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Hirokatsu Yoshimura, Kunihiko Ito, Osamu Tarutani and Toichiro Hosoya

Abstract. Both lesion (L) and adjacent normal (N) thyroid tissue from 48 patients with non-functioning adenomas and adenomatous goitres were assayed for peroxidase activity by the 'mini' assay method employing guaiacol or iodide as the second substrate. A considerable proportion of thyroids (46% of adenomas and 22% of adenomatous goitres) demonstrated no iodide oxidation activity in L although they had guaiacol oxidation activity, and these were grouped as subgroups A. The rest of these non-functioning tumours, termed subgroups B, had both guaiacol and iodide oxidation activity which was higher (3.0–4.6 times in guaiacol assay and 7.3–14.1 times in iodide assay) in L than in N. These data indicate that the non-functioning in subgroups A may be due to a lack of iodide oxidation activity and that some other defects such as an iodide transport defect may be involved in subgroups B. Furthermore, a precise and rapid assay method for thyroglobulin iodination activity of thyroid peroxidase was developed, with modifications of previous methods. On the basis of this method, we found that there is a good correlation (r = 0.94) between iodide oxidation assay and thyroglobulin iodination assay, leading to the conclusion that thyroglobulin iodination assay can be replaced by iodide oxidation assay.

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Noboru Hamada, Yoshitaka Manabe, Hifumi Saito, Takashi Mimura and Kunihiko Ito

Abstract. The course of the cAMP response to thyrotropin (TSH) in 23 specimens of differentiated thyroid carcinoma and the adjacent normal tissue was studied. In the carcinomatous tissue, the cAMP concentration in slices incubated with TSH was significantly greater after 2 h than after 15 min of incubation; the level was almost the same at both times in normal tissue. The effects of an initial exposure of thyroid slices to TSH (50 U/l on the subsequent cAMP responsiveness to the hormone were investigated in seven more differentiated thyroid carcinomas. In normal tissue, the cAMP level in slices exposed to TSH, washed, and exposed again was lower after the third incubation than in slices exposed to TSH only in the third. In contrast, the cAMP level tended to be greater after the second of 2 TSH incubations in 5 out of the 7 specimens of carcinomatous tissue. The data suggest that differentiated thyroid carcinoma lacks desensitization of the cAMP response to TSH.

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Hirokatsu Yoshimura, Kunihiko Ito, Osamu Tarutani and Toichiro Hosoya

Acta Endocrinologica (Copenh) 1988, 118: 147–153

Page 148, right column paragraph two should read:

Measurement of the rate of iodination of Tg catalyzed by TPO

The iodination activity of human TPO was determined by the method of Nakashima & Taurog (1978) with some modifications. The reaction mixture contained 0.05% human Graves' Tg (Iodine/Tg = 0.26, w/w, %), 0.1 mmol/l KI, 30–60 μCi 6.0 mmol/l glucose, 0.125 μg glucose oxidase and the enzyme source, usually containing 40 μg of protein in a total volume of 250 μl made up with 50 mmol/l sodium phosphate buffer, pH 7.4. The enzyme source was prepared as follows: after each thyroid tissue (about 1 g) had been homogenized and fractionated as described for the 'ordinary' assay method (Hosoya et al. 1985), the particulate fraction obtained was suspended in 2 ml of 50 mmol/l sodium phosphate buffer, pH 7.4, treated with 0.7% sodium cholate for 60 min at

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Yukiko Yano, Hiroshi Shibuya, Wataru Kitagawa, Mitsuji Nagahama, Kiminori Sugino, Kunihiko Ito and Koichi Ito

Objective: The objective was to evaluate the clinical behavior and outcome of 202 papillary thyroid cancers in Graves’ disease patients during the period 1994–2004.

Design: This was a retrospective, non-randomized case–control study.

Methods: Since 1994, we have included an ultrasonogram of the neck in the initial examination of thyroid disease patients who consult our outpatient clinic. We evaluated the tumor status and long-term outcome of Graves’ disease patients with thyroid cancer and of age- and tumor size-matched euthyroid papillary thyroid cancer patients as controls. Serum TSH receptor antibody (TRAb) was measured in the Graves’ disease group.

Results: A total of 154 papillary thyroid cancers were diagnosed in the Graves’ disease patients and were treated surgically. At surgery, no significant differences in multifocality, lymph node metastasis, or distant metastasis were found between the Graves’ disease group and the euthyroid group. On the whole, the clinical course of the cancers in both the Graves’ disease group and euthyroid group was relatively good. No significant correlations were found between the TRAb levels in the Graves’ disease group and multifocality or the presence of lymph node metastasis. Papillary thyroid cancer was discovered as an incidental finding in 2% of the 2356 surgically treated Graves’ disease patients, but none of them developed metastasis during the follow-up period.

