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Objective Recent studies have reported that thyroid hormone levels are associated with metabolic syndrome (MetS) even in euthyroid subjects. However, the association between thyroid autoimmunity and MetS is uncertain. This study aimed to investigate the relationship between thyroid autoimmunity and MetS in a large cohort study of euthyroid subjects. Methods A total of 4775 participants aged ≥19 years from the Korea National Health and Nutrition Examination Survey VI (2013–2015) with anti-thyroid peroxidase antibody (TPOAb) results and normal thyroid functions were included in this study. Subjects were grouped according to thyroid autoimmunity (positivity of TPOAb). We estimated the odds ratios (ORs) for MetS according to TPOAb positivity using logistic regression models, adjusted for potential confounders. Results Of the study subjects, 25% (n = 1206) were diagnosed with MetS. Subjects with MetS showed higher median TPOAb levels (6.3 vs 6.8 IU/mL, P < 0.001) and higher positivity of TPOAb (5 vs 7%, P = 0.002) than those without MetS. There was a significant difference in prevalence of MetS depending on the TPOAb positivity (25% vs 33%, P = 0.002). Subjects with TPOAb positive had a significantly greater risk of abdominal obesity (OR 1.675, 95% CI: 1.302–2.154, P < 0.001), low high-density lipoprotein cholesterol (OR: 1.603, 95% CI: 1.244–2.066, P < 0.001) and elevated blood pressure (OR: 1.418, 95% CI: 1.099–1.829, P = 0.007) as compared to those with TPOAb negative. Positivity of TPOAb was a significant risk factor for MetS even after adjusting for confounding variables including age, sex, household income, education, smoking, alcohol consumption, walking activity, thyroid-stimulating hormone and free thyroxine (OR: 1.389, 95% CI: 1.048–1.841, P = 0.022). Conclusion In euthyroid subjects, thyroid autoimmunity is associated with MetS. Further large longitudinal studies are needed to clarify causality.

The association between thyroid autoimmunity and nonalcoholic fatty liver disease (NAFLD) remains unclear. In this study, we aimed to investigate the relationship between thyroid autoimmunity and NAFLD in a large cohort of euthyroid subjects.We analyzed clinical and biochemical data from a nationwide, population-based, cross-sectional survey (KNHANES VI). A total of 1589 middle-aged participants aged 45-65 years, with normal thyroid function, were included in this study. NAFLD was defined as a hepatic steatosis index of 36. We estimated the odds ratios (ORs) for NAFLD according to anti-thyroid peroxidase antibody (TPOAb) positivity by using logistic regression models, and adjusted for potential confounders.Overall, 24% (n = 378) of the subjects had NAFLD. Subjects with NAFLD showed a higher positivity for TPOAb (11% vs 7%, P = 0.014) compared with those without NAFLD. TPOAb positivity was a significant risk factor for NAFLD [OR 1.668, 95% confidence interval (CI) 1.019-2.730, P = 0.042] even after adjusting for confounding variables, including age, sex, household income, education, smoking, alcohol consumption, walking activity, abdominal obesity, elevated blood pressure, dyslipidemia and hyperglycemia. In addition, TPOAb positivity predicted the risk of advanced liver fibrosis (OR 3.112, 95% CI 1.256-7.713, P = 0.014) in subjects with NAFLD, independent of the confounding variables.In euthyroid subjects, thyroid autoimmunity is associated with NAFLD and advanced liver fibrosis, independent of known metabolic risk factors. Large longitudinal studies in the future will help clarify the causality.

