Effects of bisphenol A on cardiovascular disease: An epidemiological study using National Health and Nutrition Examination Survey 2003-2016 and meta-analysis.

As the most widely consumed endocrine-disrupting chemical, bisphenol A (BPA) has been linked to reproductive dysfunction, diabetes mellitus, and obesity. However, the evidence for an association between BPA and cardiovascular disease (CVD) remains insufficient. In the present study, we aimed to identify the association between BPA and CVD, using data from the 2003-2016 National Health and Nutrition Examination Surveys (NHANES). We estimated urine BPA concentration after adjustments for creatinine (ng/mg) and normalized the asymmetrical distribution using natural logarithmic transformation (ln-BPA/Cr). A multivariate logistic regression was performed to evaluate the odds ratio (OR) and 95% confidence interval (CI) for CVD, with ln-BPA/Cr concentration as predictor. We then performed a Mantel-Haenszel meta-analysis with five eligible studies and NHANES 2003-2016 data. Our subjects were 11,857 adults from the NHANES data. After adjusting for age, sex, race/ethnicity, body mass index (BMI), cigarette smoking, diabetes status, hypertension, and dyslipidemia, OR between ln-BPA/Cr and CVD was 1.13 (95% CI: 1.02-1.24). After propensity-score-matching with age, sex, race/ethnicity, BMI, cigarette smoking, diabetes, hypertension, and dyslipidemia, OR continued to be significant for the association between ln-BPA/Cr and CVD (OR: 1.18, 95% CI: 1.04-1.33). A restricted cubic spline plot of this relationship revealed a dose-dependent increase in OR. However, untransformed BPA had a linear relationship with CVD only at low concentrations, whereas the OR of BPA plateaued at high concentrations. In a meta-analysis with 22,878 subjects, after adjusting for age, sex, and various cardiometabolic risk factors, OR was 1.13 (95% CI, 1.03-1.23). In conclusion, our study provides additional epidemiological evidence supporting an association between BPA and CVD.

Association between serum selenium level and the prevalence of diabetes mellitus in U.S. population.

OBJECTIVE: Selenium seems to be a risk factor for diabetes mellitus (DM) in recent studies, opposite to the previous expectation that it may contribute to prevent DM. The authors aimed to ascertain the relationship between selenium and DM. METHODS: Data were collected from the National Health and Nutrition Examination Survey conducted from 2011 to 2014. A multivariate logistic regression analysis with adjustment for age, sex, race/ethnicity, hypertension, dyslipidemia and body mass index was conducted to evaluate the odds ratio for DM. RESULTS: The total number of subjects was 19,931. Large proportion of subjects were excluded due to young age (< 20 years) and missing data. The data of 3406 participants were analyzed, and a total of 604 had DM. In a multivariate logistic regression model, the increase of 10 µg/L in selenium increased the prevalence of DM by 12% (OR: 1.12; 95% CI: 1.06-1.18). Further analysis with 1:1 propensity score matching data with age and sex showed a similar results (OR: 1.08; 95% CI: 1.01-1.15). In addition, the restricted cubic spline regression showed a dose-dependent relationship between selenium level and DM. Subgroup analysis showed a dose-dependent relationship between selenium level and DM regardless of sex or race/ethnicity CONCLUSIONS: This large population study clearly demonstrates a positive association between selenium level and DM. This finding could have implications for nutritional supplementation in clinical settings.

Association between Serum Selenium Level and the Presence of Diabetes Mellitus: A Meta-Analysis of Observational Studies.

