Background: The nature and role of the mitochondrial stress response in adipose tissue in relation to obesity are not yet known. To determine whether the mitochondrial unfolded protein response (UPRmt) in adipose tissue is associated with obesity in humans and rodents. Methods: Visceral adipose tissue (VAT) was obtained from 48 normoglycemic women who underwent surgery. Expression levels of mRNA and proteins were measured for mitochondrial chaperones, intrinsic proteases, and components of electron-transport chains. Furthermore, we systematically analyzed metabolic phenotypes with a large panel of isogenic BXD inbred mouse strains and Genotype-Tissue Expression (GTEx) data. Results: In VAT, expression of mitochondrial chaperones and intrinsic proteases localized in inner and outer mitochondrial membranes was not associated with body mass index (BMI), except for the Lon protease homolog, mitochondrial, and the corresponding gene LONP1, which showed high-level expression in the VAT of overweight or obese individuals. Expression of LONP1 in VAT positively correlated with BMI. Analysis of the GTEx database revealed that elevation of LONP1 expression is associated with enhancement of genes involved in glucose and lipid metabolism in VAT. Mice with higher Lonp1 expression in adipose tissue had better systemic glucose metabolism than mice with lower Lonp1 expression. Conclusion Expression of mitochondrial LONP1, which is involved in the mitochondrial quality control stress response, was elevated in the VAT of obese individuals. In a bioinformatics analysis, high LONP1 expression in VAT was associated with enhanced glucose and lipid metabolism.

Background: The nature and role of the mitochondrial stress response in adipose tissue in relation to obesity are not yet known. To determine whether the mitochondrial unfolded protein response (UPRmt) in adipose tissue is associated with obesity in humans and rodents. Methods: Visceral adipose tissue (VAT) was obtained from 48 normoglycemic women who underwent surgery. Expression levels of mRNA and proteins were measured for mitochondrial chaperones, intrinsic proteases, and components of electron-transport chains. Furthermore, we systematically analyzed metabolic phenotypes with a large panel of isogenic BXD inbred mouse strains and Genotype-Tissue Expression (GTEx) data. Results: In VAT, expression of mitochondrial chaperones and intrinsic proteases localized in inner and outer mitochondrial membranes was not associated with body mass index (BMI), except for the Lon protease homolog, mitochondrial, and the corresponding gene LONP1, which showed high-level expression in the VAT of overweight or obese individuals. Expression of LONP1 in VAT positively correlated with BMI. Analysis of the GTEx database revealed that elevation of LONP1 expression is associated with enhancement of genes involved in glucose and lipid metabolism in VAT. Mice with higher Lonp1 expression in adipose tissue had better systemic glucose metabolism than mice with lower Lonp1 expression. Conclusion Expression of mitochondrial LONP1, which is involved in the mitochondrial quality control stress response, was elevated in the VAT of obese individuals. In a bioinformatics analysis, high LONP1 expression in VAT was associated with enhanced glucose and lipid metabolism.

BACKGROUND: Second-generation thyroglobulin immunometric assays (Tg-IMAs) have been developed with improved sensitivity. Our aim was to compare the diagnostic value of Tg-IMA measurements using a Kryptor (BRAHMS AG) kit (Tg-K) and an ACCESS (Beckman Coulter) kit (Tg-A) with that of the first-generation Tg measurement using a Tg-plus (BRAHMS AG) kit (Tg+). METHODS: We enrolled 82 differentiated thyroid cancer patients who underwent total thyroidectomy with radioactive iodine remnant ablation and who underwent diagnostic whole body scan using recombinant human thyroid stimulating hormone (rhTSH). The Tg+, Tg-K, and Tg-A were measured before rhTSH administration during levothyroxine treatment (suppressed Tg) from the same sample. Serum Tg+ was measured after rhTSH stimulation (stimulated Tg). RESULTS: Suppressed Tg+ was more significantly correlated with suppressed Tg-K (R²=0.919, P<0.001) than with suppressed Tg-A (R²=0.536, P<0.001). The optimal cut-off values of suppressed Tg+, Tg-K, and Tg-A for predicting stimulated Tg+ of 1 ng/mL were 0.3, 0.2, and 0.2 ng/mL, respectively. The sensitivity, specificity, and accuracy of suppressed Tg+ were 67%, 100%, and 90%, respectively; those of suppressed Tg-K were 83%, 90%, and 88%; those of suppressed Tg-A were 96%, 82%, and 87%, respectively. The positive predictive and negative predictive values of Tg+ were 100% and 87%, respectively; those of Tg-K were 79% and 92%; and those of Tg-A were 73% and 98%. CONCLUSION: We could not clearly demonstrate which kit had better diagnostic performance after comparison of first-generation Tg measurements with Tg-IMA measurements. Also, there were kit-to-kit variations between Tg-IMA kits. Suppressed Tg measured by Tg-IMA was insufficient to completely substitute for a stimulated Tg measurement.
Humans ; Immunoassay* ; Iodine ; Sensitivity and Specificity ; Thyroglobulin* ; Thyroid Neoplasms ; Thyroidectomy ; Thyrotropin ; Thyrotropin Alfa ; Thyroxine ; Whole Body Imaging

