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Background Only few studies have shown the efficacy and safety of glucose-control strategies using the quadruple drug combination. Therefore, the aim of the present study was to investigate the usefulness of the quadruple combination therapy with oral hypoglycemic agents (OHAs) in patients with uncontrolled type 2 diabetes mellitus (T2DM). Methods From March 2014 to December 2018, data of patients with T2DM, who were treated with quadruple hypoglycemic medications for over 12 months in 11 hospitals in South Korea, were reviewed retrospectively. We compared glycosylated hemoglobin (HbA1c) levels before and 12 months after quadruple treatment with OHAs. The safety, maintenance rate, and therapeutic patterns after failure of the quadruple therapy were also evaluated. Results In total, 357 patients were enrolled for quadruple OHA therapy, and the baseline HbA1c level was 9.0%±1.3% (74.9±14.1 mmol/mol). After 12 months, 270 patients (75.6%) adhered to the quadruple therapy and HbA1c was significantly reduced from 8.9%±1.2% to 7.8%±1.3% (mean change, −1.1%±1.2%; P

Background : This study aimed to evaluate cardiovascular risk in subjects with pre-diabetes and diabetes in Korea. Methods : In this pan-Korean, non-interventional, cross-sectional study, data were collected from medical records of 10 hospitals between November 2013 and June 2014. Subjects (aged ≥40 years) with medical records of dysglycemia and documentation of total cholesterol level, high-density lipoprotein cholesterol level, systolic blood pressure, and smoking status in the past 6 months were included. The primary endpoint was to determine the Framingham risk score (FRS). The relationships between FRS and cardiovascular risk factors, glycated hemoglobin, and insulin usage were determined by multiple linear regression analyses. Results : Data from 1,537 subjects with pre-diabetes (n=1,025) and diabetes (n=512) were analyzed. The mean FRS (mean±standard deviation) in subjects with pre-diabetes/diabetes was 13.72±8.77. FRS was higher in subjects with diabetes than pre-diabetes (P

To compare the efficacy and safety of adding low-dose lobeglitazone (0.25 mg/day) or standard-dose lobeglitazone (0.5 mg/day) to patients with type 2 diabetes mellitus (T2DM) with inadequate glucose control on metformin and dipeptidyl peptidase (DPP4) inhibitor therapy.In this phase 4, multicentre, double-blind, randomized controlled, non-inferiority trial, patients with T2DM insufficiently controlled by metformin and DPP4 inhibitor combination therapy were randomized to receive either low-dose or standard-dose lobeglitazone. The primary endpoint was non-inferiority of low-dose lobeglitazone in terms of glycaemic control, expressed as the difference in mean glycated haemoglobin levels at week 24 relative to baseline values and compared with standard-dose lobeglitazone, using 0.5% non-inferiority margin.At week 24, the mean glycated haemoglobin levels were 6.87 ± 0.54% and 6.68 ± 0.46% in low-dose and standard-dose lobeglitazone groups, respectively (p = .031). The between-group difference was 0.18% (95% confidence interval 0.017-0.345), showing non-inferiority of the low-dose lobeglitazone. Mean body weight changes were significantly greater in the standard-dose group (1.36 ± 2.23 kg) than in the low-dose group (0.50 ± 1.85 kg) at week 24. The changes in HOMA-IR, lipid profile and liver enzyme levels showed no significant difference between the groups. Overall treatment-emergent adverse events (including weight gain, oedema and hypoglycaemia) occurred more frequently in the standard-dose group.Adding low-dose lobeglitazone to metformin and DPP4 inhibitor combination resulted in a non-inferior glucose-lowering outcome and fewer adverse events compared with standard-dose lobeglitazone. Therefore, low-dose lobeglitazone might be one option for individualized strategy in patients with T2DM.

4H leukodystrophy is a rare autosomal recessive hypomyelinating disorder characterized by several combinations of motor dysfunction, abnormal dentition, and ophthalmic and endocrine abnormalities. To date, only a single Korean case report of pediatric leukodystrophy caused by theGenetic tests of Korean sibling pairs with primary amenorrhea due to normosmic isolated hypogonadotropic hypogonadism and cognitive or behavioral symptoms were performed by whole-exome sequencing (WES). The WES results were validated by direct Sanger sequencing.We identified biallelic variations in theThe siblings reported are the first

