John Hoon Rim

A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion.

SLC30A8 encodes the β-cell-specific zinc transporter-8 (ZnT-8) expressed in insulin secretory granules. The single-nucleotide polymorphism rs13266634 of SLC30A8 is associated with susceptibility to post-transplantation diabetes mellitus (PTDM). We tested the hypothesis that the polymorphic residue at position 325 of ZnT-8 determines the susceptibility to cyclosporin A (CsA) suppression of insulin secretion. INS (insulinoma)-1E cells expressing the W325 variant showed enhanced glucose-stimulated insulin secretion (GSIS) and were less sensitive to CsA suppression of GSIS. A reduced number of insulin granule fusion events accompanied the decrease in insulin secretion in CsA-treated cells expressing ZnT-8 R325; however, ZnT-8 W325-expressing cells exhibited resistance to the dampening of insulin granule fusion by CsA, and transported zinc ions into secretory vesicles more efficiently. Both tacrolimus and rapamycin caused similar suppression of GSIS in cells expressing ZnT-8 R325. However, cells expressing ZnT-8 W325 were resistant to tacrolimus, but not to rapamycin. The Downs syndrome candidate region-1 (DSCR1), an endogenous calcineurin inhibitor, overexpression and subsequent calcineurin inhibition significantly reduced GSIS in cells expressing the R325 but not the W325 variant, suggesting that differing susceptibility to CsA may be due to different interactions with calcineurin. These data suggest that the ZnT-8 W325 variant is protective against CsA-induced suppression of insulin secretion. Tolerance of ZnT-8 W325 to calcineurin activity may account for its protective effect in PTDM.

Insufficient Discriminatory Power of Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry Dendrograms to Determine the Clonality of Multi-Drug-Resistant Acinetobacter baumannii Isolates from an Intensive Care Unit

While pulsed-field gel electrophoresis (PFGE) is recognized as the gold standard method for clonality analysis, MALDI-TOF MS has recently been spotlighted as an alternative tool for species identification. Herein, we compared the dendrograms of multi-drug-resistant (MDR) Acinetobacter baumannii isolates by using MALDI-TOF MS with those by using PFGE. We used direct colony and protein extraction methods for MALDI-TOF MS dendrograms. The isolates with identical PFGE patterns were grouped into different branches in MALDI-TOF MS dendrograms. Among the isolates that were classified as very close isolates in MALDI-TOF MS dendrogram, PFGE band patterns visually showed complete differences. We numeralized similarity among isolates by measuring distance levels. The Spearman rank correlation coefficient values were 0.449 and 0.297 between MALDI-TOF MS dendrogram using direct colony and protein extraction method versus PFGE, respectively. This study is the first paper focusing solely on the dendrogram function of MALDI-TOF MS compared with PFGE. Although MALDI-TOF MS is a promising tool to identify species in a rapid manner, our results showed that MALDI-TOF MS dendrograms could not substitute PFGE for MDR Acinetobacter baumannii clonality analysis.

Comparison of Six Automated Treponema-Specific Antibody Assays

ABSTRACT Six different Treponema (TP)-specific immunoassays were compared to the fluorescent treponemal antibody absorption (FTA-ABS) test. A total of 615 samples were tested. The overall percent agreement, analytical sensitivity, and analytical specificity of each assay compared to the FTA-ABS test were as follows: Architect Syphilis TP, 99.2%, 96.8%, and 100%; Cobas Syphilis, 99.8%, 99.4%, and 100%; ADVIA Centaur Syphilis, 99.8%, 99.4%, and 100%; HISCL Anti-TP assay kit, 99.7%, 98.7%, and 100%; Immunoticles Auto3 TP, 99.0%, 97.5%, and 99.6%; Mediace TPLA, 98.0%, 98.1%, and 98.0%. All results that were discrepant between the TP-specific assays were associated with samples from noninfectious cases (11 immunoassay false positives and 7 from previous syphilis cases). Our study demonstrated that TP-specific immunoassays generally showed high sensitivities, specificities, and percentages of agreement compared to FTA-ABS, with rare cases of false-positive or false-negative results. Therefore, most TP-specific immunoassays are acceptable for use in screening for syphilis. However, it is important to perform a thorough review of a patients clinical and treatment history for interpreting the results of syphilis serology.

Comparison and Validation of 10 Equations Including a Novel Method for Estimation of LDL-cholesterol in a 168,212 Asian Population.

