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Background/Aims: Germline mutations of the rearranged during transfection (RET) gene cause multiple endocrine neoplasia type 2 (MEN2). About 85% of RET mutations in MEN2 occur in codon Cys634. The RET D631Y mutation has recently been discovered, and we have studied its molecular expression and clinical consequences.Methods: We analyzed the clinical characteristics of a total of 34 D631Y variant MEN2 individuals from seven families. We also constructed wild-type and mutant C630Y, D631Y, and C634R/W expression vectors and investigated their effects on signaling pathways and ability to correct the phenotypes of RET mutant cells.Results: The median ages at diagnosis of pheochromocytoma and medullary thyroid carcinoma (MTC) were higher in patients with RET D631Y variant MEN2 than in those with the C634R/W variant (49:53.5 years vs. 33.5:27 years, respectively), and the penetration of the D631Y mutation with respect to MTC was lower than that of the C634R/W mutation (32.3% vs. 90%). The effects of the mutant vectors on phosphorylation of RET signaling molecules and focus formation were significantly different from those of wild type, but there were no significant differences between the mutants. D631Y scored significantly higher for chemotaxis and wound healing than C630Y, but lower than C634R and C634W.Conclusions: We suggest that the tumorigenic potential conferred by the D631Y mutation is lower than that conferred by the C634R/W mutation, but higher than that conferred by C630Y. Thus, the risk level of the RET D631Y variant appears to be higher than that of C630Y and lower than that of C634R/W.

The CDC73/HRPT2 gene, a defect which causes hyperparathyroidism–jaw tumor (HPT-JT) syndrome, encodes CDC73/parafibromin. We aimed to investigate whether CDC73 would be a target for ubiquitin–proteasome degradation. We cloned full-length cDNAs encoding a family of 58 ubiquitin-specific deubiquitinating enzymes (DUBs), also known as ubiquitin-specific proteases (USPs). Use of the yeast two-hybrid system then enabled us to identify USP37 as interacting with CDC73. The biochemical interaction between the USP37 and CDC73 and their reciprocal binding domains were studied. Co-localization of CDC73 and USP37 was observed in cells. CDC73 was found to be polyubiquitinated, and polyubiquitination of CDC73 was prominent in mutants. CDC73 was deubiquitinated via K48-specific ubiquitin chains by USP37, but not by the catalytically inactive USP37C350S mutant. Observation of the binding between deletion mutants of CDC73 and USP37 revealed that the β-catenin binding site of CDC73 and the ubiquitin-interacting motifs 2 and 3 (UIM2 and 3) of USP37 were responsible for the interaction between the two proteins. Moreover, these two enzymes co-existed within the nucleus of COS7 cells. We conclude that USP37 is a DUB for CDC73 and that the two proteins interact through specific domains, suggesting that USP37 is responsible for the stability of CDC73 in HPT-JT syndrome.

Background: With increasing survival rates after hematopoietic stem cell transplantation (HSCT), it has become important to evaluate methods of improving patients’ quality of life. Most female patients of childbearing age experience premature ovarian failure after transplantation, which results in decreased quality of life and an increase in fracture risk due to rapid bone loss. We analyzed the effects of hormone therapy (HT) on serum follicle stimulating hormone (FSH), serum estradiol, and bone mineral density (BMD) in young female HSCT recipients. Methods: This retrospective cohort study included 234 female patients who underwent allogenic HSCT between April 2009 and April 2018 at our center. The maximum age at the time of transplantation was 40 years, and patients were followed up for at least 3 years. Of the 734 patients who were initially screened, 360 patients aged

Obesity is a well-known risk factor for type 2 diabetes, but few data exist on the association between weight changes and diabetes risk in non-obese subjects. This study aimed to investigate the effect of weight changes on the incidence of type 2 diabetes in Korea, using 51,405 non-diabetic subjects. Individuals who developed type 2 diabetes were more likely to be older and male, to have high body mass index (BMI), blood pressure, fasting blood glucose, and total cholesterol, to be current smokers and frequent drinkers, to be hypertensive and hyperlipidemic, and to have a family history of diabetes, compared to those without type 2 diabetes. Compared with the consistently non-obese group, there was a higher hazard ratio for incident diabetes (95% confidence interval) in subjects becoming obese [1.49 (1.26–1.77)] and remaining obese [2.56 (2.34–2.81)] after adjustment for confounding factors. Decreased BMI was significantly associated with lower risks for incident diabetes and the trends were more evident in the non-obese group. However, overall there was no significant association of increased BMI with incident diabetes. In conclusion, weight loss was significantly associated with lower risk for diabetes both in non-obese and obese Koreans, but particularly in the non-obese.

The use of a marginal donor, such as an elderly donor, in liver transplantation has been increasing in response to organ disparity; however, major risk factors for graft and patient survivals have been reported.We retrospectively reviewed the medical records of 559 patients who underwent living-donor liver transplantation (LDLT) at our hospital from May 2003 to June 2013. Elderly donors were defined as those50 years old, and elderly recipients were defined as those60 years old. We evaluated the differences in survival according to donor and recipient ages. Furthermore, we compared post-transplantation outcomes according to donor-recipient age matching.The overall 5-year survival rate of the recipients was significantly lower in the elderly donor group than in the younger donor group (84.6% vs 58.2%; P.001). However, no significant difference in survival rate was observed according to recipient age (P = .908). The survival rate of elderly recipients who received a graft from an elderly donor was significantly lower than those of the other groups (P.001-.037). The mortality rate was significantly different among the groups (P.001), and among the causes of death, surgical complications were most frequent cause in the elderly donor group (P.001).LDLT with the use of elderly donors50 years of age could result in higher mortality rates than using younger donors. As such, elderly donor livers ideally should be matched with young recipients and attention concentrated on the surgical complications.

