Studies on thyrotropin receptor autoantibodies (TRAb) by measurement of both thyroid-stimulating antibodies (TSAb) and thyrotropin-binding inhibitory immunoglobulins (TBII) in serum from children with Graves' disease are limited in number of studies. The aim of this study was to investigate the levels of serum TSAb and TBII in children with Graves' disease, and to evaluate the clinical significance of these antibodies. We measured the serum TSAb and TBII at diagnosis and during management in 65 children with Graves' disease. Patients were divided into four groups according to their metabolic state: those with untreated active Graves' disease, those receiving treatment with antithyroid drugs, those in remission, and those in relapse. At diagnosis, both TSAb and TBII assays had high sensitivities and high specificities. In follow-up, the levels of both TSAb and TBII paralleled the course of the disease. There was a strong positive correlation between TSAb and TBII. TBII levels were significantly higher in the patients with ophthalmopathy than those without ophthalmopathy in untreated Graves' children. It was concluded that TSAb and TBII measurements are valuable in the diagnosis and management of children with Graves' disease.

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Major causes of fasting hypoglycemia in adults are insulinoma, factitious hypoglycemia and nesidioblastosis. The primary treatment for insulinoma is surgical removal of the tumor, but there are cases with hyperinsulinemia that cannot undergo surgery. Somatostatin analogue is one of the treatments used in such cases of insulinoma or persistent hyperinsulinemic hypoglycemia. We report here a patient who had undetermined hyperinsulinemia and was successfully treated with a long-acting somatostatin analogue, which had recently become available. The patient, a 72-year-old female, who had previously been diagnosed as insulinoma and undergone partial pancreatectomy, was admitted complaining of the recurrence of hypoglycemic attacks after an interval of ten years. On admission, hypoglycemia (42 mg/dl), hyperinsulinemia (IRI: 79.3 μU/m) and low HbA1c (3.6%) were present. In 75g-OGTT at 30 min after load, IRI reached 6623 μU/ml, while plasma glucose level was 88 mg/dl. The anti-insulin antibody was not present. Since attempts at tumor localization by imaging techniques failed and the patient refused further examinations or surgical treatment, we recommended her to take a medication with a somatostatin analogue. Insulin suppression test using 50 μg of octreotide improved plasma glucose and IRI levels, suggesting the usefulness of the treatment, and a monthly administration of 20 mg of long-acting octreotide has successfully controlled her symptoms of hypoglycemia for 10 months. Our case demonstrated the utility of the long-acting somatostatin analogue for long-term treatment of undetermined hyperinsulinemia. A preliminary loading test using short-acting octreotide may be useful to determine appropriate medication, especially in cases who cannot receive surgical treatment.

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The objective is to investigate the relation between the levels of two serum adipocytokines (adiponectin and resistin) and non-alcoholic fatty liver disease (NAFLD) in obese children. In this study, 113 obese children were enrolled and divided into 3 groups. Obese group 1 was defined as obese children without any liver abnormality. Obese group 2 was defined as obese children just with fatty infiltration of the liver in ultrasonic appearance and obese group 3 was defined as obese children with liver function abnormality. The controls consisted of 37 nonobese children without endocrine, metabolic or kidney disease. The levels of serum adiponectin and resistin were measured by ELISA method. Insulin resistance by homeostasis model (HOMA-IR), area under curve of glucose (AUCG), serum total cholesterol, triglyceride, alanine aminotransferase, uric acid, HDL-cholesterol, LDL-cholesterol and body mass index (BMI) were measured as well. In obese children, NAFLD were found in 63 cases (55.75%). Serum adiponectin levels of obese children were significantly lower than that of controls (3.63 vs 5.79 μg/mL, P<0.001) while serum resistin levels were not different (P = 0.876). Moreover, serum adiponectin levels in obese group 1 were significantly higher than that of group 2 and 3 (4.24 vs 3.37 and 3.12 μg/mL, all P<0.05) and no difference was found between obese group 2 and obese group 3 (P>0.05). Serum resistin levels among the three obese groups were 4.37 ng/mL, 3.72 ng/mL and 4.24 ng/mL without significant difference (P = 0.592). NAFLD, BMI, gender and HDL-cholesterol were independent determinants of serum adiponectin levels in children analyzed by multiple regression analysis, which explained 33% of the variance. Serum adiponectin levels were inversely associated with BMI, gender and NAFLD (all P<0.05) and were positively associated with HDL-cholesterol levels (P = 0.033). These results suggest that adiponectin might be a protective factor in NAFLD occurrence in obese children, and that the measurement of adiponectin should be part of the standard evaluation of the obese child and may help to evaluate the occurrence of NAFLD.

