研究者詳細 - 小野寺　理

論文 - 小野寺　理

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The clinical-genealogic and molecular-genetic characteristics of oculopharyngeal muscular dystrophy in the Republic of Sakha (Yakutia) 査読

N. R. Maksimova, I. A. Nikolaeva, M. N. Korotov, T. Ikeuchi, O. Onodera, M. Nishizawa, S. K. Stepanova, Kh. A. Kurtanov, A. L. Sukhomyasova, A. N. Nogovitcina, E. E. Gurinova, V. A. Stepanov, V. P. Puzyrev

ZHURNAL NEVROLOGII I PSIKHIATRII IMENI S S KORSAKOVA 108 ( 6 ) 52 - 60 2008年

記述言語：ロシア語掲載種別：研究論文（学術雑誌）出版者・発行元：IZDATELSTVO MEDITSINA

The clinical-genealogic and molecular-genetic investigation of oculopharyngeal muscular dystrophy (OPMD) in the Republic of Sakha (Yakutia) was performed. it was investigated 33 unrelated yakut families with 38 patients and 2 russian families with 2 patients and 59 their healthy relatives as well. The high clinical polymorphism of disease was found in patients with OPMD. The mutation in exon 1 of the PABPN1 gene resulting in the expansion of GCG-repeats up to 10 is revealed. Using direct sequencing of the PABPN1 gene in 17 families (16 yakut, 1 russian), we identified a type of this mutation as an insertion of 4 GCG-repeats. Frequency of OPMD in the yakut population is 1:11 680 that is 10-20 times higher comparing to european populations. This is a first report on the patients with OPMD from the Republic of Sakha with diagnosis confirmed by molecular-genetic analysis.

Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia 査読

N. Maksimova, K. Hara, A. Miyashia, I. Nikolaeva, A. Shiga, A. Nogovicina, A. Sukhomyasova, V. Argunov, A. Shvedova, T. Ikeuchi, M. Nishizawa, R. Kuwano, O. Onodera

JOURNAL OF MEDICAL GENETICS 44 ( 12 ) 772 - 778 2007年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BMJ PUBLISHING GROUP

Background: In total, 43 patients having short stature syndrome in 37 Yakut families with autosomal recessive prenatal and postnatal nonprogressive growth failure and facial dysmorphism but with normal intelligence have been identified.
Methods: Because Yakuts are considered as a population isolate and the disease is rare in other populations, genomewide homozygosity mapping was performed using 763 microsatellite markers and candidate gene approach in the critical region to identify the causative gene for the short stature syndrome in Yakut.
Results: All families shared an identical haplotype in the same region as the identical loci responsible for 3-M and gloomy face syndromes and a novel homozygous 4582insT mutation in Cullin 7 (CUL7) was found, which resulted in a frameshift mutation and the formation of a subsequent premature stop codon at 1553 ( Q1553X). Yakut patients with short stature syndrome have unique features such as a high frequency of neonatal respiratory distress and few bone abnormalities, whereas the clinical features of the other Yakut patients were similar to those of 3-M syndrome. Furthermore, abnormal vascularisation was present in the fetal placenta and an abnormal development of cartilage tissue in the bronchus of a fetus with CUL7 mutation.
Conclusion: These findings may provide a new understanding of the clinical diversity and pathogenesis of short stature syndrome with CUL7 mutation.

