Cheol Ryong Ku

The Prevalence and Factors Associated with Hearing Impairment in the Korean Adults: The 2010–2012 Korea National Health and Nutrition Examination Survey (Observational Study)

AbstractThere are few studies that have used audiometric testing to gauge the demographic characteristics and associated risk factors for hearing loss at the national-level. Here, we investigated the weighted prevalence and associated factors of hearing impairment in 16,040 Korean adult population. Subjects completed audiometric test and laboratory examination as part of the data from The 2010–2012 Korea National Health and Nutrition Examination Survey (KNHANES). In our respective study, the overall weighted (n = 33,762,584) prevalence of mild hearing impairment among the Korean adult population was 20.5% (95% clearance [CI], 19.6–21.6), whereas moderate-to-profound hearing impairment was 9.2% (95% CI, 8.6–9.9). The weighted prevalence of mild hearing impairment in younger adults (19–39 years’ old) was 4.4% (3.5–5.5), in middle-age adults (40–64 years), it was 21.1% (19.8–22.5), and in older adults (≥65 years’ old), it was 69.7% (67.8–71.6). Logistic regression analyses were performed for low/mid frequency or high-frequency mild hearing impairment with age, sex, tobacco use, heavy alcohol use, educational background, occupational noise exposure, obesity, hypertension, diabetes, total serum cholesterol, and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 as covariates. The analyses revealed independent correlations between increased age, tobacco use, education, hypertension, and eGFR <60 mL/min/1.73m2, and low/mid frequency and high frequency mild hearing impairment. High frequency mild hearing impairment was positively correlated with male sex, diabetes, and an increase in total serum cholesterol. Taken together, hearing impairment in Korea is highly prevalent with approximately one-fifth of Korean adult reporting mild hearing impairment. This study suggests that individuals with cardiovascular risk factors such as hypertension, diabetes, smoking, increased serum cholesterol, or decreased eGFR are at particular risk of developing hearing impairment. As such, these groups may benefit from hearing loss screening in addition to those groups typically considered to be of elevated risk including geriatrics, those of low socioeconomic status, and those with considerable occupational noise exposure.

Olfactory marker protein expression is an indicator of olfactory receptor-associated events in non-olfactory tissues

Olfactory receptor (OR)-associated events are mediated by well-conserved components in the olfactory epithelium, including olfactory G-protein (Golf), adenylate cyclase III (ACIII), and olfactory marker protein (OMP). The expression of ORs has recently been observed in non-olfactory tissues where they are involved in monitoring extracellular chemical cues. The large number of OR genes and their sequence similarities illustrate the need to find an effective and simple way to detect non-olfactory OR-associated events. In addition, expression profiles and physiological functions of ORs in non-olfactory tissues are largely unknown. To overcome limitations associated with using OR as a target protein, this study used OMP with Golf and ACIII as targets to screen for potential OR-mediated sensing systems in non-olfactory tissues. Here, we show using western blotting, real-time PCR, and single as well as double immunoassays that ORs and OR-associated proteins are co-expressed in diverse tissues. The results of immunohistochemical analyses showed OMP (+) cells in mouse heart and in the following cells using the corresponding marker proteins c-kit, keratin 14, calcitonin, and GFAP in mouse tissues: interstitial cells of Cajal of the bladder, medullary thymic epithelial cells of the thymus, parafollicular cells of the thyroid, and Leydig cells of the testis. The expression of ORs in OMP (+) tissues was analyzed using a refined microarray analysis and validated with RT-PCR and real-time PCR. Three ORs (olfr544, olfr558, and olfr1386) were expressed in the OMP (+) cells of the bladder and thyroid as shown using a co-immunostaining method. Together, these results suggest that OMP is involved in the OR-mediated signal transduction cascade with olfactory canonical signaling components between the nervous and endocrine systems. The results further demonstrate that OMP immunohistochemical analysis is a useful tool for identifying expression of ORs, suggesting OMP expression is an indicator of potential OR-mediated chemoreception in non-olfactory systems.

Olfactory receptor Olfr544 responding to azelaic acid regulates glucagon secretion in α-cells of mouse pancreatic islets.

