Prevalence of interrelated autoantibodies in thyroid diseases and autoimmune disorders.

OBJECTIVE: We determined the autoantibody profile in autoimmune thyroid diseases (AITD) and examined the distribution of thyroid-related autoantibodies in other autoimmune disorders. METHODS: We tested sera from 234 patients with Graves' disease (GD), 130 with Hashimoto's thyroiditis (HT), 249 with other autoimmune diseases, and 50 healthy controls by enzyme-linked immunosorbent assay or radioimmunoassay. RESULTS: Autoantibodies except TSH receptor antibody (Ab), anti-thyroglobulin (Tg) Ab and anti-thyroid peroxidase (TPO) Ab were not significantly prevalent in patients with AITD despite a significantly high elevation of thyroid-related Ab. Significant prevalence of autoantibodies related to AITD was observed in type 1 diabetes patients. Elevation of anti-Tg Ab was seen in patients with primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH), and anti-TPO Ab was elevated in patients with PBC. Although the prevalence of anti-acetylcholine receptor Ab and systemic lupus erythematosus (SLE)- related Ab was significant in AIH, primary Sjögren's syndrome (pSS)-related Ab were also found in both liver diseases. In myasthenia gravis (MG) patients, thyroid-related Ab and pSS-related Ab were detected in both MG groups, although SLE-related Ab were limited to the anti-muscle specific kinase Ab-positive MG patients. In patients with connective tissue diseases, anti- Tg Ab and anti-TPO Ab were significantly prevalent. CONCLUSION: Thyroid-related Ab were significantly elevated in all autoimmune diseases. Conversely, the elevations of Ab were not significant in the patients with AITD, suggesting a close relationship between AITD and other immune-mediated diseases.

Fas/FasL mediated apoptosis of thyrocytes in Graves' disease.

We examined in the present study the possible involvement of Fas and its ligand (FasL) in the process of Graves' disease. Immunohistochemical analysis showed that few normal thyrocytes expressed Fas but many thyrocytes in Graves' disease expressed this molecule. The percentage of FasL-positive thyrocytes in Graves' thyroids was, however, less than in normal thyroids. Several apoptotic thyrocytes and infiltrating mononuclear cells (MNCs) were detected scattered throughout Graves' thyroid tissues and abundant proliferating cell nuclear antigen (PCNA)-positive thyrocytes were present. Apoptotic cells, as well as PCNA-positive cells, were scarcely detectable in normal thyroid glands, however. In vitro treatment of thyrocytes by IL-1beta a cytokine found to be expressed in Graves' thyroid glands, increased Fas but reduced FasL expression. IL-1beta-stimulated thyrocytes became sensitive to apoptosis by anti-Fas IgM monoclonal antibody (mAb). Activated T cells, which strongly expressed FasL, showed cytotoxic activity toward IL-1beta-stimulated thyrocytes but not toward unstimulated thyrocytes. This cytotoxic activity involved the Fas/FasL pathway. Importantly, unstimulated thyrocytes could kill activated, but not resting, T cells. IL-1beta-stimulated thyrocytes, with down-regulated FasL expression, could not efficiently kill activated T cells. The cytotoxic activity of unstimulated thyrocytes toward activated T cells was inhibited by anti-FasL mAb. Interestingly, unstimulated thyrocytes induced apoptosis in IL-1beta-stimulated thyrocytes but not in unstimulated thyrocytes. These interactions were also blocked by anti-FasL mAb. Our results suggest that the apoptotic cell death of both thyrocytes and infiltrating MNCs found in Graves' thyroid glands is regulated by IL-1beta through Fas/FasL interactions.

Pulmonary nocardiosis associated with idiopathic thrombocytopenic purpura.

A 69-year-old woman with idiopathic thrombocytopenic purpura, who was regularly followed and treated with prednisolone and danazol, was admitted to our hospital because of shortness of breath. Chest roentgenogram showed a large amount of left-sided pleural effusion. Gram-positive branching rods, subsequently identified as Nocardia farcinica, were isolated from the fluid. Antibiotic treatment together with pleural drainage with an intercostal catheter resulted in complete remission of pyothorax. Pulmonary nocardiosis is a rare disease, but recognition of the disease in immunocompromised patients and the prompt initiation of appropriate treatments based on isolation of the pathogen can lead to a successful outcome.

