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Biomedical subjects

S Okada

Publications and source records attributed to S Okada.

At least 325 records · Page 18Linked to original sources
PubMed1998

A case of Kearns-Sayre syndrome showing a constant proportion of deleted mitochondrial DNA in blood cells during 6 years of follow-up.

Kearns-Sayre syndrome (KSS) and Pearson syndrome (PS) show quite different phenotypes despite the same underlying genetic defect, i.e. a large deletion of one population of mitochondrial (mt) DNA. The main feature of KSS is progressive encephalomyopathy; on the other hand, PS shows fatal hematological problems in early infancy. Through Southern blot analysis of mtDNA of blood cells, deletion has been consistently found in patients with PS but usually undetectable in KSS patients. Therefore, their different clinical phenotypes have been explained by the different tissue distribution of mutant mtDNA. Recently, a few cases were reported which had features of PS in infancy and later developed KSS. These observations suggest that phenotypes may also be modified by the selection process involving mtDNA within different tissues. We found a case of KSS, who initially presented endocrinological dysfunction such as insulin-dependent diabetes mellitus (IDDM) and growth hormone (GH) deficiency, and had not developed external ophthalmoplegia until the age of 17. Although he did not show any symptoms of PS, a marked proportion of mtDNA was deleted not only in muscle but also in blood cells. Analysis of his blood cells showed an unchanged proportion of deleted mtDNA at three estimations within 6 years of the follow-up period. This case provides evidence that deleted mtDNA in blood cells also has a stable replicative capacity and that a large proportion of deleted mtDNA in blood cells may not accompany hematological problems.

Anemia, Sideroblastic↗
PubMed1998

Sulfonylureas inhibit cytokine-induced eosinophil survival and activation.

Eosinophils play a key role in the pathogenesis of asthma and other allergic inflammatory diseases. We have previously shown that treatment of eosinophils with lidocaine preferentially inhibits IL-5-induced survival. This inhibition cannot be overcome by increasing concentrations of IL-5 and is not due to the blocking of Na+ channels by lidocaine. Here we report that one class of K+ channel blockers, the sulfonylureas, inhibits eosinophil survival in a manner similar to lidocaine. The sulfonylurea glyburide inhibits eosinophil survival even at high concentrations of IL-5. In contrast, increasing concentrations of IL-3 or granulocyte-macrophage CSF overcome glyburide inhibition. Glyburide also blocks cytokine-induced eosinophil superoxide production. Similar results were seen with the sulfonylureas tolbutamide and glipizide. Interestingly, the effects of glyburide are not antagonized by the ATP-sensitive K+ channel openers cromakalim, pinacidil, or diazoxide. Although Scatchard analysis of [3H]glyburide binding to eosinophil membranes indicated that the high affinity sulfonylurea receptor (SUR1) is not present on eosinophils, human eosinophils do express mRNA homologous to the sulfonylurea receptor family, in keeping with the presence of a sulfonylurea receptor. Finally, coculture of eosinophils with combinations of glyburide, lidocaine, and dexamethasone resulted in synergistic inhibition of cytokine-mediated eosinophil survival and superoxide production. These results have intriguing clinical implications for the treatment of eosinophil-associated diseases.

ATP-Binding Cassette Transporters↗
PubMed1998

Insulin receptor-mediated dissociation of Grb2 from Sos involves phosphorylation of Sos by kinase(s) other than extracellular signal-regulated kinase.

The Ras signaling pathway is rapidly activated and then down-regulated following stimulation of multiple cell-surface receptors including the insulin receptor (IR). Much recent attention has focused on elucidating the mechanism of Ras inactivation following IR engagement. Previous data suggest that IR-mediated serine/threonine phosphorylation of the Ras guanine nucleotide exchange factor Sos correlates with its decreased affinity for the adapter protein Grb2. This phosphorylation-induced disassembly of the Grb2.Sos complex is thought to be responsible, at least in part, for diminishing Ras activity in Chinese hamster ovary cells. In this report, we confirm the causal relationship between Sos phosphorylation and Grb2/Sos dissociation. We then examine several putative phosphorylation sites of Sos that could potentially regulate this event. Since a number of reports suggest that extracellular signal-regulated kinase (ERK) phosphorylates Sos, we generated a Sos mutant lacking all seven canonical phosphorylation sites for ERK. This mutant is a poor substrate of activated ERK in vitro and fails to undergo a change in its electrophoretic mobility following IR stimulation. It is, however, phosphorylated after IR stimulation when expressed in Chinese hamster ovary cells. Interestingly, the mutant protein still dissociates from Grb2 following insulin stimulation, suggesting that ERK is not the kinase responsible for regulating the stability of the Grb2.Sos complex.

