Our objective was to evaluate whether there is a multimodal distribution of thyroid volume (ThV) in iodinereplete adolescents and to examine the relation between excessive ThV and the presence of thyroid hypoechogenicity (HE), serum thyroperoxidase antibodies (anti-TPO) and TSH levels >4.5 mU/l. ThV was measured by ultrasound in adolescents aged 13 yr (N = 1083) and 17 yr (N = 1089) from 22 schools in 6 districts of eastern Slovakia and expressed as ml and ml/m² body surface area. For each age group the multimodal distribution of ThV values was tested by computing their frequency at intervals of 0.5 ml/m² and plotting the cumulative frequency on a probability scale in which each segment with normal distribution should give a straight line. In all examined subjects the HE was evaluated by ultrasound; in 924 (42.5%) of those anti-TPO was estimated by radioimmunoassay and TSH by immuno-electrochemiluminiscent assay. The medians of urinary iodine found in 55-164 spot urine samples from each of 6 districts (total number = 1003) were 126-142 μg/l, indicating an iodine-replete status. There was a trimodal distribution of ThV in each group, 80-85% in the lowest, 10-15% in the middle, and 5-7% in the upper segments. In the 10th ThV decile of the 17-yr group the frequency of HE (33/109 = 30.3%), anti-TPO (13/62 = 21.0%) and TSH (6/62 = 9.7%) was significantly higher than that in the 1st-9th decile (71/980 = 7.2%, P<0.001; 23/482 = 4.8%, P<0.001 and 5/482 = 1.0%, P<0.001, resp.). Similar differences were found in the 13-yr group (21/109 = 19.2% vs. 58/974 = 5.9%, P<0.001 for HE, 5/60 = 8.3% vs. 3/320 = 0.9%, P<0.001 for anti-TPO and 2/64 = 3.1% vs. 4/317 = 1.3% (not significant) for TSH >4.5 mU/l. Thus in the 10% of subjects with the highest ThV, the frequency of HE and anti-TPO was 4-5 times higher than in the remaining 90%. Our data indicate that an epidemiological evaluation of a large population of adolescents can detect a group with early signs of thyroid dysfunction (e.g. excessive ThV, increased frequency of HE, anti-TPO and TSH >4.5% mU/l), although such dysfunction may not be clinically apparent. This contrasts with numerous earlier reports which used a logarithmic transformation of the data in similar ThV sets, thus making the data appear homogeneous (unimodal) and with a normal distribution and obscuring the true multimodal distribution. This further prevents recognition of subjects with evidence of disordered thyroid status which thus become falsely included into a normal range.

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Background: It remains undetermined whether bone mineral density (BMD) of hemodialysis (HD) patients with diabetes mellitus (DM) is reduced or not. The present study was performed to compare BMD between HD patients with DM and chronic glomerulonephritis (CGN). We analyzed the factors which affected BMD of 139 patients with chronic HD enrolled in this cross-sectional study. Methods: BMD of forearm [1/3-radius (R) and ultradistal (UD)-R] were measured by dual-energy x-ray absorptiometry. Results: 1/3R-BMD and UDR-BMD of DM patients were comparable to those of CGN patients. In DM patients, body mass index (BMI) was positively correlated with UDR-BMD, serum levels of PTH and creatinine were negatively correlated with 1/3R-BMD, and serum level of β2-microglobulin (βMG) was positively correlated with UDR-BMD. In CGN patients, duration of HD and height were negatively correlated with 1/3R- and UDR-BMD, serum levels of uric acid and triglyceride were positively correlated with 1/3R- and UDR-BMD, and serum level of total cholesterol was positively correlated with UDR-BMD. In stepwise regression analysis, BMI and serum levels of creatinine and βMG were selected for UDR-BMD in DM patients, although serum PTH level was selected for 1/3R-BMD. Conclusion: BMD at forearm was comparable between DM and CGN in HD patients. The factors affecting BMD seemed to be different between DM and CGN.