Background Fine needle aspiration is the gold standard for differential diagnosis of thyroid nodules; however, the malignancy rate for indeterminate cytology is 20% to 50%. Objective We evaluated the efficacy of shear wave elastography added to ultrasonography for differential diagnosis of thyroid nodules. Methods We retrospectively reviewed the medical records of 258 consecutive patients. Thyroid nodules were divided into 4 categories according to maximum elasticity (EMax) and nodule depth/width (D/W) ratio: Category 1 (EMax ≥ 42.6 kPa; D/W < 0.9); Category 2 (EMax < 42.6 kPa; D/W < 0.9); Category 3 (EMax ≥ 42.6 kPa; D/W ≥ 0.9); and Category 4 (EMax < 42.6 kPa; D/W ≥ 0.9). The EMax cutoff value was set using receiver operating characteristic (ROC) curve analysis to predict nodular hyperplasia (NH) vs follicular neoplasm (FN). Cutoff value for nodule D/W ratio was set using ROC curve analysis for malignancy. Results NH was the most prevalent pathology group in Category 1, FN in Category 2, and papillary thyroid carcinoma in Category 3. Category 3 demonstrated the highest rate of malignancy (81.8%) and had 55.4% sensitivity and 90% specificity for predicting malignancy. When assessing the benign pathology of NH in follicular patterned lesion, Category 1 demonstrated the highest NH prevalence of 88.9% (34/37) and had 73.9% sensitivity and 85.0% specificity. Conclusion The performance for malignancy was highest in Category 3 and predictive ability for benign pathology of NH in follicular lesion was highest in Category 1. The information of EMax and nodule D/W ratio was useful to predict the pathology of thyroid nodules.

Background/Aims: The aim of this study was to address the role of the elasticity index as a possible predictive marker for detecting papillary thyroid carcinoma (PTC) and quantitatively assess shear wave elastography (SWE) as a tool for differ entiating PTC from benign thyroid nodules. Methods: One hundred and nineteen patients with thyroid nodules undergoing SWE before ultrasound-guided fine needle aspiration and core needle biopsy were analyzed. The mean (EMean), minimum (EMin), maximum (EMax), and standard deviation (ESD) of SWE elasticity indices were measured. Results: Among 105 nodules, 14 were PTC and 91 were benign. The EMean, EMin, and EMax values were significantly higher in PTCs than benign nodules (EMean 37.4 in PTC vs. 23.7 in benign nodules, p = 0.005; EMin 27.9 vs. 17.8, p = 0.034; EMax 46.7 vs. 31.5, p < 0.001). The EMean, EMin, and EMax were significantly associated with PTC with diagnostic odds ratios varying from 6.74 to 9.91, high specificities (86.4%, 86.4%, and 88.1%, respectively), and positive likelihood ratios (4.21, 3.69, and 4.82, respectively). The ESD values were significantly higher in PTC than in benign nodules (6.3 vs. 2.6, p < 0.001). ESD had the highest specificity (96.6%) when applied with a cut-off value of 6.5 kPa. It had a positive likelihood ratio of 14.75 and a diag nostic odds ratio of 28.50. Conclusions: The shear elasticity index of ESD, with higher likelihood ratios for PTC, will probably identify nodules that have a high potential for malignancy. It may help to identify and select malignant nodules, while reducing unnecessary fine needle aspiration and core needle biopsies of benign nodules.

Recently, we reported that the elasticity index (EI) of shear wave elastography (SWE) in the total nodular region of interest (ROI) showed higher reproducibility and better agreement in intra- and interrater assay than in the focal nodular ROI when evaluating the intraclass correlation coefficient, coefficient of variation. It may be due to the avoidance of the subjective variance of placement of ROI in the focal nodular area. Also our study showed that EI was correlated with the degree of fibrosis and the location of fibrosis in surgical histopathology was concordant with high EI area on SWE.

We present cases of separate disease categories with shear wave elastography (SWE) and surgical pathology or core needle biopsy (CNB), and discuss the diagnostic performance of SWE in the differential diagnosis of thyroid nodules to try to figure out the possible prediction of histopathology by two-dimensional SWE (2D-SWE).

