Biomedical subjects

I Komiya

Publications and source records attributed to I Komiya.

At least 73 records · Page 4Linked to original sources

PubMed1991

Streptozocin- and alloxan-induced H2O2 generation and DNA fragmentation in pancreatic islets. H2O2 as mediator for DNA fragmentation.

Streptozocin (STZ) and alloxan (ALX) exhibit the most potent diabetogenicity and are used for induction of experimental diabetes mellitus. An understanding of the mechanisms of action of the typical diabetogenic agents is important for elucidating the causes of diabetes. Okamoto proposed a model in which DNA fragmentation plays an important role in the development of diabetes. DNA fragmentation supposedly results from the accumulation of superoxide or hydroxyl radicals. However, direct evidence for this accumulation is lacking. With isolated rat pancreatic islets in vitro, we demonstrated that STZ and ALX stimulated H2O2 generation and caused DNA fragmentation. Addition of STZ or ALX resulted in an increase in H2O2 generation. On DNA analysis, when incubated without STZ or ALX, DNA sedimented as a single peak; when incubated with STZ or ALX, DNA sedimented slower as a broad peak and was fragmented. Graded doses of STZ and ALX stimulated H2O2 generation and induced DNA fragmentation; their effects on H2O2 generation and DNA fragmentation were evident at a concentration of 0.1 mM and were maximal at 1 mM. Administration of STX or ALX to rats in vivo stimulated H2O2 generation and caused DNA fragmentation in pancreatic islets. H2O2 itself also induced DNA fragmentation. These findings may support Okamoto's proposal that STZ and ALX induce diabetes through the following biochemical events: STZ and ALX----H2O2 generation----DNA fragmentation----beta-cell destruction. This study may constitute the first demonstration of STZ- and ALX-stimulated H2O2 generation, which probably acts as a mediator of STZ- and ALX-induced DNA fragmentation.

Alloxan↗

PubMed1991

In vitro and in vivo antibacterial activities of ME1220 and ME1221, novel cephalosporins.

The antibacterial activities and serum pharmacokinetic properties of ME1220 and ME1221, new aminothiazolylalkoxyiminoacetylcephalosporins having an N-alkylpyridiniumthiomethyl side chain at C-3, were compared with those of cefpirome and ceftazidime. ME1220 and ME1221 exhibited broad antibacterial activity against Gram-positive and Gram-negative bacteria. The in vitro and in vivo activities of ME1220 were similar to cefpirome, while ME1221 was superior to ceftazidime against almost all test organisms except pseudomonas. On intravenous injection in rats, ME1220 and ME1221 were excreted mainly in the urine. ME1221 was excreted moderately in the bile and showed higher serum concentration and AUC than those of ME1220.

Animals↗

PubMed1990

Test for recovery from hypothyroidism during thyroxine therapy in Hashimoto's thyroiditis.

Hypothyroid patients with Hashimoto's thyroiditis usually receive lifelong thyroxine therapy. Some are known to recover thyroid function, but identification of these patients during continued thyroxine therapy has been impossible. 92 patients with hypothyroidism after Hashimoto's thyroiditis and 70 normal controls were studied. All controls but not patient before thyroxine was started had a normal thyroid response to thyroid stimulating hormone (TSH), circulating concentrations of which were increased by administration of 500 micrograms thyrotropin releasing hormone (TRH). During treatment with thyroxine, 22 patients recovered thyroid responsiveness to TSH, and when treatment was stopped these patients have remained euthyroid for 1-8 years, whereas all 70 who did not recover thyroid TSH responsiveness became hypothyroid within 3 months. Over 20% of patients with hypothyroidism after Hashimoto's thyroiditis may recover satisfactory thyroid function, and can be identified during thyroxine treatment by their thyroid response to TSH in a TRH test.

Adolescent↗

PubMed1990

Exacerbation of autoimmune thyroid dysfunction after unilateral adrenalectomy in patients with Cushing's syndrome due to an adrenocortical adenoma.