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We report a 21-year-old woman with ectopic ACTH syndrome due to islet cell carcinoma with multiple liver metastases. On admission, she showed Cushingoid appearance (moon face, central obesity etc.) and had acute respiratory distress syndrome due to pneumocystis carinii pneumonia. Laboratory examination revealed marked elevations of plasma ACTH (735 pg/ml) and cortisol (145 μg/dl) with a profound hypokalemia (2.0 mEq/l). She was found to have multiple masses in the liver and a solid mass in the tail of pancreas by abdominal computerized tomography scanning. Treatment with octreotide successfully reduced elevated plasma ACTH and cortisol levels, and she received frequent transhepatic arterial embolization and chemotherapy. The primary pancreatic tumor was surgically removed, revealing islet cell carcinoma which contained high content of ACTH (100 μg/g wet weight) and abundantly expressed proopiomelanocortin and somatostatin receptor subtype-2 mRNAs as determined by Northern blot analysis. Postoperatively, she was free from symptoms for almost one year. However, progressive enlargement of multiple liver metastases refractory to chemotherapy led her to decide on total hepatectomy and liver transplantation from her father. After liver transplantation, she remained almost free from symptoms for a almost one year. However, metastases developed to the mediastinal and paraaortic lymph nodes as detected by ¹¹¹[In] pentetreotide scintigraphy. Eleven months after liver transplantation, she was again treated with octreotide and, 16 months after, with metyrapone, both of which were effective in reducing ACTH and cortisol levels, respectively, until she died of acute respiratory failure. This case of a young female patient with ectopic ACTH-producing islet cell carcinoma of the pancreas was quite unique in that she survived for 5 years despite the acute onset and rapid progression of the multiple liver metastases at least in part due to the long-lasting favorable response to octreotide and living-related liver transplantation.

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We studied whether Na⁺ and Ca²⁺ channels are involved in the neural mechanism responsible for the surge of gonadotropin-releasing hormone (GnRH) in proestrous rats. In experiment 1, female rats in proestrus were ip injected at 1345 h with pentobarbital sodium (35 mg/kg) to block spontaneous surge of LH and electrical stimulation was applied between 1400 and 1600 h to the preoptic area (POA) together with POA injection of 0.5 μl saline containing the Na⁺ channel blocker tetrodotoxin (TTX) at a concentration of 1 μM, 2 μM, or 5 μM. Since 5 μM TTX completely blocked the increase in serum LH concentrations evoked by the POA stimulation, we used this concentration in experiment 2 to observe the TTX effect on the spontaneous LH surge. In experiment 2, bilateral injections of 1.5 μl of 5 μM TTX at 1430 h in the POA in proestrous rats postponed the peak time and reduced the peak level of the LH surge. In experiment 3, bilateral injections of 1.5 μl of 5 μM L-type Ca²⁺ channel blocker nifedipine at 1430 h in the POA completely blocked the LH surge. Since the cell bodies of GnRH neurons are primarily concentrated in the POA in rats, these results suggest that both voltage-sensitive Na⁺ channels and Ca²⁺ channels contribute to the generation of action potentials at GnRH cell bodies for the surge release of GnRH.

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Cushing’s syndrome due to bilateral cortisol-secreting adenomas rarely occurs. We present a case of Cushing’s syndrome due to bilateral adenomas. Both adenomas had distinct cell compositions, and were compared with emphasis on immunohistochemical and enzyme histochemical analysis for cytochrome P450_11β and 3β-hydroxysteroid dehydrogenase (3βHSD). A 37 year-old female was diagnosed with ACTH-independent Cushing’s syndrome based on physical findings and hormonal evaluation. High-resolution CT scan showed bilateral adrenocortical adenomas and atrophied glands. ¹³¹I-methylnorcholesterol incorporation into both glands suggested both adenomas were functional. Clinical diagnosis prior to surgery was ACTH-independent Cushing’s syndrome due to functioning bilateral adenomas. The left adrenal gland was totally resected, while the right one was partially resected by laparoscopic approach. Both adenomas were black on cut sections, and were comparatively evaluated by immunohistochemical and enzyme histochemical analysis for P450_11β and 3βSD. The left adenoma was 1.6 cm in diameter and had a complex cellular composition and enzyme expression similar to that of primary pigmented nodular adrenocortical disease (PPNAD), while the right adenoma was 1.8 cm in diameter with compact cells typical of a solitary cortisol-producing adenoma. Adjacent bilateral adrenal cortex showed marked atrophy, but contained several micronodules. Serum cortisol levels, both at basal and after a low dose dexamethasone, normalized thirteen months after surgery. In conclusion, the present case of Cushing’s syndrome with bilateral adrenal adenomas demonstrated for the first time the simultaneous occurrence of two distinct adenomas, an ordinary cortisol-producing adenoma and a PPNAD-like adenoma. Further case reports of multiple adrenal adenomas should be well-analyzed to clarify whether the results from this case represent a new subgroup of ACTH-independent Cushing’s syndrome.

