[A new murine model of HIV-associated encephalopathy].
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AIDS Dementia Complex↗
Biomedical subjects
Hidehiro Mizusawa
Publications and source records attributed to Hidehiro Mizusawa.
[Medical treatment of dyskinesia].
Dyskinesia and dystonia are common complications of long-term levodopa therapy. Because peak-dose dyskinesia is due to excessive dopaminergic stimulation by anti-parkinsonian drugs, it is solved by reducing the whole dose or by taking frequent small doses of levodopa in order to keep relatively stable serum levels. It may be attenuated by dopamine receptor agonists or amantadine which acts as an N-methyl-D-aspartate (NMDA) receptor agonist. On the other hand, since early morning dystonia is related to the decline in the level of levodopa, it is initially treated by adding a small dose of levodopa in bedtime. Other patterns of dystonia are often treated accordingly to the treatment of wearing-off phenomenon.
Dyskinesia, Drug-Induced↗
[Autosomal dominant spinocerebellar degeneration--new forms and pathomechanisms].
In our country, hereditary spinocerebellar degeneration accounted for approximately 30% of the total cases. Most of them are autosomal dominant and include more than 20 diseases. The outlines of some new members, namely autosomal dominant cortical cerebellar atrophy linked to chromosome 16 (16q-ADCCA), SCA14, an ataxia caused by FGF14 mutation and a form of neuroferritinopathy were described. The etiology of many autosomal dominant SCDs has been identified as the abnormal expansion of CAG repeat. The latter three diseases are caused by missense mutations of the causative genes, which clearly shows the presence of other new mechanisms of cerebellar degeneration than repeat expansion. 16q-ADCCA is the most frequent after Machado-Joseph disease and SCA6 according to our genetic diagnosis of 185 SCD patients. The disease is characterized by Purkinje cell degeneration and atrophy with somatic sprouts as well as the halo-like structure surrounding the soma. The halo is positive for synaptophysin. These features are so unique that 16q-ADCCA may be diagnosed by neuropathology alone.
Humans↗
[Towards the establishment of a postgraduate training program of neurology--in the case of Tokyo Medical and Dental University].
The training as neurologist in Department of Neurology and Neurological Science, Tokyo Medical and Dental University has mainly been performed through 3rd to 5th year after the graduation. It includes training for neurophysiology, neuroradiology and neuropathology as well as clinical neurology. Neurophysiology training has the separate 3 months course where trainee residents study exclusively neurophysiology but neuroradiology and neuropathology were learned during training for clinical neurology in general. The major problem of our training program is that the quota is so small to prepare enough trainee's positions. This appears also true in many institutes in Japan according to a questionnaire survey by this workshop. The number of neurology staff should be increased to accomplish better training for Neurology in each institute. The Japanese Society of Neurology should support this effort in each institute.
Education, Medical, Graduate↗
Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition.
Mutations in DJ-1 gene have been linked to autosomal recessive early onset parkinsonism (AR-EOP). Although the mechanism of neuronal cell death due to DJ-1 mutation has not been fully elucidated, loss of DJ-1 function was considered to cause the phenotype. Here, we demonstrated that the down regulation of endogenous DJ-1 of the neuronal cell line by siRNA enhanced the cell death which was induced by oxidative stress, ER stress, and proteasome inhibition, but not by pro-apoptotic stimulus. The cell death with hydrogen peroxide was dramatically rescued by over-expression of wild-type DJ-1, but not by that of L166P mutant DJ-1. Furthermore, DJ-1 rescued the cell death caused by over-expression of Pael receptor, which was a substrate of Parkin, another gene product for autosomal recessive juvenile parkinsonism. These results suggest that loss of protective activity of DJ-1 from neuro-toxicity induced by these stresses contributes to neuronal cell death in AR-EOP with mutant DJ-1.
Animals↗
Introduction of short interfering RNA to silence endogenous E-selectin in vascular endothelium leads to successful inhibition of leukocyte adhesion.