AbstractLow-density lipoprotein cholesterol (LDL-C) is frequently estimated using the empirical Friedewald equation. We compared the accuracy of the novel equation named as the 180-cell method (180-c), which estimates LDL-C using a stratification approach, to those of 9 previously suggested formulas, including the Friedewald equation.We compared the accuracy of 10 equations by calculating intraclass correlation coefficient (ICC) and weighted kappa index in relation to direct LDL-C measurement values. Two independent populations used in the validation were the Severance Hospital LDL-C (SHL) registry (n = 164,358) and the Korea National Health and Nutrition Examination Survey (KNHANES) 2009 to 2010 (n = 3,854), each representing the hospital patient population and the general Korean population, respectively.The 180-c and DeLong equations showed the highest ICCs, indicating the best agreement with direct LDL-C measurement. The 180-c and Chen equations showed the highest kappa indices. For the hypertriglyceridemic subpopulation from SHL, the 180-c equation showed the best agreement with direct LDL-C measurement in terms of ICC.We compared the novel 180-c method for LDL-C estimation with 9 previous formulas in a non-US population as the first external validation. The 180-c equation, with Chen equation, appeared to be more accurate than the Friedewald equation. Although the DeLong equation showed better performance in the hypertriglyceridemic subpopulation, the 180-c equation performed appropriately in Asian population.

Increase of Clostridium difficile in Community; Another Worrisome Burden for Public Health

Background: Increasing rates of Clostridium difficile infection (CDI) have been reported mainly in Europe and North America; however, only limited reports have originated in Korea. The current epidemiology of CDI in the community could help to understand the outpatient healthcare environment and to extend infection control measures to outpatient settings. Methods: C. difficile isolates in NHIS Ilsan Hospital from 2012 to 2014 were included in this study. Clinical characteristics, acquisition types, and previous antimicrobial therapy were obtained via Electronic Medical Records. C. difficile culture was performed only in unformed stool. Toxin was positive by enzyme-linked fluorescent immunoassay (ELFA) in 247 specimens. In addition, toxin B and binary toxin gene were detected by PCR in 57 specimens. CDI was defined by toxigenic C. difficile isolation in unformed stool. Results: In the previous 3 years, 251 unduplicated C. difficile cases have been detected; 168 healthcare facility-associated hospital onset (HCFA-HO), 45 healthcare facility-associated community onset (HCFA-CO), and 38 community-associated (CA). Toxin positive rates by ELFA for toxin AB19:7-12)

Accuracy of Next-Generation Sequencing for Molecular Diagnosis in Patients With Infantile Nystagmus Syndrome

Importance Infantile nystagmus syndrome (INS) is a group of disorders presenting with genetic and clinical heterogeneities that have challenged the genetic and clinical diagnoses of INS. Precise molecular diagnosis in early infancy may result in more accurate genetic counseling and improved patient management. Objective To assess the accuracy of genomic data from next-generation sequencing (NGS) and phenotypic data to enhance the definitive diagnosis of INS. Design, Setting, and Participants A single-center retrospective case series was conducted in 48 unrelated, consecutive patients with INS, with or without associated ocular or systemic conditions, who underwent genetic testing between June 1, 2015, and January 31, 2017. Next-generation sequencing analysis was performed using a target panel that included 113 genes associated with INS (n = 47) or a TruSight One sequencing panel that included 4813 genes associated with known human phenotypes (n = 1). Variants were filtered and prioritized by in-depth clinical review, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Patients underwent a detailed ophthalmic examination, including electroretinography and optical coherence tomography, if feasible. Main Outcomes and Measures Diagnostic yield of targeted NGS testing. Results Among the 48 patients (21 female and 27 male; mean [SD] age at genetic testing, 9.2 [10.3] years), 8 had a family history of nystagmus and 40 were simplex. All patients were of a single ethnicity (Korean). Genetic variants that were highly likely to be causative were identified in 28 of the 48 patients, corresponding to a molecular diagnostic yield of 58.3% (95% CI, 44.4%-72.2%). FRMD7, GPR143, and PAX6 mutations appeared to be the major genetic causes of familial INS. A total of 10 patients (21%) were reclassified to a different diagnosis based on results of NGS testing, enabling accurate clinical management. Conclusions and Relevance These findings suggest that NGS is an accurate diagnostic tool to differentiate causes of INS because diagnostic tests, such as electroretinography and optical coherence tomography, are not easily applicable in young infants. Accurate application of NGS using a standardized, stepwise, team-based approach in early childhood not only facilitated early molecular diagnosis but also led to improved personalized management in patients with INS.

Association of hemoglobin levels with blood pressure and hypertension in a large population-based study: the Korea National Health and Nutrition Examination Surveys 2008–2011

BACKGROUND We investigated the association of hemoglobin (Hb) concentrations with blood pressure (BP) and hypertension in the full range of Hb concentrations, after adjusting for other hypertension risk factors. METHODS The study population consisted of a total of 20,076 subjects (8721 men, 11,355 women) aged ≥20 y who participated in the Korea National Health and Nutrition Examination Surveys conducted between 2008 and 2011. RESULTS The systolic BP (SBP) and diastolic BP (DBP) increased by 2.6mmHg and 3.2mmHg with 1mmol/l increase in the Hb concentration, respectively, after adjusting for age, body mass index, total cholesterol, alcohol drinking, current smoking, mild renal dysfunction, and diabetes mellitus both in men with Hb concentrations of ≥8.1mmol/l (13.0g/dl) and women with a hemoglobin concentration ≥6.8mmol/l (11.0g/dl). In the multiple logistic regression analysis, the Hb concentration showed significant positive association with hypertension independently of other confounding factors both in men and women. CONCLUSIONS Hb concentration was positively associated with SBP and DBP in men with Hb concentrations ≥8.1mmol/l (13.0g/dl) and women with Hb concentrations ≥6.8mmol/l (11.0g/dl) in the general Korean population.