Background and Aim Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is interrelated with renal dysfunction and disturbed bone metabolism, both of which play a key role in calcium and phosphorus homeostasis. We investigated the association between NAFLD and serum calcium and phosphorus levels in Korean subjects. Methods We performed a cross-sectional analysis of 16 592 subjects undergoing a general health checkup. NAFLD was assessed based on ultrasonographically detected fatty liver in the absence of excessive alcohol consumption and other causes of liver disease. Results The proportion of the population with fatty liver detected by ultrasonography was 43.2% for males and 17.6% for females. We observed that a higher serum albumin-corrected calcium (Cac) level was associated with smoking, hypertension, and unfavorable metabolic parameters in both genders, but the serum phosphorus levels showed an inconsistent correlation with metabolic abnormalities. After adjusting for age, gender, waist circumference, body mass index, smoking status, exercise, diabetes, hypertension, lipid profiles, and renal function, serum Cac, phosphorus, and Cac-phosphorus products were independent risk factors for fatty liver (odds ratio [OR]: 1.71, 95% confidence interval [CI]: 1.49–1.95, P

Pseudohypoparathyroidism (PHP) is a genetic disorder due to target-organ unresponsiveness to parathyroid hormone (PTH). PHP type 1A (PHP1A) is an autosomal dominant disease characterized by Albright hereditary osteodystrophy (AHO) and PTH resistance caused by defects at the GNAS locus. We analyzed the GNAS gene in a male with typical AHO and elevated PTH levels. We identified a novel de novo heterozygous mutation at the splice donor site in intron-7 (IVS7+1G>A, c.585+1G>A) of the GNAS gene. No GNAS mutations were detected in his parents. Our patient was diagnosed with PHP1A due to a heterozygous de novo mutation in the GNAS gene. Reverse transcriptase (RT) PCR analysis and sequencing revealed that this de novo splice mutation generated alternative splicing errors leading to the formation of 2 mutant transcripts: one with exon-7 deleted, the other with whole intron-7 included. To investigate whether these aberrantly spliced transcripts were stable, we assessed the differential expression of GNAS mRNAs in the proband’s blood by real-time quantitative RT-PCR. In the proband, the relative expression levels of wild-type, exon-7-deleted, and intron-7-included GNAS mRNAs were 0.21, 6.12E-07, and 1.08E-04, respectively, relative to wild-type GNAS mRNA from a healthy control (set at 1.0). This suggests that this novel de novo splicing mutation generates rapidly decaying mutant transcripts, which might affect stimulatory G-protein activity and give rise to this sporadic case. In conclusion, this is an interesting report of aberrantly spliced mRNAs from a de novo splice mutation of the GNAS gene causing PHP1A in a male.

Growing evidence suggests that obesity is a risk factor for incident psoriasis. This study was aimed to evaluate the association of obesity and metabolic status with the incidence of psoriasis. A total of 418,057 adults were followed-up using a nationwide prospective cohort study in Korea. Participants were stratified based on the body mass index categories and metabolic condition. During the follow-up visit, 11054 (2.6%) cases were found to have psoriasis. Diabetes, hypertension, hyperlipidemia, and obesity were all found to be risk factors for incident psoriasis. The metabolically unhealthy non-obese (MUNO) subjects (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.22–1.37) and metabolically unhealthy obese subjects (MUO; HR, 1.33; 95% CI, 1. 26–1.41) had a significantly higher risk of psoriasis incidence as compared to metabolically healthy non-obese subjects. The risk of psoriasis development was found to be high among the MUNO and MUO subjects in both sexes and all age groups. In conclusion, the metabolic health status was significantly associated with an increased risk of psoriasis in both obese and non-obese individuals. However, further studies are needed to evaluate whether the control of metabolic parameters can lower the incidence of psoriasis.

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

Background Recent advances in genetics revealed that 25% to 30% of head and neck paragangliomas (PGLs) are inherited tumors associated with germline mutation, mainly in the succinate dehydrogenase (SDH) gene. Methods DNA was isolated from whole blood and polymerase chain reaction (PCR) products were sequenced with an ABI3730 × 1 Genetic Analyzer. Results A 30-year-old Korean woman underwent resection of a carotid PGL. Fourteen years later, she was readmitted for a cervical mass. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT revealed a hot spot in the adrenal gland, besides the carotid mass. Surgical pathology confirmed recurrence of the carotid PGL and a concomitant pheochromocytoma. Genetic analysis revealed SDHD c.119del T (p.I40TfsX46) mutation. One daughter has been identified as a carrier. Conclusion We found a novel SDHD mutation from a Korean family that shows similar clinical features to those in other SDHD mutations, mostly from Western countries. Further studies are needed to determine whether similar genotype-phenotype correlations exist in the Asian patients with familial PGLs. © 2014 Wiley Periodicals, Inc. Head Neck 36: E131–E135, 2014

Mutations of the HRPT2 gene, which are respon- sible for hyperparathyroidism-jaw tumor (HPT-JT) syndrome, have been implicated in the development of a high propor- tion of parathyroid carcinomas. The aim of this study was to investigate differences in expression of the most important genes connected with parathyroid carcinoma between HPT-JT syndrome due to an HRPT2 splicing mutation, normal parathyroid tissue and sporadic parathyroid adenoma. Total RNAs were extracted from parathyroid carcinoma in HPT-JT syndrome harbouring HRPT2 splicing mutation or sporadic parathyroid adenoma and normal parathyroid gland, and subjected to Illumina DASL-based gene expression assay. Unsupervised hierarchical clustering analysis was used to compare gene expression in HPT-JT syndrome, sporadic parathyroid adenoma and normal parathyroid glands. We identified differentially regulated genes in HPT-JT syndrome and sporadic parathyroid adenoma relative to normal para- thyroid glands using a combination of Welch's t-test and fold-change analysis. Quantitative PCR, RT-PCR and IHC were used for validation. Sixteen genes differentially regu- lated in the parathyroid carcinoma were associated with signal pathways, MAPK, regulation of actin cytoskeleton, prostate cancer and apoptosis. FGFR1 expression was confirmed to be significantly upregulated by validation experiments. Our gene expression profiling experiments suggest that upregulated FGFR1 expression appears to be associated with parathyroid carcinoma in HPT-JT syndrome due to an HRPT2 splicing mutation.

