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Biomedical subjects

T Okubo

Publications and source records attributed to T Okubo.

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

Breast tumor aromatase: functional role and transcriptional regulation.

Aromatase has been shown to be expressed at a higher level in human breast cancer tissue than in normal breast tissue, by means of enzyme activity measurement, immunocytochemistry, and RT-PCR analysis. Cell culture including MCF-7 breast cancer cells, animal experiments using aromatase-transfected breast cancer cells, and transgenic mouse studies have demonstrated that estrogen production in situ plays a more important role than circulating estrogens in breast tumor promotion. In addition, tumor aromatase is believed to be able to stimulate breast cancer growth through both autocrine and paracrine pathways, as demonstrated by a three-dimensional cell culture study. RT-PCR and gene transcriptional studies have revealed that the aromatase promoter is switched from a glucocorticoid-stimulated promoter, I.4, in normal tissue to cAMP-stimulated promoters, I.3 and II, in cancerous tissue. Recently, we identified and characterized a cAMP-responsive element (CREaro) upstream from promoter I.3 by DNA deletion and mutational analyses. Our results from promoter functional analysis also demonstrated an interaction between the CREaro and the silencer element (S1) that was identified previously in our laboratory. In the presence of cAMP, the positive regulatory CREaro can overcome the action of the silencer on the function of promoter I.3. On the basis of results generated from our own and other laboratories, we propose that, in normal breast adipose stromal cells and fibroblasts, aromatase expression is driven by promoter I.4 (glucocorticoid dependent), and that the action of promoters I.3 and II is suppressed by the silencer negative regulatory element. However, in cancer cells and surrounding adipose stromal cells, the cAMP level increases, and aromatase promoters are switched to cAMP-dependent promoters - I.3 and II. Furthermore, we applied the yeast one-hybrid screening method to search for proteins interacting with the silencer element, S1. The major protein identified was ERRalpha-1; however, SF-1, which is present in the ovary, is not detected in breast cancer tissue. Using a reporter plasmid with the aromatase genomic fragment containing promoter I.3 and S1, in breast cancer SK-BR-3 cells, ERRalpha-1 was found to have a positive regulatory function. It is believed that the silencer element in the human aromatase gene may function differently in different tissues, as a result of distinct expression patterns of transcription factors.

Animals↗
PubMed1999

Receptor binding, behavioral, and electrophysiological profiles of nonpeptide corticotropin-releasing factor subtype 1 receptor antagonists CRA1000 and CRA1001.

Receptor binding, behavioral, and electrophysiological profiles of 2-[N-(2-methylthio-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-flu orophe nyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine (CRA1000) and 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-fluoropheny l)- 1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine (CRA1001), putative novel and selective antagonists for corticotropin-releasing factor1 (CRF1) receptor were examined. Both CRA1000 and CRA1001 inhibited 125I-ovine CRF binding to membranes of rat frontal cortex with IC50 values of 20.6 and 22.3 nM, respectively. Likewise, CRA1000 and CRA1001 inhibited 125I-ovine CRF binding to membranes of rat pituitary. In contrast, both CRA1000 and CRA1001 were without affinity for the CRF2beta receptor when examined using rat heart. In mice orally administered CRA1000 and CRA1001 reversed the swim stress-induced reduction of the time spent in the light area in the light/dark exploration task. In nonstress conditions, CRA1000 and CRA1001 were without effect on the time spent in the light area in the same task in mice. Orally administered CRA1000 and CRA1001 dose dependently reversed the effects of i.c.v. infusion of CRF on time spent in the open arms in the elevated plus-maze in rats. Lesioning of olfactory bulbs induced hyperemotionality, and this effect was inhibited by either acute or chronic oral administration of CRA1000 and CRA1001 in rats. The firing rate of locus coeruleus neurons was increased by i.c.v.-infused CRF. This excitation of locus coeruleus neurons was significantly blocked by pretreatment with i.v. administration of CRA1000 and CRA1001. CRA1000 and CRA1001 had no effects on the hexobarbital-induced anesthesia in mice, the rotarod test in mice, the spontaneous locomotor activity in mice, and a passive avoidance task in rats. These observations indicate that both CRA1000 and CRA1001 are selective and competitive CRF1 receptor antagonists with potent anxiolytic- and antidepressant-like properties in various experimental animal models, perhaps through inhibition of CRF1 receptors. CRA1000 and CRA1001 may prove effective for treating subjects with depression- and/or anxiety-related disorders without the side effects seen in the related currently prescribed medications.

