Plasma high-density lipoprotein (HDL) is a potent anti-atherogenic factor, a critical role of which is thought to be reverse cholesterol transport through the lipoprotein-associated apolipoprotein A-I (apoA-I). HDL also carries a potent bioactive lipid mediator, sphingosine 1-phophate (S1P), which exerts diverse physiological and pathophysiological actions in a variety of biological systems, including the cardiovascular system. In addition, HDL-associated apoA-I is known to stimulate intracellular signaling pathways unrelated to transporter activity. Mounting evidence indicates that multiple antiatherogenic or anti-inflammatory actions of HDL independent of cholesterol metabolism are mediated by the lipoproteinassociated S1P through S1P receptors and by apoA-I through scavenger receptor class B type I.

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The hypothalamic-pituitary-adrenal (HPA) axis is activated under various stressors. Corticotropin-releasing factor (CRF) plays a central role in controlling stress response, and regulating the HPA axis. CRF, produced in the hypothalamic paraventricular nucleus (PVN), stimulates adrenocorticotropic hormone (ACTH) production via CRF receptor type 1 (CRF₁ receptor) from the corticotrophs of the anterior pituitary (AP). Cyclic AMP (cAMP)-protein kinase A (PKA) pathway takes a main role in stimulating CRF gene transcription. Forskolin and pituitary adenylate cyclaseactivating polypeptide (PACAP) stimulate adenylate cyclase, intracellular cAMP production, and then CRF and arginine vasopressin (AVP) gene expression in hypothalamic 4B cells. Interleukin (IL)-6, produced in the PVN, both directly and indirectly stimulates CRF and AVP gene expression. Estradiol may enhance the activation of CRF gene expression in response to stress. The HPA axis is regulated by a negative feedback mechanism, because glucocorticoids inhibit both CRF production in the hypothalamic PVN and ACTH production in the pituitary. Hypothalamic parvocellular neurons in the PVN are known to express glucocorticoid receptors, and glucocorticoids are able to regulate CRF gene transcription and expression levels directly in the PVN. Glucocorticoids-dependent repression of cAMP-stimulated CRF promoter activity is mainly localized to promoter sequences between —278 and —233 bp. Both negative glucocorticoid regulatory element (nGRE) and serum response element (SRE) are involved in the repression of the CRF gene in the hypothalamic cells.

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Akt substrate of 160kDa (AS160) is a Rab GTPase activating protein (GAP) and was recently identified as a component of the insulin signaling pathway of glucose transporter type 4 (GLUT4) translocation. We and others, previously reported that the activation of Gαq protein-coupled receptors (GαqPCRs) also stimulated GLUT4 translocation and glucose uptake in several cell lines. Here, we report that the activation of GαqPCRs also promoted phosphorylation of AS160 by the 5′-AMP activated protein kinase (AMPK). The suppression of AS160 phosphorylation by the siRNA mediated AMPKα1 subunit knockdown promoted GLUT4 vesicle retention in intracellular compartments. This suppression did not affect the ratio of non-induced cell surface GLUT4 to Gαq-induced it. Rat 3Y1 cells lacking AS160 did not show insulin-induced GLUT4 translocation. The cells stably expressing GLUT4 revealed GLUT4 vesicles that were mainly localized in the perinuclear region and less frequently on the cell surface. After expression of exogenous AS160, GLUT4 on the cell surface decreased and GLUT4 vesicles were redistributed throughout the cytoplasm. Although PMA-induced or sodium fluoride-induced GLUT4 translocation was significantly increased in these cells, insulin did not affect GLUT4 translocation. These results suggest that AS160 is a common regulator of insulin- and GαqPCR activation-mediated GLUT4 distribution in the cells.

