Since the 1980s, cancer cells have been considered to be generated from well-differentiated benign cells by transformation caused by accumulating damage in their genomes. However, recent progress in gene expression analysis in thyroid malignancies has raised the possibility of another model of thyroid carcinogenesis. We propose a novel hypothesis of thyroid carcinogenesis, the fetal cell carcinogenesis hypothesis, in which cancer cells are derived from the remnants of fetal thyroid cells, instead of from normal thyroid follicular cells. This hypothesis explains well the clinical and biological features and recent molecular evidence of thyroid carcinoma. It suggests the importance of clarifying the molecular mechanism of thyroid development and the identification of fetal thyroid cells such as thyroid stem cells (TSCs), since such data will lead to a better understanding of thyroid carcinogenesis and thyroid regeneration.

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The somatostatin analogue lanreotide is effective in reducing growth hormone levels in patients with acromegaly. Acromegaly is characterized by calcium homeostasis alterations. The aim of our study was to evaluate the effects of lanreotide on bone turnover markers in a group of acromegalic patients and to verify a possible increase of intact parathormone (iPTH) levels in a transient or persistent way. Serum GH, IGF-I and serum and urinary markers of bone metabolism were measured before treatment and on months 3 and 24. In short-term treatment (3 months), lanreotide significantly decreased GH, IGF-I, serum calcium, osteocalcin and alkaline phosphatase levels, but increased iPTH level (49 ± 16.7 vs pre-treatment 28.3 ± 7.6 ng/L, p<0.001). During long-term study (24 months) GH and IGF-I were significantly still low; serum calcium and alkaline phosphatase levels returned to pre-treatment levels. iPTH level was significantly still higher compared with pre-treatment (46.4 ± 9.2 vs 28.3 ± 7.6 ng/L, p<0.05). No changes were seen in serum albumin, creatinine and vitamin D during short and long term treatment. The changes of most bone markers during lanreotide treatment can be explained by the decrease of GH and IGF-I. The increase of iPTH concentration suggests that lanreotide has ulterior and long-standing actions on calcium homeostasis: intestinal malabsorption of calcium due to the lanreotide could contribute to this "secondary" hyperparathyroidism. The clinical relevance of these long-standing effects needs to be further investigated.

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The study was planned to determine the efficacy and safety of adding rosiglitazone to a combination of glimepiride and metformin therapy with insufficiently controlled type 2 diabetes. This was an open-label study with a follow-up period of 26 weeks. Thirty patients were taking 3 mg glimepiride two times and 850 mg metformin two times per day. Patients were told to take one rosiglitazone 4 mg tablet before breakfast additionally. The primary efficacy measure was the mean change in HbA₁c from baseline to the end of the study. Secondary efficacy parameters included the mean changes from baseline to the end of the study in fasting plasma glucose (FPG) and insulin levels, as well as total cholesterol, HDL-C, LDL-C, triglycerides, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Mean HbA₁c levels decreased significantly from 7.54 ± 0.9% to 6.57 ± 0.7% (p<0,001) at 26th week. FPG levels fell from 169.39 ± 37.8 mg/dl to 135.69 ± 28.0 mg/dl (p<0.001), respectively. Insulin levels decreased from 19.60 ± 9.8 U/L to 14.66 ± 11.6 U/L (p = 0,026) at 26th week. No one experienced elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels greater than 2.5 times the upper limit of the reference range. This study confirms that the addition of rosiglitazone (4 mg/day) to sulphonylurea and metformin treatment for patients with type 2 diabetes improves glycemic control, is safe, and generally well tolerated.

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The present study investigated the diurnal variation in GH receptor (GHR) mRNA in liver and skeletal muscle of 3-month-old GH-deficient and -sufficient mice using quantitative real-time RT-PCR. lit/lit (GH deficient) or lit/+ (GH sufficient) mice were fed ad libitum and lights were on between 0600 and 2000. Tissues were collected at 0800-1000, 1200-1400 and 2000-2200. Hepatic GHR mRNA levels of lit/+ mice at 0800-1000 were significantly lower than those at 1200-1400 and 2000-2200. There was no significant variation in hepatic GHR mRNA of lit/lit mice. In skeletal muscle, GHR mRNA levels of both lit/+ and lit/lit mice at 1200-1400 were significantly higher than those at 0800-1000 and 2000-2200. There was also a diurnal change in hepatic IGF-I mRNA levels of lit/+ but not of lit/lit mice; the levels were lowest at 0800-1000 in lit/+ mice. On the other hand, there was no variation in IGF-I mRNA levels in skeletal muscle. These results suggest that 1) there is a diurnal variation in GHR expression in liver and skeletal muscle and the pattern of the variation is tissue specific; 2) GH deficiency blunted the diurnal variation in GHR mRNA in liver but not that in skeletal muscle; 3) IGF-I mRNA expression in liver is more closely related to GHR mRNA expression than that in skeletal muscle.