BACKGROUND: Epidemiological studies have suggested an association between selenium (Se) and diabetes mellitus (DM). However, different studies have reported conflicting results. Therefore, we performed a comprehensive meta-analysis to clarify the impact of Se on DM. METHODS: We searched the PubMed database for studies on the association between Se and DM from inception to June 2018. RESULTS: Twenty articles evaluating 47,930 participants were included in the analysis. The meta-analysis found that high levels of Se were significantly associated with the presence of DM (pooled odds ratios [ORs], 1.88; 95% confidence interval [CI], 1.44 to 2.45). However, significant heterogeneity was found (I²=82%). Subgroup analyses were performed based on the Se measurement methods used in each study. A significant association was found between high Se levels and the presence of DM in the studies that used blood (OR, 2.17; 95% CI, 1.60 to 2.93; I²=77%), diet (OR, 1.61; 95% CI, 1.10 to 2.36; I²=0%), and urine (OR, 1.49; 95% CI, 1.02 to 2.17; I²=0%) as samples to estimate Se levels, but not in studies on nails (OR, 1.24; 95% CI, 0.52 to 2.98; I²=91%). Because of significant heterogeneity in the studies with blood, we conducted a sensitivity analysis and tested the publication bias. The results were consistent after adjustment based on the sensitivity analysis as well as the trim and fill analysis for publication bias. CONCLUSION: This meta-analysis demonstrates that high levels of Se are associated with the presence of DM. Further prospective and randomized controlled trials are warranted to elucidate the link better.

Clinical Features of Geriatric Syndromes in Older Koreans with Diabetes Mellitus.

BACKGROUND: This study explored the prevalence and clinical characteristics of geriatric syndromes among Korean older adults with diabetes mellitus (DM). METHODS: We used data from the 2017 National Survey of Older Koreans to analyze the classic geriatric syndromes of polypharmacy, urinary incontinence, falls, cognitive impairment, and functional impairment according to the presence of DM. RESULTS: Among 10,299 participants aged 65 years or older, 2,395 had DM. The prevalence of polypharmacy was 64.1% in the DM group and 31.6% in the non-DM group (p<0.001). One or more falls per year occurred in 18.7% of participants with DM compared with 14.9% of those without DM (p<0.001). The prevalence of urinary incontinence was significantly higher in the DM group (3.8%) than in the non-DM group (2.5%) (p=0.001). The prevalence of cognitive impairment was 17.7% in the DM group versus 14.9% in the non-DM group (p=0.001). Functional impairment occurred in 32.2% of participants in the DM group compared with 26.8% of participants in the non-DM group (p<0.001). Finally, the number of geriatric syndromes was significantly associated with cardiovascular disease (CVD) and chronic kidney disease (CKD) in patients with DM. CONCLUSION: The results of this study showed a higher prevalence of geriatric syndromes among older Korean adults with DM. In addition, the coexistence of multiple geriatric syndromes was associated with CVD and CKD among patients with DM. These findings support the current guidelines for older adults with DM that recommend assessment for geriatric syndromes.

Associations between Hashimoto Thyroiditis and Clinical Outcomes of Papillary Thyroid Cancer: A Meta-Analysis of Observational Studies.

BACKGROUND: Epidemiological studies have suggested an association between Hashimoto thyroiditis (HT) and papillary thyroid cancer (PTC) development. Other studies, however, have reported a protective role of HT against PTC progression. Through this updated meta-analysis, we aimed to clarify the effects of HT on the progression of PTC. METHODS: We searched citation databases, including PubMed and Embase, for relevant studies from inception to September 2017. From these studies, we calculated the pooled odds ratios (ORs) of clinicopathologic features and the relative risk (RR) of PTC recurrence with 95% confidence intervals (CIs) using the Mantel-Haenszel method. Additionally, the Higgins I² statistic was used to test for heterogeneity. RESULTS: The meta-analysis included 71 published studies with 44,034 participants, among whom 11,132 had HT. We observed negative associations between PTC with comorbid HT and extrathyroidal extension (OR, 0.74; 95% CI, 0.68 to 0.81), lymph node metastasis (OR, 0.82; 95% CI, 0.72 to 0.94), distant metastasis (OR, 0.49; 95% CI, 0.32 to 0.76), and recurrence (RR, 0.50; 95% CI, 0.41 to 0.61). CONCLUSION: In this meta-analysis, PTC patients with HT appeared to exhibit more favorable clinicopathologic characteristics and a better prognosis than those without HT.

Subclinical Hypothyroidism and the Risk of Cardiovascular Disease and All-Cause Mortality: A Meta-Analysis of Prospective Cohort Studies.