Short interfering RNAs (siRNAs) are powerful sequence-specific reagents that suppress gene expression in mammalian cells. We report for the first time that gene silencing of endothelial E-selectin by siRNAs leads to successful inhibition of leukocyte-endothelial interaction under flow. siRNAs designed to target human E-selectin were tranfected into human umbilical vein endothelial cells (HUVEC). Western blotting analysis revealed that transfection of these siRNAs, but not the scrambled control siRNA (100nM each), attenuated E-selectin expression in HUVEC activated with TNF-alpha (10ng/ml, 4h) without affecting expression of ICAM-1. Moreover, a leukocyte adhesion assay under flow (shear stress=1.0dyne/cm(2)) demonstrated that HUVEC transfected with a siRNA against E-selectin (siE-01) supported significantly less HL60 adhesion as compared to those transfected with the control siRNA (scE-01) after activation (p<0.03). This technique provides a powerful strategy to dissect a specific function of a given molecule in leukocyte-endothelial interaction.
Cell Adhesion↗
[Diagnosis and therapy for patients with multiple system atrophy].
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Brain↗
Glucose hypometabolism in medial frontal cortex of patients with apraxia of lid opening.
PURPOSE: To determine whether regional cerebral functional abnormalities exist in patients with apraxia of lid opening (ALO). METHODS: Cerebral glucose metabolism was examined by positron emission tomography (PET) in 11 patients (8 women and 3 men, age 48-69 years); 10 with ALO accompanied by blepharospasm and 1 patient with pure ALO. Eleven normal volunteers (6 women and 5 men, age 45-66 years) were examined as controls. A comprehensive ophthalmological examination, magnetic resonance imaging (MRI), and PET were performed. The cerebral glucose metabolism was evaluated by the relative uptake of [fluorine-18]fluorodeoxyglucose by PET. The mean +/- two standard deviations of the normal controls was defined as the normal range for cerebral glucose metabolism. RESULTS: MRI revealed no particular lesion except for an infarction in the unilateral basal ganglia in two patients. Decreased glucose metabolism was observed in a wide area of the medial frontal lobe (six cases) and primary visual cortex (PVC) (four cases). Group multiple comparisons revealed a significant decrease ( P<0.0035) in the bilateral anterior cingulate gyrus, left supplementary motor area (SMA), and bilateral PVC. CONCLUSION: The results support the hypothesis that ALO is associated with hypofunction in the SMA and/or anterior cingulate gyrus.
Aged↗
Neurological dysfunctions versus regional infarction volume after focal ischemia in Mongolian gerbils.
BACKGROUND AND PURPOSE: With advances in the therapy of stroke at the postacute phase, the use of animal models for chronological and region-specific evaluation of neurological function has become increasingly important. Our aim was to test long-term behavioral dysfunction in gerbils after focal ischemia and to correlate the results with the regional distribution of infarction in the coordinating cortical regions. METHODS: Repetitive unilateral hemispheric ischemia (two 10-minute occlusions, 5-hour interval) was induced in Mongolian gerbils. The elevated body swing test (EBST), bilateral asymmetry test (BAT), and T-maze test were performed to assess asymmetrical motor behavior, somatosensory deficit, and spatial cognitive dysfunction during 4 weeks after ischemia. The results were correlated against the regional infarction volume of the primary motor, somatosensory, and primary visual cortices at 4 weeks after ischemia. RESULTS: In all postischemic gerbils, persistent sensorimotor and cognitive dysfunctions were detectable throughout the postischemic period. Histological examination revealed that a cortical zone of infarction surrounded the selective neuronal death in the ipsilateral cerebral hemisphere. The regional infarction volumes of the primary motor, somatosensory, and visual cortices were significantly correlated with the scores of the EBST, BAT, and T-maze test, respectively. These combinations had the highest regression coefficient of all pairs. CONCLUSIONS: Postischemic motor and somatosensory functions were significantly correlated with regional infarction volumes in the corresponding cortical regions. In gerbils, visual abnormality could be independently detected by the T-maze test. Such regional analyses of ischemic lesions would be useful for investigating the functional outcomes of stroke therapy.