Considerable evidence shows that increased serum calcium levels are associated with metabolic disorders, cardiovascular disease, and increased mortality. This study investigated whether serum calcium, within a normal range, is significantly associated with serum fibrinogen and homocysteine, markers of increased cardiovascular disease risk in nondiabetic Korean subjects. A cross-sectional analysis was performed on 1096 subjects (mean age, 55.1 ± 11.1 years; 36.1% women) undergoing a general health checkup. Serum biochemistry was analyzed including serum albumin-corrected calcium (Cac), insulin resistance (IR, using homeostasis model assessment [HOMA]), fibrinogen, and homocysteine. Compared with patients within the lowest Cac quartile, those with higher Cac levels had increased fibrinogen and homocysteine levels as well as an increased proportion of smoking, dyslipidemia, and HOMA-IR. Correlation analyses revealed linear relationships for Cac with fibrinogen and homocysteine in both genders. After adjustment for confounding factors, serum Cac was significantly associated with high fibrinogen (odds ratio [OR] for the highest vs the lowest quartile = 1.76, 95% confidence interval [CI] = 1.09–2.83, P = 0.02) and homocysteine (OR = 1.83, 95% CI = 1.07–3.11, P = 0.027). Multivariate regression models showed that Cac was linearly associated with fibrinogen (standardized β = 0.14, P

Background: This study investigated the association between serum gamma-glutamyltransferase (GGT) level and subclinical atherosclerosis in patients with type 2 diabetes. Methods: This cross-sectional study involved 1024 patients with type 2 diabetes mellitus. Measurement of brachial-ankle pulse wave velocity (baPWV; as a marker of arterial stiffness) and an ultrasound assessment of carotid atherosclerosis were performed. Subclinical atherosclerosis was defined by the presence of a high baPWV (>= 1720 cm/s), carotid atherosclerosis (intima-media thickness >0.8 mm or the presence of plaques), and carotid stenosis (>= 50 % of luminal narrowing). The subjects were stratified into quartiles according to GGT level, and the relationship between GGT level and subclinical atherosclerosis was analysed. Results: Serum GGT levels were closely associated with obesity, atherogenic dyslipidemia, and metabolic syndrome. However, serum GGT levels did not show a linear association with baPWV, carotid intima-media thickness, or plaque grade. The prevalence of high baPWV, carotid atherosclerosis, and carotid stenosis did not differ between the quartiles in men and women. Multivariate logistic regression analyses revealed no association between GGT level and high baPWV, carotid atherosclerosis, and carotid stenosis, either as continuous variables or quartiles. Conclusions: Serum GGT levels were significantly associated with obesity, atherogenic dyslipidaemia, and metabolic syndrome, but not with the early and late stages of atherosclerotic vascular changes, in patients with type 2 diabetes. Serum GGT level may not be a reliable marker of subclinical atherosclerosis in type 2 diabetes.

Considerable evidence suggests that hypothyroidism could promote atherosclerotic vascular changes. We planned this study to investigate whether serum free thyroxine (FT4) or thyroid-stimulating hormone (TSH) levels are associated with coronary artery calcification measured in healthy euthyroid subjects.A cross-sectional analysis was performed among subjects who visited our hospital for a health checkup. Among 1849 subjects, 669 (mean age 55.3±8.8 years; 392 men) with FT4 and TSH in the normal ranges were included after excluding those with diabetes, a history of current smoking and cardiovascular disease (CVD), or the use of drugs for hypertension, antithyroid drugs, or thyroid hormone preparations. Coronary artery calcium scores (CACS) were measured by multi-detector computed tomography.Subjects with a CACS100 had lower FT4 levels than those with a lower CACS (p=0.017), whereas no difference was observed in the TSH levels among CACS categories. FT4 levels had an odds ratio of 0.06 for high CACS (95% confidence interval=0.01-0.74; p=0.028) after the adjustment for CVD risk factors. In multivariate regression analysis, CACS was negatively correlated with FT4 levels (β=-0.823, p=0.032), and the inverse association between FT4 and CACS remained significant only in men (p=0.011).FT4 levels were inversely associated with coronary artery calcification in euthyroid healthy subjects, especially in men independent of conventional CVD risk factors. Further studies are needed to validate whether subjects with decreased FT4 levels within the normal reference range are at a high CVD risk and have poor cardiovascular outcomes.