Little is known about the factors that cause exacerbations of autoimmune thyroid dysfunction. One possibility is an alteration in adrenocortical function, since glucocorticoids are known to alter both pituitary-thyroid and immunologic function. We encountered three patients in whom overt autoimmune thyroid disease developed after unilateral adrenalectomy for Cushing's syndrome due to an adrenocortical adenoma. We compared the postoperative changes in thyroid function in these patients with those in 21 other patients with Cushing's syndrome who underwent the same treatment. After unilateral adrenalectomy, one of the three patients had transient hyperthyroidism and a low thyroid uptake of 131I, indicative of silent thyroiditis. After the same surgical procedure, the second patient had hypothyroidism, where-as the third patient had transient hyperthyroidism at first, and hypothyroidism then gradually developed. All three patients had serum antithyroid antibodies, the titers of which increased after surgery. In the remaining 21 patients (only 2 of whom had antithyroid antibodies initially), the serum concentrations of thyroxine, triiodothyronine, and thyroxine-binding globulin and the secretion of thyroid-stimulating hormone increased after surgery from values that were low or near the lower limit of normal to values still well within the normal range. None of these patients had clinically evident thyroid disease or increased antithyroid-antibody titers. We conclude that reductions in the secretion of glucocorticoid may exacerbate subclinical autoimmune thyroid disease. Patients with Cushing's syndrome due to adrenocortical adenoma who have thyroid antibodies should be followed closely after treatment, because thyroid dysfunction may develop.

Adenoma↗

PubMed1990

Compensatory capabilities of islets of BB/Wor rats exposed to sustained hyperglycemia.

To determine if discordance for autoimmune diabetes in genetically homogeneous animals might reflect differences in the compensatory capacity of their beta cells, the glycemic responses of diabetes-prone BB/Wor rats during a high rate infusion of 50% glucose were compared with normal and with 40% pancreatectomized Wistar rats similarly infused. In all three groups, the initially severe hyperglycemia declined after the first 48 hours to below the target level of 300 mg/dL despite an increasing rate of glucose infusion. The glycemic profile did not differ from controls and was lower than that of the partially depancreatized rats. Five of 20 hyperglycemic BB/Wor rats became diabetic during the 12-day infusion of 50% glucose; there was no difference between their glucose profiles and those of the 15 prediabetic BB/Wor rats that remained nondiabetic throughout the period of hyperglycemic infusion. The latter group of BB/Wor rats, many of which would ultimately have become diabetic, exhibited a 2.4-fold increase in the volume density of their beta cells, compared with a 2.1-fold increase in the Wistar controls. This clinical and morphologic evidence of beta-cell compensation in diabetes-prone rats, even in on the verge of overt diabetes, excludes the possibility that subnormal compensation by beta cells contributes to diabetes in the BB/Wor rat.

Adaptation, Physiological↗

PubMed1990

Graves' disease following hypothyroidism due to Hashimoto's disease: studies of eight cases.

Hashimoto's and Graves' diseases represent the main two types of autoimmune thyroid disease. The combination of these two is well known. However, occurrence of Graves' disease after primary hypothyroidism is rare. We report seven patients with hypothyroidism due to Hashimoto's disease, who developed Graves' disease with hyperthyroidism. We also report one patient with hypothyroidism due to Hashimoto's disease, who continued to be hypothyroid even in the presence of TSAb (thyroid stimulating antibody). These patients were divided into three groups according to the changes in thyroid function and clinical course: (1) transient hyperthyroidism due to Graves' disease following hypothyroidism; (2) persistent hyperthyroidism due to Graves' disease following hypothyroidism; and (3) persistent hypothyroidism with positive TSAb. Such changes in thyroid function and clinical course seem to be decided by three factors: (1) TSAb and (2) TSBAb (thyroid stimulation blocking antibody) activities in the blood and (3) the responsiveness of the thyroid gland to TSAb. Seven patients had hyperthyroidism, when they had TSAb, which stimulated the thyroid gland; one of these seven patients had TSBAb during the hypothyroid state and TSAb during the hyperthyroid state, indicating that the alterations in the thyroid state related to the balance between the activities of TSAB and TSBAb. Another patient continued to be hypothyroid despite the presence of TSAb; his thyroid gland was not palpable and could not respond to TSAb.

Adult↗

PubMed1990

Stimulation of porcine thyroid cell alkalinization and growth by EGF, phorbol ester, and diacylglycerol.

We studied the effects of epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate (TPA), and 1-oleoyl-2-acetyl-glycerol (OAG) on cytoplasmic pH (pHi) and cell growth in cultured porcine thyroid cells. pHi was measured using 2',7'-bis(2-carboxyethyl-5,6-carboxyfluorescein (BCECF), an internalized fluorescent pH indicator. EGF, TPA, and OAG alkalinized the thyroid cells and stimulated their growth. These EGF-, TPA-, and OAG-stimulated cell alkalinization and growth depended on extracellular Na concentrations and were inhibited by amiloride, an inhibitor of Na(+)-H+ exchanger, indicating that EGF-, TPA-, and OAG-stimulated cell alkalinization and growth may occur through activation of Na(+)-H+ exchange. Alkalinization seems to be involved in thyroid cell growth. TPA (a tumor-promoting phorbol ester) and OAG (synthetic diacylglycerol), both potent activators of protein kinase C, imitate the action of EGF in rapidly elevating pHi and stimulating cell growth in thyroid cells. Trifluoperazine, an inhibitor of protein kinase C, inhibited EGF-, TPA-, and OAG-stimulated cell alkalinization and growth. The data suggest that activation of protein kinase C may be involved in the mechanism of EGF-stimulated cell alkalinization and growth of the thyroid cells.

