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Biomedical subjects

S Tsuji

Publications and source records attributed to S Tsuji.

At least 127 records · Page 7Linked to original sources
PubMed2001

[Familial hemiplegic migraine].

Familial hemiplegic migraine (FHM) is an autosomal dominant disorder characterized by transient hemiplegia followed by migraine headache, and recently approximately half of FHM families have been elucidated to be caused by mis-sense mutations in P/Q-type Ca channel alpha(1)-subunit gene (CACNA1A). This subunit forms channel pore and is implicated in the regulation of membrane excitability as voltage sensor, therefore FHM is thought to be channelopathy. The CACNA1A gene is causative of episodic ataxia type-2 and of spinocerebellar atrophy type 6. Moreover, FHM with cerebellar ataxia is only associated with the mutation in CACNA1A, dysfunction of the calcium channel may cause cerebellar degeneration. New genotype and phenotype have been reported, more reports and analyses are expected.

English Abstract↗
PubMed2000

Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder originally described in families of Portuguese-Azorean ancestry. The cloning of the MJD1 gene allowed identification of the disease in many other populations, and MJD is now known to be the most common cause of dominant spinocerebellar ataxia. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised, both at historical and molecular levels. In the present study, we tested this hypothesis by linkage-disequilibrium analysis of tightly linked polymorphisms and by haplotype comparison, in 249 families from different countries. We typed five microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973, D14S1016, and D14S977), and three intragenic single-base-pair polymorphisms (A(669)TG/G(669)TG, C(987)GG/G(987)GG, and TAA(1118)/TAC(1118)). The results show two different haplotypes, specific to the island of origin, in families of Azorean extraction. In families from mainland Portugal, both Azorean haplotypes can be found. The majority of the non-Portuguese families also share the same intragenic haplotype seen in the families coming from the island of Flores, but at least three other haplotypes were seen. These findings suggest two introductions of the mutation into the Portuguese population. Worldwide, the sharing of one intragenic haplotype by the majority of the families studied implies a founder mutation in MJD.

Alleles↗
PubMed2000

Functional modulation of human macrophages through CD46 (measles virus receptor): production of IL-12 p40 and nitric oxide in association with recruitment of protein-tyrosine phosphatase SHP-1 to CD46.

Human CD46, formerly membrane cofactor protein, binds and inactivates complement C3b and serves as a receptor for measles virus (MV), thereby protecting cells from homologous complement and sustaining systemic measles infection. Suppression of cell-mediated immunity, including down-regulation of IL-12 production, has been reported on macrophages (Mphi) by cross-linking their CD46. The intracellular events responsible for these immune responses, however, remain unknown. In this study, we found that 6- to 8-day GM-CSF-treated peripheral blood monocytes acquired the capacity to recruit protein-tyrosine phosphatase SHP-1 to their CD46 and concomitantly were able to produce IL-12 p40 and NO. These responses were induced by stimulation with mAbs F(ab')(2) against CD46 that block MV binding or by a wild-type MV strain Kohno MV strain (KO; UV treated or untreated) that was reported to induce early phase CD46 down-regulation. Direct ligation of CD46 by these reagents, but not intracellular MV replication, was required for these cellular responses. Interestingly, the KO strain failed to replicate in the 6- to 8-day GM-CSF-cultured Mphi, while other MV strains replicated to form syncytia under the same conditions. When stimulated with the KO strain, rapid and transient dissociation of SHP-1 from CD46 was observed. These and previous results provide strong evidence that CD46 serves as a signal modulatory molecule and that the properties of ligands determine suppression or activation of an innate immune system at a specific maturation stage of human Mphi.

Animals↗
PubMed2000

High-performance liquid chromatographic determination with photodiode array detection of ellagic acid in fresh and processed fruits.