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Purpose: During the past decade, various techniques of endoscopic thyroid surgery have been introduced. We have developed a novel method of gasless endoscopic thyroidectomy via an axillary approach. The present report describes the technique of this method, and analyzes its surgical outcome. Patients and Methods: Between Nov. 2001 and Dec. 2007 (actual operation period was 50 months), 581 patients with thyroid tumors underwent gasless endoscopic thyroidectomy via an axillary approach. The clinical and pathologic characteristics of patients, operation type, operation time, post operative hospital stay and post operative complications were analyzed retrospectively. Results: Among the 581 patients, 171 patients had benign tumor and 410 patients had malignant tumor. There was no conversion to open surgery. The operating time and the length of post-operative hospital stay were 129.4±51.3 minutes, 3.3±1.7 days in benign tumor, and 135.5±47 minutes, 3.4±0.9 days in malignant tumors, respectively. The tumor size was 2.7±1.2 cm in benign tumor and 0.78±0.5 cm in malignancy. Central compartment lymph node metastasis was found in 112 (27.3%) patients and lateral neck lymph node metastasis in 13 (3.1%) patients. As post-operative complications, transient hypocalcemia occurred in 19 patients and transient hoarseness was in 13 patients and permanent vocal cord palsy occurred in 2 patients. In the TNM stage, 366 (89.2%) patients were stage I, 43 (10.5%) patients were stage III and 1 (0.2%) patient was stage IVA. Conclusion: According to our experience, gasless endoscopic thyroidectomy using a trans-axillary approach is a feasible and safe method. Endoscopic thyroid surgery has become a new treatment modality for the patients with benign tumors and can be an effective alternative treatment for the selected patients with thyroid cancer.

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Preoperative excess iodide administration for patients with Graves’ disease has been widely adopted by surgeons to perform surgery safely, because it decreases blood flow in the thyroid. However, surgeons often encounter the enlargement of thyroid volume after iodide administration, which makes surgery even more difficult. In this study, we retrospectively investigated the change in thyroid volume in Graves’ disease that was evaluated on ultrasonography between before and after iodide administration. Eighty-nine patients who received iodide administered (KI(+) patients) and 24 in whom iodide was not administrated (KI(-) patients) before surgery for Graves’ disease were enrolled in the study. The level of free T4 (FT4) significantly decreased and that of thyroid stimulating hormone (TSH) significantly increased after iodide administration. Average thyroid volume also significantly increased for KI(+) patients after iodide administration and 17% of these patients showed a 30% or more increase in thyroid volume. In KI(-) patients who were preoperatively treated only by anti-thyroid drugs, thyroid volume did not change before surgery. Preoperative TSH levels remained below measurement sensitivity in 37 of KI(+) patients, but the average thyroid volume also significantly increased after iodide administration. These findings suggest that thyroid volume in Graves’ disease can increase with iodide administration not only due to TSH stimulation but also due to reasons other than TSH. Surgeons should be careful when preoperatively iodide administering to patients with Graves’ disease, especially when the goiter is large.

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Adiponectin receptors mediate the antidiabetic effects of adiponectin. Although suggested to be mainly expressed in muscle, liver, and adipocyte cells, the expression of adiponectin receptors in β cells is unclear. Given the primary involvement of this cell type in diabetes mellitus, we presently examined the expression level of adiponectin receptor 2 (AdiR2) in β cells. Expression was significantly increased under acute hyperlipidemic conditions but impaired under chronic conditions. The impaired AdiR2 expression may play a role in worsened β cell function. Clofibrate, an agonist of peroxisome proliferator-activated receptor-alpha (PPAR-α) delayed the palmitate-induced impairment of AdiR2 expression and PPAR-α; this delay was abolished by PPAR-α targeted small interfering RNA. The results suggest that AdiR2 expression is regulated by palmit ate via PPAR-α.

