Biomedical subjects

I Kanazawa

Publications and source records attributed to I Kanazawa.

At least 163 records · Page 9Linked to original sources

PubMed1997

Superoxide dismutase-like immunoreactivity in spheroids in Hallervorden-Spatz disease.

Iron accumulation in the basal ganglia and spheroid formation are pathological hallmarks of Hallervorden-Spatz disease (HS). Since an overaccumulation of iron (iron thesaurosis) that exceeds the binding capacity of ferritin could cause oxidative damage, we studied the possible role of oxidative stress in the pathogenesis of HS. The basal ganglia and spinal cord from patients with HS were investigated at autopsy, using histochemistry for iron and immunohistochemistry for Cu/Zn superoxide dismutase (SOD1), Mn superoxide dismutase (SOD2) and ferritin. SOD1-like immunoreactivity (IR), SOD2-IR and ferritin-IR occurred frequently in spheroids observed in the basal ganglia, and associated iron accumulation indicated the possible existence of increased oxidative stress in HS patients. Spheroids in the spinal cord showed intense SOD1-IR and SOD2-IR in HS, in sharp contrast with the occasional weak SOD1-IR and SOD2-IR observed in spheroids from patients with amyotrophic lateral sclerosis (ALS). Neither increased ferritin-IR nor iron accumulation were observed in spinal spheroids from HS and ALS patients. These data may suggest that, at least in the spinal cord, SOD1-IR and SOD2-IR in spheroids in HS patients do not result from oxidative stress directly related to iron accumulation.

Adult↗

PubMed1997

Motor cortical reflex myoclonus: a case study with MEG.

Cortical reflex myoclonus usually depends for its generation on the hyperexcitability of sensory cortex, which manifests itself as an enhanced somatosensory evoked potential (SEP). A 25-year-old female, presenting with involuntary jerky dorsiflexion of the left foot, was found to have cortical reflex myoclonus which was aggravated during intended movements. The jerks were also elicited by electrical stimulation of the posterior tibial nerve, although the SEP evoked by the same stimulus was normal in latency and amplitude. Both the spontaneous spikes and the premyoclonus spike demonstrated by jerk-locked back averaging were localized to the superior frontal gyrus, just anterior to the paracentral sulcus. Paired-pulse magnetic stimulation disclosed lack of inhibition in the right hemisphere leg motor area, whereas the excitability of sensory cortex as studied by paired SEP testing was normal. This suggests that the myoclonus was caused mainly by enhanced excitability of the motor cortex and that this alone was enough for the production of long loop reflexes. We propose to designate this type of cortical myoclonus as motor cortical reflex myoclonus. It is generated in the motor cortex, but is at the same time stimulus-sensitive.

Adult↗

PubMed1997

Machado-Joseph disease gene products carrying different carboxyl termini.

Three cDNA clones for the Machado-Joseph disease gene (MJD1) were isolated, two of which have a new exon sequence and a distinct 3' terminal nucleotide sequence resulting in a new carboxyl terminal domain in the translated product. The nucleotide sequence of the other one is similar to the previously published one except for five polymorphisms, one of which is a single nucleotide substitution resulting in a change from the stop codon (TAA; allele A) to a tyrosine residue (TAC; allele C). Genetic analysis results suggest that Japanese MJD mutations are associated with allele A.

Amino Acid Sequence↗

PubMed1997

Magnetic stimulation over the cerebellum in patients with ataxia.