BACKGROUND: Thyroid cancers account for about 1% of all human malignancies, with papillary thyroid carcinomas being the most common istotype. Several investigators have recently identified the most common BRAF mutation, the T1796A transversion mutation, in 29~69% of papillary thyroid cancers. The BRAF mutation has been demonstrated as a novel prognostic biomarker for the prediction of poor clinicopathological outcomes, such as increased incidence of extrathyroid invasion and distant metastasis of the tumor. In this study, we investigated the prevalence of the BRAF mutation of thyroid tissues obtained by a thyroidectomy, and its correlation with the clinicopathological outcomes. METHODS: We studied 36 thyroid tissues obtained from 24 women and 12 men by thyroidectomies, including 30 papillary carcinomas, 3 follicular carcinomas, 1 medullary carcinoma and 2 nodular hyperplasia. The mutation was sought in all specimens using DNA sequencing. RESULTS: We studied the BRAF exon 15 T1796A in these 36 thyroid tissues. The mean age at surgery was 46.6, ranging from 18 to 72 years, with a median tumor size of 2.79, ranging from 1.5 to 4.5cm. At the time of diagnosis, 27 of the 34 patients presented with some kind of extrathyroidal invasion of the tumor, and 16 had lymph node metastases. 16, 2 and 16 patients were in stages I, II and III, respectively. There was no distant metastasis. A missense mutation was found at T1796A in exon 15 in 21 of the 30 papillary carcinomas(70%). The other thyroid diseases, including the 3 follicular carcinomas, 1 medullary carcinoma and 2 nodular hyperplasia show no exon 15 T1759A transversion mutation. No statistically significant association was found between the BRAF mutations and clinicopathological characteristics of papillary carcinomas. CONCLUSION: The BRAF mutation is a important genetic alteration, with a high prevalence in papillary thyroid carcinomas. However, there was no significant association between the BRAF mutation and any of the clinicopathological factors. Further, large scale studies will be needed to evaluate the correlation between the BRAF mutation and the clinicopathological factors
Carcinoma, Medullary ; Carcinoma, Papillary* ; Diagnosis ; Exons ; Female ; Humans ; Hyperplasia ; Incidence ; Lymph Nodes ; Male ; Mutation, Missense ; Neoplasm Metastasis ; Prevalence ; Research Personnel ; Sequence Analysis, DNA ; Thyroid Diseases ; Thyroid Gland* ; Thyroid Neoplasms ; Thyroidectomy