DOI： 10.1136/jmg.2007.051979

Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 Delta T440 mutant associated with familial Lewy body disease and variant Alzheimer's disease 査読

Hiroyuki Kaneko, Akiyoshi Kakita, Kensaku Kasuga, Hiroaki Nozaki, Atsushi Ishikawa, Akinori Miyashita, Ryozo Kuwano, Genta Ito, Takeshi Iwatsubo, Hitoshi Takahashi, Masatoyo Nishizawa, Osamu Onodera, Sangram S. Sisodia, Takeshi Ikeuchi

JOURNAL OF NEUROSCIENCE 27 ( 48 ) 13092 - 13097 2007年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SOC NEUROSCIENCE

Mutations in the PSEN1 gene encoding presenilin 1 ( PS1) are linked to a vast majority of pedigrees with early- onset, autosomal dominant forms of familial Alzheimer's disease ( FAD). Lewy body ( LB) pathology is frequently found in the brains of FAD patients harboring PSEN1 mutations. We recently reported on a novel PS1 mutation with the deletion of threonine at codon 440 (Delta T440) in a familial case diagnosed as having the neocortical type of dementia with LBs ( DLB) and variant AD. In this report, we investigated the possible involvement of PS1 Delta T440 mutation in aberrant alpha-synuclein accumulation. We established cell lines that stably express either wild- type ( WT) PS1 or the FAD- linked PS1 H163R, E280A, Delta E9, and PS1 Delta T440 mutants and now demonstrate that the expression of the PS1 Delta T440 mutant led to a marked elevation in the ratio of beta-amyloid (A beta) 42/40 peptides in a conditioned medium. More importantly, we report here that the levels of phosphorylated alpha-synuclein increase in neuronal and non- neuronal cells expressing the PS1 Delta T440 mutant compared with cells that express WT PS1 or the PS1 H163R and E280A variants that are not associated with LB pathology. This finding is consistent with our demonstration of elevated levels of phosphorylated alpha-synuclein in the detergent-resistant fraction prepared from a patient's brain with PS1 Delta T440 mutation. These observations raise the intriguing suggestion that the mechanism( s) by which the PS1 Delta T440 mutant causes DLB and variant AD are by enhancing the phosphorylation of alpha-synuclein and the ratio of A beta(42/40) peptides, respectively, in the brain.

DOI： 10.1523/JNEUROSCI.4244-07.2007

Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3. 査読国際誌

Takayoshi Shimohata, Kenju Hara, Kazuhiro Sanpei, Jin-ichi Nunomura, Tetsuya Maeda, Izumi Kawachi, Masato Kanazawa, Kensaku Kasuga, Akinori Miyashita, Ryozo Kuwano, Koichi Hirota, Shoji Tsuji, Osamu Onodera, Masatoyo Nishizawa, Yoshiaki Honma

Brain : a journal of neurology 130 ( Pt 9 ) 2302 - 9 2007年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 (average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called 'senile chorea'. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3-q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (theta = 0.00). Haplotype analysis of both the families defined the candidate region as 21.5 Mb interval flanked by M9267 and D8S1139. We named this adult-onset dominant inherited chorea 'benign hereditary chorea type 2 (BHC2)'.

DOI： 10.1093/brain/awm036

Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3. 査読国際誌

Takayoshi Shimohata, Kenju Hara, Kazuhiro Sanpei, Jin-ichi Nunomura, Tetsuya Maeda, Izumi Kawachi, Masato Kanazawa, Kensaku Kasuga, Akinori Miyashita, Ryozo Kuwano, Koichi Hirota, Shoji Tsuji, Osamu Onodera, Masatoyo Nishizawa, Yoshiaki Honma

Brain : a journal of neurology 130 ( Pt 9 ) 2302 - 9 2007年9月

記述言語：英語

Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 (average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called 'senile chorea'. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3-q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (theta = 0.00). Haplotype analysis of both the families defined the candidate region as 21.5 Mb interval flanked by M9267 and D8S1139. We named this adult-onset dominant inherited chorea 'benign hereditary chorea type 2 (BHC2)'.