Background The incidence of early-onset diabetes is increasing among young adults. However, there are limited data on the characteristics and management of young Korean adults with diabetes. This study assessed the clinical and demographic characteristics, health behaviors, and mental health among young Korean adults with diabetes mellitus. Methods This cross-sectional study included young Korean adults with diabetes (n = 225) with an onset age of 20–39 years from four university hospitals. Demographic characteristics, management of diabetes, and mental health were assessed using a questionnaire survey. Results Type 2 diabetes was the most common type (73.3%), and 13.8% of participants were classified as other types or unknown. Approximately, 64.7% of participants had a strong family history of diabetes, and 76% had treatment within three months of diagnosis. Approximately, 11.1% of participants had diabetic complications; 39.1% of participants received insulin injections, including oral anti-diabetic medications. Additionally, 30.4% were smokers, and only 28% had active physical activity; 26.5% of participants had >3 hours of screen time. One third of participants never had breakfast, and 60.5% went out to eat at least three times a week. Half of the participants showed moderate to severe stress perception, and 21.4% of patients had moderate to severe levels of depression based on the Korean version of Beck Depression Inventory score. Conclusion Early-onset diabetes was associated with a strong family history and early insulin treatment. Young adults with diabetes had poor health behaviors and frequent mental depression. These findings suggest the necessity of health policies for improving health behaviors and mental distress., Graphical Abstract

Objectives4H leukodystrophy is a rare autosomal recessive hypomyelinating disorder characterized by several combinations of motor dysfunction, abnormal dentition, and ophthalmic and endocrine abnormalities. To date, only a single Korean case report of pediatric leukodystrophy caused by the POLR1C sequence variation has been published, while there are no reports on the POLR3B, POLR3A, or POLR3K variants.MethodsGenetic tests of Korean sibling pairs with primary amenorrhea due to normosmic isolated hypogonadotropic hypogonadism and cognitive or behavioral symptoms were performed by whole-exome sequencing (WES). The WES results were validated by direct Sanger sequencing.ResultsWe identified biallelic variations in the POLR3B gene of p.Tyr685* and p.Tyr746Cys, which have not been associated with 4H leukodystrophy. Both sequence variants lie in the hybrid-binding domain of the protein RPC2. The protein structure analysis predicted that cysteine substitution of the phylogenetically conserved amino acid tyrosine can cause destabilization.DiscussionThe siblings reported are the first POLR3B-related hypomyelinating leukodystrophy cases in Korea. Our report expands the mutational spectrum of 4H leukodystrophy and suggests that it is mandatory to consider its diagnostic possibility in adult patients presenting with primary amenorrhea and mild cognitive or behavioral symptoms.

Background Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies. Docetaxel, a microtubule stabilizer, is a common chemotherapeutic agent used to treat various metastatic cancers. However, prolonged use results in various side effects and drug resistance. Flavonoids, such as baicalein, are accepted chemotherapeutic and dietary chemopreventive agents with many advantages, such as greater accessibility, affordability, and lower toxicity, compared with traditional chemotherapy agents. In this study, we evaluated whether baicalein enhances the effects of docetaxel on apoptosis and metastasis in 8505c ATC cells. Methods The 8505c cells were treated with baicalein or docetaxel individually and in combination. Cell viability was measured by MTT (thiazolyl blue tetrazolium bromide) assay, and apoptosis was detected by fluorescence microscopy of Hoechst-stained cells. The expression of apoptotic (Bax and caspase-3), anti-apoptotic (Bcl-2), angiogenic (vascular endothelial growth factor [VEGF], transforming growth factor β [TGF-β], E-cadherin, and N-cadherin), and signaling (extracellular signal-regulated kinase [ERK] mitogen activated protein kinase [MAPK], Akt, and mammalian target of rapamycin [mTOR]) proteins was determined by Western blot analysis. Results The combination of baicalein (50 or 100 μM) and docetaxel (10 nM) significantly inhibited proliferation and induced apoptosis compared with monotherapies. The combination treatment significantly inhibited the expression of Bax, caspase-3, VEGF, TGF-β1, E-cadherin, N-cadherin, and mTOR, but decreased the expression of Bcl-2 and significantly decreased the phosphorylation of ERK and Akt. Conclusion The combination of baicalein and docetaxel effectively induced apoptosis and inhibited metastasis in 8505c cells through downregulation of apoptotic and angiogenic protein expression and blocking of the ERK and Akt/mTOR pathways in 8505c cells. These results suggest that baicalein enhances the anticancer effects of docetaxel in ATC.