BACKGROUND: Thyroid cancers account for about 1% of all human malignancies, with papillary thyroid carcinomas being the most common istotype. Several investigators have recently identified the most common BRAF mutation, the T1796A transversion mutation, in 29~69% of papillary thyroid cancers. The BRAF mutation has been demonstrated as a novel prognostic biomarker for the prediction of poor clinicopathological outcomes, such as increased incidence of extrathyroid invasion and distant metastasis of the tumor. In this study, we investigated the prevalence of the BRAF mutation of thyroid tissues obtained by a thyroidectomy, and its correlation with the clinicopathological outcomes. METHODS: We studied 36 thyroid tissues obtained from 24 women and 12 men by thyroidectomies, including 30 papillary carcinomas, 3 follicular carcinomas, 1 medullary carcinoma and 2 nodular hyperplasia. The mutation was sought in all specimens using DNA sequencing. RESULTS: We studied the BRAF exon 15 T1796A in these 36 thyroid tissues. The mean age at surgery was 46.6, ranging from 18 to 72 years, with a median tumor size of 2.79, ranging from 1.5 to 4.5cm. At the time of diagnosis, 27 of the 34 patients presented with some kind of extrathyroidal invasion of the tumor, and 16 had lymph node metastases. 16, 2 and 16 patients were in stages I, II and III, respectively. There was no distant metastasis. A missense mutation was found at T1796A in exon 15 in 21 of the 30 papillary carcinomas(70%). The other thyroid diseases, including the 3 follicular carcinomas, 1 medullary carcinoma and 2 nodular hyperplasia show no exon 15 T1759A transversion mutation. No statistically significant association was found between the BRAF mutations and clinicopathological characteristics of papillary carcinomas. CONCLUSION: The BRAF mutation is a important genetic alteration, with a high prevalence in papillary thyroid carcinomas. However, there was no significant association between the BRAF mutation and any of the clinicopathological factors. Further, large scale studies will be needed to evaluate the correlation between the BRAF mutation and the clinicopathological factors
Carcinoma, Medullary ; Carcinoma, Papillary* ; Diagnosis ; Exons ; Female ; Humans ; Hyperplasia ; Incidence ; Lymph Nodes ; Male ; Mutation, Missense ; Neoplasm Metastasis ; Prevalence ; Research Personnel ; Sequence Analysis, DNA ; Thyroid Diseases ; Thyroid Gland* ; Thyroid Neoplasms ; Thyroidectomy

BACKGROUND: Fine needle aspiration(FNA) is an accurate and safe method for the diagnosis of thyroid nodules. One of the limitations of FNA is the variable rate of unsatisfactory specimens, especially in small sized, deep seated or complex cystic nodules. To overcome this problem, ultrasound-guided FNA(US-FNA) has been widely used. In this study, the adequacy of cytologic specimens by US-FNA was compared with that of conventional palpation-guided FNA(P-FNA). METHODS: The medical records of all patients who were engaged in FNA due to thyroid nodules at Chungnam National University Hospital from January 2003 to July 2004 were retrospectively examined. The US-FNA and P-FNA were performed in 114 and 185 patients, respectively. RESULTS: Comparison of the adequacy of the two techniques in providing sufficient material for the cytologic diagnosis showed that specimens in 24(13.0%) and 6(5.3%) patients collected by P-FNA and US-FNA, respectively, were unsatisfactory(P=0.031). A total of 23 patients underwent thyroid surgery due to strong suspicion of malignancy at cytologic finding and/or on clinical judgement. Seventeen patients belonged to the P-FNA group and 6 patients to the US-FNA group. In the P-FNA group, a histologic diagnosis revealed two false-negative cytologic findings, but no false-negative findings were found in the US-FNA group. CONCLUSION: Compared with P-FNA, US-FNA may reduce the possibility of unsatisfactory cytologic specimens and the rate of false-negative diagnosis, and may improve the diagnostic accuracy in investigating thyroid nodules
Biopsy, Fine-Needle* ; Chungcheongnam-do ; Diagnosis ; Humans ; Medical Records ; Needles ; Retrospective Studies ; Thyroid Gland* ; Thyroid Nodule*