We studied 20 patients with ataxia caused by various disorders using magnetic stimulation over the cerebellum. Results were compared with normal values found for 12 normal volunteers. In normal subjects, a magnetic stimulus over the cerebellum reduced the size of responses evoked by magnetic cortical stimulation when it preceded cortical stimulus by 5, 6 and 7 ms. The grand average of the ratios of the areas of conditioned responses at intervals of 5, 6 and 7 ms to those of control responses was designated the average area ratio (5-7 ms). Suppression of motor cortical excitability was reduced or absent in patients with a lesion in the cerebellum or cerebellothalamocortical pathway, but was normal in patients with a lesion in the afferent pathway to the cerebellum. Normal suppression was observed in Fisher's syndrome. The average area ratio (5-7 ms) correlated well with the severity of ataxia in patients with degenerative late-onset ataxia. These results are consistent with those for electrical stimulation of the cerebellum reported previously. We conclude that magnetic stimulation over the cerebellum produces the same effect as electrical stimulation even in ataxic patients. This less painful method can be used clinically to clarify the pathomechanisms for ataxia. Two other clinical uses of this technique were that it revealed clinically undetectable cerebellar dysfunction in patients whose extrapyramidal signs masked cerebellar signs, and that the slow progression of ataxia could be followed quantitatively in patients with degenerative late-onset ataxia.

Adult↗

PubMed1997

Huntington's disease gene product, huntingtin, associates with microtubules in vitro.

The gene responsible for Huntington's disease produces a large protein with a molecular weight of approximately 350 k, designated huntingtin. Here, we report that the protein can associate in vitro with the microtubules. Through the process of assembly and disassembly of microtubules, both wild-type and mutant huntingtin associate with microtubules to almost the same degree. Huntingtin does not bind to the tubulin-affinity column directly. Huntingtin appears to interact with polymerized tubulin. These results suggest that huntingtin may have a role in intracellular organelle transport or axonal transport by its association with microtubules.

Adult↗

PubMed1997

EAAT4, a glutamate transporter with properties of a chloride channel, is predominantly localized in Purkinje cell dendrites, and forms parasagittal compartments in rat cerebellum.

Glutamate transporters play a pivotal role in terminating glutamatergic transmission by eliminating glutamate from the synaptic cleft. Four different glutamate transporter cDNAs have been isolated thus far, and their tissue distribution has been investigated using northern blot and immunohistochemical analysis. We raised site-directed antisera against a synthetic oligopeptide corresponding to the C-terminal of EAAT4, a recently cloned human glutamate transporter, and investigated the distribution of EAAT4 in rat cerebellum. Western blot analysis demonstrated that the affinity-purified antiserum SAE4 recognized specifically a single band (about 62 kDa) in the rat cerebellum, cerebrum and spinal cord. The SAE4-immunoreactivity was localized predominantly in the dendritic spines and distal dendrites of Purkinje cells. The intensity of the immunoreactivity was uneven among Purkinje cells, forming parasagittal compartments. Since EAAT4 also has the properties of a glutamate-gated chloride channel, it should be able to modulate the transmission at the parallel fiber-Purkinje cell synapses.

Amino Acid Transport System X-AG↗

PubMed1997

Magnetic stimulation of the descending and ascending tracts at the foramen magnum level.

To test the possibility that stimulation over the foramen magnum activates ascending tracts as well as descending tracts, we studied 4 patients with myoclonic epilepsy all of whom had enhanced cortical long loop reflexes (LLRs) and 10 normal subjects, using our previously reported method (Ugawa et al., Ann. Neurol., 1994, 36: 618-624). For latency comparisons, peripheral nerve stimulation at the elbow and spinal motor root were also performed. In all patients, magnetic stimulation at the foramen magnum consistently elicited long loop reflexes as well as direct responses caused by stimulation of the descending tracts. In contrast, no LLRs were ever seen in any normal subjects. The latencies of both types of response were the same whether stimulation used upward or downward current in the brain, although the former was always more effective. This indicates that stimulation at the level of the foramen magnum activates ascending tracts as well as descending tracts at a fixed position. The threshold for LLRs was lower than that for activation of the descending tracts. This threshold difference is compatible with the hypothesis that large diameter fibers from muscle afferent conduct the central afferent volley for LLRs (Marsden et al., Brain, 1977, 100: 185-200).

Afferent Pathways↗

PubMed1997

HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain.