Elevation of serum pro-gastrin-releasing peptide in patients with medullary thyroid carcinoma and small cell lung carcinoma.

Medullary thyroid carcinoma (MTC) arises from parafollicular or C cells of the thyroid gland and produces a variety of peptides such as calcitonin (CT) and gastrin-releasing peptide (GRP). Here we measured serum levels of pro-gastrin-releasing peptide (Pro-GRP), a more stable precursor of GRP, in 15 patients with MTC (4 males, 11 females) who did not show any clinical or radiologic signs of small cell lung cancer. Serum Pro-GRP levels were elevated in 80% (12/15) patients. Significant correlation was observed between serum Pro-GRP and CT (r = 0.52) and carcinoembryonic antigen (CEA) (r = 0.56). Serum Pro-GRP levels also correlated with tumor size (r = 0.70). Serum Pro-GRP levels also decreased below the cut-off range in one patient after surgical resection. Our data suggest that Pro-GRP, which is considered to be a specific marker for small cell lung carcinoma, seems to be also helpful and additional marker for the diagnosis and monitoring the response to therapy in patients with MTC in addition to calcitonin as the main tumor marker.

Anaplastic changes associated with p53 gene mutation in differentiated thyroid carcinoma after insufficient radioactive iodine (131I) therapy.

Thirty-two patients with differentiated thyroid carcinomas with distant metastasis were examined using a radioactive iodine (131I) tracer dose prior to 131I therapy and followed up for 10 years or until death (whichever occurred first). Nineteen patients who received 131I therapy had an accumulation of 131I in the metastases (group I) and 15 of those patients were alive more than 10 years after the first 131I treatment. In contrast, all 13 patients in whom the metastases did not show accumulation of 131I died within 10 years. Of the latter group, eight patients had received 131I therapy (group II), four of whom died with anaplastic changes within 5 years of treatment. p53 gene mutation was identified by immunohistochemistry in primary thyroid carcinoma tissue from patients with anaplastic changes that were evident during total thyroidectomy. Five patients did not receive 131I therapy (group III), of whom one, who also had a p53 gene mutation in the original tumor, died with anaplastic change 10 years after thyroidectomy. Seven patients in group I had p53 gene mutations in their thyroid carcinoma tissues, but none showed anaplastic changes. Our results suggest that 131I therapy may be useful for patients with distant metastases, with or without p53 gene mutations, which show accumulation of 131I from tracer and therapeutic doses. In contrast, 131I therapy is apparently not effective in patients who do not show sufficient accumulation of 131I, but rather, may cause early anaplastic changes with a p53 gene mutation.

Etidronate inhibits human osteoblast apoptosis by inhibition of pro-apoptotic factor(s) produced by activated T cells.

Humoral factors produced by activated T cells are thought to be important in the development of bone loss in patients with rheumatoid arthritis (RA). We investigated the inhibitory effect of etidronate disodium (EHDP) on apoptosis of human osteoblasts induced by supernatants from in vitro activated T cell cultures. Human osteoblastic cell line MG63 cells and human primary osteoblast-like cells were used in the present study as human osteoblasts. T cells were incubated with interleukin-2 and further activated with 1 2-o-tetradecanoyl-phorbol 13-acetate and ionomycin, either in the presence or absence of EHDP. After we carried out the cultivation, we examined the cytotoxicity of cultured T cell supernatants toward MG63 cells and human primary osteoblast-like cells. Supernatants from activated but not resting T cell cultures efficiently induced apoptosis of MG63 cells and primary osteoblast-like cells. Supernatants from activated T cell cultures, incubated with EHDP, exhibited significantly less cytotoxicity than did supernatants incubated in the absence of EHDP. In contrast, the cytotoxicity of activated T cell culture supernatants was not affected by direct treatment of human osteoblasts with EHDP. The concentration of soluble Fas ligand in activated T cell culture supernatants was actually increased by EHDP. However, EHDP did not influence soluble Fas and tumor necrosis factor-alpha concentrations in the supernatant. Furthermore, treatment of human osteoblasts with EHDP did not alter their expression of Bcl-2/Bcl-xL or their sensitivity to anti-Fas immunoglobulin M-induced apoptosis. Our results suggest that EHDP inhibits the production of soluble factor that induces apoptosis of human osteoblasts and thus exhibits a protective action toward human osteoblast apoptosis induced by activated T cell culture supernatants. Although the exact EHDP-regulated molecule that induces apoptosis of human osteoblasts is unknown at present, our study may explain part of the therapeutic action of bisphosphonates in RA complicated by bone loss.