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To determine the effects of surgery and adjuvant therapy on the mortality rate of Japanese patients with acromegaly, 154 surgically treated patients were followed until death or December 2000. Mean follow-up period was 10.0 ± 6.5 (SD) years. Postoperative GH levels, mean values of GH levels measured in the first postoperative month, were <2.5 ng/mL in 73 (47.4%), 2.5-5.0 ng/mL in 50 (32.5%), and >5.0 ng/mL in 31 patients (20.1%). Three of 123 patients with postoperative GH levels <5.0 ng/mL underwent a second transsphenoidal surgery (TSS), the other 120 received no further treatment. Additional treatments, including second TSS, medical treatment, and gamma-knife irradiation for residual tumor, were administered to 25 of 31 patients whose postoperative GH was >5.0 ng/mL. Among the total 154 patients surveyed, 11 (7.1%) died during the follow-up period. The standard mortality ratio (SMR) was 1.17, not different from age- and sex-matched controls. The SMR of the 72 patients with postoperative GH<2.5 ng/mL was better than that of the 51 patients whose postoperative GH was 2.5-5.0 ng/mL (1.09 vs. 1.64); however, the difference was not statistically significant. In conclusion, TSS and adequate adjuvant treatment decreased the excess mortality rate of acromegalics to nearly the same level as that of the general Japanese population.

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It is generally known that even with permanent sections, the differential diagnosis between follicular adenoma and follicular carcinoma is often difficult to determine. It is not unusual to encounter patients diagnosed with benign follicular adenoma whose diagnoses have to be changed to malignancies because of recurrence or metastasis. As the monoclonal antibody HBME-1 produced by mesothelioma cells has been shown to have reactivity in thyroid carcinomas, we investigated the diagnostic usefulness of HBME-1 in follicular neoplasms. Immunohistochemical staining for HBME-1 was performed on 205 various thyroid tumors using the labeled streptavadin biotin peroxidase method. When hematoxylin-eosin (HE) staining was performed again for this study and all cases were examined in accordance with the WHO Histological Classifications 2nd Edition, 87.2% (54/62) of adenomatous goiter and 72.6% (45/62) of follicular adenoma were negative. On the other hand, 84.6% (33/39) of follicular carcinoma and 97.2% (35/36) of papillary carcinoma were positive. All anaplastic (2/2) and medullary (4/4) carcinoma were negative. Examination in follicular neoplasms had a sensitivity of 84.6%, specificity of 72.6%, positive predictive value of 66.0% and overall accuracy of 77.2%. Among the cases treated as follicular adenoma clinically, the diagnosis of 13 cases was changed to follicular carcinoma, and 6 cases to papillary carcinoma for this study. These cases showed strong HBME-1 positivity. Two of the follicular carcinoma cases experienced recurrence. We conclude that immunohistochemical staining with HBME-1 may be useful clinically to pick out cases with a high risk of recurrence in follicular carcinoma, and that benign adenoma cases need close follow-up.

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We report a rare case of virilizing adrenocortical adenoma complicated with Cushing’s syndrome, thyroid papillary carcinoma and hypergastrinemia. A 45-year-old woman had a history of amenorrhea for 10 years, hypertension for 8 years, and diabetes mellitus for 3 years. Physical examination showed a masculinized woman with severe hirsutism, male-like baldness, deep voice, acne in the precordia, and clitorism. Plasma testosterone, DHEA-S and urinary 17-KS were high, and plasma cortisol level was it at the upper limit of the normal range, but it did not show a diurnal rhythm nor was suppressed by 2 and 8 mg of dexamethasone. Abdominal CT scan showed a left adrenal tumor (4.5 cm in size). Adrenal scintigram revealed uptake of the tracer on the left side, and plasma cortisol concentration was high in a blood sample from the left adrenal vein. Left adrenalectomy was performed. Histopathological features of resected adrenal tumor were consistent with those of adrenocortical adenoma, consisting of tumor cells with eosinophilic compact cytoplasm. Immunohistochemical staining for steroidogenic enzymes showed reactivity for P450scc, 3 beta-HSD, P450c17, P450c21 and P450c11. Plasma testosterone and cortisol levels decreased to the normal range postoperatively. The patient was also found to have a papillary thyroid carcinoma and hypergastrinemia. Our patient is a rare case of virilizing adrenocortical adenoma associated with Cushing’s syndrome, thyroid papillary carcinoma, and hypergastrinemia.

