To investigate the function of the β_C and β_E subunits of activin, we overexpressed these subunits in AML12 cells, a normal hepatocyte cell line, using adenovirus vector. Overexpression of the β_C subunit increased [³H]thymidine incorporation and the cell number. In contrast, both [³H]thymidine incorporation and the cell number were reduced in the β_E overexpressing cells. When AML cells overexpressing the β_E subunit were cultured in medium containing 1% serum for 48 h, many of the cells died by apoptosis, whereas cells overexpressing the β_C subunit or β-galactosidase survived in the same condition. To examine dimer formation, the β_C and β_E subunits were expressed in AML12 cells. In these cells, the β_C homodimer, the β_E homodimer and the β_C-β_E heterodimer were detected. When the expression level of the β_E subunit was increased, formation of the β_E homodimer was increased, while formation of the β_C-β_E heterodimer was slightly reduced. Overexpression of the β_E subunit did not significantly affect the formation of the β_C homodimer. These results indicate that the β_C and β_E subunits form homo- and heterodimers, and that the functions of the two subunits are quite different.

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We evaluated the efficacy of preoperative high-resolution ultrasonography (US) for diagnosing possible concomitant thyroid disease which affects the surgical management in patients with primary hyperparathyroidism (pHPT). One hundred and nine patients with sporadic pHPT underwent US with or without ultrasound-guided fine-needle aspiration biopsy (US-FNAB). Diagnosis of concomitant thyroid nodules by US and US-FNAB were compared with the histopathological findings. Of the 109 patients, 19 (17.4%) had malignant thyroid nodules, 26 (23.9%) had benign thyroid nodules alone, and 12 (11.0%) had diffuse goiter. The sensitivity, specificity, and accuracy of diagnosing 72 thyroid nodules were 91.3%, 91.8%, and 91.7% for US, 57.9%, 94.3%, and 81.5% for US-FNAB, and 95.7%, 91.8%, and 93.1% for combined US and US-FNAB, respectively. True positive/false negative ratio of US-FNAB diagnosis was significantly lower in nodules of 5–9 mm than nodules of 10 mm or more. Four unexpected thyroid cancers existed at a different site in 3 of the 39 patients with palpable thyroid disease. Five thyroid cancers were histopathologically confirmed in 5 (7.1%) of 70 patients without palpable thyroid disease. Eight (88.9%) of the 9 non-palpable thyroid cancers were accurately diagnosed by combined US and US-FNAB. Preoperative US is useful for evaluation of possible concomitant thyroid disease, especially for prediction of malignancy.

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The aim of the study was to investigate the hypothalamo-pituitary-adrenal (HPA) axis by ACTH stimulation test and the changes in adrenal size in acute brucellosis before and after therapy in a prospective study. Sixteen patients with acute brucellosis and 15 healthy subjects were included in the study during the last two years. Cortisol levels were assessed before, 30 and 60 minutes after ACTH (250 μg i.v.) injection and the size of the adrenals was measured in both groups. Mean basal cortisol levels in the patients before the therapy and after the therapy were 22.1 ± 6.9 μg/dL and 11.3 ± 6.0 μg/dL, respectively. The difference was statistically significant (p<0.001). There was also statistically significant difference for basal cortisol levels between the healthy subjects (12.2 ± 4.6 μg/dL) and the patients before the therapy (p<0.001). Peak cortisol responses to ACTH were higher before the therapy in the patients with acute brucellosis (39.3 ± 10.7 μg/dL) than in the healthy subjects (30.4 ± 4.8 μg/dL, p = 0.014). However, there was no significant difference for peak cortisol levels in the patients before and after the therapy (32.7 ± 8.0 μg/dL). Mean basal cortisol levels and peak cortisol responses to ACTH between the patients after the therapy and the healthy controls were similar. Both the maximum width of the adrenal glands and the width of the adrenal limbs were significantly greater before the therapy compared to healthy subjects and post-treatment period. We concluded that the HPA axis is activated and the adrenal glands are enlarged in acute brucellosis, which is reduced after appropriate therapy.