Thyroid hormones influence serum leptin levels in patients with Graves' disease during suppression of beta-adrenergic receptors.

Leptin is a protein product of the ob gene, mainly produced by adipocytes. Leptin is thought to play an important role in the homeostasis of body weight by suppressing appetite and increasing energy consumption. The aim of this study was to investigate the possible effect of thyroid hormone on the regulation of the leptin system during suppression of beta-adrenergic receptors in Graves' patients. We studied 15 adult female patients with Graves' disease. Thyroid function, serum levels of leptin, and percent body fat (%BF) were examined at four different clinical conditions during therapy (A, untreated; B, beta-adrenergic antagonist only [A, B; hyperthyroid], C, beta-adrenergic antagonist and antithyroid drug; D, antithyroid drug only [C, D; euthyroid]). The use of beta-adrenergic antagonist significantly reduced heart rate in spite of hyperthyroid state, indicating sufficient suppression of beta-adrenergic receptors. During treatment with beta-adrenergic antagonist, leptin percentage of body fat (%BF) ratio significantly decreased in euthyroid state compared to that in hyperthyroid state (from 38.7 +/- 21.3 to 18.1 +/- 19.3, p = 0.003). Moreover, there was a significantly positive correlation between delta leptin/%BF and delta free thyroxine (FT4) (r = 0.51, p = 0.008). Under a euthyroid state induced by antithyroid drug treatment, leptin/%BF did not change in spite of withdrawal of beta-adrenergic antagonist. Our data indicate that thyroid hormones could increase serum leptin level during suppression of beta-adrenergic receptors in Graves' patients. Our data also suggest that the beta-adrenergic action of thyroid hormones might be partly mediated by regulation of leptin.

Treatment with propylthiouracil is associated with appearance of antineutrophil cytoplasmic antibodies in some patients with Graves' disease.

The use of propylthiouracil (PTU) for the treatment of Graves' disease is associated with few adverse effects such as skin eruptions, liver dysfunction, and agranulocytosis. Furthermore, recent studies described the development of antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis and vasculitis in patients treated with PTU. Here we investigated whether PTU therapy per se is associated with the appearance of ANCA in patients with Graves' disease. We analyzed 119 serum samples from 117 patients with Graves' disease treated with either PTU (n = 56), or methimazole (MMI) (n = 21), as well as untreated patients (n = 42). Myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA were tested by enzyme-linked immunosorbent assay (ELISA) kits. MPO-ANCA was negative in all patients treated with MMI therapy and untreated patients. However, MPO-ANCA was detected in 21 (37.5%) of 56 patients treated with PTU therapy. Furthermore, two patients who were negative for MPO-ANCA became positive after PTU therapy. The proportion of patients positive for MPO-ANCA increased with the prolongation of PTU therapy, but did not correlate with age, gender, and positive antithyroperoxidase (TPO) antibody. Among 21 MPO-ANCA positive patients, 12 had no symptoms, but 9 patients complained of myalgia, arthralgia, or common cold like symptoms after the appearance of MPO-ANCA. Three patients developed agranulocytosis or granulocytopenia, but none showed abnormal urinary findings. Our results suggest that PTU per se is associated with the production of MPO-ANCA in patients with Graves' disease.