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The purpose of this study was to identify clinical and ultrasound (US) features of malignancy in patients using cytological results of follicular neoplasm (FN) in the thyroid. We followed 165 patients with cytology diagnosed FN and evaluated the final surgical histopathology outcomes in 114 patients between March 2006 and November 2008. Patient histopathology, age, sex, tumor size, and US characteristics and the color flow pattern of the lesions were analyzed and compared between benign and carcinomas. Twenty five (21.9%) of the 114 FN were found to be follicular carcinomas (FC); 15 minimally invasive FC, 4 widely invasive FC, and 6 FVPTC. Benign included 78 FA, 8 atypical FA, and 3 Hurthle cell adenomas. The incidence of malignancy was 31.8% (7/22) in men and 19.6% (18/92) in women (p=0.253); and it was similar throughout the different age (<45 vs. >45) and nodule size groups (<2cm vs.>2cm, <4cm vs. >4cm). The difference of shape, margin, the presence of a halo, internal content, and calcifications was not statistically significant (p value =0.05). In malignancy more frequent internal central color Doppler flow was present (p=0.030). Color Doppler flow pattern of FN with other clinicopathological factors should be carefully considered when predicting the malignant potential of FN.

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Painless thyroiditis is characterized by transient thyrotoxicosis with complete recovery. Some patients, however, have repeated episodes of thyrotoxicosis, for which the mechanism of recurrence is not clear. We therefore studied the clinical characteristics in 8 patients with 4 or more episodes of thyrotoxicosis and 40 control patients. The age at onset was significantly earlier and the male-to-female ratio was significantly higher in the case group than the control group. The highest FT4 and FT3 levels were higher in the recurrent type. Multiple regression analysis showed contributions of higher peak FT4 level, male gender, presence of thyroid autoantibody, earlier onset, and smaller size of thyroid to repeated recurrence. Since the peak FT4 value, gender, autoantibody, age of onset and size of thyroid contribute to only 27.5% of the repeated recurrence cases, other factors such as genetic susceptibility or inflammatory tissue changes in thyroid may also be contributory. Further studies are needed to elucidate the mechanism underlying repeated recurrence.

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Primary thyroid lymphoma is a very rare tumor and its prevalence is approximately 0.1% of all thyroid cancers in Korea. Its clinical experience is limited and not familiar to physicians. Therefore, we performed this study to investigate the clinical characteristics of primary thyroid lymphoma in Koreans. We retrospectively analyzed the medical records of the 44 patients with primary thyroid lymphoma from 1991 to 2006 at four major referral hospitals in Korea. Out of 44 patients, eight patients were male and 36 patients were female and their average age was 57 years. Fifty-six percent of patients had underlying Hashimoto′s thyroiditis. All but two patients had non-Hodgkin′s lymphoma with B cell origin, and eighty percent of patients presented with stage IE or IIE. Twenty-one of 44 patients (48%) had diffuse large B cell lymphoma (DLBCL) and 17 (39%) had MALT lymphoma. Malignancies originating from lymphoid cells were suspected in 10 of eighteen patients with DLBCL (56%) by using fine-needle aspiration cytology (FNAC), and no difference was noted compared with MALT lymphoma (64%). Compared with DLBCL, the patients with MALT lymphoma were more frequently presented with stage I disease (DLBCL vs. MALT lymphoma: 32% vs. 65%, P=0.04). Moreover, in contrast to DLBCL, most of the patients with MALT lymphoma achieved complete response with treatments (DLBCL vs. MALT lymphoma: 53% vs. 94%, P‹0.01). Because of the low diagnostic accuracy of FNAC, thyroid biopsy should be considered for the diagnosis of thyroid lymphomas in suspicious cases. The patients with MALT lymphoma were more frequently presented with early stage diseases and this might lead to the favorable outcome to treatments than those with DLBCL.

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Somatic mutations in BRAF, especially BRAFV600E, are frequently identified in papillary thyroid cancer (PTC) tumors. It has been established that expression levels of numbers of genes are characteristically altered in PTC, however, the link between BRAF mutation and gene expression patterns are still elusive. In the present study, we analyzed relative expression levels of the wild type BRAF and BRAFV600E mRNA by using quantitative PCR (qPCR) and cDNAPCR- RFLP in 19 PTC specimens and adjacent normal thyroid tissues. BRAFV600E mRNA was detected in 17 out of 19 PTC specimens, and the expression levels were valuable among the specimens, suggesting alternative expression of BRAFV600E in each cell and/or alternative population of BRAFV600E-positive clones in the tumor. We then analyzed expression levels of 20 genes by qPCR, and analyzed for possible correlation with expression levels of BRAFV600E mRNA. Expression levels of fibronectin, vimentin and CITED1 (Cbp/p300 interacting protein with glutamic acid and aspartic acid rich carboxyl terminal domain) were positively correlated with those of BRAFV600E, suggesting pathophysiological links between activated BRAF and overexpression of these genes. Among these genes expression of vimentin was decreased by inhibiting BRAF expression in NPA cells that express BRAFV600E by means of siRNA, suggesting activated BRAF positively regulate expression of vimentin. Collectively, our analyses illustrated the possibilities that variable expression of BRAFV600E may modify characters of PTC through its effects on gene expression.

