Antley-Bixler syndrome and maternal virilization: a proposal of genetic heterogeneity.
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Abnormalities, Multiple↗
Biomedical subjects
H Ninomiya
Publications and source records attributed to H Ninomiya.
Structure and polymorphisms of the human metabotropic glutamate receptor type 2 gene (GRM2): analysis of association with schizophrenia.
Metabotropic glutamate receptors (mGluRs) belong to the class of GTP-binding protein coupled receptors and consist of eight different subtypes. The subtype 2 metabotropic glutamate receptor (mGluR2) gene (GRM2) is one of the possible candidate genes for schizophrenia. Phencyclidine (PCP)-induced increase in glutamate efflux and schizophrenia-like behavioral abnormalities were reduced by pretreatment of the mGluRII agonist LY354740 in rats and its effects are mediated via mGluR2. To evaluate involvement of the mGluR2 gene in the pathogenesis of schizophrenia, we isolated the human mGluR2 gene and determined the transcription initiation site, the entire nucleotide sequence and the chromosomal localization. The hmGluR2 gene spans 13 kb with six exons, including one non-coding exon. The gene was mapped to chromosome 3 p12-p11 by Radiation Hybrid Panel analysis. We screened polymorphisms in the coding exons of the mGluR2 gene, using the SSCP procedure. The thirteen polymorphisms identified included ten missense, one silent mutation and two one-base substitutions in the 5'-untranslated region. We genotyped 213 Japanese schizophrenics and 220 controls to study the association of polymorphisms in the mGluR2 gene with schizophrenia. As we found no statistically significant differences in allele frequencies of each polymorphism, these polymorphisms apparently do not play a major role in schizophrenia.
Brain Chemistry↗
Microvasculature of the rat eye: scanning electron microscopy of vascular corrosion casts.
Methylmethacrylate castings of the eye microvasculature were prepared from 10 Spargue-Dawley rats and studied by electron microscopy. The choroidal arterioles are larger in diameter than retinal arterioles, and have a shorter course to choroidal capillaries than retinal arterioles to retinal capillaries. Retinal capillaries are extremely thin in diameter and form a sparse retinal capillary network. The choriocapillaris is large and sinusoid-like, forming a compactly arranged network in the choroid. These differences in the microvasculature between the choroid and retina help explain the differences in ocular hemodynamics; that is, the blood flow in the choroid is faster than that in the retina. Capillaries of the iris show a zigzag configuration, which may be an accommodation for dilation and constriction of the pupil. Capillaries of the ciliary body are of large diameter forming leaf-like configurations, presumably to contribute to the secretion of the aqueous humor. Capillaries of the conjunctiva exhibit a somewhat coiled configuration, the arrangement of which reduce tension of the conjunctiva vessels caused by eyeball movement. Intra-arterial cushions, which control blood flow at the branching sites, are found in both choroidal or retinal arterioles.
Animals↗
Genetic polymorphisms and functional characterization of the 5'-flanking region of the human CYP2C9 gene: in vitro and in vivo studies.
OBJECTIVE: Genetic polymorphisms were identified in the 5'-flanking region of the human CYP2C9 gene, and their effects on the phenotype were evaluated on the basis of the luciferase reporter gene assay and the in vivo pharmacokinetics of phenytoin. METHODS: Genetic polymorphisms were screened by polymerase chain reaction-single-strand conformational polymorphism analysis, following sequencing with DNA samples obtained from 50 healthy volunteers and 133 adult epileptic patients. HepG2 hepatoma cells were cotransfected with various sequence patterns of 5'-flanking region-luciferase reporter gene constructs. Pharmacokinetic parameters of phenytoin in relation to the corresponding sequence patterns were estimated by the Bayesian method, and the results were compared with in vitro activities. RESULTS: Genetic analysis revealed the existence of 7 single nucleotide polymorphisms (SNPs). Allele frequencies of T-->C transition at position -1912 (T-1912C), C-1886G, C-1566T, G-1538A, C-1189T, G-982A, and A-162G were 0.019, 0.019, 0.077, 0.019, 0.579, 0.019, and 0.003, respectively. Some mutations occurred simultaneously, and a total of 6 sequence patterns (patterns 1-6) were observed. The luciferase reporter gene assay indicated that the presence of mutation(s) resulted in a reduction in luciferase activity of 41.4% (pattern 2) to 86.8% (pattern 5) compared with the activity of the wild-type construct. The calculated intrinsic clearance of phenytoin was also lower (up to a 40% reduction for pattern 2) when a mutation(s) was present. CONCLUSION: In addition to the two major mutations in the coding region (CYP2C9*2 and CYP2C9*3 ), mutations in the 5'-flanking region of the human CYP2C9 gene appear to contribute to the large interindividual variability in drug metabolism activity.
