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2.  Increased intestinal macromolecular permeability and urine nitrite excretion associated with liver cirrhosis with ascites 
AIM: To determine intestinal permeability, the serum tumor necrosis factor (TNF)-α level and urine nitric oxide (NO) metabolites are altered in liver cirrhosis (LC) with or without ascites.
METHODS: Fifty-three patients with LC and 26 healthy control subjects were enrolled in the study. The intestinal permeability value is expressed as the percentage of polyethylene glycol (PEG) 400 and 3350 retrieval in 8-h urine samples as determined by high performance liquid chromatography. Serum TNF-α concentrations and urine NO metabolites were determined using an enzyme-linked immunosorbent assay (ELISA) and Greiss reaction method, respectively.
RESULTS: The intestinal permeability index was significantly higher in patients with LC with ascites than in healthy control subjects or patients with LC without ascites (0.88 ± 0.12 vs 0.52 ± 0.05 or 0.53 ± 0.03, P < 0.05) and correlated with urine nitrite excretion (r = 0.98). Interestingly, the serum TNF-α concentra-tion was significantly higher in LC without ascites than in control subjects or in LC with ascites (198.9 ± 55.8 pg/mL vs 40.9 ± 12.3 pg/mL or 32.1 ± 13.3 pg/mL, P < 0.05). Urine nitrite excretion was significantly higher in LC with ascites than in the control subjects or in LC without ascites (1170.9 ± 28.7 μmol/L vs 903.1 ± 55.1 μmol/L or 956.7 ± 47.7 μmol/L, P < 0.05).
CONCLUSION: Increased intestinal macromolecular permeability and NO is probably of importance in the pathophysiology and progression of LC with ascites, but the serum TNF-α concentration was not related to LC with ascites.
doi:10.3748/wjg.14.3884
PMCID: PMC2721447  PMID: 18609714
Intestinal permeability; Tumor necrosis factor-α; Nitric oxide; Liver cirrhosis; Ascites
3.  Mitochondrial DNA Aberrations and Pathophysiological Implications in Hematopoietic Diseases, Chronic Inflammatory Diseases, and Cancers 
Annals of Laboratory Medicine  2014;35(1):1-14.
Mitochondria are important intracellular organelles that produce energy for cellular development, differentiation, and growth. Mitochondrial DNA (mtDNA) presents a 10- to 20-fold higher susceptibility to genetic mutations owing to the lack of introns and histone proteins. The mtDNA repair system is relatively inefficient, rendering it vulnerable to reactive oxygen species (ROS) produced during ATP synthesis within the mitochondria, which can then target the mtDNA. Under conditions of chronic inflammation and excess stress, increased ROS production can overwhelm the antioxidant system, resulting in mtDNA damage. This paper reviews recent literature describing the pathophysiological implications of oxidative stress, mitochondrial dysfunction, and mitochondrial genome aberrations in aging hematopoietic stem cells, bone marrow failure syndromes, hematological malignancies, solid organ cancers, chronic inflammatory diseases, and other diseases caused by exposure to environmental hazards.
doi:10.3343/alm.2015.35.1.1
PMCID: PMC4272938  PMID: 25553274
mtDNA; Aberrations; Diseases
4.  Alteration of the SETBP1 Gene and Splicing Pathway Genes SF3B1, U2AF1, and SRSF2 in Childhood Acute Myeloid Leukemia 
Annals of Laboratory Medicine  2014;35(1):118-122.
Background
Recurrent somatic SET-binding protein 1 (SETBP1) and splicing pathway gene mutations have recently been found in atypical chronic myeloid leukemia and other hematologic malignancies. These mutations have been comprehensively analyzed in adult AML, but not in childhood AML. We investigated possible alteration of the SETBP1, splicing factor 3B subunit 1 (SF3B1), U2 small nuclear RNA auxiliary factor 1 (U2AF1), and serine/arginine-rich splicing factor 2 (SRSF2) genes in childhood AML.
Methods
Cytogenetic and molecular analyses were performed to reveal chromosomal and genetic alterations. Sequence alterations in the SETBP1, SF3B1, U2AF1, and SRSF2 genes were examined by using direct sequencing in a cohort of 53 childhood AML patients.
