Sihoon Lee

Cutoff Values of Surrogate Measures of Insulin Resistance for Metabolic Syndrome in Korean Non-diabetic Adults

We investigated the cutoff values of surrogate of insulin resistance for diagnosing metabolic syndrome in Korean adults. The data from 976 non-diabetic individuals (484 men and 492 women) aged 30-79 yr were analyzed. We determined the odds ratios for the prevalence of metabolic syndrome according to the quartiles of fasting insulin, homeostasis model for insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI) as independent variables, while adjusting for age, sex, and body mass index. The cutoff values of fasting insulin, HOMA-IR, and QUICKI were estimated by the areas under the receiver-operating characteristic (ROC) curves. The cutoff points for defining insulin resistance are a fasting insulin level of 12.94 µU/mL, HOMA-IR=3.04 as the 75th percentile value, and QUICKI=0.32 as the 25th percentile value. Compared with the lowest quartile, the adjusted odds ratios for the prevalence of metabolic syndrome in the highest quartiles of fasting insulin, HOMA-IR, and QUICKI were 1.95 (1.26-3.01), 2.27 (1.45-3.56), and 2.27 (1.45-3.56), respectively. The respective cutoff values for fasting serum insulin, HOMA-IR, and QUICKI by ROC analysis were 10.57 µU/mL (sensitivity 58.5%, specificity 66.8%), 2.34 (sensitivity 62.8%, specificity 65.7%), and 0.33 (sensitivity 61.2%, specificity 66.8%). Fasting insulin, HOMA-IR, and QUICKI can be used as surrogate measures of insulin resistance in Korean non-diabetic adults.

Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia

Objective  ACTH‐independent macronodular adrenal hyperplasia (AIMAH) is a rare and unusual cause of Cushings syndrome, characterized by bilateral nodular adrenocortical hyperplasia and hypersecretion of cortisol. Familial AIMAH has rarely been reported. Recently, the aberrant expression of adrenal receptors for various ligands in AIMAH patients has become important in explaining the pathogenesis of AIMAH. In this study, we present the cases of two sisters who were affected with AIMAH.

Association between brachial-ankle pulse wave velocity and occult coronary artery disease detected by multi-detector computed tomography

BACKGROUND Arterial stiffness, assessed by aortic pulse wave velocity (PWV), has been reported to predict cardiovascular morbidity and mortality. We assessed the association between arterial stiffness, as determined by PWV, and occult coronary artery disease (CAD), as detected by multi-detector computed tomography (MDCT), in asymptomatic individuals. METHOD We retrospectively enrolled 615 consecutive South Korean individuals who had undergone both brachial-ankle PWV (baPWV) and coronary CT angiography during general routine health evaluations at the Asan Medical Center in 2008. RESULTS We found that baPWV was positively correlated with age; body mass index; blood pressure; total cholesterol, homocysteine, and fasting blood glucose concentrations; and coronary artery calcium score. When we divided subjects into two groups according to the results of MDCT, we found that baPWV was significantly higher in subjects with (diameter of stenosis >50%) than without CAD (1573.2 ± 275.6 cm/s vs. 1409.6 ± 235.6 cm/s, p<0.01). The optimal baPWV cutoff value for detection of significant coronary arterial stenosis was 1426.0 cm/s, which had a sensitivity of 77% and a specificity of 63% (area under curve=0.71). After adjusting for age, smoking status, hypertension, diabetes, and dyslipidemia, the odds ratio for significant occult CAD was 3.30 (95% CI=1.47-7.41, p<0.01). CONCLUSION We found that baPWV was associated with risk factors for cardiovascular disease, including CACS, in asymptomatic individuals, and the optimal baPWV cutoff value for occult CAD detected by MDCT was 1426 cm/s. These findings suggest that baPWV may be a useful screening tool for predicting occult CAD.