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Visfatin is an adipokine that is secreted from adipose tissue, and it is involved in a variety of physiological processes. In particular, visfatin has been implicated in metabolic diseases, such as obesity and type 2 diabetes, which are directly linked to systemic inflammation. However, the potential impacts of visfatin on the hypothalamic control of energy homeostasis, which is involved in microglial inflammation, have not fully been investigated. In this study, we found that treatment with exogenous recombinant visfatin protein led to the activation of the inflammatory response in a microglial cell line. In addition, we observed that central administration of visfatin led to the activation of microglia in the hypothalamus. Finally, we found that visfatin reduced food intake and body weight through activating POMC neurons in association with microglia activation in mice. These findings indicate that elevation of central visfatin levels may be associated with homeostatic feeding behavior in response to metabolic shifts, such as increased adiposity following inflammatory processes in the hypothalamus.

Obesity-induced monocyte/macrophage proliferation and activation play a crucial role in various chronic inflammatory metabolic disorders, such as insulin resistance, diabetes mellitus, and atherosclerosis. 4-1BBL, a member of the tumor necrosis factor superfamily expressed on monocytes/macrophages, provides inflammatory signals to modulate their proliferation, survival, and cytokine release. Previously, we demonstrated that 4-1BBL signaling promotes adipose inflammation through enhancement of macrophage activation. Here, we show that 4-1BBL stimulation on monocytes/macrophages enhanced reprogramming of glucose metabolism in the cells, and that this was accompanied by cell proliferation. 4-1BBL stimulation on macrophages increased glucose uptake, transcript/protein levels of glucose transporter 1 and glycolytic enzymes, and lactate production. It also enhanced transcript levels of genes involved in the pentose phosphate pathway and lipogenesis. The 4-1BBL-induced metabolic reprogramming was mediated by AKT-mammalian target of rapamycin signaling. The effect of 4-1BBL-induced macrophage proliferation was completely abolished by 2-deoxyglucose, a glycolytic inhibitor. These findings suggest that 4-1BBL signaling promotes cell proliferation through reprogramming of glucose metabolism in monocytes/macrophages to support their energy demands and biomass production. The 4-1BBL signaling pathway may be a valid target for controlling macrophage-mediated chronic inflammation in obesity and metabolic diseases.

We investigated the long-term efficacy and safety of gemigliptin and the efficacy and safety of gemigliptin treatment after once-daily treatment with sitagliptin 100 mg, in patients with type 2 diabetes. This was a 28-week extension of a 24-week, randomized, double-blind, parallel study of gemigliptin or sitagliptin added to ongoing metformin therapy. After randomization to sitagliptin 100 mg qd (S), gemigliptin 25 mg bid (G1) or gemigliptin 50 mg qd (G2) and after completing 24 weeks of treatment, 118 patients switched from gemigliptin 25 mg bid to 50 mg qd (G1/G2), 111 patients continued gemigliptin 50 mg qd (G2/G2) and 106 patients switched from sitagliptin 100 mg qd to gemigliptin 50 mg qd (S/G2). All 3 treatments reduced glycated haemoglobin (HbA1c) (S/G2,-0.99% [95% CI -1.25%, -0.73%]; G1/G2, -1.11% [95% CI -1.33%, -0.89%]; G2/G2, -1.06% [95% CI -1.28%, -0.85%]). The percentage of patients achieving HbA1c < 6.5% was 27.6% in the G1/G2 group at both Week 24 and Week 52, and ranged from 27.3% to 32.7% in the G2/G2 group (difference in proportions, 5% [95% CI -6%, 17%]), while it increased from 6.8% to 27.3% from Week 24 to Week 52 in the S/G2 group (difference in proportions, 20% [95% CI 7%, 34%]). Addition of gemigliptin 50 mg qd to metformin was shown to be efficacious for 52 weeks. Switching from sitagliptin 100 mg to gemigliptin 50 mg showed consistent glyacemic control over the previous treatment.

Aims/Introduction Early initiation of basal insulin therapy is recommended for normalizing fasting blood glucose in type 2 diabetes mellitus. However, basal insulin treatment might not adequately control postprandial glucose levels. The present study evaluated whether the combination of the α-glucosidase inhibitor, acarbose, and basal insulin improved blood glucose control under daily-life treatment conditions in a large sample of Korean patients. Materials and Methods The present study was a multicenter, prospective, observational study under daily-life treatment conditions. A total of 539 patients with type 2 diabetes who were treated with basal insulin and additional acarbose were enrolled and followed up for 20 weeks. Changes in hemoglobin A1c, fasting and postprandial blood glucose were evaluated at baseline and at the end of the observation period. The physician and patient satisfaction of the combination treatment and safety were assessed. Results Hemoglobin A1c decreased by 0.55 ± 1.05% from baseline (P

