optica (NMO), were identified. They showed high cerebrospinal fluid interleukin-6 and glial fibrillary acidic protein levels, an absence of oligoclonal bands and/or cloud-like enhancement on magnetic resonance imaging, which are compatible findings for NMO. Conclusion: The new diagnostic criteria are clinically useful in seronegative NMOSD.
  • S. Isose, S. Misawa, S. Omori, Sekiguchi Yu, M. Beppu, K. Watanabe, H. Amino, S. Kuwabara
    JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM 21(3) 181-182 2016年9月  
  • Yu Sekiguchi, S. Misawa, H. Amino, Y. Iwai, K. Watanabe, M. Beppu, N. Yuki, S. Kuwabara
    JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM 21(3) 208-209 2016年9月  
  • H. Masuda, M. Mori, S. Hirano, A. Uzawa, T. Uchida, R. Ohtani, N. Takahashi, S. Kuwabara
    MULTIPLE SCLEROSIS JOURNAL 22 767-768 2016年9月  
  • S. Kuwabara, S. Kusunoki
    JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM 21(3) 187-187 2016年9月  
  • Hazuki Watanabe, Naoki Atsuta, Akihiro Hirakawa, Ryoichi Nakamura, Masahiro Nakatochi, Shinsuke Ishigaki, Aritoshi Iida, Shiro Ikegawa, Michiaki Kubo, Daichi Yokoi, Hirohisa Watanabe, Mizuki Ito, Masahisa Katsuno, Yuishin Izumi, Mitsuya Morita, Kazuaki Kanai, Akira Taniguchi, Ikuko Aiba, Koji Abe, Koichi Mizoguchi, Masaya Oda, Osamu Kano, Koichi Okamoto, Satoshi Kuwabara, Kazuko Hasegawa, Takashi Imai, Akihiro Kawata, Masashi Aoki, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, Gen Sobue
    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 87(8) 851-858 2016年8月  査読有り
    Objective To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns. Methods We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs. Results We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47-8.34x10(-8)). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p= 8.6x10-10-1.1x10-7). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002). Conclusions We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.
  • Yasunobu Hoshino, Kenya Nishioka, Kauzuaki Kanai, Ryota Tanaka, Masanori Nagaoka, Satoshi Kuwabara, Nobutaka Hattori
    JOURNAL OF THE NEUROLOGICAL SCIENCES 367 361-362 2016年8月  査読有り
  • Hiroki Masuda, Masahiro Mori, Aldyuki Uzawa, Mayumi Muto, Tomohiko Uchida, Ryohei Ohtani, Ryutaro Akiba, Hirotaka Yokouchi, Shuichi Yamamoto, Satoshi Kuwabara
    JOURNAL OF THE NEUROLOGICAL SCIENCES 367 375-379 2016年8月  査読有り
    Background: Both neuromyelitis optica spectrum disorder (NMOsd) and multiple sclerosis (MS) patients experience optic neuritis (ON) attacks characterized by rapidly reduced best-correct visual acuity (BCVA) and slow recovery. Prognosis and effects of recurrence on recovery may differ between disorders but remain unclear. Objective: To compare ON severity, time and degree of recovery and effects of previous ON between NMOsd and MS patients. Methods: Retrospective chart review was performed. BCVA measurements acquired before ON, at nadir and during recovery were retrospectively reviewed. Records were obtained on 69 ON attacks in 36 NMOsd patients and 43 attacks in 28 MS patients, including first episodes and recurrences. Results: NMOsd patients exhibited significantly lower BCVA values at all time points after attack (P <0.05), reached nadir earlier (P = 0.014) and regained a smaller fraction of baseline BCVA than MS patients (P < 0.001). In NMOsd, relapsed ON resulted in worse recovery and tended to reach nadir earlier than first-episode ON (P = 0.030 and 0.059, respectively). In MS, relapsed ON also reached nadir earlier (P = 0.042); however, there was no difference in recovery. Conclusions: Recovery from ON was poorer in NMOsd than in MS and was negatively affected by previous ON attacks. (C) 2016 Elsevier B.V. All rights reserved.