OBJECTIVES: To determine the impact of subclinical hypothyroidism (SCH) on the risk of cardiovascular disease (CVD) and all-cause mortality, a comprehensive meta-analysis was performed according to the age or coexisting CVD risk status of the participants. METHODS: Studies regarding the association of SCH with all-cause mortality from PubMed and Embase databases were included. The pooled relative risk (RR) of CVD and all-cause mortality was calculated using the Mantel-Haenszel method. A subgroup analysis of participants with high CVD risk was conducted, including history of coronary, cerebral, or peripheral artery disease; dilated cardiomyopathy; heart failure; atrial fibrillation; venous thromboembolism; diabetes mellitus; or chronic kidney disease. RESULTS: In total, 35 eligible articles incorporating 555,530 participants were included. SCH was modestly associated with CVD and all-cause mortality (RR for CVD = 1.33 [confidence interval (CI) 1.14-1.54]; RR for all-cause mortality = 1.20 [CI 1.07-1.34]). However, the association was not observed in participants aged ≥65 years. Subgroup analysis showed that participants with SCH and high CVD risk showed a significantly higher risk of all-cause mortality (RR for CVD = 2.20 [CI 1.28-3.77]; RR for all-cause mortality = 1.66 [CI 1.41-1.94]), whereas those with SCH and low CVD risk did not. Additional subgroup analysis of six studies with a mean participant age of ≥65 years and high CVD risk showed a significant high risk of all-cause mortality in the SCH group (RR = 1.41 [CI 1.08-1.85]; I2 = 0%). CONCLUSIONS: SCH is associated with an increased CVD risk and all-cause mortality, particularly in participants with high CVD risk.

The Cut-off Values of Surrogate Measures for Insulin Sensitivity in a Healthy Population in Korea according to the Korean National Health and Nutrition Examination Survey (KNHANES) 2007-2010.

BACKGROUND: This study aimed to identify the gender-specific characteristics of the surrogate measures of insulin resistance and to establish valid cut-off values for metabolic abnormalities in a representative sample in Korea. METHODS: Data were collected from the datasets of the Korean National Health and Nutrition Examination Survey between 2007 and 2010. The total number of eligible participants was 10,997. We used three measures of insulin resistance: the homeostasis model assessment-insulin resistance (HOMA-IR), McAuley index, and triglyceride and glucose (TyG) index. The estimated cut-off values were determined using the highest score of the Youden index. RESULTS: The area under the curve (AUC) of the HOMA-IR, McAuley index, and TyG index were 0.737 (95% confidence interval [CI], 0.725-0.750), 0.861 (95% CI, 0.853-0.870), and 0.877 (95% CI, 0.868-0.885), respectively. The cut-off values of the HOMA-IR were 2.20 in men, 2.55 in premenopausal women, and 2.03 in postmenopausal women, and those of the McAuley index were 6.4 in men and 6.6 in premenopausal and postmenopausal women. For the TyG index, the cut-off values were 4.76 in men and 4.71 in premenopausal and postmenopausal women. CONCLUSION: In conclusion, the present study provides the valid cut-off values of the indirect surrogate measures of insulin sensitivity. These values may be used as reference for insulin sensitivity in a clinical setting and may provide a simple and supplementary method for identifying populations at risk of insulin resistance.

Association between diabetes mellitus and hearing impairment in American and Korean populations.

AIMS: The aim of this study was to evaluate ethnic- and sex-specific associations between DM and hearing impairment. METHODS: For this cross-sectional study using National Health and Nutrition Examination Survey in the U.S. and Korea, the total number of eligible participants included was 7081 in the U.S. and 15,704 in Korea. Hearing impairment was defined as a pure tone threshold level ≥ 25 dB. Multivariate logistic regression analysis was conducted, adjusting for age, sex, race/ethnicity, socioeconomic status, body mass index, noise exposure, smoking, hypertension, and dyslipidemia. RESULTS: The association between DM and hearing impairment was found to be sex-specific. The multivariate adjusted ORs of high-frequency impairment were 0.843 (95% CI, 0.524-1.356) in American men, and 1.073 (95% CI, 0.835-1.379) in Korean men, while the ORs in women from U.S. and Korea were 1.911 (95% CI, 1.244-2.935) and 1.421 (95% CI, 1.103-1.830), respectively. A subgroup analysis of each race/ethnicity among the U.S. adults showed similar results. In contrast to high-frequency impairment, there was no significant association between low-frequency impairment and DM in both men and women. CONCLUSION: Our results suggest that DM is associated with hearing impairment in only women, irrespective of race/ethnicity groups.