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In purpose of identifying thyroid tissue in patients with congenital hypothyroidism during childhood, ultrasonography is usually used as a screening examination, and scintigraphy is performed secondarily. Though these methods are useful, it is not easy to identify the accurate location of thyroid tissue by these methods. We previously reported the utility of computed tomography (CT) in identifying thyroid tissue in four cases of congenital hypothyroidism. The purpose of this study is to investigate whether CT is useful in identifying thyroid tissue, compared to ultrasonography or scintigraphy. Nineteen cases (0 month to 18 years of age) that were suspected to have ectopic thyroid tissue or thyroid agenesis on ultrasonography were examined by CT. CT was useful in diagnosing ectopic thyroid tissue or thyroid agenesis in all the cases, whereas ultrasonography or scintigraphy was less accurate in this purpose in seven cases. Plain CT had a difficulty in identifying thyroid tissue in two cases, in which contrasted image was required. This study showed that CT, especially an enhanced CT, is useful in identifying thyroid tissue, when the gland is not identified in the normal position by ultrasonography.

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Pheochromocytoma is a tumor that produces a variety of biologically active substances in addition to catecholamines. We report here a patient with a pheochromocytoma, who presented with acute inflammatory symptoms and marked abnormalities in liver function and hematological tests. A 31-year-old man, who had experienced intermittent fever, chills and weight 1oss during the previous several months, was referred to our hospital for further evaluation. Laboratory examination revealed anemia, leukocytosis with elevated inflammatory markers, and abnormalities in coagulation and liver function tests. Histological examination revealed a marked plasmacytosis in the bone marrow and lymphocyte infiltration into the portal area of the liver. Along with increases in serum catecholamine and urine catecholamine metabolites, his serum interleukin (IL)-6 level was increased to 300 pg/ml, compared with a normal range of 3–12 pg/ml. Left adrenalectomy was performed. The adrenal tumor was densely immunostained with antibody to IL-6. After resection of his adrenal tumor, his serum IL-6 level returned to normal (11 pg/ml) and all symptoms subsided with normalization of laboratory findings.

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Purpose of the study is to compare complication rates of bilateral subtotal (BST), near total (NTT) and total thyroidectomy (TT) in a cohort of patients undergoing surgery for benign multinodular goitre (MNG). Seven hundred and fifty patients undergoing surgery for MNG were studied with a median follow-up of 53 months (range 18–102). There was no operative mortality in this group and no patients required urgent re-exploration for haematoma. After BST 14 patients (14/170 – 8.2%) developed transient hypocalcaemia and 4 patients (4/170 – 2.4%) had transient and one permanent (1/170 – 0.6%) recurrent laryngeal nevre (RLN) palsy. In NTT group 39 patients (39/320 – 12.2%) developed transient hypocalcaemia and 2 patients (0.6%) transient voice disturbances. None of the patients in this group experienced permanent complications. However, in TT group 78 patients had (78/260 – 30%) transient hypocalcaemia whereas only one patient (1/260 – 0.4%) suffered permanent hypoparathyroidism and 5 patients (5/260 – 1.9%) had temporary RLN injury but none of them remained permanent. There are only 2 (2/170 – 1.2%) recurrences and those patients are in BST group. All of the patients in BST group required at least 100 μg of thyroxine supplementation following the operation. These results demonstrate low permanent complication rates following thyroid surgery. Although the incidence of transient hypoparathyroidism increases with the extent of the resection, permanent complication rates are similar for all three surgical procedures. Even with short follow-up, there is a risk of recurrence with BST and therefore NTT or TT may be the operation of choice for MNG.

