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Biomedical subjects

Y Ohashi

Publications and source records attributed to Y Ohashi.

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

Clinical effect of intravenous calcitriol administration on secondary hyperparathyroidism. A double-blind study among 4 doses.

BACKGROUND/AIMS: Although the PTH-suppressive effect of intravenous calcitriol has already been demonstrated by various studies, the precise dose-response to calcitriol has not been fully determined for uremic secondary hyperparathyroidism (2HPT). In order to investigate in detail the dose-response of intravenous calcitriol and the adequate initial dose against 2HPT, a randomized prospective double-blind study was conducted. METHOD: One-hundred and sixty-two patients with 2HPT undergoing hemodialysis three times per week were randomly assigned to four calcitriol (Ro21-5535) treatment groups, 0 (placebo), 1, 1.5 or 2 microg. Calcitriol or placebo was given intravenously after each dialysis for 12 weeks under double-blind conditions. RESULTS: Calcitriol dose-dependently reduced both intact-PTH and high-sensitivity assay mid-terminal (HS)-PTH levels. The rate of per-week change in intact-PTH was 0.0% in the placebo group, -7.8% in the 1-microg group, -18.9% in the 1.5-microg group and -24.1% in the 2-microg group. Calcitriol dose-dependently increased the rate of increase in serum Ca adjusted by albumin level. The per-week increases in adjusted serum Ca were -0.01, 0.08, 0.23 and 0.35 mg/dl in the placebo, 1-, 1.5- and 2-microg groups, respectively. Although the degree of PTH suppression was correlated with the adjusted serum Ca increase, by-patients investigation revealed that the number of patients with suppression of PTH despite of no or slight elevation of adjusted serum Ca level was largest in the 1-microg group among the three calcitriol groups. CONCLUSION: Intravenous calcitriol was found to have a clear dose-dependent effect on PTH reduction in patients with 2HPT, and the appropriate initial dose of this agent was determined to be 1 microg per dialysis session.

Adult↗
PubMed2002

Proportional hazards models with random effects to examine centre effects in multicentre cancer clinical trials.

In randomized clinical trials comparing treatment effects on diseases such as cancer, a multicentre trial is usually conducted to accrue the required number of patients within a reasonable period of time. The fundamental point of conducting a multicentre trial is that all participating investigators must agree to follow the common study protocol. However, even with every attempt having been made to standardize the methods for diagnosing severity of disease and evaluating response to treatment, for example, they might be applied differently at different centres, and these may vary from comprehensive cancer centres to university hospitals to community hospitals. Therefore, in multicentre trials there is likely to be some degree of variation (heterogeneity) among centres in both the baseline risks and the treatment effects. While we estimate the overall treatment effect using a summary measure such as hazard ratio and usually interpret it as an average treatment effect over the centre, it is necessary to examine the homogeneity of the observed treatment effects across centres, that is, treatment-by-centre interaction. If the data are reasonably consistent with homogeneity of the observed treatment effects across centres, a single summary measure is adequate to describe the trial results and those results will contribute to the scientific generalization, the process of synthesizing knowledge from observations. On the other hand, if heterogeneity of treatment effects is found, we should carefully interpret the trial results and investigate the reason why the variation is seen. In the analyses of multicentre trials, a random effects approach is often used to model the centre effects. In this article, we focus on the proportional hazards models with random effects to examine centre variation in the treatment effects as well as the baseline risks, and review the parameter estimation procedures, frequentist approach-penalized maximum likelihood method--and Bayesian approach--Gibbs sampling method. We also briefly review the models for bivariate responses. We present a few real data examples from the biometrical literature to highlight the issues.

Bias↗
PubMed2001

4-nitro-9,10-dihydrophenanthrene and a polymorphic form of 4-nitrophenanthrene.