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, known as statins, are widely used for primary and secondary prevention of coronary artery atherosclerosis. Pathogenesis of atherosclerosis is multistep processes where transendothelial migration of various leukocytes including monocytes is a crucial step. Interferon-gamma(IFN-gamma) contributes in this process by activating macrophages and T-lymphocytes, and by inducing adhesion molecules in vascular endothelial and smooth muscle cells. In this study we investigated the expression of intercellular cell adhesion molecule- 1 (ICAM-1) in transformed endothelial cell line ECV304 cells as influenced by lovastatin, tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma. Results show that lovastatin suppresses expression of ICAM-1 by inhibiting the IFN-gamma-induced extracellular signal-regulated kinase (ERK) p44/p42-STAT1 signaling pathway. In cells treated with lovastatin and IFN-gamma.ICAM-1 was expressed at a lower level than in cells treated with IFN-gamma alone. However, lovastatin does not reduce TNF-alpha induced expression of ICAM-1. A similar result was observed in cells treated with the MEKK inhibitor PD98059 and IFN-gamma. Cis-acting DNA sequence elements were identified in the 5'-flanking region of the ICAM-1 promoter that mediate inhibition by lovastatin; these sequences map to the IFN-gamma activated site which also binds the STAT1 homodimer. However, lovastatin did not inhibit IFN-gamma-mediated induction of the Y701 phosphorylated form of STAT1. But lovastatin does inhibit the IFN-gamma-mediated phosphorylation of ERK1/ERK2 (T202/Y204) and S727 phosphorylation of STAT1. TNF-alpha does not induce phosphorylation of ERK1/ERK2 and S727 in ECV304 and smooth muscle cells. The results provide the evidences that statins may have beneficial effects by inhibiting IFN-gamma action in atherosclerotic process
Animals ; Cell Line ; DNA-Binding Proteins/metabolism ; Endothelium, Vascular/cytology/*drug effects/metabolism ; Gene Expression Regulation/*drug effects ; Intercellular Adhesion Molecule-1/genetics/*metabolism ; Interferon Type II/*antagonists & inhibitors/*pharmacology ; Lovastatin/*pharmacology ; Mitogen-Activated Protein Kinases/metabolism ; Myocytes, Smooth Muscle/cytology/*drug effects/metabolism ; Phosphorylation/drug effects ; Promoter Regions (Genetics)/genetics ; RNA, Messenger/genetics/metabolism ; Rats ; Recombinant Proteins ; Trans-Activators/metabolism ; Tumor Necrosis Factor/pharmacology

Insulinoma is the most important cause of hyperinsulinemic hypoglycemia. Insulinoma can be cured by surgical management but diagnosis and localization are difficult due to their small size and variable clinical manifestation. We studied clinical manifestation of the patients who were diagnosed as insulinoma or nesidioblastosis. METHODS: We studied clinical charts of 16 patients who underwent operation under the impression of insulinoma from 1990 to 1997. RESULTS: 1) Of the 16 patients, 13 had insulinoma and 3 had nesidioblastosis. 2) Neuroglycopenic symptoms were present in all cases. Among them, loss of consciousness or confusion were present in 12 cases (75%). Adrenergic symptoms were present in 9 cases (56%). Mean symptom duration until diagnosis was 39 months(range; 15days~10years). 3) 72 hr fasting test showed hypoglycemia in all cases. 4) Insulin/glucose ratio was above 0.3 except for two cases. 5) CT and MRI had low sensitivity (38%) and specificity (33%) as a preoperative tumor localization tool, and more invasive technique, i.e., selective angiography and transhepatic portal vein sampling, were necessary in most cases. CONCLUSION: Nsidioblastosis may be more prevalent than previously suspected. Diagnosis of insulinoma is not always easy and invasive diagnostic methods should be considered when the clinical suspicion is high, even if biochemical and noninvasive localization tools give negative results.
Angiography ; Asian Continental Ancestry Group ; Diagnosis ; Fasting ; Humans ; Hypoglycemia ; Insulinoma* ; Magnetic Resonance Imaging ; Nesidioblastosis* ; Portal Vein ; Sensitivity and Specificity ; Unconsciousness