Animals↗
Proteolytic cleavage and cellular toxicity of the human alpha1A calcium channel in spinocerebellar ataxia type 6.
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by small CAG repeat expansion in the alpha1A calcium channel gene. We found that the human alpha1A calcium channel protein expressed in human embryonic kidney 293T cells produces a 75 kDa C-terminal fragment. This fragment is more toxic to cells than the full-length alpha1A calcium channel, regardless of polyglutamine tract length. In cells stably transfected with plasmids of full-length alpha1A calcium channel cDNAs, the C-terminal fragment protein is present in the mutant transformant but not in the wild-type one, indicative that this C-terminal fragment with the expanded polyglutamine tract is more resistant to proteolysis than that with the normal sized polyglutamine tract. We speculate that the toxic C-terminal fragment, in which resistance to proteolysis is rendered by the expanded polyglutamine, has a key role in the pathological mechanism of SCA6.
Calcium Channels↗
Dual impairment of GABAA- and GABAB-receptor-mediated synaptic responses by autoantibodies to glutamic acid decarboxylase.
Anti-glutamate decarboxylase autoantibodies (GAD-A) are associated with a group of patients with progressive cerebellar ataxia. We reported previously that cerebellar GABA(A)-mediated synaptic transmission was presynaptically depressed by GAD-A in the cerebrospinal fluid (CSF). Using whole-cell recording of rat cerebellar slices, we found in the present study that CSF immunoglobulins from ataxic patients reduced gamma-aminobutyric acid (GABA) release from cerebellar interneurons, thereby attenuating presynaptic inhibition on neighboring excitatory synapses through GABA(B) receptors (GABA(B)Rs). Our results suggest that in in vitro slices, GAD-A elicited the pathophysiological action of reduction in GABA release, which subsequently resulted in dual synaptic impairment in the cerebellar circuit, by depression of GABA(A) receptor (GABA(A)R)-mediated inhibitory synaptic transmissions, and attenuation of GABA(B) receptor-mediated inhibition of excitatory transmissions.
Action Potentials↗
Tumor necrosis factor-related apoptosis-inducing ligand induces neuronal death in a murine model of HIV central nervous system infection.
HIV-1 infection in the brain induces neuronal apoptosis leading to HIV-associated dementia. To explore the underlying mechanism, we developed a murine model by using human peripheral blood mononuclear cell (PBMC)-transplanted nonobese diabetic (NOD)-severe combined immunodeficiency (SCID) (hu-PBMC-NOD-SCID) mice. Administration of lipopolysaccharide (LPS) to HIV-1-infected hu-PBMC-NOD-SCID mice induced infiltration of HIV-1-infected human cells into the perivascular region of the brain and neuronal apoptosis was found in macrophage (M)-tropic but not T cell (T)-tropic HIV-1-infected brains. The apoptotic neurons were frequently colocalized with the HIV-1-infected macrophages that expressed tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Administration of a neutralizing antibody against human TRAIL but not human TNF-alpha or Fas ligand (FasL) blocked the neuronal apoptosis in the HIV-1-infected brain. These results strongly suggest a critical contribution of TRAIL expressed on HIV-1-infected macrophages to neuronal apoptosis.
Animals↗
Sera from Guillain-Barré patients enhance leakage in blood-nerve barrier model.
BACKGROUND: In Guillain-Barré syndrome (GBS), the destruction or malfunction of blood-nerve barrier (BNB) has been considered to be the beginning of the disease process. It is unclear whether sera from patients with GBS can open the BNB, and which component of patient sera is most important in the dysregulation of the BNB. METHODS: The authors evaluated the effect of sera from patients with GBS on permeability of an in vitro BNB model using bovine endoneurial microvascular endothelial cells (PnMEC) cultured on the luminal side of a collagen-coated culture insert (pore size: 0.4 micro m). RESULTS: PnMEC monolayers challenged by GBS sera showed significantly lower transendothelial electrical resistance and higher clearance of [carboxyl-(14)C]-inulin with or without complement. Sera with anti-GM1 antibody showed greater loosening of the barrier than others. This effect decreased significantly after incubation with pure GM1 antigen, suggesting the importance of anti-GM1 antibody in BNB dysregulation. Serial analyses of [carboxyl-(14)C]-inulin clearance in four patients disclosed a favorable effect of plasmapheresis in restoring BNB function in some cases. CONCLUSIONS: The authors found an unfavorable effect of sera from patients with GBS on BNB function, supporting involvement of humoral factors causing BNB derangement in the acute stage. Serial evaluation of permeability change using the authors' in vitro system might be useful for the clinical assessment of BNB derangement in individual patients.