Adult↗
Protein kinase C isoform-dependent myocardial protection by ischemic preconditioning and potassium cardioplegia.
OBJECTIVE: Ischemic preconditioning combined with potassium cardioplegia does not always confer additive myocardial protection. This study tested the hypothesis that the efficacy of ischemic preconditioning under potassium cardioplegia is dependent on protein kinase C isoform. METHODS: Isolated and crystalloid-perfused rat hearts underwent 5 cycles of 1 minute of ischemia and 5 minutes of reperfusion (low-grade ischemic preconditioning) or 3 cycles of 5 minutes of ischemia and 5 minutes of reperfusion (high-grade ischemic preconditioning) or time-matched continuous perfusion. These hearts received a further 5 minutes of infusion of normal buffer or oxygenated potassium cardioplegic solution. The isoform nonselective protein kinase C inhibitor chelerythrine (5 micromol/L) was administered throughout the preischemic period. All hearts underwent 35 minutes of normothermic global ischemia followed by 30 minutes of reperfusion. Isovolumic left ventricular function and creatine kinase release were measured as the end points of myocardial protection. Distribution of protein kinase C alpha, delta, and epsilon in the cytosol and the membrane fractions were analyzed by Western blotting and quantified by a densitometric assay. RESULTS: Low-grade ischemic preconditioning was almost as beneficial as potassium cardioplegia in improving functional recovery; left ventricular developed pressure 30 minutes after reperfusion was 70 +/- 15 mm Hg (P <.01) in low-grade ischemic preconditioning and 77 +/- 14 mm Hg (P <.001) in potassium cardioplegia compared with values found in unprotected control hearts (39 +/- 12 mm Hg). Creatine kinase release during reperfusion was also equally inhibited by low-grade ischemic preconditioning (18.2 +/- 10.6 IU/g dry weight, P <.05) and potassium cardioplegia (17.6 +/- 6.7 IU/g, P <.01) compared with control values. However, low-grade ischemic preconditioning in combination with potassium cardioplegia conferred no significant additional myocardial protection; left ventricular developed pressure was 80 +/- 17 mm Hg, and creatine kinase release was 14.8 +/- 11.0 IU/g. In contrast, high-grade ischemic preconditioning with potassium cardioplegia conferred better myocardial protection than potassium cardioplegia alone; left ventricular developed pressure was 121 +/- 16 mm Hg (P <.001), and creatine kinase release was 8.3 +/- 5.8 IU/g (P <.05). Chelerythrine itself had no significant effect on functional recovery and creatine kinase release in the control hearts, but it did inhibit the salutary effects not only of low-grade and high-grade ischemic preconditioning but also those of potassium cardioplegia. Low-grade ischemic preconditioning and potassium cardioplegia enhanced translocation of protein kinase C alpha to the membrane, whereas high-grade ischemic preconditioning also enhanced translocation of protein kinase C delta and epsilon. Chelerythrine inhibited translocation of all 3 protein kinase C isoforms. CONCLUSIONS: These results suggest that myocardial protection by low-grade ischemic preconditioning and potassium cardioplegia are mediated through enhanced translocation of protein kinase C alpha to the membrane. It is therefore suggested that activation of the novel protein kinase C isoforms is necessary to potentiate myocardial protection under potassium cardioplegia.
Animals↗
Effects of Hachimi-jio-gan in aged rats.