Conclusion: The results in this series of patients do not support the claim that thyroid cancer is more aggressive in Graves’ disease patients than in euthyroid patients.

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Tohru Yashiro, Yoshito Ohba, Hitomi Murakami, Takao Obara, Toshio Tsushima, Yoshihide Fujimoto, Kazuo Shizume and Kunihiko Ito

Abstract.

The presence of IGF-I receptors was demonstrated in normal and neoplastic tissues of human thyroid. Binding of [125I]IGF-I to thyroid membranes was dependent on time and temperature of incubation, and maximal binding was achieved at 4°C and 18 h of incubation. [125I] IGF-I binding was dose-dependently displaced by unlabelled IGF-I; half-maximal inhibition occurred at concentrations of 10–20 μg/l. IGF-II and insulin had relative potencies of 5 and 1% compared with IGF-I. Scatchard analysis of binding data revealed a single class of IGF-I receptors with high affinity (Ka: 1.2–8.6 × 109 1/mol) in normal thyroid tissues. Affinity cross-linking and autoradiography demonstrated the type I IGF receptors. Specific binding of [125I] IGF-I in thyroid cancer tissues (9.69 ± 2.07% per 200 μg protein; mean ± sem, N = 8) was significantly (p <0.05) higher than that in the surrounding normal tissues (3.03 ± 0.35%, N = 8). In contrast, there was no difference in the binding between adenoma tissues (4.19 ± 0.53%, N = 5) and the adjacent normal tissues (2.94 ± 0.24%, N = 5). The higher IGF-I binding in cancer tissues was due to an increase in the binding capacity without any change in the affinity. The presence of IGF-I receptors suggests a possible role of IGF-I and its receptors in the growth of thyroid cancer cells.

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Yasuyuki Okamoto, Noboru Hamada, Toshimichi Fujisawa, Jaeduk Noh, Junichi Yamakawa, Mariko Ohno, Kunihiko Ito and Hirotoshi Morii

Abstract.

We have reported that some anti-thyroid peroxidase antibodies inhibit the activity of thyroid peroxidase in vitro. These thyroid peroxidase activity-inhibiting immunoglobulins seem to inhibit thyroid function in some patients, but the relationship between thyroid peroxidase activity-inhibiting immunoglobulins and thyroid function is not simple. We designed this study to explore this lack of a simple relationship. We stained immunoglobulin G deposits by immunofluorescence staining or the peroxidase-antiperoxidase method, and stained endogenous thyroid peroxidase activity by enzyme histochemistry in thyroid sections. When cryostat thyroid sections were incubated with thyroid peroxidase activity-inhibiting immunoglobulins, immunoglobulin G deposits were seen as lines of stain on the apical border and as intracellular staining, and endogenous thyroid peroxidase activity was inhibited. In paraffin-embedded thyroid sections from 5 Hashimoto's patients and 6 Graves' patients, immunoglobulin G deposits were not found on the apical border of the follicular epithelium. In frozen thyroid sections from 22 Graves' patients, no clear deposits of immunoglobulin G on this apical border were seen. In organ-cultured thyroid slices incubated with thyroid peroxidase activity-inhibiting immunoglobulins, endogenous thyroid peroxidase activity was not inhibited. In conclusion, thyroid peroxidase activity-inhibiting immunoglobulins may reach its antigen only with difficulty. This is one of the reasons why no simple relationship is observed between thyroid peroxidase activity-inhibiting immunoglobulins and thyroid function.

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Noboru Hamada, Kunihiko Ito, Takashi Mimura, Naofumi Ishikawa, Naoko Momotani, Jaeduck Noh, Yasuhiro Hosoda and Hirotoshi Morii

Abstract. The results of treatment were analyzed in relation to serum microsomal antibody (MCAb) titre before treatment in 1185 patients with Graves' disease. The percentage of patients who had ablative therapy because of poor response to antithyroid drug treatment was significantly greater in those with MCAb haemagglutination test (MCHA) titres greater than 1:25 000. With 131I treatment, the patients with MCHA titres greater than 1:6400 responded significantly less to therapy, although the analysis was done in 146 selected patients with certain defined radiation doses and small goitres. With surgical treatment, the percentage of the patients entering into remission was significantly smaller for patients with MCHA titres greater than 1:25 000, because of an increase in both hypothyroidism and relapses. The incidence of hypothyroidism was significantly higher in patients with marked lymphocyte infiltration and/or lymphoid follicles. The degree of these histological findings in Graves' disease was not marked in spite of high MCAb titre and it was significantly different from that in Hashimoto's disease when analyzed in relation to the MCHA titre.

These data indicate that in Graves' patients with high MCAb titre, remission is difficult to obtain by treatment, and suggest that the significance of MCAb is different in Graves' disease and Hashimoto's disease. The titre in Graves' disease may be one expression of the activity of this disease.