  • N. Shahrizaila, G. Sobue, S. Kuwabara, S. H. Kim, Carol Birks, D. S. Fan, J. S. Bae, C. J. Hu, M. Gourie-Devi, Y. Noto, K. Shibuya, K. J. Goh, R. Kaji, C. P. Tsai, L. Cui, P. Talman, R. D. Henderson, S. Vucic, M. C. Kiernan
    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 87(8) 821-830 2016年8月  
    While the past 2 decades have witnessed an increasing understanding of amyotrophic lateral sclerosis (ALS) arising from East Asia, particularly Japan, South Korea, Taiwan and China, knowledge of ALS throughout the whole of Asia remains limited. Asia represents >50% of the world population, making it host to the largest patient cohort of ALS. Furthermore, Asia represents a diverse population in terms of ethnic, social and cultural backgrounds. In this review, an overview is presented that covers what is currently known of ALS in Asia from basic epidemiology and genetic influences, through to disease characteristics including atypical phenotypes which manifest a predilection for Asians. With the recent establishment of the Pan-Asian Consortium for Treatment and Research in ALS to facilitate collaborations between clinicians and researchers across the region, it is anticipated that Asia and the Pacific will contribute to unravelling the uncertainties in ALS.
  • Hirotaka Yokouchi, Takayuki Baba, Sonoko Misawa, Setsu Sawai, Masayasu Kitahashi, Toshiyuki Oshitari, Satoshi Kuwabara, Shuichi Yamamoto
    BRITISH JOURNAL OF OPHTHALMOLOGY 100(7) 897-901 2016年7月  査読有り
    Aims To determine whether there is a significant correlation between the peripapillary retinal thickness (pRT) and the serum level of vascular endothelial growth factor (VEGF) in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome. Methods This was a cross-sectional, observational case series. We studied 34 eyes of 17 treatment-naive patients with POEMS syndrome whose intracranial pressure was within the normal range. The spectral-domain optical coherence tomographic (SD-OCT) examinations consisted of circle scans of 3.45 mm diameter around the optic disc. The pRT was automatically measured in the SD-OCT images and was used for the statistical analysis. The serum level of VEGF was measured by ELISAs, and the correlation between the pRT and the serum level of VEGF was determined. Multivariable logistic regression analyses were used to identify independent factors that were correlated with the pRT. Results There was a significant positive correlation between the serum levels of VEGF and the average pRT of the two eyes of each patient (r=0.81, p<0.0001). There was a significant correlation between the pRT of the right and left eyes with an intraclass correlation coefficient of 0.839. Multiple regression analysis showed that the serum levels of VEGF were independent contributors to the pRT (standard regression coefficient=0.59, p=0.012). Conclusions The significant correlation between the pRT and the serum level of VEGF suggests that the higher serum level of VEGF might be associated with the development of the optic disc oedema in patients with POEMS syndrome.
  • Nimeshan Geevasinga, Clement T. Loy, Parvathi Menon, Mamede de Carvalho, Michael Swash, Maarten Schrooten, Philip Van Dammee, Malgorzata Gawel, Masahiro Sonoo, Mana Higashihara, Yu-ichi Noto, Satoshi Kuwabara, Matthew C. Kiernan, Petra Macaskill, Steve Vucic
    CLINICAL NEUROPHYSIOLOGY 127(7) 2684-2691 2016年7月  査読有り
    Objective: To determine the utility of the Awaji criteria in diagnosing amyotrophic lateral sclerosis (ALS) and to propose a novel modification so as to enhance sensitivity based on results of individual patient data (IPD). Methods: Individual patient data were available from 8 studies comparing the diagnostic accuracy of Awaji and revised El Escorial (rEEC) criteria. The sensitivity of a novel updated Awaji criteria, incorporating a "probable-laboratory supported" category, was also tested. Results: Individual patient data were available from 1086 patients, consisting of 881 ALS and 205 patients with disorders mimicking ALS. Summary sensitivities based on random effects logistic regression modelling disclosed a higher sensitivity of the Awaji criteria (0.70, 95% confidence interval [CI] 0.51-0.83) and updated Awaji criteria (0.73, 95% CI 0.56-0.85) when compared to rEEC (0.58, 95% CI 0.48-0.68). Paired analysis revealed higher sensitivities of Awaji criteria in 4 studies, and of updated Awaji criteria in 7 studies, when compared to rEEC. Conclusion: Individual patient data analysis established a higher sensitivity of Awaji criteria when compared to rEEC. The updated Awaji criteria enhanced the diagnostic sensitivity in limb-onset ALS. Significance: The updated Awaji criteria should be considered in clinical practice and future therapeutic trials. (C) 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
