Biomedical subjects

N Takamura

Publications and source records attributed to N Takamura.

At least 55 records · Page 3Linked to original sources

PubMed1998

Compound heterozygous deletion of the PROP-1 gene in children with combined pituitary hormone deficiency.

Mutations in the prophet of Pit-1 gene (PROP1) have been shown to be responsible for combined pituitary hormone deficiency (CPHD) with deficiencies of growth hormone (GH), Prolactin (Prl), thyroid-stimulating hormone (TSH) and gonadotropins. We previously reported that homozygosity for a 2bp deletion in exon 2 (296delGA) accounted for CPHD in three patients from two Russian families. Here we report a second mutational hot spot in exon 2. This 2bp 149delGA deletion results in a frame shift that leads to the same serine to stop codon change at codon 109 (S109X). The predicted proteins are each truncated at residue 108 but diverge from the wild type sequence at different points in the homeodomain. Compound heterozygosity for the two mutations (149delGA/296delGA) was detected in 5 of 14 CPHD children from 4 families (36%). This provides the first evidence of heterozygosity for two common deletions as a cause of CPHD in Russian children.

Adolescent↗

PubMed1998

Effects of fatty acids on serum binding between furosemide and valproic acid.

The effects of fatty acids, including oleate, on the interaction between furosemide and valproic acid in sera at respective serum therapeutic concentration levels were investigated using an ultrafiltration technique. The free fraction of furosemide was significantly increased in the presence of valproic acid. Mutual displacement experiments indicated that furosemide and valproic acid share a common high affinity binding site on human serum albumin (HSA). The serum free fraction of furosemide was increased by the presence of six or more fatty acid molecules per HSA molecule. This fatty acid-induced increase in the unbound fraction of furosemide was further increased by the binding of valproic acid. However, the inhibition of furosemide binding to serum for a fatty acid-valproic acid-furosemide system is nearly the same as the additive effect of fatty acid and valproic acid on the furosemide to serum. Thus, the mechanism for the displacement of HSA-bound furosemide by valproic acid was concluded to be different from that for fatty acid-catalyzed displacement.

Anticonvulsants↗

PubMed1998

A missense mutation of C1659 in the fibroblast growth factor receptor 3 gene in Russian patients with hypochondroplasia.

To carry out the genetic screening for the common mutation in the first tyrosine kinase domain (TK1) of the fibroblast growth factor receptor 3 gene (FGFR3) in a Russian population, a cohort of 16 patients with hypochondroplasia diagnosed previously were studied, among them twelve familial cases and four sporadic cases. The heterozygous N540K FGFR3 mutation was detected in 9 cases (56.3%) due to that C1659A substitution in 6 patients and C1659G substitution in 3 patients, respectively. The ratios of familial and sporadic cases among patients which carried FGFR3 mutation were similar. Seven (43.7%) patients, negative cases of N540K mutation, were all familial cases. Our results support evidence of similar frequency of common type N540K mutation of FGFR3 in Russian hypochondroplasia and of the genetic heterogeneity of hypochondroplasia, suggesting the need for further search for responsible molecular abnormalities for phenotypically similar hypochondroplasia patients negative for TK1 domain mutation in FGFR3, reported in hypochondroplasia.

Adolescent↗

PubMed1997

Novel point mutation in the uroporphyrinogen III synthase gene causes congenital erythropoietic porphyria of a Japanese family.

The molecular basis of the uroporphyrinogen III synthase (UROIIIS) deficiency was investigated in a member of a Japanese family. This defect in heme biosynthesis is responsible for a rare autosomal recessive disease: congenital erythropoietic porphyria (CEP) or Günther's disease. The patient was homozygous for a novel missense mutation: a G to T transition of nucleotide 7 that predicted a valine to phenylalanine substitution at residue 3 (V3F). The parents were heterozygous for the same mutation. The loss of UROIIIS activity was verified by an in vitro assay system. The corresponding mutated protein was expressed in Escherichia coli and no residual activity was observed. Further studies are needed to determine whether the mutations of the UROIIIS gene (UROS) have a specific profile in Japan compared to European or American countries.