Synergistic interaction between prolonged increased glycemic exposure and mildly increased urinary albumin excretion on diabetic retinopathy.

The association of mild increase in urinary albumin excretion with diabetic retinopathy (DR) in clinical studies is controversial. The aim of this study is to clarify the interaction between increased glycemic exposure and mild increase in urinary albumin excretion on risk of DR.Data were collected from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2012. Overall, data from 953 participants without microalbuminuria (477 men and 476 women) were assessed. Logistic regression analysis was constructed to evaluate the association between DR and related clinical parameters, including urinary albumin-creatinine ratio (UACR, mg/g creatinine). The biological interaction of glycemic status and UACR on DR was evaluated by 3 indices: RERI, the relative excess risk due to the interaction; AP, the attributable proportion due to the interaction; and S, the additive interaction index of synergy.We found that UACR, glycated hemoglobin (HbA1c), and diabetic duration were deeply associated with increased risk of DR (UACR, odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.02-1.07; HbA1c, OR = 1.16, 95% CI = 1.04-1.30; diabetic duration, OR = 1.06, 95% CI = 1.04-1.07). Furthermore, our interaction analysis demonstrated that synergistic interaction between HbA1c and UACR on development of DR was prominent in participants with diabetic duration of ≥10 years (adjusted RERI = 0.92, 95% CI = 0.10-1.74; adjusted AP = 0.29, 95% CI = -0.82-1.41; adjusted S = 1.76, 95% CI = 1.27-2.25), but not subjects with shorter diabetic duration.These findings imply that there is the interaction between prolonged hyperglycemic exposure and increased urinary albumin excretion may exert additive synergistic effect on vascular endothelial dysfunction in the eye, even before the appearance of overt diabetic nephropathy.

50 Years of the Korean Geriatrics Society.

The Korean Geriatrics Society was founded on October 3, 1968. Over the 50 years since then, the Society has incessantly strived to stay attuned to the aging society and to achieve an increasingly greater research impact in the field of gerontology and geriatric medicine. The Society has passed through periods of preparation for a leap forward, followed by rapid growth, expansion, and maturity. As a result, the Society has gained a firm foothold at home and abroad as a leading research society for both qualitative and quantitative achievements in geriatric medicine. At this juncture, with an ultra-aging society being just around the corner, we are celebrating its 50th anniversary and anticipating our second half-century with great enthusiasm about our mission and role as a leading geriatric research organization.

Analyzing the Factors Associated With Nocturia in Older People in the United States.

BACKGROUND: The risk factors of nocturia in older adults remain unclear. We aimed to investigate factors associated with nocturia using the National Health and Nutrition Examination Survey (NHANES) data. METHODS: Among 40,790 participants, 4,698 participants aged ≥65 years were included from the NHANES dataset between 2005 and 2012. A multivariate logistic regression analysis was performed to determine the odds ratio (OR) for nocturia. A subgroup analysis was conducted based on sex and underlying diseases. RESULTS: In the multivariate logistic regression model, obesity (OR, 1.46; 95% confidence interval [CI], 1.28-1.68), hypertension (OR, 1.28; 95% CI, 1.07-1.52), and diabetes mellitus (DM) (OR, 1.27; 95% CI, 1.11-1.45) were significantly associated with nocturia. These factors were associated with nocturia regardless of sex. In a subgroup of participants with hypertension, obesity (OR, 1.44; 95% CI, 1.25-1.67) and DM (OR, 1.26; 95% CI, 1.09-1.45) were associated with nocturia. In the additional analysis on patients with DM, nocturia was associated with obesity (OR, 1.33; 95% CI, 1.06-1.67) and duration of DM (OR, 1.02; 95% CI, 1.01-1.03). CONCLUSION: This study demonstrated that hypertension, DM, and obesity were significantly associated with the prevalence of nocturia in older adult patients regardless of sex. In particular, obesity was associated with nocturia in every subgroup analysis.