Huntington disease (HD) is associated with the expansion of a polyglutamine tract, greater than 35 repeats, in the HD gene product, huntingtin. Here we describe a novel huntingtin interacting protein, HIP1, which co-localizes with huntingtin and shares sequence homology and biochemical characteristics with Sla2p, a protein essential for function of the cytoskeleton in Saccharomyces cerevisiae. The huntingtin-HIP1 interaction is restricted to the brain and is inversely correlated to the polyglutamine length in huntingtin. This provides the first molecular link between huntingtin and the neuronal cytoskeleton and suggests that, in HD, loss of normal huntingtin-HIP1 interaction may contribute to a defect in membrane-cytoskeletal integrity in the brain.

Amino Acid Sequence↗

PubMed1997

Fatal GVHD demonstrating an involvement of respiratory muscle following donor leukocyte transfusion (DLT).

A 41-year-old female patient with AML, who relapsed after an allogeneic BMT from her HLA-identical sister, was treated by a donor leukocyte transfusion (DLT). Thereafter, bone marrow aplasia accompanied by the disappearance of leukemic blasts following the GVHD was observed. The patient died of chronic GVHD with respiratory muscle involvement 19 months after the DLT. Although the DLT was considered helpful in suppressing the proliferation of the leukemic cells, it might also have caused the severe GVHD observed in this case. Efforts to separate the lymphocyte clones responsible for GVL from those for the GVHD thus appear to be necessary for the further development of the therapeutic approach, so-called DLT.

Adult↗

PubMed1997

Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1.

Autosomal dominant cerebellar ataxia is a group of clinically and genetically heterogeneous disorders. We carried out genomewide linkage analysis in 15 families with autosomal dominant pure cerebellar ataxia (ADPCA). Evidence for linkage to chromosome 19p markers was found in nine families, and combined multipoint analysis refined the candidate region to a 13.3-cM interval in 19p13.1-p13.2. The remaining six families were excluded for this region. Analysis of CAG-repeat expansion in the alpha1A-voltage-dependent calcium channel (CACNL1A4) gene lying in 19p13.1, recently identified among 8 small American kindreds with ADPCA (spinocerebellar ataxia type 6 [SCA6]), revealed that 8 of the 15 families studied had similar, very small expansion in this gene: all affected individuals had larger alleles (range of CAG repeats 21-25), compared with alleles observed in neurologically normal Japanese (range 5-20 repeats). Inverse correlation between the CAG-repeat number and the age at onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proved in the SCA6 families that we studied. We conclude that more than half of Japanese cases of ADPCA map to 19p13.1-p13.2 and are strongly associated with the mild CAG expansion in the SCA6/CACNL1A4 gene.

Adult↗

PubMed1997

Aberrant processing of the Fugu HD (FrHD) mRNA in mouse cells and in transgenic mice.

The puffer fish ( Fugu rubripes ) has a compact genome of 400 Mbp which is approximately 7.5-fold smaller than the human genome. It contains a similar number of genes but is deficient in intergenic, intronic and dispersed repetitive sequences. Fugu is becoming established as the model vertebrate genome for the identification and characterisation of novel human genes and conserved regulatory sequences. It has also been proposed that Fugu genes may provide natural mini-genes for the production of transgenic mice. We have used the Fugu homologue of the Huntington's disease (HD) gene to test this possibility. The human and Fugu HD genes cover 170 kb and 23 kb respectively and have previously been sequenced in their entirety. In Fugu tissue, the Fugu HD gene was found to be expressed as predicted from the gene sequence but three differentially spliced forms were also detected. Despite the absence of conserved promoter sequences, the Fugu promoter was found to be functional in mouse cells. We have generated mice transgenic for the Fugu HD gene and conducted a detailed expression analysis across the entire 10 kb transcript. This revealed the presence of many aberrant splice forms which would be incompatible with the production of the Fugu huntingtin protein. The Fugu HD gene is incorrectly processed in mouse cells both in vitro and in vivo which sheds doubt on the usefulness of Fugu genes for transgenesis.

Animals↗

PubMed1997

Nine-year follow-up study of bromocriptine monotherapy for Parkinson's disease.