BACKGROUNDS: Hyperinsulinemic hypoglycemia is caused by insulinoma mostly and by nesidioblastosis. While an insulinoma is the most common functional endocrine tumor of pancreas, nesidioblastosis primarily is a childhood disease and is rarely reported in adults. Nesidioblastosis has been defined as a diffuse islet cell hyperplasia accompanied by a differentiation of the islets arising from the pancreatic ductal epithelium. Preoperative localization and proper surgical treatment are crucial because these disases can induce critical and permanent neurologic sequela from the hypoglycemia. However, nesidioblastosis has to be considered differently from the insulinoma in terms of diagnosis and therapeutic aspects in adults. METHODS: We retrospectively analyzed 13 and 3 patients who had been diagnosed as having an insulinoma and nesidioblastosis and who had undergone operations during the 8-year period from 1990 to 1998 at Asan Medical Center. We compared the 2 diseases with respect to diagnosis and therapy. RESULTS: There were 3 men and 10 women with an insulinoma and their mean age was 45 (17~64 years). There were 2 men and 1 woman with nesidioblastosis and their mean age was 45 (22~58 years). The most common clinical manifestation was loss of consciousness, and all the patients had findings compatible with Whipple's triad. The median duration of symptoms before diagnosis was 28 months (6~120 months) in insulinoma and 1.1 months (7 days~2 months) in nesidioblastosis (p=0.009). Hyperinsulinemic hypoglycemia was confirmed during prolonged fasting and the concomitant insulin level was 3~130 U/ml (median=25) in the insulinoma patients and 37~202 U/ml (median=67) in the nesidioblastosis patients (p=0.03). Insulinoma can be localized in 12 patients (93%) preoperatively. The combination of negative angiography and a lack of difference in the insulin concentration gradientin THPVC (transhepatic portal vein catheterization) suggested preoperatively a nesidioblastosis in only one patient (33.3%). All the patients with nesidioblastosis was confirmed intraoperatively by a frozen biopsy. In terms of treating the insulinoma, an enucleation was performed in 5, and pancreatic resection in 8. In nesidioblastosis, subtotal pancreatectomy was done on 2 and pybrus preserving pancreaticoduodenectomy (70%) on one patient. Following the operation, the symtoms of hypoglycemia and the laboratory values were normal in all the patients. CONCLUSION: We observed 13 cases of insulinoma (81%) and 3 of nesidioblastosis (19%). Preoperative suspicion, proper utilization of diagnostic tools, and prudent intraoperative diagnostic procedures enhanced the diagnostic accuracy for hyperinsulinemic hypoglycemia and led to better treatment strategies.
Adult* ; Angiography ; Biopsy ; Chungcheongnam-do ; Diagnosis ; Epithelium ; Fasting ; Female ; Humans ; Hyperplasia ; Hypoglycemia* ; Insulin ; Insulinoma* ; Islets of Langerhans ; Male ; Nesidioblastosis* ; Pancreas ; Pancreatectomy ; Pancreatic Ducts ; Pancreaticoduodenectomy ; Portal Vein ; Retrospective Studies ; Unconsciousness

BACKGROUND: Rapid adrenocorticotropin (ACTH) stimulation test using 250ug of ACTH (1-24) has been used as a standard test in the initial assessment of adrenal function. However, it has recently been suggested that a rnaximal cortisol response can be achieved with a much lower ACTH dose, and reducing the dose might further enhance the sensitivity of the test in the detection of mild adrenal insufficiency. This study was performed to evaluate the role of low-dose (lug) ACTH stimulation test in the assessment of adrenal function and the diagnosis of subtle adrenal insufficiency. METHODS: Twenty-two subjects with suspected adrenal insufficiency due to long-term corticosteroid use were included in this study. The correlations between clinical features and the serum cortisol responses to low dose (lug) and high dose (250 ug) ACTH stimulation were evaluated. RESULTS: In high dose test, 10 (67%) out of 15 subjects with clinical features of adrenal insufficiency showed decreased serum cortisol response (peak cortisol level <18 ug/dL), but 5 (33%) subjects showed normal response (peak cortisol level > 18ug/dL). On the other hand, 14 (93%) subjects with clinical features of adrenal insufficiency showed decreased serum cortisol response in low dose test, while only one showed normal response. In 7 subjects without clinical features of adrenal insufficiency, 5 subject (71%) showed normal response, and 2 subjects (29%) showed decreased response in both low and high dose tests. CONCLUSION: These results suggest that the 1-ug low dose ACTH stimulation test might be more sensitive than conventional 250-ug test in the detection of mild adrenal insufficiency. Further studies are needed to determine the optimal dose of ACTH and the criteria for normal response to ACTH stimulation.
Adrenal Insufficiency* ; Adrenocorticotropic Hormone* ; Cosyntropin ; Diagnosis* ; Hand ; Hydrocortisone