Protein Intake Recommendation for Korean Older Adults to Prevent Sarcopenia: Expert Consensus by the Korean Geriatric Society and the Korean Nutrition Society.

Sarcopenia, a common clinical syndrome in older adults, is defined as decreased muscle mass, strength, and physical performance. Since sarcopenia is associated with the incidence of functional decline, falls, and even mortality in older adults, researchers and health care providers have been keen to accumulate clinical evidence to advocate the screening and prevention of sarcopenia progression in older adults. The factors that may accelerate the loss of muscle mass and function include chronic diseases, inactivity, and deficiency in appropriate nutritional support. Among these, nutritional support is considered an initial step to delay the progression of muscle wasting and improve physical performance in community-dwelling older adults. However, a nationwide study suggested that most Korean older adults do not consume sufficient dietary protein to maintain their muscle mass. Furthermore, considering age-associated anabolic resistance to dietary protein, higher protein intake should be emphasized in older adults than in younger people. To develop a dietary protein recommendation for older adults in Korea, we reviewed the relevant literature, including interventional studies from Korea. From these, we recommend that older adults consume at least 1.2 g of protein per kg of body weight per day (g/kg/day) to delay the progression of muscle wasting. The amount we recommend (1.2 g/kg/day) is 31.4% higher than the previously suggested recommended daily allowance (i.e., 0.91 g/kg/day) for the general population of Korea. Also, evidence to date suggests that the combination of exercise and nutritional support may enhance the beneficial effects of protein intake in older adults in Korea. We found that the current studies are insufficient to build population-based guidelines for older adults, and we call for further researches in Korea.

Synergistic cytotoxicity of the dipeptidyl peptidase-IV inhibitor gemigliptin with metformin in thyroid carcinoma cells.

PURPOSE: The influence of the dipeptidyl peptidase-IV inhibitor, gemigliptin alone or in combination with metformin on survival, proliferation, and migration of thyroid carcinoma cells was investigated. METHODS: SW1736 and TPC-1 human thyroid carcinoma cells were used. RESULTS: Gemigliptin and metformin caused cell death in a dose-dependent manner. In cells treated with both gemigliptin and metformin, compared with metformin alone, all of the combination index values were lower than 1.0, suggesting synergistic cytotoxicity of two agents. Cell viability, the percentage of viable cells, ATP levels, and mitochondrial membrane potential decreased; however, cytotoxic activity, and the protein levels of cleaved PARP, phospho-Akt and phospho-AMP-activated protein kinase (AMPK) increased. Administration of wortmannin, but not compound C, further decreased cell viability, and further increased cytotoxic activity. Moreover, compared with control, cell proliferation and migration as well as the protein levels of p53, p21, vascular cell adhesion molecule-1 (VCAM-1), and phospho-extracellular signal-regulated kinase (ERK) 1/2 decreased. The decrement of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein levels was cell specific. CONCLUSIONS: Our results demonstrate that gemigliptin induces cytotoxic activity, and has a synergistic activity with metformin in inducing cytotoxicity via regulation of Akt and AMPK in thyroid carcinoma cells. Furthermore, gemigliptin augments the inhibitory effect of metformin on proliferation and migration through involvement of matrix metalloproteinase-2, matrix metalloproteinase-9, p53, p21, VCAM-1, and ERK in thyroid carcinoma cells.

Association of Z-Score of the Log-Transformed A Body Shape Index with Cardiovascular Disease in People Who Are Obese but Metabolically Healthy: The Korea National Health and Nutrition Examination Survey 2007-2010.

