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Biomedical subjects

H Onishi

Publications and source records attributed to H Onishi.

At least 73 records · Page 4Linked to original sources
PubMed1998

Mutation involving cytochrome P450IID6 in two Japanese patients with neuroleptic malignant syndrome.

Cytochrome P450IID6 (CYP2D6) plays an important role in the hepatic metabolism of various psychotropic drugs. We detected a mutation of the CYP2D6 gene in two patients who previously had episodes of neuroleptic malignant syndrome (NMS). They were homozygous for a mutated CYP2D6J allele conferring a poor-metabolizer phenotype. Possession of this trait may contribute to susceptibility to NMS.

Alleles↗
PubMed1998

Functional transitions in myosin: formation of a critical salt-bridge and transmission of effect to the sensitive tryptophan.

For analyzing the mechanism of energy transduction in the "motor" protein, myosin, it is opportune both to model the structural change in the hydrolytic transition, ATP (myosin-bound) + H2O --> ADP.Pi (myosin-bound) and to check the plausibility of the model by appropriate site-directed mutations in the functional system. Here, we made a series of mutations to investigate the role of the salt-bridge between Glu-470 and Arg-247 (of chicken smooth muscle myosin) that has been inferred from crystallography to be a central feature of the transition [Fisher, A. J., Smith, C. A., Thoden, J. B. , Smith, R., Sutoh, K., Holden, H. M., & Rayment, I. (1995) Biochemistry 34, 8960-8972]. Our results suggest that whether in the normal, or in the inverted, direction an intact salt-bridge is necessary for ATP hydrolysis, but when the salt-bridge is in the inverted direction it does not support actin activation. Normally, fluorescence changes result from adding nucleotides to myosin; these signals are reported by Trp-512 (of chicken smooth muscle myosin). Our results also suggest that structural impairments in the 470-247 region interfere with the transmission of these signals to the responsive Trp.

Animals↗
PubMed1998

A new informative Alw 26 I polymorphism in exon 10 of the human low density lipoprotein receptor gene. Application to prenatal diagnosis. Mutations in brief no. 145. Online.

Using DNA sequencing of the coding and exon flanking regions of the low density lipoprotein receptor (LDLR) gene we identified an Alw26 I site in exon 10 by a transition G142A. The alleles are represented by one uncut fragment (A1=108bp) or two fragments (A2=82bp and 26 pb). Two other fragments (72bp and 16bp) were systematically found within the amplified product. The alleles were detected in 157 unrelated French Caucasians with A1 frequency = 0.58 and A2=0.42. The observed heterozygoty was 44.5%. Homozygous familial hypercholesterolemie (FH) has a severe clinical picture leading to death during childhood. Because it is very informative, the present polymorphism was very useful as genetic marker for clinical diagnois and counseling as we described in linkage analysis at the LDLR locus for prenatal diagnosis in a fetus who could inherit two LDLR mutant alleles from FH heterozygote parents.

DNA-Cytosine Methylases↗
PubMed1998

A novel mutation found in an adrenoleukodystrophy patient who underwent bone marrow transplantation.

We identified a novel mutation, L322P, in a patient with X-linked adrenoleukodystrophy (ALD) who underwent bone marrow transplantation (BMT). An identification of the ALD gene mutation enabled us to employ an approach not dependent on the use of radioisotopes for detecting mixed chimerism. This assay could show more than 99.0% of the patient's peripheral white blood cells were replaced by the donor's cells.

Adrenoleukodystrophy↗
PubMed1998

Developmental and regional alteration of kappa-opioid receptors in seizure-susceptible EL mouse brain.

