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Biomedical subjects

S Tsuji

Publications and source records attributed to S Tsuji.

At least 55 records · Page 3Linked to original sources
PubMed2002

Zolmitriptan is effective and well tolerated in Japanese patients with migraine: a dose-response study.

This phase II study investigated the efficacy, tolerability and dose-response relationship of oral zolmitriptan in the treatment of a single migraine attack in Japanese patients. A bridging analysis then assessed the validity of extrapolating western clinical data to these Japanese patients. In this multicentre, randomized, double-blind, placebo-controlled study, patients received a single dose of placebo or zolmitriptan 1, 2.5 or 5 mg. The primary endpoints were 2-h headache response and the tolerability of zolmitriptan. A statistically significant dose-response relationship was observed for the 2-h headache response (P=0.003). The 2.5 mg group had significantly greater 2-h headache response than the placebo group (P=0.032). The adverse event profile was similar to that reported in western patients, and no adverse events unique to the Japanese population were observed. The bridging analysis report confirmed similar efficacy and tolerability of zolmitriptan in Japanese and western populations. In the Japanese patients, the estimated response rates were 34.3%, 45.2%, 57.7% and 66.2% for placebo, and zolmitriptan 1, 2.5 and 5 mg, respectively, while in the western population the corresponding rates were 39.9%, 49.6%, 61.2% and 71.7%. Zolmitriptan is effective and well tolerated in the acute treatment of migraine in Japanese patients. The optimal dose was 2.5 mg, although the 5 mg dose may provide further benefit for some patients. The bridging analysis supports extrapolation of data from western to Japanese patients.

Adult↗
PubMed2002

Differential diagnosis and clinical course of autoimmune neutropenia in infancy: comparison with congenital neutropenia.

AIM: Autoimmune neutropenia in infancy (AIN) is caused by granulocyte-specific autoantibodies. Clinical presentation and diagnosis have not been well studied, resulting in cumbersome diagnostic investigations and unnecessary treatment such as granulocyte colony-stimulating factor (G-CSF) therapy. METHODS: Clinical, laboratory and immunological data of 18 infants with AIN were evaluated. Granulocyte-specific autoantibodies were detected by the direct granulocyte immunofluorescence test (D-GIFT), indirect granulocyte immunofluorescence test (I-GIFT) and immunoblotting. RESULTS: The average age of onset and resolution of neutropenia in AIN was 7.4 +/- 3.4 mo (mean +/- SD) and 20.4 +/- 4.9 mo, respectively. Sixteen of the 18 patients presented with mild infectious symptoms; the other 2 patients were detected by chance and presented with no infectious symptoms. D-GIFT was positive in all patients, and I-GIFT was positive in 17 of these 18 patients. Most patients showed preferential binding to neutrophils from NA(1 + 2-)-phenotyped donors by 1-GIFT and immunoblotting. An antibiotic (sulfamethoxazole-trimethoprim) was given to 15 patients for prophylaxis. G-CSF was given to only one infectious patient. CONCLUSION: A combination of diagnostic tests for the detection of granulocyte-specific autoantibodies was useful in diagnosing AIN, thus avoiding unnecessary investigations. Continuous treatment with G-CSF was not necessary for prophylaxis, even if neutrophil counts were extremely low.

Anti-Infective Agents↗
PubMed2002

Statistical parametric mapping in brain single photon computed emission tomography after carbon monoxide intoxication.

The purpose of this retrospective study was to assess regional cerebral blood flow in patients after carbon monoxide intoxication by using brain single photon emission computed tomography and statistical parametric mapping. Eight patients with delayed neuropsychiatric sequelae and ten patients with no neuropsychiatric symptoms after carbon monoxide intoxication were studied with brain single photon emission tomography imaging with 99mTc-hexamethyl-propyleneamine oxime. Forty-four control subjects were also studied. We used the adjusted regional cerebral blood flow images in relative flow distribution (normalization of global cerebral blood flow for each subject to 50 ml x 100 g(-1) x min(-1) with proportional scaling) to compare these groups with statistical parametric mapping. Using this technique, significantly decreased regional cerebral blood flow was noted extensively in the bilateral frontal lobes as well as the bilateral insula and a part of the right temporal lobe in the patients with delayed neuropsychiatric sequelae as compared with normal volunteers (P< 0.005). In the patients with no neuropsychiatric symptoms, significantly decreased regional blood flow in the bilateral frontal lobes particularly on the left side was detected. There was a significantly decreased regional cerebral blood flow in the right frontal lobe and insula in the patients with delayed neuropsychiatric sequelae as compared to those with no neuropsychiatric sequelae. It is concluded that statistical parametric mapping is a useful technique for highlighting differences in regional cerebral blood flow in patients following carbon monoxide intoxication as compared with normal volunteers. The selectively reduced blood flow noted in this investigation supports the contention that the decrease following carbon monoxide intoxication may be prolonged and further worsen in the frontal lobe. In addition, the present study may help to clarify the characteristics of the pathophysiological alteration underlying delayed neuropsychiatric sequelae.