Animals↗
PubMed1999

A novel polymorphism (-357 G/A) of the ALDH2 gene: linkage disequilibrium and an association with alcoholism.

BACKGROUND: Human mitochondrial aldehyde dehydrogenase (ALDH2) is a major enzyme responsible for the oxidation of acetaldehyde derived from ethanol metabolism. The human ALDH2 gene shows genetic polymorphism at position 1510 with a G to A transition in exon 12. This mutation leads to ALDH2 enzyme deficiency and protection against alcoholism. As yet, no polymorphism for the promoter region of the ALDH2 gene has been reported. METHODS: We analyzed 600 nucleotides of the promoter region in addition to exon 12 from 571 Japanese, 68 Chinese, 80 Myanmar, 60 Mongolians, and 82 North-American Caucasians using single-strand conformational change polymorphism (SSCP) analysis and the polymerase chain reaction (PCR). PCR products that showed an aberrant banding pattern detected by the SSCP analysis were subjected to PCR direct sequencing. RESULTS: A novel polymorphism at -357 with a G to A substitution was found in all the population groups, including North-American Caucasians. In addition, the polymorphic status in the promoter and exon 12 suggested linkage disequilibrium between the two loci, which indicated that among Japanese, the ALDH2*2 allele is linked to the G promoter allele, and theALDH2*1 allele is linked to the A allele. A total of 206 healthy male controls and 185 alcoholic male patients with the homozygous ALDH2*1 genotype were analyzed for the polymorphism in the promoter. Genotypic frequencies of GG, GA, and AA for alcoholics were 54.1%, 44.3%, and 1.6%, and those for controls were 52.9%, 40.3%, and 6.8%, respectively. The A allele frequencies for alcoholics and controls were 0.24 and 0.27, respectively. A chi2 test for the entire 3 x 2 table indicated significant variations in the three genotypes (chi2 = 6.40, p < 0.05). However, no significant difference in allelic frequencies between the two groups was observed. CONCLUSION: This new polymorphism in the ALDH2 promoter is present in all populations studied. Further analysis in other ethnic groups is necessary to establish this as an additional risk factor for alcoholism.

Adult↗
PubMed1999

[Implication of health checkups of students from developing countries in Japan].

We investigated the prevalence of peripheral blood abnormalities, parasitic infestation, and hepatitis virus infection, by using the results of the primary screening health checkups for 423 students (male: 317, female: 106, average age +/- SD: 34.2 +/- 5.5 year-old) from abroad. Most of them were from Southeast Asia, Africa, Central and South America, and other developing countries in tropical or subtropical areas. Thalassemia-like hematological disorders, showing microcytic peripheral red blood cells without any anemia, were seen in 7.6 percent of the students, and intestinal parasites were revealed in 12.7 percent of them. The positive rate for anti-hepatitis A virus antibodies (84.3%) and the exposure rate of hepatitis B viruses (35.3%) were similar to previous reports. Compared with the positive rate for anti-hepatitis C virus antibodies (anti-HCVAb) of students from other regions (1.5%), a significantly high seropositivity for anti-HCVAb was encountered in Egyptian participants (21.1%). In recent years, population shifts and rapid transportation have facilitated the spread of certain infectious diseases from endemic to non-endemic areas. International preventive strategies, education of people regarding infectious diseases, and sufficient medical staffs for this purpose are urgently recommended.

Adult↗
PubMed1999

In vivo receptor labeling of peripheral benzodiazepine receptor by ex vivo binding of [3H]PK11195.

In vivo receptor labeling of the peripheral benzodiazepine receptor was investigated using ex vivo binding of [3H]-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carb ox-amide ([3H]PK11195). In autoradiographic studies, high level specific binding of [3H]PK11195 was observed in the olfactory bulb. Intravenous administration of PK11195 dose-dependently (0.03-3 mg/kg) inhibited ex vivo binding of [3H]PK11195 in the olfactory bulb. Likewise, N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (DAA1106), a newly identified peripheral benzodiazepine receptor-specific ligand, dose-dependently (0.1-100 mg/kg) reduced ex vivo binding of [3H]PK11195, when administered intraperitoneally. In contrast, clonazepam, a central benzodiazepine receptor-specific agonist, had negligible effects on ex vivo binding of [3H]PK11195. We propose that the ex vivo receptor binding technique we used will facilitate determination of in vivo receptor occupancy of the peripheral benzodiazepine receptor.