The binding of [3H]ethylketocyclazocine ([3H]EKC) under the suppression of mu and delta sites in the brain of EL mice (seizure-susceptible) was examined to determine the relationship between seizures and the dynorphinergic system. The density of kappa-opioid receptors in the cerebrum of adult EL mice during interictal periods significantly increased, without changes in apparent affinities, compared with that of adult ddY mice (seizure-nonsusceptible; the mother strain of EL). Subsequently, the binding of 0.8 nM [3H]EKC in 8 brain regions was examined in the 2 strains. The [3H]EKC binding in 25-day-old EL mice that had no seizures significantly increased in the hippocampus and amygdala. At the age of 50 days, EL mice displayed abortive seizures, and the number of kappa sites in EL mice was significantly greater in the hippocampus, amygdala and cerebral cortex. It was further shown that the binding of [3H]EKC in 150-day-old adult EL mice during interictal periods was markedly increased in the hippocampus, amygdala, cerebral cortex and striatum, compared with the corresponding regions in ddY mice. The up-regulation of kappa receptors in the EL mouse brain may result from deficits in endogenous dynorphins, which could be involved in the pathogenesis of seizure diathesis and seizure manifestations in the EL mouse.

Animals↗
PubMed1998

A case of depressive disorder with neuronal heterotopia.

We describe a case of depressive disorder with neuronal heterotopia. The patient, a 55-year-old woman, had a history of depressive episodes since the age of 53. Magnetic resonance imaging (MRI) disclosed bilateral periventricular heterotopia. The patient had not experienced any epileptic episodes, and an electroencephalogram did not reveal any epileptic discharge. Single photon emission computed tomography (SPECT) disclosed diffuse cerebral hypoperfusion. This is the first report on a case of depression with neural migration disorder. Patients with neural migration disorders can be detected more frequently with the increasing use of MRI.

Cell Movement↗
PubMed1998

Japanese Creutzfeldt-Jakob disease patients exhibiting high incidence of the E200K PRNP mutation and located in the basin of a river.

Seven cases with Creutzfeldt-Jakob disease (CJD) located in the basin of the Fuji river (Fuji area) in Japan were examined genetically and clinicopathologically. The onset of the disease was between 1989 and 1995. All cases were from different families, although 3 cases were family members of previously reported CJD patients. They had clinical and/or neuropathological features, corresponding to subacute spongiform encephalopathy. Five of the 7 cases, including the 3 familial cases, had the E200K mutation in the gene encoding prion protein (PRNP). It is suggested that there is a small cluster of CJD patients with a founder effect of the E200K mutation in the Fuji area, because the incidence of CJD with the E200K mutation appears to be much higher in this area than other areas in Japan. The disease penetrance of the 5 cases with the E200K mutation seems to be low, and they may have an age-related incidence in the Fuji area. These findings support the hypothesis that the phenotypes of CJD patients with the PRNP mutations are linked to the position of the mutation, but not related to ethnic or environmental factors.

Aged↗
PubMed1998

Isolation and contraction of the stress fiber.

Stress fibers were isolated from cultured human foreskin fibroblasts and bovine endothelial cells, and their contraction was demonstrated in vitro. Cells in culture dishes were first treated with a low-ionic-strength extraction solution and then further extracted using detergents. With gentle washes by pipetting, the nucleus and the apical part of cells were removed. The material on the culture dish was scraped, and the freed material was forced through a hypodermic needle and fractionated by sucrose gradient centrifugation. Isolated, free-floating stress fibers stained brightly with fluorescently labeled phalloidin. When stained with anti-alpha-actinin or anti-myosin, isolated stress fibers showed banded staining patterns. By electron microscopy, they consisted of bundles of microfilaments, and electron-dense areas were associated with them in a semiperiodic manner. By negative staining, isolated stress fibers often exhibited gentle twisting of microfilament bundles. Focal adhesion-associated proteins were also detected in the isolated stress fiber by both immunocytochemical and biochemical means. In the presence of Mg-ATP, isolated stress fibers shortened, on the average, to 23% of the initial length. The maximum velocity of shortening was several micrometers per second. Polystyrene beads on shortening isolated stress fibers rotated, indicating spiral contraction of stress fibers. Myosin regulatory light chain phosphorylation was detected in contracting stress fibers, and a myosin light chain kinase inhibitor, KT5926, inhibited isolated stress fiber contraction. Our study demonstrates that stress fibers can be isolated with no apparent loss of morphological features and that they are truly contractile organelle.