Adult↗
PubMed2001

High serum levels of additional IL-18 forms may be reciprocally correlated with IgE levels in patients with atopic dermatitis.

We established an ELISA system for determination of as yet unidentified species of interleukin 18 (IL-18), named IL-18 type 2, in human serum. Serum IL-18 levels and their effect on IgE levels were examined in 18 patients with atopic dermatitis (AD) with no other allergic symptoms. Three of these patients showed high IL-18 type 2 concentrations (25-100 ng/ml) in their blood serum, and this IL-18 type 2 was detectable only with our established ELISA system. In contrast, the level of the conventional form of IL-18 (type 1) was found to be 50-400 pg/ml in all patients by the commercially available ELISA. The levels of type 1 IL-18 showed no correlation with those of type 2 and approximately 2-fold higher in AD patients than in normal subjects. IL-12 p40 and IgE levels were correlated in the patients with no IL-18 type 2, and interestingly, relatively low IgE concentrations were detected in the three IL-18 type 2-positive patients. They showed considerable levels of IL-12 p40 unlike normal subjects. The IFNgamma-inducing activity of IL-18 type 2 was >100-fold less potent by weight ratio than that of a recombinant 'active' IL-18 preparation, even after the treatment with Caspase 1. Although the relationship between AD and serum IgE levels is not clear cut, IL-18 type 2 appears to play some roles in the Th2-polarization involving IgE production in association with immune responses occurring in local inflammatory milieu such as atopic lesions.

Adolescent↗
PubMed2001

Neuronal nuclear alterations in dentatorubral-pallidoluysian atrophy: ultrastructural and morphometric studies of the cerebellar granule cells.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease caused by a CAG repeat expansion, resulting in ubiquitinated inclusions and diffuse accumulation of mutant atrophin-1 in the neuronal nuclei in many regions of the central nervous system. In the cerebellar cortex, such nuclear abnormalities occur in the granule cells. In the present study, we performed ultrastructural and morphometric analyses on the nuclei of the cerebellar granule cells from eight patients with DRPLA (four with juvenile-onset disease and four with adult-onset disease) in an attempt to obtain further insight into the neuronal nuclear alterations that occur in CAG-repeat diseases. Ultrastructurally, all patients had intranuclear filamentous inclusions (NIIs, neuronal intranuclear inclusions) and nuclear membrane indentations (NMIs) in some of their granule cells, and chromatin tended to be sparse in the nucleoplasm of the affected nuclei. No such changes were observed in the granule cells of four control subjects. In all patients there was an association between NIIs and NMIs, and nuclei with NIIs and/or NMIs were larger than those without such changes. However, the nuclear enlargement was not due solely to the NIIs - even nuclei without NIIs or NMIs were larger in the patients than in the controls. In the DRPLA patients, there was a significant inverse correlation between the cross-sectional area of the nuclei and the disease duration. These findings indicate that NIIs and NMIs are features in the disease and occur in association with each other, and that nuclear enlargement - the degree of which may decrease with time after onset of the illness - is a more prevalent abnormality than the formation of NIIs or NMIs.

Adolescent↗
PubMed2001

A novel synthetic Arg-Gly-Asp-containing peptide cyclo(-RGDf==V-) is the potent inhibitor of angiogenesis.

Arg-Gly-Asp (RGD)-containing peptide is a ligand for integrin alpha(V)beta3 and acts as an angiogenic inhibitor. A novel cyclic RGD peptide, cyclo(-RGDf==V-) (f==V), was synthesized and its biological activities were characterized and compared with its analogs, cyclo(-RGDfV-) (fV) and cyclo(-RGDf-MeV-) (fMeV). It bound to integrin alpha(V)beta3 with almost the same affinity as the fV and fMeV analogs. All three compounds inhibited the adhesion and growth of HUVEC cells in a dose-dependent manner in vitro. Out of three, fMeV had the strongest effect, f==V was almost as strong as fMeV, and fV had the least effect. However, in vivo, f==V significantly decreased the intratumoral microvessel density (MVD) in the DLD-1 (human colon cancer cell) inoculated mice, while fMeV had little effect. These results suggest the potential usefulness of the cyclo(-RGDf==V-) as an antiangiogenic agent for clinical use in the future.

Animals↗
PubMed2001

Amino acid sequences flanking polyglutamine stretches influence their potential for aggregate formation.

