論文 - 久原　真

小脳性運動失調を主徴とした抗contactin-1(CNTN1)抗体陽性nodopathyの一例

河田 由香, 池田 和奈, 種本 真将, 横川 和樹, 山田 稔, 齋藤 太郎, 岩原 直敏, 松村 晃寛, 鈴木 秀一郎, 緒方 英紀, 磯部 紀子, 久原 真

臨床神経学 ( (一社)日本神経学会 )  63 ( 11 ) 778 - 778  2023年11月

小脳性運動失調を主徴とした抗contactin-1(CNTN1)抗体陽性nodopathyの一例

河田 由香, 池田 和奈, 種本 真将, 横川 和樹, 山田 稔, 齋藤 太郎, 岩原 直敏, 松村 晃寛, 鈴木 秀一郎, 緒方 英紀, 磯部 紀子, 久原 真

臨床神経学 ( (一社)日本神経学会 )  63 ( 11 ) 778 - 778  2023年11月

神経筋疾患の問題症例 亜急性に進行した小脳性運動失調症と脱髄性ニューロパチーの一例

河田 由香, 池田 和奈, 山田 稔, 齋藤 太郎, 津田 玲子, 鈴木 秀一郎, 緒方 英紀, 磯部 紀子, 久原 真

臨床神経生理学 ( (一社)日本臨床神経生理学会 )  51 ( 5 ) 508 - 508  2023年10月

発症早期の自己免疫性てんかんの臨床的特徴の検討

種本 真将, 横川 和樹, 齋藤 太郎, 岩原 直敏, 松村 晃寛, 鈴木 秀一郎, 山本 彬広, 外山 祐一郎, 古山 裕康, 溝渕 雅広, 佐光 一也, 久原 真

臨床神経学 ( (一社)日本神経学会 )  63 ( Suppl. ) S321 - S321  2023年09月

クリーゼ中に胸腺摘除術を施行し良好な転帰が得られた胸腺腫合併抗AChR抗体陽性全身型重症筋無力症の一例

河田 由香, 種本 真将, 山田 稔, 横川 和樹, 齋藤 太郎, 岩原 直敏, 松村 晃寛, 鈴木 秀一郎, 久原 真, 高瀬 貴章, 宮島 正博, 渡辺 敦

臨床神経学 ( (一社)日本神経学会 )  63 ( 5 ) 325 - 325  2023年05月

高齢発症の抗GluR抗体陽性脳炎にリツキシマブ療法が効果を示した1例

種本 真将, 山本 彬広, 河田 由香, 横川 和樹, 山田 稔, 齋藤 太郎, 岩原 直敏, 松村 晃寛, 鈴木 秀一郎, 高橋 幸利, 久原 真

臨床神経学 ( (一社)日本神経学会 )  63 ( 5 ) 325 - 325  2023年05月

クリーゼ中に胸腺摘除術を施行し良好な転帰が得られた胸腺腫合併抗AChR抗体陽性全身型重症筋無力症の一例

河田 由香, 種本 真将, 山田 稔, 横川 和樹, 齋藤 太郎, 岩原 直敏, 松村 晃寛, 鈴木 秀一郎, 久原 真, 高瀬 貴章, 宮島 正博, 渡辺 敦

臨床神経学 ( (一社)日本神経学会 )  63 ( 5 ) 325 - 325  2023年05月

Anti-signal Recognition Particle Antibody-positive Immune-mediated Myopathy after mRNA-1273 SARS-CoV-2 Vaccination.

Masanobu Tanemoto, Ryosuke Oda, Yuichiro Toyama, Hirohiko Shizukawa, Kazuki Yokokawa, Taro Saito, Syuuichirou Suzuki, Akihiro Matsumura, Shin Hisahara

Internal medicine (Tokyo, Japan)   61 ( 23 ) 3605 - 3609  2022年12月  [国内誌]

　概要を見る

A 26-year-old Japanese woman developed a fever, myalgia and gait disturbance one day after receiving the second dose of the mRNA-1273 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. A neurological examination revealed symmetrical weakness and myalgia in proximal lower limbs, and a blood examination showed prominent elevation of creatinine kinase. Magnetic resonance imaging (MRI) revealed a high signal intensity in the thigh muscles on short-tau inversion recovery images, and antibody testing revealed positive findings for anti-signal recognition particle (SRP) antibody. Thus, anti-SRP antibody-positive immune-mediated myopathy was diagnosed. We initiated immunotherapy, and she was ultimately able to walk stably.

DOI PubMed

脱髄性ニューロパチーを認めたサルコイドーシスの1例

河田 由香, 種本 真将, 山田 稔, 横川 和樹, 齋藤 太郎, 岩原 直敏, 松村 晃寛, 鈴木 秀一郎, 久原 真, 松浦 洋介

臨床神経学 ( (一社)日本神経学会 )  62 ( 12 ) 975 - 975  2022年12月

てんかん発作で発症した自己免疫性神経疾患8症例の検討

種本 真将, 横川 和樹, 齋藤 太郎, 松村 晃寛, 鈴木 秀一郎, 久原 真

臨床神経学 ( (一社)日本神経学会 )  62 ( 12 ) 978 - 978  2022年12月

mRNA-1273 SARS-CoV-2ワクチン接種後に発症した抗SRP抗体陽性ミオパチーの1例

種本 真将, 鈴木 秀一郎, 松村 晃寛, 横川 和樹, 久原 真, 静川 裕彦

神経治療学 ( (一社)日本神経治療学会 )  39 ( 6 ) S263 - S263  2022年10月

脳神経内科外来のパーキンソン病患者における便秘の有訴者数と臨床像

鈴木 秀一郎, 河田 由香, 種本 真将, 池田 和奈, 横川 和樹, 松村 晃寛, 久原 真

神経治療学 ( (一社)日本神経治療学会 )  39 ( 6 ) S288 - S288  2022年10月

Activation of SIRT1 promotes membrane resealing via cortactin

Naotoshi Iwahara, Kuya Azekami, Ryusuke Hosoda, Iyori Nojima, Shin Hisahara, Atsushi Kuno

Scientific Reports ( Springer Science and Business Media LLC )  12 ( 1 )  2022年09月

　概要を見る

Abstract Muscular dystrophies are inherited myopathic disorders characterized by progressive muscle weakness. Recently, several gene therapies have been developed; however, the treatment options are still limited. Resveratrol, an activator of SIRT1, ameliorates muscular function in muscular dystrophy patients and dystrophin-deficient mdx mice, although its mechanism is still not fully elucidated. Here, we investigated the effects of resveratrol on membrane resealing. We found that resveratrol promoted membrane repair in C2C12 cells via the activation of SIRT1. To elucidate the mechanism by which resveratrol promotes membrane resealing, we focused on the reorganization of the cytoskeleton, which occurs in the early phase of membrane repair. Treatment with resveratrol promoted actin accumulation at the injured site. We also examined the role of cortactin in membrane resealing. Cortactin accumulated at the injury site, and cortactin knockdown suppressed membrane resealing and reorganization of the cytoskeleton. Additionally, SIRT1 deacetylated cortactin and promoted the interaction between cortactin and F-actin, thus possibly enhancing the accumulation of cortactin at the injury site. Finally, we performed a membrane repair assay using single fiber myotubes from control and resveratrol-fed mice, where the oral treatment with resveratrol promoted membrane repair ex vivo. These findings suggest that resveratrol promotes membrane repair via the SIRT1/cortactin axis.

DOI

Ubiquitin-dependent rapid degradation conceals a cell-protective function of cytoplasmic SIRT3 against oxidative stress

Takashi Hayashi, Takashi Matsushita, Shin Hisahara, Naotoshi Iwahara, Atsushi Kuno, Risa Kunimoto, Ryusuke Hosoda, Masaya Tanno, Shun Shimohama, Yoshiyuki Horio

The Journal of Biochemistry ( Oxford University Press (OUP) )  171 ( 2 ) 201 - 213  2022年02月

　概要を見る

Abstract SIRT3 is an NAD+-dependent protein deacetylase localized in mitochondria. Several studies reported localization of SIRT3 in the cytoplasm or nucleus, but data of these studies were not consistent. We detected expression of mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs in the mouse brain, and we also found SIRT3 immunostaining of mitochondria and cytoplasm in the brain and cultured neural cells. However, expression levels of SIRT3ct in COS cells transfected with SIRT3ct cDNA were much lower than those of SIRT3mt. We found that SIRT3ct but not SIRT3mt was promptly degraded by ubiquitin-dependent degradation, in which SIRT3ct degradation was mediated mainly by ubiquitination of NH2-terminal methionine and partly by that of lysine residues of SIRT3ct. SIRT3ct expression level was significantly enhanced by the treatment of cells with staurosporine or H2O2. H2O2 treatment promoted nuclear translocation of SIRT3ct and induced histone H3 deacetylation and superoxide dismutase 2 expression. Overexpression of SIRT3ct decreased cell death caused by H2O2 at levels similar to those achieved by overexpression of SIRT3mt. Knockdown of Sirt3 mRNA increased cell death caused by amyloid-β (Aβ), and overexpression of SIRT3ct suppressed the toxic function of Aβ in PC12 cells. These results indicate that SIRT3ct promotes cell survival under physiological and pathological conditions.

DOI

臨床病型が大きく異なりFUS遺伝子変異のmosaicismが示唆された家族性ALS母子例

久原 真, 西山 亜由美, 津田 笑子, 鈴木 秀一郎, 松村 晃寛, 石川 亜貴, 櫻井 晃洋, 元池 育子, 青木 正志, 青木 洋子, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  61 ( Suppl. ) S293 - S293  2021年09月

Sporadic Amyotrophic Lateral Sclerosis Due to a FUS P525L Mutation with Asymmetric Muscle Weakness and Anti-ganglioside Antibodies.

Masanobu Tanemoto, Shin Hisahara, Kazuna Ikeda, Kazuki Yokokawa, Tatsuo Manabe, Reiko Tsuda, Daisuke Yamamoto, Takashi Matsushita, Akihiro Matsumura, Syuuichirou Suzuki, Shun Shimohama

Internal medicine (Tokyo, Japan)   60 ( 12 ) 1949 - 1953  2021年06月  [国内誌]

　概要を見る

Amyotrophic lateral sclerosis (ALS) due to a fused in sarcoma (FUS) P525L mutation is characterized by a rapidly progressive course. Multifocal motor neuropathy (MMN) may resemble ALS in early stage and is associated with anti-ganglioside antibodies. A 38-year-old woman was admitted to our hospital because of progressive muscle weakness in the right limbs. She had mild mental retardation and minor deformities. Initially, we suspected MMN given the asymmetric muscle weakness and detection of anti-ganglioside antibodies. However, physical and electrophysiological tests did not support MMN, instead suggesting ALS. We confirmed a heterozygous P525L mutation and finally diagnosed this case as ALS due to an FUS mutation.

DOI PubMed

SIRT1 decelerates morphological processing of oligodendrocyte cell lines and regulates the expression of cytoskeleton-related oligodendrocyte proteins.

Shin Hisahara, Naotoshi Iwahara, Takashi Matsushita, Syuuichirou Suzuki, Akihiro Matsumura, Mai Fujikura, Kazuki Yokokawa, Taro Saito, Tatsuo Manabe, Jun Kawamata, Yoshiyuki Horio, Shun Shimohama

Biochemical and biophysical research communications   546   7 - 14  2021年03月  [国際誌]

　概要を見る

SIRT1 is involved in the regulation of a variety of biological processes such as metabolism, stress response, autophagy and differentiation. Although progenitor cells of oligodendrocytes (OPCs) express high level of SIRT1, its function on differentiation is unknown. Because we have shown that SIRT1 plays a pivotal role in differentiation of neural precursor cells, we hypothesized that SIRT1 may also participate in the differentiation of oligodendrocytes (OLGs). We examined whether SIRT1 was expressed in two human oligodendrocyte cell lines: KG-1-C and MO 3.13 OLG. Transfection of cell lines with SIRT1-siRNA and SIRT2-siRNA promoted the extension of cellular processes. SIRT1-siRNA and SIRT2-siRNA increased acetyl-α-tubulin level, conversely, over expression of SIRTs resulted in decreased the ratio of acetyl-α-tubulin to α-tubulin. We also found knockdown of SIRT1 and SIRT2 induced overexpression of βIV-tubulin and tubulin polymerization promoting protein (TPPP) (OLG-specific cytoskeleton-related molecules) that distributed widely in cell bodies. Taken together, SIRT1 may play a role in oligodenroglial differentiation and myelinogenesis.

DOI PubMed

Possible Somatic Mosaicism of Novel FUS Variant in Familial Amyotrophic Lateral Sclerosis.