Amiloride↗

PubMed1990

Reduced beta-cell glucose transporter in new onset diabetic BB rats.

Previous studies from our laboratories have suggested a defect in glucose transport in islets isolated from BB rats on the first day of overt diabetes. To quantitate by immunostaining the glucose transporter of beta-cells (GLUT-2) before and at the onset of autoimmune diabetes we employed an antibody to its COOH-terminal octapeptide. On the first day of overt diabetes, defined as the day the daily blood glucose first reached 200 mg/dl, the volume density ratio of GLUT-2-positive to insulin-positive beta-cells was only 0.48 +/- 0.06, compared to 0.91 +/- 0.02 in age-matched nondiabetic diabetes-resistant controls (P less than 0.001). In age-matched nondiabetic diabetes-prone rats, most of which would have become diabetic, the ratio was 0.85 +/- 0.02, also less than the controls (P less than 0.05). Protein A-gold labeling of GLUT-2 in beta-cells of day 1 diabetic rats revealed 2.17 +/- 0.16 gold particles per micrometer length of microvillar plasma membranes compared to 3.91 +/- 0.14 in controls (P less than 0.001) and 2.87 +/- 0.24 in the nondiabetic diabetes-prone rats (P less than 0.02). Reduction in GLUT-2 correlates temporally with and may contribute to the loss of glucose-stimulated insulin secretion that precedes profound beta-cell depletion of autoimmune diabetes.

Animals↗

PubMed1990

Cytoplasmic pH in the action of insulin-like growth factor-I in cultured porcine thyroid cells.

The effects of insulin-like growth factor-I (IGF-I) on cytoplasmic pH (pHi) and [3H]thymidine incorporation were studied in primary cultures of porcine thyroid cells. IGF-I alkalinized thyroid cells and stimulated thymidine incorporation in a dose-dependent manner; the effects of IGF-I on alkalinization (the maximal rates of change of cytoplasmic pHi/min ((dpHi/dt)max)) and thymidine incorporation were observed at 2 ng/ml and were maximal at 100 ng/ml, with half-maximal stimulation at approximately 10 ng/ml. The results indicate that Na+/H+ exchange or cell alkalinization may function as a transmembrane signal transducer in the action of IGF-I on thyroid cell proliferation. Several mitogens and comitogens which activate sodium hydrogen exchange, including epidermal growth factor, platelet-derived growth factor and nerve growth factor, have been listed. Activation with IGF-I has not, however, been presented before. Thus the present study constitutes the first demonstration of IGF-I-stimulated activation of Na+/H+ exchange or cell alkalinization.

Amiloride↗

PubMed1990

Synthesis and biological activity of (cyclopentenopyridinium) thiomethylcephalosporins.

Substituted (cyclopentenopyridinium)thiomethyl groups were introduced as C-3 substituents of (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-oxyimino]acetami docephalosporins. Structure-activity relationships of this class of cephalosporins are discussed on the basis of their MIC. The selected compounds, 3a and 4a (ME1221), having an acidic substituent, showed excellent in vivo efficacy and low toxicity.

Animals↗

PubMed1990

[Diverse hemostatic abnormalities in a patient with biclonal multiple myeloma].

A 58-year-old female was referred to us because of M-proteinemia and anemia. Bone marrow showed normal cellularity with 14.8% of atypical plasma cells. Serum electrophoresis on cellulose acetate membrane revealed a single M-peak (56.9%). Immunoelectrophoresis showed large M-bows against anti-IgA and anti-lambda, together with small M-bows against anti-IgG and anti-kappa of the same electrophoretic mobility. In the urine, lambda type Bence Jones protein was found. The skull X-ray showed multiple punched out lesions. APTT was 61 seconds, fibrinogen 118 mg/dl, factor VIII clotting activity 25% with normal factor VIII related antigen, and factor IX clotting activity 38%. Circulating anticoagulants were not detected. These hemostatic abnormalities were thought ascribable to the interference of clotting activities by paraproteins. On the 33rd hospital day, she suffered from intracerebral hemorrhage, which was possibly due to these hemostatic abnormalities.