Osteopetrosis is a rare genetic bone disease characterized by increased bone density but prone to breakage due to defective osteoclastic function. Among two primary types of autosomal dominant osteopetrosis (ADO), osteopetrosis type II is characterized by sclerosis of bones, predominantly involving the spine, the pelvis, and the skull base. Fragility of bones and dental abscess are leading complications. This report presents a case of osteopetrosis in a 52-years-old female, which was complicated by the development of cavernous sinus thrombophlebitis and meningitis. She was suffered from multiple fractures since one year ago. Laboratory data revealed elevated serum levels of tartrate resistant acid phosphatase (TRAP) without carbonic anhydrase II DNA mutation. A thoracolumbar spine X-ray showed, typical findings of ADO type II (ADO II; Albers-Schonberg disease), prominent vertebral endplates so called the 'rugger jersey spine'. Her older sister also showed same typical spine appearance. We report a case of ADO II with cavernous sinus thrombophlebitis and meningitis that was successfully treated with long-term antibiotics with right sphenoidotomy.

4-1BB, a member of the TNF receptor superfamily, has a role in various inflammatory pathologies through its interaction with 4-1BB ligand. We previously demonstrated that it participates in initiating and promoting obesity-induced adipose inflammation in a rodent model. In this study, we examined whether 4-1BB is related to obesity-induced adipose inflammation and metabolic parameters in humans. A total of 50 subjects, 25 obese (body mass index (BMI)⩾25 kg m−2) and 25 lean (BMI

OBJECTIVE α-Melanocyte–stimulating hormone (α-MSH) and agouti-related peptide (AgRP) control energy homeostasis by their opposing actions on melanocortin receptors (MC3/4R) in the hypothalamus. We previously reported that thyroid transcription factor-1 (TTF-1) controls feeding behavior in the hypothalamus. This study aims to identify the function of TTF-1 in the transcriptional regulation of AgRP and α-MSH synthesis for the control of feeding behavior. RESEARCH DESIGN AND METHODS TTF-1 activity in AgRP and pro-opiomelanocortin (POMC) transcription was examined using gel-shift and promoter assays and an in vivo model of TTF-1 synthesis inhibition by intracerebroventricular injection of an antisense (AS) oligodeoxynucleotide (ODN). Double immunohistochemistry was performed to colocalize TTF-1 and AgRP or α-MSH in the hypothalamic arcuate nucleus (ARC). To determine whether TTF-1 action on food intake is mediated through MC3/4R, we measured changes in food intake upon intracerebroventricular injection of MC3/4R antagonists (SHU9119 and AgRP) into rat brain preinjected with the AS ODN. RESULTS TTF-1 stimulated AgRP but inhibited POMC transcription by binding to the promoters of these genes. TTF-1 was widely distributed in the hypothalamus, but we identified some cells coexpressing TTF-1 and AgRP or α-MSH in the ARC. In addition, intracerebroventricular administration of leptin decreased TTF-1 expression in the hypothalamus, and AS ODN-induced inhibition of TTF-1 expression decreased food intake and AgRP expression but increased α-MSH expression. Anorexia induced by the AS ODN was attenuated by the administration of MC3/4R antagonists. CONCLUSIONS TTF-1 transcriptionally regulates synthesis of AgRP and α-MSH in the ARC and affects feeding behavior via the melanocortin pathway.

Thyroid transcription factor-1 (TTF-1) belongs to the Nkx family of homeodomain-containing proteins and regulates expression of several important genes in the brain. Our previous studies showed that TTF-1 plays an important role in water homeostasis in the subfornical organ of rats and is involved in cerebrospinal fluid formation by regulation of aquaporin-1 transcription in the choroid plexus. In this study, we examined changes in TTF-1 transcription in response to hypertonicity using promoter assays. TTF-1 was synthesized in several osmosensitive regions of the rat brain. TTF-1 promoter activity was diminished by treatment with hypertonic solutions in a time- and dose-dependent manner in brain-derived cell lines. Additionally, TTF-1 was involved in the regulation of angiotensinogen (Aogen) transcription under a hyperosmotic condition through specific binding domains in the Aogen promoter. These results suggest a possible role of TTF-1 in brain fluid homeostasis in response to changes in the osmotic environment.

In the brain, aquaporin-1 (AQP-1), a water channel for high osmotic water permeability, is mainly expressed in the apical membrane of the ventricular choroid plexus and regulates formation of cerebrospinal fluid (CSF). Although the physiology of AQP-1 has been the subject of several publications, much less is known about the trans-acting factors involved in the control of AQP-1 gene expression. Here we report that TTF-1, a homeodomain-containing transcriptional regulator, is coexpressed with AQP-1 in the rat brain choroid plexus and enhances AQP-1 gene transcription by binding to conserved core TTF-1-binding motifs in the 5'-flanking region of the AQP-1 gene. Intracerebroventricular administration of an antisense TTF-1 oligodeoxynucleotide significantly decreased AQP-1 synthesis and reduced CSF formation. In addition, blockade of TTF-1 synthesis increased survival of the animals following acute water intoxication-induced brain edema. These results suggest that TTF-1 is physiologically involved in the transcriptional control of AQP-1, which is required for CSF formation.