Adult↗

PubMed1997

Interactions of aldosterone antagonist diuretics with human serum proteins.

PURPOSE: The purpose of this study was to investigate the binding mechanism of aldosterone antagonist diuretics with human serum proteins, human serum albumin (HSA) and alpha 1-acid glycoprotein (AGP), as well as to identify the binding sites of the drugs on these proteins. METHODS: Binding activities of spironolactone (SP) and its pharmacologically active metabolite canrenone (CR) to serum and serum protein were examined by ultrafiltration and spectroscopic techniques. The data for the binding of these drugs to HSA were analyzed on the basis of a theoretical model of simultaneous binding of the ligands. RESULTS: The binding percentages of antagonist diuretics SP and CR to human serum proteins were 88.0% and 99.2%, respectively, at therapeutic concentrations. SP bound strongly only to HSA. In addition, the displacement results found using fluorescent probes and ultrafiltration methods demonstrated that SP bound to site I, particularly to the warfarin region on HSA, and to the basic binding site on AGP, while CR bound to the warfarin region on HSA. CONCLUSIONS: The limited results presented here stress the need for caution on coadministration of acidic drugs which bind to the warfarin region on HSA and basic drugs which bind to AGP with SP and its metabolite CR.

Blood Proteins↗

PubMed1997

Effects of uremic toxins and fatty acids on serum protein binding of furosemide: possible mechanism of the binding defect in uremia.

To elucidate the mechanism of impaired serum binding of furosemide observed in patients with renal dysfunction, we examined in vitro the serum protein binding of furosemide in the absence and presence of uremic toxins that are endogenously retained solutes in uremic serum and act as inhibitors of drug binding. Analysis of the binding data of furosemide at its therapeutic concentration (6.6 mg/L) indicated that, among the four uremic toxins studied, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) showed the greatest inhibitory potency for the binding of furosemide to serum; moreover, the inhibition was competitive. CMPF thus most likely represents the primary determinant for the serum binding defect of furosemide in uremia. However, CMPF and oleate appear to exert a synergistic effect on the inhibition of furosemide serum binding--perhaps through a cascade effect on furosemide-binding inhibition in the oleate-CMPF-furosemide system, in which the binding of oleate to its low-affinity sites indirectly displaces furosemide from albumin and thus increases the transiently liberated CMPF molecules. Similar cascade effects on furosemide binding in the presence of CMPF were also originated by other long-chain (C18) fatty acids, linoleate and stearate, although to a lesser extent. Because CMPF is not effectively removed by ordinary hemodialysis treatment, the combined direct and cascade effects of CMPF and fatty acids appear to contribute to the increase in the free fraction of furosemide during hemodialysis.

Adult↗

PubMed1996

A novel point mutation in congenital erythropoietic porphyria in two members of Japanese family.

The molecular basis of the uroporphyrinogen III synthase (UROIIIS) deficiency was investigated in two members of a Japanese family. This defect in heme biosynthesis is responsible for a rare autosomal recessive disease: congenital erythropoietic porphyria (CEP) or Gnther's disease. The first patient was homoallelic for a novel missense mutation: a T to C transition of nucleotide 634 that predicted a serine to proline substitution at residue 212 (S212P). The second patient appeared heteroallelic, carrying the same missense mutation and a nonsense mutation: a C to T change at nucleotide 745, resulting in a premature stop at codon 249, instead of a glutamine (Q249X). The corresponding mutated proteins were expressed in Escherichia coli and no residual activity was observed. A family study was also performed to determine the carrier status.

Adult↗

PubMed1996

Mode of interaction of loop diuretics with human serum albumin and characterization of binding site.

PURPOSE: The purpose of this study was to investigate the binding mechanism of loop diuretics with HSA and to characterize the binding site on HSA. METHODS: Quantitative analysis of potential interaction between ligands bound to HSA was performed by equilibrium dialysis and data for binding of the two ligands to HSA were analyzed on the basis of a theoretical model of simultaneous binding of two ligands. RESULTS: The binding of loop diuretics is dependent upon the N-B transition, conformational change of albumin. Furthermore, from the results of binding of the drugs to modified HSA, the lysine residue seems to be involved in the binding of loop diuretics to HSA. CONCLUSIONS: Analysis using models describing independent, competitive, cooperative and anti-cooperative binding led to the conclusion that loop diuretics bind to site I, particularly to the warfarin region on HSA.