Animals↗
PubMed1998

Electro-optic Properties of Colloidal Crystals As Studied by Reflection Spectroscopy.

Electro-optic properties of colloidal crystals of silica spheres in the exhaustively deionized aqueous suspension have been studied by the reflection spectroscopy using a T-type cell. Acoustic shear waves are induced when sine-wave electric fields ranging from 0.01 to 1 Hz are applied. Modulation effects of the crystals on the applied AC fields such as phase delay, change in response intensity, waveform transformation, and harmonics generation are observed. The shear waves propagate outside the electrodes where the electric field is absent. The synchronous fluctuation of the colloidal spheres including expanded electrical double layers in the crystal lattice will be one of the main causes of the electro-optic nature of the crystals. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Surface Tension of Biological Polyelectrolyte Solutions.

Surface tensions, gamma, of biological polyelectrolytes in aqueous solutions are studied systematically as possible at the air-water interface by the Wilhelmy method. The polyelectrolytes measured are sodium chondroitin sulfates A (NaCRA) and C (NaCRC), sodium poly-alpha,l-glutamate (NaPGA), poly-l-lysine hydrobromide (PLL . HBr), deoxyribonucleic acid (DNA), lysozyme (LZ), and bovine serum albumin (BSA). Linear-type macroions such as NaCR, NaPGA, PLL . HBr, and DNA have no surface activity in a wide range of polymer concentrations below the critical polymer concentration, m*, and increases as the concentration increases above m*. Surface activity of the undissociated state of macroions is rather high in general. Globule-like macroions such as LZ and BSA show high surface activity at isoelectric point above m* accompanied with orientation of the molecules along the air-water interface. Separation into the hydrophobic and hydrophilic parts at the interface and balancing in their strength are important for appearance of surface activity. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Novel mutations in the promoter and coding region of the human 5-HT1A receptor gene and association analysis in schizophrenia.

Dysfunction of serotonin systems has been implicated in schizophrenia. In the present study, the human 5-HT1A receptor gene containing the 5' untranslated region was screened in order to detect genetic variations, through which alteration of protein function or level of expression might contribute to schizophrenia. Genomic DNAs were isolated from whole-blood samples of 61 unrelated schizophrenic patients and 100 healthy controls. Genetic variations were screened systematically by single-strand conformational polymorphism (SSCP) analysis, followed by direct sequencing of polymerase chain reaction (PCR) product as well as restriction fragment-length polymorphism (RFLP). The novel mutations (-51T --> C, -152C --> G, -321G --> C, -480delA, and -581C --> A) were found in the 5' untranslated region. Furthermore, we found a novel missense mutation (Gly272Asp) in the coding region in addition to the mutations (Pro16Leu, 294G --> A, and 549C --> T) reported previously. No significant differences in genotype frequencies as well as allele frequencies were found between patients and controls. Our data provided no evidence of association between schizophrenia and the variants in the 5' untranslated region as well as the coding region of the human 5-HT1A receptor gene.

Genetic Markers↗
PubMed1998

Kinetic Analyses of Colloidal Crystallization in Alcoholic Organic Solvents and Their Aqueous Mixtures As Studied by Reflection Spectroscopy.

Reflection spectroscopy is used for the kinetic analyses of the nucleation and growth process of colloidal crystals of silica spheres (110 nm in diameter) in exhaustively deionized suspensions of purely alcoholic organic solvents (methyl alcohol, ethyl alcohol, and ethylene glycol) and aqueous mixtures with alcohols (methyl, ethyl, n-propyl, and n-butyl alcohols and ethylene glycol). Sphere concentrations studied range from 0.001 to 0.01 in volume fraction, rather high compared with those in water. Induction periods are from 5 to 2000 s and are prolonged with decreasing sphere concentration. Nucleation rates are 10(-3) to 10(3) mm-3 s-1 and increase sharply as sphere concentration increases. The crystal growth rates, v have been determined from the increase of intensity in the sharpened reflection peaks. Values of v range from 1 to 27 µm/s and decrease linearly as the reciprocal sphere concentration increases. Nucleation and crystallization rates decrease sharply as the fraction of the organic solvents increases in the mixtures with water. The importance of the electrostatic intersphere repulsion through the electrical double layers and the cooperative and synchronized fluctuation of colloidal spheres in the crystallization processes is supported. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

[Research on the contents of material safety data sheets].