Adult↗
Absence of association between codon 129/219 polymorphisms of the prion protein gene and Alzheimer's disease in Japan.
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Aged↗
Brain perfusion SPECT in patients with corticobasal degeneration: analysis using statistical parametric mapping.
We sought to determine the characteristics of brain perfusion in patients with corticobasal degeneration (CBD) using single photon emission computed tomography (SPECT) and statistical parametric mapping (SPM). Thirteen patients with CBD and 10 age-matched healthy volunteers were examined using brain perfusion SPECT and (99m)Tc-ethyl cysteinate dimer (ECD). Regional cerebral blood flow (rCBF) measurements were performed noninvasively using a graphic analysis method. Both the absolute rCBF data (raw data) and the adjusted rCBF data (global CBF normalized to 50 ml/100 g/min) were used in the SPM analysis. A significant decrease in the absolute rCBF was observed in extended areas of the brain in CBD patients compared to the control group. These areas included the frontal, parietal, and temporal cortices; basal ganglia; thalamus; and pontocerebellar regions. Our results suggest that the extent of the reduced rCBF region in CBD patients is more widespread than previously reported.
Aged↗
Physical map and haplotype analysis of 16q-linked autosomal dominant cerebellar ataxia (ADCA) type III in Japan.
Autosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. We previously mapped a gene locus for ADCA with pure cerebellar syndrome (ADCA type III) to a 3-cM region in chromosome 16q, and found a common haplotype among affected individuals. This region was exactly within the locus for another ADCA, spinocerebellar ataxia type 4 (SCA4). To identify the gene causing 16q-linked ADCA type III, we constructed a contig with 38 bacterial artificial chromosome clones between D16S3043 and D16S3095. The size of this contig was estimated to be 4.8 Mb. We found more than 500 nucleotide tandem repeats, including 9 CAG/CTG repeats in this candidate region, although none of the 94 tandem repeats analyzed were expanded in affected individuals. However, we found 11 new polymorphic markers, giving 22 markers spanning the candidate region. By typing these markers on eight Japanese families with ADCA type III, including two new families, we found that a common "founder" haplotype is seen in a more restricted 3.8-Mb region, spanning markers GGAA05 and D16S3095. We present here a newly refined critical interval of 16q-ADCA type III/SCA4. Data of 11 new DNA markers on 16q22.1 would also be useful for other research of genes mapped to this region.
Cerebellar Ataxia↗
Down-regulation of an ankyrin repeat-containing protein, V-1, during skeletal muscle differentiation and its re-expression in the regenerative process of muscular dystrophy.
Using Western blot analysis and immunohistochemical methods, we examined the expression of V-1, a member of the ankyrin repeat-containing protein family, during differentiation and regeneration of skeletal muscle. The expression of V-1 was high in cultured myoblasts and decreased during their differentiation into myotubes, while high expression was maintained when muscle differentiation was inhibited by treatment with basic fibroblast growth factor. Down-regulation of V-1 also occurred during in vivo muscle differentiation from embryonic to postnatal stages, reaching an undetectable level in mature skeletal muscle. In contrast, strong V-1 immunoreactivity was detected again in myoblasts and regenerating muscle fibers with a small diameter, which were observed in Duchenne muscular dystrophy and its animal model, mdx mouse. Thus, it seems that V-1 is a good marker for early stage of muscle regeneration and changes of its expression suggest that V-1 plays a role in prenatal muscle differentiation and postnatal muscle regeneration.
Adult↗