  • Yuta Iwai, Kazumoto Shibuya, Sonoko Misawa, Yukari Sekiguchi, Keisuke Watanabe, Hiroshi Amino, Satoshi Kuwabara
    PLOS ONE 11(7) e0158596 2016年7月  査読有り
    Wide-spread fasciculations are a characteristic feature in amyotrophic lateral sclerosis (ALS), suggesting motor axonal hyperexcitability. Previous excitability studies have shown increased nodal persistent sodium conductances and decreased potassium currents in motor axons of ALS patients, both of the changes inducing hyperexcitability. Altered axonal excitability potentially contributes to motor neuron death in ALS, but the relationship of the extent of motor neuronal death and abnormal excitability has not been fully elucidated. We performed multiple nerve excitability measurements in the median nerve at the wrist of 140 ALS patients and analyzed the relationship of compound muscle action potential (CMAP) amplitude (index of motor neuronal loss) and excitability indices, such as strength-duration time constant, threshold electrotonus, recovery cycle and current-threshold relationships. Compared to age-matched normal controls (n = 44), ALS patients (n = 140) had longer strength-duration time constant (SDTC: a measure of nodal persistent sodium current; p < 0.05), greater threshold changes in depolarizing threshold electrotonus (p < 0.05) and depolarizing current threshold relationship (i.e. less accommodation; (p < 0.05), greater superexcitability (a measure of fast potassium current; p < 0.05) and reduced late subexcitability (a measure of slow potassium current; p < 0.05), suggesting increased persistent sodium currents and decreased potassium currents. The reduced potassium currents were found even in the patient subgroups with normal CMAP (> 5mV). Regression analyses showed that SDTC (R = -0.22) and depolarizing threshold electrotonus (R = -0.22) increased with CMAP decline. These findings suggest that motor nerve hyperexcitability occurs in the early stage of the disease, and precedes motor neuronal loss in ALS. Modulation of altered ion channel function could be a treatment option for ALS.
  • Daichi Yokoi, Naoki Atsuta, Hazuki Watanabe, Ryoichi Nakamura, Akihiro Hirakawa, Mizuki Ito, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Masaya Oda, Koji Abe, Kouichi Mizoguchi, Osamu Kano, Satoshi Kuwabara, Ryuji Kaji, Gen Sobue
    JOURNAL OF NEUROLOGY 263(6) 1129-1136 2016年6月  査読有り
    The clinical courses of sporadic amyotrophic lateral sclerosis (ALS) show extensive variability. Our objective was to elucidate how age of onset influences the progression of regional symptoms and functional losses in sporadic ALS. We included 648 patients with sporadic ALS from a multicenter prospective ALS cohort. We investigated the distribution of initial symptoms and analyzed the time from onset to events affecting activities of daily living (ADL) as well as the longitudinal changes in each regional functional rating score among four groups with different ages of onset. The frequencies of dysarthria and dysphagia as initial symptoms were higher in the older age groups, whereas weakness of upper limbs was the most common initial symptom in the youngest age group. The survival times and the times from onset to loss of speech and swallowing were significantly shorter in the older age group (p < 0.001), although the times from onset to loss of upper limb function were not significantly different among the age groups. According to joint modeling analysis, the bulbar score declined faster in the older age groups (< 50 vs. 60-69 years: p = 0.029, < 50 vs. a parts per thousand yen70 years: p < 0.001), whereas there was no significant correlation between the age of onset and decline in the upper limb score. Our results showed that age of onset had a significant influence on survival time and the progression of bulbar symptoms, but had no influence on upper limb function in sporadic ALS.
