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Biomedical subjects

I Kanazawa

Publications and source records attributed to I Kanazawa.

At least 109 records · Page 6Linked to original sources
PubMed1999

Air-puff-induced facilitation of motor cortical excitability studied in patients with discrete brain lesions.

Air-puff stimulation applied to a fingertip is known to exert a location-specific facilitatory effect on the size of the motor evoked potentials elicited in hand muscles by transcranial magnetic stimulation. In order to clarify its nature and the pathway responsible for its generation, we studied 27 patients with discrete lesions in the brain (16, 9 and 2 patients with lesions in the cerebral cortex, thalamus and brainstem, respectively). Facilitation was absent in patients with lesions affecting the primary sensorimotor area, whereas it was preserved in patients with cortical lesions that spared this area. Facilitation was abolished with thalamic lesions that totally destroyed the nucleus ventralis posterolateralis (VPL), but was preserved with lesions that at least partly spared it. Lesions of the spinothalamic tract did not impair facilitation. The size of the N20-P25 component of the somatosensory evoked potential showed a mild correlation with the amount of facilitation. The facilitation is mainly mediated by sensory inputs that ascend the dorsal column and reach the cortex through VPL. These are fed into the primary motor area via the primary sensory area, especially its anterior portion, corresponding to Brodmann areas 3 and 1 (possibly also area 2), without involving other cortical regions. The spinothalamic tract and direct thalamic inputs into the motor cortex do not contribute much to this effect. Some patients could generate voluntary movements despite the absence of the facilitatory effect. The present method will enable us to investigate in humans the function of one of the somatotopically organized sensory feedback input pathways into the motor cortex, and will be useful in monitoring ongoing finger movements during object manipulation.

Brain Injuries↗
PubMed1999

Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients.

Dentatorubral-pallidoluysian atrophy (DRPLA) is one among an increasing number of hereditary neurodegenerative diseases determined as being caused by unstable expansion of CAG repeats coding for polyglutamine stretches. To investigate the molecular mechanisms underlying CAG repeat instability, we established three transgenic lines each harboring a single copy of a full-length human mutant DRPLA gene carrying a CAG repeat expansion. These transgenic mice exhibited an age-dependent increase (+0.31 per year) in male transmission and an age-dependent contraction (-1.21 per year) in female transmission. Similar tendencies in intergenerational instabilities were also observed in human DRPLA parent-offspring pairs. The intergenerational instabilities of the CAG repeats may be interpreted as being derived from the instability occurring during continuous cell division of spermatogonia in the male, and that occurring during the period of meiotic arrest in the female. The transgenic mice also exhibited an age-dependent increase in the degree of somatic mosaicism which occurred in a cell lineage-dependent manner, with the size range of CAG repeats being smaller in the cerebellum than in other tissues including the cerebrum, consistent with observations in autopsied tissues of DRPLA patients. Thus, the transgenic mice described in this study exhibited age-dependent intergenerational as well as somatic instabilities of expanded CAG repeats comparable with those observed in human DRPLA patients, and are therefore expected to serve as good models for investigating the molecular mechanisms of instabilities of CAG repeats.

Adult↗
PubMed1999

PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival.

A novel gene, designated PQBP-1, which encodes a 265 residue protein that binds to the polyglutamine tract of the brain-specific transcription factor Brn-2, was identified. PQBP-1, which also interacts with the polyglutamine tract of triplet repeat disease gene products, binds with a higher affinity to an expanded polyglutamine tract. PQBP-1 has several functional domains, including hepta- and di-amino acid repeat sequences rich in polar residues essential for its interaction with the polyglutamine tract, a WWP/WW domain which binds to proline-rich motifs in other proteins, a putative nuclear localization signal sequence and a C2domain implicated in Ca2+-dependent phospholipid signaling. PQBP-1 is located in the nucleus and inhibits transcriptional activation by Brn-2. Overexpression of PQBP-1 in P19 embryonic carcinoma cells suppresses their growth rate and enhances their susceptibility to various stresses including serum deprivation, retinoic acid treatment and UV irradiation. Northern blot and in situ hybridization analyses revealed that PQBP-1 is a ubiquitous protein and is expressed primarily in neurons throughout the brain, with abundant levels in hippocampus, cerebellar cortex and olfactory bulb. These results suggest that PQBP-1 mediates important cellular functions under physiological and pathological conditions via its interaction with polyglutamine tracts.

Amino Acid Sequence↗
PubMed1999

Abundant expression and cytoplasmic aggregations of [alpha]1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6.