A high-performance liquid chromatographic (HPLC) procedure based on an isocratic elution with photodiode array detection has been developed for a simple and rapid determination of ellagic acid (EA) in fresh and processed fruits. The homogenized sample was refluxed with methanol and then the extract was refined using a solid-phase cartridge before HPLC. We analyzed EA in 40 kinds of fresh fruits and 11 kinds of processed fruits by the developed method. EA was found in several berries, fueijoa, pineapple and pomegranate. This is the first occurrence of the detection of EA in bayberry, fueijoa and pineapple.

Chromatography, High Pressure Liquid↗
PubMed2000

Ganglioside GD3 and its mimetics induce cytochrome c release from mitochondria.

Ganglioside GD3 induced the release of cytochrome c from isolated rat liver mitochondria. This process was completely prevented by cyclosporin A and partially prevented by a cysteine protease inhibitor, n-acetyl-leu-leu-norleucinal. Cyclosporin A is a potent inhibitor of the permeability transition pore, whereas n-acetyl-leu-leu-norleucinal has no effect on this pore. These results indicate that the release of cytochrome c from mitochondria requires both the opening of the permeability transition pore and a cysteine protease inhibitor-sensitive mechanism. Gangliosides GD1a, GD1b, GT1b, and GQ1b along with the synthetic GD3 mimetics TMS-42 and CI-22, which are glycerophospholipids carrying a disialo residue, also induced cytochrome c release. In contrast, gangliosides GM1, GM2, and GM3 did not induce cytochrome c release. These results indicate that two sialo residues must play an important role in the induction of cytochrome c release by gangliosides.

Animals↗
PubMed2000

Paraspinal motor evoked potentials by magnetic stimulation of the motor cortex.

The authors studied five patients with MS and four patients with HTLV-1 associated myelopathy (HAM) to investigate the usefulness of paraspinal motor evoked potentials (MEP) after magnetic stimulation of the motor cortex. In patients with MS, MEP disappeared or onset latencies were delayed below the lesion. In patients with HAM, the onset latencies were prolonged bilaterally. Thus, paraspinal MEP are very useful in detecting spinal cord lesions.

Adult↗
PubMed2000

Introduction of a foreign gene into medakafish using the particle gun method.

We developed a procedure to introduce a foreign gene into fertilized eggs of medakafish (Oryzias latipes) using the particle gun method, which is one of the easiest and most reliable techniques for gene transfer. A plasmid construct with the green fluorescence protein (GFP) gene driven by the madakafish beta-actin gene promoter was successfully introduced into eggs, and the expression of GFP was observed in 20% of the primary transfectant (chimera) fish. In addition, germ line transmission of GFP was observed in 13% of the GFP-positive primary transfectant fish. The new application described here should enable us to investigate gene expression using the fish model on a routine basis without high technical sophistication. J. Exp. Zool. 287:285-293, 2000.

Animals↗
PubMed2000

A CAG trinucleotide repeat expansion and familial schizophrenia.

Studies which showed anticipation in families with schizophrenia suggested that a trinucleotide repeat expansion mechanism may be involved in the pathogenesis of familial schizophrenia. Furthermore, some studies involving the repeat expansion detection (RED) method showed the median length of CAG repeats to be longer in probands with schizophrenia than that in control subjects. We screened for a possible expanded CAG repeat by means of the direct identification of repeat expansion and cloning technique in 23 subjects (affected, 14; unaffected, 9) from six families with schizophrenia which showed anticipation. The polymorphism of a long and unstable CAG/CTG trinucleotide repeat, Dir1, was studied by PCR. No unusual expanded CAG/CTG trinucleotide repeat was detected in the subjects with familial schizophrenia. There was no significant difference between the affected and unaffected subjects in the allele frequency of Dir1. Our results suggest that a CAG expansion is not the mechanism underlying familial schizophrenia.

Adult↗
PubMed2000

Apolipoprotein E allele-dependent antioxidant activity in brains with Alzheimer's disease.