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The aim of this study was to define the preoperative diagnosis of thyroid follicular carcinoma by the vascular pattern and velocimetric parameters using high resolution pulsed and power Doppler ultrasonography (US). We compared the vascular pattern and the velocimetric parameters, such as peak systolic velocity (Vmax), end-diastolic velocity (Vmin), pulsatility index (PI), or resistance index (RI) between follicular adenoma (FA, n = 25) and follicular carcinoma (FC, n = 10) and analysed them by means of receiver characteristics curves (ROC). Of 10 patients with FC, 8 (80%) patients presented a moderate increase of intranodular vascularization using power Doppler US. In contrast, the majority (84%, 21 out of 25 cases) of FA cases showed only a peripheral rim of color flow even by power Doppler US. These color flow imagings by power Doppler US were suggested to be a reliable tool for the differential diagnosis of thyroid follicular tumor with a sensitivity of 87.5% and a specificity of 92%. In velocimetric analyses, the Vmax/Vmin ratios, PI, and RI were significantly higher in the patients with FC than those with FA (p<0.001, p<0.005, and p<0.001, respectively). By means of ROC, FC could be diagnosed with a cutoff value of ratio of PI (>1.35), RI (>0.78), and Vmax/Vmin (>3.79). The diagnostic efficiency evaluated by ROC curves were 0.898 for PI, 0.876 for RI, and 0.888 for Vmax/Vmin, respectively. In conclusion, the evaluation of the vascular pattern and the velocimetric parameters using pulsed and power Doppler ultrasound may provide important information that is useful in making correct differential diagnosis of malignant or benign thyroid follicular tumor preoperatively.

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Leptin is considered to play a role in maintenance of energy balance and body weight by neuroendocrine mechanisms. The physiological mechanisms for thyroid hormone-induced alteration in serum leptin are not well known. In the present study, the relationship between thyroid hormones and leptin levels was investigated in patients with overt hypothyroidism and hyperthyroidism before and after successful treatment. Leptin levels were determined by radioimmunoassay and body mass index (BMI) was calculated for each subject. Serum leptin levels of 26 hypothyroid and 22 hyperthyroid patients were compared with those of 20 healthy volunteers who comprised the controls. Serum leptin levels of hypothyroid patients (28.4 ± 4.1 ng/ml) were found to be significantly higher than the controls (19.1 ± 3.2 ng/ml) (p<0.01), whereas hyperthyroid patients had lower levels (10.7 ± 1.2 ng/ml) (p<0.01). In hypothyroid patients, serum leptin levels were decreased significantly to 20.6 ± 2.1 ng/ml with thyroxin treatment (p<0.05). However, in hyperthyroid group, serum leptin levels were increased to 12.4 ± 2.2 ng/ml by treatment (p>0.05). BMI was not changed with the treatment in either group. The serum leptin levels were correlated with BMI and thyrotropin (TSH) in both hypothyroid and hyperthyroid patients. Serum leptin levels are affected in thyroid disorders and the correlation of leptin with TSH is independent of thyroid hormones.

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Sheehan's syndrome frequently causes hypopituitarism either immediately or after a delay of several years, depending on the degrees of postpartum ischemic pituitary necrosis. A 55 year-old woman whose last child was born 27 yr ago with massive hemorrhage was diagnosed as postpartum hypopituitarism. She had deficiency of growth hormone, prolactin, gonadotropins and thyrotropin. However, she interestingly had apparent hypercortisolism without suppression response to the dexamethasone tests. We found an adrenal mass with distant metastases to the liver and lung while investigating the origin of the hypercortisolism. Hyperandrogenism and very high levels of 17α hydroxyprogesterone were present. Accordingly, the patient was diagnosed as hypopituitarism due to Sheehan's syndrome accompanied by Cushing's syndrome as a result of an adrenocortical carcinoma.

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To determine the usefulness of parathyroid scintigraphy in histological estimation for secondary hyperparathyroidism (2HPT) using Tc-99m sestamibi or Tc-99m tetrofosmin. Tc-99m sestamibi (MIBI) and Tc-99m tetrofosmin (Tetro) parathyroid imaging following double-phase study, magnetic resonance imaging (MRI), and ultrasound were performed on 14 patients with 2HPT. All patients underwent parathyroidectomy. The uptake of two tracers in parathyroid areas was compared with the histopathologic findings. Forty-nine parathyroid glands were surgically explored and histologically proven to be hyperplastic. Of these, 42 were diagnosed with nodular type (N-type) hyperplasia, and 7 with diffuse type (D-type) hyperplasia. MIBI and Tetro parathyroid imagings detected 34 and 35 parathyroid glands, respectively. The sensitivity of MIBI was determined to be 76.2% (32/42) for N-type, and 28.6% (2/7) for D-type. The sensitivity of Tetro was determined to be 78.6% (33/42) for N-type and 28.6% (2/7) for D-type. The sensitivity of both MIBI and Tetro was significantly higher for N-type than for D-type, 76.2% (32/42) vs. 28.6% (2/7) in MIBI, P = 0.022; 78.6% (33/42) vs. 28.6% (2/7) in Tetro, P = 0.015. The sensitivity of MRI was determined to be 76.2% (32/42) for N-type and 42.9% (3/7) for D-type, and the sensitivity of ultrasound was 71.4% (30/42) for N-type and 71.4% (5/7) for D-type. There was no significant difference in the sensitivity of MRI or ultrasound between N-type and D-type. The uptake ratios of MIBI and Tetro were also greater for N-type than for D-type. The detectability of both MIBI and Tetro was greater for N-type than for D-type. Tc-99m MIBI or Tc-99m Tetro parathyroid scintigraphy therefore may be used clinically to distinguish N-type from D-type parathyroid gland hyperplasia.