Spinocerebellar ataxia type 6 (SCA6) is one of the eight neurodegenerative diseases caused by a tri-nucleotide (CAG) repeat expansion coding polyglutamine (CAG repeat/polyglutamine diseases) and is characterized by late onset autosomal dominant cerebellar ataxia and predominant loss of cerebellar Purkinje cells. Although the causative, small and stable CAG repeat expansion for this disease has been identified in the [alpha]1A voltage-dependent calcium channel gene (CACNA1A), the mechanism which leads to predominant Purkinje cell degeneration is totally unknown. In this study, we show that the calcium channel mRNA/protein containing the CAG repeat/polyglutamine tract is most intensely expressed in Purkinje cells of human brains. In SCA6 brains, numerous oval or rod-shaped aggregates were seen exclusively in the cytoplasm of Purkinje cells. These cytoplasmic inclusions were not ubiquitinated, which contrasts with the neuronal intra-nuclear inclusions of other CAG repeat/polyglutamine diseases. In cultured cells, formation of perinuclear aggregates of the channel protein and apoptotic cell death were seen when transfected with full-length CACNA1A coding an expanded polyglutamine tract. The present study indicates that the mechanism of neurodegeneration in SCA6 is associated with cytoplasmic aggregations of the [alpha]1A calcium channel protein caused by a small CAG repeat/polyglutamine expansion in CACNA1A.

Animals↗
PubMed1999

Lambert-Eaton myasthenic syndrome associated with idiopathic thrombocytopenic purpura and diffuse panbronchiolitis: long-term remission after a course of intravenous immunoglobulin combined with low-dose prednisolone.

We report a case of Lambert-Eaton myasthenic syndrome (LEMS) associated with idiopathic thrombocytopenic purpura (ITP) and diffuse panbronchiolitis (DPB). An extensive search for malignancy yielded negative results. Interestingly, ITP and DPB developed simultaneously when the patient suffered from myasthenic symptoms. This is the first report in the Japanese or English literature of an association of LEMS, ITP, and DPB. The use of cholinesterase blocker alone did not improve the myasthenic symptoms, and the symptoms and signs relapsed with the tapering of prednisolone (PSL) dosage. However, after administration of immunoglobulin (IVIG) (0.4 g/kg/day x 5 days), low-dose PSL (20 mg/day) alleviated the LEMS and ITP, and the diseases have remained in remission for 8 months without additional IVIG. We suspect that there is a synergistic relationship between IVIG and PSL.

Anti-Inflammatory Agents↗
PubMed1999

Intracortical inhibition of the motor cortex is normal in chorea.

Intracortical inhibition of the motor cortex was investigated using a paired pulse magnetic stimulation method in 14 patients with chorea caused by various aetiologies (six patients with Huntington's disease, one with chorea acanthocytosis, a patient with systemic lupus erythematosus with a vascular lesion in the caudate, three with senile chorea and three with chorea of unknown aetiology). The time course and amount of inhibition was the same in the patients as in normal subjects, suggesting that the inhibitory mechanisms of the motor cortex studied with this method are intact in chorea. This is in striking contrast with the abnormal inhibition seen in patients with Parkinson's disease or focal hand dystonia, or those with a lesion in the putamen or globus pallidus. It is concluded that the pathophysiological mechanisms responsible for chorea are different from those producing other involuntary movements.

Adult↗
PubMed1999

Clinical, neuropathological, and molecular study in two families with spinocerebellar ataxia type 6 (SCA6).

To clarify the clinical, neuropathological, and molecular characteristics of spinocerebellar ataxia type 6 (SCA6), two unrelated Japanese families with SCA6 were studied. A clinical feature of the two families was late onset "pure" cerebellar ataxia. Pathologically, three SCA6 brains consistently showed Purkinje cell dominant cortical cerebellar degeneration. Morphometric analysis showed that loss of the cerebellar granule cells and inferior olivary neurons were very mild compared with the severity of Purkinje cell loss. There was no obvious ubiquitin immunoreactive nuclear inclusions. All affected patients had identical expanded alleles, and the expansion was also homogeneously distributed throughout the brain without mosaicism. The present study showed that SCA6 is characterised by Purkinje cell dominant cortical cerebellar degeneration, highly stable transmission of the CAG repeat expansion, and lack of ubiquitin immunoreactive nuclear inclusions.

Adult↗
PubMed1999

Monospecific anti-GD1b IgG is required to induce rabbit ataxic neuropathy.

Of 22 rabbits sensitized with GD1b, 12 developed experimental sensory ataxic neuropathy. The affected rabbits had a higher level of serum IgG monospecific to GD1b than the unaffected ones. The GD1b-positive neuronal cytoplasms of rabbit dorsal root ganglia had larger diameters than the negative ones. IgG antibody monospecific to GD1b may preferentially bind to large primary sensory neurons, causing sensory ataxic neuropathy.

Animals↗
PubMed1999

[The clinical usefulness of high-dose intravenous immunoglobulin therapy for chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy].