BACKGROUND: We aimed at evaluating the effect of the z-score of the log-transformed A Body Shape Index (LBSIZ) on cardiovascular disease (CVD) outcomes according to obesity phenotype. METHODS: Data were collected from the Korea National Health and Nutrition Examination Survey conducted from 2007 to 2010. Obesity was defined as a body mass index above 25 kg/m2 and metabolic abnormality was defined as the presence of two or more metabolic risk factors of the Adult Treatment Panel III definition. The participants were classified by obesity and metabolic healthy status: metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO). Each group was further classified into three groups based on the tertile of LBSIZ. A multivariate logistic regression analysis with adjustment for age, sex, smoking status, income, education level, physical activities, alcohol, and energy intake was conducted to evaluate the odds ratio (OR) for CVD events. RESULTS: In the multivariate logistic regression model, MHO participants who are within the third tertile of LBSIZ had a significantly higher OR for CVD events, whereas those who are within the first and second tertile of LBSIZ were not at high risk of developing CVDs compared to MHNO participants who are within the first tertile of LBSIZ. In addition, a similar increase in the OR was observed in MUNO or MUO participants. CONCLUSION: LBSIZ had the lowest risk for CVDs in the first tertile of LBSIZ and a linear relationship with all its tertiles in MHO, MUNO, and MUO participants.

The dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with NVP-AUY922 has a cytotoxic activity in thyroid carcinoma cells.

The effect of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the heat shock protein 90 inhibitor NVP-AUY922 (AUY922) on survival of thyroid carcinoma cells was elucidated. The SW1736 and TPC-1 human thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, cytotoxic activity, the percentage of apoptotic cells, and mitochondrial membrane potential were measured. To evaluate the combined effect of gemigliptin with AUY922, the interactions were estimated by calculating combination index. Gemigliptin led to cell death in conjunction with overexpression of the phosphorylated protein levels of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase. In gemigliptin-treated cells, wortmannin augmented cell death, whereas AZD6244 and compound C did not affect cell survival. Wortmannin decreased phosphorylated adenosine monophosphate-activated protein kinase protein levels, and AZD6244 increased phosphorylated Akt protein levels. Meanwhile, cotreatment of both gemigliptin and AUY922, compared with treatment of AUY922 alone, potentiated cell death. All the combination index values were lower than 1.0, suggesting synergistic cytotoxicity of gemigliptin with AUY922. In treatment of both gemigliptin and AUY922, compared with AUY922 alone, the protein levels of total and phosphorylated Akt, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated adenosine monophosphate-activated protein kinase increased without alteration in those of total extracellular signal-regulated kinase 1/2 and total adenosine monophosphate-activated protein kinase. The percentage of apoptotic cells increased. The protein levels of Bax and cleaved poly (ADP-ribose) polymerase increased, whereas Bcl2 protein levels were unchanged, resulting in increment of Bax/Bcl2 ratio. Transfection of Bax small interfering RNA did not cause any variation in cell viability, the percentage of viable cells and cytotoxic activity. Our results demonstrate that gemigliptin exerts a cytotoxic activity with concomitant alterations in expression of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase in thyroid carcinoma cells. Furthermore, gemigliptin synergizes with AUY922 in induction of cytotoxicity via regulation of Akt, extracellular signal-regulated kinase 1/2, and adenosine monophosphate-activated protein kinase as well as involvement of Bcl2 family proteins in thyroid carcinoma cells.

The influence of physical activity on risk of cardiovascular disease in people who are obese but metabolically healthy.

The metabolic outcomes of metabolically healthy obesity (MHO) remain controversial. The aim of the present study was to determine the effect of physical activity on the cardiovascular disease (CVD) outcomes of MHO. The study included participants who were followed for 10 years and recruited from the Korean Genome and Epidemiology Study (KoGES), a population-based cohort study. Participants with previously recorded CVDs or cancer, or who had received steroids or anticoagulants at baseline were excluded. A total of 8144 participants (3,942 men and 4,202 women) fulfilled inclusion criteria. In a multivariate Cox regression model adjusted for age and sex, MHO participants were not at elevated risk of CVD compared with their metabolically healthy non-obese (MHNO) counterparts (HR, 1.28; 95% CI, 0.96-1.71), although both the non-obese (HR, 1.50; 95% CI, 1.19-1.90) and obese (HR, 1.85; 95% CI, 1.48-2.30) participants with metabolic abnormalities were at elevated risk. However, in the subgroup analysis by physical activity, physically inactive MHO participants had a significantly higher HR for CVD events compared to active MHNO participants (HR, 1.54; 95% CI, 1.03-2.30), while active MHO participants were not at elevated risk (HR, 1.15; 95% CI, 0.70-1.89). Physically inactive MHO participants had significantly increased risk of CVD compared to physically active MHNO participants whereas physically active MHO participants did not.