Shin Hisahara, Ayumi Nishiyama, Emiko Tsuda, Syuuichirou Suzuki, Akihiro Matsumura, Aki Ishikawa, Akihiro Sakurai, Ikuko N Motoike, Masashi Aoki, Yoko Aoki, Shun Shimohama

Neurology. Genetics   7 ( 1 ) e552  2021年02月  [国際誌]

DOI PubMed

異なる臨床病型を呈し母にFUS遺伝子変異のmosaicismが示唆された家族性ALSの親子例

久原 真, 津田 笑子, 鈴木 秀一郎, 松村 晃寛, 石川 亜貴, 櫻井 晃洋, 西山 亜由美, 元池 育子, 青木 正志, 青木 洋子, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  61 ( 1 ) 55 - 55  2021年01月

非典型的な臨床型のFUS遺伝子変異による孤発性と考えられるALSの1例

種本 真将, 眞部 建郎, 横川 和樹, 池田 和奈, 山本 大輔, 松村 晃寛, 鈴木 秀一郎, 久原 真, 松下 隆司, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  61 ( 1 ) 55 - 55  2021年01月

A case of Charcot-Marie-Tooth disease type 2Z caused by MORC2 S87L mutation mimicking spinal muscular atrophy

Daisuke Yamamoto, Ryosuke Oda, Shin Hisahara, Aki Ishikawa, Tomoo Ogi, Shun Shimohama

Clinical Neurology ( Societas Neurologica Japonica )  61 ( 4 ) 262 - 264  2021年

　概要を見る

A 33-year-old man with an unremarkable family history has had limb muscle weakness, joint contracture and skeleton deformation from early childhood. He was diagnosed with spinal muscular atrophy (SMA) by a pediatrician. He needed assistance and used orthoses in his daily life. There was no subjective sensory disturbance. However, physical examination showed slight sensory impairment, and nerve conduction study indicated sensory motor axonal neuropathy. This finding suggested Charcot-Marie-Tooth disease (CMT). Gene analysis detected MORC2 S87L mutation, leading to a diagnosis of CMT type 2Z. Patients with MORC2 S87L mutation are known to exhibit a severe phenotype, and may mimic SMA. It is important to demonstrate subclinical sensory neuropathy in patients with MORC2 S87L mutation mimicking SMA.

DOI PubMed

Hyperemesis-induced Wernicke-Korsakoff Syndrome due to Hypergastrinemia during Long-term Treatment with Proton Pump Inhibitors.

Rei Miyanaga, Shin Hisahara, Ikkei Ohhashi, Daisuke Yamamoto, Akihiro Matsumura, Syuuichirou Suzuki, Katsumasa Tanimoto, Masahiro Hirakawa, Jun Kawamata, Junji Kato, Shun Shimohama

Internal medicine (Tokyo, Japan)   59 ( 21 ) 2783 - 2787  2020年11月  [国内誌]

　概要を見る

We herein report a patient with Wernicke-Korsakoff syndrome (WKS) who had neither a history of alcoholism or of history of gastric surgery. A 56-year-old woman was transferred to our hospital because of the loss of consciousness and she was diagnosed to have Wernicke encephalopathy. She showed proton pump inhibitor-induced refractory hypergastrinemia with the subsequent development of hyperemesis and a vitamin B1 deficiency.

DOI PubMed

Severe mononeuritis multiplex due to rheumatoid vasculitis in rheumatoid arthritis in sustained clinical remission for decades

Masanobu Tanemoto, Shin Hisahara, Bungo Hirose, Kazuna Ikeda, Takashi Matsushita, Shuichiro Suzuki, Tatsuo Manabe, Tomihiro Imai, Shun Shimohama

Internal Medicine ( Japanese Society of Internal Medicine )  59 ( 5 ) 705 - 710  2020年03月

　概要を見る

Rheumatoid vasculitis (RV) usually occurs in patients with refractory rheumatoid arthritis (RA). An 80-year-old woman was transferred to our hospital because of muscle weakness and paresthesia in all 4 limbs. She had been diagnosed with RA 30 years ago and achieved sustained clinical remission. At presentation, polyarthritis and drop foot were observed, and rheumatoid factor was prominently elevated. A peripheral nerve conduction test revealed mononeuritis multiplex in her limbs. We suspected that RV had developed rapidly despite RA having been stable for many years and started immunosuppression therapy with steroids combined with azathioprine. The treatment prevented worsening of muscle weakness and paresthesia.

DOI PubMed

16SrRNA解析と膿瘍培養でFusobacterium nucleatumとStreptococcus intermediusの感染が判明した脳膿瘍の一例

真部 建郎, 種本 真将, 小田 亮介, 松村 晃寛, 久原 真, 下濱 俊

日本病院総合診療医学会雑誌 ( (一社)日本病院総合診療医学会 )  16 ( 臨増1 ) 65 - 65  2020年02月

16SrRNA解析と膿瘍培養でFusobacterium nucleatumとStreptococcus intermediusの感染が判明した脳膿瘍の一例

曹 博, 種本 真将, 廣瀬 文吾, 池田 和奈, 津田 玲子, 真部 建郎, 松下 隆司, 松村 晃寛, 鈴木 秀一郎, 久原 真, 高橋 聡, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  60 ( 1 ) 94 - 94  2020年01月

神経変性疾患に対する脳血流123I-IMP-SPECTにおけるCIScore解析の検証

松村 晃寛, 浅沼 治, 横川 和樹, 齋藤 太郎, 藤倉 舞, 岩原 直敏, 眞部 建郎, 津田 玲子, 山本 大輔, 松下 隆司, 鈴木 秀一郎, 臼井 桂子, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  59 ( Suppl. ) S266 - S266  2019年11月

神経変性疾患に対する脳血流123I-IMP-SPECTにおけるCIScore解析の検証

松村 晃寛, 浅沼 治, 横川 和樹, 齋藤 太郎, 藤倉 舞, 岩原 直敏, 眞部 建郎, 津田 玲子, 山本 大輔, 松下 隆司, 鈴木 秀一郎, 臼井 桂子, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  59 ( Suppl. ) S266 - S266  2019年11月

孤発性神経核内封入体病(NIID)の1例

廣瀬 文吾, 松下 隆司, 鈴木 秀一郎, 久原 真, 上杉 春雄, 川又 純, 今井 富裕, 曽根 淳, 祖父江 元, 下濱 俊

日本老年医学会雑誌 ( (一社)日本老年医学会 )  56 ( 4 ) 545 - 545  2019年10月

Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress.

Yokokawa K, Iwahara N, Hisahara S, Emoto MC, Saito T, Suzuki H, Manabe T, Matsumura A, Matsushita T, Suzuki S, Kawamata J, Sato-Akaba H, Fujii HG, Shimohama S

Journal of Alzheimer's disease : JAD   72 ( 3 ) 867 - 884  2019年10月  [査読有り]  [国際誌]

　概要を見る

Mesenchymal stem cells (MSC) are increasingly being studied as a source of cell therapy for neurodegenerative diseases, and several groups have reported their beneficial effects on Alzheimer's disease (AD). In this study using AD model mice (APdE9), we found that transplantation of MSC via the tail vein improved spatial memory in the Morris water maze test. Using electron paramagnetic resonance imaging to evaluate the in vivo redox state of the brain, we found that MSC transplantation suppressed oxidative stress in AD model mice. To elucidate how MSC treatment ameliorates oxidative stress, we focused on amyloid-β (Aβ) pathology and microglial function. MSC transplantation reduced Aβ deposition in the cortex and hippocampus. Transplantation of MSC also decreased Iba1-positive area in the cortex and reduced activated ameboid shaped microglia. On the other hand, MSC transplantation accelerated accumulation of microglia around Aβ deposits and prompted microglial Aβ uptake and clearance as shown by higher frequency of Aβ-containing microglia. MSC transplantation also increased CD14-positive microglia in vivo, which play a critical role in Aβ uptake. To confirm the effects of MSC on microglia, we co-cultured the mouse microglial cell line MG6 with MSC. Co-culture with MSC enhanced Aβ uptake by MG6 cells accompanied by upregulation of CD14 expression. Additionally, co-culture of MG6 cells with MSC induced microglial phenotype switching from M1 to M2 and suppressed production of proinflammatory cytokines. These data indicate that MSC treatment has the potential to ameliorate oxidative stress through modification of microglial functions, thereby improving Aβ pathology in AD model mice.

DOI PubMed

脊髄梗塞と鑑別を要しステロイドパルス療法で改善が得られた急性脊髄炎の1例

種本 真将, 鈴木 秀一郎, 廣瀬 文吾, 池田 和奈, 久原 真, 下濱 俊

神経治療学 ( (一社)日本神経治療学会 )  36 ( 6 ) S282 - S282  2019年10月

Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer's disease.

Saito T, Hisahara S, Iwahara N, Emoto MC, Yokokawa K, Suzuki H, Manabe T, Matsumura A, Suzuki S, Matsushita T, Kawamata J, Sato-Akaba H, Fujii HG, Shimohama S

Free radical biology & medicine   145   20 - 32  2019年09月  [査読有り]

DOI PubMed

悪性リンパ腫に合併した抗アクアポリン4抗体陽性散在性脳白質病変の1例

山田 稔, 津田 玲子, 山本 大輔, 松村 晃寛, 岩原 直敏, 松下 隆司, 鈴木 秀一郎, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  59 ( 6 ) 391 - 391  2019年06月

Evaluation of Mitochondrial Oxidative Stress in the Brain of a Transgenic Mouse Model of Alzheimer's Disease by in vitro Electron Paramagnetic Resonance Spectroscopy.

Manabe T, Matsumura A, Yokokawa K, Saito T, Fujikura M, Iwahara N, Matsushita T, Suzuki S, Hisahara S, Kawamata J, Suzuki H, Emoto MC, Fujii HG, Shimohama S

Journal of Alzheimer's disease : JAD   67 ( 3 ) 1079 - 1087  2019年  [査読有り]

DOI PubMed

CD14 and Toll-Like Receptor 4 Promote Fibrillar Aβ42 Uptake by Microglia Through A Clathrin-Mediated Pathway.

Mai Fujikura, Naotoshi Iwahara, Shin Hisahara, Jun Kawamata, Akihiro Matsumura, Kazuki Yokokawa, Taro Saito, Tatsuo Manabe, Takashi Matsushita, Syuuichirou Suzuki, Shun Shimohama

Journal of Alzheimer's disease : JAD   68 ( 1 ) 323 - 337  2019年  [国際誌]

　概要を見る

We previously demonstrated that microglia play an essential role in clearance of amyloid-β (Aβ) in Alzheimer's disease (AD)-like pathology. Our prior work also showed that several receptors expressed on microglia participated in Aβ phagocytosis. However, clathrin-mediated endocytosis (CME), which is associated with production and release of Aβ in neurons, has received much less attention in the context of microglial Aβ uptake. To elucidate the detailed mechanisms of microglial Aβ uptake pathways, we focused on CD14 and Toll-like receptor 4 (TLR4), which have been shown to mediate fibrillar Aβ1 - 42 (fAβ42) phagocytosis in microglia. CD14 has also been known to control lipopolysaccharide-induced internalization of TLR4 in a clathrin-dependent manner. However, it remains unclear whether CD14 and TLR4 engage in CME in microglial fAβ42 uptake, including whether CD14 interacts with TLR4 in the process. In the present study, we found that CD14-positive microglia increased in an age-dependent manner in the cortex of AD model mice. Immunostaining showed that CD14 interacted with TLR4 to internalize fAβ42 in the mouse microglial cell line MG6. Knock-down of CD14 and TLR4 in MG6 cells significantly reduced intracellular fAβ42, showing their involvement in fAβ42 uptake. We also found that clathrin participated in fAβ42 uptake by MG6 cells. Furthermore, CD14 and TLR4 mediated fAβ42 uptake via clathrin-dependent mechanisms. These results indicate that CD14 and TLR4 participate not only in phagocytosis but also in clathrin-dependent fAβ42 internalization in microglia. These findings provide novel molecular understanding of microglial fAβ42 uptake, which could be of therapeutic relevance for AD.

DOI PubMed

筋力低下を主訴とした孤発性成人発症型ネマリンミオパチーの1例

倉内 麗徳, 山本 大輔, 松村 晃寛, 鈴木 秀一郎, 松下 隆司, 村原 貴史, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

日本老年医学会雑誌 ( (一社)日本老年医学会 )  55 ( 4 ) 698 - 698  2018年10月

Arterial spin labelingが早期診断に貢献した進行性多巣性白質脳症の一例

松下 隆司, 中村 祐貴, 齋藤 太郎, 津田 玲子, 山本 大輔, 松村 晃寛, 鈴木 秀一郎, 津田 笑子, 久原 真, 川又 純, 菅原 太郎, 杉田 真太朗, 中道 一生, 下濱 俊

NEUROINFECTION ( 日本神経感染症学会 )  23 ( 2 ) 225 - 225  2018年10月

脳血流IMP-SPECTにおけるCIScore解析によるDLB・AD鑑別の検証

松村 晃寛, 浅沼 治, 蒲生 直希, 横川 和樹, 齋藤 太郎, 藤倉 舞, 岩原 直敏, 真部 建郎, 津田 玲子, 山本 大輔, 松下 隆司, 鈴木 秀一郎, 臼井 桂子, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

Dementia Japan ( (一社)日本認知症学会 )  32 ( 3 ) 452 - 452  2018年09月

[Sporadic adult-onset neuronal intranuclear inclusion disease with abnormal electroretinogram, nerve conduction studies and somatosensory evoked potential].

