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Biomedical subjects

Gen Sobue

Publications and source records attributed to Gen Sobue.

At least 55 records · Page 3Linked to original sources
PubMed2005

[The efficacy of olanzapine for delusion in patients with Parkinson's disease].

We investigated the usefulness of quetiapine and olanzapine for delusion in nine patients with Parkinson's disease (PD). Two of five patients initially treated with quetiapine showed resolution of delusion on low dose (25 mg and 50 mg/day), whereas three patients had no improvement in spite of increasing the dose to 300 mg/day. Quetiapine non-responders had a tendency to more severe delusion and dementia compared with responders. Not only all four patients initially treated but also two of three quetiapine non-responders showed a remarkable resolution of delusion on olanzapine. In particular, three of seven patients responded to an extremely low dose of 0.625 mg/day. However, severe motor debilitation was observed in one patient treated with 1.25 mg/day. Olanzapine might be useful for delusion of PD in patients not responded to quetiapine, although it should be started at a very low dosage to ameliorate worsening parkinsonism.

Aged↗
PubMed2005

[Pathogenesis and treatment of CIDP].

CIDP is an autoimmune peripheral polyneuropathy. Clinical and electrophysiologic features indicate its heterogeneity, and such wide spectrum of the phenotype makes difficult to clarify complete pathogenesis. IVIg is an effective therapy no less than corticosteroids and plasmaphresis, and getting as the first choice for CIDP treatment due to the easy administration and less side effect. However, we have noticed that there is certain amount of non-responder, and this therapeutic heterogeneity could correspond to independent pathogenesis. In our previous report, axonal dysfunction, such as muscle atrophy and decreased CMAPs, is a significant factor to represent non-responder. Not only about therapy responsiveness, but aspect of long-term prognosis, subjects that show unfavorable prognosis indicate significant muscle atrophy and loss of myelinated fibres. Hence, decreased axonal function in peripheral nerve should critically affect CIDP pathogenesis. In practice, clinician should select proper treatment modality in light of clinical symptoms and appropriate medical costs, and if each one does not show enough efficacies, another should be admitted because responder for each modality is not necessarily overlapped. Although immunosuppressive agents might be admitted for non-responder to any other modalities, large randomized control trial is not done yet.

Humans↗
PubMed2004

Retinoic-acid-concentration-dependent acquisition of neural cell identity during in vitro differentiation of mouse embryonic stem cells.

Retinoic acid (RA) is one of the most important morphogens, and its embryonic distribution correlates with neural differentiation and positional specification in the developing central nervous system. To investigate the concentration-dependent effects of RA on neural differentiation of mouse embryonic stem cells (ES cells), we investigated the precise expression profiles of neural and regional specific genes by ES cells aggregated into embryoid bodies (EBs) exposed to various concentrations of RA or the BMP antagonist Noggin. RA promoted both neural differentiation and caudalization in a concentration-dependent manner, and the concentration of RA was found to regulate dorso-ventral identity, i.e., higher concentrations of RA induced a dorsal phenotype, and lower concentrations of RA induced a more ventral phenotype. The induction of the more ventral phenotype was due to the higher expression level of the N-terminus of sonic hedgehog protein (Shh-N) when treated with low concentration RA, as it was abrogated by an inhibitor of Shh signaling, cyclopamine. These findings suggest that the concentration of RA strictly and simultaneously regulates the neuralization and positional specification during differentiation of mouse ES cells and that it may be possible to use it to establish a strategy for controlling the identity of ES-cell-derived neural cells.

Animals↗
PubMed2004

Physical and functional interaction between Dorfin and Valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders.