Results
Childhood AML patients did not harbor any recurrent SETBP1 gene mutations, although our study did identify a synonymous mutation in one patient. None of the previously reported aberrations in the mutational hotspot of SF3B1, U2AF1, and SRSF2 were identified in any of the 53 patients.
Conclusions
Alterations of the SETBP1 gene or SF3B1, U2AF1, and SRSF2 genes are not common genetic events in childhood AML, implying that the mutations are unlikely to exert a driver effect in myeloid leukemogenesis during childhood.
doi:10.3343/alm.2015.35.1.118
PMCID: PMC4272941  PMID: 25553291
SETBP1; SF3B1; U2AF1; SRSF2; AML; Childhood
6.  Profiling of Biomarkers for the Exposure of Polycyclic Aromatic Hydrocarbons: Lamin-A/C Isoform 3, Poly[ADP-ribose] Polymerase 1, and Mitochondria Copy Number Are Identified as Universal Biomarkers 
BioMed Research International  2014;2014:605135.
This study investigated the profiling of polycyclic aromatic hydrocarbon- (PAH-) induced genotoxicity in cell lines and zebrafish. Each type of cells displayed different proportionality of apoptosis. Mitochondrial DNA (mtDNA) copy number was dramatically elevated after 5-day treatment of fluoranthene and pyrene. The notable deregulated proteins for PAHs exposure were displayed as follows: lamin-A/C isoform 3 and annexin A1 for benzopyrene; lamin-A/C isoform 3 and DNA topoisomerase 2-alpha for pentacene; poly[ADP-ribose] polymerase 1 (PARP-1) for fluoranthene; and talin-1 and DNA topoisomerase 2-alpha for pyrene. Among them, lamin-A/C isoform 3 and PARP-1 were further confirmed using mRNA and protein expression study. Obvious morphological abnormalities including curved backbone and cardiomegaly in zebrafish were observed in the 54 hpf with more than 400 nM of benzopyrene. In conclusion, the change of mitochondrial genome (increased mtDNA copy number) was closely associated with PAH exposure in cell lines and mesenchymal stem cells. Lamin-A/C isoform 3, talin-1, and annexin A1 were identified as universal biomarkers for PAHs exposure. Zebrafish, specifically at embryo stage, showed suitable in vivo model for monitoring PAHs exposure to hematopoietic tissue and other organs.
doi:10.1155/2014/605135
PMCID: PMC4121044  PMID: 25114913
7.  Serum Parathyroid Hormone Is a New Potential Risk Factor in Multiple Myeloma 
BioMed Research International  2014;2014:804182.
We hypothesized that serum PTH might be associated with various clinicopathological parameters in multiple myeloma (MM). So we investigated the implications of serum PTH in MM patients and the relationship with other risk factors of MM. A total of 115 patients who were newly diagnosed with MM were enrolled. Serum PTH level was 24.7 ± 34.9 (ranged 0.0–284.1) pg/mL. Serum levels of IgG, IgM, FLC-lambda, albumin, and LDH were in positive correlation with serum PTH. Compared to non-high PTH (<68.3 pg/mL) group, the hazard ratio (HR) for overall survival was higher for group with high PTH level (≥68.3 pg/mL) (HR, 1.710). Furthermore, the patient group with high PTH level showed inferior progression-free survival than non-high PTH group (P = 0.056). Interestingly, subgroup analysis showed that serum PTH level at diagnosis was associated with risk factors and clinical outcome in MM patients, especially in complete remission group, transplantation cases, ISS stage II cases, and cases without chromosome abnormality. In conclusion, this study showed that blood PTH level in MM at diagnosis was associated with risk factors and clinical outcome in MM patients.
doi:10.1155/2014/804182
PMCID: PMC4055219  PMID: 24967406
9.  Spectra of Chromosomal Aberrations in 325 Leukemia Patients and Implications for the Development of New Molecular Detection Systems 
Journal of Korean Medical Science  2011;26(7):886-892.