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This study assessed the dose-dependent efficacy and safety of exenatide over 12 weeks in Japanese patients with type 2 diabetes suboptimally controlled despite therapeutic doses of sulfonylurea (SU), SU plus biguanide, or SU plus thiazolidinedione. Patients were randomly assigned to placebo (N = 40), 2.5 μg (N = 38), 5 μg (N = 37), or 10 μg (N = 38) exenatide administered subcutaneously twice daily (BID). Patients randomly assigned to 10 μg exenatide received 5 μg BID for the first 4 weeks, with the dose escalated to 10 μg BID for the final 8 weeks. Patients were 60.3 ± 9.7 years old, with body mass index 25.3 ± 4.3 kg/m² and hemoglobin A1c (HbA1c) 8.0 ± 0.8%. Baseline-to-endpoint HbA1c changes (%) were +0.02 ± 0.1 (placebo), -0.9 ± 0.1 (2.5 μg), -1.2 ± 0.1 (5 μg), and -1.4 ± 0.1 (10 μg) (all p < 0.001 vs. placebo). Of patients with baseline HbA1c -7%, 5.1% (placebo), 50.0% (2.5 μg), 71.4% (5 μg), and 79.4% (10 μg) achieved HbA1c <7% at endpoint (p < 0.001, trend test). Baseline-to-endpoint fasting plasma glucose changes (mg/dL) were +6.0 ± 4.8 (placebo), -18.6 ± 5.7 (2.5 μg), -25.0 ± 7.0 (5 μg), and -28.9 ± 5.9 (10 μg) (all p ≤ 0.001 vs. placebo). Treatment-emergent adverse events were mostly mild; dose-dependent increases in incidence were observed for hypoglycemia, nausea, anorexia, decreased appetite, and diarrhea (all p ≤ 0.044, trend test). Over 12 weeks, exenatide dose-dependently improved glycemic control in Japanese patients with type 2 diabetes.

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This study investigated the serum levels of resistin, adiponectin and leptin during the physiological menstrual cycle. Sixteen women (age: 19-30 years; body mass index: 19.46-24.9) with regular menstrual cycles participated. Fasting blood samples were collected on alternate days throughout a full menstrual cycle. Mean resistin concentrations were slightly higher during the luteal phase (5.30±0.23 ng/ml) compared to the follicular (4.68±0.07 ng/ml) and midcycle (4.86±0.09 ng/ml) phases (p=0.032). Mean leptin concentrations during the follicular phase (18.14±0.28 ng/ml) were significantly lower compared to the midcycle (21.79±0.29 ng/ml, p=0.006) and luteal phases (23.75±0.64 ng/ml, p<0.001). The variation of adiponectin concentrations throughout the menstrual cycle was not significant. According to the results, circulating resistin, likewise leptin concentrations vary significantly during the physiological menstrual cycle presenting with higher values during the luteal phase. This pattern, although its physiological importance is not clear, suggests that resistin, likewise to leptin, may have a role in the regulation of cyclic female reproductive functions. The stable adiponectin concentrations throughout the menstrual cycle indicate that this adipokine probably does not play a considerable role in female reproductive functions.