Bungo Hirose, Shin Hisahara, Haruo Uesugi, Jun Sone, Gen Sobue, Shun Shimohama

Rinsho shinkeigaku = Clinical neurology   58 ( 6 ) 407 - 410  2018年06月  [国内誌]

　概要を見る

A 70-year-old man, a urinary retention of unknown origin from 10 years ago, decreased cognitive function from 4 years ago, vision impairment advanced a year ago. Brain MRI with DWI showed high intensity erea in the cortico-medullary junction. We diagnosed as intranuclear inclusion body disease (NIID) because of p62-positive intranuclear inclusion bodies by skin biopsy. Electroretinogram revealed amplitude reduction in the cone response superiority. Nerve conduction test showed mild conduction velocity reduction. Furthermore, in the somatosensory evoked potential of the lower limb, latency of the first cortical component was prolonged. These electrophysiological abnormalities were considered to be associated with the pathological features of NIID.

DOI PubMed

網膜電図、末梢神経伝導検査、体性感覚誘発電位異常を伴った孤発性神経核内封入体病の1例

廣瀬 文吾, 久原 真, 上杉 春雄, 曽根 淳, 祖父江 元, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  58 ( 6 ) 407 - 410  2018年06月

　概要を見る

症例は70歳の男性、10年前より原因不明の尿閉、4年前より認知機能低下、1年前より視力障害が進行した。頭部MRI拡散強調画像で皮質下皮髄境界に弧状の高信号を、皮膚生検で神経核内封入体を認めたため神経核内封入体病(neuronal intranuclear inclusion disease;NIID)と診断した。神経伝導検査では軽度の伝導速度低下を、下肢体性感覚誘発電位では早期皮質潜時の延長が見られた。視力低下の原因精査で行った網膜電図では錐体応答優位に振幅低下を認めていた。これらの所見は他に明らかな原因がなくNIIDに伴う異常と考えられた。視力低下は臨床徴候として知られておらず詳細な文献的考察は少ない。症例の集積が必要であると考えられる。(著者抄録)

Non-HIV-PMLの診断後2年以上生存した1症例

中村 祐貴, 齋藤 太郎, 津田 玲子, 山本 大輔, 松下 隆司, 松村 晃寛, 鈴木 秀一郎, 津田 笑子, 久原 真, 川又 純, 下濱 俊, 菅原 太郎, 杉田 真太朗, 中道 一生

臨床神経学 ( (一社)日本神経学会 )  58 ( 5 ) 358 - 358  2018年05月

Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis.

Yusei Miyazaki, Masaaki Niino, Eri Takahashi, Masako Suzuki, Masanori Mizuno, Shin Hisahara, Toshiyuki Fukazawa, Itaru Amino, Fumihito Nakano, Masakazu Nakamura, Sachiko Akimoto, Naoya Minami, Naoto Fujiki, Shizuki Doi, Shun Shimohama, Yasuo Terayama, Seiji Kikuchi

Clinical immunology (Orlando, Fla.)   187   95 - 101  2018年02月  [国際誌]

　概要を見る

Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease.

DOI PubMed

修正型電気けいれん療法(mECT)施行後、著明なparkinsonismの改善を認めた重度精神症状合併Parkinson病の2例

大橋 一慶, 鈴木 秀一郎, 山本 大輔, 松村 晃寛, 松下 隆司, 久原 真, 川又 純, 下濱 俊, 石田 智隆, 松山 清治, 河西 千秋, 柏木 智則

臨床神経学 ( (一社)日本神経学会 )  57 ( 12 ) 815 - 815  2017年12月  [査読有り]

尿閉が先行し、経過中に網膜電図異常を伴う視力低下を認めた孤発性神経核内封入体病(NIID)の1例

廣瀬 文吾, 土谷 円花, 宮永 怜, 眞部 建郎, 山本 大輔, 松下 隆司, 松村 晃寛, 鈴木 秀一郎, 久原 真, 川又 純, 上杉 春雄, 今井 富裕, 下濱 俊, 曽根 淳, 祖父江 元

臨床神経学 ( (一社)日本神経学会 )  57 ( 12 ) 815 - 815  2017年12月

Effect of local cooling on excitation-contraction coupling in myasthenic muscle: Another mechanism of ice-pack test in myasthenia gravis

Daisuke Yamamoto, Tomihiro Imai, Emiko Tsuda, Takayoshi Hozuki, Rika Yamauchi, Shin Hisahara, Jun Kawamata, Shun Shimohama

CLINICAL NEUROPHYSIOLOGY ( ELSEVIER IRELAND LTD )  128 ( 11 ) 2309 - 2317  2017年11月  [査読有り]

　概要を見る

Objective: The ice-pack test is a convenient diagnostic testing procedure for myasthenia gravis (MG). We investigated the underlying mechanism of the ice-pack test performed on bilateral masseters.& para;& para;Methods: We performed trigeminal repetitive nerve stimulation (RNS), excitation-contraction (E-C) coupling assessment (lmai's method) and bite force measurement before and after cooling of the masseters in MG patients and normal controls. After placing the ice-pack on the masseters for 3 min, serial recordings of the three tests were performed at various time intervals during 10 min after cooling.& para;& para;Results: The bite force increased significantly after cooling in ice-pack-positive MG patients. The acceleration and acceleration ratio (acceleration at a given time to baseline acceleration) of jaw movement increased significantly after cooling of the masseters in ice-pack-positive MG patients compared to ice-pack-negative patients and normal controls. The prolonged effect of cooling continued until the end of recording even though decremental response to RNS had returned to baseline value.& para;& para;Conclusions: Cooling of myasthenic muscle may induce two effects. One is relatively short effect on electrical synaptic transmission at the endplate, and another is prolonged effect on E-C coupling in the muscle.& para;& para;Significance: The ice-pack test induces a prolonged effect of ameliorating impaired E-C coupling in MG. (C) 2017 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI PubMed

急性硬膜下血腫開頭術後に発症した硬膜動静脈瘻の1例

大橋 一慶, 山本 大輔, 松村 晃寛, 鈴木 秀一郎, 松下 隆司, 村原 貴史, 津田 笑子, 齊藤 正樹, 久原 真, 川又 純, 宮田 圭, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  57 ( 6 ) 324 - 324  2017年06月

四肢腱反射が亢進し、病的反射が陽性であったギランバレー症候群の1例

倉内 麗徳, 山本 大輔, 松村 晃寛, 鈴木 秀一郎, 松下 隆司, 村原 貴史, 津田 笑子, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  57 ( 6 ) 321 - 321  2017年06月

末梢神経障害を伴った強皮症の1例

山田 稔, 津田 笑子, 鈴木 秀一郎, 松村 晃寛, 村原 貴史, 松下 隆司, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  57 ( 6 ) 322 - 322  2017年06月

Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice.

Naotoshi Iwahara, Shin Hisahara, Jun Kawamata, Akihiro Matsumura, Kazuki Yokokawa, Taro Saito, Mai Fujikura, Tatsuo Manabe, Hiromi Suzuki, Takashi Matsushita, Syuuichirou Suzuki, Shun Shimohama

Journal of Alzheimer's disease : JAD   55 ( 3 ) 1235 - 1247  2017年  [国際誌]

　概要を見る

In response to changes of the central nervous system environment, microglia are capable of acquiring diverse phenotypes for cytotoxic or immune regulation and resolution of injury. Alzheimer's disease (AD) pathology also induces several microglial activations, resulting in production of pro-inflammatory cytokines and reactive oxygen species or clearance of amyloid-β (Aβ) through phagocytosis. We previously demonstrated that microglial activation and increase in oxidative stress started from the middle age in APPswe/PS1dE9 mice, and hypothesized that M1 activation occurs in middle-aged AD mice by Aβ stimulation. In the present study, we analyzed in vivo expressions of pro-inflammatory cytokines (M1 microglial markers), M2 microglial markers, and suppressor of cytokine signaling (SOCS) family, and examined the microglial phenotypic profile in APPswe/PS1dE9 mice. Then we compared the in vitro gene expression patterns of Aβ- and lipopolysaccharide (LPS)-stimulated primary-cultured microglia. Microglia in APPswe/PS1dE9 mice exhibited an M1-like phenotype, expressing tumor necrosis factor α (TNFα) but not interleukin 6 (IL6). Aβ-stimulated primary-cultured microglia also expressed TNFα but not IL6, whereas LPS-stimulated primary-cultured microglia expressed both pro-inflammatory cytokines. Furthermore, both microglia in APPswe/PS1dE9 mice and Aβ-stimulated primary-cultured microglia expressed SOCS3. Reduction of SOCS3 expression in Aβ-challenged primary-cultured microglia resulted in upregulation of IL6 expression. Our findings indicate that SOCS3 suppresses complete polarization to M1 phenotype through blocking IL6 production, and Aβ-challenged primary-cultured microglia replicate the in vivo gene expression pattern of microglia in APPswe/PS1dE9 mice. Aβ may induce the M1-like phenotype through blocking of IL6 by SOCS3.

PubMed

右正中神経前腕部で伝導ブロックを呈し、多巣性運動ニューロパチーが疑われた1例

倉内 麗徳, 山本 大輔, 松村 晃寛, 鈴木 秀一郎, 松下 隆司, 村原 貴史, 津田 笑子, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  56 ( 11 ) 801 - 801  2016年11月

FUS/TLS R521L変異を認めた家族性筋萎縮性側索硬化症(FALS)の1家系

大橋 一慶, 山本 大輔, 松村 晃寛, 鈴木 秀一郎, 松下 隆司, 村原 貴史, 津田 笑子, 齊藤 正樹, 久原 真, 川又 純, 鈴木 昭治, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  56 ( 11 ) 803 - 803  2016年11月

下垂足を呈し末梢神経障害との鑑別を要した胸髄症の1例

池田 和奈, 石田 智隆, 蒲生 直希, 山本 大輔, 鈴木 秀一郎, 津田 笑子, 久原 真, 村原 貴史, 松下 隆司, 松村 晃寛, 齊藤 正樹, 川又 純, 下濱 俊, 今井 富裕

臨床神経学 ( (一社)日本神経学会 )  56 ( 11 ) 802 - 802  2016年11月

けいれん重積を来したAngiomyxomatous tumorの一例

横川 和樹, 池田 和奈, 越智 龍太郎, 村原 貴史, 臼井 桂子, 松下 隆司, 松村 晃寛, 津田 笑子, 鈴木 秀一郎, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊, 江夏 怜, 三國 信啓, 杉田 真太朗, 長谷川 匡

臨床神経学 ( (一社)日本神経学会 )  56 ( 11 ) 802 - 802  2016年11月

肥厚性硬膜炎様の頭部MRI所見を呈したびまん性大細胞型B細胞リンパ腫の1例

蒲生 直希, 池田 和奈, 鈴木 秀一郎, 津田 笑子, 村原 貴史, 松下 隆司, 松村 晃寛, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  56 ( 11 ) 804 - 804  2016年11月

首下がりで発症した重症筋無力症の1例

山田 稔, 倉内 麗徳, 村原 貴史, 津田 笑子, 鈴木 秀一郎, 林 貴士, 齊藤 正樹, 久原 真

日本老年医学会雑誌 ( (一社)日本老年医学会 )  53 ( 4 ) 441 - 441  2016年10月

ANCA-negative granulomatosis with polyangiitis presenting with orbital apex syndrome and recurrent pachymeningitis: A case report.

Shin Hisahara, Minoru Yamada, Yousuke Matsuura, Emiko Tsuda, Yukinori Akiyama, Masaki Saitoh, Jun Kawamata, Nobuhiro Mikuni, Shun Shimohama

Journal of the neurological sciences   368   175 - 7  2016年09月  [国際誌]

DOI PubMed

Fingolimod suppresses bone resorption in female patients with multiple sclerosis.

Yusei Miyazaki, Masaaki Niino, Ippei Kanazawa, Masako Suzuki, Masanori Mizuno, Shin Hisahara, Toshiyuki Fukazawa, Eri Takahashi, Itaru Amino, Ryutaro Ochi, Masakazu Nakamura, Sachiko Akimoto, Naoya Minami, Naoto Fujiki, Shizuki Doi, Shun Shimohama, Yasuo Terayama, Seiji Kikuchi

Journal of neuroimmunology   298   24 - 31  2016年09月  [国際誌]

　概要を見る

Fingolimod is a sphingosine-1-phosphate receptor agonist used to inhibit the inflammatory activity of multiple sclerosis (MS), and has been shown to suppress osteoporosis in mouse models. In this study, levels of bone turnover markers were quantified in serum and urine samples from MS patients treated with fingolimod. Compared with untreated MS patients and healthy controls, fingolimod-treated MS patients had a significantly lower level of the bone resorption marker type I collagen cross-linked N-telopeptide in urine. This finding was prominent in female but was not seen in male subjects. Our results suggest that fingolimod may have a beneficial effect on bone mass loss in female MS patients.