Dorfin, a RING-IBR type ubiquitin ligase (E3), can ubiquitylate mutant superoxide dismutase 1, the causative gene of familial amyotrophic lateral sclerosis (ALS). Dorfin is located in ubiquitylated inclusions (UBIs) in various neurodegenerative disorders, such as ALS and Parkinson's disease (PD). Here we report that Valosin-containing protein (VCP) directly binds to Dorfin and that VCP ATPase activity profoundly contributes to the E3 activity of Dorfin. High through-put analysis using mass spectrometry identified VCP as a candidate of Dorfin-associated protein. Glycerol gradient centrifugation analysis showed that endogenous Dorfin consisted of a 400-600-kDa complex and was co-immunoprecipitated with endogenous VCP. In vitro experiments showed that Dorfin interacted directly with VCP through its C-terminal region. These two proteins were colocalized in aggresomes in HEK293 cells and UBIs in the affected neurons of ALS and PD. VCP(K524A), a dominant negative form of VCP, reduced the E3 activity of Dorfin against mutant superoxide dismutase 1, whereas it had no effect on the autoubiquitylation of Parkin. Our results indicate that VCPs functionally regulate Dorfin through direct interaction and that their functional interplay may be related to the process of UBI formation in neurodegenerative disorders, such as ALS or PD.

Adenosine Triphosphatases↗
PubMed2004

Widespread active inflammatory lesions in a case of HTLV-I-associated myelopathy lasting 29 years.

An autopsy case of human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) of 29 years' duration is reported. The patient had no history of surgery or blood transfusion and likely contracted HTLV-I sexually while traveling in an endemic area. At age 45, the patient began to experience gait disturbance; he later developed spastic tetraparesis. Autopsy revealed marked gross spinal cord atrophy, particularly in the middle to lower thoracic levels. Myelin and axonal degeneration were identified predominantly in the middle to lower thoracic spinal cord, extending into the medulla oblongata and lumbar cord. Inflammatory infiltrates of mononuclear cells were diffuse in the white and gray matter of the spinal cord and medulla oblongata, particularly in perivascular areas. These infiltrates were also observed in perivascular areas of the pons, midbrain, cerebellum, and cerebrum. More than half of the infiltrating cells were positive for the pan-T cell marker UCHL-1, but some were positive for the B cell marker SL-26. There were far more CD8-positive cells than CD4-positive cells in the spinal parenchyma and perivascular areas. Neurons in the anterior horn, Clarke's column, and intermediolateral column were relatively well preserved. Active chronic inflammation was indicated. Despite the 29-year history of HAM, the presence of an active inflammatory reaction is surprising. We discuss possible modulation of the histopathological manifestations of HAM by corticosteroid therapy.

Human T-lymphotropic virus 1↗
PubMed2004

Distribution of tuft-shaped astrocytes in the cerebral cortex in progressive supranuclear palsy.

The deposition of abnormal levels of tau protein is a major neuropathological feature of progressive supranuclear palsy (PSP), and the presence of tuft-shaped astrocytes is a neuropathological hallmark of PSP. We examined the topographic distribution of tuft-shaped astrocytes in the cerebral hemisphere by Gallyas-Braak silver staining in three Japanese autopsy cases of typical PSP. The distribution of tuft-shaped astrocytes was relatively uniform between cases. Tuft-shaped astrocytes were identified predominantly in posterior frontal areas such as the precentral gyrus and premotor and supplementary motor areas (Brodmann areas 4, 6 and 8). Tuft-shaped astrocytes were most dense in areas of cortical convexity, and they were more abundant in the crests of the cerebral gyri than in the valleys of the cerebral sulci. The temporal, parietal and occipital cortices, including the hippocampal formation and cingulate gyrus, were relatively free of tuft-shaped astrocytes. We confirmed involvement of the cerebral cortex in the pathology of PSP, and showed the widespread presence of tuft-shaped astrocytes, particularly in the precentral gyrus and premotor and supplementary motor areas, to be an essential neuropathological feature of PSP. The extra-pyramidal and pyramidal signs, supranuclear oculomotor abnormalities and other cortical signs associated with PSP may be related to the high density of tuft-shaped astrocytes in the precentral gyrus and premotor and supplementary motor areas. Dementia, apraxia, aphasia and frontal lobe signs may also result, at least in part, from this cortical involvement.