A Homozygous [Cys25]PTH(1‐84) Mutation That Impairs PTH/PTHrP Receptor Activation Defines a Novel Form of Hypoparathyroidism

Hypocalcemia and hyperphosphatemia are encountered in idiopathic hypoparathyroidism (IHP) and pseudohypoparathyroidism type Ib (PHP1B). In contrast to PHP1B, which is caused by resistance toward parathyroid hormone (PTH), the genetic defects leading to IHP impair production of this important regulator of mineral ion homeostasis. So far, only five PTH mutations were shown to cause IHP, each of which is located in the hormones pre‐pro leader segment and thus impair hormone secretion. In three siblings affected by IHP, we now identified a homozygous arginine‐to‐cysteine mutation at position 25 (R25C) of the mature PTH(1‐84) polypeptide; heterozygous family members are healthy. Depending on the assay used for evaluating these patients, plasma PTH levels were either low or profoundly elevated, thus leading to ambiguities regarding the underlying diagnosis, namely IHP or PHP1B. Consistent with increased PTH levels, recombinant [Cys25]PTH(1‐84) and wild‐type PTH(1‐84) were secreted equally well by transfected COS‐7 cells. However, synthetic [Cys25]PTH(1‐34) was found to have a lower binding affinity for the PTH receptor type‐1 (PTH1R) than PTH(1‐34) and consequently a lower efficiency for stimulating cAMP formation in cells expressing this receptor. Consistent with these in vitro findings, long‐term infusion of [Cys25]PTH(1‐34) resulted only in minimal calcemic and phosphaturic responses, despite readily detectable levels of [Cys25]PTH(1‐34) in plasma. The mineral ion abnormalities observed in the three IHP patients are thus most likely caused by the inherited homozygous missense PTH mutation, which reduces bioactivity of the secreted hormone. Based on these findings, screening for PTH(1‐84) mutations should be considered when clinical and laboratory findings are consistent with PHP1B, but GNAS methylation changes have been excluded. Differentiating between IHP and PHP1B has considerable implications for genetic counseling, therapy, and long‐term outcome because treatment of IHP patients with inappropriately high doses of active vitamin D and calcium can contribute to development of nephrocalcinosis and chronic kidney disease.

Postoperative Cervical Cord Compression Induced by Hydrogel Dural Sealant (DuraSeal

Cerebrospinal fluid (CSF) leakage is a potential complication of cranial and spinal surgery. Postoperative CSF leakage can induce delayed healing, wound infection and meningitis. DuraSeal® (Covidien, Waltham, MA, USA) is a synthetic product which has been increasingly used to facilitate watertight repair of dural defects after cranial and spinal surgery. Despite some advantages of Duraseal®, the authors report a patient who developed cord compression following the use of DuraSeal® in cervical spine surgery in which the expansion of the DuraSeal® was believed to be the causative factor.

Identification and characterization of C106R, a novel mutation in the DNA-binding domain of GCMB, in a family with autosomal-dominant hypoparathyroidism

Overview  Glial cells missing B (GCMB) is a transcription factor that is expressed in the parathyroid hormone (PTH)‐secreting cells of the parathyroid glands. Several mutations in GCMB have been reported to cause hypoparathyroidism (HP). We identified a family with two individuals in two generations (mother and son), who are affected by autosomal‐dominant hypoparathyroidism (AD‐HP). A novel heterozygous mutation in exon 2 of GCMB was identified in both affected individuals that changes cysteine at position 106 of the putative DNA‐binding domain of GCMB to arginine (C106R).

Identification and characterization of D410E, a novel mutation in the loop 3 domain of CASR, in autosomal dominant hypocalcemia and a therapeutic approach using a novel calcilytic, AXT914

Activating mutations of the calcium‐sensing receptor (CASR) gene are associated with autosomal dominant hypocalcemia (ADH) characterized by benign hypocalcemia, inappropriately low (PTH) levels and mostly hypercalciuria. Herein, we report a novel activating mutation in the CASR gene in a Korean family with ADH.