This study investigated the spectrum of chromosomal abnormalities in 325 leukemia patients and developed optimal profiles of leukemic fusion genes for multiplex RT-PCR. We prospectively analyzed blood and bone marrow specimens of patients with acute leukemia. Twenty types of chromosomal abnormalities were detected in 42% from all patients by commercially available multiplex RT-PCR for detecting 28 fusion genes and in 35% by cytogenetic analysis including FISH analysis. The most common cytogenetic aberrations in acute myeloid leukemia patients was PML/PARA, followed by AML1/MGT8 and MLL1, and in acute lymphoid leukemia patients was BCR/ABL, followed by TEL/AML1 and MLL1 gene rearrangement. Among the negative results for multiplex RT-PCR, clinically significant t(3;3)(q21;q26.2), t(8;14)(q24;q32) and i(17)(q10) were detected by conventional cytogenetics. The spectrum and frequency of chromosomal abnormalities in our leukemia patients are differed from previous studies, and may offer optimal profiles of leukemic fusion genes for the development of new molecular detection systems.
doi:10.3346/jkms.2011.26.7.886
PMCID: PMC3124718  PMID: 21738341
Leukemia; Chromosomal Abnormalities; Molecular Detection System
10.  Plasma proGRP Concentration is Sensitive and Specific for Discriminating Small Cell Lung Cancer from Nonmalignant Conditions or Non-small Cell Lung Cancer 
Journal of Korean Medical Science  2011;26(5):625-630.
To date, most clinical data on pro-gastrin-releasing peptide (proGRP) have been based on serum concentrations. This study evaluated the agreement between proGRP levels in fresh serum and plasma in patients with various lung diseases. Pairs of serum and EDTA plasma were collected from 49 healthy individuals. At the same time, EDTA plasma of 118 lung cancer patients and 23 patients with benign pulmonary diseases were prospectively collected. Compared to serum, plasma proGRP concentrations were higher by an average of 103.3%. Plasma proGRP was higher in malignancy (336.4 ± 925.4 pg/mL) than in benign conditions (40.1 ± 11.5 pg/mL). Small cell lung cancer (SCLC) patients showed higher levels of proGRP (1,256.3 ± 1,605.6 pg/mL) compared to other types of lung cancer. Based on the ROC curve analyses at a specificity of 95%, the diagnostic sensitivity of plasma proGRP was estimated to be 83.8% in distinguishing SCLC from all the other conditions, and 86.5% for discriminating SCLC from the nonmalignant cases. Among the SCLC cases, limited stage disease had lower levels of plasma proGRP than extensive disease. When measuring circulating levels of proGRP, the use of plasma is preferred over serum. Plasma proGRP has a potential marker for discriminating SCLC from nonmalignant conditions or non-small cell lung cancer.
doi:10.3346/jkms.2011.26.5.625
PMCID: PMC3082113  PMID: 21532852
pro-gastrin-releasing peptide (31-98); Serum; Plasma; Small Cell Lung Carcinoma
11.  Mitochondrial DNA Aberrations of Bone Marrow Cells from Patients with Aplastic Anemia 
Journal of Korean Medical Science  2008;23(6):1062-1067.
This study was undertaken primarily to test the hypothesis that mitochondrial DNA (mtDNA) mutations may be associated with aplastic anemia. Complete mtDNA nucleotide sequence was analyzed in nine and eight bone marrow specimens from Korean patients with aplastic anemia and healthy individuals, respectively. We found a large number of polymorphisms as well as apparent new mutations in both patients and controls throughout the entire mtDNA genome; 12 mutations harbored amino acid changes in patients and none of the mutations in controls produced amino acid changes. There were heteroplasmic mutations and more nonsynonymous mtDNA changes observed in patients, so the mean number of mtDNA aberrations of bone marrow cells showed statistically significant difference overall between patients (mean=25.6) and controls (mean=12.8) (p=0.019). Our data may support an association of mtDNA aberrations with aplastic anemia.
doi:10.3346/jkms.2008.23.6.1062
PMCID: PMC2610644  PMID: 19119453
Anemia, Aplastic; DNA, Mitochondrial; Mutation
12.  Evaluation of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry-Based VITEK MS System for the Identification of Acinetobacter Species from Blood Cultures: Comparison with VITEK 2 and MicroScan Systems 
Annals of Laboratory Medicine  2014;35(1):62-68.