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The relationship between blood levels of N-carboxymethyl-lysine (CML) or pentosidine and the severity of microangiopathy was investigated in patients with type 2 diabetes. Blood CML and pentosidine levels were measured by ELISA in 97 type 2 diabetics (46 men and 51 women). CML and pentosidine levels were significantly higher in patients with chronic renal failure than in those with normoalbuminuria, microalbuminuria, or macroalbuminuria (all p<0.05). Among the diabetics without nephropathy (n = 49), blood CML levels were significantly higher in the patients who had proliferative diabetic retinopathy than in those without retinopathy or those who had background retinopathy (both p<0.01). In contrast, blood pentosidine levels showed no significant differences among the three retinopathy groups. These findings suggest that the blood level of CML is related to the severity of both nephropathy and retinopathy, while the pentosidine level is only related to the severity of nephropathy.

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The aim of this study was to investigate the effect of cilostazol, a cAMP phosphodiesterase inhibitor, on carotid artery intima-media thickness (IMT) and on the incidence of cardiovascular events in Japanese subjects with type 2 diabetes. A total of 62 type 2 diabetic subjects were allocated equally to the cilostazol treatment group (n = 31) and the control group (n = 31). Carotid IMT was evaluated before and after treatment using B-mode ultrasonography. After the study period (mean ± SD: 2.6 ± 0.17 years), carotid IMT showed a significantly greater increase in the control group than in the cilostazol group (0.12 ± 0.14 mm vs. 0.04 ± 0.02 mm, p<0.05). In the control group, 1 out of 31 patients suffered from symptomatic cerebral infarction and 1 had angina pectoris during the observation period. On the other hand, no subject in the cilostazol group developed cardiovascular events during the study period. At baseline, the diabetic patients given cilostazol had a significantly lower HbA_1c level than the control subjects, but the other atherosclerotic risk factors (BMI, blood pressure, and serum lipids) and the duration of diabetes did not differ between the two groups. These results indicate that cilostazol therapy can attenuate the increase of carotid artery IMT in Japanese subjects with type 2 diabetes.

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We describe a novel missense mutant of arginine vasopressin (AVP)-dependent neurohypophyseal diabetes insipidus in an autosomal dominant family. A 54-year-old woman was admitted to our hospital because of thyroidectomy for thyroid cancer. After thyroidectomy she was found to have hypernatremia and polyuria and polydipsia both of which had been present from childhood. She had no obstructive hydronephrosis. Her father, father's younger sister and her third son also had polyuria and polydipsia. Basal plasma AVP concentration at normal plasma osmolality was normal but did not respond to increased plasma osmolality despite hyperosmolality during infusion of hypertonic saline infusion, indicating that plasma AVP secretion was impaired. Sodium concentration in urine and urine osmolality were low and increased after nasal administration of DDAVP. There was a diminished but bright signal of pituitary posterior gland on magnetic resonance T1 weighted image. Molecular genetic analysis demonstrated that the patient and her son had a single heterozygous missense mutation (G→A) at nucleotide 1829 in 1 AVP allele, yielding an abnormal AVP precursor with lacking Glu-47 in its neurophysin II moiety. The abnormal AVP precursor may be related to the impaired AVP secretion.

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A 31-year-old woman had ureterolithiasis related to hypercalcemia, and when she was admitted to our hospital ultrasonography and technetium-99 m sestamibi scintigraphy did not detect parathyroid abnormalities. Serum concentrations of calcium and intact parathyroid hormone were 9.7 mg/dl and 153 pg/ml, respectively, but subsequently increased to 13.5 mg/dl and decreased to 10 pg/ml, respectively. Diagnostic interview revealed that she had been taking excessive calcium supplements of 3,000˜5,000 mg/day because she was worried about developing osteoporosis. Her hypercalcemia was cured after she stopped taking the supplements. The present case indicates that calcium supplementation of more than 2,500 mg/day elicits adverse effects on body mineral balance. Clear indications of the upper limits to supplements should be made known to the consumers.