CD4+ T cell-mediated cytotoxicity toward thyrocytes: the importance of Fas/Fas ligand interaction inducing apoptosis of thyrocytes and the inhibitory effect of thyroid-stimulating hormone.

The accumulation of activated CD4+ T cells and antigen (Ag)-dependent cellular interactions between thyrocytes and CD4+ T cells have been determined in thyroid gland from patients with Graves' disease. The Fas/Fas ligand (FasL) interaction between antigen-presenting cells and T cells regulates the apoptosis of the former cells triggered by the latter cells. The inhibition of Fas-mediated apoptosis in thyrocytes could be a underlying mechanism of hyperplasia of thyrocytes in patients with Graves' disease. We investigated the potential role of Fas/FasL interaction between thyrocytes and CD4+ T cells in the induction of Fas-mediated apoptosis of the former cells induced by the latter cells. The presence of only a few specific T cells responsive to a putative autoantigen has hampered the investigation of specific T cell activation toward antigen-presenting cells (APCs). Therefore, we used a superantigen, staphylococcal enterotoxin B (SEB), to examine specific T cell activation toward thyrocytes in vitro since it stimulates a large proportion of T cells with particular Vbeta elements. Spontaneous apoptosis of thyrocytes in culture was not found even in the presence of various kinds of cytokines. In contrast, a clear induction of Fas-mediated apoptosis by anti-Fas IgM was determined in interferon-gamma (IFN-gamma)-stimulated thyrocytes. In addition, a significant cytotoxicity of purified CD4+ T cells toward IFN-gamma-stimulated thyrocytes in the presence of SEB was induced, and the addition of anti-HLA-DR and -DQ monoclonal antibodies (mAbs) or blockade of the Fas/FasL interaction reduced this cytotoxicity. FasL expression of CD4+ T cells cocultured with IFN-gamma-stimulated thyrocytes in the presence of SEB was clearly induced. Furthermore, the addition of mAbs against CD54 and CD58 inhibited both cytotoxicity and FasL expression of CD4+ T cells. The cytotoxicity of CD4+ T cells toward IFN-gamma-stimulated, SEB-pulsed thyrocytes was markedly inhibited when we used thyrocytes cultured with IFN-gamma in the presence of thyroid-stimulating hormone (TSH) as target cells. Our results suggest that 1) CD4+ T cells were activated by thyrocytes expressing MHC class II molecules in an SEB-dependent manner and then expressed FasL. 2) These activated FasL+ CD4+ T cells killed thyrocytes by interacting with Fas on thyrocytes and FasL on activated CD4+ T cells. The presence of costimulating molecules such as CD54 and CD58 on thyrocytes was also necessary to generate activated FasL+ CD4+ T cells. 3) Since the actions of thyroid stimulating antibody (TSAb) toward thyrocytes are similar to those of TSH, one goitrogenic activity of TSAb may, in part, be due to the inhibitory effect on Fas-mediated apoptosis of thyrocytes triggered by activated CD4+ T cells.

Effect of 22-oxa-1,25-dihydroxyvitamin D3 on human thyroid cancer cell growth.

To examine whether synthetic vitamin D3 analog, 22-oxa-1,25(OH)2D3 (OCT) has an inhibitory effect on the growth of thyroid carcinoma, we tested the in vitro and in vivo effects of OCT on the growth of a well-differentiated thyroid cancer cell line, NPA. OCT bound to its receptor at the same rate as 1,25(OH)2D3, and inhibited the proliferation of NPA cells in vitro in a dose-dependent manner, similar to that observed with 1,25 (OH)2D3. Northern blot analysis showed that steady-state and fetal bovine serum-stimulated levels of c-myc mRNA were suppressed after 0.5-4 hour treatment with OCT. Transfection studies with the deletion mutants of the 5'-up-stream flanking region of c-myc/chloramphenicol acetyltransferase chimera genes indicated the presence of an OCT responsive element between -410 and -106. Next, we examined OCT effects in implanted NPA tumor cells in nude mice. OCT showed no remarkable hypercalcemic effect compared to 1, 25 (OH2)D3, but OCT and 1, 25 (OH2)D3, had no significant inhibitory effect in vivo after either intra-tumor or intra-peritoneum injection. Our results demonstrate that OCT inhibits the proliferation of well-differentiated thyroid cancer in an in vitro system associated with the suppression of c-myc mRNA, but this inhibitory effect was not reproducible in in vivo model.