DOI PubMed

Oxidation and interaction of DJ-1 with 20S proteasome in the erythrocytes of early stage Parkinson's disease patients.

Yoshiro Saito, Yoko Akazawa-Ogawa, Akihiro Matsumura, Kazumasa Saigoh, Sayoko Itoh, Kenta Sutou, Mayuka Kobayashi, Yuichiro Mita, Mototada Shichiri, Shin Hisahara, Yasuo Hara, Harutoshi Fujimura, Hiroyuki Takamatsu, Yoshihisa Hagihara, Yasukazu Yoshida, Takao Hamakubo, Susumu Kusunoki, Shun Shimohama, Noriko Noguchi

Scientific reports   6   30793 - 30793  2016年07月  [国際誌]

　概要を見る

Parkinson's disease (PD) is a progressive, age-related, neurodegenerative disorder, and oxidative stress is an important mediator in its pathogenesis. DJ-1, the product of the causative gene of a familial form of PD, plays a significant role in anti-oxidative defence to protect cells from oxidative stress. DJ-1 undergoes preferential oxidation at the cysteine residue at position 106 (Cys-106) under oxidative stress. Here, using specific antibodies against Cys-106-oxidized DJ-1 (oxDJ-1), it was found that the levels of oxDJ-1 in the erythrocytes of unmedicated PD patients (n = 88) were higher than in those of medicated PD patients (n = 62) and healthy control subjects (n = 33). Elevated oxDJ-1 levels were also observed in a non-human primate PD model. Biochemical analysis of oxDJ-1 in erythrocyte lysates showed that oxDJ-1 formed dimer and polymer forms, and that the latter interacts with 20S proteasome. These results clearly indicate a biochemical alteration in the blood of PD patients, which could be utilized as an early diagnosis marker for PD.

DOI PubMed

MFN2遺伝子点変異を有するシャルコー・マリー・トゥース病の1例

横川 和樹, 池田 和奈, 村原 貴史, 齊藤 正樹, 鈴木 秀一郎, 津田 笑子, 林 貴士, 久原 真, 川又 純, 下濱 俊, 外山 祐一郎

臨床神経学 ( (一社)日本神経学会 )  56 ( 6 ) 453 - 453  2016年06月

ネフローゼ症候群、潰瘍性大腸炎、再生不良性貧血を合併した抗MuSK抗体陽性重症筋無力症の1例

安食 さえ子, 横川 和樹, 津田 笑子, 久原 真, 鈴木 秀一郎, 林 貴士, 齊藤 正樹, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  56 ( 6 ) 452 - 452  2016年06月

肛門周囲の感覚障害で発症し、前立腺生検にて診断に至った血管内リンパ腫(IVL)の1例

齋藤 太郎, 中村 祐貴, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊, 村瀬 和幸, 高田 弘一

臨床神経学 ( (一社)日本神経学会 )  56 ( 6 ) 451 - 451  2016年06月

遅発性顔面神経麻痺を呈したフィッシャー症候群の1例

清水 将輝, 平野 理都子, 齋藤 太郎, 山本 大輔, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 廣瀬 文吾, 山田 稔, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  56 ( 6 ) 453 - 453  2016年06月

三叉神経障害で発症した多発性硬化症の一例

平野 理都子, 中村 祐貴, 齋藤 太郎, 眞部 建郎, 山本 大輔, 松下 隆司, 鈴木 秀一郎, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  56 ( 6 ) 447 - 447  2016年06月

嚥下障害が残存した抗SRP抗体陽性ミオパチーの2症例

中村 祐貴, 齋藤 太郎, 松下 隆司, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊, 岡本 賢三

臨床神経学 ( (一社)日本神経学会 )  56 ( 6 ) 452 - 452  2016年06月

出産直後に再発を認めた視神経脊髄炎の1例

池田 和奈, 安食 さえ子, 津田 笑子, 久原 真, 鈴木 秀一郎, 林 貴士, 齊藤 正樹, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  56 ( 6 ) 447 - 447  2016年06月

Impaired post-tetanic potentiation of muscle twitch in myasthenia gravis

Daisuke Yamamoto, Tomihiro Imai, Emiko Tsuda, Takayoshi Hozuki, Rika Yamauchi, Shin Hisahara, Jun Kawamata, Shun Shimohama

CLINICAL NEUROPHYSIOLOGY ( ELSEVIER IRELAND LTD )  127 ( 2 ) 1689 - 1693  2016年02月  [査読有り]

　概要を見る

Objective: The aim of this study was to evaluate post-tetanic potentiation of muscle twitch in myasthenia gravis (MG). Methods: Post-tetanic potentiation was evaluated by recording the compound muscle action potential (CMAP) of abductor pollicis brevis and movement-related potential (MRP) of the thumb using an accelerometer after tetanic stimulation of the median nerve at the wrist. After baseline recording, tetanic stimulation was delivered to the median nerve at a frequency of 10 Hz for 10 s. The CMAP and MRP were successively recorded at baseline and at 5, 10, 30, 60, 90 and 120 s after tetanic stimulation. The chronological changes of CMAPs and MRPs were recorded bilaterally in 11 patients with MG, 9 patients with myopathies (disease controls), and 25 healthy control subjects. Results: Maximal acceleration of MRP was significantly elevated during 10 s after tetanic stimulation without any CMAP changes in all groups. However, statistical analysis detected a significant decrease in post-tetanic potentiation of maximal acceleration of MRP in MG patients only compared to healthy controls, but not in myopathy patients, which may imply impairment of excitation-contraction coupling in MG. Conclusions: Post-tetanic potentiation of muscle twitch is significantly diminished in MG, suggesting impaired excitation-contraction coupling. Significance: Measurement of post-tetanic potentiation using an accelerometer is a simple and sensitive method to detect impairment of excitation-contraction coupling in MG. (C) 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI

短期間で再増悪した脱髄性ニューロパチーの一例

加賀 理都子, 中村 祐貴, 山田 稔, 山本 大輔, 松下 隆司, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 12 ) 944 - 944  2015年12月

当初CLIPPERSを疑い難治に経過した脳炎の1例

野中 隆行, 山田 稔, 村原 貴史, 安食 さえ子, 齋藤 太郎, 鈴木 秀一郎, 津田 笑子, 山内 理香, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 12 ) 946 - 946  2015年12月

嚥下障害が遷延した浸透圧性脱髄症候群の1例

山田 稔, 村原 貴史, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 12 ) 944 - 944  2015年12月

GalNAc-GD1a IgM抗体陽性急性運動感覚性軸索型ニューロパチー(AMSAN)の1例

齋藤 太郎, 山本 大輔, 鈴木 秀一郎, 津田 笑子, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 廣瀬 文吾, 鈴木 昭治, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 12 ) 944 - 944  2015年12月

低血糖をきたした非福山型先天性筋ジストロフィーの1例

中村 祐貴, 吉崎 那保, 山田 稔, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 12 ) 947 - 947  2015年12月

当施設における筋萎縮性側索硬化症(ALS)患者の人工呼吸器選択について

川又 純, 山本 大輔, 鈴木 秀一郎, 津田 笑子, 山内 理香, 齊藤 正樹, 久原 真, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( Suppl. ) S378 - S378  2015年12月

メフロキンおよびミルタザピン投与によりJCV DNA-PCRが陰性化したPMLの1例

横川 和樹, 松浦 洋介, 池田 和奈, 津田 笑子, 久原 真, 鈴木 秀一郎, 林 貴士, 齊藤 正樹, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 12 ) 945 - 945  2015年12月

Tolosa-Hunt症候群と鑑別が困難であった肥厚性硬膜炎の1例

安食 さえ子, 中村 祐貴, 山田 稔, 松下 隆司, 村原 貴史, 矢澤 省吾, 林 貴士, 鈴木 秀一郎, 津田 笑子, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 12 ) 948 - 948  2015年12月

パーキンソニズムを呈するSCA6の1例

池田 和奈, 大岩 修太郎, 津田 笑子, 齊藤 正樹, 鈴木 秀一郎, 林 貴士, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 12 ) 945 - 945  2015年12月

肥厚性硬膜炎、大脳病変を呈した多発血管炎性肉芽腫症が疑われた1例

山田 稔, 松浦 洋介, 津田 笑子, 鈴木 秀一郎, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 9 ) 682 - 682  2015年09月

ボリコナゾールによる診断的治療が有用であった深在性アスペルギルス症の1例

横川 和樹, 山本 大輔, 鈴木 秀一郎, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

神経治療学 ( (一社)日本神経治療学会 )  32 ( 5 ) 787 - 787  2015年09月

Metronidazoleにより脳症と末梢神経障害を来した1例

廣瀬 文吾, 小林 未来, 山本 大輔, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 9 ) 681 - 681  2015年09月

多彩な非運動症状を呈した重症筋無力症の1例

倉内 麗徳, 津田 笑子, 山本 大輔, 鈴木 秀一郎, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 9 ) 682 - 682  2015年09月

Latitude and HLA-DRB1 alleles independently affect the emergence of cerebrospinal fluid IgG abnormality in multiple sclerosis.

Niino M, Sato S, Fukazawa T, Yoshimura S, Hisahara S, Matsushita T, Isobe N, Yoshida K, Houzen H, Miyazaki Y, Shimohama S, Kikuchi S, Kira J

Multiple sclerosis (Houndmills, Basingstoke, England)   21 ( 9 ) 1112 - 1120  2015年08月  [査読有り]  [国際誌]

　概要を見る

BACKGROUND: It is unclear whether the prevalence of oligoclonal IgG bands (OCBs) in multiple sclerosis (MS) is different between northern and southern regions of Asia. OBJECTIVE: This study aimed to compare the prevalence of OCBs and positive cerebrospinal fluid (CSF) findings between northern and southern regions of Japan and to investigate the association of these CSF findings with HLA-DRB1 alleles. METHODS: The study included 180 MS patients from Hokkaido (northern Japan) and 184 patients from Kyushu (southern Japan). The IgG index was defined as increased if it was >0.658. Presence of CSF OCBs and/or increased IgG index was defined as positive CSF findings. RESULTS: Positive CSF findings and OCB positivity were significantly higher in MS patients from Hokkaido than in those from Kyushu (p < 0.0001 for both). Logistic regression analysis revealed that after adjusting for covariates that can be related to abnormal CSF IgG production, the geographic region (Hokkaido) showed odds ratios (ORs) of 4.08 and 2.57, whereas the HLA-DRB1*04:05 allele showed ORs of 0.36 and 0.30 for positive CSF findings and OCB positivity, respectively. CONCLUSIONS: The results indicate that latitude and HLA-DRB1 alleles independently affect the emergence of CSF IgG abnormalities in Japanese patients with MS.

DOI PubMed

Evaluation of oxidative stress in the brain of a transgenic mouse model of Alzheimer disease by in vivo electron paramagnetic resonance imaging.

Matsumura A, Emoto MC, Suzuki S, Iwahara N, Hisahara S, Kawamata J, Suzuki H, Yamauchi A, Sato-Akaba H, Fujii HG, Shimohama S

Free radical biology & medicine   85   165 - 173  2015年08月  [査読有り]

DOI PubMed

A Heterozygous Missense Mutation in Adolescent-Onset Very Long-Chain Acyl-CoA Dehydrogenase Deficiency with Exercise-Induced Rhabdomyolysis

Shin Hisahara, Takashi Matsushita, Hiroyasu Furuyama, Go Tajima, Yosuke Shigematsu, Tomihiro Imai, Shun Shimohama

TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE ( TOHOKU UNIV MEDICAL PRESS )  235 ( 4 ) 305 - 310  2015年04月  [査読有り]

　概要を見る

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is characterized by impaired mitochondrial beta-oxidation of fatty acids. The fatty acid oxidation plays a significant role in energy production especially in skeletal muscle. VLCAD is one of four acyl-CoA dehydrogenases with different-chain length specificity and catalyzes the initial step in mitochondrial beta-oxidation of fatty acids. While the clinical phenotypes in neonates and infants are described as severe, adolescent-onset or adult-onset VLCAD deficiency has a more benign course with only skeletal muscle involvement. These myopathic phenotypes are characterized by episodic muscle weakness and rhabdomyolysis triggered by fasting and strenuous exercise. We report a male teenager who manifested repeated episodes of rhabdomyolysis immediately after exertional exercise. Rhabdomyolysis was diagnosed based on the marked elevation of serum creatine kinase and nnyoglobinuria. Acylcarnitine analysis by tandem mass spectrometry (MS/MS) revealed elevation of serum tetradecenoylcarnitine (C14:1-AC), which represents an abnormal acylcarnitine profile associated with the mitochondrial beta-oxidation defect. High performance liquid chromatographic analysis showed decreased production of 2-hexadecenoyl-CoA (C16:1) from palmitoyl-CoA (C16:0), indicating the defect of VLCAD activity. Direct sequencing of the acyl-CoA dehydrogenase, very long-chain gene (ACADVL) that codes VLCAD revealed a heterozygous mutation (c.1242G>C) in exon 12 (E414D), which is a novel mutation in myopathic-type VLCAD deficiency. Because VLCAD functions as a homodimer, we assume that this heterozygous mutation may exhibit dominant-negative effect. This patient remains asymptomatic thereafter by avoiding exertional exercise. The findings of reduction of enzyme activity and clinical features associated with this novel missense mutation of VLCAD are discussed.