Aims. To evaluate shear-wave elastography (SWE) as a tool to detect postoperative cervical lymph node (LN) metastasis in patients with papillary thyroid carcinoma (PTC). Methods. Forty-three LNs of 43 patients with PTC undergoing ultrasound (US) and SWE before ultrasound-guided fine-needle aspiration (FNA) for the evaluation of postoperative cervical LN recurrences were analyzed. The mean (EMean), minimum (EMin), maximum (EMax), and standard deviation (ESD) of SWE elasticity indices were measured. Results. Among 43 indeterminate or suspicious LNs, 12 were malignant and 31 were benign. The EMean, EMin, EMax, and ESD values were significantly higher in malignant LNs than in benign LNs (EMean: 37.1 kPa in malignant versus 11.8 kPa in benign LNs, P<0.001; EMin: 11.3 kPa versus 5.1 kPa, P=0.046; EMax: 50.5 kPa versus 23.7 kPa, P<0.001; and ESD: 7.8 kPa versus 4.1 kPa, P=0.006). EMax had the highest accuracy (93.0%) when applied with a cut-off value of 37.5 kPa. It had a positive likelihood ratio of 25.83 and a diagnostic odds ratio of 150.0. Conclusions. The shear elasticity index of EMax, with higher likelihood ratios for malignant LNs, may help identify postoperative cervical LN metastasis in PTC patients with indeterminate or suspicious LNs.

Background Although shear wave elastography (SWE) is reported to be useful in detecting malignant thyroid nodules, it shows a wide range of cut-off values of elasticity index (EI) in detecting malignant nodules. The cause of discrepancy remains unclear. Fibrosis of the tumors is known to increase the EI in SWE, and matching of SWE and surgical histopathology has not been fully illustrated in thyroid cancer. We aimed to evaluate the reproducibility of the new total nodular region of interest (ROI) method excluding the subjective features of focal circular ROI placement and to determine the lesion that causes the elevation of EI on SWE and on histopathology. Methods A total of 29 thyroid cancers from 28 patients were included. We evaluated the reproducibility of EI in the new total nodular ROI using Q-Box Trace program and compared the EI in focal nodular ROI using a 3-mm circular area. We analyzed the correlation between fibrosis and EI. Result The coefficient of variation (CV) of the intrarater assay was significantly lower in total nodular ROI than in focal nodular ROI within the image in rater 1 (1.7% vs. 13.4%, p p p = 0.040) and in rater 2 (7.5% vs. 19.8%, p = 0.004). Moreover, CV of the interrater assay showed similar results (14.9% vs. 19%, p = 0.030). Interrater intraclass correlation coefficient showed better agreement in total nodular ROI than in focal nodular ROI (0.863 vs. 0.783). The degree of fibrosis on histopathology showed significant correlations with EI (EMean, p Max, p = 0.027), and the location of fibrosis was concordant with the high EI area on SWE. Conclusion Our study revealed that the new total nodular ROI method showed higher reproducibility and better agreement in intra- and interrater assay than the focal nodular ROI method, suggesting a valuable and standardized method in clinical practice. Moreover, our results showed that fibrosis in the histopathology increased EI on SWE and might lead to the discrepancy of the cut-off values in detecting thyroid cancer.

Fine-needle aspiration biopsy (FNAB) cannot distinguish a follicular thyroid carcinoma (FTC) from a follicular adenoma in follicular lesions. We designed this study to determine whether the preoperative thyroglobulin (Tg) and change in serum Tg during thyroid-stimulating hormone (TSH) suppression can predict FTC in thyroid nodules with a cytological diagnosis of follicular lesion.Among 854 patients who underwent thyroid surgery, the 198 patients who presented with thyroid nodules with a cytological diagnosis of follicular lesion were analyzed. Predictive factors for malignancy were evaluated using multivariate logistic regression models. Subgroup analyses of patients with TSH suppression therapy by levothyroxine were also conducted.Thirty-two patients (16%) had FTC, and 166 patients had confirmed benign nodules. The median preoperative serum Tg levels were significantly higher in patients with FTC compared to those with benign pathology (449 vs. 34 ng/mL, p0.001). The serum Tg (odds ratios (OR) 10.311, p0.001) and tumor volume (OR 4.500, p = 0.035) were found to be independent predictors for FTC in all patients with a cytological diagnosis of follicular lesion. Forty-eight patients received TSH suppression therapy. When we performed subgroup analyses on the patients with TSH suppression therapy, decrease less than 15% in serum Tg during TSH suppression was found to be an independent predictor of FTC (OR 13.918, p = 0.018).Preoperative serum Tg and changes in serum Tg during TSH suppression independently predict FTC in thyroid nodules with a cytological diagnosis of follicular lesion.