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We encountered a 60-year-old woman with remarkably elevated thyroid-stimulating hormone (TSH) level as measured by electrochemiluminescent immunoassay (ECLIA), but with no specific symptoms, and with normal levels of free T3 and free T4. We performed the following investigations: polyethylene glycol (PEG) precipitation test, human antimouse IgG antibody (HAMA) interference test, and 3 additional TSH measurements by chemiluminescent immunoassay (CLIA). We then performed 2 gel filtration chromatography (GFC) procedures; one was at pH 7.2, and the other was at pH 3.0. Although the recovery of TSH shown by the PEG precipitation test was 4% which was extremely low, no HAMA interference was observed. Moreover, 3 CLIA instruments also showed various high values. The first GFC showed that the main peak of TSH immunoreactivity by ECLIA was located at a slightly larger molecular weight position than that of IgG. By the second GFC, the sample from the peak fraction of the first GFC showed that the TSH peak disappeared completely at the previous retention time but newly appeared at the same retention time as the TSH monomer. Protein G-Agarose gel removed the majority of the TSH complex. In conclusion, the majority of TSH in her serum was macro-TSH; TSH and anti- TSH IgG autoantibody complex. We should keep the possibility of macro-TSH in mind in cases with unexpectedly high TSH values, especially in autoimmune thyroidal disorders.

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Osteocalcin (OCN), the most abundant non-collagenous protein of the bone matrix, whose function is not fully understood, was recently suggested to act as endocrine factor regulating energy metabolism. Besides OCN, osteoblasts also express MMP-13, a matrix metallo-proteinase important for bone development and remodeling. Although differentially, both genes are regulated by 1,25-dihydroxy vitamin D3 (1,25D3) and T3, important hormones for bone metabolism. In mouse osteoblasts with a distinct differentiation status, T3 increases the expression of both proteins. By contrast, 1,25D3 stimulates the expression of MMP-13 but inhibits the expression of OCN in these cells. In humans, however, 1,25D3 upregulates both genes while T3 inhibits the OCN expression. Using northern blot hybridization we studied gene expression in the mouse osteoblastic cell line MC3T3-E1. We show that MMP-13 expression was strongly increased by T3 when the stimulation of OCN was low and, inversely, that the MMP-13 increase was low when T3 strongly stimulated the OCN expression. These findings suggest an interrelationship between OCN and MMP-13 expression. In fact, we observed that externally added OCN attenuated the T3 induced MMP-13 expression dose dependently and, furthermore, increased the 1,25D3 stimulated MMP-13 expression. Using a protein kinase A inhibitor we were able to show that this inhibitor mimics the effect of OCN suggesting a PKA dependent pathway to be involved in this regulatory process. We therefore hypothesize that OCN is a modulator of the hormonally regulated MMP-13 expression.

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Recently, nuclear genes encoding two mitochondrial complex II subunit proteins, SDHD and SDHB, have been found to be associated with the development of familial pheochromocytomas and paragangliomas (hereditary pheochromocytoma/paraganglioma syndrome: HPPS). Growing evidence suggests that the mutation of SDHB is highly associated with abdominal paraganglioma and the following distant metastasis (malignant paraganglioma). In the present study, we report the case of a novel SDHB mutation (L157X) in a Japanese patient with abdominal paraganglioma following malignant lung metastasis. In addition, we identified an asymptomatic carrier of the SDHB mutation in this family.

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An association between psychological factors and diabetes has been suspected for a long time. However, epidemiological data on this association is limited. We investigated the association between psychological factors (perceived mental stress and type A behavior) and the onset of diabetes in a community-based, prospective cohort study in a large number of middle-aged Japanese adults. A total of 55,826 subjects (24,826 men and 31,000 women) aged 40-69 years were followed for 10 years. A self-administered questionnaire on medical conditions including diabetes and other lifestyle factors was performed at baseline and 5 and 10 years later. Psychological factors and diabetes were assessed based on the questionnaire results. During the 10-year follow-up period, we documented 1,601 incident cases (6.4%) of diabetes among men and 1,093 cases (3.5%) among women. The risk of diabetes increased with an increasing stress level, especially among men. Multivariate adjusted odds ratios for high stress compared with low stress were 1.36 (1.13 to 1.63) among men and 1.22 (0.98 to 1.51) among women. The risk of diabetes increased with an increasing level of type A behavior only among women. Multivariate adjusted odds ratios for high levels of type A behavior compared with low levels of type A behavior were 1.09 (0.94 to 1.27) among men and 1.22 (1.01 to 1.47) among women. We found an association between perceived mental stress and the incidence of diabetes, especially among men. We also found an association between type A behavior and the incidence of diabetes among women. In addition, inverse association between coffee consumption and the incidence of diabetes which was consistent with other studies was observed.