Expression of parathyroid hormone-related peptide in human thyroid tumours.

The purpose of this study was to evaluate the distribution of parathyroid hormone-related peptide (PTHrP) in human thyroid tissues. The presence of PTHrP was studied immunohistochemically in 107 consecutive patients with human thyroid tumours. PTHrP expression was revealed in 97.6 per cent of carcinomas, but not in paranodal normal thyroid epithelial cells. Although there were no differences in the incidence of PTHrP positivity among papillary, follicular, and anaplastic carcinoma cases, PTHrP expression levels were correlated with the growth pattern of thyroid cancer. Strong immunopositivity was detected in 67.3 per cent of papillary growth tissues in papillary carcinomas. A tissue growth pattern consisting of colloid-absent follicles had a high incidence of strong immunopositivity irrespective of the histological type of tumour. Anaplastic carcinoma without colloid production also showed strong immunoreactivity in all cases. In contrast, a growth pattern of colloid-rich follicles did not show strong immunopositivity in either papillary or follicular carcinomas. Follicular adenomas showed positive immunostaining in only one case, and no adenomatous goitres showed PTHrP antigens. In situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) revealed strong PTHrP mRNA in thyroid cancer tissues, but not in normal thyroid tissues. PTHrP expression was not associated with metastasis, calcification, or hypercalcaemia in thyroid cancers. These results suggest that the expression of PTHrP in human thyroids is closely related to the malignant alteration of normal thyroid epithelial cells, especially in the growth pattern of thyroid carcinoma tissues.

Growth hormone directly and indirectly stimulates articular chondrocyte cell growth.

Although growth hormone (GH) is known to regulate cartilage growth and differentiation during development, it is still unclear whether the cell growth of articular chondrocytes is stimulated directly by GH or mediated by GH-induced insulin-like growth factor-I (IGF-I). In the present study, we focused on whether GH directly or indirectly stimulates articular chondrocyte proliferation. Monolayer articular chondrocytes from 5-week-old male Sprague-Dawley rats were cultured in Ham's F-12/Dulbecco's modified essential medium supplemented with 10% fetal bovine serum. Stimulation of DNA synthesis by GH was dose-dependent between 0.1 and 1 microg/ml, and the maximum active concentration of GH was 500 ng/ml, which induced a 3.5-fold increase over control values. Anti-IGF-I antiserum neutralized about 80% of GH-induced DNA synthesis. GH stimulated the secretion of IGF-I into the conditioned medium in a dose-responsive manner. To determine whether GH stimulated DNA synthesis directly, we investigated the time-course changes in mRNA expression of IGF-I and the proto-oncogene c-myc. Induction of IGF-I mRNA occurred at 4 h, and reached a maximum level at 12 h, whereas the expression of c-myc mRNA was induced within 4 h, and continued to increase until 72 h after GH treatment. Furthermore, administration of cycloheximide, an inhibitor of protein synthesis, resulted in the superinduction of both IGF-I and c-myc mRNAs. These results suggest that early induction of c-myc is due to a direct stimulatory effect of GH, and that long-term induction of c-myc was attributable to an indirect effect of GH in which GH-induced secondary proliferative factors may act in an autocrine/paracrine manner. The superinduction of c-myc gene by cycloheximide also indicates that fresh protein synthesis of an intermediate protein was not required for GH-induced c-myc expression. Western ligand blot analysis of IGF-binding proteins revealed that cultured rat articular chondrocytes produced a predominant 41 kDa and a faint 32 kDa form, and that GH significantly stimulated the secretion of the 41 kDa form without affecting expression of the 32 kDa form. Furthermore, a specific IGF-I binding study suggested that the increase in DNA synthesis induced by GH was not associated with changes in affinity or in the number of IGF-I binding sites. These results support the conclusion that the stimulatory effect of GH was mainly mediated by GH-induced IGF-I production in monolayer rat articular chondrocytes. However, it is likely that GH may also have a direct stimulatory effect by inducing c-myc proto-oncogene expression.