Thiobarbituric acid-reactive substances (TBARS), an index of lipid peroxidation, were assayed in postmortem brain. Basal TBARS levels were increased and oxidative stimulation produced more TBARS in AD relative to control brains. In addition, apolipoprotein E isoforms showed differing antioxidant activities, with E2 > E3 > E4, suggesting that the lowest antioxidant activity of E4 could contribute to its association with AD.

Aged↗
PubMed2000

Redefined substrate specificity of ST6GalNAc II: a second candidate sialyl-Tn synthase.

The acceptor substrate specificities of ST6GalNAc I and II, which act on the synthesis of O-linked oligosaccharides, were reexamined using ovine submaxillary mucin, [Ala-Thr(GalNAc)-Ala]n polymer (n = 7-11). It has been suggested that only ST6GalNAc I can synthesize carbohydrate structures of sialyl-Tn-antigen; i.e., NeuAc alpha2-6GalNAc-O-Thr/Ser [Kurosawa et al., J. Biol. Chem. 269, 19048-19053 (1994)] based on the result that ST6GalNAc I, not ST6GalNAc II, exhibited activity toward asialoagalacto-fetuin. In this study, we present evidence that both ST6GalNAc I and II exhibit activity toward asialo-OSM (ovine submaxillary mucin) and [Ala-Thr(GalNAc)-Ala]n polymer (n = 7-11) which have only the GalNAc-O-Thr/Ser-structures. These results strongly indicate that not only ST6GalNAc I but also II are candidates for sialyl-Tn synthases.

Animals↗
PubMed2000

Regional cerebral blood flow in male schizophrenic patients performing an auditory discrimination task.

Regional cerebral blood flow (rCBF) was measured in 11 schizophrenic patients amid 10 normal controls, both at rest and while performing an auditory discrimination task. Single photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime was used for quantitative evaluation of rCBF. The schizophrenic patients showed greater rCBF in the temporal and parietal regions at rest than the controls, but no abnormalities were found in frontal perfusion. During task performance. on the other hand, the patients showed a reduced frontal rCBF. whereas there was no group difference in rCBF in the temporal and parietal regions. In addition, the left> right hemisphere asymmetries of rCBF observed in the controls during task performance were not present in the patients. although there was no group difference in hemisphere laterality in rCBF at rest. These findings suggest that the employment of a cognitive task for neuroimaging studies is useful for detecting abnormalities of brain activation. such as hypofrontality and altered hemisphere laterality. in patients with schizophrenia.

Adult↗
PubMed2000

The B cell-restricted adaptor BASH is required for normal development and antigen receptor-mediated activation of B cells.

B cell antigen receptor signals development, activation, proliferation, or apoptosis of B cells depending on their condition, and its proper signaling is critical for activation and homeostasis of the immune system. The B cell-restricted adaptor protein BASH (also termed BLNK/SLP-65) is rapidly phosphorylated by the tyrosine kinase Syk after BCR ligation and binds to various signaling proteins. BASH structurally resembles SLP-76, which is essential for T cell development and T cell receptor signaling. To evaluate the role for BASH in B cell development and function in vivo, we disrupted BASH alleles in embryonic stem cells by means of homologous recombination and used these cells to complement lymphocyte-incompetent blastocysts from RAG2-deficient mice. In the resultant chimeric mice, T cell development was apparently normal, but B cell development was impaired, and a normally rare population of large preB cells expressing preB cell receptor dominated in the bone marrow in place of small preB cells, although they were mostly noncycling. In addition, the mature B cell populations in the periphery and the bone marrow profoundly decreased in size, as did B-1 cells in the peritoneal cavity, and serum Ig was severely reduced. The BASH-deficient B cells scarcely proliferated or up-regulated B7-2 in response to BCR ligation and poorly proliferated upon CD40 ligation or lipopolysaccharide stimulation. This phenotype indicates that BASH is critical for preB cell receptor signaling inducing proliferation of large preB cells and the following differentiation, for peripheral B cell maturation, and for BCR signaling inducing activation/proliferation of B cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter.