DOI： 10.1093/brain/awm036

Generation of intracellular domain of insulin receptor tyrosine kinase by gamma-secretase 査読

K. Kasuga, H. Kaneko, M. Nishizawa, O. Onodera, T. Ikeuchi

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 360 ( 1 ) 90 - 96 2007年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

The proteolytic cleavage of a precursor protein into alpha- and beta-subunits by furin is required to form functional insulin receptor (IR). In this study, we examined if IR undergoes the additional presenilin (PS)/gamma- secretase-dependent processing. In cells treated with gamma-secretase inhibitors or expressing the dominant-negative PS1 variant led to the accumulation of an endogenous IR C-terminal fragment. In the presence of proteasome inhibitors, we detected a PS/gamma-secretase cleavage product of the IR, termed the IR intracellular domain (ICD). Cellular fractionation and confocal microscopy analyses showed that the IR-ICD is predominantly detected in the nucleus. These data indicate that IR is a tyrosine kinase receptor, which undergoes PS/gamma-secretase-dependent processing. We also show that the auto-phosphorylation levels of the IR P-subunit upon insulin stimulation were decreased by the inactivation of PS/gamma-secretase, raising the possibility that the PS/gamma-secretase proteolysis of IR may play a modulatory role in insulin signaling. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.06.022

Sacsin-related ataxia with neither retinal hypermyelination nor spasticity 査読

Kenju Hara, Junsuke Shimbo, Hiroaki Nozaki, Koki Kiku-Awa, Osamu Onodera, Masatoyo Nishizawa

MOVEMENT DISORDERS 22 ( 9 ) 1362 - 1363 2007年7月

Daytime hypoxemia, sleep-disordered breathing, and laryngopharyngeal findings in multiple system atrophy 査読

Takayoshi Shimohata, Hideo Shinoda, Hideaki Nakayama, Tetsutaro Ozawa, Kenshi Terajima, Hirohisa Yoshizawa, Yoko Matsuzawa, Osamu Onodera, Satoshi Naruse, Keiko Tanaka, Sugata Takahashi, Fumitake Gejyo, Masatoyo Nishizawa

ARCHIVES OF NEUROLOGY 64 ( 6 ) 856 - 861 2007年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER MEDICAL ASSOC

Background: The mechanism underlying nocturnal sudden death in patients with MSA remains unclear. It may be explained by upper airway obstruction, such as vocal cord abductor paralysis; an impairment of the respiratory center, such as Cheyne- Stokes respiration; or an impaired hypoxemic ventilatory response.
Objective: To investigate the mechanism of sleep-disordered breathing in multiple system atrophy ( MSA).
Design: We recruited 21 patients with probable MSA who were admitted sequentially to our hospital, and performed daytime blood gas analysis, pulmonary function tests, polysomnography, and fiberoptic laryngoscopy during wakefulness and with the patient under anesthesia.
Results: A decrease in arterial oxygen pressure and an increase in alveolar- arterial oxygen gradient significantly correlated with disease duration ( P=. 045 and.046, respectively). Polysomnography demonstrated CheyneStokes respiration in 3 ( 15%) of 20 patients. Fiberoptic laryngoscopy during wakefulness showed that 3 ( 14%) of the 21 patients exhibited vocal cord abductor paralysis, and laryngoscopy under anesthesia showed that 9 ( 45%) of 20 patients exhibited vocal cord abductor paralysis. Laryngoscopy under anesthesia also revealed that 11 ( 55%) of 20 patients showed upper airway obstruction in places other than the vocal cords, including obstruction at the base of the tongue or soft palate. In addition, it demonstrated novel laryngopharyngeal findings, such as floppy epiglottis and airway obstruction at the arytenoid.
Conclusions: We observed daytime hypoxemia with an increased alveolar- arterial oxygen gradient, CheyneStokes respiration, and novel abnormal laryngopharyngeal movements in patients with MSA. We also found that laryngoscopy under anesthesia might be useful for evaluating upper airway obstruction. The significance of these findings to the mechanism of sudden death in those with MSA needs to be examined.