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Recently a new procedure for measuring serum TSH receptor (TSHR) autoantibody (TRAb) was reported by Smith et al. in which the autoantibodies inhibit binding of a human monoclonal thyroid stimulating antibody M22 (labeled with biotin) to TSHR-coated ELISA plate wells (pTRAb_3rd assay). The aim of this study was to compare the performance of pTRAb_3rd assay with pTRAb_2nd assay based on inhibition of TSH-biotin binding to TSHR-coated ELISA plate wells. In addition, we evaluated the applicability of TRAb3rd assay to discriminate between untreated Graves' disease (GD) and painless thyroiditis (PT). Analysis of sera from 230 healthy controls indicated that only 1 (0.43%) gave inhibition of M22-binding values of greater than 15% (32.8% inhibition). To define the clinical cut-off point for a positive serum with autoantibodies to the TSHR, we performed receiver operating characteristic curve of the data from 244 untreated GD and three different control groups for pTRAb_3rd assay. With a sensitivity of 99.6% at a cut-off of 14.5%, 22.0% and 22.0% inhibition of M22 binding, the specificity of healthy controls without PT, with PT and with PT excluding postpartum PT and PT during remission of GD was 99.6%, 96.6% and 97.5%, respectively. The pTRAb_3rd assay was closely correlated to pTRAb_2nd assay in the 244 untreated Graves' sera (r = 0.911). The pTRAb_3rd assay detected 243 of 244 (99.6%) untreated GD, whereas 9.2% of PT and 6.7% of the subacute thyroiditis (SAT) were detectable. In contrast, pTRAb _2nd assay detected 242 of 244 (99.2%) Graves' same sera, while 16.8 % from PT's same sera and 13.3% from SAT were detectable. In conclusion, pTRAb_3rd assay has significantly (p = 0.0026) superior diagnostic accuracy for GD and PT, compared to that of pTRAb_2nd assay.

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Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two risk groups for type 2 diabetes. Type 2 diabetes is characterized by both impaired insulin secretion and insulin resistance but their relative contribution to the development of hyperglycemia may differ due to heterogeneity of the disease. Combined glucose intolerance (CGI), on the other hand, seems to represent a more advanced stage of prediabetes that bears a distinctly higher risk of progression to diabetes and its comorbidities. This study has the aim to compare isolated IFG and CGI categories with respect to the degree of early phase insulin secretion abnormalities and insulin resistance. Subjects who had IFG (fasting glucose: 110–126 mg/dl) were included in the study. A 75-g oral glucose tolerance test (OGTT) with insulin response was done and subjects were classified according to the WHO criteria. Six subjects were excluded because they had diabetic glucose tolerance. A total of 66 patients (53.4 ± 11.1 years, female/male: 48/18) were divided into two groups according to their glucose tolerance in OGGT (Group 1: isolated IFG and group 2: CGI). Early phase insulin secretion was measured by intravenous glucose tolerance test (IVGTT) and OGTT. Insulin resistance was assessed by the R value of the homeostasis model assessment (HOMA). We did not find any statistically significant difference between groups according to age, gender, body mass index (BMI), fasting glucose, fasting insulin, insulin-AUC (0–180 min) and HOMA-R values. In OGGT there was no statistically significant difference between 0', 30', 60' and 90' insulin levels of the groups; only 120' and 180' insulin levels were higher in CGI than in IFG group (p<0.05). In IVGTT, there was no statistically significant difference between glucose levels of the groups. Furthermore, insulin response to intravenous glucose was higher in IFG than in CGI (p<0.05). Our data demonstrate that isolated IFG and CGI are similar with respect to the degree of insulin resistance, and that subjects with CGI had a more prominent deficit in early phases of insulin secretion.