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Jaeduk Noh, Noboru Hamada, Hifumi Saito, Midori Yoshimoto, Hiroyuki Iwasaki, Osamu Ozaki, Yasuyuki Okamoto, Kunihiko Ito and Hirotoshi Morii

Abstract.

Recently, thyroid microsomal antigen was identified as thyroid peroxidase, and thyroid microsomal antibody was found to inhibit thyroid peroxidase activity in vitro. We investigated the possibility that anti-microsomal antibody inhibits the iodination of tyrosine, in vivo. Immunoglobulin G with or without anti-microsomal antibody from hypothyroid patients with goitrous Hashimoto's thyroiditis inhibited thyroid hormone synthesis in cultured slices of normal human thyroid tissue. IgGs with anti-microsomal antibody inhibited 125I thyroidal uptake and thyroid hormone synthesis stimulated by TSH more than normal IgG did. However, the same results were obtained with IgGs without anti-microsomal antibody. This effect did not involve anti-microsomal antibody, anti-thyroglobulin antibody, TSH-binding inhibitor immunoglobulin, thyroid stimulation-blocking immunoglobulin, or the cAMP level of the thyroid tissue. The ratio of organic I to inorganic I with stimulation by TSH in slices incubated with IgG from hypothyroid patients with goitrous Hashimoto's thyroiditis or normal IgG was not significantly different, but was significantly higher in slices incubated with methylmercaptoimidazole. Therefore, IgG from hypothyroid patients with goitrous Hashimoto's thyroiditis mainly suppressed 125I thyroidal uptake, rather than inhibiting thyroid peroxidase activity. In addition, this IgG was present in the serum of 11 of the 12 hypothyroid patients with Hashimoto's thyroiditis studied. This IgG may be involved in the mechanism that causes hypothyroidism in some patients with goitrous Hashimoto's disease.

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Mayumi Matsunaga, Katsumi Eguchi, Takaaki Fukuda, Hiroshi Tezuka, Yukitaka Ueki, Yojiro Kawabe, Chikako Shimomura, Toshio Otsubo, Naofumi Ishikawa, Kunihiko Ito and Shigenobu Nagataki

Abstract. The present study was undertaken to examine whether thyrocytes possess phagocytic activity and whether the phagocytic activity is influenced by cytokines, such as interleukin 1, 2 (IL 1, IL 2) and interferon-α, -β, and -γ (IFN-α, β, and γ), and drugs, such as methimazole and dexamethasone. Thyroid glands were obtained from patients with Graves' disease. Thyrocytes were prepared by collagenase digestion. Thyrocytes were pre-incubated in the presence or absence of cytokines and drugs at 37°C for 20 h and were further incubated with fluoresceinated latex beads at 37°C for 60 min. The number of phagocytic thyrocytes was determined by FACS IV. Phagocytosis of latex beads was indeed seen within thyrocytes and gradually increased in a time-dependent manner. The rate of phagocytosis in thyrocytes was extremely slow as compared with that in macrophages. Phagocytic activity was detected in thyrocytes from patients with Graves' disease and from normal thyroid tissue adjacent to thyroid cancer. Phagocytosis was inhibited by IL 1, but was enhanced by IL 2. Although the enhanced phagocytosis with IFN-β was consistently seen, little effect was detected with IFN-α and -γ. Both methimazole and dexamethasone markedly inhibited phagocytosis. These results indicated that thyrocytes had phagocytic properties and that their phagocytic activity was modulated by cytokines, antithyroidal drugs and dexamethasone.

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Katsumi Eguchi, Atsushi Kawakami, Munetoshi Nakashima, Hiroaki Ida, Souko Sakito, Masahiro Sakai, Kaoru Terada, Yojiro Kawabe, Takaaki Fukuda, Naofumi Ishikawa, Kunihiko Ito and Shigenobu Nagataki

We investigated whether a potent vasoconstrictor, endothelin, stimulated the proliferation of human thyroid epithelial cells (thyrocytes). [3H]-thymidine incorporation into normal thyrocytes and thyrocytes from patients with Graves' disease was significantly increased at 10−9 mol/l endothelin. reaching a plateau at 10−8 mol/l. The proliferative responses of the thyrocytes obtained from patients with Graves' disease were similar to those of normal thyrocytes. Furthermore, the cell number of thyrocytes stimulated by endothelin was increased as compared with that of unstimulated thyrocytes. Neither indomethacin nor heparin affected this endothelin-stimulated thyrocyte proliferation. When thyrocytes were cultured with both endothelin and recombinant interleukin 1β, there was an additive effect on thyrocyte proliferation. The Ca2+ entry blocker, verapamil, inhibited both the proliferative responses of thyrocytes to endothelin and the additive effect of endothelin and recombinant interleukin 1β on thyrocyte proliferation. These results suggest that endothelin functions as a growth-promoting factor for human thyrocytes, presumably through intracellular calcium influx.