Effect of transforming growth factor-beta on the insulin-like growth factor-I autocrine/paracrine axis in cultured rat articular chondrocytes.

Transforming growth factor-beta (TGF-beta) and insulin-like growth factor-I (IGF-I) are essential anabolic factors in articular cartilage. In this study, we concentrated on the elucidation of TGF-beta interaction with IGF-I on cell growth and differentiation in monolayer articular chondrocytes obtained from 5-week-old rats. TGF-beta (1 ng/ml) and IGF-I (25 ng/ml) stimulated DNA synthesis about 6.5- and 2.1-fold over control values, respectively. When TGF-beta and IGF-I were added in combination, DNA synthesis was enhanced about 10.4-fold, indicating that the two peptides act in synergism. This synergistic action was also present in the expression of aggrecan mRNA. To study the mechanism of synergistic action, the effect of TGF-beta on the IGF-I autocrine/paracrine axis was investigated. Administration of increasing concentrations of TGF-beta (0.1-10 ng/ml) resulted in a dose-dependent decrease in medium IGF-I concentration that was reflected by decreased levels of IGF-I mRNA. TGF-beta also inhibited the production of a 41-kDa IGF-binding protein into the culture medium. Pretreatment with TGF-beta (1 ng/ml) for 12 h increased the binding of [125I]IGF-I to 140% of control by increasing the number of receptors without changes of affinity. Immunoprecipitation against phosphorylated tyrosine indicated that IGF-I-dependent autophosphorylation of IGF-I receptor beta-subunit was inhibited by simultaneous TGF-beta stimulation. These observations demonstrate that TGF-beta acts synergistically with IGF-I and regulates the IGF-I autocrine/paracrine axis via a complex regulatory mechanism with decreased production of IGF-I and IGFBPs and dephosphorylation of IGF-I receptor, whereas there is an apparent up-regulation of the binding of [125I]IGF-I.

Correlation between suppression of c-myc and antiproliferative effect of transforming growth factor-beta 1 in thyroid carcinoma cell growth.

The growth regulatory activity of transforming growth factor-beta 1 (TGF beta 1) was studied in a clonal strain of thyroid papillary carcinoma cell (NPA). Despite the presence of TGF beta 1 and its receptor messenger RNA in thyroid carcinoma, the molecular mechanism of TGF beta 1 action on cell growth of thyroid carcinoma has not yet been elucidated. Exogenously added TGF beta 1 inhibited DNA synthesis and cell growth in a dose- and time-dependent manner at concentrations of 0.1-10 ng/ml. TGF beta 1 inhibited not only basal but also fetal bovine serum-stimulated cell proliferation. Steady state levels of c-myc messenger RNA transcripts were inhibited by TGF beta 1 after 0.5-h treatment. Antisense, but not sense, c-myc oligodeoxynucleotides also caused suppression of NPA cell growth in a dose-responsive manner. Transfection studies of the 5'-up-stream flanking region (UFR) of c-myc/chloramphenicol acetyltransferase chimera genes suggest the presence of a TGF beta 1-responsive DNA element in the 2.3-kilobase c-myc 5'-UFR. Deletion mutant studies indicate the element lies between -106 to 70 relative to the P1 transcription start site. Studies with the gel mobility shift assay using 23-basepair double strand DNA showed the presence of at least two nuclear factors in NPA cell. TGF beta 1 treatment did not cause any alteration in TGF beta 1-induced mobility; however, the reduction of a positive band was selectively observed during 30 min to 2 h after treatment with TGF beta 1. In contrast, the position and intensity of another band were not altered by TGF beta 1 treatment. These results demonstrate that the inhibition of a nuclear factor binding to the c-myc 5'-UFR and subsequent suppression of c-myc gene expression are directly involved in the antiproliferative action of TGF beta 1 in NPA cell growth.

