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Biomedical subjects

K Shizume

Publications and source records attributed to K Shizume.

At least 55 records · Page 3Linked to original sources
PubMed1992

Autocrine role of insulin-like growth factor (IGF)-I in a human thyroid cancer cell line.

An established cell line (TC-cell, clone 78) derived from human thyroid papillary cancer cells was investigated for production of peptide growth factors. The cells had specific binding sites for insulin-like growth factor-I (IGF-I) and responded to this growth factor with increased proliferation. Culture medium conditioned by TC cells was found to contain insulin-like growth factor (IGF)-I and IGF-binding protein(s). Furthermore, reverse transcription-polymerase chain reaction revealed expression of IGF-I mRNA. When monoclonal antibody to IGF-I receptors (alpha IR3) was added, the growth of TC cells cultured in serum-free medium was significantly reduced. The growth rate of the cells was restored when the antibody was removed from the medium. These results strongly suggest that TC cells produce IGF-I, which is involved in the regulation of their own growth.

Carcinoma, Papillary↗
PubMed1992

Clinical and basic aspects of an anorexiant, mazindol, as an antiobesity agent in Japan.

The Japanese Mazindol study group investigated the action of an anorexiant, mazindol, and found that it reduced food intake by directly suppressing neurons in the lateral hypothalamus, inhibited gastric acid secretion, increased motor activity, decreased glucose absorption, and inhibited insulin secretion. It thus appears that the main effect of mazindol is to decrease food intake through suppressing feeding centers in the hypothalamus. A multicenter open study of mazindol in Japan revealed that loss of body weight and relative body weight in 14 wk were 4.6 kg and 9.2%, respectively, with suppression of appetite in the majority of obese patients. A multicenter double-blind study demonstrated that mazindol was superior to the placebo in the treatment of simple obesity. We also suggest that mazindol is effective in the maintenance of reduced body weight after obesity therapy and in the treatment of obesity-related diseases such as diabetes, hypertension, or hyperlipidemia.

Animals↗
PubMed1992

Opposite regulation of deoxyribonucleic acid synthesis and iodide uptake in rat thyroid cells by basic fibroblast growth factor: correlation with opposite regulation of c-fos and thyrotropin receptor gene expression.

Basic fibroblast growth factor (bFGF) increases DNA synthesis in rat FRTL-5 thyroid cells, as measured by increased incorporation of tritiated thymidine into DNA. We show that this action is associated with the ability of bFGF to increase cytosolic Ca2+ levels and transiently increase c-fos mRNA levels. Other agents that increase c-fos mRNA levels and DNA synthesis in FRTL-5 cells include TSH, insulin, insulin-like growth factor-I, phorbol esters, A23187, and alpha 1-adrenergic agents; the last two agents also act by increasing cytosolic Ca2+ levels. Despite its enhancement of DNA synthesis, however, bFGF decreases TSH-induced cAMP-mediated iodide uptake. This action appears to reflect two separate actions of bFGF. First, bFGF decreases TSH receptor mRNA levels and the ability of TSH to acutely increase cAMP levels in FRTL-5 cells. The ability of bFGF to negatively regulate TSH receptor mRNA levels is additive to and independent of the ability of TSH and its cAMP signal to negatively autoregulate TSH receptor mRNA levels. This is consistent with the effect of bFGF on cytosolic Ca2+ levels and the ability of increased cytosolic Ca2+ to decrease TSH receptor mRNA levels. Second, bFGF inhibits cAMP signal expression, as evidenced by its ability to inhibit (Bu)2cAMP-induced iodide uptake in FRTL-5 cells. Both effects are, presumably, associated with the ability of bFGF to counteract TSH/cAMP-induced increases in thyroid peroxidase mRNA levels, which we demonstrate. We suggest, therefore, that bFGF causes opposite effects on DNA synthesis and iodide uptake because of its effect on cytosolic Ca2+ levels and because increases in cytosolic Ca2+ can have opposite effects on gene transcription, particularly in the case of the TSH receptor and c-fos genes.

Animals↗
PubMed1992

Comparison of the incidence of association of periodic paralysis and hyperthyroidism in Japan in 1957 and 1991.

Periodic paralysis has been known to be associated with thyrotoxicosis in Japan. The incidence was 8.6% among male and 0.4% among female thyrotoxic patients according to a survey performed in the three major thyroid clinics in Japan in 1957. To determine the changes in the incidence during the intervening 34 years, the same type of survey was carried out again in 1991 at the same three major thyroid clinics previously involved. The incidence of paralysis in 1991 was 4.3% among male and 0.04% among female thyrotoxic patients, indicating more than a 40% decrease in the incidence. The possible cause of the decrease is related to the changes in food consumption, namely, to the fact that less carbohydrate and more potassium were taken in 1991 than in 1957.