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We evaluated the usefulness and accuracy of diagnostic tests for adrenocorticotropic hormone (ACTH)- dependent Cushing’s syndrome, based on our experience of 88 cases, including 73 cases with Cushing’s disease, and 15 cases with ectopic ACTH syndrome (EAS). In our study, 0.5 mg of dexamethasone failed to suppress the morning cortisol secretion in 100% of cases with Cushing’s disease and EAS. Plasma ACTH levels were significantly increased by desmopressin (DDAVP) in 86% of cases with Cushing’s disease, especially in microadenomas (90%), while these levels were not affected in normal subjects. In EAS, 44% responded to DDAVP. Plasma ACTH levels were increased in response to the human corticotropin-releasing hormone (CRH) test in 100% of microadenomas and 73% of macroadenomas with Cushing’s disease, but only in 27% of cases with EAS. A high dose (8 mg) of dexamethasone suppressed the morning cortisol secretion in 89% of microadenomas with Cushing’s disease, and in 82% of all cases with Cushing’s disease, while it did in only 20% of cases with EAS. Taken together, the 0.5 mg dexamethasone suppression test (DST) and DDAVP test are considerably useful for the screening of ACTH-dependent Cushing’s syndrome. The CRH test and 8 mg DST would be effective for the diagnosis of Cushing’s diseases, because our study shows a sensitivity of 81% in cases with Cushing’s disease when these tests are considered together. These data were submitted to prepare the diagnostic criteria for Cushing’s disease, suggested by the working group of the Ministry of Health, Labour, and Welfare of Japan.

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Blood pressure can be determined more precisely with the use of 24 hours ambulatory measurement in type 1 diabetics. Nitric oxide (NO) has been suggested to be responsible for the vascular changes described in early diabetic nephropathy. We aimed to investigate serum NO concentration along with ambulatory blood pressure monitoring (ABPM) parameters in type 1 diabetic patients and to find out whether there are correlation between serum NO level and ABPM parameters. Forty type 1 diabetic subjects and 35 controls were enrolled. Diabetic subjects were grouped as microalbuminuric (n=16) and normalbuminuric (n=24). Casual and ambulatory blood pressure parameters and serum NO concentrations were measured in all study population. Microalbuminuric subjects had higher nighttime systolic blood pressure (SBP), 24 hours diastolic blood pressure (DBP) and 24 hours mean arterial pressure (MAP) than controls. Both microalbuminuric and normalbuminuric subjects had also significantly higher nighttime DBP and nighttime MAP than controls. Serum NO concentrations were higher in normalbuminuric and microalbuminuric subjects than controls. Serum NO concentrations were positively correlated with daytime DBP and MAP, nighttime SBP, DBP and MAP, and 24 hours DBP and MAP in microalbuminuric subjects. Serum NO concentrations were also positively correlated with nighttime DBP in normalbuminuric subjects. Multiple linear regression analysis revealed that serum NO₂- + NO₃- concentrations and 24 hours DBP were independently associated with the development of microalbuminuria. Albuminuria seems to be closely associated with serum NO concentrations and ABPM parameters in type 1 DM patients. A prospective follow-up study on diabetic patients with normo- and micro- albuminuria is needed to confirm the predictive values of increased NO concentrations and ABPM parameters on the development of albuminuria.