Binding Sites↗

PubMed1996

Development of a competitive enzyme-linked immunosorbent assay for diethylcarbamazine.

A sensitive and reproducible competitive enzyme-linked immunosorbent assay (ELISA) for the determination of the concentration of diethylcarbamazine (DEC) in biological fluids was developed. Since DEC has no functional group to conjugate with bovine serum albumin (BSA), N-(2-aminoethyl)-N-ethyl-4-methyl-1-piperazinecarboxamide (DEC-NH2) was first synthesized. This compound was then converted to carboxyl DEC (DEC-COOH) and conjugated to BSA and to poly-L-lysine for use as immunogen and solid-phase marker, respectively. The competitive ELISA was conducted by simultaneously incubating DEC with mouse anti-DEC antiserum over DEC-poly-L-lysine solid phase. Subsequently, the binding of anti-DEC antibody was detected by using sheep anti-mouse IgG peroxidase conjugate as a tracer. The reliability, determined by the coefficient of variation for inter and intra-assay, was satisfactory. The cross-reactivities of anti-DEC antibodies with DEC metabolites, related compounds and ivermectin were negligible. Using this assay, DEC levels were easily determined in serum of Mongolian jirds (Meriones unguiculatus) up to 4 hours following a single dose of DEC citrate base (100 mg/kg of body weight) via intraperitoneal route.

Animals↗

PubMed1996

Ocular complication in congenital erythropoietic porphyria.

Congenital erythropoietic porphyria (CEP), classically known as "Günther disease', is an extremely rare autosomal recessively inherited disorder characterized by mutilating cutaneous photosensitivity and abnormal porphyrin heam biosynthesis in the bone marrow. So far there is no effective therapy for CEP. Because of severe cutaneous photosensitivity, treatment of CEP has mainly been focused upon the avoidance of sunlight and trauma of the skin to minimize skin symptoms. Recently we have encountered ocular complications, especially scleral involvement, in 5 CEP patients. From this point of view, we should pay attention not only to cutaneous symptoms but also to scleral involvement and ophthalmological examination is required to assess the quality of life of CEP patients.

Adult↗

PubMed1995

A single missense mutation in codon 918 of the RET proto-oncogene in sporadic medullary thyroid carcinomas.

The RET proto-oncogene is expressed in human medullary thyroid carcinoma and pheochromocytoma. Recently germline mutations of the RET proto-oncogene were reported in four syndromes (MEN 2A, MEN 2B, familial medullary thyroid carcinoma and Hirschprung's disease) and somatic mutation was also found in sporadic medullary thyroid carcinoma. To determine the incidence of RET mutations in medullary thyroid carcinoma in Japan, we investigated 14 medullary thyroid carcinomas (comprising 1 case of MEN 2A, 1 case of MEN 2B, 2 cases of familial medullary thyroid carcinoma and 10 cases of sporadic). Tumors from all cases were screened by PCR-SSCP on exons 10 and 11. DNA sequencing on these exons was performed for the hereditary medullary thyroid carcinoma cases. The PCR products of exon 16 from tumor DNA were analyzed by means of Fok1 restriction enzyme digestion analysis and mutations confirmed by DNA sequencing. We found no structural abnormalities in either exon 10 or exon 11 in any of the cases examined, but in four of 10 sporadic cases we detected a common point mutation at codon 918 (ATG to ACG) in exon 16, where methionine was replaced with threonine. Our results support the theory that a point mutation of exon 16 of the RET proto-oncogene may be related to the oncogenesis of sporadic medullary thyroid carcinomas. However, further studies on the entire RET proto-oncogene are needed to clarify the relationship between its expression and thyroid tumorigenesis.