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The serum T₃ to T₄ ratio is a useful indicator for differentiating destruction-induced thyrotoxicosis from Graves' thyrotoxicosis. However, the usefulness of the serum free T₃ (FT ₃) to free T₄ (FT₄) ratio is controversial. We therefore systematically evaluated the usefulness of this ratio, based on measurements made using two widely available commercial kits in two hospitals. Eighty-two untreated patients with thyrotoxicosis (48 patients with Graves' disease and 34 patients with painless thyroiditis) were examined in Kuma Hospital, and 218 patients (126 with Graves' disease and 92 with painless thyroiditis) and 66 normal controls were examined in Ito Hospital. The FT₃ and FT₄ values, as well as the FT₃/FT₄ ratios, were significantly higher in the patients with Graves' disease than in those with painless thyroiditis in both hospitals, but considerable overlap between the two disorders was observed. Receiver operating characteristic (ROC) curves for the FT₃ and FT₄ values and the FT₃/FT₄ ratios of patients with Graves' disease and those with painless thyroiditis seen in both hospitals were prepared, and the area under the curves (AUC), the cut-off points for discriminating Graves' disease from painless thyroiditis, the sensitivity, and the specificity were calculated. AUC and sensitivity of the FT₃/FT₄ ratio were smaller than those of FT₃ and FT₄ in both hospitals. The patients treated at Ito hospital were then divided into 4 groups according to their FT₄ levels (A: ≤2.3, B: >2.3~≤3.9, C: 3.9~≤5.4, D: >5.4 ng/dl), and the AUC, cut-off points, sensitivity, and specificity of the FT₃/FT₄ ratios were calculated. The AUC and sensitivity of each group increased with the FT₄ levels (AUC: 57.8%, 72.1%, 91.1%, and 93.4%, respectively; sensitivity: 62.6%, 50.0%, 77.8%, and 97.0%, respectively). The means ± SE of the FT₃/FT₄ ratio in the Graves' disease groups were 3.1 ± 0.22, 3.1 ± 0.09, 3.2 ± 0.06, and 3.1 ± 0.07, respectively, versus 2.9 ± 0.1, 2.6 ± 0.07, 2.5 ± 0.12, and 2.3 ± 0.15, respectively, in the painless thyroiditis groups. In the painless thyroiditis patients, the difference in the FT₃/FT₄ ratio between group A and group D was significant (p<0.05). Thus, the FT₃/FT₄ ratio in patients with Graves' disease likely remains unchanged as the FT₄ level rises, whereas this ratio decreases as the FT₄ level rises in patients with painless thyroiditis. In conclusion, the FT₃/FT ₄ ratios of patients with painless thyroiditis overlapped with those of patients with Graves' disease. However, this ratio was useful for differentiating between these two disorders when the FT₄ values were high.

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A 47-year-old man had suffered from prolonged fever for two months without clinical evidence of infection. Blood biochemistry and endocrine dysfunction indicated that he had pituitary insufficiency. Thorough whole body imaging studies merely identified a 22 × 14 mm mass lesion in the sella turcica. Tumor pathology and special cell marker study revealed the infiltration of atypical T-lymphoid cells and concomitant presence of some B-lymphoid cells. The fever subsided gradually following subtotal tumor resection and steroid supplementation. However, the mass lesion had invaded the cavernous sinus and optic chiasma shortly after surgery. Six months after his initial visit, metastasis lesions in the liver, the left adrenal gland, and retroperitoneal lymph nodes were discovered. In contrast to cells in the pituitary, the pathological investigation of the liver mass confirmed it to be exclusively of T-cell origin. Therefore, it is plausible that the pituitary dysfunction was related to an inflammatory process, namely hypophysitis, as well as the T-cell lymphoma. This case exemplifies the rarely noted condition of primary pituitary lymphoma with concomitant hypophysitis. Clinical diagnosis is indiscernible until the occurrence of systemic tumor metastasis.