Background
Acinetobacter species are the leading cause of bloodstream infection (BSI), but their correct identification is challenging. We evaluated the matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS)-based VITEK MS (bioMérieux, France), and two automated systems, VITEK 2 (bioMérieux) and MicroScan (Siemens, USA) for identification of Acinetobacter BSI isolates.
Methods
A total of 187 BSI isolates recovered at a university hospital in Korea between 2010 and 2012 were analyzed. The identification results obtained using VITEK MS and two automated systems were compared with those of rpoB sequencing.
Results
Of 187 isolates analyzed, 176 were identified to the species level by rpoB sequencing: the Acinetobacter baumannii group (ABG; 101 A. baumannii, 43 A. nosocomialis, 10 A. pittii isolates) was most commonly identified (82.4%), followed by Acinetobacter genomic species 13BJ/14TU (5.3%), A. ursingii (2.1%), A. soli (2.1%), A. bereziniae (1.1%), and A. junii (1.1%). Correct identification rates to the species group (ABG) level or the species level was comparable among the three systems (VITEK MS, 90.3%; VITEK 2, 89.2%; MicroScan, 86.9%). However, VITEK MS generated fewer misidentifications (0.6%) than VITEK 2 (10.8%) and MicroScan (13.1%) (P<0.001). In addition, VITEK MS demonstrated higher specificity (100%) for discrimination between ABG and non-ABG isolates than the other systems (both, 31.8%) (P<0.001).
Conclusions
The VITEK MS system is superior to the VITEK 2 and MicroScan systems for identification of Acinetobacter BSI isolates, with fewer misidentifications and better discrimination between the ABG and non-ABG isolates.
doi:10.3343/alm.2015.35.1.62
PMCID: PMC4272967  PMID: 25553282
VITEK MS; VITEK 2; MicroScan; Acinetobacter; Identification
13.  OCT-1, ABCB1, and ABCG2 Expression in Imatinib-Resistant Chronic Myeloid Leukemia Treated with Dasatinib or Nilotinib 
Chonnam Medical Journal  2014;50(3):102-111.
This study explored drug transporter expression levels and their impact on clinical response to imatinib and second-generation tyrosine kinase inhibitors (TKIs) in imatinib- resistant chronic myeloid leukemia (CML). Imatinib-resistant chronic phase CML patients treated with dasatinib (n=10) and nilotinib (n=12) were enrolled. The mRNA expression of the OCT-1, ABCG2, and ABCB1 genes was quantified by using paired bone marrow samples obtained before administering imatinib and at the point of detecting imatinib resistance (just before starting second-generation TKIs). The expression levels of OCT-1 and ABCG2 were lower in follow-up than in imatinib-naïve samples. ABCB1 revealed highly variable expression levels before and after imatinib treatment. In addition, median ABCB1 expression in follow-up samples was lower in patients achieving complete cytogenetic response or major molecular response during imatinib treatment than in failed patients. Higher ABCG2 expression in imatinib-exposed samples showed a negative impact on optimal response to dasatinib. Patients with higher ABCG2 expression in imatinib-exposed samples also had shorter progression- free survival with dasatinib treatment. However, no significant correlation was found between these drug transporter expression levels in imatinib-naïve or imatinib- exposed samples and responses to nilotinib. In imatinib-resistant CML, OCT-1 and ABCG2 mRNA expression decreased after imatinib treatment. Patients with higher ABCG2 expression in imatinib-exposed samples showed poor treatment outcome with dasatinib. On the other hand, a higher expression level of ABCB1 in imatinib-exposed samples did not affect second-generation TKI responses but was correlated with poor imatinib responses.
doi:10.4068/cmj.2014.50.3.102
PMCID: PMC4276791  PMID: 25568846
ABCB1 protein; ABCG2 protein; Myeloid leukemia; Imatinib
14.  Identification, Genotypic Relation, and Clinical Features of Colistin-Resistant Isolates of Acinetobacter Genomic Species 13BJ/14TU from Bloodstreams of Patients in a University Hospital 
Journal of Clinical Microbiology  2014;52(3):931-939.