Background We previously reported a patient with congenital adrenal hyperplasia (CAH) with compound heterozygous mutations in the cytochrome P450 17A1 (CYP17A1) gene. One allele had a p.His373Leu and the other a new p.Glu383fsX36 mutation. The aim of this study was to investigate the functional properties of a new allele present in a compound heterozygote of CYP17A1. Methods To understand how p.His373Leu and p.Glu383fsX36 affect P450c17 enzymatic activity, wild type and mutant CYP17A1 cDNAs were cloned into flag-tagged pcDNA3 vector and introduced into human embryonic kidney cells 293T (HEK293T) cells. Protein expression levels of CYP17A1 were then analyzed. And the activities of 17α-hydroxylase and 17,20-lyase of CYP17A1 were evaluated by measuring the conversion of progesterone to 17α-hydroxyprogesterone and of 17α-hydroxypregnenolone to dehydroepiandrosterone, respectively. In addition a computer model was used to create the three-dimensional structure of the mutant CYP17A1 enzymes. Results Production of the p.His373Leu mutant protein was significantly lower than that of the wild type protein, and the p.Glu383fsX36 protein was hardly produced. Similarly the enzymatic activity derived from the p.His373Leu mutant vector was significantly lower than that obtained from the wild type vector, and little activity was obtained from the p.Glu383fsX36 vector. Three-dimensional modeling of the enzyme showed that p.His373 was located in region important for heme-binding and proper folding. Neither the p.His373Leu nor the p.Glu383fsX36 mutant protein formed a heme-binding structure. Conclusion Enzyme activity measured in both mutants disappeared completely in both 17α-hydroxylase and 17,20-lyase. This result accounts for the clinical manifestations of the patient with the compound heterozygous CYP17A1 mutations.

Changes in bone and mineral metabolism that occur after gastrectomy have long been recognized. Gastrectomy has been identified as a risk factor for decreased bone mass and the increased fracture incidence. Previous investigations concerning postgastrectomy bone disease have been observational studies. No prospective studies have been reported that quantify the amount of bone loss after gastrectomy within the same patients. This study investigated 46 patients undergoing gastrectomy for gastric adenocarcinoma and analyzed 36 patients (58.1+/-10.8 years, 24 men and 12 women) who had dual energy X-ray absorptiometry (DXA) performed before and 1 year after gastrectomy. Systemic adjuvant chemotherapy was administered to 14 patients. Blood was sampled from all patients to determine serum calcium, phosphorous, and bone turnover marker levels before gastrectomy and at 1, 3, 6 and 12 months after surgery and for serum parathyroid hormone (PTH) and 25-hydroxyvitamin D levels before and 12 months after surgery. The mean bone loss in the lumbar spine, total hip, femoral neck, and trochanter, which was calculated as the percentage change from the baseline to the level measured at 12 months, was 5.7% (P

Objectives Oxidative stress may contribute to atherosclerosis and increased activation of the coagulation pathway. Bilirubin may reduce activation of the hemostatic system to inhibit oxidative stress, which would explain its cardioprotective properties shown in many epidemiological studies. This study investigated the association of serum bilirubin with fibrinogen and plasminogen activator inhibitor-1 (PAI-1), respectively. Methods A cross-sectional analysis was performed on 968 subjects (mean age, 56.0 ± 11.2 years; 61.1% men) undergoing a general health checkup. Serum biochemistry was analyzed including bilirubin subtypes, insulin resistance (using homeostasis model of assessment [HOMA]), C-reactive protein (CRP), fibrinogen, and PAI-1. Results Compared with subjects with a total bilirubin (TB) concentration of 17.1 μmol/L had a smaller waist circumference, a lower triglyceride level, a lower prevalence of metabolic syndrome, and decreased HOMA-IR and CRP levels. Correlation analysis revealed linear relationships of fibrinogen with TB and direct bilirubin (DB), whereas PAI-1 was correlated with DB. After adjustment for confounding factors, bilirubin levels were inversely associated with fibrinogen and PAI-1 levels, respectively. Multivariate regression models showed a negative linear relationship between all types of bilirubin and fibrinogen, whereas there was a significant linear relationship between PAI-1 and DB. Conclusions High bilirubin concentrations were independently associated with low levels of fibrinogen and PAI-1, respectively. The association between TB and PAI-1 was confined to the highest TB concentration category whereas DB showed a linear association with PAI-1. Bilirubin may protect against the development of atherothrombosis by reducing the hemostatic response.

Current evidence suggests that high normal albuminuria is significantly associated with increased cardiovascular risk. This study investigated the association between urine albumin-to-creatinine ratio (ACR) within the normal range and subclinical atherosclerosis in Korean patients with type 2 diabetes.This cross-sectional study involved 521 type 2 diabetic patients with normoalbuminuria. Brachial-ankle pulse wave velocity (baPWV) measurement and ultrasound assessment of carotid atherosclerosis was done. Subclinical atherosclerosis was assessed by the presence of high baPWV (1682 cm/s), carotid atherosclerosis (intima-media thickness0.8 mm or the presence of plaques), and carotid stenosis (≥50% of luminal narrowing). Across the tertiles of ACR, there was a trend for an increasing prevalence of high baPWV (16.8%, 20.0%, and 38.2%, P0.001), carotid atherosclerosis (46.9%, 55.4%, and 64.7%, P0.001), and carotid stenosis (12.7%, 16.0%, and 30.1%, P0.001). In multivariate analysis, patients in the highest ACR tertile had an odds ratio of 2.05 (95% confidence interval [CI], 1.13-3.72, P = 0.019) for high baPWV, 1.78 (95% CI, 1.08-2.93, P = 0.024) for carotid atherosclerosis, and 2.72 (95% CI, 1.44-5.11, P = 0.002) for carotid stenosis compared to those in the lowest tertile. The relation of ACR with carotid atherosclerosis and stenosis remained significant even in patients without diabetic retinopathy.High normal albuminuria was significantly associated with atherosclerotic vascular changes, independent of retinopathy and other cardiovascular risk factors. High normal albuminuria may be an early marker for subclinical atherosclerosis in type 2 diabetes.