The Material Safety Data Sheet (MSDS) system for the safe management of chemical substances was officially promulgated in 1993 and has been gradually put into practice through administrative guidance in Japan. However, little research has been done on the quality of such data sheets provided from various sectors of industries. We examined two sets of MSDSs obtained from a refractory ceramic plant. In the first survey in 1995, the set of MSDSs was from July, 1992 to March, 1994; and in the second survey in 1997, the set was from April, 1994 to November, 1996. The number of MSDSs examined in these two surveys was 159 and 81, respectively. The number of MSDSs in which "Hazard Identification" was indicated was 100 (63%) in the 1995 survey and 75 (93%) in the 1997 survey. The number of those in which "Toxicological Information (Stability and Reactivity)" was indicated was 81 (51%) and 80 (99%), respectively. The description rates for the essential items, including the above two, were found to be improving.

Data Collection↗
PubMed1998

Clinical significance of inhibitors in acquired von Willebrand syndrome.

Of 260 patients enrolled, 25 patients (9.6%) were associated with acquired von Willebrand syndrome (AvWS). We studied 25 patients with AvWS, retrospectively. AvWS was diagnosed by reduced levels of von Willebrand factor (vWF) (decrease of von Willebrand factor antigen [vWF:Ag] and von Willebrand ristocetin cofactor [vWF:RCoF]), a decrease of ristocetin-induced platelet agglutination (RIPA), sometimes decreased high-molecular-weight multimers, and prolonged bleeding time with neither prior nor family histories of bleeding problems and the evidence of normal vWF:RCoF in their families. The inhibitor of vWF was determined by mixing patient plasma with pooled normal plasma. Eight patients in this study had the inhibitors to vWF that were of the IgG class; the subclasses were IgG1 (7 cases) and IgG2 (1 case). Multimeric analysis of vWF showed selective loss of large multimers in most patients with AvWS similar to that of congenital type-2 von Willebrand disease (vWD). All inhibitors blocked ristocetin-mediated vWF binding to platelets. Five out of 6 IgGs evaluated here recognized the 39/34-kD fragment (residues 480/481-718) and Fragment III (residues 1-1365) that implied binding domain of glycoprotein Ib (GPIb), whereas 1 recognized Fragment I (residues 911-1365). A close relationship was found between the presence of the inhibitor and bleeding tendency. Of the 7 patients with inhibitors, 6 patients (86%) had a bleeding tendency, as well as 1 of the 15 patients without inhibitors (6%). The efficacy of treatment of underlying diseases and/or therapy with deamino D-arginine vasopressin (DDAVP) for the treatment of AvWS also depends on the presence of an inhibitor. Four of 8 patients with inhibitors (50%) had poor response to treatment of the underlying disease and/or therapy with DDAVP, as well as 1 of the 16 patients without inhibitors (6%). These results indicate that patients with AvWS developing inhibitors to vWF are likely to have bleeding problems and might be resistant to treatment of underlying diseases and/or therapy with DDAVP for bleeding to AvWS. We also showed evidence that intravenous immunoglobulin therapy (0.3 g/kg, 3 days) was effective to correct a hemostatic defect and manage severe bleeding in a patient with AvWS developing inhibitors. We might consider an additional treatment including expensive high-dose immunoglobulin therapy when uncontrollable bleeding is continued after the treatment of the underlying diseases and/or therapy with DDAVP.

Adult↗
PubMed1998

Inhibition of inducible nitric oxide synthase prevents LPS-induced acute lung injury in dogs.