Background: Human papillary thyroid carcinoma (PTC) is often associated with Hashimoto's thyroiditis (HT); their coexistence improves PTC prognosis. Osteopontin, a secreted glycoprotein, plays a role in cell survival, immunity, and tumor progression, its expression being associated with a poor prognosis and metastasis in several malignancies. Osteopontin overexpression correlates with aggressive clinicopathological features in PTC. Lymph node metastases and large tumor size positively correlate with osteopontin positivity. This study aimed to: (1) confirm osteopontin overexpression in human PTC samples; (2) compare osteopontin expression levels in PTC cases with and without HT; and (3) identify correlations between tumor aggressiveness and osteopontin expression levels. Materials and Methods: Plasma osteopontin was assessed in 45 patients with PTC, 22 patients with PTC and HT, and 24 healthy controls by enzyme-linked immunosorbent assay. Thyroid tissue osteopontin mRNA and protein levels were analyzed by reverse transcription-polymerase chain reaction and Western blotting, respectively. Results: Plasma osteopontin levels were significantly higher in PTC patients than in healthy controls. Plasma osteopontin, tissue osteopontin mRNA, and tissue osteopontin protein levels were significantly lower in patients with PTC and HT than in those with PTC alone. In advanced disease stage cases, osteopontin mRNA and protein expression levels were lower in patients with PTC and HT than in those with PTC alone. However, the osteopontin expression level was not significantly associated with the TNM stage. Conclusions: Plasma osteopontin, tissue osteopontin mRNA, and tissue osteopontin protein levels were significantly lower in patients with PTC and HT than in those with PTC alone, suggesting that HT attenuates PTC aggressiveness through negative regulation of osteopontin expression.

background There are many reports that diagnostic accuracy of fine-needle aspiration (FNA) of thyroid is improved with ultrasound guidance, especially for impalpable nodules. Despite its general acceptance, routine use of ultrasound-guided fine-needle aspiration (USGFNA) has been the source of much controversy due to the lack of large-scale studies and lack of data on the natural course of well-differentiated thyroid cancer of small size. objective The aim of our study was to define the rate of malignancy in relatively large numbers of patients with incidentally detected impalpable thyroid nodules and to assess the extent of disease in patients with suspicious or malignant cytology on USGFNA of thyroid nodules by surgery. patients We retrospectively reviewed the medical records of the 267 patients who underwent USGFNA of incidental thyroid nodules from January 2000 to December 2001. results Three hundred and seventeen nodules from 267 patients were aspirated. The average size of nodules was 0·9 ± 0·3 cm, a range of 0·2 cm to 1·5 cm. All 317 lesions were impalpable. Cytological diagnosis included 101 inadequate specimen (32%), 139 benign (44%), 29 indeterminate (9%), four suspicious of follicular or Hurthle cell neoplasm (1%), 42 papillary carcinoma (13%) and two others. The size of the nodule was not related to the probability of getting an adequate specimen for cytological diagnosis. Forty of 48 patients with suspicious or malignant cytology underwent surgery. All 35 patients with a cytological diagnosis of papillary carcinoma were confirmed to have papillary carcinoma on histological results. One of three patients with a cytological diagnosis of follicular neoplasm had a follicular carcinoma. In 36 patients with well-differentiated thyroid cancer, extrathyroidal extension was observed in 44% (16/36), regional lymph node metastasis was found in 50% (18/36) and multifocal tumours were found in 39% (14/36). conclusions The rate of malignancy in incidentally detected impalpable thyroid nodules was 12% in retrospective analysis of our patients. In this subgroup, 69% (25/36) of patients had either extrathyroidal extension or regional node involvement and 39% had multifocal tumours at surgery. This suggests that the small size alone does not guarantee low risk in incidentally found thyroid cancers. USGFNA is a useful diagnostic method in these patients.