A 9-year nationwide study of bromocriptine monotherapy and combination therapy with bromocriptine and levodopa in Parkinson's disease is reported. Eleven patients were on bromocriptine monotherapy, 35 patients were on combined treatment of bromocriptine and levodopa for a certain time during a 9-year period. Maintenance doses of bromocriptine at the end of the 9th year in the two groups were 11.1 mg/day in the monotherapy and 12.7 mg/day in the combination therapy group with levodopa. Changes in Hoehn and Yahr's grading between the time of trial start and the end of 108 months' treatment revealed that 5 of 11 cases in the monotherapy group remained in the same stages, the other 2 cases improved in condition from stage II to I, and another 4 deteriorated compared with pretreatment grade. On the other hand, 20 of 35 cases in the combination-therapy group reached more advanced stages, 3 patients moving to stage V. Four of them, however, improved, and 11 did not change at the end of 9 years of treatment. Although it is difficult to prove the neuroprotective effect of a dopamine receptor agonist, our long-term nation-wide collaborative studies will help us to answer the question of how bromocriptine works in pharmacokinetic aspects.

Aged↗

PubMed1997

Nationwide multicenter prospective study on the long-term effects of bromocriptine for Parkinson's disease. Final report of a ten-year follow-up.

A 10-year nationwide multicenter prospective study on the long-term efficacy of bromocriptine for Parkinson's disease is reported. Six patients remained on bromocriptine monotherapy for 10 years, while 22 patients achieved good disease control with bromocriptine plus levodopa (added during the course of the study). In the 6 patients on bromocriptine alone, the disease remained in Hoehn and Yahr stage I or II for 10 years. In the other 22 patients on bromocriptine plus levodopa therapy, disease progression was very slow for 7-8 years. None of the 6 patients remaining on bromocriptine monotherapy experienced adverse reactions like the wearing-off phenomenon, dyskinesia, or the on-off phenomenon. Among the 22 patients who started levodopa therapy during the course of the study, these adverse reactions to levodopa were infrequent (10, 3, and 3 patients, respectively). Thus, early introduction and long continuation of bromocriptine therapy with restricted concomitant use of levodopa may have led to very slow disease progression and the suppression of adverse reactions. Although the patients who could be maintained long-term on bromocriptine monotherapy might represent a population who have very slowly progressive disease, their adequate disease control and the low incidence of adverse reactions in the patients who later started concomitant levodopa suggest that the unwanted effects of levodopa may be reduced by early and sustained treatment with bromocriptine. Introduction of bromocriptine monotherapy at an early stage of Parkinson's disease or with restricted use of additional levodopa therapy to bromocriptine when necessary may be a useful strategy for achieving adequate and sustained disease control.

Aged↗

PubMed1997

Effects of chronic levodopa therapy on dopa pharmacokinetics.

We reevaluate here the effects of chronic administration of levodopa on its peripheral pharmacokinetics and the contribution of the pharmacokinetics to the pathogenesis of the wearing-off phenomenon. The peak levodopa concentration (Cmax) and the area under the time-concentration curve (AUC) were markedly increased after long-term levodopa therapy, whereas the time to the peak concentration (Tmax) and the elimination half-life (T(1/2)) were decreased. These results suggest that long-term levodopa therapy accelerates the absorption of levodopa. Furthermore, the wearing-off group had a markedly higher Cmax and AUC, and a shorter Tmax and T(1/2) than the stable group. We speculate that the clinical expression of 'stable' or 'wearing-off' depends on the absorption of levodopa as well as the presynaptic terminal and postsynaptic receptors.

Aged↗

PubMed1997

Unusual MRI and pathologic findings of progressive multifocal leukoencephalopathy complicating adult Wiskott-Aldrich syndrome.

We present a long-surviving patient with Wiskott-Aldrich syndrome complicated by atypical progressive multifocal leukoencephalopathy (PML). MRI showed multiple tiny spots of Gd-DTPA-enhanced lesions on the T1-weighted image. Pathologic findings for brain biopsy were patchy demyelinated vascularized lesions infiltrated by a surprising number of eosinophils. The presence of polyomavirus JC was confirmed by in situ hybridization and polymerase chain reaction. PML should be included in the differential diagnosis when Gd-DTPA-enhanced spotty lesions are present in the white matter, especially in patients who have a mild immunologic defect.