The crystal structures of 4-nitro-9,10-dihydrophenanthrene, C14H11NO2, (I), and 4-nitrophenanthrene, C14H9NO2, (II), the latter having two crystallographically independent molecules, show that the molecules are not planar. The dihedral angles between the phenyl rings of the biphenyl skeletons are 28.64 (8) degrees for (I), and 10.34 (15) and 11.75 (13) degrees for the two molecules of (II). The differences in the dihedral angles have an effect on the photochemical reactivity of the molecules.

Journal Article↗
PubMed2001

Crosstalk of prolyl isomerases, Pin1/Ess1, and cyclophilin A.

Previous studies have indicated that Ess1/Pin1, a gene in the parvulin family of peptidyl-prolyl isomerases (PPIases), plays an important role in regulating the G(2)/M transition of the cell cycle by binding cell-cycle-regulating proteins in eukaryotic cells. Although the ess1 gene has been considered to be essential in yeast, we have isolated viable ess1 deletion mutants and demonstrated, via analysis of yeast gene expression profiles using microarray techniques, a novel regulatory role for ESS1 in the G(1) phase. Although the overall expression profiles in the tested strains (C110-1, W303, S288c, and RAY-3AD) were similar, marked changes were detected for a number of genes involved in the molecular action of ESS1. Among these, the expression levels of a cyclophilin A gene, also a member of the PPIase family, increased in the ess1 null mutant derived from C110-1. Subsequent treatment with cyclosporin A significantly retarded growth, which suggests that ESS1 and cyclophilin A are functionally linked in yeast cells and play important roles at the G(1) phase of the cell cycle.

Base Sequence↗
PubMed2001

Enhancement of learning capacity and cholinergic synaptic function by carnitine in aging rats.

The effects of a carnitine derivative, acetyl-L-carnitine (ALCAR), on the cognitive and cholinergic activities of aging rats were examined. Rats were given ALCAR (100 mg/kg) per os for 3 months and were subjected to the Hebb-Williams tasks and a new maze task, AKON-1, to assess their learning capacity. The learning capacity of the ALCAR-treated group was superior to that of the control. Cholinergic activities were determined with synaptosomes isolated from the cortices. The high-affinity choline uptake by synaptosomes, acetylcholine synthesis in synaptosomes, and acetylcholine release from synaptosomes on membrane depolarization were all enhanced in the ALCAR group. This study indicates that chronic administration of ALCAR increases cholinergic synaptic transmission and consequently enhances learning capacity as a cognitive function in aging rats.

Acetylcarnitine↗
PubMed2001

Identification of anti-herpes simplex virus antibody-producing B cells in a patient with an atypical RAG1 immunodeficiency.

Mutations of the RAG1 or RAG2 protein that eliminate their recombination activity result in T-B-severe combined immunodeficiency (SCID), whereas mutations retaining partial recombination activity lead to Omenn syndrome, a peculiar SCID characterized by increased host T cells and absence of circulating B cells. The prognosis of this disease is fatal, unless hematopoietic stem cell transplantation is performed. This study reports a case of atypical SCID, carrying RAG1 mutations. The patient survived for 6 years without hematopoietic stem cell transplantation. The missense mutation, tested by in vivo recombination assay, revealed residual recombination activity. By the age of 5 years, the patient developed host B cells, but not T cells, possibly due to engrafted maternal T cells. In addition, the host B cells were able to produce antibodies, including anti-herpes simplex virus-antibodies. The fact that host B cells could produce antibodies in this patient could explain not only the mild phenotype observed but also, at least in part, how patients with Omenn syndrome produce immunoglobulin E and sometimes immunoglobulin M, as the same missense mutation of RAG1 gene has been reported in a patient with Omenn syndrome.

Adult↗
PubMed2001

Direct observation of deuterium migration in crystalline-state reaction by single-crystal neutron diffraction. III. Photoracemization of 1-cyanoethyl cobaloxime complexes.