Colistin resistance remains rare among clinical isolates of Acinetobacter species. We noted the emergence of colistin-resistant bloodstream isolates of the Acinetobacter genomic species (GS) 13BJ/14TU from patients at a university hospital between 2003 and 2011. We report here, for the first time, the microbiological and molecular characteristics of these isolates, with clinical features of Acinetobacter GS 13BJ/14TU bacteremia. All 11 available patient isolates were correctly identified as Acinetobacter GS 13BJ/14TU using partial rpoB gene sequencing but were misidentified using the phenotypic methods Vitek 2 (mostly as Acinetobacter baumannii), MicroScan (mostly as A. baumannii/Acinetobacter haemolyticus), and the API 20 NE system (all as A. haemolyticus). Most isolates were susceptible to commonly used antibiotics, including carbapenems, but all were resistant to colistin, for which it is unknown whether the resistance is acquired or intrinsic. However, the fact that none of the patients had a history of colistin therapy strongly suggests that Acinetobacter GS 13BJ/14TU is innately resistant to colistin. The phylogenetic tree of multilocus sequence typing (MLST) showed that all 11 isolates formed a separate cluster from other Acinetobacter species and yielded five sequence types. However, pulsed-field gel electrophoresis (PFGE) revealed 11 distinct patterns, suggesting that the bacteremia had occurred sporadically. Four patients showed persistent bacteremia (6 to 17 days), and all 11 patients had excellent outcomes with cleared bacteremia, suggesting that patients with Acinetobacter GS 13BJ/14TU-associated bacteremia show a favorable outcome. These results emphasize the importance of precise species identification, especially regarding colistin resistance in Acinetobacter species. In addition, MLST offers another approach to the identification of Acinetobacter GS 13BJ/14TU, whereas PFGE is useful for genotyping for this species.
doi:10.1128/JCM.02868-13
PMCID: PMC3957785  PMID: 24403305
16.  Accuracy of Species-Level Identification of Yeast Isolates from Blood Cultures from 10 University Hospitals in South Korea by Use of the Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry-Based Vitek MS System 
Journal of Clinical Microbiology  2013;51(9):3063-3065.
We assessed the accuracy of yeast bloodstream isolate identification performed over a 1-year period at 10 South Korean hospitals, using the matrix-assisted laser desorption ionization–time of flight (MALDI-TOF)-based Vitek MS system. The overall phenotypic misidentification rate was 3.4% (18/533), with considerable variation between hospitals (0.0% to 19.0%), compared to 1.1% (6/533) for the Vitek MS system.
doi:10.1128/JCM.00945-13
PMCID: PMC3754637  PMID: 23784123
17.  3′ Splice Site Sequences of Spinal Muscular Atrophy Related SMN2 Pre-mRNA Include Enhancers for Nearby Exons 
The Scientific World Journal  2014;2014:617842.
Spinal muscular atrophy (SMA) is a human genetic disease which occurs because of the deletion or mutation of SMN1 gene. SMN1 gene encodes the SMN protein which plays a key role in spliceosome assembly. Although human patients contain SMN2, a duplicate of SMN1, splicing of SMN2 produces predominantly exon 7 skipped isoform. In order to understand the functions of splice site sequences on exon 7 and 8, we analyzed the effects of conserved splice site sequences on exon 7 skipping of SMN2 and SMN1 pre-mRNA. We show here that conserved 5′ splice site sequence of exon 7 promoted splicing of nearby exons and subsequently reduced splicing of distant exons. However, to our surprise, conserved 3′ splice site sequence of exon 7 and 8 did not promote splicing of nearby exons. By contrast, the mutation inhibited splicing of nearby exons and subsequently promoted splicing of distant exons. Our study shows that 3′ splice sites of exon 7 and 8 contain enhancer for their splice site selection, in addition to providing cleavage sites.
doi:10.1155/2014/617842
PMCID: PMC3925570  PMID: 24616638
18.  Comparison of the Vitek 2, MicroScan, and Etest Methods with the Agar Dilution Method in Assessing Colistin Susceptibility of Bloodstream Isolates of Acinetobacter Species from a Korean University Hospital 
Journal of Clinical Microbiology  2013;51(6):1924-1926.