Identification of the Mutations in the Prostaglandin Transporter Gene, SLCO2A1 and Clinical Characterization in Korean Patients with Pachydermoperiostosis

Pachydermoperiostosis (PDP), or primary hypertrophic osteoarthropathy, is a rare genetic disease affecting both skin and bones. Both autosomal dominant with incomplete penetrance and recessive inheritance of PDP have been previously confirmed. Recently, hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1) were reported as pathogenic genes responsible for PDP. Both genes are involved in prostaglandin E2 (PGE2) degradation. We aimed to identify responsible genes for PDP and the clinical features in Korean patients with PDP. Six affected individuals and their available healthy family members from three unrelated Korean families with PDP were studied. All of the patients displayed complete phenotypes of PDP with finger clubbing, pachydermia, and periostosis. Mutation analysis revealed a novel heterozygous mutation in the SLCO2A1 gene at nucleotide 302 causing a substitution of the amino acid isoleucine to serine at codon 101 (p.IIe101Ser) in affected individuals. We also identified known SLCO2A1 mutations, one homozygous for c.940+1G>A, and another compound heterozygous for c.940+1G>A and c.1807C>T (p.Arg603*) from two PDP families. Genetic analyses of the PDP patients showed no abnormality in the HPGD gene. Our study further supports the role of mutations in the SLCO2A1 gene in the pathogenesis of PDP and could provide additional clues to the genotype-phenotype relations of PDP.

Modifications of T-scores by quantitative ultrasonography for the diagnosis of osteoporosis in koreans.

To identify a proper T-score threshold for the diagnosis of osteoporosis in Koreans using quantitative ultrasonography (QUS), normative data from 240 females and 238 males (ages 20-29 yr) were newly generated. Then, the osteoporosis prevalence estimate for men and women over 50 yr of age was analyzed using previous World Health Organization (WHO) methods and heel QUS. T-scores were calculated from the normative data. There were definite negative correlations between age and all of the QUS parameters, such as speed of sound (SOS), broadband ultrasound attenuation (BUA), and estimated heel bone mineral density (BMD) (p<0.0001). After applying the recently determined prevalence of incident vertebral fracture in Koreans over 50 yr of age (11.6% and 9.1%, female vs male, respectively) to the diagnosis of osteoporosis by T-scores from heel BMD as measured by QUS, it was revealed that applicable T-scores for women and men were -2.25 and -1.85, respectively. These data suggest that simply using a T-score of -2.5, the classical WHO threshold for osteoporosis, underestimates the true prevalence when using peripheral QUS. Further prospective study of the power of QUS in predicting the absolute risk of fracture is needed.

Angiogenesis inhibitor attenuates parathyroid hormone-induced anabolic effect ☆

In vivo osteogenic responses to anabolic stimuli are expected to be accompanied by angiogenesis as well as in the process of remodeling of bone. Consequently, angiogenesis might play an important role in mediating bone forming stimulating effect of parathyroid hormone (PTH). To investigate this relationship, we used actively growing young Sprague-Dawley rats and CKD-732, one of the angiogenesis inhibitor (AI) to reveal the relationship of angiogenesis in the effect of PTH. The groups were divided as (1) vehicle [VEH group], (2) PTH(1-84) [PTH group], (3) AI alone [AI group], (4) PTH(1-84)+AI concomitance [PTH-AI group] and were treated for 6 weeks. The bone mineral density (BMD) of PTH group was higher than VEH group and the gain of bone mass was attenuated in PTH-AI group. The maximal failure load in PTH group was higher than VEH group, but it was definitely attenuated by concurrent use of AI. Moreover, the toughness showed similar significant deterioration in PTH-AI group. General bone turnover was also significantly decreased in PTH-AI group as shown by the absence of increase in osteocalcin and beta-crosslaps and by decrease in metaphyseal length. The BMD or the biomechanic data of AI only group were similar to the VEH group, suggesting the minimal effect of AI itself on the normal modeling phase of the growing rats. In conclusion, the angiogenesis seemed to contribute to completing the anabolic effect of PTH especially for bone strength.