OBJECTIVE: To evaluate the effects of Hachimi-jio-gan, a traditional Japanese Kampo medication composed of eight medicinal herbs used for treating older people. SUBJECTS: Sixteen laboratory-bred Fischer 344 rats DESIGN: The rats were divided into two groups. One was the control group and the other was given chow containing 7% Hachimi-jio-gan powder for a period 110-120 weeks. OUTCOME MEASURES: The rats were assessed for wheel running and an inclined screen test from weeks 119-120; then laboratory and histologic examinations were performed. RESULTS: The group receiving Hachimi-jio-gan was more active in spontaneous mobility during wheel running; they maintained a significantly higher angle of retaining posture than the control group on the inclined screen; there was no significant difference in laboratory and histologic findings. CONCLUSIONS: Aged rats that received Hachimi-jio-gan were more active and stronger than the control group rats. The findings suggest that Hachimi-jio-gan is a safe and effective Kampo prescription for aging rats.
Aging↗
Isolation of NPC1-deficient Chinese hamster ovary cell mutants by gene trap mutagenesis.
Chinese hamster ovary cell mutants defective in the NPC1 gene (NPC1-trap) were generated by retrovirus-mediated gene trap mutagenesis from a parental cell line JP17 expressing an ecotropic retrovirus receptor. Insertion of the gene trap vector in the NPC1 gene and the absence of the gene product were verified by 5'RACE and immunological analyses, respectively. NPC1-trap cells showed intracellular accumulation of low-density lipoprotein (LDL)-derived cholesterol and had an increased level of unesterified cellular cholesterol. Cholesterol biosynthesis through the mevalonate pathway was upregulated in the mutant cells as assessed by [(14)C]acetate incorporation into cellular sterols. When JP17 cells were depleted of lipoproteins and then loaded with LDL, cell surface LDL receptors were promptly downregulated and the mature form of the sterol regulatory element-binding protein-1 disappeared from the nucleus. These responses to LDL were obviously retarded in NPC1-trap cells, suggesting an impaired response of the cholesterol-regulatory system to LDL. NPC1-trap cells will be a useful tool to study the regulation of cellular cholesterol homeostasis and the pathogenesis of Niemann-Pick disease type C.
Animals↗
Phenytoin intoxication induced by fluvoxamine.
A patient had phenytoin intoxication after administration of fluvoxamine, a selective serotonin reuptake inhibitor. The serum concentration of phenytoin increased dramatically from 16.6 to 49.1 microg/mL when fluvoxamine was coadministered, although the daily dosage of phenytoin and other drugs had not changed. During phenytoin and fluvoxamine treatment, ataxia, a typical side effect of phenytoin, was observed. The genotypes of CYP2C9 and 2C19, the enzymes responsible for phenytoin metabolism, were homozygous for the wild-type alleles (CYP2C9*1/*1 and 2C19*1/ *1). The interaction may be a result of inhibition of both CYP2C9 and 2C19 by fluvoxamine.
Alleles↗
Association study of polymorphisms in the GluR5 kainate receptor gene (GRIK1) with schizophrenia.
The glutamatergic dysfunction hypothesis suggests genes involved in glutamatergic transmission as candidates for schizophrenia susceptibility genes. We screened single nucleotide polymorphisms (SNPs) in the entire coding sequence of the GluR5 kainate receptor gene, GRIK1, by polymerase chain reaction-single strand conformation polymorphism and direct sequencing. We identified six SNPs including three known ones, 522A/C (174T, synonymous), 1173C/T (391D, synonymous), and 2705C/T (902L/S), as well as three novel ones, 995C/T (332A/V), 2400C/T (800L, synonymous), and 2585A/G (862R/Q). We genotyped Japanese samples of schizophrenia (n = 193-203) and healthy controls (n = 199-215) for three SNPs those were commonly observed in our samples, 522A/C, 1173C/T, and 2705C/T. We observed no significant associations of the SNPs and their haplotypes with schizophrenia. Therefore, we conclude that GRIK1 does not play a major role in schizophrenia pathogenesis in the Japanese population.
Base Sequence↗
DEFECT 11 syndrome associated with agenesis of the corpus callosum.