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The aim of this study was to determine the prevalence and risk factors for neuropathy in type 2 diabetic patients attending a major Turkish diabetes center. Eight hundred and sixty-six consecutive type 2 diabetic patients were included in the study. A single observer performed biothesiometry studies on these patients. The presence of diabetic neuropathy was investigated using neurological symptom scale (NSS) and neurological disability score (NDS) performed. Neuropathy was determined with standardized neurological examinations and defined as the presence of abnormal NSS and NDS together with abnormal sensory or motor signs and symptoms as well as decreased great toe vibration perception. Overall, 60% (n = 520) of the patients were diagnosed as having neuropathy. The prevalence of neuropathy increased with age (p<0.001) and duration of diabetes (p<0.001). Multiple logistic regression analysis revealed the duration of diabetes (p<0.001) and HbA1c levels (p<0.001) as the risk factors for neuropathy. The overall prevalence of neuropathy in Turkish type 2 diabetic population was 60%. Age, duration of diabetes, and poor glycemic control were considered to be the risk factors for neuropathy.

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Exposure to a low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a variety of toxic manifestations, including fetal death. In order to evaluate the effects of low dose TCDD on placental function, pregnant Holtzman rats were given a single oral dose of 1600 ng TCDD/kg body wt or an equivalent volume of vehicle (control) on gestation day 15 (GD15), and changes in the gene expression in the placenta on GD20 were analyzed by two comprehensive methods, representational difference analysis (RDA) and DNA microarray technology. Candidates of TCDD-inducible and -suppressive genes were selected. Quantitative real-time PCR analysis was then performed to verify the induction or suppression levels of the candidate genes. Finally, we identified 81 TCDD-inducible and 21 TCDD-suppressive genes from the placenta of TCDD-treated Holtzman rats on GD20. One of the remarkable profiles of the gene expression was that glucose transporters were strongly up-regulated by the TCDD treatment. Furthermore, many interferon-inducible genes were also up-regulated by the treatment. They included several cytokines such as IP-10 known as a potent angiogenesis inhibitor. In addition, interferon molecules are known to suppress angiogenesis. The above observations suggest that activation of the interferon signaling pathway and the induction of anti-angiogenic factors by TCDD might have a role in causing the inhibition of neovascularization, resulting in the hypoxic state of placenta and increased incidence of fetal death.

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Granulocyte colony-stimulating factor (G-CSF) levels in serum were determined by a highly-sensitive chemiluminescent enzyme immunoassay (limit of detection, 0.5 pg/ml) in 54 patients with Graves' disease including 6 patients complicated with methimazole-induced agranulocytosis. Serum G-CSF levels in patients with Graves' disease were not different from normal subjects and did not correlate with serum FT₄ level or circulating neutrophil counts. Before the onset of agranulocytosis, there was no difference in serum G-CSF level between the patients complicated with agranulocytosis and the uncomplicated patients. When circulating neutrophil counts decreased to less than 0.5 × 10⁹/L, serum G-CSF level elevated with the mean of 106.8 ± 82.2 (SD) pg/ml, but the level did not correlate with the duration of agranulocytosis. Interestingly, maximum serum G-CSF level during the treatment with recombinant human G-CSF (100 μg/day) was related to bone marrow finding at the onset of agranulocytosis and correlated with the duration of agranulocytosis (r = 0.824, p<0.05). In conclusion, measuring serum G-CSF levels with a highly-sensitive chemiluminescent enzyme immunoassay revealed that 1) thyrotoxicosis does not affect serum G-CSF level, 2) serum G-CSF level during antithyroid drug treatment does not play an important role in development of agranulocytosis, 3) the maximum serum G-CSF level in the course of agranulocytosis is related to the responsiveness of bone marrow to G-CSF and the recovery time from agranulocytosis.

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Adiponectin, secreted specifically from adipocytes, is thought to play a key role in the metabolic syndrome. Plasma adiponectin concentrations were studied in 36 typical nonalcoholic fatty liver (NAFL) women which is commonly associated with the metabolic syndrome. They were diagnosed as NAFL by ultrasound brightness, slightly elevated serum ALT levels and the exclusion of history of alcohol abuse and other known liver diseases. Compared with 64 control women, NAFL had a significant increase in the variables of the metabolic syndrome, other hepatic enzymes and leptin levels, while a reduction in AST/ALT ratio and adiponectin before (mean ± SE: 7.2 ± 0.5 vs 9.0 ± 0.4 μg/ml, p<0.005) and after adjustment for body fat mass (0.24 ± 0.02 vs 0.34 ± 0.02, p<0.0001), atherogenic Index [(total cholesterol – HDLC)/HDLC: 3.2 ± 0.3 vs 4.6 ± 0.3, p<0.005] or calculated insulin resistance (HOMA-R) (6.6 ± 1.9 vs 8.6 ± 0.9, p<0.005). BMI and amylase were positive, and adiponectin/BMI was negative significant independent determinants of ALT value in multiple regression model. In conclusion, while hypoadiponectinemia was observed in NAFL, hypoadiponectinemia provides the possibility of fat accumulation in the liver.