The H atoms bonded to the chiral C atoms (stereogenic center) of the 1-cyanoethyl groups in two cobalt complexes, [(R)-1-cyanoethyl]bis(dimethylglyoximato)(pyridine)cobalt(III) (2) and [(R,S)-1-cyanoethyl]bis(dimethylglyoximato)(piperidine)cobalt(III) (3), were replaced with D atoms, such as Co--C*D(CH(3))CN. The crystals of the two cobalt complexes were irradiated with a xenon lamp for 72 h and 27 d, respectively. The unit-cell dimensions were gradually changed with retention of the single-crystal form. The crystal structures after irradiation were determined by neutron diffraction. In each crystal the chiral 1-cyanoethyl group of one of the two crystallographically independent molecules was partly inverted to the opposite configuration, whereas that of the other molecule kept the original configuration. The C*--D bond in the inverted group was completely conserved in the process of the inversion of the chiral alkyl group. This suggests that the inversion of the chiral 1-cyanoethyl group proceeds with the rotation of the cyanoethyl radical after the Co--C bond cleavage by photo-irradiation so that the opposite side of the radical faces the Co atom. This is followed by recombination of the Co--C bond to form the inverted 1-cyanoethyl group.

Journal Article↗
PubMed2001

Energy-transfer rate in crystals of double-complex salts composed of [Ru(N-N)3](2+) (N-N = 2,2'-bipyridine or 1,10-phenanthroline) and [Cr(CN)6](3-): effect of relative orientation between donor and acceptor.

A block single-crystal was obtained using a diffusion method with a concentrated acetone-water (vol. 1/1) solution of [Ru(phen)(3)]Cl(2).6H(2)O (phen = 1,10-phenanthroline) and a concentrated aqueous solution of K(3)[Cr(CN)(6)], without evaporating solvents. The crystal was identified as a double-complex salt including two acetone and fourteen solvent water molecules, [Ru(phen)(3)](2)[Cr(CN)(6)]Cl.2(CH(3))(2)CO.14H(2)O (1). Measurement of the X-ray diffraction pattern of the double-complex salt was performed using an X-ray diffractometer with an Imaging-Plate (IP) Weissenberg camera. 1 crystallizes in the triclinic space group P1, with a = 13.930(5) A, b = 14.783(5) A, c = 11.137(6) A, alpha = 89.87(4) degrees, beta = 107.47(3) degrees, gamma = 96.68(3) degrees, and Z = 2. The crystal structure is very different from that of [Ru(bpy)(3)](2)[Cr(CN)(6)]Cl.8H(2)O (2) (bpy = 2,2'-bipyridine), which could be obtained using the same procedure and crystallizes in the monoclinic space group C2, with a = 22.414(2) A, b = 13.7686(15) A, c = 22.207(2) A, beta = 90.713(8) degrees, and Z = 4. The distance between the central-metal ions of ruthenium(II) and chromium(III) complexes in [Ru(phen)(3)](2)[Cr(CN)(6)]Cl.2(CH(3))(2)CO.14H(2)O (7.170 A) is shorter than that in [Ru(bpy)(3)](2)[Cr(CN)(6)]Cl.8H(2)O (9.173 A) by about 2 A, while the rate of energy transfer from the (3)MLCT state of [Ru(N-N)(3)](2+) to the (2)E(g) state of [Cr(CN)(6)](3-) in the former salt (9.5 x 10(5) s(-1)) is far slower than that in the latter one (6.0 x 10(6) s(-1)) at 77 K. These results indicate that the energy-transfer rate strongly depends, not upon the distance between central metal ions, rather, upon the mutual relative orientation between the donor and the acceptor complexes in double-complex salts.

Journal Article↗
PubMed2001

A new phosphoglycerolipid, 'phosphatidylglucose', found in human cord red cells by multi-reactive monoclonal anti-i cold agglutinin, mAb GL-1/GL-2.