Background Although shear wave elastography (SWE) is reported to be useful in detecting malignant thyroid nodules, it showed a wide range of cut-off values of elasticity index (EI) in detecting malignant nodules. The cause of discrepancy has not been clarified yet. Fibrosis of the tumors is known to increase the EI in SWE, and matching of SWE and surgical histopathology has not been fully illustrated in thyroid cancer. We aimed to evaluate the reproducibility of the new total nodular region of interest (ROI) method excluding the subjective features of focal circular ROI placement and to determine the lesion that causes the elevation of EI on SWE and on histopathology. Methods A total of 29 thyroid cancers from 28 patients were included. We evaluated the reproducibility of EI in the new total nodular ROI using Q-Box Trace program and compared the EI in focal nodular ROI using a 3-mm circular area. We analyzed the correlation between fibrosis and EI. Result The coefficient of variation (CV) of the intrarater assay was significantly lower in total nodular ROI than in focal nodular ROI within the image in rater 1 (1.7% vs. 13.4%, p

Background Recent studies have shown an association between thyroid hormone levels and metabolic syndrome (MetS) among euthyroid individuals; however, there have been some inconsistencies between studies. Here, we evaluated the relationship between thyroid hormone levels and MetS in euthyroid middle-aged subjects in a large cohort. Methods A retrospective analysis of 13,496 euthyroid middle-aged subjects who participated in comprehensive health examinations was performed. Subjects were grouped according to thyroid stimulating hormone, total triiodothyronine (T3), total thyroxine (T4), and T3-to-T4 ratio quartile categories. We estimated the odds ratios (ORs) for MetS according to thyroid hormone quartiles using logistic regression models, adjusted for potential confounders. Results Of the study patients, 12% (n=1,664) had MetS. A higher T3 level and T3-to-T4 ratio were associated with unfavourable metabolic profiles, such as higher body mass index, systolic and diastolic blood pressure, triglycerides, fasting glucose and glycated hemoglobin, and lower high density lipoprotein cholesterol levels. The proportion of participants with MetS increased across the T3 quartile categories (P for trend

The relationship between iodine intake and development of thyroid diseases shows a U-shaped curve with an increase of risk in both deficient and excessive iodine intakes. Our aim was to investigate the relationship between iodine intake and thyroid cancer in patients with thyroid nodules in an iodine-replete area. Retrospective analysis of 1170 patients with thyroid nodules was performed. Urinary iodine concentration (UIC) was measured by inductively-coupled plasma mass spectrometry. Predictive factors for thyroid cancer were evaluated using multivariate logistic regression models. The median UIC in all patients with thyroid nodules was 360 μg/L (range from 4 to 9631 μg/L). More than half of the patients (650/1170, 56 %) belonged to the category of excessive iodine intake (UIC ≥ 300 μg/L) according to WHO iodine recommendations. Patients with thyroid cancer were more likely to be distributed in UIC

Background It is a very important social issue for Korea to have a healthy old age as an aged society. Aging causes a lot of physical changes, especially sarcopenia. Sarcopenia is defined as a persistent decrease in skeletal muscle and muscle strength. Sarcopenic obesity is a phenomenon in which fat is replaced instead of muscle. The purpose of this study was to examine the prevalence of sarcopenia and sarcopenic obesity in Korean elderly and to analyze the relationship with chronic disease. Methods Data from the 2008 to 2011 the Korea National Health and Nutrition Survey were used. A total of 3,492 patients were classified into 3 groups (non-sarcopenia, sarcopenia, sarcopenic obesity), and general, anthropometry, health behavior, nutrient intake and chronic disease status were compared by the statistical analysis. Results The rate of moderate exercise was significantly lower in the sarcopenia and sarcopenic-obesity group than in the non-sarcopenia group (P=0.007). The sarcopenic obesity group had significantly higher energy (P=0.005), protein (P=0.046) and fat (P=0.001) intake than the sarcopenic group. The sarcopenic-obesity group had the highest ratio of diabetes (P=0.023) and dyslipidemia (P=0.004) in the 3 groups. Compared with the non-sarcopenia group, in the sarcopenia and sarcopenic obesity groups, the odds ratios (ORs) of diabetes was increased by 1.24 and 2.16 while the ORs of dyslipidemia was increased by 1.12 and 1.50, respectively. Conclusions Regular exercise and adequate nutrient intake (energy, protein and fat) are essential for the prevention of sarcopenia in Korean elderly, and management of chronic disease in sarcopenic obesity elderly is important.