Olfactory receptors (ORs) are extensively expressed in olfactory as well as non-olfactory tissues. Although many OR transcripts are expressed in non-olfactory tissues, only a few studies demonstrate the functional role of ORs. Here, we verified that mouse pancreatic α-cells express potential OR-mediated downstream effectors. Moreover, high levels of mRNA for the olfactory receptors Olfr543, Olfr544, Olfr545, and Olfr1349 were expressed in α-cells as assessed using RNA-sequencing, microarray, and quantitative real-time RT-PCR analyses. Treatment with dicarboxylic acids (azelaic acid and sebacic acid) increased intracellular Ca(2+) mobilization in pancreatic α-cells. The azelaic acid-induced Ca(2+) response as well as glucagon secretion was concentration- and time-dependent manner. Olfr544 was expressed in α-cells, and the EC50 value of azelaic acid to Olfr544 was 19.97 μM, whereas Olfr545 did not respond to azelaic acid. Our findings demonstrate that Olfr544 responds to azelaic acid to regulate glucagon secretion through Ca(2+) mobilization in α-cells of the mouse pancreatic islets, suggesting that Olfr544 may be an important therapeutic target for metabolic diseases.

The Effects of High Fat Diet and Resveratrol on Mitochondrial Activity of Brown Adipocytes

Background Resveratrol (RSV) is a polyphenolic phytoalexin that has many effects on metabolic diseases such as diabetes and obesity. Given the importance of brown adipose tissue (BAT) for energy expenditure, we investigated the effects of RSV on brown adipocytes. Methods For the in vitro study, interscapular BAT was isolated from 7-week-old male Sprague Dawley rats. For the in vivo study, 7-week-old male Otsuka Long Evans Tokushima Fatty (OLETF) rats were divided into four groups and treated for 27 weeks with: standard diet (SD); SD+RSV (10 mg/kg body weight, daily); high fat diet (HFD); HFD+RSV. RSV was provided via oral gavage once daily during the in vivo experiments. Results RSV treatment of primary cultured brown preadipocytes promoted mitochondrial activity, along with over-expression of estrogen receptor α (ER-α). In OLETF rats, both HFD and RSV treatment increased the weight of BAT and the differentiation of BAT. However, only RSV increased the mitochondrial activity and ER-α expression of BAT in the HFD-fed group. Finally, RSV improved the insulin sensitivity of OLETF rats by increasing the mitochondrial activity of BAT, despite having no effects on white adipocytes and muscles in either diet group. Conclusion RSV could improve insulin resistance, which might be associated with mitochondrial activity of brown adipocyte. Further studies evaluating the activity of RSV for both the differentiation and mitochondrial activity of BAT could be helpful in investigating the effects of RSV on metabolic parameters.

Surgical and Endocrinological Outcomes in the Treatment of Growth Hormone-Secreting Pituitary Adenomas According to the Shift of Surgical Paradigm

BACKGROUND: Extensive data exist regarding the success rates and long-term outcomes of transsphenoidal adenomectomy (TSA) of growth hormone (GH)-secreting pituitary tumors; however, few data exist regarding the extent of adenomectomy. OBJECTIVE: To evaluate surgical outcomes for the treatment of GH-secreting pituitary adenomas with regard to the extent of adenomectomy. METHODS: A retrospective study of 282 patients with GH-secreting pituitary tumors who underwent TSA. Three surgical paradigms (1, 2, and 3) were applied, all of which differed in extent of adenomectomy. All participants were evaluated with oral glucose tolerance tests (OGTTs) at 6-month intervals for 1.5 years and combined pituitary function tests at 1.5-year intervals after TSA. All surgeries were conducted by a single neurosurgeon at a single medical center. Biochemical remission was defined with insulinlike growth factor 1 and OGTT results. RESULTS: The overall surgical remission rates were 89%, 87%, 64%, 70%, and 50% (nadir GH <1 ng/mL on OGTTs: 96%, 95%, 73%, 84%, and 56%) for modified Hardy classifications I, II, IIIA, IIIB, and IV, respectively. The remission rates for modified Hardy classification I-IIIB improved to 42%, 68%, and 84% after application of surgical paradigms 1, 2, and 3, respectively (P = .002). Aggressive surgical resection did not worsen hypopituitarism. Among the 42 patients with modified Hardy classification IV, 24 (57%) achieved remission without recurrence after applying the aggressive paradigm 3 surgery. CONCLUSION: An aggressive surgical approach may be critical to managing GH-secreting pituitary adenomas and does not increase the risk of postoperative hypopituitarism. ABBREVIATIONS: ACTH, corticotropin CPFT, combined pituitary function test CV, coefficient of variation GH, growth hormone OGTT, oral glucose tolerance test PRL, prolactin TSA, transsphenoidal adenomectomy TSH, thyroid-stimulating hormone