Cord red cell membranes express many differentiation-related molecules. To study such molecules, we have established human cell lines, termed GL-1 and GL-2, by the Epstein-Barr virus transformation method, both of which produce monoclonal anti-i cold agglutinin [Y. Nagatsuka et al., Immunol. Lett. 46 (1995) 93-100]. Thin layer chromatography immunoblotting analysis revealed that these antibodies had broad specificities reacting with a variety of glycolipid antigens. Of the immunoreactive lipid antigens, a new phosphoglycerolipid containing glucose from human cord red cells was found. The isolated lipid was unstable to alkaline hydrolysis and contained glucose as a sole sugar. Secondary ion mass spectrum-collision-induced dissociation mass spectrometric analysis of this lipid gave the main molecular ion peak at m/z 885 corresponding to phosphatidylhexose. This antigen was susceptible to phospholipases A2, C and D but resistant to phosphatidylinositol-specific phospholipase C. Two-dimensional nuclear magnetic resonance spectroscopy confirmed that glucose is linked to the sn-glycerol 3-phosphate residue with a beta-anomeric configuration. Based upon these combined results, we identified this lipid as phosphatidyl-beta-D-glucose. This is the first report showing the presence of the glucosylated glycerophospholipid in mammalian sources.

Agglutinins↗
PubMed2001

Developmental profile of the changes in the prothoracicotropic hormone titer in hemolymph of the silkworm Bombyx mori: correlation with ecdysteroid secretion.

A very sensitive time-resolved fluoroimmunoassay for the prothoracicotropic hormone (PTTH) of the silkworm Bombyx mori has been established. The lower limit of detection in this assay was 0.1 pg. With this assay method, the amounts of PTTH in the central nervous system and hemolymph were quantified. PTTH was detected only in the brain within the central nervous system, and, in the fifth instar, its content in the brain increased gradually with larval growth and decreased rapidly after the beginning of wandering. A substantial amount of PTTH was also found in the retrocerebral complex of day-3 fifth instar larvae, accounting for 28% of total PTTH. The PTTH titer in hemolymph changed dramatically during Bombyx development, with a small peak in the middle of the fourth instar, medium-sized peaks at the wandering and prepupal stages in the fifth instar, and a large prolonged peak during early pupal-adult development. The changes were overall closely correlated with those in hemolymph ecdysteroid titer. However, some unexpected aspects of PTTH dynamics in hemolymph have also been disclosed. Based on these observations, the significance of PTTH secretion in the control of insect development is discussed.

Animals↗
PubMed2001

Immunohistochemical investigation of caspase-1 and effect of caspase-1 inhibitor in delayed neuronal death after transient cerebral ischemia.

The localization of caspase-1 protein, interleukin-1beta (IL-1beta)-converting enzyme, was immunohistochemically examined in the hippocampal CA-1 subfield by a transient occlusion of bilateral common carotid arteries in Mongolian gerbils. Immunoreactivities for caspase-1 were found in microglias, astrocytes, endothelial cells of capillaries and some non-pyramidal neurons. Immunopositive microglias increased in number from 3 days until 7 days from the transient ischemia, and astrocytes also increased in number from 3 days until 28 days. At the electron microscopic level, caspase-1 immunoreaction endproducts were associated with Golgi apparatus in glial cells, endothelial cells of blood vessels and non-pyramidal neurons. The delayed neuronal death of CA-1 pyramidal cells was significantly protected by the treatment of specific caspase-1 inhibitor (Ac-WEHD-CHO) or broad caspase family inhibitor (z-VAD-FMK). Cell death was protected in a dose dependent manner by the former by 43-57%, and by the latter by 66-91% when injected at 1 and 10 microg, respectively. On the other hand, the protective effect of specific caspase-3 inhibitor (Ac-DMQD-CHO) was less significant at higher dose (10 microg) by 33% (P<0.05), and not detectable at lower dose (1 microg) by 13% (P=0.27). Furthermore, a significant decrease of microglias and astrocytes was found in the CA-1 as well as the reduction of IL-1beta and caspase-1 immunoreactivities by the treatment of Ac-WEHD-CHO. Extravasation of serum albumin was also extremely reduced by this treatment. These findings suggest that the inhibition of caspase-1 activity ameliorates the ischemic injury by inhibiting the activity of IL-1beta.

