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Biomedical subjects

T Inaba

Publications and source records attributed to T Inaba.

At least 289 records · Page 16Linked to original sources
PubMed1992

Haloperidol metabolism in psychiatric patients: importance of glucuronidation and carbonyl reduction.

In 39 patients who received haloperidol regularly we measured plasma concentrations of haloperidol glucuronide (HAL-GL), reduced haloperidol glucuronide (RHAL-GL), haloperidol (HAL), reduced haloperidol (RHAL), and HAL reductase activity in red blood cells. Plasma HAL-GL concentrations were significantly higher than HAL, RHAL, or RHAL-GL concentrations. Concentration ratios of total glucuronide to nonglucuronide and RHAL/HAL ratios were calculated as indices of glucuronidation and reduction capacity in each patient. The plasma glucuronidation ratios showed a significant negative correlation (r = -0.63, p less than 0.001) with the dose, while the reduction ratios showed a positive correlation (r = 0.75, p less than 0.001). No correlations were found between the HAL reductase activity in red blood cells and either the dose or RHAL/HAL. Based on these findings we suggest that glucuronidation of HAL is the major metabolic pathway of HAL in humans and its activity is important in determining steady-state plasma HAL concentrations. Glucuronidation may also be a major contributing factor in the interindividual variability of HAL metabolism.

Adolescent↗
PubMed1991

Occurrence of multiple aberrantly spliced mRNAs upon a donor splice site mutation that causes familial lipoprotein lipase deficiency.

A donor splice site mutation was found in the lipoprotein lipase (LPL) gene of a patient with familial LPL deficiency. The mutation, a G----A substitution, occurred at the first nucleotide of intron 2. Northern blot analysis of total RNA from the patient showed strikingly low levels of LPL-specific mRNAs. Using the polymerase chain reaction, the LPL mRNA splicing was analyzed in detail. The results demonstrated that no normal splicing occurred at the authentic splice site; rather a cryptic splice site 18 bases upstream from the mutation site was preferentially utilized. Although the resulting alteration in mRNA was a minute in-frame 18-base deletion, the amount of the abnormal transcript was only 1/12 that of the normal. In addition to this major cryptic splice site, we also identified multiple minor sites which were utilized at extremely lower efficiencies. Unexpectedly, one of these minor sites was also used as an alternative splice site in the normal subject at a comparably low efficiency. The sequences of these minor cryptic sites possessed many of the characteristics common to those of other normal splice sites, indicating that even such minor sites should have also been selected according to the general rules for splice site selection. These results demonstrate that upon mutation, a broad spectrum of cryptic splice sites is activated in vivo at the sites' respective efficiencies.

Adult↗
PubMed1991

Dominant expression of a distinctive V14+ T-cell antigen receptor alpha chain in mice.

A distinctive variable region 14-positive (V14+) alpha chain (V alpha 14+) of the T-cell antigen receptor is predominantly expressed in multiple mouse subspecies. The V alpha 14 family has two members, V alpha 14.1 and V alpha 14.2, which differ by only three amino acids at positions 50-52. Based on the EcoRI restriction fragment length polymorphism of the gene encoding V alpha 14, mice can be divided into three groups: type I with an 11.2-kilobase (kb) fragment, type II with a 2.0-kb fragment, and type III with the 2.0-kb and 11.2-kb fragments. Usage of V alpha 14-J alpha 281, where J alpha 281 is an alpha-chain joining segment, with a one-base N region dominates at the level of 0.02-1.5% of alpha chains in all laboratory strains, Mus musculus castaneus, and Mus musculus domesticus but not in Mus musculus molossinus, Mus musculus musculus, and Mus spicilegus samples. The preferential V alpha 14-J alpha 281 expression seems to be due to positive selection because the V-J junctional region is always glycine, despite the ability of the V alpha 14 gene to associate with J alpha other than J alpha 281. As V alpha 14-J alpha 281 expression is independent of known major histocompatibility complex antigens, including H-2, TLA, Qa, and HMT, the selecting ligand must be a monomorphic molecule of the mouse, expressed in a subspecies-specific manner. Additional observations, such as the expression of homogeneous V alpha 14-J alpha 281 in athymic mice, suggest that the positive selection of V alpha 14+ T cells occurs extrathymically.

Amino Acid Sequence↗
PubMed1991

Mucin-histochemical and immunohistochemical profiles of epithelial cells of several types of hepatic cysts.