DOI PubMed

診断に苦慮した中枢神経サルコイドーシスの1例

山田 稔, 池田 和奈, 廣瀬 文吾, 小林 未来, 山本 大輔, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 2 ) 132 - 132  2015年02月

大脳皮質基底核変性症(CBD)と筋萎縮性側索硬化症(ALS)の合併が疑われた1例

小林 未来, 廣瀬 文吾, 山本 大輔, 鈴木 秀一郎, 岩原 直敏, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 2 ) 131 - 131  2015年02月

後骨間神経麻痺様の経過を呈した若年性一側上肢筋萎縮症(平山病)の一例

倉内 麗徳, 山本 大輔, 池田 和奈, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 2 ) 129 - 129  2015年02月

頸髄病変にopen-ring状の造影効果を認めた一例

松浦 洋介, 山本 大輔, 廣瀬 文吾, 小林 未来, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  55 ( 2 ) 132 - 132  2015年02月

Intravenous mesenchymal stem cell administration exhibits therapeutic effects against 6-hydroxydopamine-induced dopaminergic neurodegeneration and glial activation in rats.

Suzuki S, Kawamata J, Iwahara N, Matsumura A, Hisahara S, Matsushita T, Sasaki M, Honmou O, Shimohama S

Neuroscience letters   584   276 - 281  2015年01月  [査読有り]  [国際誌]

　概要を見る

To explore a novel therapy against Parkinson's disease (PD), we evaluated the therapeutic effects of human bone marrow-derived mesenchymal stem cells (hBM-MSCs), pluripotent stromal cells with secretory potential of various neurotrophic and anti-inflammatory factors, in a hemi-parkinsonian rat model. The unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were injected hBM-MSCs (1.0 × 10(7)cells) or PBS intravenously 16 days after lesioning. Administration of hBM-MSCs inhibited methamphetamine-stimulated rotational behavior at 7, 14, 21 and 28 days after transplantation. Immunohistochemical analysis also showed that number of TH-positive neurons in the substantia nigra pars compacta was significantly preserved in hBM-MSCs-transplanted rats compared to sham-operated rats, whereas the immunoreactivity of ionized calcium binding adaptor molecule 1 was markedly inhibited. In this study, we demonstrated the therapeutic effects of intravenous hBM-MSCs administration in parkinsonian model rats presenting distinct parkinsonian phenotype at 16 days after 6-OHDA lesioning. The favorable findings raise the possibility that hBM-MSCs could be a novel therapeutic option to promote survival of dopaminergic neurons in PD.

DOI PubMed

Temporal changes of CD68 and α7 nicotinic acetylcholine receptor expression in microglia in Alzheimer's disease-like mouse models.

Matsumura A, Suzuki S, Iwahara N, Hisahara S, Kawamata J, Suzuki H, Yamauchi A, Takata K, Kitamura Y, Shimohama S

Journal of Alzheimer's disease : JAD   44 ( 2 ) 409 - 423  2015年  [査読有り]  [国際誌]

　概要を見る

We previously reported that activated microglia are involved in amyloid-β (Aβ) clearance and that stimulation of α7 nicotinic acetylcholine receptors (nAChR) in microglia enhances Aβ clearance. Nevertheless, how microglia and α7 nAChR in microglia are affected in Alzheimer's disease (AD) remains unknown. The present study aimed to collect fundamental data for considering whether microglia are potential targets for AD treatment and the appropriate timing of therapeutic intervention, by evaluating the temporal changes of Aβ, microglia, neurons, presynapses, and α7 nAChR by immunohistochemical studies in mouse models of AD. In an Aβ-injected AD mouse model, we observed early accumulation of CD68-positive microglia at Aβ deposition sites and gradual reduction of Aβ. Microglia were closely associated with Aβ deposits, and were confirmed to participate in clearing Aβ. In a transgenic mouse model of AD, we observed an increase in Aβ deposition from 6 months of age, followed by a gradual increase in microglial accumulation at Aβ deposit sites. Activated microglia in APdE9 mice showed two-step transition: a CD68-negative activated form at 6-9 months and a CD68-positive form from 12 months of age. In addition, α7 nAChR in microglia increased markedly at 6 months of age when activated microglia appeared for the first time, and decreased gradually coinciding with the increase of Aβ deposition. These findings suggest that early microglial activation is associated with α7 nAChR upregulation in microglia in APdE9 mice. These novel findings are important for the development of new therapeutic strategy for AD.

DOI PubMed

Long-term clinical and radiological improvement of chronic acquired hepatocerebral degeneration after obliteration of portosystemic shunt: Report of a case

Shin Hisahara, Takashi Matsushita, Mizuki Kitamura, Shinichi Mezawa, Michio Nonaka, Tomihiro Imai, Shun Shimohama

JOURNAL OF THE NEUROLOGICAL SCIENCES ( ELSEVIER SCIENCE BV )  346 ( 1-2 ) 303 - 306  2014年11月  [査読有り]

　概要を見る

Neurological manifestations are common in patients with decompensated cirrhosis. The majority of these patients show hepatic encephalopathy or chronic acquired (non-Wilsonian) hepatocerebral degeneration (CAHD). They characteristically present with dysarthria, ataxia, involuntary movements, and altered mental status. Neuroradiological examination in patients with hepatic encephalopathy often shows abnormal signals in multiple regions of the brain, such as the pallidum, putamen, caudate nucleus, hemispheric white matter, and ventral midbrain. The pathogenesis of hepatic encephalopathy and CAHD is poorly understood and the response to conventional therapies is often poor. We report a male patient with cirrhosis of unknown cause, who developed slowly progressive cerebellar truncal and limb ataxia and slurred speech. Magnetic resonance imaging (MRI) showed focal T2 hyperintensity in bilateral dentate nuclei and middle cerebellar peduncles (MCPs). After treatment by obliteration of the portosystemic shunt, clinical manifestations and MM abnormalities were dramatically improved. He was followed for six years until he died of uncontrollable bleeding due to hepatocellular carcinoma. At the last examination 9 months before death, he showed no apparent aggravation of neurological symptoms, and no abnormal signal intensities in the MCPs and supratentorial compartment. The clinical course and changes of brain MM findings of this case are extremely rare, suggesting that obliteration of the portosystemic shunt may be effective for CAHD over long term. (C) 2014 Elsevier B.V. All rights reserved.

DOI PubMed

家族歴のある自己免疫性脳症と考えられた一例

田中 真理子, 村原 貴史, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  54 ( 10 ) 834 - 834  2014年10月

Painful tonic spasmを呈したNMOSDの1例

藤倉 舞, 山本 大輔, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  54 ( 10 ) 834 - 834  2014年10月

全般性認知機能障害を伴わない緩徐進行性失行の1例

池田 和奈, 山本 大輔, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  54 ( 10 ) 837 - 837  2014年10月

脊髄性筋萎縮症様の所見および不整脈、心機能低下を呈し、新規LaminA/C遺伝子変異を認めた1例

岩原 直敏, 山本 大輔, 津田 玲子, 林 貴士, 鈴木 秀一郎, 津田 笑子, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  54 ( 10 ) 838 - 838  2014年10月

Alzheimer病モデル動物脳におけるmicrogliaの経時的動態

松村 晃寛, 鈴木 紘美, 山内 綾乃, 岩原 直敏, 鈴木 秀一郎, 久原 真, 川又 純, 高田 和幸, 北村 佳久, 下濱 俊

Dementia Japan ( (一社)日本認知症学会 )  28 ( 4 ) 481 - 481  2014年10月

診断に苦慮した中枢神経サルコイドーシスの1例

池田 和奈, 山本 大輔, 鈴木 秀一郎, 津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

神経治療学 ( (一社)日本神経治療学会 )  31 ( 5 ) 627 - 627  2014年09月

3-[(2,4-Dimethoxy)benzylidene]-anabaseine dihydrochloride protects against 6-hydroxydopamine-induced parkinsonian neurodegeneration through α7 nicotinic acetylcholine receptor stimulation in rats.

Suzuki S, Kawamata J, Matsushita T, Matsumura A, Hisahara S, Takata K, Kitamura Y, Kem W, Shimohama S

Journal of neuroscience research ( 3 )  91 ( 3 ) 462 - 471  2013年03月  [査読有り]  [国際誌]

　概要を見る

To explore a novel therapy against Parkinson's disease through enhancement of α7 nicotinic acetylcholine receptor (nAChR), we evaluated the neuroprotective effects of 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (DMXBA; GTS-21), a functionally selective α7 nAChR agonist, in a rat 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian model. Microinjection of 6-OHDA into the nigrostriatal pathway of rats destroys dopaminergic neurons selectively. DMXBA dose dependently inhibited methamphetamine-stimulated rotational behavior and dopaminergic neuronal loss induced by 6-OHDA. The protective effects were abolished by methyllycaconitine citrate salt hydrate, an α7 nAChR antagonist. Immunohistochemical study confirmed abundant α7 nAChR expression in the cytoplasm of dopaminergic neurons. These results indicate that DMXBA prevented 6-OHDA-induced dopaminergic neuronal loss through stimulating α7 nAChR in dopaminergic neurons. Injection of 6-OHDA elevated immunoreactivities to glial markers such as ionized calcium binding adaptor molecule 1, CD68, and glial fibrillary acidic protein in the substantia nigra pars compacta of rats. In contrast, these immunoreactivities were markedly inhibited by comicroinjection of DMXBA. Microglia also expressed α7 nAChR in both resting and activated states. Hence, we hypothesize that DMXBA simultaneously affects microglia and dopaminergic neurons and that both actions lead to dopaminergic neuroprotection. The findings that DMXBA attenuates 6-OHDA-induced dopaminergic neurodegeneration and glial activation in a rat model of Parkinson's disease raisethe possibility that DMXBA could be a novel therapeutic compound to prevent Parkinson's disease development.

DOI PubMed

原因不明のまま治療開始した頭蓋底病変の予後 多発性脳神経障害を呈した感染症を中心に

松村 晃寛, 今井 富裕, 齊藤 正樹, 久原 真, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  53 ( 1 ) 9 - 18  2013年01月

　概要を見る

過去12年間に当施設で経験した頭蓋底病変による多発性脳神経障害患者19例を感染症群11例と非感染症群8例に分類し、患者背景、臨床経過、検査所見、治療反応性について比較検討した。糖尿病などの易感染状態や耳鼻科領域感染症が背景にある患者では炎症反応・真菌マーカーの有無にかかわらず真菌感染の可能性を考慮すべきであり、診断確定が困難なばあいは抗真菌剤による診断的治療が必要であった。頭部Gd造影MRIは病変の描出に有用だが、質的診断には注意を要した。抗真菌剤は病歴、合併症、薬剤過敏性、髄膜浸潤の有無などの検討から選択され、早期から適切な抗真菌剤の投与を開始することによって予後の改善が期待できた。(著者抄録)

[Treatment outcome of patients with cranial base lesions of unknown etiology: focusing on infectious cases with multiple cranial nerve disorders].

Akihiro Matsumura, Tomihiro Imai, Masaki Saito, Shin Hisahara, Shun Shimohama

Rinsho shinkeigaku = Clinical neurology   53 ( 1 ) 9 - 18  2013年  [国内誌]

　概要を見る

Involvement of cranial nerves caused by cranial base lesions manifests diverse symptoms according to the localization of lesions. These localization-related symptoms are classified into syndromes such as orbital apex syndrome, cavernous sinus syndrome, and jugular foramen syndrome. Since the lesions may have various etiologies including infection, inflammation and tumor, etiological diagnosis should be performed simultaneously if possible. However, previous reports have described poor and/or fatal outcome following inappropriate treatment mainly due to difficulties in making a definitive pathological diagnosis. Nineteen patients with multiple cranial nerve involvement caused by skull base lesions were enrolled over the past 12 years. The patients were divided into an "infectious" group (n=11) and a "noninfectious" group (n=8) based on the final diagnosis. Chi-square analysis was conducted to examine the sensitivity and specificity of various factors including patient characteristics, clinical course and treatment response in infectious and noninfectious groups. Consequently, we identified some patients with good outcome irrespective of infectious or noninfectious etiology, even though a pathological diagnosis was not reached before the initial treatment. These patients with good outcome consistently received antifungal therapy in the early stage if infectious etiologies were suspected. We recommend conducting diagnostic therapy with antifungal drugs in patients with skull base lesions of unknown origin although infection cannot be excluded, when a pathological diagnosis is difficult due to various patient conditions.