Amino Acid Chloromethyl Ketones↗
PubMed2001

Molecular cloning and cultivar specific expression of MAP kinases from Capsicum annuum.

Two MAP kinases, MK1 and MK2, were cloned from Capsicum annuum (pepper) cv. Subicho using a parsley MAP kinase gene as a heterologous probe. MK1 and MK2 encode stress-inducible protein kinases that can contribute to the response to wounding, UV-C, and cold. MK1 has a 92% amino acid identity with WIPK of tobacco. It was transcriptionally induced in response to wounding. In contrast, no detectable MK1 transcript was found in unwounded leaves of pepper. MK2 has a high level of amino acid homology to MAP kinases, such as NTF4 and SIPK and was constitutively expressed in all tissues. Both MK transcripts were downregulated by UV-C treatment. Each MK protein activation was independently wound-inducible in a cultivar dependent manner. MK1 is phosphorylated in cv. Pungchon but not cv. Subicho; whereas, the MK2 protein activation by wounding is restricted to cv. Subicho. In addition, de novo synthesis of the MK1 protein and tyrosine phosphorylation was rapidly and transiently induced in cv. Pungchon by wounding. In contrast, it is highly unlikely that the MK1 protein is produced in cv. Subicho, even though there is an abundant expression of MK1 mRNA after wounding in this cultivar. In Escherichia coli, which overexpresses MK1, autophosphorylation is observed at conserved threonine and tyrosine phosphorylation sites.

Amino Acid Sequence↗
PubMed2001

Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.

The p16INK4a cyclin-dependent kinase inhibitor is implicated in replicative senescence, the state of permanent growth arrest provoked by cumulative cell divisions or as a response to constitutive Ras-Raf-MEK signalling in somatic cells. Some contribution to senescence presumably underlies the importance of p16INK4a as a tumour suppressor but the mechanisms regulating its expression in these different contexts remain unknown. Here we demonstrate a role for the Ets1 and Ets2 transcription factors based on their ability to activate the p16INK4a promoter through an ETS-binding site and their patterns of expression during the lifespan of human diploid fibroblasts. The induction of p16INK4a by Ets2, which is abundant in young human diploid fibroblasts, is potentiated by signalling through the Ras-Raf-MEK kinase cascade and inhibited by a direct interaction with the helix-loop-helix protein Id1 (ref. 11). In senescent cells, where the Ets2 levels and MEK signalling decline, the marked increase in p16INK4a expression is consistent with the reciprocal reduction of Id1 and accumulation of Ets1.

Animals↗
PubMed2001

Fluorescence-based DHPLC for allelic quantification by single-nucleotide primer extension.

We have investigated the possibility of determining quantitatively the alleles of binary DNA polymorphisms by single-nucleotide primer extension (SNuPE) and fluorescence-based DHPLC. Using a polymorphism of interest to our group, ROX-labeled dideoxy CTP (ROX-ddCTP) was incorporated at the 3' end of the primer annealed to the template adjacent to the polymorphic site. The primer extension product was then resolved from the unincorporated dye terminator by ion-pair reversed-phase liquid chromatography. The signal intensity of incorporated ROX-ddCTP correlated well over one order of magnitude with the relative amount of the C-allele present in the genomic DNA template. We conclude that SNuPE, when combined with fluorescence-based DHPLC, can accurately determine the relative molar proportion of one allele in total DNA.

Alleles↗
PubMed2001

Deficient activity of von Willebrand factor-cleaving protease in patients with Upshaw-Schulman syndrome.