Supplemental Digital Content is available in the text, Rationale: Adrenal myelolipomas are rare benign tumors, composed of a variable mixture of mature adipose tissue and hematopoietic tissue. These tumors are frequently detected incidentally and are usually asymptomatic, and hormonally inactive. Patient Concerns: During a routine health checkup, a 52-year-old man was found to have a tumor on the bilateral adrenal glands. Abdominal computed tomography revealed a well-defined, heterogeneously enhanced bilateral adrenal mass, suggesting a myelolipoma. Diagnoses: The hormonal evaluation revealed adrenocorticotropic hormone (ACTH) dependent Cushing syndrome. Interventions: The patient underwent left adrenalectomy, and transsphenoidal resection of a pituitary mass. The final diagnosis was adrenal myelolipoma associated with Cushing disease. Outcomes: Growth of right adrenal myelolipoma was detected during the 7-year follow-up. There were enhancing pituitary lesions in repeat magnetic resonance imaging of the sellar region, which implies persistent or recurrent pituitary adenoma. This case reinforces relationship between Cushing disease and adrenal myelolipoma. Lessons: To the best of our knowledge, this is the first reported pathologically confirmed bilateral adrenal myelolipoma associated with Cushing disease. This report supports the idea that ACTH is associated with the development of adrenal myelolipoma.

BACKGROUND Recent studies have correlated serum cystatin C (CysC) with vascular complications, but few studies have investigated this correlation in diabetes patients without nephropathy. This study aimed to evaluate if higher serum CysC levels increase the risk for vascular complications in type 2 diabetes mellitus patients with normal renal function or mild renal impairment. METHODS A total of 806 consecutive patients with type 2 diabetes mellitus who were admitted to the diabetes center of Soonchunhyang University Hospital for blood glucose control were retrospectively reviewed. Patients with nephropathy were excluded. Subjects were categorized into quartiles of serum CysC levels (Q1, ≤0.65 mg/L; Q2, 0.66 to 0.79 mg/L; Q3, 0.80 to 0.94 mg/L; and Q4, ≥0.95 mg/L). RESULTS The proportion of patients with diabetic retinopathy (DR) (P for trend

So Ra Kim, Mi-Kyung Kwak, Hye Ran Kang, Seug Yun Yoon, Seong Soon Kwon, Bo Young Kim, Hoo Nam Choi, Hye Jeong Kim, Jae Wook Kim, So-Young Jin, Hyeong Kyu Park, Dong Won Byun, Kyoil Suh, Myung-Hi Yoo Division of Endocrinology and Metabolism, Department of Internal Medicine, Departments of Otorhinolaryngology-Head and Neck Surgery and Pathology, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea

Background The purpose of this study was to determine the clinicopathologic characteristics of patients with papillary thyroid carcinoma (PTC) by the number of tumor foci. Methods A retrospective analysis of 2095 patients with PTC was performed. The study population was divided into 4 groups based on the number of tumor foci: N1 (1 tumor focus), N2 (2 foci), N3 (3 foci), and N4 (4 or more foci). Results An increasing number of tumor foci was significantly associated with older age at diagnosis (p = .006), cervical lymph node metastasis (p < .001), and advanced TNM stage of disease (p = .001) at initial surgery. The multivariate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for the N2, N3, and N4 groups compared to the N1 group for lateral lymph node metastasis were OR 1.53 (95% CI, 1.05–2.22), OR 2.57 (95% CI, 1.50–4.42), and OR 2.88 (95% CI, 1.42–5.84), respectively. Conclusion An increase in the number of tumor foci was strongly associated with older age at diagnosis, cervical lymph node metastasis, and advanced TNM stage of PTC. The number of tumor foci independently predicted lateral lymph node metastasis. © 2014 Wiley Periodicals, Inc. Head Neck 37: 650–654, 2015