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Adolescent↗
Protective effect of neurotropin against lipopolysaccharide-induced hypotension and lethality linked to suppression of inducible nitric oxide synthase induction.
Neurotropin is a non-protein extract from the dermis of rabbits inoculated with vaccinia virus and has been clinically used as an analgesic in Japan. We present in the current report evidence for its potential therapeutic value against endotoxin shock. Administration of this compound prior to lipopolysaccharide (LPS) challenge resulted in a reversal of a decrease of the mean arterial pressure in rats and also amelioration of lethality in mice. Anti-inducible nitric oxide synthase (iNOS) Western blotting of tissue extracts from LPS-treated mice revealed almost complete suppression of iNOS induction by Neurotropin. The findings in vivo were reproduced in in vitro experiments in which cultured human umbilical vascular endothelial cells were challenged with LPS. Simultaneous treatment of the cells with Neurotropin resulted in complete suppression of iNOS induction and significant reduction of cell death. These results suggested a therapeutic value of Neurotropin in the treatment of endotoxin shock that was linked, at least in part, to suppression of iNOS induction and reduced cell damage in vascular endothelial cells.
Animals↗
Pivotal role of 5-lipoxygenase in the activation of human eosinophils: platelet-activating factor and interleukin-5 induce CD69 on eosinophils through the 5-lipoxygenase pathway.
CD69 is an activation-related cell surface molecule on human eosinophils. It has been reported that interleukin (IL)-5, but not platelet-activating factor (PAF), can induce CD69 on human eosinophils in vitro. In this study, PAF induced CD69 intensely on eosinophils from patients with hypereosinophilic syndrome (HES), while only weakly on those from normal donors. Because HES eosinophils contain abundant cytosolic phospholipase A2 (cPLA2) and 5-lipoxygenase (5-LO), we examined the roles of several enzymes involved in the metabolism of arachidonic acid in the PAF- or IL-5-induced CD69 expression on eosinophils. The CD69 expression induced by PAF and IL-5 on HES eosinophils and that by IL-5 on normal eosinophils were both inhibited by AA861 and MK-886, inhibitors of 5-LO activity. In addition, AACOCF3, a selective cPLA2 inhibitor, inhibited IL-5-induced CD69 expression on normal eosinophils, although it hardly affected either IL-5- or PAF-induced CD69 expression on HES eosinophils. Moreover, PAF alone induced CD69 only weakly on normal eosinophils, but exogenous arachidonic acid remarkably enhanced PAF-induced CD69 expression on them. These findings suggest that IL-5 activates both cPLA2 and 5-LO but PAF activates only 5-LO. It is suggested that 5-LO plays a critical role in the induction of CD69 on eosinophils.
Antigens, CD↗
[Niemann-Pick disease type C].
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Animals↗
Vacuolar H(+)-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts in cultured human saphenous vein.
BACKGROUND: The molecular mechanism of neointimal hyperplasia after vein graft surgery remains elusive. Vacuolar H(+)-ATPase (V-ATPase) is involved in intracellular trafficking and may play a crucial role in neointimal cell growth. METHODS AND RESULTS: Cultured human saphenous vein segments developed neointimal formation within 10 days. Neointimal cells were positive for vimentin and alpha-smooth muscle actin but negative for desmin, which is indicative of myofibroblasts. Those myofibroblasts were found to have originated from periadventitial fibroblasts, which upregulated the expression of 16-kDa proteolipid of V-ATPase before proliferation and phenotypic modulation. Neointimal myofibroblast growth and survival were highly sensitive to inhibition of V-ATPase by bafilomycin A(1) (BA(1)), because the incorporation of [(3)H]thymidine into the myofibroblasts was significantly inhibited by nanomolar concentrations of BA(1) and apoptotic cell death was induced by a similar concentration range of BA(1). In contrast, endothelial cells and differentiated smooth muscle cells were resistant to apoptosis by BA(1). CONCLUSIONS: These results suggest that V-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts that contributes to neointimal formation in cultured human saphenous vein.
Adult↗
Contribution of ecto-5'-nucleotidase to the inhibition of platelet aggregation by human endothelial cells.