Blood Coagulation Disorders↗

PubMed1990

Novel type of ornithine-glutathione double conjugate excreted as a major metabolite into the bile of rats administered clebopride.

Rats orally given radioactive Clebopride [[14C]CP; N-(1'-benzyl-4'-piperidyl)-2-[14C]methoxy-4-amino-5-chlorobenzamide++ +], an antiulcer agent, excreted a novel type of ornithine (Orn)-GSH double conjugate in the bile as a major metabolite [( 14C]BMCP), corresponding to 18% of the dose. The present study provides the first evidence for Orn conjugation of a xenobiotic in mammals and demonstrates that the structure of the radioactive conjugate differs fundamentally from those known in birds and reptiles. The structure of the biliary metabolite, [14C]BMCP, purified to homogeneity by silica gel thin layer and reverse phase high pressure liquid chromatography, was elucidated as S-[2-ornithylamino-4-[14C]methoxy-5-(1'-methyl-4'-piperidylamin o) carboxyphenyl]glutathione, based mainly on the following facts: 1) BMCP showed a protonated molecular ion (M + H)+ peak at m/z 683 in the secondary ion mass spectrum and 2) [14C]BMCP afforded Orn, glutamic acid, glycine, S-(2-amino-4-[14C]methoxy-5-carboxyphenyl)cysteine [( 14C]AMCC), and 1-methyl-4-aminopiperidine (MAP) quantitatively, in an equal molar ratio, by complete hydrolysis with peptidase. Thus, BMCP was a metabolite with three enzymatically hydrolyzable amide bonds in addition to the one existing originally in the parent structure of the drug, which produces MAP by peptic digestion. Of the three additional amide bonds of BMCP, one was a novel type of bond formed by condensation of the alpha-carboxylic acid group of Orn with the primary aromatic amino group of the drug and the other two were in the S-glutathionyl residue, substituted for the chlorine atom vicinal to the Orn-conjugating primary amino group in the aromatic ring and affording glutamic acid, glycine, and the S-cysteine conjugate AMCC by hydrolysis of BMCP with the peptidase. Substitution of a methyl group for the benzyl group at the piperidine ring nitrogen atom, leading to the formation of MAP by peptic digestion, also occurred during metabolism of CP to BMCP.

Animals↗

PubMed1990

[Giant abdominal myeloblastoma preceding overt acute myelogenous leukemia].

A 34-year-old man noted an abdominal mass in February 1986. Peripheral blood was normal, but barium enema disclosed a Borrmann 1 type tumor of the ascending colon. In April, his abdominal mass was increased up to 15 x 20 cm in size. He was admitted to our hospital. Peripheral blood and bone marrow showed overt leukemic picture (acute myelogenous leukemia). Colonic fiberscopy and biopsy as well as abdominal CT scan were done, and the abdominal mass proved to be a myeloblastoma. He received chemotherapy and 60Co irradiation. He was induced to complete remission, kept it for 11 months, and relapsed. After relapse, leukemic state became refractory. But leukemic cells did not form any mass. He died of pulmonary aspergillosis in November 1987. Autopsy showed hypocellular leukemic bone marrow, but we could detect no myeloblastoma.

Adult↗

PubMed1989

Insulin-like growth factor I stimulates inositol phosphate accumulation, a rise in cytoplasmic free calcium, and proliferation in cultured porcine thyroid cells.

Insulin-like growth factor (IGF-I) stimulates thyroid cell proliferation. Using primary cultured porcine thyroid cells, we studied the intracellular pathways that mediate the action of IGF-I on thyroid cell proliferation. IGF-I stimulates inositol phosphate accumulation, a rise in cytoplasmic free calcium [( Ca2+]i), and cell proliferation. Exposure to IGF-I results in a time- and dose-dependent accumulation of inositol monophosphate, inositol bisphosphate, and inositol trisphosphate. IGF-I also increases [Ca2+]i, measured using fura-2, a fluorescent Ca2+ indicator; the IGF-I-induced [Ca2+]i response occurs immediately, reaches a maximum within 1 min, and then slowly declines. IGF-I stimulates thyroid cell proliferation, stimulates thymidine incorporation, and increases cell numbers. The IGF-I-induced inositol phosphate accumulation and [Ca2+]i response parallel thyroid cell proliferation in a dose-dependent manner; the maximal response is observed at a concentration of 100 ng/ml IGF-I, with half-maximal stimulation at approximately 10 ng/ml. Inositol phosphate accumulation and [Ca2+]i response after IGF-I stimulation may function as intracellular messengers for thyroid cell proliferation. This report may constitute the first demonstration of IGF-I-stimulated inositol phosphate accumulation and [Ca2+]i response in the cells.