BackgroundSeveral cross-sectional studies have reported that thyroid hormone levels are associated with cardiovascular risk markers and metabolic syndrome (MetS) even in euthyroid subjects. However, the prognostic role of serum thyroid hormone levels in the risk of incident MetS has not been elucidated.AimWe aimed to investigate the associations of baseline serum thyroid hormone levels with the development of MetS in healthy subjects.MethodsThis 6-year, cross-sectional, longitudinal and follow-up study was conducted in 12 037 euthyroid middle-aged subjects without MetS subjected to comprehensive health examinations. Subjects were grouped according to total triiodothyronine (T3) quartiles. The hazard ratio (HR) for the development of MetS according to T3 quartiles was estimated using Cox proportional hazards model.ResultsDuring the 6-year period, 3544 incident cases of MetS (29%) were identified. The proportion of subjects with incident MetS increased across the T3 quartiles (Pfor trend P ConclusionIn euthyroid middle-aged subjects, serum T3 levels are associated with increased risk for future development of MetS.

Both deficient and excessive iodine intake leads to thyroid disease, which shows U-shaped curves. Our previous study showed that a relatively low [urinary iodine concentration (UIC)

Background: Recent studies have shown an association between thyroid hormone levels and metabolic syndrome (MetS) among euthyroid individuals; however, there have been some inconsistencies between studies. Here, we evaluated the relationship between thyroid hormone levels and MetS in euthyroid middle-aged subjects in a large cohort. Methods: A retrospective analysis of 13,496 euthyroid middle-aged subjects who participated in comprehensive health examinations was performed. Subjects were grouped according to thyroid stimulating hormone, total triiodothyronine (T3), total thyroxine (T4), and T3-to-T4 ratio quartile categories. We estimated the odds ratios (ORs) for MetS according to thyroid hormone quartiles using logistic regression models, adjusted for potential confounders. Results: Of the study patients, 12% (n=1,664) had MetS. A higher T3 level and T3-to-T4 ratio were associated with unfavourable metabolic profiles, such as higher body mass index, systolic and diastolic blood pressure, triglycerides, fasting glucose and glycated hemoglobin, and lower high density lipoprotein cholesterol levels. The proportion of participants with MetS increased across the T3 quartile categories (P for trend

Background: Recent evidence indicates that elevated COX-2 expression is associated with the carcinogenesis of numerous neoplasms. In this study, we investigated COX-2 expression in various thyroid specimens in order to elucidate its physiological role in pathologic conditions, and to evaluate the efficiency of COX-2 protein expression as a molecular marker of malignancy in the thyroid gland. Methods: COX-2 expression was studied immunohistochemically in 19 papillary carcinomas, 8 follicular carcinomas, 14 follicular adenomas, 2 Hurthle cell carcinomas, 4 Hurthle cell adenomas, 8 nodular hyperplasias, 3 Graves' diseases, 3 Hashimoto's thyroiditis, 2 medullary carcinomas, 1 anaplastic carcinoma, and 20 normal thyroid tissues. Results: COX-2 staining was not seen in any of the normal thyroid, Graves' disease, or nodular hyperplasia specimens. In contrast, COX-2 staining was observed in all of papillary carcinomas, Hashimoto's thyroiditis, Hurthle cell carcinomas, and Hurthle cell adenomas tissues. Moreover, 7 of 8 follicular carcinomas and 11 of 14 follicular adenomas showed COX-2 staining. Conclusion: These results indicate that COX-2 is not useful as a marker of malignancy. Since COX-2 expression was evident in follicular adenomas and in papillary and follicular carcinomas. Thus, the enzyme may be involved in the early process of thyroid tumorigenesis.

The transport proteins such as thyroxine-binding-globulin (TBG), albumin and transthyretin carry over 99% of circulating thyroid hormones. TBG is a major thyroid hormone transport protein in serum. Although TBG deficiency does not have metabolic conse quences, it has diagnostic implications as it can lead to an incorrect interpretation of thyroid function tests. We experienced a case that a man who had an abnormal thyroid function showed unexpectedly low concentrations of serum total thyroxine. We detected the low TBG in his serum and he was diagnosed the TBG deficiency. We report this case along with a review of the related literature.