PubMed

呼吸不全の進行と横隔神経複合筋活動電位の低下が相関しないALSの臨床的特徴

山内 理香, 今井 富裕, 保月 隆良, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  52 ( 12 ) 1607 - 1607  2012年12月

Pure autonomic neuropathyの臨床病理学的特徴

小池 春樹, 橋本 里奈, 冨田 稔, 川頭 祐一, 飯島 正博, 児矢野 繁, 桃尾 隆之, 湯浅 浩之, 三竹 重久, 東原 真奈, 海田 賢一, 山本 大輔, 久原 真, 下濱 俊, 中江 啓晴, 城倉 健, 祖父江 元

臨床神経学 ( (一社)日本神経学会 )  52 ( 12 ) 1542 - 1542  2012年12月

The spectrum of clinicopathological features in pure autonomic neuropathy.

Haruki Koike, Rina Hashimoto, Minoru Tomita, Yuichi Kawagashira, Masahiro Iijima, Shigeru Koyano, Takayuki Momoo, Hiroyuki Yuasa, Shigehisa Mitake, Mana Higashihara, Kenichi Kaida, Daisuke Yamamoto, Shin Hisahara, Shun Shimohama, Yoshiharu Nakae, Ken Johkura, Steven Vernino, Gen Sobue

Journal of neurology   259 ( 10 ) 2067 - 75  2012年10月  [国際誌]

　概要を見る

We assessed the clinicopathological features of nine patients with pure autonomic neuropathy, that is, neuropathy without sensory or motor deficits. The duration from symptom onset to diagnosis ranged from 1 month to 13 years. Of eight patients in whom serum antiganglionic acetylcholine receptor antibody was determined, four were positive. All patients who tested positive for this antibody manifested widespread autonomic dysfunction, with the exception of one patient who only experienced orthostatic hypotension. However, patients who were negative for the antiganglionic acetylcholine receptor antibody presented with partial autonomic failure. One of these patients had diffuse parasympathetic failure and generalized hypohidrosis but no orthostatic hypotension, which is clinically compatible with postganglionic cholinergic dysautonomia. Electron microscopic examination revealed a variable degree of reduction in unmyelinated fibers. Compared with normal controls, the patients had a significantly increased density of collagen pockets (p < 0.05). Additionally, the percentage of Schwann cell subunits with axons (out of the total number of Schwann cell subunits associated with unmyelinated fibers) was significantly decreased (p < 0.01). The density of unmyelinated fibers tended to decrease with increasing time between the onset of autonomic symptoms and biopsy (p < 0.05). In conclusion, the clinical and pathological features of pure autonomic neuropathy vary in terms of progression, autonomic involvement, presence of the antiganglionic acetylcholine receptor antibody, and loss of unmyelinated fibers.

DOI PubMed

Early effect of tacrolimus in improving excitation-contraction coupling in myasthenia gravis

Tomihiro Imai, Emiko Tsuda, Takayoshi Hozuki, Rika Yamauchi, Masaki Saitoh, Shin Hisahara, Hiroaki Yoshikawa, Masakatsu Motomura, Jun Kawamata, Shun Shimohama

CLINICAL NEUROPHYSIOLOGY ( ELSEVIER IRELAND LTD )  123 ( 9 ) 1886 - 1890  2012年09月  [査読有り]

　概要を見る

Objectives: Tacrolimus (FK506) is a macrolide T-cell immunomodulator used to treat myasthenia gravis (MG). Besides immunosuppression, tacrolimus has been reported to have the potential to increase muscle strength by enhancing ryanodine receptor (RyR) function. However, few attempts have been made to demonstrate the early effect of tacrolimus as an RyR enhancer in clinical investigation. Methods: In 20 MG patients, masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRPs) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The excitation-contraction (E-C) coupling time (ECCT) was calculated by the latency difference between CMAP and MRP. Bite force was measured using a pressure-sensitive sheet. Serial assessments of % decrement in masseteric repetitive nerve stimulation (RNS), ECCT and bite force were performed before and within 4 weeks of tacrolimus (3 mg day (1)) treatment. The median (mean, range) interval of assessment was 2 (2.4, 1-4) weeks. We also measured serum antibodies against RyR, acetylcholine receptor and muscle-specific receptor tyrosine kinase. Results: Bite force increased after tacrolimus treatment accompanying clinical improvement assessed by Myasthenia Gravis Foundation of America classification, but the bite force difference did not reach statistical significance. Wilcoxon matched-pairs signed-ranks test detected a significant ECCT shortening in 12 patients assessed after 1-2 weeks of tacrolimus treatment as well as in eight patients assessed after 3-4 weeks. In contrast, masseteric CMAP and % decrement showed no significant changes after shortterm tacrolimus treatment. Significance: This early effect of tacrolimus may imply a pharmacological enhancement of RyR function to improve E-C coupling in MG. (C) 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI PubMed

Relationship between dysphagia and depressive states in patients with Parkinson's disease

Meng Han, Hirofumi Ohnishi, Michio Nonaka, Rika Yamauchi, Takayoshi Hozuki, Takashi Hayashi, Masaki Saitoh, Shin Hisahara, Tomihiro Imai, Shun Shimohama, Mitsuru Mori

Parkinson's Disease: Diagnosis, Treatment and Prognosis     201 - 208  2012年07月

　概要を見る

Aspiration pneumonia related to dysphagia is known to be the leading cause of death in patients with Parkinson's disease (PD). We investigated the relationship between depressive states and dysphagia in patients with PD. A hundred and twenty-seven PD patients gave their informed consent and were enrolled in this study. We used the Beck Depression Inventory II (BDI-II) questionnaire to determine the participants' depressive states, and also used a questionnaire to assess participants' state of dysphagia. Participants were divided into four groups according to their BDI-II score. We compared the PD patients with Swallowing Disturbances Questionnaire (SDQ) scores of more than or equal to 11 with the SDQ scores of less than 11 regarding depressive categories. A logistic regression analysis was conducted to calculate odds ratios (ORs) and their 95% confidence intervals (95%CI) adjusting for age, sex, disease duration, wearing-off phenomenon and severity of movement disorder. OR (95%CI) of depressive categories,in which the trivial class was set as a reference group, were 3.28 (0.93-11.55), 13.44 (3.10-58.16), 30.35 (5.65-162.97) in the mild class, the moderate class and the severe class, respectively. This study suggests that there may be a strong relationship between depressive states and dysphagia in patients with PD. © 2012 Nova Science Publishers, Inc. All rights reserved.

Contribution of anti-ryanodine receptor antibody to impairment of excitation-contraction coupling in myasthenia gravis

Tomihiro Imai, Emiko Tsuda, Takayoshi Hozuki, Hiroaki Yoshikawa, Rika Yamauchi, Masaki Saitoh, Shin Hisahara, Masakatsu Motomura, Jun Kawamata, Shun Shimohama

CLINICAL NEUROPHYSIOLOGY ( ELSEVIER IRELAND LTD )  123 ( 6 ) 1242 - 1247  2012年06月  [査読有り]

　概要を見る

Objective: The aim of this study was to elucidate the relationship between the impairment of excitation-contraction (E-C) coupling and anti-ryanodine receptor (RyR) antibody in patients with myasthenia gravis (MG). Methods: Masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRPs) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The E-C coupling time (ECCT) was calculated as the latency difference between CMAP and MRP. For each patient, we selected a representative data set when there was no abnormal decrement in response to repetitive nerve stimulation. The 26 data sets were divided into an anti-RyR-positive group (n = 12) and an anti-RyR-negative group (n = 14). Results: Masseteric ECCT was significantly longer (p = 0.017) in anti-RyR-positive group (median, mean, range; 3.6, 3.8, 3.0-5.9 ms) than in anti-RyR-negative group (3.1, 3.1, 2.7-4.0) although there were no significant differences in masseteric CMAP amplitude and % decrement between the two groups. The bite force was significantly lower in anti-RyR-positive group than in normal controls. Conclusions: Presence of anti-RyR antibodies is associated with significantly prolonged masseteric ECCT compared to absence of the antibodies in MG. Significance: Anti-RyR antibody contributes to E-C coupling impairment in the masseter muscle in patients with MG. (C) 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI PubMed

咬筋のend-plateは生理的刺激頻度では伝達ブロックが起きにくい

今井 富裕, 津田 笑子, 山内 理香, 保月 隆良, 齊藤 正樹, 久原 真, 川又 純, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  51 ( 12 ) 1461 - 1461  2011年12月

筋萎縮性側索硬化症における鼻腔吸気圧測定『開放法』と『閉鎖法』

山内 理香, 山本 大輔, 松村 晃寛, 津田 笑子, 保月 隆良, 林 貴士, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  51 ( 12 ) 1365 - 1365  2011年12月

赤血球画分を用いた酸化DJ-1定量の検討

松村 晃寛, 久原 真, 齊藤 正樹, 川又 純, 今井 富裕, 下濱 俊, 斎藤 芳郎, 野口 範子, 二木 鋭雄

臨床神経学 ( (一社)日本神経学会 )  51 ( 12 ) 1266 - 1266  2011年12月

Relationship between dysphagia and depressive states in patients with Parkinson&apos;s disease

Meng Han, Hirofumi Ohnishi, Michio Nonaka, Rika Yamauchi, Takayoshi Hozuki, Takashi Hayashi, Masaki Saitoh, Shin Hisahara, Tomihiro Imai, Shun Shimohama, Mitsuru Mori

PARKINSONISM & RELATED DISORDERS ( ELSEVIER SCI LTD )  17 ( 6 ) 437 - 439  2011年07月  [査読有り]

　概要を見る

Aspiration pneumonia related to dysphagia is known to be the leading cause of death in patients with Parkinson's disease (PD). We investigated the relationship between depressive states and dysphagia in patients with PD. A hundred and twenty-seven PD patients gave their informed consent and were enrolled in this study. We used the Beck Depression Inventory (BDI) questionnaire to determine the participants' depressive states, and also used a questionnaire to assess participants' state of dysphagia. Participants were divided into four groups according to their BDI score. We compared the PD patients with Swallowing Disturbances Questionnaire (SDQ) scores of more than or equal to 11 with the SDQ scores of less than 11 regarding depressive categories. A logistic regression analysis was conducted to calculate odds ratios (ORs) and their 95% confidence intervals (95%CI) adjusting for age, sex, disease duration, wearing-off phenomenon and severity of movement disorder. OR (95%CI) of depressive categories, in which the trivial class was set as a reference group, were 3.28 (0.93-11.55), 13.44(3.10-58.16), 30.35 (5.65-162.97) in the mild class, the moderate class and the severe class, respectively. This study suggests that there may be a strong relationship between depressive states and dysphagia in patients with PD. (C) 2011 Elsevier Ltd. All rights reserved.

DOI PubMed

Painful legs and moving toesの1例

津田 笑子, 林 貴士, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  51 ( 3 ) 225 - 225  2011年03月

FAP ATTR Val30Metの1弧発例

山本 大輔, 津田 笑子, 今井 富裕, 林 貴士, 齊藤 正樹, 久原 真, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  51 ( 3 ) 226 - 226  2011年03月

ステロイドパルスが有効であった特発性全身性無汗症の1例

保月 隆良, 松村 晃寛, 山本 大輔, 津田 玲子, 津田 笑子, 山内 理香, 林 貴士, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  51 ( 3 ) 224 - 224  2011年03月

Bartter症候群を基盤に低K性ミオパチーの一例

津田 玲子, 山内 理香, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  51 ( 3 ) 226 - 226  2011年03月

脳有鉤嚢虫症の1例

保月 隆良, 山本 大輔, 松村 晃寛, 津田 玲子, 津田 笑子, 山内 理香, 林 貴士, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  51 ( 3 ) 226 - 226  2011年03月

Toxin-Induced and Genetic Animal Models of Parkinson's Disease

Shin Hisahara, Shun Shimohama

PARKINSONS DISEASE ( HINDAWI PUBLISHING CORPORATION )  2011   951709  2011年  [査読有り]

　概要を見る

Parkinson's disease (PD) is a common progressive neurodegenerative disorder. The major pathological hallmarks of PD are the selective loss of nigrostriatal dopaminergic neurons and the presence of intraneuronal aggregates termed Lewy bodies (LBs), but the pathophysiological mechanisms are not fully understood. Epidemiologically, environmental neurotoxins such as pesticides are promising candidates for causative factors of PD. Oxidative stress and mitochondrial dysfunction induced by these toxins could contribute to the progression of PD. While most cases of PD are sporadic, specific mutations in genes that cause familial forms of PD have led to provide new insights into its pathogenesis. This paper focuses on animal models of both toxin-induced and genetically determined PD that have provided significant insight for understanding this disease. We also discuss the validity, benefits, and limitations of representative models.