Dominantly inherited, late-onset pure cerebellar ataxia is a group of genetically heterogeneous neurodegenerative disorders. Approximately half of these disorders in the Japanese population are caused by moderate expansion of a CAG repeat in the coding region of the CACNA1A gene on chromosome 19p13 (SCA6). However, neither the loci nor the specific mutations for the remaining disorders have been determined. We performed systematic linkage analysis in a three-generation Japanese family with a locus or mutation that differed from those of known spinocerebellar ataxias. The family members with a late onset (> or =39 years old) exhibited pure cerebellar ataxia, whereas those with an early onset (< or =27 years old) first showed intermittent axial myoclonus followed by ataxia. Other neurological signs were sparse, and neuroimaging studies revealed that atrophy was confined to the cerebellum. Multipoint analysis and haplotype reconstruction ultimately traced this novel spinocerebellar ataxia locus (SCA14) to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter (Zmax = 4.08, corrected for age-dependent penetrance).

Adolescent↗
PubMed2000

An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene.

We report the neuropathologic and genetic features of a 70-year-old man with autosomal-recessive juvenile parkinsonism (AR-JP). At the age of 32 years, he developed a dystonic gait, followed by hand tremor, rigidity, bradykinesia, and impaired postural reflex. Levodopa was effective in ameliorating these symptoms. Pathologic examination of autopsy specimens from this patient revealed loss of pigmented neurons and gliosis in the substantia nigra pars compacta (SNPC), being most pronounced in the medial and ventrolateral regions, and locus ceruleus (LC). The melanin content of the remaining SNPC neurons was low. This feature was less marked in the LC. There were no Lewy bodies, as confirmed by immunostaining for alpha-synuclein. An additional, significant finding in this patient was neuronal loss and fibrillary gliosis in the substantia nigra pars reticulata; this feature has not been reported previously in AR-JP. Gene analysis revealed that this autopsied patient and his siblings had the parkin gene mutation (homozygous exon 4 deletion) that is responsible for the disease.

Aged↗
PubMed2000

Innate immune therapy for cancer. Screen for molecules capable of activating the innate immune system.

Tumor cells usually express antigens which are distinguishable from normal "self" antigens and are thereby recognized by the host immune system. However, the host immune system barely responds to tumors in patients. Supplementation with adjuvant (such as BCG-CWS) in patients with cancer contributes to regression of intrinsically growing cancer. The adjuvant targets antigen-presenting cells, i.e. innate immunity, but not lymphocytes, and promotes up-regulation of MHC, co-stimulators and initial cytokines in antigen-presenting cells. We hypothesized that the role of the adjuvant is to provide conditions suitable for antigen-presentation where antigens are available and the lack of adjuvant-induced priming of antigen-presenting cells results in unresponsiveness to tumor antigens. Here, we report innate immune therapy applicable to cancer patients by supplementation with adjuvants for induction of potent immune responses against tumors.

Humans↗
PubMed2000

Dentatorubral-pallidoluysian atrophy (DRPLA).

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by expansion of CAG repeats coding for a polyglutamine stretch. The prominent anticipation and broad spectrum in the clinical presentations of DRPLA have been demonstrated to be tightly correlated with the instability of CAG repeats in the DRPLA gene. Discovery of the causative gene for DRPLA has made it possible to investigate molecular mechanisms of neurodegeneration caused by expanded polyglutamine stretches. Recent investigations suggest that nuclear transport of mutant proteins containing expanded polyglutamine stretches and intranuclear aggregate formation play important roles in neuronal degeneration. We have recently demonstrated that the aggregate formation and apoptosis are partially suppressed by transglutaminase inhibitors, raising the possibility that transglutaminase is involved in the aggregate body. The results may open new prospects for developing therapeutic measures for the polyglutamine diseases.

Anticipation, Genetic↗