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For this study we enrolled 1,615 males who were admitted to our hospital for a general health check-up. Plasma glucose (PG) and insulin were measured during 75 g OGTT, and abdominal obesity was assessed by ultrasonography in all subjects. We divided them into several groups: normal glucose tolerance (NGT), high-normal glucose tolerance (h-NGT) who showed >10.0 nmol/l at 1 hr PG among those with NGT, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG + IGT, and DM, according to the results of 75 g OGTT. The aim of the present study was to clarify the clinical characteristics of pre-diabetic disorders relating to metabolic syndrome by comparing various parameters including body mass index (BMI), blood levels of various lipids and abdominal wall fat index (AFI) calculated from the thickness of preperitoneal (Pmax) and subcutaneous (Smin) fat layer in the abdomen estimated by ultrasonography with insulin sensitivity determined by homeostatic model assessment (HOMA-IR) in each type of abnormal glucose regulation as classified by PG changes in 75 g OGTT. We also investigated the relationship between insulin secretion capability and insulin sensitivity to delineate the characteristics of each type of abnormal glucose regulation, and compared the area under the insulin curve (AUCins) and the time axis, and the ability of early insulin secretion by glucose loading (insulinogenic index: I.I.) in each type of abnormal glucose regulation. There was a significant positive correlation between HOMA-IR and Smin or Pmax, suggesting that Smin and Pmax may reflect insulin sensitivity. Abdominal obesity, which was diagnosed from the data of AFI, was present in the h-NGT and IFG + IGT groups, suggesting that those groups belong to the clinical entity of metabolic syndrome. HOMA-IR was higher in IFG than in IGT, although I.I. was reduced and AUCins was increased in IFG as well as in IGT. h-NGT demonstrated a slightly lower I.I. and higher AUCins, compared with IGT. IFG demonstrated much stronger insulin resistance than IGT, although I.I. was reduced and AUCins was increased in IFG and IGT. Thus, it is suggested that insulin sensitivity may partly account for the difference in pathogenesis between IFG and IGT; and that h-NGT, which showed abdominal obesity assessed as AFI by ultrasonography, should be recognized as a disease state of metabolic syndrome with impaired glucose regulation.

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To decrease total body iodine is a key point in preparation for radioiodine study and therapy. We introduced a stringent self-managed low iodine diet (LID) and compared the outcome to that of the conventional restricted iodine diet (RID) for outpatients. We measured urine iodine to creatinine ratios (I/Cr) in patients prepared with RID for one week, LID for one week, or LID for two weeks. Mean urinary iodine excretion after RID for one week (n = 210) was 182.2 μg/gCr (range, 13–986 μg/gCr; standard deviation (SD) = 158.5) not reaching below the recommended level (I/Cr<100 μg/gCr). Urinary iodine excretion after LID for one week (n = 15) showed a lower mean urinary iodine level (I/Cr 119.4 μg/gCr; range, 23–218 μg/gCr; SD = 55.9) than RID for one-week, and two-week LID (n = 17) showed an even lower mean level (I/Cr 63.1 μg/gCr; range, 7–134 μg/gCr; SD = 38.7). The one-week LID period adequately (recommended level of I/Cr being less than 100 μg/gCr) prepared 26% of the patients, while two-weeks on the diet adequately prepared 70% of the patients. Furthermore, none of the two-week LID patients had I/Cr>150 μg/gCr, although a significantly greater number of one-week LID patients (19%) did. Our self-managed, outpatient LID successfully induced iodine deficiency, and two-week LID may be recommended for preparation in radioiodine study and therapy for thyroid cancer.