Animals↗

PubMed1989

Cytoplasmic pH in cultured porcine thyroid cells: alkalinization by epidermal growth factor.

We studied the effects of epidermal growth factor (EGF), thyroid-stimulating hormone (TSH) and amiloride on cytoplasmic pH (pHi) in cultured porcine thyroid cells. We used 2',7'-bis(2-carboxyethyl)-5- (and 6-)carboxyfluorescein (BCECF), an internalized fluorescent pH indicator, to measure pHi. EGF stimulated thyroid cell alkalinization and proliferation, which were blocked by amiloride. EGF-stimulated thyroid cell alkalinization depended on extracellular Na+ concentrations. EGF stimulation resulted in an activation of Na+/H+ exchange, which alkalinized the cells. The results indicated that Na+/H+ exchange or cell alkalinization might function as a transmembrane signal transducer in the action of EGF. In the present system, TSH did not stimulate alkalinization or proliferation.

Amiloride↗

PubMed1989

Molecular and cellular responses of islets during perturbations of glucose homeostasis determined by in situ hybridization histochemistry.

We have evaluated in situ hybridization histochemistry as a means of estimating simultaneously the level of prohormone mRNA and the dimensions of rat pancreatic islets. Localization of the 27-mer 32P-labeled oligonucleotide probes for rat proinsulin I, glucagon, and prosomatostatin I corresponded with localization of antibodies to the three hormones. In normal rats subjected to chronic hyperglycemic clamping, the density of the proinsulin mRNA signal increased 54%, islet size and number increased approximately 100%, while proglucagon mRNA signal was reduced 81%. Resection of 50% of the pancreas increased proinsulin mRNA 36% and proglucagon mRNA 500%; islet area doubled and islet number increased 50%. In 150-day-old diabetic ob/ob mice, there was an 18-fold expansion in islet area, a 4-fold increase in islet number, but no increase in insulin gene expression. In insulin-dependent streptozotocin-treated diabetic rats, islet area and number were profoundly reduced; insulin deprivation failed to raise proinsulin mRNA in surviving beta cells above control levels. Proglucagon mRNA was high despite the hyperglycemia but was reduced by insulin within 1 hr, suggesting that insulin regulates glucagon gene expression or is required for its regulation by glucose. In situ hybridization of rat islets provides a valid semiquantitative index of insulin and glucagon biosynthesis and of islet dimensions and reveals that normal but not diabetic islets meet increased insulin demand by increasing both number and biosynthetic activity of beta cells.

Animals↗

PubMed1989

Effects of hypoglycemia and prolonged fasting on insulin and glucagon gene expression. Studies with in situ hybridization.

In situ hybridization of proinsulin and proglucagon mRNA was performed in rat pancreas to assess prohormone gene expression during various glucopenic conditions. During a 4-d fast mean blood glucose declined by 48 mg/dl; proinsulin mRNA signal density remained normal while proglucagon mRNA signal density more than doubled. At the end of a continuous 12-d insulin infusion blood glucose averaged 53 +/- 12 mg/dl; proinsulin mRNA signal density declined to 30% of controls while proglucagon mRNA signal density more than doubled. In insulinoma-bearing NEDH rats blood glucose averaged 34 +/- 3.5 mg/dl; the proinsulin mRNA signal was virtually undetectable and proglucagon mRNA signal density was more than twice the controls. There was no detectable change in either beta-cell area or islet number in rats subjected to fasting or insulin infusion, but in insulinoma-bearing rats beta cell area was markedly reduced. Thus compensation during 4 d of starvation involves an increase in glucagon gene expression without change in insulin gene expression or beta cell mass. In moderate insulin-induced hypoglycemia glucagon gene expression is increased and insulin gene expression decreased. In more profound insulinoma-induced hypoglycemia, in addition to the foregoing changes in hormone gene expression, there is a profound reduction in the number of insulin-expressing cells.

Animals↗

PubMed1989

Cytoplasmic pH in cultured porcine thyroid cells: alkalinization by Ca2+.

The role of calcium in cytoplasmic pH (pHi) changes was studied using 2',7'-bis(2-carboxyethyl)-5-(and 6-)carboxyfluorescein, an internalized fluorescent pH indicator, in cultured porcine thyroid cells. The Ca2+ ionophores A23187 and ionomycin stimulated thyroid cell alkalinization. An increase in cytoplasmic free calcium resulted in activation of Na+/H+ exchange which alkalinized the cells.

Animals↗