This study prospectively investigated the changes of the serum levels of the sex steroids, IL-7, soluble receptor activator of nuclear factor kappaB ligand (sRANKL) and osteoprotegerin (OPG) in bone marrow transplantation (BMT) recipients. This study also examined whether the changes of these cytokine levels and sex steroids actually influence bone turnover and post-BMT bone loss by correlation analysis. Data were analyzed from 39 patients (33.6+/-6.4 years, 19 men and 20 women) who had DXA performed before BMT and at 1 year after BMT. The bone turnover markers, sex steroids and the cytokine levels were measured before BMT and serially after BMT. The mean bone loss in the lumbar spine and the total proximal femur was 5.9% (P < 0.01) and 11.3% (P < 0.01), respectively. During the immediate post-BMT period, bone formation decreased, whereas the bone resorption increased. For the female recipients, the estradiol levels declined at 1 week after BMT, and they did not recover to the basal levels. For the male recipients, the testosterone levels decreased at 1 week and then it increased to its baseline level. The IL-7 levels reached their maximum at 1 week and then declined to baseline level by 3 months. The serum sRANKL, OPG levels and the sRANKL/OPG ratio showed their peak at post-BMT 3 weeks. The mean daily dose of steroid was associated with suppressed bone formation, enhanced bone resorption and increased sRANKL levels. The IL-7 levels were also noted to be either positively correlated with the levels of ICTP or they were negatively correlated with the levels of osteocalcin at 1 and 3 weeks after BMT. Bone loss at the lumbar spine and the proximal femur was influenced by the decreased sex steroids and increased IL-7 levels. During the observation period, the IL-7 levels showed positive correlations with the sRANKL levels and the sRANKL/OPG ratio. For the female patients, the serum IL-7 levels were negatively associated with the estradiol levels at 1 and 3 weeks after BMT. All these findings suggest that IL-7 plays an important role for post-BMT bone loss, and this possibly happens via the RANKL pathway. These data also suggest that the up-regulation of IL-7 during the early post-BMT period may result from a deficiency of estrogen.

The loss of bone mass often occurs after bone marrow transplantation (BMT), particularly during the early posttransplant period. There are few reports on the role of growth factors and osteoprotegerin (OPG) in the post-BMT bone loss. This study prospectively investigated 110 patients undergoing BMT and analyzed 36 patients who had dual-energy x-ray absorptiometry performed before BMT and 1 yr after BMT. The biochemical markers of bone formation and resorption were measured at the short-term intervals during the year-long follow-up. The serum IGF-I, IGF binding protein (IGFBP)-3, fibroblast growth factor-2, macrophage-colony stimulating factor (M-CSF), and OPG levels were measured before and 1 wk, 3 wk, and 3 months after BMT. The mean bone loss in the lumbar spine and the total proximal femur, which was calculated as the percent change from the baseline to the level at 1 yr, was 5.2% (P < 0.05) and 11.6% (P < 0.01), respectively. During the immediate post-BMT period, bone formation decreased, whereas bone resorption increased, which was indicated by the biochemical markers of bone turnover. The serum IGF-I levels also decreased progressively until 3 wk and then increased to the basal values at 3 months. The serum IGFBP-3 levels decreased progressively until 3 months. The serum fibroblast growth factor-2 levels decreased to the nadir at 1 wk and gradually recovered to the basal values at 3 months. The serum M-CSF levels increased immediately after BMT, which declined to its baseline level by 3 months. The serum OPG levels increased progressively, reached a peak at 3 weeks, and declined thereafter. There were significant correlations between the IGF-I and osteocalcin levels before BMT and at 3 wk after BMT (r = 0.45, P < 0.01; r = 0.54, P < 0.01). During the observation period, the serum IGFBP-3 and M-CSF levels showed positive correlations with the osteocalcin and serum collagen I carboxyl-terminal telopeptide levels, respectively. Although statistically not significant, the OPG levels tended to be positively associated with the serum collagen I carboxyl-terminal telopeptide levels. Significant correlations were observed between the percent changes from the baseline to 1 yr in the bone mineral density at the proximal femur and the serum IGF-I levels at 3 wk and 3 months after BMT (r = 0.52, P < 0.01; r = 0.41, P < 0.05).

Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is interrelated with renal dysfunction and disturbed bone metabolism, both of which play a key role in calcium and phosphorus homeostasis. We investigated the association between NAFLD and serum calcium and phosphorus levels in Korean subjects.We performed a cross-sectional analysis of 16,592 subjects undergoing a general health checkup. NAFLD was assessed based on ultrasonographically detected fatty liver in the absence of excessive alcohol consumption and other causes of liver disease.The proportion of the population with fatty liver detected by ultrasonography was 43.2% for males and 17.6% for females. We observed that a higher serum albumin-corrected calcium (Ca(c)) level was associated with smoking, hypertension, and unfavorable metabolic parameters in both genders, but the serum phosphorus levels showed an inconsistent correlation with metabolic abnormalities. After adjusting for age, gender, waist circumference, body mass index, smoking status, exercise, diabetes, hypertension, lipid profiles, and renal function, serum Cac , phosphorus, and Cac -phosphorus products were independent risk factors for fatty liver (odds ratio [OR]: 1.71, 95% confidence interval [CI]: 1.49-1.95, P 0.001; OR: 1.34, 95% CI: 1.22-1.48, P 0.001; and OR: 1.20, 95% CI: 1.14-1.26, P 0.001, respectively), and the risk of fatty liver increased in a graded manner over the quartiles.Serum calcium and phosphorus levels are significantly associated with NAFLD. Further investigation is needed to verify whether calcium and phosphorus levels indicate a higher risk of NAFLD.