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Disulfide-bond-A oxidoreductase-like protein (DsbA-L) has been suggested to take part in the disulfide bond formation progress of proteins, including insulin and adiponectin. Recent study has demonstrated that expression of DsbA-L was decreased in obese mice and human subject, indicating that DsbA-L might be a potential target for treatment of metabolic diseases. We investigated the association of SNP-1308G/T (rs1917760) of DsbA-L gene with metabolic diseases. 589 normal glucose tolerance (NGT) subjects and 556 type 2 diabetes (T2DM) subjects were recruited. Each group was divided into normal weight (NW) (BMI‹24 kg/m²) subgroup and overweight/obesity (OW/OB) (BMI≥24 kg/ m²) subgroup. Genotype distributions and allele frequencies of SNP (-1308G/T) in DsbA-L gene were not associated with T2DM and obesity. However, it was observed that T allele carriers had better insulin secretion function compared with non-T allele carriers in NGT-NW group, not only the first phase insulin secretion (P=0.007) but also the second phase insulin secretion (P=0.031). Multiple linear regression analysis revealed that SNP-1308G/T polymorphism (rs1917760) was independently correlated with both first and second phase insulin secretion in NGT-NW group (R²=0.055, P=0.007; R²=0.029, P=0.041). Otherwise, T carriers had more visceral fat than non-T carriers (P=0.020) in NGT-OW/OB group. In conclusion, the SNP-1308G/T (rs1917760) genotypes of DsbA-L gene might participate in insulin secretion and body fat distribution. It is possible that polymorphisms of DsbA-L gene associated with metabolic diseases.

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Synchronous associations of Cushing’s syndrome (CS) and primary aldosteronism (PA) with multiple adrenocortical adenomas secreting each hormone independently have rarely been reported. Herein, we describe a unique case of PA associated with CS with detailed clinical and pathological investigations. Bilateral adrenal masses with clinical symptoms of CS and PA were found in a 43-year-old woman. Venous sampling demonstrated excess secretion of cortisol, and aldosterone from right, and left tumor, respectively. A bilateral laparoscopic partial adrenalectomy was undergone. The right adrenal tumor (3 cm) was yellow in color with abundant lipofuscin granules, and was composed of both eosinophilic compact cells and clear cells. In situ hybridization showed that both mRNAs for HSD3B2 and CYP17A1 were strongly expressed in the tumor, suggesting cortisol synthesis. Left adrenal tumor (2.4 cm) was golden-yellow in color, and composed of clear cells only. Expression of HSD3B2 and CYP11B mRNAs were observed in the tumor compatible with the aldosterone synthesis. Furthermore, minute nodules were found at the surface of normal-appearing cortex on both sides of the adrenal glands, and the expression of HSD3B2 and CYP11B mRNAs was clearly demonstrated within the nodules, indicating aldosterone synthesis. We diagnosed that the present case had 1) cortisol-producing right adrenocortical adenoma, 2) aldosterone producing left adrenocortical adenoma, and 3) cortical minute nodules with aldosterone production in both adrenal glands compatible with idiopathic adrenal hyperplasia. We reviewed the cases reported, and discussed the significance of the minute nodules in the adrenal cortex, often found in association with the adrenocortical adenoma.

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Macrofollicular variant is a rare entity of papillary carcinoma. We previously demonstrated that this variant accounts for 0.3% of papillary carcinoma in Japan. In this study, we investigated the biological characteristics of 5 cases of macrofollicular variant. We reviewed the diagnosis and clinical course of 5 patients with macrofollicular variant. On preoperative ultrasonographic study, 2 cases were diagnosed as having benign nodule and the remaining 3 suspected of having papillary carcinoma, although they lacked typical ultrasonographic findings of papillary carcinoma. Cytological findings suggested papillary carcinoma for 3 cases and the remaining 2 were diagnosed as indeterminate. Based on both examinations, 4 of 5 patients were diagnosed as having or suspected of having papillary carcinoma. All patients underwent thyroidectomy with lymph node dissection. Three patients underwent central node dissection and the remaining 2 underwent modified radical neck dissection. None of these patients showed clinically apparent node metastasis or massive extrathyroid extension, although 3 of these patients had latent node metastasis confirmed by pathological examination. All patients survived with no evidence of carcinoma recurrence during follow-up (145-235 months). It is therefore suggested that patients with macrofollicular variant can be diagnosed as having or suspected of having papillary carcinoma if ultrasonographic and cytological examinations are appropriately performed and show an excellent prognosis possibly because this variant lacks the aggressive characteristics of papillary carcinoma.