We evaluated three commercial colistin susceptibility testing methods using 213 bloodstream Acinetobacter isolates identified by gene sequencing. Compared to the agar dilution reference method, excellent categorical agreements (both 99.1%) were observed using Vitek 2 and Etest, compared to 87.3% (95.7% for Acinetobacter baumannii and 80.7% for non-baumannii Acinetobacter isolates) using MicroScan.
doi:10.1128/JCM.00427-13
PMCID: PMC3716055  PMID: 23536402
19.  Ex vivo expansion of canine cytotoxic large granular lymphocytes exhibiting characteristics of natural killer cells 
Canine NK cells still are not well-characterized due to the lack of information concerning specific NK cell markers and the fact that NK cells are not an abundant cell population. In this study, we selectively expanded the canine cytotoxic large granular lymphocytes (CLGLs) that exhibit morphologic, genetic, and functional characteristics of NK cells from normal donor PBMCs. The cultured CLGLs were characterized by a high proportion of CD5(dim) expressing cells, of which the majority of cells co-expressed CD3 and CD8, but did not express TCRαβ and TCRγδ. The phenotype of the majority of the CLGLs was CD5(dim)CD3+CD8+ TCRαβ−TCRγδ−CD4−CD21−CD11c+/−CD11d+/−CD44+. The expression of mRNAs for NK cell-associated receptors (NKG2D, NKp30, NKp44, Ly49, perforin, and granzyme B) were highly upregulated in cultured CLGLs. Specifically, NKp46 was remarkably upregulated in the cultured CLGLs compared to PBMCs. The mRNAs for the NKT-associated iTCRα gene in CLGLs was present at a basal level. The cytotoxic activity of the CLGLs against canine NK cell-sensitive CTAC cells was remarkably elevated in a dose-dependent manner, and the CLGLs produced large amounts of IFN-γ. The antitumor activity of CLGLs extended to different types of canine tumor cells (CF41.Mg and K9TCC-pu-AXC) without specific antigen recognition. These results are consistent with prior reports, and strongly suggest that the selectively expanded CLGLs represent a population of canine NK cells. The results of this study will contribute to future research on canine NK cells as well as NK cell-based immunotherapy.
doi:10.1016/j.vetimm.2013.03.006
PMCID: PMC3769186  PMID: 23548866
Canine; Cytotoxic large granular lymphocytes; NK cells; Expansion; Cytotoxicity
20.  Autoantibodies with Mimicking Specificity Detected by the Dilution Technique in Patients with Warm Autoantibodies 
Annals of Laboratory Medicine  2013;33(5):343-348.
Background
The aim of this study was to investigate the frequency of autoantibodies with mimicking specificity by using the dilution technique, to assess the usefulness of the combination of the dilution technique and red blood cell (RBC) phenotyping, and to establish a pre-transfusion testing algorithm in patients with warm autoantibodies.
Methods
Serum samples from 71 patients with warm autoantibodies were tested using the dilution technique. Among them, 25 samples were adsorbed with allogeneic ZZAP (a combination of dithiothreitol and enzyme) or polyethylene glycol (PEG) and their RBC phenotypes were determined. Thirty-nine patients were transfused with our pre-transfusion testing algorithm using a combination of dilution technique and RBC phenotyping.
Results
Autoantibodies with mimicking specificity were detected by the dilution technique in 26.8% (19/71) of the patients and most of them were directed against Rh system antigens. The agreement of the results obtained with the dilution technique in combination with RBC phenotyping and those from ZZAP or PEG adsorption was 100% (18/18) in patients who have autoantibodies with mimicking specificity and/or alloantibodies. No clinical symptoms indicating severe acute or delayed hemolytic transfusion reactions were reported in the 39 patients transfused with our pre-transfusion testing algorithm.