Pregnancy-associated plasma protein-A (PAPP-A) has been identified as the insulin-like growth factor (IGF)-dependent IGF-binding protein-4 (IGFBP-4) protease produced by human fibroblasts. Recently, we found that serum proteases induced during human pregnancy cleaved IGFBP-4 in both an IGF-II-dependent and an IGF-II-independent fashion. This study sought to determine whether PAPP-A is the predominant IGFBP-4 protease in human pregnancy serum (PS) and to assess the in vitro role of serum PAPP-A. Immunoprecipitation with PAPP-A antibody effectively depleted PAPP-A from the PS and completely abolished both IGF-II-dependent and IGF-II-independent IGFBP-4 proteolytic activity in PS. Direct addition of PAPP-A antibody to PS completely blocked IGFBP-4 proteolysis and partially blocked IGFBP-5 proteolysis, but had no effect on IGFBP-3 proteolysis. To evaluate the role of serum PAPP-A, we tested whether PAPP-A in PS modulated the inhibitory activity of IGFBP-4 on IGF-II-induced cell proliferation in human osteosarcoma MG63 cells. The wild-type IGFBP-4 (WTBP-4; 200 ng/mL) failed to inhibit proliferation of the cells treated with PS (0.1% or 0.3%) alone or in combination with IGF-II (40 ng/mL), whereas the inhibitory effect of WTBP-4 was observed in the cells treated with nonpregnancy serum alone or in combination with IGF-II (P < 0.05). In contrast to WTBP-4, a protease-resistant IGFBP-4 was able to inhibit proliferation of the cells treated with PS alone or in combination with IGF-II (P < 0.05). In the presence of PAPP-A neutralizing antibody, the inhibitory effect of WTBP-4 on proliferation of the cells treated with IGF-II and PS was restored. In summary, these data demonstrate 1) that PAPP-A represents the predominant IGFBP-4 protease in PS; 2) that PAPP-A may in part contribute to IGFBP-5, but not IGFBP-3, proteolytic activity in PS; and 3) that PAPP-A enhances the bioactivity of IGFs in vitro by degrading IGFBP-4.

Insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4), a consistent inhibitor of IGF action, is subject to proteolytic cleavage by the IGF-II-dependent IGFBP-4 protease. However, regulation of the IGF-II-dependent IGFBP-4 protease in vivo is not known. As IGFBP proteases are known to be triggered during pregnancy, we systematically evaluated the changes in IGFBP-4 proteolysis by serum collected throughout human pregnancy. Results from in vitro protease assays using recombinant IGFBP-4 revealed that IGFBP-4 proteolysis determined in both the presence and absence of exogenous IGF-II significantly increased during the first and second trimesters and reached a plateau by the third trimester. However, in the absence of IGF-II, IGFBP-4 proteolysis by pregnancy serum was only observed after prolonged incubation. IGF-II dose dependently increased IGFBP-4 proteolysis by pregnancy serum, with maximal stimulation observed at a concentration of 0.7 mol/L relative to IGFBP-4. In contrast, IGF-II at an equimolar...

The purpose of this study was to determine the clinicopathologic characteristics of patients with papillary thyroid carcinoma (PTC) by the number of tumor foci.A retrospective analysis of 2095 patients with PTC was performed. The study population was divided into 4 groups based on the number of tumor foci: N1 (1 tumor focus), N2 (2 foci), N3 (3 foci), and N4 (4 or more foci).An increasing number of tumor foci was significantly associated with older age at diagnosis (p = .006), cervical lymph node metastasis (p.001), and advanced TNM stage of disease (p = .001) at initial surgery. The multivariate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for the N2, N3, and N4 groups compared to the N1 group for lateral lymph node metastasis were OR 1.53 (95% CI, 1.05-2.22), OR 2.57 (95% CI, 1.50-4.42), and OR 2.88 (95% CI, 1.42-5.84), respectively.An increase in the number of tumor foci was strongly associated with older age at diagnosis, cervical lymph node metastasis, and advanced TNM stage of PTC. The number of tumor foci independently predicted lateral lymph node metastasis.