Expanded polyglutamine stretches have been shown to form aggregates and to be toxic to cells. In this study, we hypothesized that amino acid sequences flanking the polyglutamine stretches influence the aggregate formation potential of these stretches. Green fluorescent protein (GFP) fusion proteins containing glutamine repeats of various lengths and a fixed number of flanking amino acids of ataxin-2, huntingtin, dentatorubral-pallidoluysian atrophy protein (DRPLAP) or ataxin-3 were transiently expressed in COS-7 cells. The aggregate formation potential of ataxin-2 and DRPLAP increased in a CAG-repeat-length-dependent manner, with a threshold between 34 and 36. Truncated ataxin-2-Q56-GFP and truncated huntingtin-Q56-GFP showed a significantly higher aggregate formation potential than truncated DRPLAP-Q56-GFP or truncated ataxin-3-Q56-GFP. These results are in agreement with the clinical observation that ages of disease onset in patients with spinocerebellar ataxia type 2 or Huntington's disease are lower than those in patients with DRPLA or Machado-Joseph disease having expanded CAG repeats of the same length. Furthermore, mutagenesis of the flanking sequence of ataxin-2 markedly reduced its aggregate formation potential. These results indicate that the amino acid sequences flanking the polyglutamine stretches significantly influence their aggregate formation potential.

Amino Acid Sequence↗
PubMed2001

Decreased susceptibility to pentylenetetrazol-induced seizures after low-frequency transcranial magnetic stimulation in rats.

We studied the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) on seizure susceptibility in rats. rTMS of 1000 pulses at 0.5 Hz led to a prolonged latency for seizure development after an intraperitoneal injection of pentylenetetrazol. The rTMS effectively prevented the development of status epilepticus of pentylenetetrazol-induced convulsions. These findings indicate that low-frequency rTMS affects the neural excitability, in the direction of anticonvulsive, and therefore, suggest the possibility of therapeutic use of rTMS in epilepsy.

Animals↗
PubMed2001

B cell adaptor containing src homology 2 domain (BASH) links B cell receptor signaling to the activation of hematopoietic progenitor kinase 1.

The B cell adaptor containing src homology 2 domain (BASH; also termed BLNK or SLP-65), is crucial for B cell antigen receptor (BCR)-mediated activation, proliferation, and differentiation of B cells. BCR-mediated tyrosine-phosphorylation of BASH creates binding sites for signaling effectors such as phospholipase Cgamma (PLCgamma)2 and Vav, while the function of its COOH-terminal src homology 2 domain is unknown. We have now identified hematopoietic progenitor kinase (HPK)1, a STE20-related serine/threonine kinase, as a protein that inducibly interacts with the BASH SH2 domain. BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation. Furthermore, HPK1 augmented, whereas its kinase-dead mutant inhibited IkappaB kinase beta (IKKbeta) activation by BCR engagement. These results reveal a novel BCR signaling pathway leading to the activation of HPK1 and subsequently IKKbeta, in which BASH recruits tyrosine-phosphorylated HPK1 into the BCR signaling complex.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Cytotoxic T cell activity against the peptide, AYRARALEL, from Yo protein of patients with the HLA A24 or B27 supertype and paraneoplastic cerebellar degeneration.

OBJECTIVE: To determine a peptide that reacts with cytotoxic T cells (CTL) of patients with paraneoplastic cerebellar degeneration and anti-Yo antibodies with either HLA A24 or B27 supertype. METHOD: We studied CTL activity of four patients, three were HLA A24-positive and one did not have HLA A24 but had B27 supertype. After an incubation of mononuclear cells with or without peptide and IL-2, CD8-rich fraction was prepared by treatment with Magnetic Cell Sorting system (MACS) twice. CTL activity was calculated by 51Cr release from transfectant, C1RA*2402 as target cells. The peptide-binding assay was examined by flow cytometry. RESULTS: Two of three HLA A 24-positive patients demonstrated CTL activity against the Yo peptide, AYRARALEL. CTL activity was found to be 19.5% and 11.7% at the effector/target (E/T) ratio of 23:1 and 11:1, respectively. A patient who did not have HLA A24 but had A2 and B27 supertype possessed a CTL activity of 19.4% with 15:1 as E/T ratio. The peptide could bind to HLA A*2402 molecules but not to A*0201. CONCLUSIONS: We showed CTL activity in two of three Japanese patients with HLA A24 by using HLA A*2402 transfectant cells as the target. In addition, we identified the first Japanese patient who had B27 supertype, and suggested that the same peptide, AYRARALEL, could be recognized by CTL in this patient.