Adult↗

PubMed1997

[Clinical classifications of Parkinson's disease].

Although typical clinical features of Parkinson's disease are widely accepted, the symptoms of individual parkinsonian patient are variable. We reviewed here the possible classification of the disease in terms 1) degree of response to levodopa, 2) rates of progression, 3) age of onset, and 4) main symptoms. In order to select a most appropriate therapeutic drug, we proposed other points for classification, 5) development of wearing-off, 6) with or without severe dementia and 7) characteristic clinical features, i.e. akinetic form, frozen form and so on. For the evaluation of long-term effects of anti-parkinsonian drugs, it is important to classify the patients by the course of alteration of cardinal or characteristic symptoms.

Age of Onset↗

PubMed1997

[Guillain-Barré syndrome and Fisher syndrome].

Guillain-Barré syndrome is an acute inflammatory polyneuropathy that usually follows infections. Fisher syndrome is a variant of Guillain-Barré syndrome, the triads of which are ophthalmoplegia, ataxia and areflexia. Although the agents for the preceding infections cannot be determined in many cases, those viruses such as Cytomegalovirus, Epstein-Barr virus, and HIV as well as Mycoplasma and bacteria including Campylobacter jejuni have been reported. The pathogenetic mechanisms may be immune-mediated. Frequent elevation of antiglycolipid antibodies in acute phase sera from patients with Guillain-Barré syndrome has recently been reported. They are useful diagnostic markers and clues for elucidation of the pathogenetic mechanism. In particular, IgG anti-GQ1b antibody is known to be specifically associated with Fisher syndrome and Guillain-Barré syndrome with ophthalmoplegia.

Animals↗

PubMed1997

[Shearing injuries of parasagittal white matter, corpus callosum and basal ganglia: possible radiological evidences of hemiplegia in diffuse axonal injury].

The relationship between spastic hemiplegia in diffuse axonal injury (DAI) and neuroradiological findings was studied in 100 cases. These cases were prospectively collected from the files of Automobile Insurance Rating Organization in Japan between 1993 from to 1996. Requirements for entry to this study were as follows: presence of initial unconsciousness after head injury without any lucid interval. Existence of CT scan or MRI film obtained within 12 hours of injury showing no significant mass effects, as well as follow-up CT scan or MRI film obtained more than 3 months after the injury. Psychosocial outcome was described both by the medical professional and the caregiver. The hemiplegia was rated severe, mild, or none. The outcome and diffuse ventriculomegaly were classified as reported by the authors previously. Spastic hemiplegia or quadriplegia was documented in the chronic stage in 63 cases, including 53 severe cases with difficulty in walking and 10 mild cases with only pyramidal signs detected. Chi-square analysis showed significant correlation between hemiplegia and the DAI outcome level or ventriculomegaly rating. Focal brain contusion was noticed in 33 cases, but did not correlate with the hemiplegia at all. Radiological findings included 25 cases of parasagittal white matter injury (gliding contusion), 20 cases of callosal injury, 19 cases of basal ganglionic region injury, 5 cases of brain-stem injury, and 3 cases of cerebellar injury. Chi-square analyses of hemiplegia and contralateral presence of these injuries were significant in the former three types of injury. Presence of at least one of these 3 lesions was defined as GCB injury. There were altogether 46 GCB injury cases which were significantly correlated with contralateral hemiplegia by chi-square analysis and by Spearman rank analysis. Partial correlation analysis with hemiplegia as the target variable indicated highly significant correlation only with GCB injury and outcome level. In conclusion, spastic hemiplegia in DAI is a manifestation of primary shear injury. Neuroradiological findings of GCB injury were statistically able to be significantly correlated with the presence of hemiplegia, and suggested pyramidal tract injury either at the corona radiata or the internal capsule level.

Adolescent↗