Recent advances in genetics revealed that 25% to 30% of head and neck paragangliomas (PGLs) are inherited tumors associated with germline mutation, mainly in the succinate dehydrogenase (SDH) gene.DNA was isolated from whole blood and polymerase chain reaction (PCR) products were sequenced with an ABI3730 × 1 Genetic Analyzer.A 30-year-old Korean woman underwent resection of a carotid PGL. Fourteen years later, she was readmitted for a cervical mass. (18) F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT revealed a hot spot in the adrenal gland, besides the carotid mass. Surgical pathology confirmed recurrence of the carotid PGL and a concomitant pheochromocytoma. Genetic analysis revealed SDHD c.119del T (p.I40TfsX46) mutation. One daughter has been identified as a carrier.We found a novel SDHD mutation from a Korean family that shows similar clinical features to those in other SDHD mutations, mostly from Western countries. Further studies are needed to determine whether similar genotype-phenotype correlations exist in the Asian patients with familial PGLs.

BACKGROUND: Considerable evidence suggests that bilirubin is a potent physiologic antioxidant that may provide important protection against cardiovascular disease (CVD) and inflammation. We investigated the relationship between serum total bilirubin (TB) levels and arterial stiffness, measured by the brachial-ankle pulse wave velocity (baPWV), in patients with type 2 diabetes. METHODS: We conducted a cross-sectional analysis of 1,711 subjects with type 2 diabetes (807 men and 904 women; mean age, 57.1 years). The subjects were stratified based on gender-specific tertiles of TB values, and a high baPWV was defined as greater than 1,745 cm/s ( >75th percentile). RESULTS: The serum TB concentration was negatively correlated with the duration of diabetes, HbA1c, the 10-year Framingham risk score, and baPWV and was positively correlated with high-density lipoprotein cholesterol and the eGFR in both genders. Inverse association between TB categories and unadjusted prevalence of high PWV was only observed in women. After adjusting for confounding factors, the TB levels were inversely associated with a greater risk of a high baPWV, both as a continuous variable [a 1-SD difference; odds ratio (OR), 0.70; 95% confidence interval (CI), 0.54-0.90; P = 0.005] and when categorized in tertiles (the highest vs. the lowest tertile; OR, 0.49; 95% CI, 0.28-0.85; P = 0.011) in women but not in men. The relationship remained significant even after adjusting for retinopathy and nephropathy. CONCLUSIONS: Low TB levels were significantly associated with arterial stiffness in Korean women with type 2 diabetes. Our data suggested that bilirubin may protect against macrovascular disease in diabetic women.

Background It has been reported that many peripheral vasodilating drugs might improve insulin resistance. Cilostazol, a antithrombotic agent, increases peripheral blood flow in non-insulin dependent diabetic patients. The effect of cilostazol treatment on insulin resistance in streptozotocin (STZ)-induced non-insulin dependent diabetic Wistar rats was examined. Methods About a half of two-day old neonate siblings were injected intraperitoneally with STZ and maintained for six months, at which time they were compared with age-matched control rats for intraperitoneal glucose tolerance test (IPGTT) and for glucose infusion rate (GINF) in a euglycemic hyperinsulinemic glucose-clamp study. After that, these studies were also performed after feeding rat chow containing cilostazol (100 mg/kg/day) to rats with STZ-induced non-insulin dependent diabetes mellitus for four-weeks and compared with those of age-matched control rats. Results In the intraperitoneal glucose tolerance test studies, plasma glucose levels of STZ-induced non-insulin dependent diabetic rats were significantly higher and plasma insulin levels significantly lower than those of age-matched control rats in the age of six months. Glucose infusion rate was lower in STZ-induced non-insulin dependent diabetic rats than those of age-matched control rats. However, after a four-week cilostazol treatment, glucose infusion rate of STZ-induced non-insulin dependent diabetic rats was not significantly different from that of control rats. Conclusion These findings suggested that cilostazol may improve insulin resistance in STZ-induced non-insulin dependent diabetic rats.

A complementary DNA expression library derived from marrow samples from myeloma patients was recently screened and human macrophage inflammatory protein-1alpha (hMIP-1alpha) was identified as an osteoclastogenic factor expressed in these samples. hMIP-1alpha enhanced osteoclast (OCL) formation in human marrow cultures and by highly purified OCL precursors in a dose-dependent manner (5-200 pg/mL). Furthermore, hMIP-1alpha enhanced OCL formation induced by human interleukin-6 (IL-6), which is produced by marrow stromal cells when they interact with myeloma cells. hMIP-1alpha also enhanced OCL formation induced by parathyroid hormone-related protein (PTHrP) and receptor activator of nuclear factor kappaB ligand (RANKL), factors also implicated in myeloma bone disease. Time-course studies revealed that the hMIP-1alpha acted during the last 2 weeks of the 3-week culture period. Reverse transcription-polymerase chain reaction analysis showed that the chemokine receptors for hMIP-1alpha (CCR1 and CCR5) were expressed by human bone marrow and highly purified early OCL precursors. Furthermore, hMIP-1alpha did not increase expression of RANKL. These data demonstrate that hMIP-1alpha is an osteoclastogenic factor that appears to act directly on human OCL progenitors and acts at the later stages of OCL differentiation. These data further suggest that in patients with myeloma, MIP-1alpha produced by myeloma cells, in combination with RANKL and IL-6 that are produced by marrow stromal cells in response to myeloma cells, enhances OCL formation through their combined effects on OCL precursors. (Blood. 2001;97:3349-3353)