Animals↗
PubMed2004

Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor. Unifying mechanisms have been implicated in the pathogenesis of polyQ-dependent neurodegenerative diseases including SBMA, Huntington disease and spinocerebellar ataxias. It has been suggested that mutant protein containing polyQ inhibits histone acetyltransferase activity, resulting in transcriptional dysfunction and subsequent neuronal dysfunction. Histone deacetylase (HDAC) inhibitors alleviate neurological phenotypes in fly and mouse models of polyQ disease, although the therapeutic effect is limited by the toxicity of these compounds. We studied the therapeutic effects of sodium butyrate (SB), an HDAC inhibitor, in a transgenic mouse model of SBMA. Oral administration of SB ameliorated neurological phenotypes as well as increased acetylation of nuclear histone in neural tissues. These therapeutic effects, however, were seen only within a narrow range of SB dosage. Our results indicate that SB is a possible therapeutic agent for SBMA and other polyQ diseases, although an appropriate dose should be determined for clinical application.

Acetylation↗
PubMed2004

Clinical analysis of longstanding subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 years after its ban.

One thousand and thirty-one longstanding patients with subacute myelo-optico-neuropathy (SMON; 275 males, 756 females; mean age +/- S.D., 72.9 +/- 9.6 years; age at onset 37.6 +/- 9.8 years; duration of illness 35.3 +/- 4.0 years) were examined in 2002, 32 years after banning of clioquinol. At onset, 66.7% of patients were unable to walk, and 4.7% complete blindness. At present time, about 41% of patients were still difficult to walk independently, including 15.8% of completely loss of locomotion. One point six percent of patients were in complete blindness and 5.8% had severe visual impairment. The majority (95.6 - 97.7%) of patients exhibited sensory disturbances including superficial and vibratory sensations and dysesthesia. Dysautonomia was observed as leg hypothermia in 79.8%, urinary incontinence in 60.7%, and bowel disturbance in 95.3%. As complication, high incidence was revealed with cataract (56.2%), hypertension (40.2%), vertebral disease (35.5%), and limb articular disease (31.5%). These results indicate the serious sequelae of clioquinol intoxication, SMON.

Aged↗
PubMed2004

Polyglutamine diminishes VEGF; passage to motor neuron death?

Altered gene transcription has been implicated in the pathogenesis of polyglutamine-dependent neurodegeneration. In this issue of Neuron, Sopher et al. demonstrate that androgen receptors containing expanded polyglutamine cause decreased expression of vascular endothelial growth factor (VEGF) by interfering with cAMP response element binding protein binding protein (CBP), thereby contributing to the motor neuron degeneration in spinal and bulbar muscular atrophy.

Animals↗
PubMed2004

Spinal and bulbar muscular atrophy: ligand-dependent pathogenesis and therapeutic perspectives.

Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. SBMA exclusively affects males, while females are usually asymptomatic. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract in the first exon of the androgen receptor (AR) gene. The histopathological hallmark is the presence of nuclear inclusions containing mutant truncated ARs with expanded polyQ tracts in the residual motor neurons in the brainstem and spinal cord, as well as in some other visceral organs. The AR ligand, testosterone, accelerates AR dissociation from heat shock proteins and thus its nuclear translocation. Ligand-dependent nuclear accumulation of mutant ARs has been implicated in the pathogenesis of SBMA. Transgenic mice carrying the full-length human AR gene with an expanded polyQ tract demonstrate neuromuscular phenotypes, which are profound in males. Their SBMA-like phenotypes are rescued by castration, and aggravated by testosterone administration. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, inhibits nuclear accumulation of mutant ARs, resulting in the rescue of motor dysfunction in the male transgenic mice. However, flutamide, an androgen antagonist promoting nuclear translocation of the AR, yielded no therapeutic effect. The degradation and cleavage of the AR protein are also influenced by the ligand, contributing to the pathogenesis. Testosterone thus appears to be the key molecule in the pathogenesis of SBMA, as well as main therapeutic target of this disease.