Adaptor Proteins, Signal Transducing↗
PubMed1998

How platelet aggregation affects B16BL6 melanoma cell trafficking.

In blood-borne metastasis, intravasated metastatic tumor cells are thought to localize at the target site via a series of processes involving platelet aggregation, adhesion to endothelium, and invasion through the basal membrane. In the present study, we examined how platelet aggregation contributes to the trafficking of metastatic tumor cells in vivo by use of an inhibitor of platelet aggregation. Highly invasive B16BL6 melanoma cells were labeled with [2-18F]2-fluoro-2-deoxy-D-glucose and injected into mice to determine cell trafficking non-invasively by positron emission tomography. Both platelet aggregation inhibitor cyclo(RSarDPhg), which could not inhibit metastasis, and metastatic inhibitor cyclo(GRGDSPA) suppressed the accumulation of B16BL6 cells in the lung by about 12%, suggesting that platelet aggregation partly affects cell trafficking but not to a great extent, and that platelet aggregation is not the essential step for B16BL6 cell arrest in targets.

Animals↗
PubMed1998

Insulin regulates the dynamic balance between Ras and Rap1 signaling by coordinating the assembly states of the Grb2-SOS and CrkII-C3G complexes.

Insulin stimulation of Chinese hamster ovary cells expressing the human insulin receptor resulted in a time-dependent decrease in the amount of GTP bound to Rap1. The inactivation of Rap1 was associated with an insulin-stimulated decrease in the amount of Rap1 that was bound to Raf1. In parallel with the dissociation of Raf1 from Rap1, there was an increased association of Raf1 with Ras. Concomitant with the inactivation of Rap1 and decrease in Rap1-Raf1 binding, we observed a rapid insulin-stimulated dissociation of the CrkII-C3G complex which occurred in a Ras-independent manner. The dissociation of the CrkII-C3G was recapitulated in vitro using a GST-C3G fusion protein to precipitate CrkII from whole cell detergent extracts. The association of GST-C3G with CrkII was also dose dependent and demonstrated that insulin reduced the affinity of CrkII for C3G without any effect on CrkII protein levels. Furthermore, the reduction in CrkII binding affinity was reversible by tyrosine dephosphorylation with PTP1B and by mutation of Tyr221 to phenylalanine. Together, these data demonstrate that insulin treatment results in the de-repression of Rap1 inhibitory function on the Raf1 kinase concomitant with Ras activation and stimulation of the downstream Raf1/MEK/ERK cascade.

Adaptor Proteins, Signal Transducing↗
PubMed1998

In-vacuum undulators of SPring-8.

Most of the SPring-8 insertion devices are in-vacuum undulators except for the soft X-ray devices and one elliptical wiggler. The standard-type SPring-8 in-vacuum undulator has a period of 32 mm and a minimum gap of 8 mm. The fundamental radiation energy ranges from 5.2 to 18.5 keV. Three standard in-vacuum undulators are already installed in the ring and are operating without any problems. The magnetic field correction, the vacuum system and the commissioning of the in-vacuum undulators are described in this paper.

Journal Article↗
PubMed1998

Needle tract implantation of hepatocellular carcinoma after percutaneous ethanol injection.