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Several cardiovascular risk factors correlate with adiponectin levels. It is not known whether total homocysteine, folate and γ-glutamyl transferase levels correlate with adiponectin. We cross-sectionally analyzed the association between adiponectin and these cardiovascular risk factors in diabetic patients. One hundred and two male inpatients with type 2 diabetes without overt nephropathy or insulin use were studied. In a regression analysis of the quartiles of adiponectin, plasma levels of adiponectin were associated positively with HDL-cholesterol and age, and inversely with body mass index and HbA_1c, but not with total homocysteine, folate or γ-glutamyl transferase. Non-traditional cardiovascular risk factors such as homocysteine and folate levels were not associated with adiponectin levels in male type 2 diabetic patients who are not subject to insulin therapy.

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Progesterone is involved in various functions of the cardiovascular system, including those of vascular smooth muscle cells (VSMCs) via progesterone receptor (PR). Progesterone has also been postulated to be involved in inhibition of VSMC proliferation via PR. However, the details of PR expression have remained largely unknown in human cardiovascular VSMCs. Therefore, we first examined the relative levels of PR isoform (PR-A and PR-B) expression in VSMCs, using both immunohistochemistry and quantitative RT-PCR analysis. PR-B was equally expressed between male and female aorta, but PR-A was more abundant in female than in male aorta. This finding demonstrated that the status of PR subtype expression was associated with the difference of genders.

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To clarify whether quantitative insulin sensitivity check index (QUICKI) is useful as an indicator of insulin resistance in Japanese metabolically obese, normal-weight (MONW, body mass index (BMI) <25 and visceral fat area (VFA) ≥100 cm² by abdominal computed tomography scanning) subjects with normal glucose tolerance (NGT). Insulin resistance was measured by QUICKI and euglycemic hyperinsulinemic clamp study (clamp IR) in 27 MONW and 27 normal subjects (BMI <25 and visceral fat area <100 cm²). QUICKI (P<0.01) and clamp IR (p<0.01) were significantly decreased in MONW subjects compared with normal subjects. QUICKI was significantly associated with VFA [MONW subjects: r = –0.459, p<0.02; all (MONW and normal) subjects: r = –0.506, p<0.0001] and with the serum levels of triglycerides (MONW subjects: r = –0.386, p<0.05; all subjects: r = –0.505, p<0.001) in MONW and all subjects. There were significant correlations between clamp IR and VFA (MONW subjects: r = –0.562, p<0.01; all subjects: r = –0.575, p<0.0001), fasting serum levels of insulin (MONW subjects: r = –0.673, p<0.001; all subjects: r = –0.619, p<0.0001) or serum levels of triglycerides (MONW subjects: r = –0.485, p<0.02; all subjects: r = –0.565, p<0.0001) in MONW and all subjects. QUICKI was significantly correlated with clamp IR in MONW (r = 0.754, p<0.0001) and in all subjects (r = 0.568, p<0.0001). QUICKI may be an useful method for assessing insulin resistance in Japanese MONW subjects with NGT.

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An open-label prospective cross-over trial was performed to evaluate the antioxidative effect of fluvastatin in Japanese type 2 diabetics with hyperlipidemia. The study subjects were 10 patients who were on pravastatin (10 mg/day) or simvastatin (5 mg/day). After at least 12 weeks of continuous pravastatin or simvastatin therapy, the drugs were washed out for 12 weeks and replaced with fluvastatin (30 mg/day), then the treatment was continued for another 12 weeks. Total cholesterol and LDL cholesterol were efficiently and comparably reduced by all three statin agents. There were no differences in serum parameters of oxidative stress such as malondialdehyde-modified low-density lipoprotein, thiobarbituric acid-reactive substances, and 8-iso-prostaglandin F2α between pravastatin/simvastatin and fluvastatin. However, fluvastatin, but not pravastatin/simvastatin, significantly reduced 3,5,7-cholestatriene in erythrocyte membrane, representing the extent of membrane cholesterol peroxidation. Our data demonstrated that fluvastatin has a unique anti-oxidative effect in patients with type 2 diabetes and hyperlipidemia, compared with other statins.