DOI PubMed

筋萎縮性側索硬化症(ALS)における呼吸不全の進展様式と頸髄病理所見の対応

山内 理香, 山本 大輔, 松下 隆司, 豊島 貴信, 松村 晃寛, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊, 野中 道夫, 荻野 次郎, 外岡 暁子, 中西 勝也

臨床神経学 ( (一社)日本神経学会 )  50 ( 12 ) 1126 - 1126  2010年12月

Resveratrolによる神経系細胞における酸化ストレス耐性の検討

久原 真, 齊藤 正樹, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  50 ( 12 ) 1240 - 1240  2010年12月

Subclinicalなneuropathyを合併した原因不明の脊髄炎の1例

山本 大輔, 津田 笑子, 矢澤 省吾, 今井 富裕, 林 貴士, 齊藤 正樹, 久原 真, 下濱 俊

臨床神経生理学 ( (一社)日本臨床神経生理学会 )  38 ( 5 ) 331 - 331  2010年10月

【意識障害 緊急を要する病状・病態の初期診療と意識障害への初期対応】神経内科でみる意識障害

齊藤 正樹, 松村 晃寛, 津田 笑子, 久原 真

月刊レジデント ( (株)医学出版 )  3 ( 9 ) 92 - 98  2010年09月

左正中神経単麻痺を呈したライム病の一例

山本 大輔, 松村 晃寛, 林 貴士, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  50 ( 8 ) 603 - 603  2010年08月

ステロイドパルス療法(IVMP)と高圧酸素療法(HBO)が奏効した間歇型一酸化炭素中毒の一例

矢島 秀教, 豊島 貴信, 津田 笑子, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊, 文屋 尚文, 蕨 玲子, 浅井 康文

臨床神経学 ( (一社)日本神経学会 )  50 ( 8 ) 602 - 602  2010年08月

抗NMDA受容体抗体が関連したと考えられる脳炎の一例

津田 笑子, 矢島 秀教, 豊島 貴信, 保月 隆良, 久原 真, 齊藤 正樹, 今井 富裕, 下濱 俊, 高橋 幸利

臨床神経学 ( (一社)日本神経学会 )  50 ( 8 ) 603 - 603  2010年08月

脊髄MRIで異常所見を認めた脳脊髄液減少症の一例

佐藤 さゆり, 山本 大輔, 津田 笑子, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  50 ( 8 ) 600 - 600  2010年08月

Correlation of bite force with excitation-contraction coupling time of the masseter in myasthenia gravis

Emiko Tsuda, Tomihiro Imai, Takayoshi Hozuki, Rika Yamauchi, Masaki Saitoh, Shin Hisahara, Hiroaki Yoshikawa, Masakatsu Motomura, Shun Shimohama

CLINICAL NEUROPHYSIOLOGY ( ELSEVIER IRELAND LTD )  121 ( 7 ) 1051 - 1058  2010年07月  [査読有り]

　概要を見る

Objective: The aim of this study was to elucidate the relationship between the impairment of excitation-contraction (E-C) coupling of masseter and the bite force in patients with myasthenia gravis (MG). Methods: In 20 patients with MG, masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRP) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The E-C coupling time (ECCT) was calculated by the latency difference between CMAP and MRP. Bite force was measured using a pressure-sensitive sheet. Serial assessments of % decrement in masseteric repetitive nerve stimulation (RNS), ECCT, and bite force were performed before and after corticosteroid therapy alone or in various combinations with FK506, cyclosporin A, intravenous immunoglobulin and immunoabsorption. Results: Percent amplitude decrement in RNS and ECCT decreased significantly accompanying an increase in bite force after treatment. Simple regression analysis demonstrated a linear correlation among % decrement, ECCT and bite force. However, ECCT shortening accompanying bite force recovery without reduction in % decrement was observed in 4 patients. Conclusions: Masseteric E-C coupling is impaired in some MG patients, and functional recovery of E-C coupling contributes at least in part to the increase in bite force after treatment. Significance: Impaired E-C coupling contributes to muscle weakness in patients with MG. (C) 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI PubMed

パーキンソン病患者の抑うつ症状と嚥下障害との関連

韓 萌, 大西 浩文, 野中 道夫, 山内 理香, 保月 隆良, 林 貴士, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊, 森 満

総合リハビリテーション ( (株)医学書院 )  38 ( 7 ) 677 - 683  2010年07月

　概要を見る

パーキンソン病(PD)患者における抑うつと嚥下障害の関連について検討した.札幌医科大学附属病院神経内科に通院するPD患者連続78名を解析対象とし,BDI-IIベック抑うつ質問票と嚥下障害質問票から患者の自記式で得た回答を既定の評価基準に従って点数化した.H&Y重症度分類と抑うつカテゴリーが重症になるほど嚥下障害の頻度が増加した.また,嚥下障害の有無を従属変数とした多重ロジスティック回帰分析では,抑うつカテゴリーが中等症,重症となるほど嚥下障害に対するオッズ比が有意に増大しており,嚥下障害予防の観点からはPD患者の抑うつ状態にも留意することが重要である.(著者抄録)

ステロイドパルス療法直後の骨代謝マーカーの推移

保月 隆良, 今井 富裕, 津田 笑子, 松村 晃寛, 山本 大輔, 山内 理香, 林 貴士, 齊藤 正樹, 久原 真, 下濱 俊

神経治療学 ( (一社)日本神経治療学会 )  27 ( 3 ) 413 - 413  2010年05月

Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure.

Tanno M, Kuno A, Yano T, Miura T, Hisahara S, Ishikawa S, Shimamoto K, Horio Y

The Journal of biological chemistry   285 ( 11 ) 8375 - 8382  2010年03月  [査読有り]

DOI PubMed

大量免疫グロブリン療法を施行したMPO-ANCA陽性肥厚性硬膜炎の1例

保月 隆良, 松村 晃寛, 山本 大輔, 林 貴士, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  50 ( 2 ) 129 - 129  2010年02月

3,4-diaminopyridine治療を開始した非担癌性Lambert-Eaton症候群の1例

松村 晃寛, 松下 隆司, 保月 隆良, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  50 ( 2 ) 127 - 127  2010年02月

Response of Serum Carboxylated and Undercarboxylated Osteocalcin to Risedronate Monotherapy and Combined Therapy with Vitamin K-2 in Corticosteroid-Treated Patients: A Pilot Study

Takayoshi Hozuki, Tomihiro Imai, Emiko Tsuda, Akihiro Matsumura, Daisuke Yamamoto, Takanobu Toyoshima, Syuuichiro Suzuki, Rika Yamauchi, Takashi Hayashi, Shin Hisahara, Shun Shimohama

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE )  49 ( 5 ) 371 - 376  2010年  [査読有り]

　概要を見る

Objective The aim of this study was to investigate the responses of serum osteocalcin (OC), undercarboxylated osteocalcin (ucOC) and N-terminal telopeptide of type I collagen (NTx) to corticosteroids, and to examine the effects of risedronate therapy with or without vitamin K-2 supplementation on bone metabolic markers in corticosteroid-treated patients. Methods Sixteen patients on corticosteroid therapy for neuromuscular disorders were assigned randomly to 2 groups (A: risedronate monotherapy, n=8; B: combined risedronate and vitamin K-2 therapy, n=8) and treated for 1 year. Another 6 patients who received intravenous steroid pulse therapy were assigned to group C for investigation of the effects of corticosteroids on OC and ucOC 1 month after pulse therapy. Results Serial measurements revealed that significant decreases of OC, ucOC and NTx persisted with a similar time course profile during 1 year of treatment in groups A and B, and between-group analysis failed to demonstrate any additional effects of vitamin K-2 on risedronate therapy. Intravenous steroid pulse therapy induced a transient depression of OC and ucOC within 1 week in group C. Conclusion These results indicate that serum concentrations of OC and ucOC become consistently low during corticosteroid administration despite risedronate therapy with or without vitamin K-2 supplementation, and the serum ucOC level may not be a reliable indicator of vitamin K status under corticosteroid administration.

DOI PubMed

多発脳神経障害を呈する頭蓋底感染症の診断的治療について 当施設における12年間の経験から

松村 晃寛, 津田 玲子, 山本 大輔, 豊島 貴信, 松下 隆司, 鈴木 秀一郎, 津田 笑子, 山内 理香, 保月 隆良, 林 貴士, 齊藤 正樹, 久原 真, 今井 富裕, 下濱 俊

NEUROINFECTION ( 日本神経感染症学会 )  14 ( 2 ) 147 - 147  2009年10月

Transcriptional activation of NAD+-dependent protein deacetylase SIRT1 by nuclear receptor TLX

Naotoshi Iwahara, Shin Hisahara, Takashi Hayashi, Yoshiyuki Horio

Biochemical and Biophysical Research Communications   386 ( 4 ) 671 - 675  2009年09月

　概要を見る

An orphan nuclear receptor TLX is a transcriptional repressor that promotes the proliferation and self-renewal of neural precursor cells (NPCs). SIRT1, an NAD+-dependent protein deacetylase, is highly expressed in the NPCs and participates in neurogenesis. Here, we found that TLX colocalized with SIRT1 and knockdown of TLX by small interfering RNAs decreased SIRT1 levels in NPCs. TLX increased the SIRT1 expression by binding to the newly identified TLX-activating element in the SIRT1 gene promoter in HEK293 cells. Thus, TLX is an inducer of SIRT1 and may contribute to neurogenesis both as a transactivator and as a repressor. © 2009 Elsevier Inc. All rights reserved.

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神経・筋疾患における嚥下障害の当科治療経験例

山本 大輔, 津田 笑子, 今井 富裕, 鈴木 秀一郎, 小田 美月, 保月 隆良, 久原 真, 野中 道夫, 山口 浩司, 金泉 悦子, 下濱 俊

静脈経腸栄養 ( (株)ジェフコーポレーション )  24 ( 3 ) 849 - 849  2009年05月

原因不明のまま治療開始した頭蓋底病変の予後 多発脳神経障害を呈した感染症を中心に

松村 晃寛, 山本 大輔, 豊島 貴信, 鈴木 秀一郎, 津田 笑子, 山内 理香, 保月 隆良, 林 貴士, 久原 真, 今井 富裕, 下濱 俊

神経治療学 ( (一社)日本神経治療学会 )  26 ( 3 ) 389 - 389  2009年05月

無菌性髄膜炎、胸腰髄病変を呈した再発性多発軟骨炎の1例

松村 晃寛, 小田 美月, 久原 真, 野中 道夫, 今井 富裕, 下濱 俊, 荻野 次郎, 土田 哲人

臨床神経学 ( (一社)日本神経学会 )  49 ( 5 ) 313 - 313  2009年05月

頸部放射線治療の7年後に一側性の副神経麻痺・腕神経叢障害を発症した遅発性放射線障害の1例

松村 晃寛, 保月 隆良, 久原 真, 野中 道夫, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  49 ( 1 ) 67 - 67  2009年01月

パーキンソン病患者のADLとQOLに対する抑うつの影響

韓 萌, 大西 浩文, 森 満, 林 貴士, 久原 真, 野中 道夫, 今井 富裕, 下濱 俊

北海道公衆衛生学雑誌 ( 北海道公衆衛生学会 )  22 ( 1特別付録 ) 65 - 65  2008年11月

Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation.

Hisahara S, Chiba S, Matsumoto H, Tanno M, Yagi H, Shimohama S, Sato M, Horio Y

Proceedings of the National Academy of Sciences of the United States of America ( 40 )  105   15599 - 15604  2008年10月  [査読有り]

DOI PubMed

家族歴の判然としない遅発成人型DRPLAの1例

松村 晃寛, 小田 美月, 久原 真, 野中 道夫, 今井 富裕, 下濱 俊

臨床神経学 ( (一社)日本神経学会 )  48 ( 8 ) 589 - 589  2008年08月

Thyrotoxic myopathy mimicking myasthenic syndrome associated with thymic hyperplasia.

Tsuda E, Imai T, Matsumura A, Hisahara S, Nonaka M, Shiraishi H, Motomura M, Shimohama S

Internal medicine (Tokyo, Japan) ( 5 )  47 ( 5 ) 445 - 447  2008年  [査読有り]  [国内誌]

　概要を見る

A 41-year-old man with progressive limb weakness manifested fluctuating muscle weakness as seen in myasthenia gravis (MG). Laboratory investigations revealed hyperthyroidism without the complication of MG. Electrophysiological studies demonstrated abnormal features of neuromuscular transmissions resembling those of the Lambert-Eaton myasthenic syndrome rather than those of MG. A CT scan showed a mediastinal mass that suggested thymic hyperplasia which often complicates MG or hyperthyroidism. Medical treatment of hyperthyroidism resulted in resolution of MG-like symptoms and regression of thymic hyperplasia on CT concomitant with normalization of thyroid function. This case highlights the fact that careful investigations are needed to differentiate MG-like symptoms from genuine MG in cases of hyperthyroidism with thymic lesions.