Interferon-gamma inhibition of human thyrotropin receptor gene expression.

To evaluate the role of interferon-gamma (IFN gamma) on human thyroid-specific gene expression, the effect of IFN gamma on TSH- and cAMP-induced TSH receptor gene expression was studied using cultured thyroid cells obtained from normal thyroid glands and those from patients with Graves' disease. Incubation of Graves' thyroid cells with 1.0 U/L bovine TSH or 1.0 mM 8-bromo-cAMP resulted in a 2-fold increase in TSH receptor mRNA expression, which was markedly inhibited in the presence of IFN gamma in a dose- and time-dependent manner. This inhibitory effect was completely neutralized by monoclonal antibody against IFN gamma. IFN alpha and -beta had no influence on TSH- and cAMP-stimulated TSH receptor mRNA expression. Paranodular normal thyroid cells showed the same results as those obtained using Graves' thyroid cells. Scatchard analysis of the [125I]TSH binding study showed that IFN gamma inhibited the number of TSH receptors up-regulated by TSH on the cell surface at the low affinity binding site (4.1 vs. 8.2 x 10(5)/cell). These results indicate that IFN gamma suppresses TSH- and cAMP stimulated human TSH receptor gene expression, resulting in a decrease in the number of TSH receptors. In conclusion, IFN gamma interacts via an intermediate pathway of TSH signal transduction and attenuates TSH receptor synthesis in normal and Graves' thyroid cells.

Endoscopic removal of foreign bodies in the mentally and physically handicapped.

Although foreign bodies of the gastrointestinal tract are common in children, they are rare in the adult. Complications of the foreign bodies are well recognized to be a cause of obstruction, bleeding and perforation of the intestine, or furthermore, they sometimes lead to death unfortunately. On the other hand, it is very difficult to diagnose and treat foreign bodies in the handicapped because of disability of complaining the symptoms. This paper reports a 31-year-old severe handicapped man suffering from foreign bodies in the esophagus and the small intestine, and was successful removed by endoscope.

Expression of parathyroid hormone related peptide in human pituitary tumours.

The presence of parathyroid hormone related peptide (PTHrP) was studied in 20 patients with pituitary adenomas and one patient with pituitary adenocarcinoma. PTHrP expression was shown in almost all of the pituitary adenomas (95%) and in 100% (n = 7) growth hormone producing pituitary adenomas. A metastatic lesion from a pituitary growth hormone producing adenocarcinoma revealed strongly expressed PTHrP. It was weakly detected in normal pituitary cells in all of the specimens (n = 10). There was no significant correlation, however, between PTHrP expression and the clinical or pathological features of growth hormone producing tumours. Apart from an important role in the physiological function of the pituitary gland, PTHrP may be closely related to somatotroph tumorigenicity.

Skeletal muscle glucose transporter gene expression is not affected by injecting growth-hormone-secreting cells in young rats.

To elucidate the diabetogenic effect of growth hormone on glucose metabolism the regulation of glucose transporter (GLUT) gene expression was examined in rat skeletal muscles. Female Wistar-Furth rats were implanted subcutaneously with growth-hormone-producing pituitary tumour (GH3) cells. Animals were killed 4 or 9 weeks after GH3 cell injection. Although body weight, serum growth hormone and insulin-like growth factor I levels were remarkably elevated during the 4-9 week period, serum blood glucose levels were within normal range. Muscles were obtained from the quadriceps muscle, diaphragm and heart, respectively. Northern blot analysis and Western blot analysis were performed using specific cDNA probes and antibodies. During the 4-9 week period, the levels of muscle GLUT1 and 4 mRNA (corrected by beta-actin mRNA level) in each muscle from the rats injected with tumour cells were not significantly different from those of control rats. Chronic elevation of growth hormone in these rats did not cause any change in GLUT 1 and 4 expression compared to the controls during the euglycaemic period. These results provide the first evidence that chronic growth hormone elevation itself does not affect a key gene of in vivo glucose metabolism.