Clinical Implications of Immunoglobulin G4 to Graves' Ophthalmopathy.

BACKGROUND: This study aimed to explore the relation of immunoglobulin G4 (IgG4) to clinical and laboratory characteristics of patients newly diagnosed with Graves' disease (GD) without or with Graves' ophthalmopathy (GO) and to analyze association of IgG4 with development and grade of GO in GD patients. METHODS: Sixty-four GD patients and 64 sex- and age-matched euthyroid subjects were enrolled. Serum levels of thyroid hormones, thyroid autoantibodies, immunoglobulin G (IgG), and IgG4 were measured, and ophthalmological and ultrasonographical evaluation was performed. RESULTS: In GD patients compared with euthyroid subjects, levels of thyroid hormones, thyroid autoantibodies and IgG4 as well as the IgG4/IgG ratio were elevated. GD patients having GO in comparison to not having GO were characterized by a female predominance; a high incidence of smoking history; high levels of T3, free T4, TSH receptor autoantibody (TRAb) and IgG4; and a high IgG4/IgG ratio after adjusting for sex. In GD patients, the IgG4 level was the independent factor associated with GO development on multivariate analysis. When severity and activity of GO were classified using the European Group on Graves' Orbitopathy criteria in GD patients with GO, IgG4 levels and IgG4/IgG ratio were elevated in the moderate-to-severe group compared with the mild group and in the active group compared with the inactive group. IgG4 levels and IgG4/IgG ratio became elevated as clinical activity score increased. IgG4 levels were positively correlated with TRAb levels. The high IgG4 group in comparison to the normal IgG4 group had a high incidence of family history of autoimmune thyroid disease, high levels of free T4, TRAb and IgG4, a high IgG4/IgG ratio and extensive hypoechogenicity. CONCLUSIONS: These results suggest that IgG4 levels are elevated in newly diagnosed GD patients compared with euthyroid subjects and in the presence of GO compared with the absence of GO. Moreover, our findings suggest that IgG4 levels are associated with the development and grade of GO in GD patients.

Cytotoxic effect of celastrol alone or in combination with paclitaxel on anaplastic thyroid carcinoma cells.

The influence of celastrol alone or in combination with paclitaxel on survival of anaplastic thyroid carcinoma cells was investigated. In 8505C and SW1736 cells, after treatment of celastrol, cell viability decreased, and cytotoxic activity increased. The protein levels of heat shock protein (hsp) 90, hsp70, Bax, death receptor 5, cleaved caspase-3, cleaved poly (ADP-ribose) polymerase, phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), and phospho-c-Jun N-terminal kinase (JNK) were elevated, and those of Bcl2, phospho-nuclear factor-kappaB (NF-κB), and total and phospho-Akt were reduced. The endoplasmic reticulum stress markers expression and reactive oxygen species production were enhanced. In celastrol-treated cells, N-acetylcysteine increased cell viability and phospho-NF-κB protein levels, and decreased reactive oxygen species production and cytotoxic activity. The protein levels of cyclooxygenase 2, phospho-ERK1/2, phospho-JNK and Bip were diminished. After treatment of both celastrol and paclitaxel, compared with paclitaxel alone, cell viability and the percentage of viable cells were reduced, and death rate and cytotoxic activity were elevated. The protein levels of phospho-ERK1/2, phospho-JNK, Bip, and cyclooxygenase 2, and reactive oxygen species production were enhanced. All of the Combination Index values calculated by Chou-Talalay equation were lower than 1.0, implying the synergism between celastrol and paclitaxel in induction of cell death. In conclusion, our results suggest that celastrol induces cytotoxicity through involvement of Bcl2 family proteins and death receptor, and modulation of phospho-NF-κB, Akt, and mitogen-activated protein kinase in association with endoplasmic reticulum stress and reactive oxygen species production in anaplastic thyroid carcinoma cells. Moreover, celastrol synergizes with paclitaxel in induction of cytotoxicity in anaplastic thyroid carcinoma cells.