Base Sequence↗

PubMed1995

[A male case of primary Sjögren's syndrome with interstitial pneumonitis and interstitial tubulo-nephritis in the absence of dry eye and dry mouth: parotid gland MRI is a useful diagnostic method for Sjögren's syndrome].

Here we report a case of primary Sjögren's syndrome with hilar lymphadenopathy, interstitial pneumonitis and interstitial tubulo-nephritis. A 60-year old man was admitted to our hospital in May 1993 because of general fatigue and fever. He was noted to have hypergammaglobulinemia and had positive antibodies to nuclear antigens since 1990 in the absence of clinical manifestations. Since 9 months before admission, he presented with general fatigue, low grade fever and uveitis. On admission, chest X-ray and CT scan showed bilateral hilar lymphadenopathy and interstitial pneumonitis. The negative results for both serum angiotensin converting enzyme and histological findings of the cervical lymph node and the lung excluded the diagnosis of sarcoidosis. Serological examination exhibited marked elevation of polyclonal IgG level and anti-nuclear antibody, but neither anti-SS-A (Ro) nor anti-SS-B (La) antibody was detected. He did not have symptoms of xerophthalmia and xerostomia. Keratoconjunctivitis sicca was diagnosed by positive Schirmer's and rose bengal tests. His labial gland biopsy demonstrated severe mononuclear cell infiltration around the ducts. MRI findings of the parotid glands revealed heterogeneous and dotted high signal intensity similar to those in fat tissues in the T1- and T2-weighted images. These findings depicted that bilateral parotid gland was extensively destructed and was replaced by lipid tissue. Renal biopsy showed interstitial tubulo-nephritis. On the basis of the above findings, he was diagnosed to have primary Sjögren's syndrome and uveitis. Therefore, MR image of the parotid gland is considered to be a noninvasive and useful method for diagnosis of Sjögren's syndrome.

Humans↗

PubMed1995

[Congenital erythropoietic porphyria].

Congenital erythropoietic porphyria (CEP, Günther's disease) is an extremely rare autosomal recessive disease (There have been only 33 case reports in Japan to date.), characterized by mutilating cutaneous photosensitivity and abnormal haem synthesis in the bone marrow. Reduced activity of uroporphyrinogen III synthase (UROIIIS), the fourth enzyme of haem biosynthetic pathway causes this disease. Recent progresses of molecular biology enable us to analyze genetic defect at the molecular level of porphyrias. Also in CEP, it has been reported several reports of mutations of the UROIIIS gene since isolation of a full-length human cDNA encoding UROIIIS by Desnick et al. Here we report about epidemiology, signs and symptoms, laboratory findings and therapies of CEP.

Female↗

PubMed1994

Interaction of benzothiadiazides with human serum albumin studied by dialysis and spectroscopic methods.

The interaction of a series of benzothiadiazides with human serum albumin (HSA) was investigated by equilibrium dialysis (ED) and spectroscopic methods including circular dichroism (CD). The primary binding site of benzothiadiazides was designated site II, the diazepam site on the HSA molecule, as indicated by displacement experiments using different site-selective probes. Tyrosine and lysine amino acid residues were probably involved in the binding site of these compounds to HSA. Both electrostatic and hydrophobic interactions were found to play a role in the binding of these compounds to HSA. Among the compounds tested, chlorothiazide had the highest affinity (K1 = 5.5 x 10(4) M-1, K2 = 5.8 x 10(3) M-1). The primary binding affinity of the compounds for HSA was of the order: chlorothiazide > cyclopenthiazide > polythiazide > ethiazide > trichlormethiazide = methyclothiazde > hydrochlorothiazide. Binding was insensitive to the N-B transition of HSA. The binding site is proposed to consist of a cationic site on the surface of the HSA molecular with a hydrophobic crevice to accommodate the aromatic ring of the compounds. Positions 3 and 7 of the benzothiadiazide molecule is thought to affect the binding affinity to HSA.

Benzothiadiazines↗

PubMed1993

Effects of simetryne on growth of various freshwater algal taxa.