Clinical predictors of GH deficiency in surgically cured acromegalic patients

OBJECTIVE Even in patients with cured acromegaly, GH deficiency (GHD) after transsphenoidal adenomectomy (TSA) adversely affects body composition and inflammatory biomarkers of cardiovascular risk. In this study, clinical parameters for predicting GHD after TSA in 123 cured acromegalic patients were investigated. DESIGN AND METHODS GH levels were measured at 6, 12, 18, 24, 48, and 72 h after TSA and serial insulin tolerance tests were conducted at 6 months, 2 years, and then every 2 years after TSA. RESULTS GHD was found in 12 patients (9.8%) at 4.1 (range: 0.5-4.1) years after TSA. IGF1 levels were significantly lower at 6 months after TSA in GHD group than intact GH group (175.9 vs 316.8 μg/l, range: 32.0-425.0 and 96.9-547.3 respectively, P=0.008). Adenomas involving both sides of the pituitary gland were significantly more frequent in GHD patients (29.7 vs 83.3%; P=0.002). Furthermore, immediate postoperative 72-h GH levels after TSA were significantly lower (0.17 vs 0.45, range: 0.02-0.93 and 0.02-5.95 respectively, P=0.019) in GHD patients. In multiple logistic regression analysis, bilaterality of tumor involvement (odds ratio (OR)=10.678, P=0.003; 95% CI=2.248-50.728) and immediate postoperative 72-h GH level (OR=0.079, P=0.047; 95% CI=0.006-0.967) showed significant power for predicting GHD. CONCLUSIONS These data suggest that bilateral involvement of a pituitary adenoma and severely decreased immediate postoperative serum GH levels at 72 h after TSA may be independent risks factor for accelerated GHD in acromegalic patients.

Characteristics of Acromegaly in Korea with a Literature Review

Acromegaly is a slowly progressive disease caused by excessive growth hormone (GH), which is related to a GH secreting pituitary tumor in most cases. Herein, we describe the epidemiology, clinical characteristics, and treatment of acromegaly in Korea with a literature review. The average annual incidence of acromegaly in Korea was 3.9 cases per million people, which was within the range of previous Western studies. The primary treatment for acromegaly was also transsphenoidal adenomectomy, which accounted for 90.4% of patients whose primary therapeutic options were known. The overall surgical remission rates were 89%, 87%, 64%, 70%, and 50% for modified Hardy classification I, II, IIIA, IIIB, and IV, respectively. An updated and larger study regarding the treatment outcome of medical/radiotherapy in Korean acromegalic patients is needed.

GLI1 Transcription Factor Affects Tumor Aggressiveness in Patients With Papillary Thyroid Cancers

Abstract A significant proportion of patients with papillary thyroid cancer (PTC) present with extrathyroidal extension (ETE) and lymph node metastasis (LNM). However, the molecular mechanism of tumor invasiveness in PTC remains to be elucidated. The aim of this study is to understand the role of Hedgehog (Hh) signaling in tumor aggressiveness in patients with PTC. Subjects were patients who underwent thyroidectomy from 2012 to 2013 in a single institution. Frozen or paraffin-embedded tumor tissues with contralateral-matched normal thyroid tissues were collected. Hh signaling activity was analyzed by quantitative RT-PCR (qRT-PCR) and immunohistochemical (IHC) staining. Datasets from Gene Expression Omnibus (GEO) (National Center for Biotechnology Information) were subjected to Gene Set Enrichment Analysis (GSEA). BRAFT1799A and telomerase reverse transcriptase promoter mutation C228T were analyzed by direct sequencing. Among 137 patients with PTC, glioma-associated oncogene homolog 1 (GLI1) group III (patients in whom the ratio of GLI1 messenger ribonucleic acid (mRNA) level in tumor tissue to GLI1 mRNA level in matched normal tissue was in the upper third of the subject population) had elevated risk for ETE (odds ratio [OR] 4.381, 95% confidence interval [CI] 1.414–13.569, P = 0.01) and LNM (OR 5.627, 95% CI 1.674–18.913, P = 0.005). Glioma-associated oncogene homolog 2 (GLI2) group III also had elevated risk for ETE (OR 4.152, 95% CI 1.292–13.342, P = 0.017) and LNM (OR 3.924, 95% CI 1.097–14.042, P = 0.036). GSEA suggested that higher GLI1 expression is associated with expression of the KEGG gene set related to axon guidance (P = 0.031, false discovery rate < 0.05), as verified by qRT-PCR and IHC staining in our subjects. GLI1 and GLI2 expressions were clearly related to aggressive clinicopathological features and aberrant activation of GLI1 involved in the axon guidance pathway. These results may contribute to development of new prognostic markers, as well as novel therapeutic targets.