Epithelial cells of several types of hepatic cysts were examined by mucin histochemistry and immunohistochemically. There were some differences in mucus and antigenic expression among the hepatic cysts examined. Epithelial cells of non-parasitic simple cysts and adult-type polycystic liver showed similar mucin-histochemical and immunohistochemical features, and were characterized by little mucin and weak immunoreactivities to several antibodies examined. Epithelial cells of hepatic hilar cysts were characterized by much mucin and moderate immunoreactivities to carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA) and epithelial membrane antigen (EMA). Epithelial cells of ciliated hepatic foregut cysts were characterized by much mucin and immunoreactivities to actin and tubulin which were positive in cilia. Epithelial cells of biliary cystadenoma were characterized by much mucin and moderate to strong immunoreactivities to cytokeratins CAM5.2 and AE1 and 3 as well as to CA 19-9, CEA, EMA and DU-PAN-2. Epithelial cells of biliary cyst-adenocarcinoma were characterized by much mucin and moderate to strong immunoreactivities to cytokeratins CAM5.2 and AE1 and 3 as well as to CA 19-9, CEA, EMA and DU-PAN-2. These differences in epithelial mucus and antigenic expression among several types of hepatic cysts may reflect differences in their origin and biological characteristics. These differences may be helpful in the differential diagnosis of hepatic cysts in small biopsy specimens.

Antigens↗
PubMed1991

Double-step and inverse polymerase chain reaction for sensitive detection and cloning of T cell receptor variable region sequences.

We have developed a sensitive and rapid method for detection and cloning of cDNA amplified by double-step and inverse polymerase chain reaction (PCR) techniques. The blunt-ended double-strand cDNA libraries were circularized with T4 ligase and subsequently amplified by double-step PCR with two sets of primers of outward orientation (at amounts of 1-10 pmol in the first step and 100 pmol in the second step) which hybridize with the known region of the target DNA. This method is useful for analysis of the repertoires of TCR or immunoglobulins, in particular TCR alpha-chains, which are encoded by a single known constant region gene and greater than 100 unknown variable and joining region gene segments. By using this method, we detected at least 10(4) copies of TCR alpha-chain transcripts in the original samples which are equivalent to 10(3) T cells. The use of 1-10 ng of cytoplasmic RNA allowed us to make approximately 10(3) independent TCR alpha-chain libraries and to determine the sequence of unknown TCR alpha-chain cDNA by this method. We also show the frequency of a TCR alpha-chain usage in naive spleen and tumor-infiltrating lymphocytes.

Animals↗
PubMed1991

Identification of a new variant CYP2D6 allele lacking the codon encoding Lys-281: possible association with the poor metabolizer phenotype.

A variant CYP2D6(C) P450 protein was found in a liver characterized by deficient microsomal metabolism of bufuralol and sparteine, prototypical substrates for the debrisoquine-sparteine drug oxidation polymorphism. This protein was present at decreased levels in liver and had a slightly different relative mobility on SDS-polyacrylamide gels. The cDNA cloning and sequencing of the variant, designated CYP2D6(C), revealed that its mRNA lacked a single codon resulting in deletion of Lys281. This was the result of a three base pair deletion at the 3' end of CYP2D6 exon 5. The CYP2D6(C) P450, produced in HepG2 cells using vaccinia virus mediated cDNA expression displayed Km values toward bufuralol, debrisoquine and sparteine that were not significantly different from wild type CYP2D6. These data suggest that the poor metabolizer phenotype in livers expressing CYP2D6(C) is not due to a catalytically defective enzyme but perhaps due to decreased levels of the P450 protein in microsomal membranes. Low microsomal CYP2D6(C) contents could result from deficient membrane insertion or decreased stability of the P450 protein. A polymerase chain reaction-based procedure, developed to detect CYP2D6(C) alleles, indicates that this variant probably represents less than 1.5% of all CYP2D6 alleles.

Alleles↗
PubMed1991

Oxidation of reduced haloperidol to haloperidol: involvement of human P450IID6 (sparteine/debrisoquine monooxygenase).

1. The conversion of haloperidol (HAL) to reduced haloperidol (RHAL) and then back to HAL has been established in vivo and observed in psychiatric patients. The reduction of HAL to RHAL is known to be catalysed by a ketone reductase, while the nature of oxidation back to HAL is the subject of the present study. 2. We examined the in vitro oxidation of RHAL to HAL in human livers. The activity was microsomal and evidence is presented to suggest that the sparteine/debrisoquine metabolizing isoenzyme P450IID6 contributes to this oxidation. 3. Reciprocal inhibition studies between RHAL and sparteine, a specific substrate for cytochrome P450IID6, indicated that both compounds compete for the same binding site. Quinidine, the most specific inhibitor for this cytochrome P450 potently inhibited the oxidative conversion of reduced haloperidol to haloperidol. A significant correlation (rs = 0.62, P less than 0.01) was found between RHAL oxidation and sparteine oxidation in a study involving 17 human liver samples.