  • Notturno F, Kokubun N, Sekiguki Y, Nagashima T, De Lauretis A, Yuki N, Kuwabara S, Uncini A
    Journal of the neurological sciences 365 132-136 2016年6月  査読有り
  • T. Yamamoto, T. Uchiyama, Y. Higuchi, M. Asahina, S. Hirano, Y. Yamanaka, S. Kuwabara
    MOVEMENT DISORDERS 31 S7-S7 2016年6月  
  • Y. Sekiguchi, M. Mori, S. Misawa, S. Sawai, N. Yuki, M. Beppu, S. Kuwabara
    EUROPEAN JOURNAL OF NEUROLOGY 23(6) 1058-1063 2016年6月  査読有り
    Background and purpose: Fisher syndrome (FS) may overlap with Guillain-Barre syndrome (GBS), in particular the pharyngeal-cervical-brachial variant form (PCB-GBS), or Bickerstaff brainstem encephalitis (BBE). Our aim was to elucidate the frequency of this overlap and the patterns of clinical progression in patients with FS. Methods: Sixty consecutive patients with FS were studied. FS/PCB-GBS was diagnosed when the patients developed pharyngeal, cervical and/or brachial weakness. Patients with flaccid tetraparesis were diagnosed as having FS/conventional GBS. FS/BBE was defined as the development of consciousness disturbances. Results: All 60 patients initially developed the FS clinical triad alone (pure FS). Of these, 30 (50%) patients had pure FS throughout their course, whereas the remaining 50% of patients showed an overlap: PCB-GBS in 14 (23%) patients, conventional GBS in nine (15%) patients and BBE in seven (12%) patients. The median (range) durations from FS onset to progression to FS/PCB-GBS, FS/GBS or FS/BBE were 5 (1-7), 3 (1-4) and 3 (1-5) days, respectively. Patients with overlap syndromes more frequently received immune-modulating treatment, and the outcomes were generally favourable. The frequencies of positivity for anti-GQ1b, GT1a, GD1a, GD1b, GalNAc-GD1a and GM1 antibodies were not significantly different amongst the four groups. Conclusions: Of the patients with pure FS, 50% later developed an overlap with PCB-GBS, conventional GBS or BBE. The overlap occurred within 7 days of FS onset; thus, physicians should pay attention to the possible development of this overlap during the first week after FS onset.
  • T. Uchiyama, T. Yamamoto, K. Suzuki, T. Kadowaki, Y. Watanabe, K. Hashimoto, T. Shingo, K. Kaga, C. Shibata-Yamaguchi, T. Yamanishi, R. Sakakibara, S. Kuwabara, K. Hirata
    MOVEMENT DISORDERS 31 S109-S109 2016年6月  
  • S. Hirano, S. Furukawa, M. Asahina, T. Yamamoto, T. Uchiyama, Y. Yamanaka, Y. Higuchi, T. Horikoshi, T. Uno, N. Saeki, S. Kuwabara
    MOVEMENT DISORDERS 31 S449-S449 2016年6月  
  • Tatsuya Yamamoto, Masato Asahina, Yoshitaka Yamanaka, Tomoyuki Uchiyama, Shigeki Hirano, Atsuhiko Sugiyama, Ryuji Sakakibara, Satoshi Kuwabara
    MOVEMENT DISORDERS CLINICAL PRACTICE 3(3) 275-281 2016年5月  査読有り
    Background: MSA is clinically classified into two phenotypes: parkinsonism predominant (MSA-P) and cerebellar ataxia predominant (MSA-C). However, little is known about the differences in urinary dysfunctions between MSA-C and MSA-P. We investigated the differences in urinary and cardiovascular dysfunctions between MSA-C and MSA-P.Methods: We retrospectively reviewed the medical records of patients with MSA diagnosed as having probable or possible MSA according to Gilman's second consensus criteria from January 2007 to September 2013 in our hospital. Data regarding the initial symptoms, onset of urinary symptoms, and results of urodynamic (including anal sphincter electromyography) and head-up tilt tests were collected.Results: A total of 100 patients with MSA, including 59 patients with MSA-C and 41 with MSA-P, were reviewed. Initial symptoms were autonomic (n = 12) and cerebellar (n = 47) in the MSA-C phenotype and were autonomic (n = 14) and parkinsonian (n = 27) in the MSA-P phenotypes. Urodynamic study indicated that bladder contraction was more severely impaired in patients with MSA-P than in those with MSA-C. In the head-up tilt test, the decrease in diastolic blood pressure was significantly larger in the MSA-P phenotype than that in the MSA-C phenotype. Acontractile bladder during the pressure flow study increased likelihood that the phenotype is MSA-P (odds ratio: 6.67; 95% confidence interval: 1.004-44.284; P = 0.050).Conclusions: Urinary dysfunctions were more severe in MSA-P compared with MSA-C. Detailed urodynamic study was helpful for detecting subtle differences between MSA-C and MSA-P.