Association between low-grade albuminuria and cardiovascular risk in Korean adults: the 2011-2012 Korea National Health and Nutrition Examination Survey.

Background Recent studies have indicated that low UACR levels (<30 μg/mg) previously considered to be in the normal range (‘low-grade albuminuria’) are associated with cardiovascular morbidity and mortality in the general population. Methods We studied 9,736 participants with albuminuria in the normal range from the 2011–2012 Korea National Health and Nutrition Examination Survey (KNHANES). Results The weighted prevalences of metabolic syndrome (MS) and the 10-year risk for coronary heart disease measured using the Framingham risk score (FRS) ≥ 20% (high risk) were 22.5 ± 0.7% and 14.5 ± 0.7%, respectively, in males and 23.3 ± 0.8% and 8.5 ± 0.4%, respectively in females. Weighted comparisons among the tertiles of UACR revealed that the prevalences of MS and high-risk FRS increased with increasing UACR (MS: males, 15.9 ± 1.1, 20.2 ± 1.2, 32.4 ± 1.5%, respectively; P < 0.001; and females, 17.6 ± 1.0, 22.7 ± 1.0, 30.2 ± 1.4%, respectively; P < 0.001. High-risk FRS: males, 9.5 ± 0.7, 12.3 ± 0.9, 22.5 ± 1.2, respectively; P < 0.001; and females, 5.8 ± 0.6, 7.9 ± 0.7, 12.0 ± 0.9%, respectively; P < 0.001). The positive association persisted after adjusting for hypertension and diabetes. The weighted comparisons among the deciles of UACR revealed that the prevalences of MS and high-risk FRS began to increase at the ranges of 3.89–5.15 and 5.16–7.36 mg/g Cr, respectively. Conclusion Low-grade albuminuria was significantly associated with estimated cardiovascular risk and MS in a nationally representative sample of Koreans.

A Metabolic Phenotype Based on Mitochondrial Ribosomal Protein Expression as a Predictor of Lymph Node Metastasis in Papillary Thyroid Carcinoma

Abstract Metabolic reprogramming has been regarded as an essential component of malignant transformation. However, the clinical significance of metabolic heterogeneity remains poorly characterized. The aim of this study was to characterize metabolic heterogeneity in thyroid cancers via the analysis of the expression of mitochondrial ribosomal proteins (MRPs) and genes involved in oxidative phosphorylation (OxPhos), and investigate potential prognostic correlations. Gene set enrichment analysis (GSEA) verified by reverse transcription polymerase chain reaction and gene network analysis was performed using public repository data. Cross-sectional observational study was conducted to classify papillary thyroid cancer (PTC) by the expression of MRP L44 (MRPL44) messenger RNA (mRNA), and to investigate the clinicopathological features. GSEA clearly showed that the expression of OxPhos and MRP gene sets was significantly lower in primary thyroid cancer than in matched normal thyroid tissue. However, 8 of 49 primary thyroid tumors (16.3%) in the public repository did not show a reduction in OxPhos mRNA expression. Remarkably, strong positive correlations between MRPL44 expression and those of OxPhos and MRPs such as reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) 1 &agr; subcomplex, 5; succinate dehydrogenase complex, subunit D; cytochrome c, somatic; adenosine triphosphate synthase, H+ transporting, mitochondrial Fo complex, subunit C1 (subunit 9); and MRP S5 (MRPS5) (P < 0.0001) were clearly denoted, suggesting that MRPL44 is a representative marker of OxPhos and MRP expressions. In laboratory experiments, metabolic heterogeneity in oxygen consumption, extracellular acidification rates (ECARs), and amounts of OxPhos complexes were consistently observed in BCPAP, TPC1, HTH-7, and XTC.UC1 cell lines. In PTCs, metabolic phenotype according to OxPhos amount defined by expression of MRPL44 mRNA was significantly related to lymph node metastasis (LNM) (P < 0.001). Furthermore, multivariate analysis clearly indicated that expression of MRPL44 is associated with an increased risk of lateral neck LNM (odds ratio 9.267, 95% confidence interval 1.852–46.371, P = 0.007). MRPL44 expression may be a representative marker of metabolic phenotype according to OxPhos amount and a useful predictor of LNM.