Background Malignant follicular lesion is not differentiated from benign lesions cytologically. The objective of this study was to assess the rate and the risk of malignancy in thyroid nodules which were cytologically diagnosed as follicular neoplasm by fine-needle aspiration (FNA) cytology. Methods All the patients who had undergone surgery with cytological diagnosis of follicular neoplasm from January 1996 through December 2001 in Asan Medical Center were studied retrospectively. Patients' and nodule characteristics were analyzed for factors associated with the presence of cancer. Two hundred and fifteen patients (196 females, 19 males) were included and their mean age was 39.4 years (range: 12-76). Results About half of the patients (102 out of 215, 47.4%) had malignancy with 29 papillary carcinomas, 57 follicular carcinomas, 15 Hurthle cell carcinomas and 1 medullary carcinoma. Previously suggested factors associated with risk for malignancy, such as male gender, large tumor size (> 4 cm) or age of patients (> 45 years), were not associated with increased risk. Diagnosis of Hurthle cell neoplasia on FNA was also not associated with increased risk. Only the extremes in age of the patients (below 20 or above 60 years) were associated with increased risk for malignancy. Conclusion In our findings, prevalence of carcinoma in thyroid nodule patients with cytological diagnosis of follicular neoplasm was much higher than those reported. Clinical characteristics, such as male gender, age and nodule size, are not useful predictors for the presence of malignancy. Thyroid nodules with cytological diagnosis of follicular neoplasm warrant immediate surgery.

Obesity, a condition characterized by increased fat content and altered secretion of adipokines, is a risk factor for postmenopausal breast cancer. Visfatin has recently been established as a novel adipokine that is highly enriched in visceral fat. Here we report that visfatin regulated proliferation of MCF-7 human breast cancer cells. Exogenous administration of recombinant visfatin increased cell proliferation and DNA synthesis rate in MCF-7 cells. Furthermore, visfatin activated G1-S phase cell cycle progression by upregulation of cyclin D1 and cdk2 expression. Visfatin also increased the expression of matrix metalloproteinases 2, matrix metalloproteinases 9, and vascular endothelial growth factor genes, suggesting that it may function in metastasis and angiogenesis of breast cancer. Taken together, these findings suggest that visfatin plays an important role in breast cancer progression.

TTF-1 is a member of the NKx family of homeodomain genes, and is required for morphogenesis and fetal diencephalon development. Our previous studies have shown that TTF-1 expression is maintained in some regions of the postnatal rat brain and transactivates the gene expression of several neuropeptides. In this study, a potential role for TTF-1 in the regulation of feeding behavior was identified. Immunohistochemical analysis showed that TTF-1 is present in several hypothalamic nuclei of the adult rat brain involved in the control of feeding behavior. Food deprivation for two days markedly increased the hypothalamic levels of TTF-1 mRNA and protein. Intracerebroventricular administration of an antisense TTF-1 oligodeoxynucleotide significantly decreased TTF-1 protein abundance in the hypothalamus. This TTF-1 decrease was followed by a significant decrease in neuropeptide Y mRNA content and an increase in proopiomelanocortin mRNA content, and in turn resulted in a decrease of the animal's food intake and body weight. These results suggest a novel role for TTF-1 in the regulation of feeding behavior in the rat hypothalamus.

Summary objective We prospectively screened consecutive patients with Graves’ hyperthyroidism by ultrasonography (USG), regardless of presence of palpable nodules, and evaluated patients with nodule(s) by fine-needle aspiration (FNA) and by resulting surgery to define the prevalence of thyroid cancer in patients with Graves’ disease. methods Two hundred and forty-five consecutive Graves’ disease patients without prior thyroid surgery or radio-iodine treatment were enrolled at Asan Medical Centre endocrinology clinic. All patients with nodule(s) of 5 mm or greater were reviewed for evaluation by FNA, and of these 90·0% (n = 62) underwent FNA. All patients with suspicious/malignant cytology or those with positive immunostaining with GAL-3 antibody underwent surgery. results Among 245 patients, thyroid nodule(s) were detected in 35·1% (86/245) by USG. Nodule prevalence significantly increased according to age, which was the only significant variable predicting the presence of nodule(s) in logistic regression analysis. Among patients with thyroid nodule(s), 69 patients had nodule(s) of 5 mm or greater in size, and 62 cases of them (90·0%) underwent FNA. In eight patients, thyroid cancers were histologically confirmed (all papillary thyroid cancers), so the prevalence of thyroid cancer was at least 3·3% (8/245) in Graves’ patients. Of eight patients with thyroid cancer, only one case was detected by palpation and the other seven patients were detected only by USG. In pathologic examination, mean size of tumour was 10·0 ± 6·7 mm (5–25 mm), three cases had extrathyroidal extension (37·5%), four cases had cervical node metastasis (50·0%) and one case had multifocal tumour (12·5%). Thus, five of eight patients had locally advanced cancers (pT4 or pN1 lesion), but none had distant metastasis. Prevalence of thyroid cancers in Graves’ disease tended to be higher in patients of 45 years or greater than younger patients (6·7%vs. 1·3%, P = 0·05), and that of the locally advanced cancers was significantly higher in older patients (5·6%vs. 0%, P