Diet↗
PubMed1992

Treatment of 46 patients with Turner's syndrome with recombinant human growth hormone (YM-17798) for three years: a multicentre study.

A total of 46 patients with Turner's syndrome were treated for three years with recombinant hGH. Nineteen patients received hGH at a weekly dosage of 0.5 IU.kg-1.week-1, while 27 received 1.0 IU.kg-1.week-1 by daily sc injection. Both treatment groups showed a statistically significant growth increase during treatment. The increase in height over three years' treatment, as expressed by SD score (SDS) for chronological age, did not differ significantly between patients treated with 0.5 IU and those with 1.0 IU hGH. Seventeen of 22 patients over the age of 14 had exceeded their expected adult height. Plasma IGF-1 levels were elevated and no remarkable advances in bone age were observed during the treatment in either treatment group. There were no other significant changes in physical or laboratory examinations. No glucose intolerance was observed. These results indicate that hGH treatment is useful for accelerating growth velocity in patients with Turner's syndrome. However, further study will be required to find the best treatment dosage.

Adolescent↗
PubMed1992

Urinary excretion of parathyroid hormone-related protein as a predictor of hypercalcemia in patients with adult T-cell leukemia.

Hypercalcemia with adult T-cell leukemia (ATL) is chiefly caused by an excessive production by tumor cells of parathyroid hormone-related protein (PTHrP). We have previously reported hypercalcemic patients with solid tumors to excrete a large amount of the C-terminal fragments of PTHrP (C-PTHrP) into their urine. To elucidate whether PTHrP production correlates with or predicts the development of hypercalcemia, we studied the urinary excretion of C-PTHrP in 36 ATL patients. The urinary excretion of C-PTHrP was in the normal range (< 0.40 nmol equivalent to PTHrP (109-141)/g creatinine) in HTLV-1-positive carriers (n 3), ATL patients in complete remission (n 2) and chronic type ATL patients (n 2). It was marginally increased in seven patients in partial remission, and gradually increased as the disease progressed. In 20 patients who died without or with hypercalcemia, it was increased to 1.98 +/- 0.69 (n 9) and 7.6 +/- 2.1 nmol/g creatinine (mean +/- SD, n 11, P < 0.01), respectively. Urinary C-PTHrP excretion was significantly correlated with serum calcium and LDH levels as well as with CD25-positive cells in the peripheral blood. In four patients whose urinary excretion had been serially determined, it increased prior to the development of hypercalcemia. The findings suggest the urinary excretion of C-PTHrP to be of use as a predictor of the development of hypercalcemia in ATL patients. In ATL patients whose urinary excretion of C-PTHrP is progressively increasing, the serum calcium concentration should be carefully monitored to prevent hypercalcemic crisis.

Adult↗
PubMed1992

Effects of insulin-like growth factor I or human growth hormone in fasted rats.

To study the effect of insulin-like growth factor I (IGF-I) treatment on growth and metabolism in fasted rats and compare it with the effect of human growth hormone (hGH), we infused 120 micrograms/ml IGF-I continuously or injected 200 micrograms hGH twice a day in fasted rats. After a 3 1/2-day administration of IGF-I in fasted rats, the body weights, kidney, spleen and adrenal gland weights were greater than those for untreated fasted rats (control). The body weights and the organ weights in hGH treated rats did not differ from those in control rats. Serum IGF-I levels in control, hGH treated and IGF-I treated rats were 64.0 +/- 6.1, 107.5 +/- 6.9 and 129.8 +/- 6.3 ng/ml, respectively, which were significantly different from each other. Blood urea nitrogen (BUN) levels were 13.9 +/- 1.1 ng/ml in IGF-I treated rats, which were significantly lower than those of control rats. Human GH treatment did not change BUN but affected nonesterified fatty acid (NEFA) and triglyceride. In IGF-I treated rats three-day urinary excretion of nitrogen and creatine were 163.5 +/- 14.6 mg and 9.53 +/- 1.53 mg, which were significantly less than those in control rats. These data indicate that IGF-I infusion inhibits body weight loss and catabolism in fasted rats and might be a useful therapy in catabolic conditions.

Adrenal Glands↗
PubMed1991

[GH-secretion capacity in Turner syndrome and its relations to clinical characteristics and effect of GH treatment--a comparison with pituitary dwarfism. The Committee for hGH treatment in Turner syndrome].