ZMYND10 stabilizes intermediate chain proteins in the cytoplasmic pre-assembly of dynein arms

Zinc finger MYND-type-containing 10 (ZMYND10), a cytoplasmic protein expressed in ciliated cells, causes primary ciliary dyskinesia (PCD) when mutated; however, its function is poorly understood. Therefore, in this study, we examined the roles of ZMYND10 using Zmynd10–/–mice exhibiting typical PCD phenotypes, including hydrocephalus and laterality defects. In these mutants, morphology, the number of motile cilia, and the 9+2 axoneme structure were normal; however, inner and outer dynein arms (IDA and ODA, respectively) were absent. ZMYND10 interacted with ODA components and proteins, including LRRC6, DYX1C1, and C21ORF59, implicated in the cytoplasmic pre-assembly of DAs, whose levels were significantly reduced in Zmynd10–/–mice. LRRC6 and DNAI1 were more stable when co-expressed with ZYMND10 than when expressed alone. DNAI2, which did not interact with ZMYND10, was not stabilized by co-expression with ZMYND10 alone, but was stabilized by co-expression with DNAI1 and ZMYND10, suggesting that ZMYND10 stabilized DNAI1, which subsequently stabilized DNAI2. Together, these results demonstrated that ZMYND10 regulated the early stage of DA cytoplasmic pre-assembly by stabilizing DNAI1.

Central obesity is an independent risk factor for microalbuminuria in both the general Korean women and nondiabetic nonhypertensive subpopulation: Association of microalbuminuria and metabolic syndrome from the Korea National Health and Nutrition Examination Survey 2011-2012

BACKGROUND We investigated the major contributing component of metabolic syndrome (MetS) that results in microalbuminuria (MAU) in the general population as well as in nondiabetic nonhypertensive subjects. METHODS The study population consisted of a total of 9961 subjects (4429 men and 5532 women) who participated in the Korea National Health and Nutrition Examination Surveys conducted in 2011 and 2012. MAU was defined as a urine albumin-to-creatinine ratio of >3.39mg/mmol. After analyzing the contribution of each five MetS components for the presence of MAU with adjustment for other risk factors in the total population, we further examined the contribution of these components to MAU in the nondiabetic nonhypertensive subpopulation. RESULTS The most significantly associated factors for MAU in both genders were high blood pressure, followed by impaired fasting glucose, and high triglycerides. In addition, central obesity contributed significantly to MAU only in women. For the nondiabetic nonhypertensive subpopulation, high blood pressure in both genders and central obesity in women were important risk factors for MAU. We suggest two possible hypotheses for the gender different phenomenon. CONCLUSIONS Central obesity was an independent risk factor for MAU in the general Korean women as well as in the nondiabetic nonhypertensive women.

Effects of two types of medical contrast media on routine chemistry results by three automated chemistry analyzers

OBJECTIVES The use of iodinated contrast media has grown in popularity in the past two decades, but relatively little attention has been paid to the possible interferential effects of contrast media on laboratory test results. Herein, we investigate medical contrast media interference with routine chemistry results obtained by three automated chemistry analyzers. METHODS Ten levels of pooled serum were used in the study. Two types of medical contrast media [Iopamiro (iopamidol) and Omnipaque (iohexol)] were evaluated. To evaluate the dose-dependent effects of the contrast media, iopamidol and iohexol were spiked separately into aliquots of serum for final concentrations of 1.8%, 3.6%, 5.5%, 7.3%, and 9.1%. The 28 analytes included in the routine chemistry panel were measured by using Hitachi 7600, AU5800, and Cobas c702 analyzers. We calculated the delta percentage difference (DPD) between the samples and the control, and examined dose-dependent trends. RESULTS When the mean DPD values were compared with the reference cut-off criteria, the only uniformly interferential effect observed for all analyzers was in total protein with iopamidol. Two additional analytes that showed trends toward interferential effects only in few analyzers and exceeded the limits of the allowable error were the serum iron and the total CO2. The other combinations of analyzer and contrast showed no consistent dose-dependent propensity for change in any analyte level. CONCLUSIONS Our study suggests that many of the analytes included in routine chemistry results, except total protein and serum iron, are not significantly affected by iopamidol and iohexol. These results suggest that it would be beneficial to apply a flexible medical evaluation process for patients requiring both laboratory tests and imaging studies, minimizing the need for strict regulations for sequential tests.