We identified unusually large von Willebrand factor (vWF) multimers caused by deficient activity of vWF-cleaving protease in 2 patients with Upshaw-Schulman syndrome. The autoantibodies that inhibited the protease activity were not detected in the plasma of either patient. Periodic fresh-frozen plasma transfusion was effective for management of the hemolysis and thrombocytopenia. We detected enriched enzyme activity in a particular plasma fraction, although molecular cloning of this specific protease is needed to determine a more detailed pathogenesis and to develop new therapeutic approaches.

ADAM Proteins↗
PubMed2001

Early phase II study of S-1, a new oral fluoropyrimidine, for advanced non-small-cell lung cancer.

BACKGROUND: The efficacy and safety of S-1, a new oral fluoropyrimidine, were evaluated in patients with non-small-cell lung cancer (NSCLC). The objective of this study was to determine whether the drug should be investigated in a late phase II study. METHODS: Each treatment course consisted of an oral dose of S-1, 50 mg/body or 75 mg/body, twice a day for 28 days followed by a 2-week washout period. RESULTS: Fifty-six eligible patients were enrolled. Five of the 40 previously untreated patients (12.5%; 90% confidence interval, 6.2%-23.5%) showed a partial response (PR), and no tumor response was observed in the 16 previously treated patients. The median survival duration in all eligible patients was 8.4 months, with a 1-year survival rate of 27.3%. The incidences of grade 3 or more severe adverse effects were: anemia, 5.4%; leukopenia, 5.4%; neutropenia, 5.4%; thrombocytopenia, 1.8%; anorexia, 3.6%; diarrhea, 3.6%; and general fatigue, 5.4%. These effects disappeared after cessation of the drug or appropriate treatment. One patient died as a result of aggravated interstitial pneumonitis, but the relationship of this event to S-1 was not clear. CONCLUSION: S-1 showed modest activity with mild toxicity in the treatment of non-small-cell lung cancer. Based on this result, we will progress to the next stage of a late phase II study for advanced NSCLC, and a phase II study of S-1 and cisplatin for advanced gastric cancer. Final results will be reported as they are obtained.

Administration, Oral↗
PubMed2001

The effects of FK506, a specific calcineurin inhibitor, on methamphetamine-induced behavioral change and its sensitization in rats.

RATIONALE: FK506 inhibits calcineurin activity, resulting in the inhibition of calcium-dependent intracellular processes. Recent studies have suggested that intracellular calcium is likely to be involved in methamphetamine (MAP)-induced locomotor activity and stereotyped behavior, and in the development of sensitization to MAP. OBJECTIVES: We investigated the effects of FK506 on MAP-induced behavioral changes and the development of sensitization in rats. METHODS: In experiment 1, animals were administered IP 2 mg/kg FK506 or vehicle followed 10 min later by MAP (1, 2, 4 and 8 mg/kg, IP). Another set of animals were administered FK506 (0.1, 2, 5 and 10 mg/kg) followed by 2 mg/kg MAP. Locomotor activity and stereotyped behavior were assessed. In experiment 2, animals received repeated IP injections of 2 mg/kg MAP pretreated with 2 mg/kg FK506 or vehicle for 5 consecutive days. One week later, rats were challenged with 1 mg/kg MAP. RESULTS: Pretreatment with 2 mg/kg FK506 caused a rightward shift of the inverted U-shaped response curve of the locomotor activity induced by 1-8 mg/kg MAP. The same pretreatment significantly attenuated augmentation of the MAP-induced stereotyped behavior. FK506 at doses of 0.1-10 mg/kg dose-dependently inhibited the behavioral response induced by 2 mg/kg MAP. Coadministration of 2 mg/kg FK506 with 2 mg/kg MAP for 5 consecutive days resulted in significant suppression of the behavioral response to challenge with 1 mg/kg MAP. CONCLUSIONS: These results suggest that calcineurin plays an important role in MAP-induced behavioral changes and sensitization, especially the latter.

Animals↗