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This report concerns a 79-year-old woman with coexisting anaplastic thyroid carcinoma (ATC) and Graves' disease (GD). The patient was referred to our clinic because of palpitation and a palpable mass on the left side of her neck. Thyroid function tests showed hyperthyroidism with elevated thyroid-stimulating antibodies. Ultrasonography of the thyroid demonstrated an adenomatous nodule-like marcated nodule (27.6 × 26.5 × 36.4 mm) with cystic degeneration inside the left lobe. ¹²³I thyroid scintigraphic imaging showed a cold area corresponding to the nodule with continuous uptake in the remaining thyroid tissue despite suppressed TSH levels. These findings led to a diagnosis of GD. On the other hand, the thyroid nodule could not be definitely diagnosed even after fine needle aspiration biopsy (FNAB) which produced findings suggestive of both papillary thyroid carcinoma and ATC. Open biopsy of the nodule showed an ATC. Regional lymph node metastases as well as multiple lung metastases, which could not be found at the initial visit, had been already developed by that time. Our case is pathophysiologically interesting because it suggests that GD or thyroid-stimulating antibodies (TSAb) may stimulate malignant transformation of differentiated carcinoma. It is also clinically important because it indicates that all thyroid nodules, particularly palpable cold nodules, associated with GD require careful management to detect malignancy because they are at higher risk of harboring malignancy.

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A 34-year-old woman was referred to our hospital complaining of sore throat and arthralgia. She had low-grade fever, tachycardia, and goiter with tenderness. Laboratory data revealed thyrotoxicosis and tests for acute inflammatory markers were positive. Thyroidal radioactive iodine uptake was below normal. Ultrasonography of thyroid revealed mild thyroid enlargement and hypoechogenic areas consistent with tenderness. Subacute thyroiditis was diagnosed and prednisone was administered. Two years later, her identical twin sister, who lives separately, was referred to our hospital because of neck pain, low-grade fever, and palpitation. She exhibited the same clinical picture as her twin sister, and was also diagnosed as having subacute thyroiditis. Although the cause of subacute thyroiditis remains unclear, viral infection has been implicated in the onset of subacute thyroiditis in genetically predisposed individuals. We could not identify the viruses, but heterozygotes for HLA-B35, which has been reported to be linked with subacute thyroiditis, were found in the twins. This supports the suspicion that genetic factors, including this HLA haplotype, play a critical role in the onset of subacute thyroiditis.

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We retrospectively investigated the effects of adding glimepiride in patients with type 2 diabetes showing suboptimal control by insulin therapy. Of 63 patients with poorly controlled insulin-treated type 2 diabetes (baseline HbA1c, 8.4 ± 0.6%), 32 were treated with insulin alone and 31 were given glimepiride in addition to insulin. HbA1c values, daily insulin dose, body weight, blood pressure, plasma lipid concentrations, and the number of hypoglycemic events were recorded at weeks 0, 12, 24, 36, 48, 60, and 72. HbA1c decreased by 1.1%, from 8.5 ± 0.6% to 7.4 ± 0.8% (P<0.0001) in patients treated with insulin plus glimepiride at 12 weeks, and improved glycemic control continued throughout the study. Required insulin dose was reduced significantly in patients treated with insulin plus glimepiride (from 29.4 ± 14.5 to 22.3 ± 12.1 units/day, P = 0.0187). Body weight increased significantly in patients treated with insulin plus glimepiride (from 57.0 ± 8.7 to 59.5 ± 9.2 kg, P = 0.0232). Adding glimepiride showed little effect on blood pressure, plasma total cholesterol, triglyceride, or HDL-cholesterol. Serum C peptide concentrations increased significantly in patients treated with insulin plus glimepiride (from 1.01 ± 0.71 to 1.28 ± 0.65 ng/ml, P = 0.0367). The number of hypoglycemic events did not differ between groups. Adding glimepiride to insulin therapy resulted in sustained improvement of glycemic control in patients with poorly controlled type 2 diabetes.

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The association between growth hormone (GH) replacement and malignancy has long been debated. We report a case of Hodgkin lymphoma that developed in temporal association with the initiation of GH replacement in a 57-year-old woman with panhypopituitarism secondary to a non-secretory pituitary macroadenoma. Treatment of her pituitary tumor included transphenoidal surgery, external beam radiation, Bromocriptine and Cabergaline therapy. In addition to replacement steroid, thyroid and sex hormones, she insisted on GH replacement. Approximately 2 years after GH initiation, the diagnosis of Hodgkin lymphoma was made. Although the exact contribution of GH to the development of Hodgkin disease in our patient is unclear and a causal effect cannot be concluded, the temporal association is suggestive, and warrants reporting as part of ongoing surveillance for potential complications of GH replacement.