BACKGROUND: Percutaneous ethanol injection (PEI) therapy currently is widely used for small hepatocellular carcinoma (HCC). However, only limited information is available regarding needle tract implantation after PEI treatment. METHODS: Records of HCC patients who underwent PEI between March 1990 and April 1997 at the National Cancer Center Hospital (n = 177) were reviewed to clarify the incidence, risk factors, and outcome of needle tract implantation of HCC. RESULTS: PEI was performed for 348 HCC patients with a median tumor size of 20 mm. Needle tract implantation was found in 4 patients (10, 13, 15, and 46 months, respectively, after PEI). The size of the PEI-treated HCC tumors in these patients was 20, 27, 28, and 30 mm, respectively, in greatest dimension. All tumors were enhanced in the early phase on dynamic computed tomography (CT), and were found to have moderate tumor cell differentiation on biopsied specimens. Of the four implanted tumors, three were resected and the remaining tumor was treated with extrabeam radiotherapy. At last follow-up, 2 of the 4 patients had died (1 of variceal bleeding 60 months after PEI and the other from cancer 61 months after PEI) and 2 were still alive (14 and 20 months, respectively, after PEI) with no evidence of active tumor. CONCLUSIONS: Needle tract implantation after PEI is not unusual, especially when HCC tumors are > or =2 cm in greatest dimension, enhanced in the early phase on dynamic CT, and/or moderately differentiated on biopsied specimens.

Administration, Cutaneous↗
PubMed1998

Lidocaine and its analogues inhibit IL-5-mediated survival and activation of human eosinophils.

Eosinophils and cytokines active on eosinophils, especially IL-5, are believed to be critically involved in chronic allergic diseases. IL-5 activates eosinophils and enhances their survival in vitro by delaying apoptosis. In this study, we found that lidocaine and six analogues blunt responses of eosinophils to IL-5. Lidocaine and its derivatives inhibit IL-5-mediated eosinophil survival in a concentration-dependent manner (IC50 = 110 microM for 30 pg/ml IL-5). At suboptimal lidocaine concentrations, the eosinophil survival response to IL-5 shifts and more IL-5 is required to maintain survival. The inhibitory effect requires at least 24-h exposure of eosinophils to lidocaine, and the protein kinase C activator, PMA, completely reverses the inhibition. A multiparameter flow-cytometric analysis shows that lidocaine hastens the apoptosis of eosinophils normally delayed by IL-5. Lidocaine does not affect IL-5R expression or IL-5-induced protein tyrosine phosphorylation. Lidocaine also inhibits eosinophil survival mediated by IL-3 or granulocyte-macrophage CSF, although less potently than that mediated by IL-5. Furthermore, lidocaine inhibits eosinophil superoxide production stimulated by IL-5, granulocyte-macrophage CSF, or IL-3, but not that stimulated by platelet-activating factor, immobilized IgG, or PMA. Lidocaine and its derivatives show novel immunomodulatory properties and are able to blunt eosinophil responses to cytokines in addition to their local anesthetic or antiarrhythmic properties. Thus, lidocaine and its derivatives may represent a new class of therapeutic agents to treat patients with allergic diseases.

Apoptosis↗
PubMed1998

A physiologic role of Bcl-xL induced in activated macrophages.

Activated macrophages produce nitric oxide (NO) that is an important effector molecule for their antimicrobial and antitumor activities. Since this NO is also toxic for themselves, they have self-defense mechanisms. To elucidate the mechanisms in a physiologic condition, expression of bcl-2 family genes were examined in peritoneal macrophages and RAW264 macrophage cell line activated with IFN-gamma and LPS. Bcl-xL, but not bcl-2 and bax mRNA, was highly inducible within 3 h after stimulation. The induction required new protein synthesis, but was independent of effects of synthesized NO. Since activated RAW264 were more resistant to NO-induced apoptosis mediated by the exposure to S-nitroso-N-acetyl-penicillamine (SNAP) than nonactivated RAW264, the inducible Bcl-xL may play a role in the protection from NO toxicity. To confirm the protective function, RAW264 were stably transfected with bcl-xL. Those transfectants activated with IFN-gamma and LPS appeared highly resistant to NO-induced cell death detected within 24 h after stimulation, although their NO production was similar to those of parental RAW264 and neomycin control-transfected cells. Furthermore, bcl-xL transfectants displayed substantial protection from SNAP-induced apoptosis. These results establish a link between self-defense to the synthesized NO and the induction of Bcl-xL in activated macrophages.