To explore the optimum dose of intravenous immunoglobulin (i.v.Ig) for treating patients with chronic inflammatory demyelinating polyrneuropathy and multifocal motor neuropathy, we compared the usefulness of i.v.Ig among 3 treatment doses. Fifty-nine patients were randomly divided into three treatment dosage groups: 20 patients for Group I using 50 mg/kg/day x 5 days, 19 patients Group II using 200 mg/kg/day x 5 days, and 20 patients Group III using 400 mg/kg/day x 5 days. We assessed clinically and electrophysiologically the effectiveness of the treatment at 5 weeks after the initial infusion. For patients in Group I and II who had not improved (or worsened) with the first treatment, we gave a one-step larger dose in the second treatment (i.e. 200 mg/kg/day x 5 days for those who had been given 50 mg/kg/day x 5 days, 400 mg/kg/day x 5 days for those who had been given 200 mg/kg/day x 5 days) after more than 9 weeks. We found that 15% of the patients in Group I, 21% in Group II and 60% in Group III improved dose-dependently with the first intravenous immunoglobulin treatment. Seven (47%) of 16 patients in Group I and 4 (40%) of 11 patients in Group II improved after the second treatment with larger doses. Adverse reactions including chill sensation, fever, skin eruption and increase in blood GOT and GPT levels were transient and mild. One patient in Group III developed left hemiparesis showing the small infarction in the right thalamus during the course of the treatment, but the symptom was mild. In conclusion, the high-dose intravenous immunoglobulin therapy (400 mg/kg/day x 5 days) is useful for treating patients with CIDP and MMN, although care must be taken of the risk of causing cerebral infarctions.

Adolescent↗
PubMed1998

Different complex formations of dentatorubral-pallidoluysian atrophy (DRPLA) protein in human and rat neurons.

Dentatorubral-pallidoluysian atrophy (DRPLA) is caused by expansion of a glutamine repeat in DRPLA protein. Rat DRPLA protein, homologous in sequence to human DRPLA protein, was identified in rat brains. Immunoblots of human control and rat brain tissues with and without reduction show that human DRPLA protein forms more disulfide-bond complexes than rat DRPLA protein. An immunohistochemical study and a subcellular fractionation experiment show that human DRPLA protein produces complexes within the cytoplasm of neurons, whereas rat DRPLA protein rarely does. In spite of the close homology of their amino acid sequences, human and rat DRPLA protein have different protein characters. The differences in these characters suggest structural differences and may be related to these proteins functions.

Aged↗
PubMed1998

Polar amino acid-rich sequences bind to polyglutamine tracts.

Polyglutamine tracts are found in different proteins including transcription factors and cofactors as well as in triplet repeat disease gene products. To characterize the protein motif that binds to the polyglutamine tract, we screened a human embryonic brain cDNA library with the polyglutamine tract of Brn-2 as bait using the yeast two-hybrid method. All six isolated clones encoding polyglutamine tract binding proteins were rich in polar amino acids. Three of these clones could form polar helical structures. These observations suggest that polar amino acid-rich sequences are essential for binding to the polyglutamine tract.

Amino Acid Sequence↗
PubMed1998

Cloning and mapping of ZNF231, a novel brain-specific gene encoding neuronal double zinc finger protein whose expression is enhanced in a neurodegenerative disorder, multiple system atrophy (MSA).

A novel brain-specific gene, neuronal double zinc finger protein (ZNF231), was cloned and mapped. We used the high-density cDNA filter method to analyze the gene-expression profile in brains with multiple system atrophy (MSA). MSA is a sporadic progressive neurodegenerative disease characterized clinically by cerebellar symptoms, parkinsonism, autonomic dysfunction, or their various combinations, but its pathogenesis has yet to be clarified. In total, 8300 cDNA clones were screened, and a novel gene, ZNF231, was identified, whose expression was elevated in cerebella of patients with MSA. Its transcript is approximately 16 kb long and encodes an open reading frame of 3926 amino acid residues that has several interesting motifs; two glycine-proline dipeptide repeats (aa 22-32 and aa 61-74), a pair of homologous C8 double zinc finger motifs (aa 169-226 and aa 465-521), a leucine zipper motif (aa 561-582), a SH3 domain-binding motif (aa 825-831), two nuclear targeting signals (aa 1011-1028 and aa 1071-1091), two glutamine-rich domains (aa 2428-2473 and aa 3775-3804), and a histidine-rich domain (aa 3597-3682). These features suggest that the new gene encodes a nuclear protein or transcription regulator. Northern blot and RT-PCR analyses showed that its expression is specific to the brain and apparently restricted to the neurons. Elevation of ZNF231 expression may be involved in the pathogenesis of multiple system atrophy. The gene for ZNF231 is located on chromosome 3p21.

Amino Acid Sequence↗
PubMed1998

Human genes for KNSL4 and MAZ are located close to one another on chromosome 16p11.2.

KNSL4 (Kid; kinesin-like DNA-binding protein) is a member of the kinesin family that is involved in spindle formation and the movements of chromosomes during mitosis and meiosis. Myc-associated zinc finger protein (MAZ) participates in both the initiation and the termination of transcription of target genes. We isolated genomic DNA clones that encoded KNSL4 and MAZ from a human cosmid library. Sequence analysis revealed that the two genes were very close to one another. The distance between the two genes was only 1. 2 kb, and this intervening 1.2-kb region was extremely GC-rich. The gene for KNSL4 spanned 16 kb and consisted of 14 exons and 13 introns, while the gene for MAZ spanned 6 kb and consisted of 5 exons and 4 introns. The two genes were mapped to chromosome 16p11.2 by fluorescence in situ hybridization.

Chromosome Mapping↗