Summary objective Quantitative ultrasound (QUS) of bone is a new radiation-free, low-cost method that measures both bone mass and quality. We investigated associations between QUS parameters and polymorphisms of vitamin D receptor (VDR), oestrogen receptor α (ERα) and transforming growth factor-β1 (TGF-β1) genes in postmenopausal women residing in a community. design QUS and anthropometric characteristics were measured in postmenopausal women, and compared with regard to the VDR, ERα and TGF-β1 genotypes. patients Among the 552 women who participated in the population-based Chung-Up osteoporosis prevalence study, 206 postmenopausal women, aged 60–69 years, were included. measurements Broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured at the left calcaneus using QUS measurement of bone, and a stiffness index (SI) was calculated. We determined the BsmI and FokI polymorphisms of VDR gene and the XbaI and PvuII polymorphisms of ERα gene using the polymerase chain reaction-restriction fragment length polymorphism method, and Τ29 → C polymorphism of TGF-β1 gene using an allele-specific polymerase chain reaction assay. results The XbaI polymorphism of ERα gene was significantly associated with SI (T-score) and BUA (P = 0·040 and P = 0·024, respectively). There were no significant differences in any QUS parameters among the genotypes of VDR and TGF-β1. However, significant genetic interactions between the VDR and TGF-β1 genotypes, were noted (P = 0·017 for SI and P = 0·028 for BUA between the BsmI and Τ29 → C polymorphisms; P = 0·038 for SI and P = 0·035 for BUA between the FokI and T29 → C polymorphisms). The combined genotypes between the BsmI and T29 → C polymorphisms or between the FokI and T29 → C polymorphisms, were significantly associated with the QUS parameters. conclusions This study indicates that the XbaI polymorphism of ERα gene may influence the Quantitative ultrasound parameters in postmenopausal women, and suggests the need for further investigations about the interactions between the VDR and TGF-β1 genes.

Background Malignant follicular lesion is not differentiated from benign lesions cytologically. The objective of this study was to assess the rate and the risk of malignancy in thyroid nodules which were cytologically diagnosed as follicular neoplasm by fine-needle aspiration (FNA) cytology. Methods All the patients who had undergone surgery with cytological diagnosis of follicular neoplasm from January 1996 through December 2001 in Asan Medical Center were studied retrospectively. Patients' and nodule characteristics were analyzed for factors associated with the presence of cancer. Two hundred and fifteen patients (196 females, 19 males) were included and their mean age was 39.4 years (range: 12-76). Results About half of the patients (102 out of 215, 47.4%) had malignancy with 29 papillary carcinomas, 57 follicular carcinomas, 15 Hurthle cell carcinomas and 1 medullary carcinoma. Previously suggested factors associated with risk for malignancy, such as male gender, large tumor size (> 4 cm) or age of patients (> 45 years), were not associated with increased risk. Diagnosis of Hurthle cell neoplasia on FNA was also not associated with increased risk. Only the extremes in age of the patients (below 20 or above 60 years) were associated with increased risk for malignancy. Conclusion In our findings, prevalence of carcinoma in thyroid nodule patients with cytological diagnosis of follicular neoplasm was much higher than those reported. Clinical characteristics, such as male gender, age and nodule size, are not useful predictors for the presence of malignancy. Thyroid nodules with cytological diagnosis of follicular neoplasm warrant immediate surgery.

BACKGROUND/OBJECTIVE: Visfatin, also known as nicotiamide phosphoribosyltransferase or pre-B cell colony enhancing factor, is a pro-inflammatory cytokine whose serum level is increased in sepsis and cancer as well as in obesity. Here we report a pro-inflammatory role of visfatin in the brain, to mediate sickness responses including anorexia, hyperthermia and hypoactivity. METHODOLOGY: Rats were intracerebroventricularly (ICV) injected with visfatin, and changes in food intake, body weight, body temperature and locomotor activity were monitored. Real-time PCR was applied to determine the expressions of pro-inflammatory cytokines, proopiomelanocortin (POMC) and prostaglandin-synthesizing enzymes in their brain. To determine the roles of cyclooxygenase (COX) and melanocortin in the visfatin action, rats were ICV-injected with visfatin with or without SHU9119, a melanocortin receptor antagonist, or indomethacin, a COX inhibitor, and their sickness behaviors were evaluated. PRINCIPAL FINDINGS: Administration of visfatin decreased food intake, body weight and locomotor activity and increased body temperature. Visfatin evoked significant increases in the levels of pro-inflammatory cytokines, prostaglandin-synthesizing enzymes and POMC, an anorexigenic neuropeptide. Indomethacin attenuated the effects of visfatin on hyperthermia and hypoactivity, but not anorexia. Further, SHU9119 blocked visfatin-induced anorexia but did not affect hyperthermia or hypoactivity. CONCLUSIONS: Visfatin induced sickness responses via regulation of COX and the melanocortin pathway in the brain.