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Implantation refers to a series of interactions between embryo and endometrium including hatching, attachment, and outgrowth. We investigated the expression and function of β₁ integrin and focal adhesion kinase (FAK) in human decidual cells during implantation. Immunofluorescent staining localized β₁ integrin to surfaces of cultured decidual cells. Double staining for β₁ integrin and mediators of intracellular signaling involving β₁ integrin, such as FAK and vinculin, colocalized β₁ integrin with these substances, suggesting that human decidual cells express β₁ integrin in the focal adhesion region. We next investigated the actions of β₁ integrin and FAK in implantation of co-culturing mouse embryos and human decidual cells. Mouse blastocysts attached to cultured decidual cells after embryo hatching, usually within 24 h of culture initiation. Blastocysts attached to decidual cells exhibited extensive outgrowth at 48 h. Treatment of decidual cells with an antibody against β₁ integrin or with an antisense FAK oligonucleotide did not affect hatching or attachment of blastocysts, but either one could inhibit outgrowth. Thus, it was concluded that human decidual β₁ integrin and FAK participate in this final step of implantation.

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There are two local subtypes of extravillous trophoblast (EVT): one is the proliferative phenotype of EVT, which primarily consists of proximal cells and the other is the invasive phenotype of EVT, which is composed mainly of distal cells of cell columns. The mechanism of invasion of EVT to the decidua remains obscure. In order to elucidate the potential role of apoptosis along the invasion of EVT to the decidua, we have assessed the expression of apoptosis-regulating proteins including Fas antigen (Fas), Fas-ligand (Fas-L) and Bcl-2 protein, and apoptosis in the proliferative phenotype of EVT and the invasive phenotype of EVT in term (37 to 38 wk) placenta. Fas, Fas-L and Bcl-2 protein expression were examined by avidin/biotin immunoperoxidase method. Apoptosis was assessed by in situ DNA 3′-end labeling method. Appearance of apoptotic nuclei in EVT was also examined by transmission electron microscopy. Mean percentage of apoptosis-positive nuclei in the invasive phenotype of EVT was significantly higher than that in the proliferative phenotype of EVT. Transmission electron microscopy revealed the presence of apoptotic nuclei in the invasive phenotype of EVT. Immunohistochemical analyses revealed that Fas and Fas-L expression in the invasive phenotype of EVT were more abundant than those in the proliferative phenotype of EVT, while Bcl-2 protein expression in the invasive phenotype of EVT was less abundant than that in the proliferative phenotype of EVT. The present findings suggest that Fas/Fas-L and Bcl-2 protein expression participate in the regulation of apoptosis in EVT along the invasion to the decidua, and that the increased occurrence of apoptosis in the invasive phenotype of EVT may be attributable to the increased expressions of Fas and Fas-L and decreased expression of Bcl-2 protein in those cells in term placentas.

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In a random sample of 200 patients with type 2 diabetes mellitus, immunoreactivities to ACE (angiotensin converting enzyme) were measured by ELISA. Immunoreactivities were positive for 129 (64.5%) patients, and were positive in 30 (83.3%) out of 36 patients in the early stage of clinical diabetic nephropathy. Serum ACE activity in rabbits immunized with ACE decreased to 50% of the control level after 7 months (78.0±3.8 IU/L/37°C, basal, 42.0±5.0 at 7 months and 33.3±3.5 IU/L/37°C at 8 months, respectively). When rabbit serum containing antiACE antibodies was mixed, after heat-treatment at 56°C for 30 min, with normal human serum, the ACE activity was reduced in a concentration-dependent manner. These results suggested that anti-ACE autoantibody may be present in patients with type 2 diabetes mellitus. However, the absence of data on the epitope for the antibody does not allow any conclusion except that the immunoreactivities to ACE are higher in type 2 diabetic patients than in non-diabetic individuals.