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Thyroglobulin is the precursor of the thyroid hormones, triiodothyronine and thyroxine. Because the molecular size of thyroglobulin is relatively large (660 kDa), it could have other additional functions besides serving as the precursor of the thyroid hormones. In this report, we examined the proliferative effects of thyroglobulins purified from bovine and porcine thyroid tissues on the growth of a rat thyroid follicular cell line, FRTL-5, as well as the primary culture of porcine thyroid epithelial cells. Bovine and porcine thyroglobulins stimulated the proliferation of not only FRTL-5 cells but also porcine thyroid epithelial cells in a dose-dependent manner. The proliferative effect of thyroglobulin was neutralized by an anti-thyroglobulin monoclonal antibody but not by two different anti-fibroblast growth factor antibodies. The stimulatory signal of thyroglobulin was transmitted via the phosphatidylinositol 3-kinase pathway. Also, removal of the N-linked oligosaccharides on thyroglobulin reduced the proliferative activity of porcine thyroglobulin, suggesting that the proliferative effect of thyroglobulin is in part exerted by its carbohydrate moiety. Taken together, we have demonstrated for the first time that thyroglobulin possesses proliferative effect on thyroid epithelial cells in addition to being the precursor of the thyroid hormones.

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Infradian rhythms of sex hormones in women are important in several physiological and pathophysiological processes. Detailed analyses of these rhythms are difficult due to problems with sampling. Salivary levels of sex steroids are widely used when repeated sampling is needed. However, a description of variation during the menstrual cycle with daily sampling is lacking. In our study salivary levels of testosterone, estradiol and progesterone were measured in samples collected daily by 17 young healthy women (21,2±0,7 years) during one menstrual cycle. Sex steroid levels were determined using radioimmunoassay. The dynamics of salivary sex steroids in our study resembles the known dynamics in plasma. Similar patterns for estradiol and testosterone confirm the hypothesis that in women testosterone serves as a precursor for estradiol. The primary (periovulatory) peak and secondary (luteal) peak of testosterone are followed by similar peaks of estradiol. Progesterone reaches maximum concentrations during the luteal phase. This study shows that analysis of salivary levels of sex steroids are informative and can be used in neuroendocrine, chronobiological and other research areas, when repeated sampling is needed.

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The aim of our study was to investigate the effect of the peripheral administration of ghrelin, a peptide hormone secreted from the stomach, on cellular proliferation and differentiation of progenitor cells in the adult hippocampus. Double immunohistochemical staining revealed that Ki-67-positive hippocampal progenitor cells expressed ghrelin receptors. In mice treated with ghrelin (80 μg/kg, i.p.) for 8 days, bromodeoxyuridine incorporation and doublecortin-positive neuroblasts were significantly increased in the dentate subgranular zone. We also found that the numbers of bromodeoxyuridine- and doublecortin-immunoreactive cells were significantly reduced after anti-ghrelin antibody (10 μg/kg, i.p.) treatment for 8 days. Therefore, our results indicate that ghrelin induces proliferation and differentiation of adult hippocampal progenitors, suggesting an involvement of ghrelin in hippocampal neurogenesis.

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The authors’ names should be read as not Benhalima KATRIEN, Mertens ANN, Van den Bruel ANNICK, Laga KATRIEN, Vanderschueren DIRK, Samson IGNACE, Van Damme BOUDEWIJN and Bouillon ROGER, but Katrien BEBHALIMA, Ann MERTENS, Annick VAN DEN BRUEL, Katrien LAGA, Dirk VANDERSCHUEREN, Ignace SAMSON, Boudewijin VAN DAMME and Roger BOUILLON. The first name and the family name had been reversed.

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