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Many studies have been carried out to determine G_s α and TSHR mutations in autonomously functioning thyroid nodules. Variable prevalences for somatic constitutively activating TSHR mutations in hot nodules have been reported. Moreover, the increased prevalence of toxic multinodular goiters in iodine-deficient regions is well known. In Turkey, a country with high incidence rates of goiter due to iodine deficiency, the frequency of mutations in the thyrotropin receptor signal transduction pathway has not been evaluated up to now. In the present study, a part of the genes of the TSHR, G_sα and the catalytic subunit of the PKA were checked for activating mutations. Thirty-five patients who underwent thyroidectomy for multinodular goiters were examined. Genomic DNAs were extracted from 58 hyperactive nodular specimens and surrounding normal thyroid tissues. Mutation screening was done by single-strand conformational polymorphism (SSCP) analysis. In those cases where a mutation was detected, the localization of the mutation was determined by automatic DNA sequencing. No G_sα or PKA mutations were detected, whereas ten mutations (17%) were identified in the TSHR gene. All mutations were somatic and heterozygotic. In conclusion, the frequency of mutations in the cAMP signal transduction pathway was found to be lower than expected in the Turkish population most likely because of the use of SSCP as a screening method and sequencing only a part of TSHR exon 10.

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It has been noted that hypothyroidism in pregnant women can adversely affect the children's subsequent psychoneurotic development. Also, transient elevation of serum free thyroxine is occasionally seen in the first trimester of normal pregnancy. However, normal thyroid function during pregnancy and the puerperal period has not been clearly defined in Japan. The aim of this study was to assess maternal thyroid function during pregnancy and puerperal period in Japan. The concentrations of thyroid stimulating hormone (TSH), free triiodo-thyronine (free T₃), free thyroxine (free T₄) and thyroid binding capacity (TBC) of 522 normal pregnant and puerperal women (119 in the first trimester; 132 in the second trimester; 135 in the third trimester and 136 in the early puerperium) were measured by electrochemiluminescence immunoassay. We compared the measured data with those of healthy nonpregnant control. Twenty-six (21.8%) of 119 women in the first trimester had lower TSH levels and 23 (16.9%) of 136 women in the early puerperium had higher TSH levels than the normal range of healthy nonpregnant controls. Free T₃ gradually decreased during pregnancy, although it remained within the normal control range. Eight (6.7%) of 119 women in the first trimester had high free T₄ levels, which gradually decreased during pregnancy. Sixty (44.4%) of 135 women in the third trimester had low free T₄ levels. The values of TBC in the second trimester increased compared with the first trimester and did not change in the third trimester and decreased after delivery. There were no correlations between maternal TSH and levels of thyroid hormones (free T₃ or free T₄), except for TSH and free T₄ in the first trimester. In conclusion, we showed that maternal thyroid function, especially TSH and free T₄, changed during the course of pregnancy. In assessing the thyroid function associated with pregnancy, one needs to keep in mind the tendency toward low free T₄ levels in the third trimester and high TSH levels in the early puerperal period.

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Insulin receptor substrate-1 (IRS-1) is an endogenous substrate for the insulin receptor tyrosine kinase, which plays a key role in insulin signaling. Recent studies have identified several polymorphisms in the human IRS-1 gene (Irs-1) that are increased in prevalence among type 2 diabetic patients. To determine whether variation in the Irs-1 contributes to genetic susceptibility to type 2 diabetes in Turkish people, PCR-RFLP and DNA sequencing method were utilized to analyze the coding region of Irs- 1 in 70 subject and 116 control patients. Three missense mutations were detected (Gly972Arg, Ala512Pro, Ser892Gly). There was no significant association found with any of these variants and diabetes. The Gly972Arg mutation, however, was relatively more common in with 10/70 diabetic patients and 15/116 non-diabetic controls being heterozygous and 1/70 being and 0/116 non-diabetic controls being homozygous for this variant. As a conclusion, Ala512Pro, Ser892Gly mutations were rare and Met613Val, Ser1043Tyr and Cys1095Tyr mutations were not found in the populations studied. Gly972Arg is more common than other known mutations in our population but may not be a major determinant in genetic susceptibility to type 2 diabetes.