Background Inflammation plays a role in the response to metabolic stress in type 2 diabetes. However, the effects of rosiglitazone on inflammation of skeletal muscle have not been fully examined in type 2 diabetes. Methods We investigated the effects of the insulin-sensitizing anti-diabetic agent, rosiglitazone, on the progression of skeletal muscle inflammation in Otsuka Long-Evans Tokushima Fatty (OLETF) type 2 diabetic rats. We examined the expression of serologic markers (serum glucose, insulin and free fatty acid) and inflammatory cytokines (tumor-necrosis factor-α, interleukin [IL]-1β and IL-6) in OLETF rats from early to advanced diabetic stage (from 28 to 40 weeks of age). Results Serum glucose and insulin concentrations were significantly decreased in rosiglitazone-treated OLETF rats compared to untreated OLETF rats. Rosiglitazone treatment significantly decreased the concentrations of serum inflammatory cytokines from 28 to 40 weeks of age. The mRNA expression of various cytokines in skeletal muscle was reduced in rosiglitazone-treated OLETF rats compared with untreated OLETF rats. Furthermore, rosiglitazone treatment resulted in the downregulation of ERK1/2 phosphorylation and NF-κB expression in the skeletal muscle of OLETF rats. Conclusion These results suggest that rosiglitazone may improve insulin sensitivity with its anti-inflammatory effects on skeletal muscle.

Background: Streptozotocin-induced diabetic animals are characterized by hyperphagia due to deficiencies of insulin and leptin. Forkhead box-containing protein of the O subfamily-1 (FoxO1) regulates energy homeostasis by regulating energy expenditure and food intake as well as mediating insulin and leptin signals in the hypothalamus. To identify the mediator of diabetic hyperphagia, we examined the effects of insulin or leptin on hypothalamic FoxO1 expression in a diabetic animal model. Methods: Diabetes was induced in mice (C57BL/6) by intraperitoneal administration of streptozotocin (200 mg/kg). Stainless steel cannula w as implanted into the lateral ventricle of the brain in each mouse. After three weeks, the mice were administered saline, insulin or leptin via intracerebroventricular (ICV) route. The medial hypothalamus was isolated to evaluate the mRNA expressions of FoxO1 and neuropeptides. Results: Streptozotocin-induced diabetic mice exhibited significant elevations of blood glucose and food intake and significantly low levels of serum insulin and leptin . The levels of hypothalamic FoxO1 mRNA were significantly increased in diabetic mice. The hypothalamic expression of neuropeptide Y (NPY) mRNA was increased, but the expression of preproopiomelanocortin (POMC) mRNA was decreased in diabetic mice. ICV administration of insulin or leptin attenuated the upregula tion of hypothalamic FoxO1 mRNA, and resulted in downregulation of NP Y mRNA and upregulation of POMC mRNA in diabetic mice. Conclusion: We observed that the expression of hypothalamic FoxO1 mRNA was increased in streptozotocin-induced diabetic mice, and that it was significantly attenuated by central administration of insulin or leptin. These results suggest that hypothalamic FoxO1 is the direct mediator of diabetic hyperphagia. (Korean Diabetes J 33:375-381, 2009)

Parathyroid carcinoma is a rare malignancy that is responsible for only 0.5 to 4% of all cases of primary hyperparathyroidism. Surgery is the only curative treatment. We report a case of a 46-year-old woman referred for a severe osteoporosis with frequent bone fracture associated with hypercalcemia. Initially, though she had multiple osteolytic lesions, we thought that the lesions were brown tumors resulting from hyperparathyroidism. The patient underwent surgery and was diagnosed with parathyroid carcinoma. After surgery, her intact PTH level normalized for brief period of time, but it was again elevated at 6 weeks after surgery. We suggest that the multiple osteolytic lesions were metastases because there was no evidence of local recurrence of parathyroid carcinoma, and the lesions looked like metastases on CT and PET-CT. The patient was treated with radiation therapy on the lumbar vertebra, one a site of the metastatic lesions. After radiotherapy, her serum intact PTH was decreased.