Autoantigens↗
PubMed2001

Protection of outer hair cells from reperfusion injury by an iron chelator and a nitric oxide synthase inhibitor in the guinea pig cochlea.

To examine whether an active process of the cochlea was injured by ischemia-reperfusion, time courses of distortion-product otoacoustic emissions (DPOAEs) were examined before, during and after 30 min cochlear ischemia using albino guinea pigs. DPOAEs decreased to the minimum level when the animals were subjected to ischemia. When the cochlea was recirculated, DPOAEs initially recovered with time until 20 min after the onset of reperfusion. However, thereafter the amplitude of DPOAEs gradually decreased toward the noise level. Administration of deferoxamine (an iron chelator) or N-nitro-L-arginine (a nitric oxide synthase inhibitor) ameliorated this decrease of DPOAEs during reperfusion and significantly increased the DPOAE amplitudes 60 min after the onset of reperfusion as compared with those in non-treated animals. These results suggest that cochlear reperfusion as well as ischemia injured the active process of the cochlea and that free radicals and nitric oxide play important roles in this injury.

Animals↗
PubMed2001

Dendritic cells presenting pyruvate kinase M1/M2 isozyme peptide can induce experimental allergic myositis in BALB/c mice.

Polymyositis (PM) is an inflammatory muscle disease caused by autoimmune dysfunction, considered to be caused by cytotoxic CD8 T cells. To date, no autoantigens have been identified. We attempted to induce an experimental allergic myositis (EAM) in BALB/c mice by inoculating syngeneic dendritic cells (DC) presenting peptides that are expected to match the binding anchor motif of H-2K(d) (BALB/c). We selected peptides that are highly expressed in skeletal muscle. Only when we inoculated syngeneic bone marrow-derived DC presenting pyruvate kinase M1/M2 peptide 464-472 in BALB/c mice, 41.7% of the mice (EAM) developed pathological changes in skeletal muscle compatible to human PM. Under other conditions (when we inoculated DC presenting no synthetic peptides into BALB/c or C57BL/6 mice and DC presenting pyruvate kinase M1/M2 peptide into C57BL/6 mice), there were no necrotizing and inflammatory lesions. Induction of EAM in the same manner as above also induced CTL activity against P815 cells with the same peptide and syngeneic differentiated cultured myotubes without peptides by the chromium release assay. Consistent with the similarity of the binding anchor motif of H-2K(d) (BALB/c) and HLA A*2402, we conclude that pyruvate kinase M1/M2 peptide is a candidate autoantigen not only in BALB/c-EAM but also in human-PM with the HLA A*2402 allele.

Animals↗
PubMed2001

SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein.

Genetic etiologies of at least 20% of autosomal dominant cerebellar ataxias (ADCAs) have yet to be clarified. We identified a novel spinocerebellar ataxia (SCA) form in four Japanese pedigrees which is caused by an abnormal CAG expansion in the TATA-binding protein (TBP) gene, a general transcription initiation factor. Consequently, it has been added to the group of polyglutamine diseases. This abnormal expansion of glutamine tracts in TBP bears 47--55 repeats, whereas the normal repeat number ranges from 29 to 42. Immunocytochemical examination of a postmortem brain which carried 48 CAG repeats detected neuronal intranuclear inclusion bodies that stained with anti-ubiquitin antibody, anti-TBP antibody and with the 1C2 antibody that recognizes specifically expanded pathological polyglutamine tracts. We therefore propose that this new disease be called SCA17 (TBP disease).

Adult↗
PubMed2001

Localization of a novel susceptibility gene for familial ovarian cancer to chromosome 3p22-p25.

We performed genome-wide linkage analysis in 58 patients and nine unaffected members among 28 families with no mutation in BRCA1 or BRCA2, employing a set of 410 microsatellite markers. We initially screened the whole genome, including the X chromosome, by a non-parametric method using the GENEHUNTER program. As a result, chromosome 3p22-p25 showed a suggestive score for linkage [LOD = 3.49 and non-parametric LOD (NPL) = 2.77 at D3S3611] based on a multipoint analysis. Additionally, based on a two-point analysis using dense markers, this 3p22-p25 region showed a P-value < 0.05 at 10 markers and there is suggestive evidence for linkage at two markers within approximately 19 cM (NPL = 2.60 and 2.49 at D3S1597 and D3S3611, respectively). To explore whether the candidate gene in this 3p22-p25 region contributed to carcinogenesis of familial ovarian cancer in a similar fashion to the tumor suppressor gene, we performed loss of heterozygosity (LOH) analysis. It was observed that the frequency of LOH at four markers in this region was >50% only in tumor tissues from patients with no mutation in BRCA1 or BRCA2, not in those with a BRCA1 mutation.

Adult↗