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A 63-year-old man was admitted to our hospital for the evaluation of hypercalcemia and anterior neck mass. Laboratory findings revealed hypercalcemia, hypophosphatemia, and hypercalciuria, as well as elevated serum levels of parathyroid hormone (PTH) and alkaline phosphatase. Computerized tomography and magnetic resonance images showed that the mass contained a cystic area. Parathyroid scintigraphy using either ^99mTc-sestamibi alone or ²⁰¹Tl-chloride in conjunction with ^99mTc-pertechnetate for thyroid image subtraction showed uptake of the radioactivity into the cyst wall, suggesting that the mass originated from the parathyroid. Fine needle aspiration biopsy revealed that the cyst fluid was serous and bloody with extremely high concentrations of both PTH and CA19-9. The patient was diagnosed as primary hyperparathyroidism caused by parathyroid cyst and cervical exploration was performed. The cyst was dissected away along with the right lobe of the thyroid gland. After tumor removal, serum calcium and PTH levels were normalized. Histological study showed that the tumor possessed malignant potential with capsular invasion as well as moderate cellular atypia with trabecular pattern in arrangement. Parathyroid cells in the wall of the cystic tumor were immunostained positively for CA19-9, suggesting that CA19-9 in the cyst fluid was produced from the cells.

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We describe a case of rhabdomyolysis associating hypothyroidism. Hypothyroidism frequently leads to myalgias, muscle stiffness, cramps and sometimes elevated leves of muscle enzymes, but rhabdomyolysis is quite rate. This report describes a case of rhabdomyolysis associating hypothyroidism in a 19-year old man. Muscle enzyme levels were typical of rhabdomyolysis. Muscle biopsy and electromyograpic findings were compatible with hypothyroid myopathy. Muscle functions completely recovered with levothyroxine therapy. The present case represents rhabdomyolysis secondary to undiagnosed hypothyroidism in a developed stage which manifests itself with rhabdomyolysis.

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A subtype of idiopathic type 1 diabetes with a rapid onset and no diabetes-related antibodies has been recently advocated as non-autoimmune fulminant type 1 diabetes. However, it is not definite yet that this subtype is always caused by non-autoimmune mechanism. A 48-year-old man was admitted to our hospital because of high plasma glucose and renal insufficiency. Laboratory findings were as follows: plasma glucose 1052 mg/dL, urinary ketone bodies (±), arterial blood pH 7.44, bicarbonate 23.8 mmol/L, base excess 0.3 mmol/L, plasma osmolality 342 mOsm/L, serum creatinine 2.1 mg/dL, blood urea nitrogen 69.7 mg/dL, and serum creatine kinase 1024 IU/L, giving a diagnosis of acute renal failure secondary to rhabdomyolysis associated with diabetes. Urinary C-peptide reactivity was 4.7 μg/day. The level of HbAlc was 7.0%, not so high as compared to that of plasma glucose, indicating an aggravation of diabetes within the recent short period. Antibodies to islet cell antigen, IA-2 and insulin were negative, while those to glutamic acid decarboxylase (GAD) were positive at 13.1 U/mL, which were negative half a year and two years and a half later. Serum amylase level was within normal range at admission, increased to 380 IU/L and normalized in 4 to 5 weeks as serum creatinine lowered. These data are compatible to the diagnosis of fulminant type 1 diabetes. However, the present case is different from others in positive antibodies to GAD at admission that turned to be negative subsequently. Considering our results and others together, further investigations are necessary to clarify whether all cases of fulminant type 1 diabetes are non-autoimmune or some of them are caused by autoimmune mechanism.

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Circulating concentrations of adiponectin, an adipocyte-derived protein, are increased by thiazolidinediones and by weight reduction, accompanied with improvement in insulin sensitivity. The effect of exercise training, another therapy to increase insulin sensitivity (SI), on adiponectinemia is currently unclear. The present study was undertaken to clarify whether exercise training-induced increase in SI is related to changes in adiponectinemia in healthy men. Twelve healthy non-obese men underwent ergometer training at lactate threshold (LT) intensity for 60 min/day for 5 days/week for 6 weeks. An insulin-modified intravenous glucose tolerance test was performed before and at 16 h and 1 week after the last training session to determine SI using a minimal-model approach. Serum levels of adiponectin were determined at the same time. After the exercise training, Vo₂max and LT were significantly increased by 7.2% and 22.3% (P<0.01), while BMI and body fat mass remained unchanged. SI was significantly increased at 16 h after the last training session (from 7.0 ± 3.1 to 9.6 ± 3.6 [×10^-4·(μU/ml)^-1·min^-1], P<0.01), but returned toward the basal levels at 1 week after the cessation of the training. Serum adiponectin concentrations before the training (20.9 ± 7.4 μg/ml) were positively correlated with SI. The concentrations were slightly but significantly decreased at 16 h (17.2 ± 6.6 μg/ml, P<0.05), and returned to the basal values at 1 week after the training. From these results, it can be concluded that exercise training-induced increase in SI is not dependent on the increase in adiponectinemia in healthy men.

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