The relations of GH secretion capacity by stimulation tests to clinical characteristics and the effect of GH treatment were studied in 151 girls with Turner syndrome and were compared with those in 128 patients with pituitary dwarfism. GH secretion capacity expressed by mean peak GH was not associated with clinical characteristics related to growth such as height SDS and growth velocity SDS in Turner syndrome and was influenced by % overweight, whereas it was associated with growth-related clinical characteristics in pituitary dwarfism. Because GH secretion capacity does not affect growth in Turner syndrome, it is not reasonable to diagnose low peak GH in stimulation tests as GH deficiency in Turner syndrome. GH treatment increased the growth velocity and growth velocity SD score in Turner syndrome in a dose-dependent manner. In pituitary dwarfism, the effect of GH treatment expressed by the increase in growth velocity SD score had a negative correlation with growth velocity SD score before GH treatment and GH secretion capacity, which indicated that GH treatment was replacement therapy. In Turner syndrome, the effect of GH treatment had a negative correlation with growth velocity and growth velocity SD score before GH treatment, but had no relation to GH secretion capacity, which suggested that GH treatment did not provide replacement GH but had another pharmacological effect.

Adolescent↗
PubMed1991

Urinary excretion of parathyroid hormone-related protein fragments in patients with humoral hypercalcemia of malignancy and hypercalcemic tumor-bearing nude mice.

To investigate whether parathyroid hormone-related protein (PTHrP), a hypercalcemia-inducing factor responsible for malignancy-associated hypercalcemia (MAH), is excreted into urine of these patients, radioimmunoassay was established using antiserum specific for the C-terminal region of PTHrP-(127-141). Immunoreactive PTHrP (iPTHrP) was detected in the urine of all patients with MAH (n = 6) in whom nephrogenous cyclic AMP excretion was elevated. However, iPTHrP was not detected in the urine of normal subjects (n = 25) or hypercalcemic patients with primary hyperparathyroidism (n = 8). In normocalcemic patients with malignant disorders iPTHrP was not detected in the urine in most cases (24 of 25 patients) but was detectable in 1 of 25 patients. iPTHrP was also detected in the urine of hypercalcemic nude mice transplanted with PTHrP-producing tumors, but not in the urine of control and normocalcemic nude mice transplanted with PTHrP-nonproducing tumor. Furthermore, size-exclusion high-performance liquid chromatography revealed that the molecular weight of iPTHrP is about 2000-6000 daltons in the urine of patients as well as tumor-bearing nude mice. These data indicate that the fragments of the C-terminal region of PTHrP are excreted into the urine of patients with MAH and in a few normocalcemic patients with malignancies, suggesting that the measurement of iPTHrP in the urine is potentially useful in the differential diagnosis of hypercalcemia, particularly in differentiating humoral hypercalcemia of malignancy and primary hyperparathyroidism.

Adult↗
PubMed1991

Single sc administration of insulin-like growth factor I (IGF-I) in normal men.

Total and free form of IGF-I in plasma increased in a dose dependent manner after sc IGF-I administration. Peak values of total IGF-I were obtained at 3-4 h after the administration, and then the values decreased gradually. However, peak values of free form of IGF-I were obtained at 2 h, and then rapidly decreased thereafter. The blood glucose, serum insulin and C-peptide levels decreased until 4 h after IGF-I administration in a dose dependent manner. Plasma IGF-II values significantly decreased at 4-12 h after IGF-I administration. Urinary urea nitrogen and sodium excretion decreased after IGF-I administration. Urinary GH excretion also decreased after 0.06 mg/kg IGF-I administration. These data demonstrate that IGF-I may play a role in glucose, protein and electrolyte metabolism, and plasma IGF-II levels and GH secretion might be regulated by IGF-I in man.

Adult↗
PubMed1991

Transforming growth factor (TGF)-alpha in human milk.

Transforming growth factor (TGF)-alpha and epidermal growth factor (EGF) were measured in human milk by means of homologous radioimmunoassay. As previously reported, EGF concentration in the colostrum was approximately 200 ng/ml and decreased to 50 ng/ml by day 7 postpartum. The value of immunoreactive (IR)-TGF-alpha was 2.2-7.2 ng/ml, much lower than that of EGF. In contrast to EGF, the concentration of IR-TGF-alpha was fairly stable during the 7 postpartum days. There was no relationship between the concentrations of IR-TGF-alpha and IR-EGF, suggesting that the regulatory mechanism in the release of the two growth factors is different. On gel-chromatography using a Sephadex G-50 column, IR-EGF appeared in the fraction corresponding to that of authentic human EGF, while 70%-80% of the IR-TGF-alpha was eluted as a species with a molecular weight greater than that of authentic human TGF-alpha. Although the physiological role of TGF-alpha in milk is not known, it is possible that it is involved in the development of the mammary gland and/or the growth of newborn infants.