Conclusions
Autoantibodies with mimicking specificity detected by the dilution technique in patients with warm autoantibodies are relatively frequent, can be discriminated from alloantibodies by employing a combination of dilution technique and RBC phenotyping, and might not appear to cause severe acute or delayed hemolytic transfusion reactions.
doi:10.3343/alm.2013.33.5.343
PMCID: PMC3756238  PMID: 24003424
Autoantibody; Dilution technique; Mimicking specificity
21.  In Vitro Fluconazole and Voriconazole Susceptibilities of Candida Bloodstream Isolates in Korea: Use of the CLSI and EUCAST Epidemiological Cutoff Values 
Annals of Laboratory Medicine  2013;33(3):167-173.
Background
At present, the clinical breakpoints (CBPs) of both fluconazole and voriconazole are available only for 3 common Candida species in the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) methods. Epidemiological cutoff values (ECVs) were recently applied to both methods to detect the emergence of acquired resistance (i.e., non-wild-type isolates) among 5 common Candida species.
Methods
We performed a nationwide study to determine the fluconazole and voriconazole susceptibility of Candida bloodstream isolates (BSIs) using both the CLSI and EUCAST methods. A total of 423 BSIs of 5 Candida species were collected from 8 hospitals. The azole susceptibilities were assessed on the basis of the species-specific CBPs and ECVs.
Results
Of the 341 BSIs of 3 common Candida species (i.e., C. albicans, C. tropicalis, and C. parapsilosis), 0.3% and 0.9%, 0.0% and 1.5% of isolates were categorized as fluconazole and voriconazole resistant according to the CLSI and EUCAST CBPs, respectively. Of 423 total BSIs, 1.4% and 2.6% had fluconazole minimum inhibitory concentrations (MICs) exceeding the ECVs according to the CLSI and EUCAST, respectively; 1.0% and 2.1% had voriconazole MICs exceeding the ECVs according to the CLSI and EUCAST, respectively. Categorical agreement between the methods using ECVs was 98.3% for fluconazole and 98.3% for voriconazole.
Conclusions
The EUCAST and CLSI methods using ECVs provide highly concordant results. Moreover, non-wild-type isolates with possibly acquired azole resistance were rare among the BSIs of 5 common Candida species in Korea.
doi:10.3343/alm.2013.33.3.167
PMCID: PMC3646190  PMID: 23667842
Candida; Fluconazole; Voriconazole; EUCAST; CLSI; epidemiological cutoff value
22.  Allelic Expression Imbalance of JAK2 V617F Mutation in BCR-ABL Negative Myeloproliferative Neoplasms 
PLoS ONE  2013;8(1):e52518.
The discovery of a single point mutation in the JAK2 gene in patients with BCR/ABL-negative myeloproliferative neoplasms (MPNs) has not only brought new insights and pathogenesis, but also has made the diagnosis of MPNs much easier. Although, to date, several mechanisms for the contribution of single JAK2V617F point mutation to phenotypic diversity of MPNs have been suggested in multiple studies, but it is not clear how a unique mutation can cause the phenotypic diversity of MPNs. In this study, our results show that allelic expression imbalance of JAK2 V617F mutant frequently occurs and contributes to phenotypic diversity of BCR-ABL-negative MPNs. The proportion of JAK2 V617F mutant allele was significantly augmented in RNA levels as compared with genomic DNA differently by distinct MPNs subtypes. In detail, preferential expression of JAK2 mutant allele showed threefold increase from the cDNA compared with the genomic DNA from patients with essential thrombocythemia and twofold increase in polycythemia vera. In conclusion, allelic expression imbalance of JAK2 V617F mutant proposes another plausible mechanism for the contribution of single JAK2 point mutation to phenotypic diversity of MPNs.
doi:10.1371/journal.pone.0052518
PMCID: PMC3551963  PMID: 23349688
23.  Associations of BDNF Genotype and Promoter Methylation with Acute and Long-Term Stroke Outcomes in an East Asian Cohort 
PLoS ONE  2012;7(12):e51280.