Organ transplantation is now the treatment of choice for many patients with life-threatening chronic diseases. A new set of side effects unique to these groups of patients has become recognized, and bone disease is one of these complications. However, little is known about the effects of myeloablative treatment followed by bone marrow transplantation (BMT) on bone mineral metabolism. We have prospectively investigated 31 patients undergoing BMT for hematologic diseases. Serum concentrations of calcium, phosphorus, creatinine, gonadotropins, sex hormones, and the biochemical markers of bone turnover were measured. The samples were collected before BMT and 1, 2, 3, 4, and 12 weeks, 6 months, and 1 year after BMT. Bone mineral density (BMD) was measured with dual-energy X-ray absorptiometry before BMT and 1 year after BMT. The serum carboxy-terminal cross-linked telopeptide of type I collagen increased progressively until 4 weeks after BMT. Thereafter, it began to decrease and reached basal values after 1 year. Serum osteocalcin decreased progressively until 3 weeks after BMT. After that, it increased and reached basal values after 3 months. No distinct differences were observed in the serum biochemical turnover markers between males and females, or between patients who received total body irradiation and those who did not. One year after BMT, lumbar spine BMD had decreased by 2.2%, and total proximal femoral BMD had decreased by 6.2%. Eighty-six percent of the women (12/14) went into a menopausal state immediately after BMT. This was caused by high gonadotropin levels and low estradiol levels. In contrast, gonadotropin levels and testosterone levels did not change significantly in the male patients after BMT. In conclusion, the rapid impairment of bone formation and the increase in bone resorption, as shown by the biochemical markers in this study, might play a role in post-BMT bone loss.

A diagnosis of central hypothyroidism (CH) can be missed easily or delayed without a high index of suspicion due to normal or slightly altered thyroid stimulating hormone (TSH) levels during the initial screening test for thyroid dysfunction. A correct diagnosis of CH is very important for safely treating patients. Specifically, doctors must ensure a proper evaluation of combined adrenal insufficiency to prevent a fatal adrenal crisis. Here we report a case of CH combined with secondary adrenal insufficiency in a 42-year-old woman with Dyke-Davidoff-Masson syndrome, which is a rare neurological disease.

The risk for parathyroid carcinoma is high in those with the HPT-JT syndrome. Parafibromin is a protein derived from HRPT2 gene and its inactivation has been coupled to familial form of parathyroid malignancy. We previously identified altered transcripts resulting from splice site mutation of the HRPT2 gene in a family with this syndrome. In the present work, we investigated the stability of the altered HRPT2 transcripts and translation products produced in the HPT-JT syndrome. We quantified the differentially expressed HRPT2 mRNAs using real-time RT-PCR and developed a novel monoclonal parafibromin antibody to study the expression of parafibromin in the HPT-JT syndrome. The relative quantification ratios of the wild type HRPT2 mRNA, 23 bp deleted HRPT2 mRNA, and 70 bp deleted HRPT2 mRNA in the HPT-JT syndrome were 0.68, 0.17 and 0.15, respectively. But endogenous parafibromin expression was not detectable in the HPT-JT syndrome carcinoma. The altered HRPT2 mRNAs resulting from the splice site mutation in the HPT-JT syndrome were stable, but their parafibromin translation products from the HPT-JT syndrome carcinoma were probably degraded rapidly. Additional studies that aim to fully characterize the consequences of altered HRPT2 mRNAs in HPT-JT syndrome are required to explore these possibilities.

It has been suggested that oxidative stress is associated with the pathogenesis of osteoporosis. The objective of this study was to explore the association between a marker of oxidative stress and either bone turnover markers or bone mineral density (BMD) in postmenopausal women. In addition, the effects of oxidative stress on the formation of osteoclasts in human bone marrow cell culture were examined. We performed a cross-sectional analysis in healthy postmenopausal women aged 60-78 years (n = 135, 68.2 +/- 4.9). Oxidative stress was evaluated in the serum by measuring 8-hydroxy-2'-deoxyguanosine (8-OH-dG) levels. The biochemical markers of bone turnover and areal BMD were measured in all participants. Multivariate linear regression analysis revealed a negative association between 8-OH-dG levels and BMD of the lumbar spine, total hip, femoral neck, and trochanter and positive association with type I collagen C-telopeptide (ICTP) levels. The odds ratio of 8-OH-dG for osteoporosis was 1.54 (1.14-2.31, P = 0.003). In cultures of primary human marrow cells, H2O2 caused concentration-dependent activation of TRAP-positive multinucleated giant cells. H2O2 also increased the area of pits per osteoclast activity assay substrate. RT-PCR showed that H2O2 stimulated the expression of M-CSF and RANKL and increased the RANKL/OPG ratio. The data support the view that oxidative stress is associated with increased bone resorption and low bone mass in otherwise healthy women. In addition, RANKL and M-CSF stimulation induced by oxidative stress may participate in osteoclastogenesis in human bone.

Aims The aim of this study was to investigate changes in the clinical characteristics of diabetic ketoacidosis (DKA) in Korea over the last two decades. Methods A retrospective medical record review of all episodes of DKA from 1982 to 2002 in four University-affiliated urban hospitals in Korea was performed. A total of 255 episodes of DKA (217 patients) were identified and divided into three consecutive 7-year periods to compare trends over time. Clinical characteristics including precipitating factors and hospital mortality were analyzed. Results A dramatic increase in DKA admissions has occurred over the last two decades, accompanied by a marked increase in admissions of diabetic patients. The clinical characteristics of DKA remained constant over the observation period. Non-compliance to treatment was the most common precipitating factor of DKA. A total of 30 patients died in hospital (11.8% of all episodes). Older age and infection appeared to influence mortality. Conclusions Our results suggest that rapidly increasing episodes of DKA in Korea, in parallel with increases in the numbers of diabetic patients, continue to be associated with significant mortality.