Epidermal Growth Factor↗
PubMed1991

Insulin-like growth factor-II (IGF-II)/Mannose-6-phosphate receptors are increased in primary human thyroid neoplasms.

Insulin-like growth factor (IGF)-II receptors were demonstrated in normal and neoplastic tissues of human thyroid. Specific binding of [125I]IGF-II to thyroid membranes was dependent on the time and temperature of incubation, and a steady state was achieved after 22 h of incubation at 4 degrees C. The binding of [125I]IGF-II was dose-dependently displaced by unlabelled IGF-II with 50% inhibition at an IGF-II concentration of 6 ng/ml. IGF-I had a relative potency of 1% compared to IGF-II, and insulin showed no inhibition at concentrations as high as 2000 ng/ml. Scatchard analysis of the binding data revealed a single class of IGF-II receptor with high affinity. Affinity crosslinking and autoradiography demonstrated the type II IGF receptors. Specific binding of [125I]IGF-II to thyroid papillary cancer tissues (mean [S.D.]13.2[1.3]% per 200 micrograms protein, n = 8) was significantly (P less than 0.01) higher than that to the surrounding normal tissues (4.8 [0.5]%). The binding in follicular cancer and follicular adenoma was also significantly higher than that in the corresponding normal tissues. The higher IGF-II binding to neoplastic tissues was due to an increase in the number of binding sites without any change of affinity. These results suggest that the increased IGF-II receptors may be involved in growth or functions of thyroid neoplasms.

Binding, Competitive↗
PubMed1991

Effects of glucocorticoids and calcitonin on parathyroid hormone-related protein (PTHrP) gene expression and PTHrP release in human cancer cells causing humoral hypercalcemia.

Glucocorticoids are widely used for the treatment of malignancy-associated hypercalcemia to delay the occurrence of an escape phenomenon inherent in calcitonin therapy. Using parathyroid hormone-related protein (PTHrP)-producing squamous carcinoma cells (T3M-1 and EC-GI) established in our laboratory, we investigated the in vitro effects of glucocorticoids and calcitonin on PTHrP mRNA expression in the cells and release of PTHrP into the culture medium. The PTHrP gene was constitutively expressed in the logarithmic growth phase in both squamous carcinoma cell lines. When these cells became superconfluent, PTHrP mRNA expression was greatly diminished in T3M-1 cells but was not distinctly diminished in EC-GI cells. Hydrocortisone inhibited the PTHrP mRNA expression in T3M-1 cells and EC-GI cells in a dose-dependent manner. In accordance with the decreased expression of PTHrP mRNA, the release of immunoreactive as well as bioactive PTHrP also decreased in the conditioned medium of glucocorticoid-treated cells. The minimal effective concentration of prednisolone was about 10(-7) M, which is readily attainable in the serum of patients treated with the agent. Calcitonin and indomethacin did not affect the PTHrP mRNA expression or PTHrP release into the medium. Calcitonin did not modulate the hydrocortisone-induced inhibition of PTHrP production. These in vitro findings suggest that the combined use of glucocorticoids and calcitonin plays a beneficial role in the treatment of malignancy-associated hypercalcemia, since the steroid hormone can suppress PTHrP mRNA expression and release of bioactive PTHrP in certain PTHrP-producing tumors.

Aged↗
PubMed1991

Phorbol ester, not growth hormone releasing factor, consistently stimulates growth hormone release from somatotroph adenomas in culture.

In order to study the mechanism of GH secretion from somatotroph adenoma cells, we have compared the effect of 12-O-tetradecanoyl phorbol-13-acetate (TPA) with that of growth hormone releasing factor (GRF) on GH secretion from human somatotroph adenoma cells cultured in monolayer. Pituitary adenoma cells were obtained from 13 patients with acromegaly undergoing surgery. On the 7th day of culture, the cells were exposed for 2 h to secretagogues. All 13 adenoma cell cultures (100%) responded to TPA (1.6-16.0 nmol/l) with a two- to six-fold increase in GH release (240 +/- 37% increase of control: mean +/- SE). The response was detectable within 10 min, and was maximal at 2 h. Phospholipase C (7.7 mmol/l) also stimulated a two- to ten-fold increase in GH release in all four adenomas examined (100%). GH release was stimulated by GRF (2.0 nmol/l) in eight out of 12 adenoma cells (67%), but the magnitude of the responses to GRF (60 +/- 18% increase of control: mean +/- SE) were much smaller than that of TPA. Five out of 13 adenomas secreted detectable amount of PRL into the medium and these five adenomas (100%) responded to TPA (16.0 nmol/l) with a two- to six-fold increase. These observations indicate that the activation of protein kinase C is the consistent stimulator in GH and PRL secretion in human somatotroph adenoma cells. However, it is not determined whether the protein kinase C is involved in the in-vivo production of GH in patients with acromegaly.