DOI： 10.1001/archneur.64.6.856

TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation 査読

Chun-Feng Tan, Hiroto Eguchi, Asako Tagawa, Osamu Onodera, Takuya Iwasaki, Akira Tsujino, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

ACTA NEUROPATHOLOGICA 113 ( 5 ) 535 - 542 2007年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

Recently, 43-kDa TAR DNA-binding protein (TDP-43) was identified as a component of ubiquitinated inclusions (UIs) in sporadic amyotrophic lateral sclerosis (SALS). To clarify whether TDP-43 immunoreactivity is present in neuronal inclusions in familial ALS (FALS), we examined immunohistochemically the brains and spinal cords from four cases of FALS, two with Cu/Zn superoxide dismutase (SOD1) gene mutation and two without, together with three cases of SALS and three control subjects, using two antibodies, one polyclonal and one monoclonal, against TDP-43. Neuropathologically, the SOD1-related FALS cases were characterized by Lewy body-like hyaline inclusions (LBHIs) in the lower motor neurons. On the other hand, the SOD1-unrelated FALS cases showed degeneration restricted to the upper and lower motor neuron systems, with Bunina bodies (BBs) and UIs in the lower motor neurons, being indistinguishable from SALS. No cytoplasmic TDP-43 immunoreactivity was observed in the control subjects or SOD1-related FALS cases; LBHIs were ubiquitinated, but negative for TDP-43. UIs observed in the SALS and SOD1-unrelated FALS cases were clearly positive for TDP-43. BBs were negative for this protein. Interestingly, in these SALS and FALS cases, glial cells were also found to have cytoplasmic TDP-43-positive inclusions. These findings indicate that the histological and molecular pathology of SALS can occur as a phenotype of FALS without SOD1 mutation.

DOI： 10.1007/s00401-007-0206-9

New mutation in the non-gigantic exon of SACS in Japanese siblings 査読

Yuhei Takado, Kenju Hara, Takayoshi Shimohata, Susumu Tokiguchi, Osamu Onodera, Masatoyo Nishizawa

MOVEMENT DISORDERS 22 ( 5 ) 748 - 749 2007年4月

Multiplex families with multiple system atrophy 査読

Kenju Hara, Yoshio Momose, Susumu Tokiguchi, Mitsuteru Shimohata, Kenshi Terajima, Osamu Onodera, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Motoyuki Hirasawa, Yoshikuni Mizuno, Katsuhisa Ogata, Jun Goto, Ichiro Kanazawa, Masatoyo Nishizawa, Shoji Tsuji

ARCHIVES OF NEUROLOGY 64 ( 4 ) 545 - 551 2007年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER MEDICAL ASSOC

Background: Multiple system atrophy (MSA) has been considered a sporadic disease, without patterns of inheritance.
Objective: To describe the clinical features of 4 multiplex families with MSA, including clinical genetic aspects.
Design: Clinical and genetic study. Setting: Four departments of neurology in Japan.
Patients: Eight patients in 4 families with parkinsonism, cerebellar ataxia, and autonomic failure with age at onset ranging from 58 to 72 years. Two siblings in each family were affected with these conditions.
Main Outcome Measures: Clinical evaluation was performed according to criteria by Gilman et al. Trinucleotide repeat expansion in the responsible genes for the spinocerebellar ataxia (SCA) series and for dentatorubral-pallidoluysian atrophy (DRPLA) was evaluated by polymerase chain reaction. Direct sequence analysis of coding regions in the alpha-synuclein gene was performed.
Results: Consanguineous marriage was observed in 1 of 4 families. Among 8 patients, 1 had definite MSA, 5 had probable MSA, and 2 had possible MSA. The most frequent phenotype was MSA with predominant parkinsonism, observed in 5 patients. Six patients showed pontine atrophy with cross sign or slitlike signal change at the posterolateral putaminal margin or both on brain magnetic resonance imaging. Possibilities of hereditary ataxias, including SCA1 (ataxin 1, ATXN1), SCA2 (ATXN2), Machado-Joseph disease/SCA3 (ATXN1), SCA6 (ATXN1), SCA7 (ATXN7), SCA12 (protein phosphatase 2, regulatory subunit B, beta isoform; PP2R2B), SCA17 (TATA box binding protein, TBP) and DRPLA (atrophin 1; ATN1), were excluded, and no mutations in the alpha-synuclein gene were found.
Conclusions: Findings in these multiplex families suggest the presence of familial MSA with autosomal recessive inheritance and a genetic predisposition to MSA. Molecular genetic approaches focusing on familial MSA are expected to provide clues to the pathogenesis of MSA.