Background/Aims The relationship between Runt-related transcription factor 3 (RUNX3) gene inactivation and various solid tumors has been reported; however, little information is available about RUNX3 in thyroid cancers. Methods We evaluated the DNA methylation of RUNX3 in 13 papillary thyroid cancer tissues and four thyroid cancer cell lines. Additionally, using reverse transcriptase-polymerase chain reaction, we analyzed RUNX3 gene expression in several thyroid cancer cell lines after treating with the demethylating agent 5-aza-2'-deoxycytidine (DAC). Results RUNX3 was hypermethylated in many thyroid cancer cell lines and in 10 of the 12 papillary thyroid cancer tissues. Treatment with DAC increased the expression of RUNX3 in some thyroid cancer cell lines. Conclusions We suggest that RUNX3 is associated with thyroid carcinogenesis, and RUNX3 methylation is a potentially useful diagnostic marker for papillary thyroid cancer.

Familial neurohypophyseal diabetes insipidus (FNDI; OMIM 192340) is a rare inherited disorder with an autosomal dominant inheritance pattern. It is characterized by persistent polydipsia and polyuria induced by deficient or absent secretion of arginine vasopressin (AVP). We report a Korean kindred in whom FNDI is associated with a novel deletion mutation in exon 2 of the AVP-NPII gene encoding the neurophysin II moiety. An 18-yr-old man with polyuria and polydipsia was shown to have central diabetes insipidus by using the water deprivation test. Four family members were suspected to have symptomatic vasopressin-deficient diabetes insipidus. Direct sequencing of the AVP-NPII gene showed a heterozygous GAG deletion mutation in exon 2, which results in in-frame deletion of glutamic acid (c.232_234delGAG; p.Glu78del). The mutation was predicted to yield an abnormal AVP precursor lacking Glu78 (E78) in its neurophysin II moiety. Because Glu78 is essential for neurophysin II molecules to form a salt bridge with AVP, the function of neurophysin as a carrier protein for AVP would be impaired. The proband's mother and sister have the same mutation. Presence of this mutation suggests that the portion of the neurophysin peptide encoded by this sequence is important for the appropriate expression of vasopressin.

Background Recently, it has been suggested that decrease in serum sodium level is associated with osteoporosis. However, no study in Korea has reported the association of decrease in serum sodium level with osteoporosis. In this study, we investigated the relationship between the decrease in serum sodium level and severity of osteoporotic fracture in patients. Methods We enrolled 290 subjects who were admitted and operated at Soonchunhyang University Hospital due to major fractures. For the control group, we enrolled 1,027 subjects who visited a health promotion center. We carried a 1:1 matching with age and sex from the case group. Results In a total of 164 age- and sex-matched subjects, serum sodium level was significantly lower in the fracture group than in the non-fracture group (P=0.001). Serum sodium level was significantly lower in the severe osteoporosis group than that in the non-severe osteoporosis group (P=0.002). Old age and decrease in serum sodium level were independent risk factors of osteoporosis (odds ratio [OR]=1.088, P=0.008, confidence interval [CI]=[1.022-1.157]; OR= 0.840, P=0.037, CI=0.713-0.989). Conclusions Serum sodium level was significantly lower in the fracture group than that in the non-fracture group and in the severe osteoporosis group than that in the non-severe osteoporosis group. Based on our results, the decrease in serum sodium level could be an independent risk factor for osteoporosis.

Focal adhesion kinase (FAK) is a tyrosine kinase that is found in cellular structures called focal adhesions. FAK appears to be a key element in signal transduction pathways involved in cell adhesion and locomotion. FAK is overexpressed in various tumors, including tumors derived from regions of the head and neck, colon, breast, prostate, and liver. In this study, we investigated immunohistochemically whether FAK expression was increased in thyroid cancers. FAK staining was not seen in any of the 20 normal thyroid tissues or the 6 nodular hyperplasia specimens. In contrast, FAK staining was observed in all of 17 papillary carcinomas, 9 follicular carcinomas, 8 medullary carcinomas, and 2 anaplastic carcinomas. Nine of 17 follicular adenomas showed FAK immunoreactivity. FAK was not expressed in normal tissue and nodular hyperplasia, but was expressed in some of the follicular adenoma, and all of the follicular, papillary, medullary and anaplastic thyroid carcinoma. This result indicates that the up-regulation of FAK may play a role in the development of thyroid carcinogenesis.