Adenoma↗
PubMed1991

Antiserum against homologous atrial natriuretic peptide diminishes the natriuretic response during mineralocorticoid escape in rats.

To elucidate the physiological role of atrial natriuretic peptide (ANP) in plasma during mineralocorticoid escape, we investigated the effects of passive immunization with ANP-specific antiserum on deoxycorticosterone (DOCA)-treated rats. Sodium was retained in excess of intake during the first day after treatment with DOCA, and sodium balance returned to control values by the second day, whereas the excretion of potassium exceeded the intake during all days after DOCA treatment. These changes in electrolyte balance were associated with a significant increase in plasma levels of ANP. Administration of ANP-specific antiserum significantly impaired the return to normal sodium balance as well as the augmented kaliuresis that were observed on the second day after injection of DOCA. No significant effect was observed on either sodium or potassium balance after the injection of normal rabbit serum. These results suggest that plasma ANP plays an important role in mineralocorticoid escape.

Animals↗
PubMed1991

Identification and characterization of basic fibroblast growth factor in porcine thyroids.

Fibroblast growth factor (FGF) is one of the most potent endothelial cell growth factors and has been found in almost all tissues in the body. However, there is no definitive report showing that FGF exists in the thyroid. In this report, we describe heparin binding endothelial cell growth factor activity in porcine thyroids. The extract from normal adult porcine thyroids was loaded onto a heparin-sepharose affinity column. The mitogenic activity on endothelial cells was found to elute from the column with 0.9 M-2.0 M NaCl. Polyacrylamide gel electrophoresis and an immunoblotting of bioactive fractions showed the basic FGF immunoreactivity in a double band with a molecular weight of 18K and 20K. These results strongly imply that the adult porcine thyroid-derived heparin binding endothelial cell growth factor may be authentic basic FGF and one of its high molecular weight forms. In support of this conclusion, basic FGF mRNA was detected in poly A+ RNA isolated from cultured porcine thyroid cells. On the other hand, recombinant human basic FGF at the concentration of 0.1-10 ng/ml increased the incorporation of 3H-thymidine into FRTL-5 cells and porcine thyroid follicular cells in culture. The stimulatory effects were also observed when the biologically active fractions of heparin-sepharose column of the thyroid extract were added to the culture. In addition, both recombinant human basic FGF at 10 ng/ml and heparin binding fractions from porcine thyroids inhibited TSH-induced iodide uptake by porcine thyroid cells in culture. These results suggest that basic FGF may be one of the important local modulators of thyroid function, cell growth, and angiogenesis.

Animals↗
PubMed1991

Methimazole regulation of thyroglobulin biosynthesis and gene transcription in rat FRTL-5 thyroid cells.

Methimazole (MMI) increases thyroglobulin (Tg) mRNA levels in FRTL-5 rat thyroid cells. The increase reflects a transcriptional action of the antithyroid agent and is inhibited by cycloheximide, as is the transcriptional action of TSH. It takes several hours to be apparent, is maximal between 24-48 h, and is specific, in that thyroid peroxidase and beta-actin mRNA levels are not increased simultaneously. The increased mRNA levels are associated with increased recovery of immunoprecipitable Tg in the medium of cells exposed to [35S]methionine. The MMI effect appears to be independent of the action of TSH or its cAMP signal, since the MMI-induced increase in Tg mRNA levels is evident in cells treated with TSH or maintained in its absence and is associated not with increases in cAMP levels but, rather, under some circumstances with a decrease. The effect is evident under conditions in which the ability of insulin or insulin-like growth factor-I to increase Tg mRNA levels is already maximal. The MMI-induced increase is inhibited by concentrations of iodide associated with autoregulation of FRTL-5 rat thyroid cells, is inhibited but not mimicked by propylthiouracil, and is not altered by T3. The increase in Tg mRNA levels does not correlate with increased DNA synthesis as a function of MMI concentration either in cells treated with TSH or in those maintained in its absence. A concentration of MMI (5 mM) that increases Tg mRNA levels can also inhibit 8-bromo-cAMP- or phorbol ester-induced increases in [3H]thymidine incorporation into DNA.

Animals↗