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A total of 1,228,551 newborn babies, who were almost all of babies born in Osaka for 14 years (168 months), were screened for congenital primary hypothyroidism by an identical mass-screening program using the thyrotropin method, and 429 patients with hypothyroidism due to thyroid dysgenesis (dysgenetic hypothyroidism) were found. The occurrence of the patients in every month was not random but episodic and the incidence was higher in the late autumn (from October to December). These observations support a hypothesis that some environmental factors may cause this disorder overtime and the possibility of relation with intrauterine viral infection was discussed.

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Somatostatin is well known to inhibit the hormone secretion of various peptides. This action has been considered to be generally mediated via six different specific somatostatin receptors (sstr), sstr1, sstr2A, sstr2B, sstr3, sstr4, and sstr5. It then becomes very important to demonstrate the localization of these sstr subtypes in order to elucidate the possible biological and/or clinical significance of somatostatin actions. These sstr subtypes have been demonstrated to be expressed throughout the human body, including the central nervous system, gastrointestinal tract, pancreas, kidney, and other organs, but its details, especially its systemic distribution and localization in tissue compartments, have yet to be examined thoroughly in human. Therefore, in this study, we examined the systemic localization of all six somatostatin receptors in normal human organs using immunohistochemistry with recently developed specific antibodies against these receptor subtypes. In all of the human tissues examined, various sstr subtypes were detected not only in parenchymal cells but also in various stromal cells such as lymphocytes, fibroblasts, and endothelial cells. Among human tissues in which the presence of sstr has not been previously reported, the parotid gland demonstrated immunoreactivity for sstr2B and sstr5, bronchial gland for sstr1, 2B, 3, 4, 5, parathyroid gland for sstr1, 3, 4, and duodenum for all subtypes immunoreactivity. The great majority of other organs examined demonstrated results consistent with those of previously reported biochemical studies. In pancreatic islet cells, only sstr2A was positive in all the cases but other sstr subtypes were associated with marked intraislet heterogeneity in their distribution. In stomach, all subtypes of receptor were detected in various cell types of the mucosa, but none in ECL cells of fundic gland. These findings demonstrated the broad systemic actions of somatostatin in non-endocrine cells.

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There are many intricacies in the surgical treatment of locally advanced thyroid cancer, including the medical management of the remaining functional organ and any cosmetic impairments, which are sometimes very difficult to manage and eventually carry a relatively high morbidity and mortality. Here, we report on a case of a 65-year-old female with an extremely locally-advanced thyroid cancer involving both lobes of the thyroid, blood vessels, trachea and esophagus. Despite the severity of her condition, oral administration of vitamin D3 (alphacalcido) has stalled both the tumor growth and further increases of serum thyroglobulin (Tg) level, and has led to a good preservation of quality of life for the last two years. Several reports have previously demonstrated the efficacy of vitamin D3 to inhibit the proliferation of thyroid cancer cell lines in vitro, but clinical evidence has been limited so far. Therefore, this case report provides important evidence for the effectiveness of vitamin D3 therapy against advanced thyroid cancers.

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Two brothers and their mother, who had allergic rhinitis caused by Japanese cedar pollen, developed silent thyroiditis in spring. In addition, these three patients had the same HLA haplotype. Another brother, the father, and the paternal grandmother, who did not have allergic rhinitis caused by Japanese cedar pollen, did not show symptoms of silent thyroiditis. The present study indicates that genetic and/or environmental factors are important in the development of this familial type of silent thyroiditis.