Animals↗
PubMed1998

Dimethylarsinic acid, a main metabolite of inorganic arsenics, has tumorigenicity and progression effects in the pulmonary tumors of A/J mice.

The pulmonary tumorigenicity of dimethylarsinic acid (DMAA), a main metabolite of inorganic arsenics, was examined in A/J mice fed with drinking water containing DMAA for 25 and 50 weeks. Mice fed with 400 ppm DMAA for 50 weeks produced more pulmonary tumors than untreated mice (mean number per animal 1.36 versus 0.50; P < 0.05). Histological examination revealed that the number of mice which bore adenocarcinomas or papillary adenomas correlated with the concentration of DMAA given (untreated versus 400 ppm; P = 0.002), suggesting that DMAA could promote tumorigenic processes. These results are consistent with the epidemiological studies on the pulmonary carcinogenesis of arsenics and suggest that DMAA alone can act as a carcinogen in mice.

Animals↗
PubMed1998

Manganese concentration in rat brain: manganese transport from the peripheral tissues.

54Mn distribution in the brain and peripheral tissues was studied with the course of time after intravenous injection of 54MnCl2 to see manganese (Mn) transport from the peripheral tissues, i.e. the liver, to the brain. One hour after injection, 54Mn concentrations in the brain were 0.15-0.25% dose/g, and 54Mn was largely concentrated in the choroid plexus. One day after injection, 54Mn in the choroid plexus decreased remarkably. 54Mn in other brain regions increased gradually after then, and reached 0.30-0.40% dose/g 6 days after injection. This increase of 54Mn was due to the redistribution from the peripheral tissues such as liver and pancreas, in which 54Mn was maintained at high levels (2.0-4.0% dose/g). The increment of 54Mn 1 h to 6 days after injection was the largest in the hippocampus, but not in the striatum. These results suggest that the delivery of Mn from the liver to the brain is not involved in preferential Mn accumulation in the basal nuclei under physiological condition. This delivery may be important for brain function.

Animals↗
PubMed1998

Non-peptide inhibitors of HCV serine proteinase.

We screened a chemical library of 2000 compounds for inhibitors of hepatitis C virus (HCV) serine proteinase using an in vitro screening method measuring the hydrolysis of the peptide substrate. Three compounds were found to be the most potent inhibitors (IC50 < 10(-5) M). Two of them had a similar structure, that of halogenated benzanilide, and were not inhibitory for common serine proteinases. They inhibited the enzyme non-competitively with the substrate. Together with the result of the analogous compounds in the chemical library, the presumed structural requirements of the inhibition are pointed out.

Amino Acid Sequence↗
PubMed1998

Human galactocerebrosidase gene: promoter analysis of the 5'-flanking region and structural organization.

Galactocerebrosidase (GALC; EC 3.2.1.46) is a lysosomal enzyme which hydrolyzes several galactolipids and the deficiency of GALC is responsible for Krabbe disease. Recently, we cloned cDNAs for human and murine GALC. In this study we characterized the genomic organization and the promoter of the human gene. The gene was about 60 kb in length and consisted of 17 exons as reported by Luzi et al. DNA sequence analysis showed that the 5'-flanking region of the first exon was GC-rich and had not typical TATA-box but ten GC-box-like sequences within a 200 bp sequence upstream from the initiation codon. Another inframe ATG, which has better Kozak consensus sequence, was found at 48 bp upstream to the first ATG reported]. Promoter analysis using a luciferase assay in COS 7 cells showed that the -149 to -112 nucleotide (from the initiation codon A) region has dominant promoter activity. In this region three GC-box-like sequence and one YY1 binding site were detected. Primer extension revealed several transcription start sites within the region of -146 to -103 nucleotide. In this study we firstly demonstrated that the YY1 binding site and subsequent GC-box-like sequences could be a promoter in a housekeeping gene.