Cytochrome P-450 CYP2D6↗
PubMed1991

Detection of minimal residual myeloma cells by dual parameter analysis of DNA and cytoplasmic immunoglobulin.

We demonstrated the utility of dual parameter analysis of DNA and cytoplasmic immunoglobulin for the detection of minimal residual myeloma cells in bone marrow and peripheral blood. This method is sensitive: even 0.1% of contaminating myeloma cells could be detected in peripheral blood of myeloma patients and in the model experiments using cell lines. This method is useful for the selection of patients undergoing high-dose chemotherapy and autologous blood stem cell transplantation.

Bone Marrow↗
PubMed1991

Conversion of bromperidol to reduced bromperidol in human liver.

Bromperidol (BRP) is an analog of haloperidol, a potent butyrophenone neuroleptic. Reductive conversion of BRP carbonyl group to reduced bromperidol (RBRP) was confirmed in vitro using human liver. This NADPH-dependent reduction of BRP showed a similar inhibition pattern and Michaelis constants to haloperidol carbonyl reductase.

Alcohol Oxidoreductases↗
PubMed1991

Clonal analysis of transient myeloproliferative disorder in Down's syndrome.

Three Down's syndrome patients with transient myeloproliferative disorder were studied for clonality of the proliferating blast cells using the X chromosome-linked polymorphic gene phosphoglycerate kinase, immunoglobulin heavy chain (IgH) gene and T-cell antigen receptor (TCR) (beta, gamma, delta) genes. None of the three cases showed rearrangements of IgH, TCR beta, gamma, or delta genes, indicating the non-lymphoid nature of the proliferating blast cells. The X chromosome inactivation pattern showed that the cells in the blast population in all of the three cases of transient myeloproliferative disorder were clonal. These data suggest that at least some of this disorder can be due to a spontaneously regressing clone of malignant cells.

Adolescent↗
PubMed1991

Neuronal cytochrome P450IID1 (debrisoquine/sparteine-type): potent inhibition of activity by (-)-cocaine and nucleotide sequence identity to human hepatic P450 gene CYP2D6.

Catalytic, pharmacological, and molecular criteria have been used to identify cytochrome P450IID1 in mammalian brain (enzyme, P450IID; gene, CYP2D). Sparteine metabolism in canine striatal membranes was shown to be inhibited in a concentration-dependent and stereoselective manner by quinidine (Ki, approximately 51 nM), quinine (Ki, approximately 5.9 microM), and various other known substrates and inhibitors of hepatic P450IID1 activity. In addition, canine striatal P450IID1 was inhibited with high affinity by dopamine uptake blockers, such as (-)-cocaine (Ki, approximately 74 nM), d-amphetamine (Ki, approximately 4.5 microM), and methylphenidate (Ki, approximately 15 microM). Inhibitory constants (Ki) of numerous compounds for inhibition of sparteine metabolism in canine striatal membranes correlated well with (a) Ki values observed in human liver microsomes (r = 0.95), (b) [3H]GBR-12935 binding to P450IID1 in canine striatal membranes (r = 0.85), and (c) the inhibition (IC50) of sparteine metabolism in HepG2 cells expressing human CYP2D6 cDNA (r = 0.93). Moreover, antibodies raised against rat hepatic enzyme inhibited, in a concentration-dependent manner, sparteine metabolism in canine striatal membranes. Enzymatic activity was unevenly distributed throughout the canine brain and ranged from 0.5 to 21 pmol/mg of protein/hr in cerebellum and supraorbital cortex, respectively, with the striatum displaying moderate levels of activity (8 pmol/mg of protein/hr). The polymerase chain reaction was used to amplify cDNA from a human caudate lambda gt11 library encoding exons 6-9 of the human CYP2D6 gene, which revealed, upon sequencing, 100% nucleic acid sequence identity. These data indicate that P450IID1 is expressed centrally and is similar, at the functional and molecular levels, to the human hepatic P450IID1 enzyme. Because the debrisoquine/sparteine mono-oxygenase is a polymorphic enzyme, in which 5-10% of caucasians are deficient in metabolism of various drugs, a genetic difference in human brain metabolism of P450IID1 substrates may possibly lead to differences in drug response and toxicity.