The sensitivity of 56 algal strains, representing 7 taxonomic groups to the triazine herbicide, simetryne, was examined using EC50 values for growth. There was a wide range of values from 6.5 to 1500 microg litre(-1). The Volvocales (Chlorophyceae, Chlorophyta) and Cyanophyceae (Cyanophyta) as a whole were the most sensitive, whereas the Desmidiales (Charophyceae, Chlorophyta) and Bacillariophyceae (Chromophyta) were the most tolerant, although sensitivity differed among strains of a single species. Sensitive and tolerant species were both isolated from samples collected at the same site. The results suggest that changes in species composition and relative abundance will occur when herbicides are applied in natural habitats.

Journal Article↗

PubMed1990

Effects of 2-phenyl-1,4-benzoquinone and 2,5-dihydroxybiphenyl on two-stage mouse skin carcinogenesis.

Two metabolites of sodium o-phenylphenate (OPP-Na), 2-phenyl-1,4-benzoquinone (PBQ) and 2,5-dihydroxybiphenyl (5-OH), were examined for initiating, promoting or complete carcinogenic activity for skin carcinogenesis in female CD-1 mice. While PBQ treatment (1 mg per mouse, twice a week for 34 weeks) did cause sustained hyperplasia like 12-O-tetradecanoylphorbol 13-acetate (TPA) treatment (2.5 micrograms, twice/week for 34 weeks), it showed weak, but not statistically significant, tumor promoting potential for skin tumor development initiated with 7,12-dimethylbenz[a]anthracene (DMBA, 10 micrograms x 10 in 5 weeks). On the other hand, 5-OH applied at a dose of 10 mg/mouse using a similar protocol did not exert any promoting influence, and neither of these chemicals administered continually for 40 weeks without prior DMBA initiation treatment induced any skin tumors. Furthermore, both chemicals applied 10 times in 5 weeks at higher doses (2 mg for PBQ and 20 mg for 5-OH) in association with subsequent TPA treatment did not initiate any skin tumor development. Thus, neither of the OPP-Na metabolites demonstrated any capacity to influence skin tumor development in any manner, despite the fact that OPP-Na itself was previously found to exert skin tumor promoting potential in the mouse.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1989

[Twenty-eight day repeated dose toxicity testing of diphenylamine in F344 rats].

A twenty-eight day repeated dose toxicity test of diphenylamine (DPA) was carried out in male and female F344 rats at dose levels of 1000, 333, 111 or 0 mg/kg/day. Thirty-six animals of both sexes were divided into 6 groups of equal number, 4 groups being used for the 28 days dosing study and the remainder for investigation of recovery. Inhibition of body weight gain, increase of liver, spleen and kidney weights, and anemia were observed in the highest dose groups in both sexes. The same groups demonstrated mucosal hyperplasia in the forestomach, dilatation, degeneration or necrosis of renal tubules in the corticomedullary junction, and hyperplasia in the bone marrow histopathologically. Slight increase of spleen, liver and kidney weights as well as slight degeneration of renal tubules were evident in several animals receiving the dose level of 333 mg/kg/day. Repair of histopathological lesions and anemia occurred within 14-day resting period. Based on these findings, under the present experimental conditions, the no observable effect level of DPA was 111 mg/kg/day.

Administration, Oral↗

PubMed1988

Promoting effect of peroxisome proliferators in two-stage rat renal tumorigenesis.

A two-stage rat renal tumorigenesis model was employed to examine the promoting effects of peroxisome proliferators in the kidney. Groups of 20 male F344 rats were given 0.05% N-ethyl-N-hydroxyethylnitrosamine (EHEN) orally for the first 2 weeks as the initiator. Subsequently they were treated with clofibrate, simfibrate or di(2-ethylhexyl)phthalate (DEHP), respectively, at dietary concentrations of 0.35%, 0.35% and 1.2% for 24 weeks and killed for microscopical examination of the kidney. The incidences of renal cell tumors (RCT) and the numbers of RCT/kidney in rats given DEHP after initiation were significantly increased as compared to the controls. On the other hand, renal promoting effects were not evident in groups given clofibrate or simfibrate. Under the condition of this study, DEHP was found to act as a renal promoter.

Animals↗