Actin Cytoskeleton↗
PubMed1998

Pancreatic exocrine dysfunction associated with mitochondrial tRNA(Leu)(UUR) mutation.

We report on pancreatic exocrine dysfunction in families that have the mitochondrial tRNA(Leu)(UUR) gene mutation. These families exhibited maternally inherited diabetes mellitus (DM) and an A to G substitution at nt 3243 of the mitochondrial tRNA(Leu)(UUR) gene (A3243G mutation). Pancreatic necropsy samples from one proband showed accumulation of degenerated mitochondria in pancreatic acinar cells. Pancreatic exocrine dysfunction was recognised by a functional pancreatic study. This study indicates that exocrine pancreatic dysfunction may be associated with the A3243G mutation.

4-Aminobenzoic Acid↗
PubMed1998

Lack of association between neuroleptic malignant syndrome and polymorphisms in the 5-HT1A and 5-HT2A receptor genes.

OBJECTIVE: The molecular basis of neuroleptic malignant syndrome is unclear, but studies suggest that genetic factors are involved in its pathogenesis. Considering possible involvement of the serotonergic system in neuroleptic malignant syndrome, the authors examined the association between neuroleptic malignant syndrome and polymorphisms of the 5-HT1A and 5-HT2A receptor genes. METHOD: The authors examined the frequencies of gene polymorphisms in the 5-HT1A (Arg219Leu) and 5-HT2A (Thr25Asn and His452Tyr) receptor genes in 29 patients previously diagnosed with neuroleptic malignant syndrome, 94 neuroleptic-treated patients with schizophrenia who had no history of neuroleptic malignant syndrome, and 94 healthy comparison subjects. Polymerase chain reaction and restriction fragment length polymorphism analyses were used to screen gene mutations. RESULTS: No polymorphic allele was detected in the patients who had experienced the neuroleptic malignant syndrome. CONCLUSIONS: The authors cannot conclude that polymorphisms in the 5-HT1A and 5HT2A receptor genes are factors determining susceptibility to the neuroleptic malignant syndrome.

Adult↗
PubMed1998

In vivo properties of the conjugates of mitomycin C with estradiol benzoate and estradiol: pharmacokinetics and antitumor characteristics against P388 leukemia and sarcoma 180.

Conjugates of mitomycin C (MMC) with estradiol benzoate and estradiol via glutaric acid, abbreviated to EB-glu-MMC and E-glu-MMC, respectively, as previously reported, were examined concerning their pharmacokinetic behaviors and antitumor effects against two kinds of general and popular tumors, P388 leukemia and Sarcoma 180. EB-glu-MMC and E-glu-MMC were dissolved in propylene glycol. Their solution was administered intraperitoneally to rats and mice in order to examine their plasma concentration-time profiles and antitumor characteristics, respectively. After the administration of EB-glu-MMC, EB-glu-MMC was detected slightly in blood only in the initial stage, while E-glu-MMC and MMC were observed there for a prolonged period. In the administration of E-glu-MMC, a similar phenomenon was observed but the drug retention effect seemed lower than that in EB-glu-MMC. In the antitumor test against P388 leukemia, E-glu-MMC exhibited a better effect than EB-glu-MMC; however, neither conjugate surpassed the effect of MMC. The toxic side effect was improved in each conjugate. As to the growth inhibition against Sarcoma 180, EB-glu-MMC and E-glu-MMC produced good effect and improved the toxic side effect. Especially, in the administration of EB-glu-MMC at the dose of 30 mg eq MMC/kg, a decrease in tumor volume was observed in the latter stage. EB-glu-MMC and E-glu-MMC were demonstrated to produce prolonged retention, to enter the systemic circulation to a fair extent, and to exhibit a good effect against the general solid tumor, Sarcoma 180, in vivo.