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Opiates suppress TSH in experimental animals but are reported to increase TSH in human subjects. We describe a patient in severe pain treated with morphine, whose previously normal TSH fell to a level usually associated with hyperthyroidism. After returning to a normal concentration, TSH again decreased with morphine administration. This suggests that, in contrast to the stimulation of TSH secretion that has been reported in unstressed experimental subjects, morphine can inhibit TSH secretion during stress in man as it does in experimental animals. This observation is consistent with the known sensitization of opiate receptors by stress. Consideration should be given to the possibility that severe suppression of TSH by opiates in stressed patients may induce clinically significant central hypothyroidism.

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The octanoylation of Ser3 is essential for the biological function of ghrelin. We examined the concentrations of the n-octanoylated active-form ghrelin in cord and neonatal blood using an RIA system that specifically recognized n-octanoylated ghrelin, as well as a system that measured the total ghrelin concentration. Plasma levels of active ghrelin in cord blood ranged from 7.7 to 38.4 pmol/l and correlated excellently with those of total ghrelin (r = 0.81, p<0.0001). The active ghrelin/total ghrelin (A/T) ratio ranged from 0.038 to 0.12 (median 0.072). The active ghrelin concentrations negatively correlated with birth body weight (r = –0.34, p = 0.01) and IGF-1 concentrations (r = –0.40, p = 0.003), but did not correlate with growth hormone (GH) concentrations. A considerable level of active ghrelin was detected in premature newborns. Venous cord blood samples showed a significantly higher active ghrelin concentration (p = 0.03) and A/T ratio (p = 0.01) than those in the artery. In neonatal blood, active ghrelin concentrations ranged from 4.6 to 22.6 pmol/l and the A/T ratio ranged from 0.02 to 0.081. These results demonstrate the existence of active-form ghrelin in fetal and neonatal circulation and may suggest the energy supply-dependent regulation of ghrelin expression/secretion in utero.

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Octreotide is one of the somatostatin analogue used for the treatment of endocrine tumors principally to suppress hormone secretion and to inhibit tumor growth. We experienced a case with multiple endocrine neoplasia type 1 who small amount of octreotide dramatically relieved the lumber pain caused by metastatic bone tumor. He had recurrent bronchial carcinoid tumors that metastasized to liver and bones. The spontaneous and radiated pain by bone tumors subsided within a few minutes after the initial injection of octreotide and the effect persisted for several hours. Combination therapy of octreotide and interferon α-2b significantly reduced the size of metastatic liver tumors and inhibited further growth of metastatic bone tumors for the last 27 months. The use of octreotide may be a good option for controlling pain by metastatic bone disease and combination therapy of octreotide and interferon α-2b is worth to try for patients with inoperable metastatic carcinoid tumor.

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The simultaneous occurrence of different types of thyroid carcinoma in a single patient is an unusual event. We report the case of a 52-year-old man with the history of two previous thyroid operations for benign goiters, who developed a recurrent goiter. The patient was referred to our department for thyroidectomy. In the pathohistological examination the specimen showed a 5 cm follicular carcinoma and a 0.3 cm papillary microcarcinoma in the right lobe as well as a 1.5 cm medullary carcinoma in the left lobe. All tumors were clearly separated from each other, representing the pure entity of each type. Postoperatively, RET germline mutation was ruled out by sequence analysis of peripheral blood leucocytes. Postoperative I-131-radioiodine scan showed multiple lung and liver metastases, while calcitonin was negative. There is no known common cause of these three different tumor types and they developed most independently from each other. The personal history of our patient was interesting in two aspects: (1) he suffered a period of severe staphylococcal sepsis with temporal immunosuppression and (2) he worked for long years as a coremaker in a foundry. This work represented possible long term exposure to inhalative carcinogenous toxins like hydrazine, which caused thyroid parafollicular cell adenomas in an animal model.

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