Animals↗
PubMed2004

Cognitive impairments in Machado-Joseph disease.

BACKGROUND: Cognitive function of Machado-Joseph disease (MJD) patients has not been clarified. OBJECTIVES: To determine the characteristics of cognitive dysfunction in MJD patients and to assess the relationship of dysfunction to age at onset, age at examination, disease duration, education, ataxia, depression, anxiety, and CAG repeat length. DESIGN: Case-control study. SETTING: Research-oriented hospitals. PARTICIPANTS: Sixteen genetically confirmed MJD patients able to complete neuropsychological tests and 20 control subjects matched to patients by age and education. MAIN OUTCOME MEASURES: Neuropsychological tests, including general cognition, verbal and visual memory, working memory, visuospatial and constructional ability, language, executive function, depression, and anxiety. RESULTS: Machado-Joseph disease patients scored significantly lower than controls in verbal and visual memory, in visuospatial and constructional tasks, and in phonemic and semantic fluency tasks. None of these impairments correlated with CAG repeat length, age at onset, age at examination, disease duration, or education. Verbal fluency (words named in a category) correlated with the International Cooperative Ataxia Rating Scale score. CONCLUSION: Machado-Joseph disease patients have verbal and visual memory deficits, visuospatial and constructional dysfunction, and verbal fluency deficits, all unrelated to CAG repeat length.

Adult↗
PubMed2004

Dorfin prevents cell death by reducing mitochondrial localizing mutant superoxide dismutase 1 in a neuronal cell model of familial amyotrophic lateral sclerosis.

Abstract Dorfin is a RING-finger type ubiquitin ligase for mutant superoxide dismutase 1 (SOD1) that enhances its degradation. Mutant SOD1s cause familial amyotrophic lateral sclerosis (FALS) through the gain of unelucidated toxic properties. We previously showed that the accumulation of mutant SOD1 in the mitochondria triggered the release of cytochrome c, followed by the activation of the caspase cascade and induction of neuronal cell death. In the present study, therefore, we investigated whether Dorfin can modulate the level of mutant SOD1 in the mitochondria and subsequent caspase activation. We showed that Dorfin significantly reduced the amount of mutant SOD1 in the mitochondria, the release of cytochrome c and the activation of the following caspase cascade, thereby preventing eventual neuronal cell death in a neuronal cell model of FALS. These results suggest that reducing the accumulation of mutant SOD1 in the mitochondria may be a new therapeutic strategy for mutant SOD1-associated FALS, and that Dorfin may play a significant role in this.

Amyotrophic Lateral Sclerosis↗
PubMed2004

[Development of a brief communication ability scale for Japanese demented elderly].

We developed a brief scale to evaluate communication ability of the demented elderly. This scale assesses not only abilities related to overall communication such as verbal function, judgment and emotional function, but also non-verbal communication such as eye-contact, nodding and smiling. The scale places little burden on the demented elderly subject and takes only a few minutes to perform, even if the dementia is severe. We evaluated 106 demented elderly residents of nursing homes using this brief communication ability scale, and the following results were obtained. The validity of this scale was confirmed by the high correlation coefficient between this scale and the formal caregiver questionnaire scores concerning communication ability, and the high-correlation coefficient between this scale and intellectual functions (r = -0.904), emotional functions (r = -0.841) and motor functions (r = -0.679) of dementia syndromes rating scale (Gottfries, Bråne, Steen scale; GBS scale), Hasegawa's Dementia Scale-Revised (HDS-R) (r = 0.625) and the Mini-Mental State Examination (MMS) (r = 0.733). The reliability of this scale was confirmed by the high interrater reliability coefficient of 0.828, test-retest reliability coefficient of 0.940 and Cronbach alpha coefficient of 0.938. These results indicate that the new scale is useful in the assessment of communication ability among the demented elderly.

Aged↗