Animals↗
PubMed1998

Smooth muscle myosin. Amino acid residues responsible for the hydrolysis of ATP.

From their crystallographic comparisons, Fisher et al. (Biochemistry 34, 8960-8972, 1995) have proposed that in an important transition of myosin heads (M), M.ATP-->M.ADP.Pi, an interdomain rotation occurs in Gly468 (of chicken smooth muscle myosin) and that the rotated state is stabilized by newly-formed interdomain contacts including the salt link between Glu470 and Arg247 (of chicken smooth muscle myosin). Here, we have studied the effects of Gly468, Glu470, and Arg247 mutations on the hydrolysis of ATP. The G468A HMM did not show a significant ATPase activity, a stoichiometric initial phosphate burst, and tryptophan fluorescence enhancement attributed to bound ADP.Pi. The E470A HMM also did not show a significant ATPase activity and the phosphate burst, but the mutant gave tryptophan response attributed to bound ATP. The E470R/R247E HMM exhibited an ATPase activity and the phosphate burst which were comparable to those of the wild-type HMM, whereas neither the E470R HMM nor the R247E HMM showed such a significant ATPase activity and burst. We thus propose that both an unhindered rotation and a salt link that stabilizes the rotated state are necessary for ATP hydrolysis.

Adenosine Triphosphate↗
PubMed1997

Functional transitions in myosin: role of highly conserved Gly and Glu residues in the active site.

It has been proposed from crystallographic comparisons [Fisher, A. J., Smith, C. A., Thoden, J. B., Smith, R., Sutoh, K., Holden, H. M., & Rayment, I. (1995) Biochemistry 34, 8960-8972] that in one of the important transitions of myosin head (M), M x ATP --> M x ADP x Pi, a rotation occurs in Gly468 (of chicken smooth muscle myosin). We find that mutation of this Gly to Ala does block the transition. Searching for proton acceptors in ATPase catalysis, we also find that mutation of a candidate (Glu470 of chicken smooth muscle myosin) blocks the transition. Interpretations of both findings are examined.

Actins↗
PubMed1997

6-Pyruvoyl-tetrahydropterin synthase deficiency with generalized dystonia and diurnal fluctuation of symptoms: a clinical and molecular study.

We report the case of a 44-year-old woman with a partial 6-pyruvoyl tetrahydropterin synthase (6-PTS) deficiency, whose predominant clinical symptom was generalized dystonia with marked diurnal fluctuation. Dystonia was present in the eyelids, oromandibular region, trunk, and extremities (Meige syndrome plus double hemiplegia-like dystonia). A marked and sustained positive response to levodopa was observed. A molecular genetic study revealed a homozygous mutation (I114V) in the 6-PTS gene. This study indicates that genetic abnormality in the 6-PTS gene may be a hereditary dystonia disorder. We speculate that our patient has residual 6-PTS activity in the central nervous system, such as in the liver, and we suggest that residual, but insufficient production of tetrahydrobiopterin may play an important role in causing diurnal fluctuation of symptoms.

Adult↗
PubMed1997

Neuroleptic malignant syndrome and hydroxylase gene mutations: no association with CYP2D6A or CYP2D6B.

To examine a possible association between debrisoquine 4-hydroxylase gene mutations and neuroleptic malignant syndrome, we assessed frequencies of wild type and A and B mutant alleles of the CYP2D6 gene in 24 patients with a history of neuroleptic malignant syndrome, 50 patients with neuroleptic-treated schizophrenia but no history of neuroleptic malignant syndrome, and 50 healthy controls. Allele frequencies did not differ significantly between these groups. Homozygotes for CYP2D6A and for CYP2D6B, which indicate a poor-metabolizer phenotype for the CYP2D6 substrate, were not detected among the neuroleptic malignant syndrome cases. This result indicates no excess of poor CYP2D6 metabolizers in neuroleptic malignant syndrome. The aetiology of neuroleptic malignant syndrome is not explainable in terms of CYP2D6 gene mutations.

Alleles↗