DOI PubMed

両視床の異常信号を伴う認知症を呈した硬膜動静脈瘻の1例

松村 晃寛, 小田 美月, 保月 隆良, 野中 道夫, 久原 真, 今井 富裕, 下濱 俊, 原口 浩一, 野中 雅, 秋葉 英成

臨床神経学 ( (一社)日本神経学会 )  47 ( 6 ) 371 - 371  2007年06月

上矢状静脈洞の著明な拡張と血栓を伴った全身性エリテマトーデスの1例

小泉 武, 大久保 由希子, 静川 裕彦, 久原 真, 野中 道夫, 今井 富裕, 千葉 進, 松本 博之, 大坂 美鈴, 宝金 清博

臨床神経学 ( (一社)日本神経学会 )  45 ( 1 ) 61 - 61  2005年01月

Caspase-11 Mediates Inflammatory Dopaminergic Cell Death in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson's Disease

Tsuyoshi Furuya, Hideki Hayakawa, Masanori Yamada, Kenji Yoshimi, Shin Hisahara, Masayuki Miura, Yoshikuni Mizuno, Hideki Mochizuki

Journal of Neuroscience ( 8 )  24 ( 8 ) 1865 - 1872  2004年02月  [査読有り]

　概要を見る

The present study was designed to elucidate the inflammatory and apoptotic mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a model of Parkinson's disease. Our results showed that mutant mice lacking the caspase-11 gene were significantly more resistant to the effects of acute treatment with MPTP than their wild-type mice. Thus, the neurotoxicity of MPTP seems to be mediated by the induction of both mitochondrial dysfunction and free radical generation. Previously, we showed that overexpression of the Apaf-1 dominant-negative inhibitor inhibited the mitochondrial apoptotic cascade in chronic MPTP treatment but not in acute MPTP treatment. The present results indicate that MPTP neurotoxicity may be mediated via activation of the caspase-11 cascade and inflammatory cascade, as well as the mitochondrial apoptotic cascade.

DOI PubMed

Caspases determine the vulnerability of oligodendrocytes in the ischemic brain

M Shibata, S Hisahara, H Hara, T Yamawaki, Y Fukuuchi, JY Yuan, H Okano, M Miura

JOURNAL OF CLINICAL INVESTIGATION ( AMER SOC CLINICAL INVESTIGATION INC )  106 ( 5 ) 643 - 653  2000年09月  [査読有り]

　概要を見る

Although oligodendrocytes (OLGs) are thought to be vulnerable to hypoxia and ischemia, little is known about the detailed mechanism by which these insults induce OLG death. From the clinical viewpoint, it is imperative to protect OLGs as well as neurons against ischemic injury (stroke), because they are the only myelin-forming cells of the central nervous system. Using the Cre/loxP system, we have established a transgenic mouse line that selectively expresses p35, a broad-spectrum caspase inhibitor, in OLGs. After hypoxia, cultured OLGs derived from wild-type mice exhibited significant upregulation of caspase-11 and substantial activation of caspase-3, which led to cell loss. Expression of p35 or elimination of caspase-11 suppressed the caspase-3 activation and conferred significant protection against hypoxic injury. Expression of p35 in OLGs in vivo resulted in significant protection from ischemia-induced cell injury, thus indicating that caspases are involved in the ischemia-induced cell death of OLGs. Furthermore, the induction of caspase-11 was evident in the ischemic brains of wild-type mice, and OLGs exhibited resistance to brain ischemia in mice deficient in caspase-11, suggesting that caspase-11 is critically implicated in the mechanism(s) underlying ischemia-induced OLG death. Caspases may therefore offer a good therapeutic target for reducing ischemia-induced damage to OLGs.

Nerve growth factor protects oligodendrocytes from tumor necrosis factor-alpha-induced injury through Akt-mediated signaling mechanisms

R Takano, S Hisahara, K Namikawa, H Kiyama, H Okano, M Miura

JOURNAL OF BIOLOGICAL CHEMISTRY ( AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC )  275 ( 21 ) 16360 - 16365  2000年05月  [査読有り]

　概要を見る

Tumor necrosis factor-alpha is thought to be one of the most important inflammatory cytokines associated with the demyelinating disease multiple sclerosis, We determined whether neurotrophins could protect oligodendrocytes from tumor necrosis factor-alpha-mediated cytotoxicity. Among the neurotrophins tested, nerve growth factor was most effective at preventing cell death. Nerve growth factor also prevented the tumor necrosis factor-induced loss of mitochondrial membrane potential. Overexpression of constitutively active Akt, a downstream target of phosphatidylinositol 3-kinase, but not of constitutively active MEK, protected oligodendrocytes from tumor necrosis factor-induced injury. Moreover, overexpression of dominant-negative Akt negated the protective effects of nerve growth factor on tumor necrosis factor-mediated oligodendrocyte cytotoxicity. These findings indicate that the Akt pathway is crucial in nerve growth factor-mediated oligodendrocyte protection.

Role of caspase-1 subfamily in cytotoxic cytokine-induced oligodendrocyte cell death

S Hisahara, R Takano, S Shoji, H Okano, M Miura

ADVANCES IN RESEARCH ON NEURODEGENERATION, VOL 7 ( SPRINGER-VERLAG WIEN )  7   135 - 142  2000年  [査読有り]

　概要を見る

Oligodendrocytes are myelin forming cells in mammalian central nervous system. About 50% of oligodendrocytes (OLGs) undergo cell death in normal development. In addition, OLG cell deaths have been observed in demyelinating diseases including multiple sclerosis (MS). Clinical observations and in vitro cell culture studies have suggested that cytokines mediate OLG cell damage in multiple sclerosis (MS). Among the cytokines, tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of OLGs in MS. The administration of TNF-alpha to primary cultures of OLGs induced DNA fragmentation, and significantly decreased the number of live OLGs. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1 (ICE)-like proteases) enhanced the survival of TNF-a treated OLGs better than Ac-DEVD-CHO (a specific inhibitor of caspase-3 (CPP32)-like proteases). These results indicate that caspase-1-mediated cell-death pathway are activated in TNF-induced OLG cell death. Caspase-11 is involved in activation of caspase-1. Oligodendrocytes from caspase-11-deficient mice are partially resistant to TNF-induced OLG cell death. Our results suggest that the inhibition of caspase-1 sufamily may be a novel therapeutic approach to treat MS.

Role of caspase-1 subfamily in cytotoxic cytokine-induced oligodendrocyte cell death

S Hisahara, R Takano, S Shoji, H Okano, M Miura

JOURNAL OF NEURAL TRANSMISSION-SUPPLEMENT ( SPRINGER-VERLAG )  ( 58 ) 135 - 142  2000年  [査読有り]

　概要を見る

Oligodendrocytes are myelin forming cells in mammalian central nervous system. About 50% of oligodendrocytes (OLGs) undergo cell death in normal development. In addition, OLG cell deaths have been observed in demyelinating diseases including multiple sclerosis (MS). Clinical observations and in vitro cell culture studies have suggested that cytokines mediate OLG cell damage in multiple sclerosis (MS). Among the cytokines, tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of OLGs in MS. The administration of TNF-alpha to primary cultures of OLGs induced DNA fragmentation, and significantly decreased the number of live OLGs. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1 (ICE)-like proteases) enhanced the survival of TNF-alpha treated OLGs better than Ac-DEVD-CHO (a specific inhibitor of caspase-3 (CPP32)-like proteases). These results indicate that caspase-1-mediated cell-death pathway are activated in TNF-induced OLG cell death. Caspase-11 is involved in activation of caspase-1. Oligodendrocytes from caspase-11-deficient mice are partially resistant to TNF-induced OLG cell death. Our results suggest that the inhibition of caspase-1 sufamily may be a novel therapeutic approach to treat MS.

Conditional expression of anti-apoptotic protein p35 by Cre-mediated DNA recombination in cardiomyocytes from loxP-p35-transgenic mice

T. Araki, M. Shibata, R. Takano, S. Hisahara, S. I. Imamura, Y. Fukuuchi, T. Saruta, H. Okano, M. Miura

Cell Death and Differentiation ( Nature Publishing Group )  7 ( 5 ) 485 - 492  2000年  [査読有り]

　概要を見る

p35, a viral inhibitor of caspase, prevents cell death induced by various stimuli. We established an experimental system to study the involvement of caspases in cell death, using primary cultured cells from p35 transgenic mice in which the p35 open reading frame (ORF) had been disrupted by the insertion of a DNA segment flanked by loxP sites, the Cre recognition sites. In this system, p35 expression can be initiated by Cre recombinase. Cardiomyocytes, which are highly sensitive to hypoxic stress, were infected with an adenovirus carrying the cre gene (AxCANCre). Expression of p35 by infection with AxCANCre resulted in inhibition of caspase-3 activation and resistance to hypoxia-induced cell death. Hypoxia-induced cytochrome c release was also attenuated in p35-expressing cardiomyocytes. Our transgenic mice can be used as an experimental model for studying the involvement of caspases in various degenerative diseases as well as programmed cell death both in vitro and in vivo.

DOI PubMed

Proapoptotic activity of Caenorhabditis elegans CED-4 protein in Drosophila: Implicated mechanisms for caspase activation

H Kanuka, S Hisahara, K Sawamoto, S Shoji, H Okano, M Miura

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA ( NATL ACAD SCIENCES )  96 ( 1 ) 145 - 150  1999年01月  [査読有り]

　概要を見る

CED-4 protein plays an important role in the induction of programmed cell death in Caenorhabditis elegans through the activation of caspases. However, the precise mechanisms by which it activates caspases remain unknown. To investigate the conservation of CED-4 function in evolution, transgenic Drosophila lines that express CED-4 in the compound eye were generated. Ectopic expression of CED-4 in the eyes induced massive apoptotic cell death through caspase activation. An ATP-binding site (P-loop) mutation in CED-4 (K165R) causes a loss of function in its ability to activate Drosophila caspase, and an ATPase inhibitor blocks the CED-4-dependent caspase activity in Drosophila S2 cells. Immunoprecipitation analysis showed that both CED-4 and CED-4 (K165R) bind directly to Drosophila caspase drICE, and the overexpression of CED-4 (K165R) inhibits CED-4-, ecdysone-, or cycloheximide-dependent caspase activation in S2 cells. Furthermore, CED-4 (K165R) partially prevented cell death induced by CED-4 in Drosophila compound eyes. Thus, CED-4 function is evolutionarily conserved in Drosophila, and the molecular mechanisms by which CED-4 activates caspases might require ATP binding and direct interaction with the caspases.

DOI PubMed CiNii

Involvement of caspases in cytotoxic cytokine-mediated oligodendrocyte cell death

M Miura, S Hisahara, R Takano, S Shoji, H Okano

PROTOPLASMA ( SPRINGER-VERLAG WIEN )  206 ( 4 ) 219 - 223  1999年  [査読有り]

　概要を見る

Oligodendrocytes are myelin-forming cells in the mammalian central nervous system. About 50% of oligodendrocytes undergo cell death in normal development. In addition, massive oligodendrocyte cell death has been observed in multiple sclerosis. Tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of oligodendrocytes in multiple sclerosis. The addition of TNF-alpha to primary cultures of oligodendrocytes significantly decreased the number of live cells in 72 h. DNA fragmentation was detected in TNF-treated oligodendrocytes at 36 h by TUNEL assay. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1 [ICE]-like proteases) as well as Ac-DEVD-CHO (a specific inhibitor of caspase-3[CPP32]-like proteases) enhanced the survival of oligodendrocytes treated with TNF-alpha, indicating that caspase-1- and the caspase-3-mediated cell-death pathways are activated in TNF-induced oligodendrocyte cell death. Caspase-11 is involved in activation of caspase-1. Oligodendrocytes from CASP-11-deficient mice are partially resistant to TNF-induced oligodendrocyte cell death. Our results suggest that the inhibition of caspases may be a novel approach to treat multiple sclerosis.

Involvement of caspases in the TNF-alpha-mediated oligodendrocyte cell death

S Hisahara, S Shoji, H Okano, M Miura

NEURAL DEVELOPMENT-BOOK ( SPRINGER-VERLAG TOKYO )  2   350 - 354  1999年  [査読有り]

　概要を見る

Oligodendrocytes (OLGs) are selectively destroyed in chronically demyelinated multiple sclerosis (MS) lesions. Tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of OLGs in MS. The addition of TNF-alpha to primary cultures of mouse OLGs, which express caspase-1 and caspase-3 bur not caspase-2, significantly decreased the number of live OLGs in 72 h. DNA fragmentation was detected in TNF-treated OLGs at 36h with TUNEL staining. Z-Asp-CH(2)-DCB, a broad inhibitor of the caspase family, prevented TNF-induced cell death of OLGs. Furthermore, Ac-YVAD-CHO (a specific inhibitor of caspase-1-like proteases) as well, as Ac-DEVD-CHO (a specific inhibitor of caspase-3-lilte proteases) enhanced the survival of OLGs treated with TNF-alpha, indicating that the caspase-1- and the caspase-3-mediated cell-death pathways are involved in TNF-induced OLG cell death. Our results suggest that inhibition of caspases may be a novel approach to treat MS.

Execution mechanisms of programmed cell death by caspase (ICE/CED3) family proteases

M Miura, S Hisahara, T Araki, H Okano

HEART AND VESSELS ( SPRINGER VERLAG )    66 - 70  1997年  [査読有り]

　概要を見る

Molecular genetic study of Caenorhabditis elegans revealed the cell death-executing gene ced-3 Structural and functional similarities between CED-3 and mammalian ICE family (caspase) gene products provide the evidence that mammalian caspases are common mediators in executing programmed cell death. These findings suggest that the execution mechanisms of cell death by caspase family protease may be evolutionarily conserved from worms to mammals. This report summarizes the unique properties of caspases in apoptosis.