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Exposure to endocrine disrupting chemicals (EDCs) has been raised in relation to its potential for adverse health outcomes. Bisphenol A (BPA) is an estrogenic EDC widely found in plastic products. We determined BPA concentrations in premenopausal women by an enzyme-linked immunosorbent assay and evaluated possible linkage between its contamination levels and endometrial hyperplasia, an estrogen-related disorder of the uterus. It has been implied that higher levels of BPA, which binds to estrogen receptor and plays estrogenic roles may, enhance endometrial hyperplasia. Serum BPA was detectable in all subjects and its concentrations in healthy controls with normal endometrium were 2.5 ± 1.5 ng/ml (mean ± SD). BPA levels in patients with simple endometrial hyperplasia with benign nature were 2.9 ± 2.0 ng/ml and were not significantly different from the controls. Unexpectedly, BPA levels in patients with complex endometrial hyperplasia with malignant potential were 1.4 ± 0.4 ng/ml and significantly lower compared to both control and simple endometrial hyperplasia groups. In addition, we measured the serum BPA levels in postmenopausal endometrial cancer patient (1.4 ± 0.5 ng/ml), which were also significantly lower than control and simple endometrial hyperplasia groups. These findings suggest the presence of associations between BPA exposure and complex endometrial hyperplasia and endometrial cancer. The mode of action of BPA may be more complex than expected and the contradictory results may serve as a clue to addressing the mechanisms of linkage between occurrence of estrogen-dependent diseases and endocrine disruption.

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The purpose of this study was to determine whether polycystic ovary syndrome (PCOS) and nonclassic 21-hydroxylase deficiency (CAH) are related to hyperhomocysteinemia, and to investigate if there is a correlation between homocysteine levels and insulin sensitivity in women with PCOS and CAH. Fifty patients with PCOS, 50 patients with CAH and 25 control women were included in the study. Blood samplings were performed in the early follicular phase for measuring hormone profile, Vitamin B₁₂, folate, homocysteine levels and fasting blood glucose. Ovulatory status was assessed with timed serum progesterone measurements. Homeostasis model assessment-insulin resistance (HOMA-IR) was calculated as a measure of insulin resistance. Mean homocysteine levels were found as (8.9 + 1.9 umol/l and 17.7 + 3.6 umol/l) in the normal group and PCOS respectively (p<0.001), but there was no statistical significance between nonclassic 21-hydroxylase deficiency (9.0 + 2.2 umol/l) and control group. Most of the patients in PCOS group (35 of 50) were significantly insulin resistant. However, there was no insulin resistant patient in CAH or control group. When we compare the two subgroups of PCOS women, the patients with insulin resistance had significantly higher homocysteine levels than the ones who were not insulin resistant. There were positive correlations among serum homocysteine, insulin and androgen levels in PCOS patients. There were no correlations among these parameters in CAH and control groups. Increased homocysteine levels may contribute to increased cardiovascular disease risk in patients with PCOS. The reason for hyperhomocysteinemia seems to be related to insulin resistance but not high androgen levels.

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Interleukin (IL)-12 is a key factor in cell-mediated immunity that drives the development of Th1 cells and stimulates T lymphocytes and natural killer cells to produce interferon (INF)-γ. The IL-12B gene, which encodes the p40 subunit of IL-12, is located at chromosome 5q31-33 and a linkage finding for autoimmune thyroid disease (AITD) on 5q31-33 in a Japanese population has been reported. It is also reported that the A/C polymorphism in the 3' untranslated region (UTR) of the IL-12B gene (1188A/C) is associated with IL12B mRNA expression levels. We attempted to determine whether genetic polymorphisms of the IL-12B gene are associated with AITD. One hundred three patients with Hashimoto's thyroiditis, 90 patients with Graves' disease, and 123 healthy control subjects were recruited. We detected the 1188A/C polymorphism using a PCR-RFLP method and the A/T polymorphism in intron 4 of the IL-12B gene using a cycle sequencing method. These IL-12B gene polymorphisms showed strong linkage disequilibrium, and their genotype and allele frequencies in the patients did not differ from those in the control subjects. Our results suggest that IL-12B gene polymorphisms were unlikely to have an effect on the development of Hashimoto's thyroiditis or Graves' disease in Japanese patients.

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