研究者詳細 - 久原　真

論文 - 久原　真

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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]

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]

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]

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]

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]

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

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]

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]

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

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