DOI： 10.1001/archneur.64.4.545

Clinical and genetic characterizations of 16q-linked autosomal dominant spinocerebellar ataxia (AD-SCA) and frequency analysis of AD-SCA in the Japanese population 査読

Hiroaki Nozaki, Takeshi Ikeuchi, Akio Kawakami, Akio Kimura, Reiji Koide, Miyuki Tsuchiya, Yuusaku Nakmura, Tatsuro Mutoh, Hiroko Yamamoto, Naoki Nakao, Ko Sahashi, Masatoyo Nishizawa, Osamu Onodera

MOVEMENT DISORDERS 22 ( 6 ) 857 - 862 2007年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-LISS

Autosomal dominant spinocerebellar ataxias (AD-SCAs) form a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, a single nucleotide substitution in the 5'-untranstated region of the puratrophin-1 gene was found to be associated with one type of AD-SCA linked to chromosome 16q (16q-SCA). To obtain further insight into the contribution of the C-to-T substitution in the puratrophin-1 gene to the clinical and genetic characteristics of patients with 16q-SCA, we analyzed 686 families with 719 individuals diagnosed with progressive ataxia. We found C-to-T substitution in the puratrophin-1 gene in 57 unrelated families with 65 affected individuals. The mean age at onset in the patients with 16q-SCA was 59.1 (range, 46-77). Ataxia is the most common initial symptom. The elderly patients over 65 occasionally showed other accompanying clinical features including abnormalities in tendon reflexes, involuntary movements, and reduced vibration sense. We also examined the frequency of the AD-SCA subtype, considering the effects of age at onset. In the 686 AD-SCA families, SCA6 and Machado-Joseph disease/ SCA3 are frequent subtypes, followed by dentatorubral-pallidoluysian atrophy and 16q-SCA. 16q-SCA is not a rare subtype of Japanese AD-SCA, particularly in patients with ages at onset over 60. (c) 2007 Movement Disorder Society.

DOI： 10.1002/mds.21443

Botulinum toxin A injections improve apraxia of eyelid opening without overt blepharospasm associated with neurodegenerative diseases 査読

Masato Kanazawa, Takayoshi Shimohata, Masahisa Sato, Osamu Onodera, Keiko Tanaka, Masatoyo Nishizawa

MOVEMENT DISORDERS 22 ( 4 ) 597 - 598 2007年3月

New locus for benign hereditary chorea with adult-onset maps to chromosome 8q22.2-q23.3 査読

Kenju Hara, Takayoshi Shimohata, Sanpei Kazuhiro, Jin-ichi Nunomura, Izumi Kawachi, Masato Kanazawa, Kensaku Kasuga, Akinori Miyashita, Ryozo Kuwano, Koichi Hirota, Shoji Tsuji, Osamu Onodera, Masatoyo Nishizawa, Yoshiaki Honma

NEUROLOGY 68 ( 12 ) A326 - A327 2007年3月

Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons 査読

Asako Tagawa, Chun-Feng Tan, Koki Kikugawa, Masayuki Fukase, Ryoichi Nakano, Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi

ACTA NEUROPATHOLOGICA 113 ( 2 ) 205 - 211 2007年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