We studied the role of adenosine (Ado), which is generated from adenine nucleotides via the activity of ecto-5'-nucleotidase (ecto-5'-NT), in the inhibition of platelet aggregation by endothelial cells (ECs). The enzymatic activity of nucleotidases on human umbilical vein endothelial cells (HUVECs) was examined with regard to (1) the inhibition of adenosine diphosphate (ADP)-induced platelet aggregation and (2) the liberation of inorganic phosphate from adenine nucleotides. Adenosine 5'-monophosphate (AMP) preincubated with HUVECs significantly inhibited ADP-induced platelet aggregation. This was completely blocked by the treatment of HUVECs with a specific inhibitor of ecto-5'-NT, 5'-[alphabeta-methylene] diphosphate (APCP), or by the addition of an A(2a) receptor antagonist. Neither nitric oxide nor prostacyclin was involved in this inhibitory activity, suggesting that Ado generated in the incubation medium by the activity of 5'-NT on HUVECs inhibited platelet aggregation. When ADP was incubated on HUVECs, it lost most of its agonistic activity for platelets. Pretreatment of HUVECs with APCP at a concentration that abolished ecto-5'-NT activity partially restored ADP-induced platelet aggregation. Ecto-5'-NT contributes to EC function by inhibiting platelet aggregation in cooperation with ATP diphosphohydrolase, which degrades ADP to AMP.
5'-Nucleotidase↗
Nasal natural killer cell lymphoma in a post-renal transplant patient.
Posttransplant lymphoproliferative disorders in organ allograft recipients are most commonly of B-cell origin and only occasionally of T-cell origin. We present here a case of nasal natural killer cell lymphoma associated with Epstein-Barr virus that occurred in a recipient of a renal transplant 4 years posttransplantation. Immunohistochemically, the lymphoma cells showed CD2-, surface CD3-, cytoplasmic CD3E+, CD56+, CD57-, CD16-, and CD43+ phenotype. Analyses of T-cell receptor beta and gamma genes showed germ line configurations. EBER-1 was detectable in the lymphoma cells. The patient was diagnosed as having natural killer cell lymphoma and was treated with six courses of combination chemotherapy for non-Hodgkin's lymphoma He has been in remission for more than 3 years thereafter. To the best of our knowledge, this is the first report of a posttransplant NK cell lymphoma associated with Epstein-Barr virus.
Adult↗
Cholesterol oxidation switches the internalization pathway of endothelin receptor type A from caveolae to clathrin-coated pits in Chinese hamster ovary cells.
We investigated the mechanism of endothelin receptor type A (ETA) internalization in Chinese hamster ovary cells using two assays; flow cytometric quantification of cell surface myc-ETA and in situ localization of Cy5-labeled ET-1. In both assays, agonist-dependent internalization of myc-ETA was inhibited by nystatin and filipin, both of which disrupt internalization via caveolae, whereas it was barely affected by chlorpromazine and hypertonic sucrose, both of which disrupt internalization via clathrin-coated pits. In addition to myc-ETA, ET-1 caused intracellular translocation of caveolin-1 and this translocation was also blocked by nystatin but not by chlorpromazine. These results strongly argue that ETA is internalized via caveolae but not clathrin-coated pits. Treatment of the cells with cholesterol oxidase reduced cellular cholesterol and caused intracellular translocation of caveolin-1 but did not affect cell surface localization of myc-ETA. In cholesterol oxidase-treated cells, however, both chlorpromazine and hypertonic sucrose effectively blocked ET-1-induced myc-ETA internalization and nystatin was less effective than in untreated cells. Accordingly, expression of a dominant negative form of beta-arrestin blocked myc-ETA internalization in cholesterol oxidase-treated cells but not in untreated cells. These results suggest that, in Chinese hamster ovary cells, 1) agonist-occupied ETA can be internalized either via caveolae or clathrin-coated pits; 2) of the two, the former is the default pathway; and 3) the oxidative state of cell surface cholesterol is one of the factors involved in the pathway selection.
Animals↗
Two novel serine repeat length polymorphisms (1043insS and 1043insSS) at exon 23 of the TSC1 gene.
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Exons↗