Nitric oxide (NO) is produced by inducible NO synthase (iNOS) after LPS stimulation, and reacts with superoxide to form peroxynitrite. We hypothesize that in LPS-induced lung injury, NO generated by iNOS plays a key role through the formation of peroxynitrite. We developed an acute lung injury dog model by injecting LPS, and examined the effects of selective iNOS inhibitors, aminoguanidine (AG) and S-methylisothiourea sulfate (SMT), on the LPS-induced lung injury. At 24 h after LPS injection, arterial oxygen tension and mean arterial pressure decreased, and shunt ratio and lung wet-to-dry weight ratio increased. On histology, the LPS group had marked neutrophil infiltration and widening of the alveolar septa. On immunohistochemistry, iNOS and nitrotyrosine, a major product of nitration of protein by peroxynitrite, were observed in the interstitium, capillary wall, and neutrophils in the airspaces of the LPS group. Treatments with AG and SMT prevented worsening of gas exchange, hemodynamics, and wet-to-dry weight ratio. On histology, AG and SMT treatments markedly suppressed lung injury, iNOS protein, and nitrotyrosine production. We conclude that NO released by iNOS may play a critical role in the pathogenesis of LPS-induced acute lung injury. This study suggests that iNOS inhibitors may have potential in the treatment of LPS-induced acute respiratory distress syndrome.

Animals↗
PubMed1998

Comparison of the qualified occupational physician systems in the United Kingdom and Japan.

The British educational system of occupational medicine was compared to the Japanese system. Furthermore, a comparison was carried out between the certified occupational physician (COP) recognized by the Japan Society for Occupational Health in Japan and the Associateship of the Faculty of Occupational Medicine (AFOM) by the Faculty of Occupational Medicine (FOM) which is a part of the Royal College of Physicians in the United Kingdom. Judging from the comparison of the minimum total training period, the clinical training period, the occupational health training period, the method of examination and the success rate between COP and AFOM, it is suggested that the British system of occupational physicians may be better as a training system for occupational medicine and may regard occupational clinical training as more important than the Japanese system does. A comparison of a Diploma in Occupational Medicine (Dip Occ Med) approved by the FOM and the certification of occupational physicians by the Japan Medical Association has shown that the former has an examination but there is no test system in the latter. It should be discussed whether an examination system for the certification of occupational physicians should be introduced into the Japanese system in the near future.

Education, Medical, Continuing↗
PubMed1998

DNA cleavage and 8-hydroxydeoxyguanosine formation caused by tamoxifen derivatives in vitro.

DNA damage caused by tamoxifen and its derivatives was examined by estimating the conversion of supercoiled pUC18 plasmid DNA to linear form by means of agarose gel electrophoresis. N-Desmethyltamoxifen induced DNA cleavage and its effect was enhanced by the addition of reducing agents such as dithiothreitol, NADPH and 2-mercaptoethanol. 4-Hydroxytamoxifen itself had little effect, but the cleavage was slightly enhanced by the addition of reducing agents. DNA damage was higher with alpha-hydroxytoremifene than with alpha-hydroxytamoxifen, which had a prominent effect only at high concentration. The cleavage by alpha-hydroxy derivatives were not enhanced by reducing agents. No damage was induced by tamoxifen, toremifene, 3-hydroxytamoxifen or N-desmethyltoremifene. The DNA cleavage by N-desmethyltamoxifen was inhibited by the addition of EDTA, mannitol, sodium azide, methionine, catalase and superoxide dismutase. The formation of 8-hydroxy-2'-deoxyguanosine was also examined with calf thymus DNA in vitro. A slight increase of its level was found with 4-hydroxytamoxifen in the presence of dithiothreitol and also with N-desmethyltamoxifen in the presence of NADPH, but alpha-hydroxytoremifene and alpha-hydroxytamoxifen were ineffective. These experimental data suggest that among metabolites of tamoxifen, N-desmethyltamoxifen and probably also 4-hydroxytamoxifen cause oxidative DNA damage in which redox cycling is involved. The DNA damage by alpha-hydroxytoremifene appears to involve a different mechanism from that by N-desmethyltamoxifen. Tamoxifen and toremifene are possibly metabolized to the forms contributing to DNA damage.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

[Mitral valve replacement for three cases of hypertrophic obstructive cardiomyopathy--surgical treatment].

Three patients with obstructive cardiomyopathy underwent surgical treatment. Mitral valve replacement was performed in all three cases and myectomy of hypertrophic septal muscle was performed in one case. The pressure gradients between the left ventricle and the aorta was less than 10 mmHg in all cases after surgery, Clinical symptoms strikingly improved in three cases. An accurate surgical treatment could be achieved by choosing either myotomy-myectomy, mitral valve replacement or both in the setting of individual condition of each patients.

Cardiomyopathy, Hypertrophic↗