  • Akiyuki Uzawa, Tetsuya Kanai, Naoki Kawaguchi, Fumiko Oda, Keiichi Himuro, Satoshi Kuwabara
    SCIENTIFIC REPORTS 6 25886 2016年5月  査読有り
    Myasthenia gravis (MG) is an autoimmunological inflammatory disorder of the neuromuscular junction. Inflammation could be a key player for understanding the pathogenesis of MG. We measured the serum levels of 24 inflammatory cytokines in 43 patients with anti-acetylcholine receptor antibody-positive MG and 25 healthy controls. In patients with MG, serum levels of a proliferation- inducing ligand (APRIL), IL-19, IL-20, IL-28A and IL-35 were significantly increased as compared with controls (p < 0.05). Among them, IL-20, IL-28A and IL-35 were significantly decreased after treatment (p < 0.05). In clinical subtype analyses, APRIL and IL-20 were increased in patients with late- onset MG and IL-28A levels were increased in patients with thymoma-associated MG compared with healthy controls (p < 0.01). The results of the present study demonstrate both anti-inflammatory and inflammatory cytokines are upregulated in MG, reflecting the importance of cytokine-mediated inflammation and its regulation in MG pathophysiology.
  • Shibuya Kazumoto, Misawa Sonoko, Kimura Hideki, Noto Yu-ichi, Sekiguchi Yukari, Iwai Yuta, Shimizu Toshio, Mizuno Toshiki, Nakagawa Masanori, Kuwabara Satoshi
    NEUROLOGY AND CLINICAL NEUROSCIENCE 4(3) 108-111 2016年5月  査読有り
  • Tomoya Muto, Chikako Ohwada, Setsu Sawai, Minako Beppu, Shokichi Tsukamoto, Yusuke Takeda, Naoya Mimura, Masahiro Takeuchi, Emiko Sakaida, Kazuyuki Sogawa, Sonoko Misawa, Naomi Shimizu, Tohru Iseki, Fumio Nomura, Satoshi Kuwabara, Chiaki Nakaseko
    TRANSFUSION AND APHERESIS SCIENCE 54(2) 276-281 2016年4月  査読有り
    We describe two cases of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome patients with deteriorated extravascular volume overload without increased levels of vascular endothelial growth factor after the administration of cyclophosphamide + granulocyte colony-stimulating factor for stem cell mobilization. We then measured the serum levels of 27 cytokines from these cases using a multiplex suspension array system. The analysis revealed the changes of cytokine profiles before cyclophosphamide + granulocyte colony-stimulating factor and after the development of capillary leak symptoms in both cases. This may improve our current level of understanding of the pathogenesis of POEMS syndrome not driven by vascular endothelial growth factor. (C) 2015 Elsevier Ltd. All rights reserved.
  • Tetsuya Kanai, Akiyuki Uzawa, Naoki Kawaguchi, Tateo Sakamaki, Yasumasa Yoshiyama, Keiichi Himuro, Fumiko Oda, Satoshi Kuwabara
    JOURNAL OF THE NEUROLOGICAL SCIENCES 363 116-118 2016年4月  査読有り
    Background: Myasthenia gravis (MG) is an autoimmune disorder presumed to be associated with genetic susceptibility. This study aims to determine whether HLA is associated with MG in Japanese patients. Methods: We included 58 MG patients with anti-acetylcholine receptor antibody (AChR + MG) and 14 MG patients with muscle-specific receptor tyrosine kinase (MuSK + MG) and determined HLA-A, B, DRB1 and -DQB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide and primers. AChR + MG was classified into the three subgroups: early-onset MG (EOMG; n = 11), late-onset MG (LOMG; n = 20), and thymoma-associated MG (n = 27). Healthy volunteers (n = 100) served as controls. Results: A significant positive association was observed between MuSK + MG with the DRB1*14 [57.1%, MuSK + MG vs. 18.0%, healthy controls (HC); odds ratio (OR): 6.1] and DQB1*05 [78.6%, MuSK + MG vs. 30.0%, HC; odds ratio (OR): 8.5]. We found a negative association between LOMG and DQB1*04 [5.0%, LOMG vs. 37.0%, HC; OR: 0.09]. There was no association between other MG subgroups and HLA alleles. Conclusion: HLA-DRB1*14 and DQB1*05 were associated with MuSK + MG, therefore these alleles may play important roles in developing MuSK + MG across the races. (C) 2016 Elsevier B.V. All rights reserved.