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An 82-year-old woman with type 2 diabetes had been treated with recombinant human insulin for 16 years. She developed large swellings in both sides of her lower abdomen. The masses were soft, painless, and located around her insulin injection sites. Based on the history and clinical features, a diagnosis of insulin-induced lipohypertrophy was made. Total resection revealed that the lesions were composed entirely of fatty tissue. Microscopic examination showed nests of mature adipocytes expanding toward the dermal reticular layer. The hypertrophic adipocytes were twice as large as those from normal subcutaneous areas and contained numerous small lipid droplets. Electron microscopic analysis also revealed a minor population of small adipocytes, suggesting active differentiation or proliferation. Thus, the possible in vivo effects of insulin on adipocytes were clearly observed in this case of insulin-induced lipohypertrophy. To our knowledge, this is the first report of insulin-induced lipohypertrophy with detailed histological examinations.

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The patient was an 83-year-old woman who was admitted to our hospital for evaluation and treatment of chronic hypoglycemia that was first identified 3 years earlier. Serum insulin and C-peptide levels were both elevated during hypoglycemia. Contrast abdominal computed tomography revealed a tumor in the body of the pancreas with blushing during the early phase, and insulinoma was diagnosed. The patient declined surgery because of advanced age, so treatment was started with octreotide, a somatostatin analogue. Hypoglycemia has been successfully controlled with low-dose, once-daily octreotide over 33 months. Few reports have described long-term octreotide administration for benign insulinoma. Moreover, this case is interesting from the perspective of hypoglycemic control using only low-dose, once-daily octreotide. Although somatostatin may induce hypoglycemia in insulinoma, treatment may be useful in patients who are not candidates for surgery, provided that careful monitoring is maintained.

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Several clinical reports have suggested that prolactin (PRL) plays an important role in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). We have investigated the influence of PRL on immune system, by evaluating the effects of PRL on the expression of CD69 and CD25 on human peripheral blood mononuclear cells (PBMCs). Human PBMCs obtained from healthy female volunteers were incubated with phytohemagglutinin (PHA) in the presence or absence of various concentrations of PRL. The expression of CD69 and CD25 was monitored using immunofluorescence staining and flow cytometry. PRL significantly enhanced the expression of CD69 and CD25 on activated PBMCs compared with that in the absence of PRL (p<0.05, paired t-test). Increasing doses of PRL enhanced the expression of CD69 up to 2 μg/ml and CD25 up to 1 μg/ml. The enhanced expression of CD69 was observed on CD8+ T lymphocytes but not on CD4+ T lymphocytes. Our data suggest that PRL can significantly enhance the expression of CD69 and CD25 molecule on human PBMCs when induced by PHA. However, PRL would have to be at optimal concentration in order to enhance their expression.

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We encountered a Japanese patient with goitrous hypothyroidism due to iodide organification defect in the thyroid gland. Sequence analysis identified two novel mutations (E378K in exon 8 and a heterozygous 10 base deletion of the intron 15-exon 16 boundary) in the thyroid peroxidase (TPO) gene. As individuals with goitrous hypothyroidism caused by TPO gene mutation develop thyroid cancer, regular and careful follow-up for such patients must be done.

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Graves' disease is a rare disorder in children, particularly in infants. Ocular manifestations of Graves' disease in children are even more rare and are mild compared to adults. We report a 3-year-old girl with Graves' ophthalmopathy who visited our clinic because of lacrimation. Her family had also noticed exophthalmos, goiter, irritability and increased appetite for more than 3 months. The ophthalmologist noted bilateral proptosis, eyelid erythema, lacrimation, entropion of the lower eyelid, and superficial keratitis. Her serum concentrations of free thyroxine and free triiodothyronine were high, and thyroid-stimulating hormone (TSH) was low. Serum samples were markedly positive for antibodies to TSH receptor (TRAb) and thyroid-stimulating antibody (TSAb). Although hyperthyroidism was controlled with propylthiouracil within 3 weeks, her eye signs did not improve. We administered methylprednisolone pulse therapy for ophthalmopathy, but the effect was limited and the lacrimation due to entropion and superficial keratitis persisted. Titers of both TRAb and TSAb decreased slightly and transiently with the pulse therapy. One year later, both titers remained high and eye signs did not improve any more though she was clinically euthyroid. This might indicate that both TRAb and TSAb levels correlate with the clinical course. Therefore, TRAb or TSAb might be good indicators of progress of Graves' ophthalmopathy. Ocular manifestations of Graves' disease should be followed closely with measurements of both TRAb and TSAb even in infant cases.

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