Animals↗
PubMed1998

Detection of human herpesvirus 7 (HHV-7) DNA in breast milk by polymerase chain reaction and prevalence of HHV-7 antibody in breast-fed and bottle-fed children.

Twenty-nine breast milk mononuclear cell samples were analyzed for human herpesvirus 7 (HHV-7) DNA, human herpesvirus 6 (HHV-6) DNA, and human cytomegalovirus (HCMV) DNA by polymerase chain reaction (PCR). In addition, peripheral blood mononuclear cell samples from 13 puerperants were analyzed for HHV-7 DNA by PCR, and seropositivity of HHV-7 was also analyzed in breast-fed and bottle-fed children. HHV-7 DNA was detected in 3 of 29 breast milk samples. HCMV DNA was also detected in 3 of 29 breast milk samples, but HHV-6 DNA was not detected. HHV-7 DNA was detected in 11 of 13 samples of peripheral blood mononuclear cells. Though the seropositivity rate for HHV-7 in breast-fed children was slightly higher than that in bottle-fed children at 18 and 24 months old, the difference was not statistically significant. From these results, we speculate that breast-feeding may be one of the transmission routes of HHV-7, although this is not the main route.

Antibodies, Viral↗
PubMed1998

Early hepatocellular carcinoma as an entity with a high rate of surgical cure.

Early hepatocellular carcinoma (HCC) has been defined as a well-differentiated cancer containing Glisson's triad, but it remains unknown whether this lesion is curable. We prospectively studied 70 patients (enrolled from 1,172 referrals between 1982 and 1991) who had a diagnosis of a single HCC 2 cm or less in diameter (Stage T1) and who underwent curative hepatectomy and long-term follow-up (range, 0.2 to 14.3 years). Patients were eligible for surgery if they had a tumor that met the diagnostic criteria for HCC and were in Child-Pugh class A (n = 59) or B (n = 11) status. Among the 70 patients, there was 1 operative death. Based on our typing system, the tumors were assigned as early HCC (n = 15), overt HCC (n = 52), and non-HCC tumor (n = 3). The rate of microscopic regional spread was lower in early HCCs than in overt HCCs (7% vs. 42%; P = .01). The early HCC group had a longer time to recurrence than did the overt HCC group (3.9 vs. 1.7 years; P < .001) and had no local recurrence. After a median follow-up of 6.3 years, both overall survival and recurrence-free survival in the early HCC group were significantly better than those in the overt HCC group (P = .01; P = .001). In these two groups, the 5-year rates of overall survival were 93% and 54% (P = .01), and those of recurrence-free survival were 47% and 16% (P = .05), respectively; a significant survival benefit persisted over a decade (57% vs. 21%; P = .05). The early HCC group was at a lower risk of recurrence (relative risk, 0.31; 95% CI, 0.15 to 0.65; P = .002) and death (relative risk, 0.26; 95% CI, 0.09 to 0.73; P = .01) than was the overt HCC group. Early HCC is a distinct clinical entity with a high rate of surgical cure, thereby justifying its definition. It can be a lesion that corresponds to "Stage 0" cancer in other organs.

Carcinoma, Hepatocellular↗
PubMed1998

Profiles of circulating inflammatory- and anti-inflammatory cytokines in patients with hemolytic uremic syndrome due to E. coli O157 infection.

The systemic inflammatory response to Escherichia coli O157 infection was studied from the profiles of circulating inflammatory and anti-inflammatory cytokines. Twelve patients transferred sequentially to our hospital for the intensive care with acute illness due to Escherichia coli O157 infection and the possible form of haemolytic uraemic syndrome were included in this study. Increased circulating concentrations of tumour necrosis factor, interleukin 6, interleukin 8, granulocyte colony-stimulating factor, and interleukin 10 were found in patients with various stages of this infection and haemolytic uraemic syndrome. Especially, the degree of the increase of circulating interleukin 10 in those who had a typical signs of haemolytic uraemic syndrome was higher than those of other inflammatory cytokines. Two groups of E. coli infection could be classified into one with a typical haemolytic uraemic syndrome and the other with atypically bacteremic state over haemolytic uraemic syndrome according to these cytokine levels.

Adult↗