Animals↗
PubMed1991

[Chronic lymphocytic leukemia with bilateral exophthalmos and visual disturbance].

A 61-year-old male was admitted to our hospital because of progressive bilateral exophthalmos and visual disturbance. He was diagnosed as chronic lymphocytic leukemia (CLL) with stage I of Rai system. Ophthalmologic examinations suggested that CLL cells might have invaded diffusely to bilateral orbits. Radiation to orbital lesions might result in other ophthalmologic complications such as cataract, therefore we tried to treat him with chemotherapy alone. As a result, combination chemotherapy consisting of vincristine, cyclophosphamide, prednisolone and doxorubicin (VEPA) and additional daily oral administration of cyclophosphamide were effective enough for his ophthalmologic recovery.

Exophthalmos↗
PubMed1991

Philadelphia chromosome positive precursor B-cell acute lymphoblastic leukemia with a translocation t(2;14)(p13;q32).

A female patient with precursor B-cell acute lymphoblastic leukemia (precursor B-ALL) was analyzed cytogenetically. Karyotyping of the leukemic cells showed a Philadelphia chromosome (Ph1), and also showed a translocation between 2p13 and 14q32, which is thought to be specific for children with B-cell chronic lymphocytic leukemia. DNA analysis with both conventional and pulsed-field gel electrophoresis revealed the rearrangement of the c-abl gene, the BCR gene outside the 5.8 kb breakpoint cluster region (bcr or M-BCR), and the comigration of an abnormal Not I pHabl 5' and 3'-bcr fragment, indicating the presence of BCR/c-abl recombination. The JH gene was rearranged, but the JK gene showed a germline configuration, as with previously reported cases with a t(2;14). This case is the first report of a patient with Ph1-positive precursor B-ALL, in whom a specific translocation t(2;14)(p13;q32) is found simultaneously.

Adult↗
PubMed1991

[Differentiation of intestinal candidial colonization from invasive candidiasis by measuring serum level of D-arabinitol in combination with oral administration of low dose amphotericin B].

The measurement of D-arabinitol in serum has been reported to be useful for the diagnosis of invasive candidiasis. However, excessive proliferation of Candida species in intestinal tract often leads false positive result of serum D-arabinitol. Based on the evidence that amphotericin B (AMPH) is scarcely absorbed from intestinal tract and inhibits the proliferation of Candida species only in intestinal tract, we have developed a simple differentiation method of intestinal candida colonization from invasive candidiasis by measuring serum level of D-arabinitol in combination with oral administration of low dose AMPH. AMPH, 600 mg/day for 2 days was orally administered to five patients with hematological malignancies who showed more than 1.7 mumol/mg of D-arabinitol/creatinine ratio (D/C ratio) in serum without any evidence of invasive candidiasis. D/C ratios were markedly decreased and normalized after the oral administration of low dose AMPH. While, in a patient with invasive candidiasis in whom Candida species was detected by blood cultures, D/C ratio remained unchanged in spite of oral administration of AMPH. These observations suggest that this method is a simple and reliable diagnostic method to distinguish intestinal candida colonization from true invasive candidiasis.

Administration, Oral↗
PubMed1991

[The efficacy of VAD chemotherapy for refractory lymphoid malignancies].

Thirty patients with refractory lymphoid malignancies [multiple myeloma (MM): 8, plasma cell leukemia (PCL): 2, acute lymphocytic leukemia (ALL): 5, chronic myelogenous leukemia in blast crisis: 1, chronic lymphocytic leukemia in blast crisis: 1, adult T-cell leukemia: 1, non-Hodgkin lymphoma (NHL): 9, Hodgkin's disease (HD): 3] were treated with VAD regimen (vincristine, doxorubicin, dexamethasone). Of 28 evaluable patients, 4 patients achieved complete response or remission [MM1, ALL1, NHL1, HD1], 10 attained partial response or remission [MM5, PCL1, NHL3, HD1], and 2 patients with MM attained minor response. The remission duration ranged from 1 month to over 14 months. The response rate was high in patients with MM (75%) and lymphoma (60%), however 4 patients with T-cell malignancies achieved no response except one with NHL. In three patients who showed resistance to VAD, diltiazem was administered in addition to VAD and one patient with MM had response. Atrio-ventricular block was also observed in one patient during the period of diltiazem administration. Nine patients developed documented infections, 5 of which suffered from candida infections. From these observations, we concluded that VAD regimen might be useful as a salvage therapy especially in patients with MM and lymphoma.

Adult↗