  • Nobuyuki Araki, Sonoko Misawa, Kazumoto Shibuya, Satoshi Ota, Takashi Oide, Asuka Kawano, Minako Beppu, Yukio Nakatani, Satoshi Kuwabara
    ORPHANET JOURNAL OF RARE DISEASES 11 35 2016年4月  査読有り
    Background: Calciphylaxis is a syndrome consisting of vascular calcification, thrombosis, and skin necrosis. The syndrome develops often in chronic hemodialysis patients. However, there have been several case reports on calciphylaxis in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome, a systemic disease associated with plasma cell dyscrasia and upregulation of vascular endothelial growth factor (VEGF). Methods: In 76 POEMS patients and 86 age- and gender-matched disease controls, we studied abnormal small vessel calcification by computed tomography (CT) of the soft tissues. Clinical and laboratory profiles were compared between POEMS patients with and without calciphylaxis. Histological examination was performed in six autopsy cases. Results: Small vessel calcification on CT was found in 17 % of POEMS patients and in none of the controls (P < 0.001). Autopsy confirmed calciphylaxis in 2 (33 %) patients. Among POEMS patients, higher disease activity, including more severe neuropathy and ascites, higher serum levels of interleukin-6, and lower serum albumin levels, was associated with the development of calciphylaxis. Serum levels of creatinine, calcium, and phosphate were not related to the presence of calciphylaxis. Conclusions: Calciphylaxis is often present in patients with POEMS syndrome. Upregulation of multiple inflammatory cytokines such as VEGF and interleukin-6 may contribute to the development of calciphylaxis, by entirely different mechanism from that in chronic dialysis. POEMS syndrome should be recognized as a potential cause of calciphylaxis.
  • Ryoichi Nakamura, Jun Sone, Naoki Atsuta, Genki Tohnai, Hazuki Watanabe, Daichi Yokoi, Masahiro Nakatochi, Hirohisa Watanabe, Mizuki Ito, Jo Senda, Masahisa Katsuno, Fumiaki Tanaka, Yuanzhe Li, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Koji Abe, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Masashi Aoki, Nobutaka Hattori, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, Gen Sobue
    NEUROBIOLOGY OF AGING 39 219.e1-8 2016年3月  査読有り
    We investigated the frequency and contribution of variants of the 28 known amyotrophic lateral sclerosis (ALS)-related genes in Japanese ALS patients. We designed a multiplex, polymerase chain reaction-based primer panel to amplify the coding regions of the 28 ALS-related genes and sequenced DNA samples from 257 Japanese ALS patients using an Ion Torrent PGM sequencer. We also performed exome sequencing and identified variants of the 28 genes in an additional 251 ALS patients using an Illumina HiSeq 2000 platform. We identified the known ALS pathogenic variants and predicted the functional properties of novel nonsynonymous variants in silico. These variants were confirmed by Sanger sequencing. Known pathogenic variants were identified in 19 (48.7%) of the 39 familial ALS patients and 14 (3.0%) of the 469 sporadic ALS patients. Thirty-two sporadic ALS patients (6.8%) harbored 1 or 2 novel nonsynonymous variants of ALS-related genes that might be deleterious. This study reports the first extensive genetic screening of Japanese ALS patients. These findings are useful for developing genetic screening and counseling strategies for such patients. (C) 2016 Elsevier Inc. All rights reserved.
  • Atsuhiko Sugiyama, Makoto Kobayashi, Hanako Moriishi, Hajime Tanaka, Ryoto Mitsuyoshi, Takashi Matsunaga, Satoshi Kuwabara
    JOURNAL OF THE NEUROLOGICAL SCIENCES 362 196-197 2016年3月  査読有り
  • 鈴木 政秀, 仲野 義和, 枡田 大生, 渡辺 慶介, 関口 縁, 桑原 聡
    臨床神経学 56(3) 219-219 2016年3月  

MISC

 1029

書籍等出版物

 77

講演・口頭発表等

 84

担当経験のある科目(授業)

 3

共同研究・競争的資金等の研究課題

 64