We describe a new family with adult onset amyotrophic lateral sclerosis (FALS), in which the disease was characterized clinically by relatively rapid progression of bulbar symptoms. Gene analysis of Cu/Zn superoxide dismutase (SOD1) performed in one patient showed no mutations. Autopsy of another patient demonstrated degenerative changes restricted to the upper and lower motor neuron systems; no evident changes were observed in the posterior column, Clarke's column or spinocerebellar tracts. The presence of Bunina bodies and ubiquitin-positive skein-like inclusions in the lower motor neuron was of considerable interest. Cases of FALS with such pathological features are quite rare in the literature. Identification of the gene responsible for the disease is desirable in order to shed further light on the molecular pathology of not only familial, but also sporadic, ALS.

DOI： 10.1007/s00401-006-0151-z

Novel mutation in EIF2B gene in a case of adult-onset leukoencephalopathy with vanishing white matter 査読

Masaru Matsui, Kotaro Mizutani, Hiroaki Ohtake, Yukio Miki, Koichi Ishizu, Hidenao Fukuyama, Takayoshi Shimohata, Osamu Onodera, Masatoyo Nishizawa, Yoshihiro Takayama, Hiroshi Shibasaki

EUROPEAN NEUROLOGY 57 ( 1 ) 57 - 58 2007年

Spinocerebellar ataxia with ocular motor apraxia and DNA repair 査読

Osamu Onodera

NEUROPATHOLOGY 26 ( 4 ) 361 - 367 2006年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BLACKWELL PUBLISHING

At least four disorders, ataxia telangiectasia (AT), an ataxia-telangiectasia-like disorder, early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia type 1 (AOA1), and ataxia with oculomotor apraxia type 2, are accompanied by ocular motor apraxia (OMA), which is an impairment of saccadic eye movement initiation. The characteristic pathological findings of EAOH/AOA1 and AT are a severe loss of Purkinje cells, severe myelin pallor of the posterior columns, and moderate neuronal loss in the dorsal root ganglia and anterior horn. Purkinje cells stimulate the fastigial nucleus and suppress omnipause neurons to initiate saccadic eye movement. The selective loss of Purkinje cells might cause OMA and disturb the cancellation of the vestibulo-ocular reflex. These disorders have the following common clinical features: ataxia, involuntary movements, and peripheral neuronopathy. In addition, the causative genes for these disorders are associated with the DNA/RNA quality control system. The impairment of DNA/RNA integrity results in selective neuronal loss in these recessive-inherited ataxias.

DOI： 10.1111/j.1440-1789.2006.00741.x

Long-terms therapeutic efficacy and safety of low-dose tacrolimus (FK506) for myasthenia gravis 査読

Masayoshi Tada, Takayoshi Shimohata, Mari Tada, Mutsuo Oyake, Shuichi Igarashi, Osamu Onodera, Satoshi Naruse, Keiko Tanaka, Shoji Tsuji, Masatoyo Nishizawa

JOURNAL OF THE NEUROLOGICAL SCIENCES 247 ( 1 ) 17 - 20 2006年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

Objective: To elucidate the long-term therapeutic efficacy and safety of low-dose FK506 (tacrolimus) in patients with myasthenia gravis (MG).
Patients and methods: We treated nine patients with MG (all women: age range: 35-83years (mean: 51.1 years); MGFA classification: 4 type IIa, 4 type IIb, and 1 type IVb patients) with FK506 for more than 24months (observation period: 24-46months). All the patients had undergone extended thymectomy before FK506 treatment; two patients (22.2%) had noninvasive thymoma and six (66.7%) had thymic hyperplasia. We evaluated total Quantitative MG (Q-MG) score, anti-acetylcholine receptor (AM) antibody titer in the blood, interleukin 2 (IL-2) production in peripheral blood mononuclear cells (PBMCs), administration dosage of prednisolone (PSL), and adverse effects of FK506.
Results: A reduction in steroid dosage of 50 50% without worsening of the symptoms was observed 1 year after FK506 administration in three out of six steroid-dependent MG patients (50.0%). The total Q-MG scores (range: 0-39 points) at 6months and l year after FK506 administration improved by 3 points or more in six (66.7%) and seven (77.8 %) out of nine patients, respectively. The efficacy of FK506 was maintained for more than 2years. Although adverse effects were observed in three patients (33.3 %), these were not serious.
Conclusions: Our study indicates that low-dose FK506 treatment may be efficacious not only in controlling intractable myasthenic symptoms, but also in reducing steroid dosage, and that FK506 is safe as an adjunctive drug to PSL for MG treatment for a maximum of 3 years. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2006.03.010