We developed a blood glucose management system using the Internet and short message service (SMS) which can lessen the social economic burden and materialize an individualized diabetes mellitus management. A total of 185 diabetic patients participated in this study and their mean age was 42.4 years old (8–79 year-old). Participants sent their self-measured blood glucose levels, medication and its dosages, amount of meal, and degree of exercise to their health providers in this specialized web-based diabetes management system for 3 months. The health providers consisting of endocrinology specialists, dietitians, and nurses sent recommendations for individualized diabetes management according to the data on the web. Laboratory tests including lipid profiles and glycated hemoglobin (HbA1c), and a survey of satisfaction about this system were performed before and after the study period. The mean HbA1c improved from 7.5 ± 1.5 to 7.0 ± 1.1% after using the management program (P = 0.003). The mean serum triglyceride and HDL–cholesterol levels turned for the better also. HbA1c improved from 8.4 ± 1.2 to 7.5 ± 1.0% after applying this program to patients with the HbA1c of 7% or higher at baseline (P = 0.010). We propose this web-based diabetic patient management system as a new tool for communication between health care providers and patients. © 2004 Elsevier Ireland Ltd. All rights reserved.

We used polymerase chain reaction (PCR)-selective complementary DNA (cDNA) subtraction hybridization with an immortalized murine osteoclast (OCL) precursor cell line to identify genes that are highly expressed in OCLs compared with OCL precursors and which may be involved in the OCL differentiation process. ADAM8 was one of the 50 genes identified. ADAM (a disintegrin and metalloproteinase) peptides are membrane-bound proteins that can act as cell-to-cell and cell-to-matrix adhesion molecules, degrade the extracellular matrix, and play a role in tissue morphogenesis. Addition of antisense (AS) S-oligonucleotides for ADAM8 (1-10 nM) to mouse bone marrow cultures treated with 10(-9) M 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] significantly inhibited OCL formation compared with treatment with the control S-oligonucleotide. Furthermore, conditioned media from 293 cells transiently transfected with a secretable form of the ADAM8 cDNA increased OCL formation in a dose-dependent manner. In addition, treatment of OCLs with soluble ADAM8 conditioned media significantly increased pit formation per dentin slice compared with control OCLs. Time course studies indicated that ADAM8 increased OCL formation only when it was present during days 4-7 of the 7-day culture period. Structural analysis, using truncated constructs of ADAM8, showed that the cysteine-rich/disintegrin domain was responsible for its OCL stimulatory activity. Western blot analysis confirmed that the soluble form of ADAM8 is present in normal marrow cultures. These data suggest that ADAM8 plays an important role in OCL formation and acts primarily at the later stages of OCL differentiation.

Introduction Narcolepsy and idiopathic hypersomnia are known to show hypersomnia related to central nervous system origin with symptom of excessive daytime sleepiness. But little is known about the differences of clinical characteristics between narcolepsy without cataplexy and idiopathic hypersomnia. The aim of this study is to compare the clinical, polysomnographic and multiple sleep latency test characteristics of narcolepsy without cataplexy and idiopathic hypersomnia. Materials and methods Seventy-nine narcolepsy with cataplexy patients and Seventy-one idiopathic hypersomnia patients were recruited at Sleep Center of St. Vincent’s hospital. The demographic, clinical data, the multiple sleep latency test data and polysomnographic findings from the time of their diagnosis were reviewed. Results Results indicated that Epworth sleepiness scale score and nocturnal sleep disturbance were not significantly different between two groups. 25.0% of narcolepsy without cataplexy patients showed hypnagogic hallucinations positive, while 35.0% of idiopathic hypersomnia patients were hypnagogic hallucinations positive with no statistical differences. 33.3% of narcolepsy without cataplexy patients reported sleep paralysis, while 28.8% of idiopathic hypersomnia patients experienced sleep paralysis. Results showed no significant differences between two groups in onset age of hallucinations or onset age of sleep paralysis. Mean sleep latency was shorter in narcolepsy without cataplexy, and the number of SOREMPs were lower in idiopathic hypersomnia. The sleep efficiency was significantly greater in narcolepsy without cataplexy patients. The REM latency was shorter in narcolepsy without cataplexy patients. The percentage of REM sleep was significantly greater in narcolepsy without cataplexy patients. Conclusion The narcolepsy without cataplexy and idiopathic hypersomnia showed no significant differences in clinical characteristics although they have significant differences in objective findings such as mean sleep latency, REM latency, and percentage of REM sleep. Acknowledgements No conflicts of interest.

Introduction Pharmacotherapy is currently widely used in the treatment of insomnia can be helpful in transient insomnia, but research regarding its effectiveness and safety of long-term use is not enough. Therefore, to complement the limitations of pharmacotherapy in the treatment of patients with insomnia, non-pharmacologic treatment methods (cognitive behavioral therapy; CBT) are used. But CBT for insomnia appear to be costly and time-consuming compared to pharmacotherapy, clinical practice in the field can be difficult to apply. The authors took the format of group therapy rather than individual therapy to complement the disadvantages of CBT and now we would like to have a thought into its meaning by reporting several cases of patients who reduced taking sleeping pills through group CBT. Materials and methods Patients were recruited at Sleep Center of St. Vincent’s hospital, 2 men and 3 women led to a group of five patients. CBT is a treatment for correction factors that cause and maintain insomnia, it includes a variety of techniques such as sleep hygiene education, stimulus control, sleep restriction, relaxation and cognitive therapy. A series of treatment were performed five sessions once a week with a frequency from February to March 2012 and were proceeded for about 1hour and 30 min per session. Results Results indicated that the subjective quality of sleep and sleep efficiency of all patients improved and PSQI (Pittsburgh Sleep Quality Index) and BDI (Beck Depression Inventory) were decreased in spite of reducing dose of medication. Conclusion Like these cases, we can contribute to reduce the time and economic burden by performing group therapy for insomnia CBT rather than individual therapy. Acknowledgements Keywords: Insomnia, Cognitive Behavioral Therapy, Group therapy. Pharmacotherapy There are no conflicts of interests.