New HSN2 mutation in Japanese patient with hereditary sensory and autonomic neuropathy type 2 査読

M Takagi, T Ozawa, K Hara, S Naruse, T Ishihara, J Shimbo, S Igarashi, K Tanaka, O Onodera, M Nishizawa

NEUROLOGY 66 ( 8 ) 1251 - 1252 2006年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Hereditary sensory and autonomic neuropathies (HSANs) are heterogenous disorders characterized by a loss of pain sensation and autonomic abnormalities caused by peripheral nerve degeneration. (1) HSANs are clinically classified into five entities based on the inheritance pattern and clinical presentations. Mutations in at least six genes, SPTLC1, RAB7, HSN2, IKBKAP, TRKA, and NGFB, are known to be causative for the clinical varieties of HSANs. (1)
HSAN2 is clinically characterized by autosomal recessive inheritance, the onset of symptoms in infancy or early childhood, the occurrence of paronychia, whitlows, ulcers of distal extremities, unrecognized fractures of the foot and hand, anhidrosis, sensory loss that affects all modalities of sensations in the lower and upper limbs, the absence or diminution of tendon reflexes, the absence of sensory nerve action potentials (SNAPs), and the virtual absence of myelinated fibers with a decreased number of unmyelinated fibers in sural nerves. (1)
To date, seven truncated mutations of the HSN2 gene have been identified among HSAN2 families from Quebec, Newfoundland, and Nova Scotia in Canada, and Lebanon, Italy, and Austria. (2-5) Here, we describe a new truncated mutation in the HSN2 gene of a Japanese patient with HSAN2.

DOI： 10.1212/01.wnl.0000208415.90685.cd

Oral cyclophosphamide therapy for multifocal fibrosclerosis with hypertrophic intracranial pachymeningitis 査読

Masayoshi Tada, Osamu Onodera, Kenju Hara, Keiko Tanaka, Hitoshi Takahashi, Shoji Tsuji, Masatoyo Nishizawa

Clinical Neurology 46 ( 2 ) 128 - 133 2006年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）

A 54-year-old man was admitted to our hospital because of a headache, dry cough, low grade fever and hearing loss sustained for 6 months. Physical and neurological examinations revealed bilateral conjunctival hyperemia, fine crackles in the lower lungs, cutaneous scars, horizontal gaze evoked nystagmus, bilateral moderate sensorineural deafness and mild hyperreflexia. Hypertrophic intracranial pachymeningitis (HIP) accompanied by episcleritis, pulmonary fibrosis, subcutaneous fibrosis of the trunk and upper limbs, bilateral chronic otitis media and sinusitis of the paranasal cavities were observed. Histopathological investigation of biopsied tissues from the dura matter, lung, skin and nasal mucosa showed marked fibrosis with lymphocyte and plasma cell infiltrations. The diagnosis of multifocal fibrosclerosis (MF) was made
this is a rare syndrome of unknown etiology characterized by fibrosis involving multiple organ systems. Although steroid pulse therapy and cyclophosphamide (CP) pulse therapy was not effective in his illnesses, the combination therapy of corticosteroid and oral CP was dramatically effective. We concluded that HIP can be a manifestation of MF, and additional oral CP should be considered as a treatment for steroid-resistant MF with HIP.

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22
23
24
25