Background
Brain derived neurotrophic factor (BDNF) has been shown to play an important role in poststroke recovery. BDNF secretion is influenced by genetic and epigenetic profiles. This study aimed to investigate whether BDNF val66met polymorphism and promoter methylation status were associated with outcomes at two weeks and one year after stroke.
Methods and Findings
A total of 286 patients were evaluated at the time of admission and two weeks after stroke, and 222 (78%) were followed one year later in order to evaluate consequences of stroke at both acute and chronic stages. Stroke outcomes were dichotomised into good and poor by the modified Rankin Scale. Stroke severity (National Institutes of Health Stroke Scale), physical disability (Barthel Index), and cognitive function (Mini-Mental State Examination) were measured. Associations of BDNF genotype and methylation status on stroke outcomes and assessment scale scores were investigated using logistic regression, repeated measures ANOVA and partial correlation tests. BDNF val66met polymorphism was independently associated with poor outcome at 2 weeks and at 1 year, and with worsening physical disability and cognitive function over that period. Higher BDNF promoter methylation status was independently associated with worse outcomes at 1 year, and with the worsening of physical disability and cognitive function. No significant genotype-methylation interactions were found.
Conclusions
A role for BDNF in poststroke recovery was supported, and clinical utility of BDNF genetic and epigenetic profile as prognostic biomarkers and a target for drug development was suggested.
doi:10.1371/journal.pone.0051280
PMCID: PMC3519835  PMID: 23240009
24.  Dysfunction of Natural Killer T Cells in Patients with Active Mycobacterium tuberculosis Infection 
Infection and Immunity  2012;80(6):2100-2108.
Natural killer T (NKT) cells are known to play a protective role in the immune responses of mice against a variety of infectious pathogens. However, little is known about the detailed information of NKT cells in patients with Mycobacterium tuberculosis infection. The aims of this study were to examine NKT cell levels and functions in patients with active M. tuberculosis infection, to investigate relationships between NKT cell levels and clinical parameters, and to determine the mechanism responsible for the poor response to α-galactosylceramide (α-GalCer). NKT cell levels were significantly lower in the peripheral blood of pulmonary tuberculosis and extrapulmonary tuberculosis patients, and the proliferative responses of NKT cells to α-GalCer were also lower in patients, whereas NKT cell levels and responses were comparable in latent tuberculosis infection subjects and healthy controls. Furthermore, this NKT cell deficiency was found to be correlated with serum C-reactive protein levels. In addition, the poor response to α-GalCer in M. tuberculosis-infected patients was found to be due to increased NKT cell apoptosis, reduced CD1d expression, and a defect in NKT cells. Notably, M. tuberculosis infection was associated with an elevated expression of the inhibitory programmed death-1 (PD-1) receptor on NKT cells, and blockade of PD-1 signaling enhanced the response to α-GalCer. This study shows that NKT cell levels and functions are reduced in M. tuberculosis-infected patients and these deficiencies were found to reflect the presence of active tuberculosis.
doi:10.1128/IAI.06018-11
PMCID: PMC3370582  PMID: 22409933
25.  Detection of Amphotericin B Resistance in Candida haemulonii and Closely Related Species by Use of the Etest, Vitek-2 Yeast Susceptibility System, and CLSI and EUCAST Broth Microdilution Methods 
Journal of Clinical Microbiology  2012;50(6):1852-1855.
The emerging fungal pathogens Candida haemulonii and Candida pseudohaemulonii often show high-level resistance to amphotericin B (AMB). We compared the utilities of five antifungal susceptibility testing methods, i.e., the Etest using Mueller-Hinton agar supplemented with glucose and methylene blue (Etest-MH), the Etest using RPMI agar supplemented with glucose (Etest-RPG), the Vitek-2 yeast susceptibility system, and the Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution methods, for the detection of AMB-resistant isolates of C. haemulonii and closely related species. Thirty-eight clinical isolates (8 C. haemulonii, 10 C. pseudohaemulonii, and 20 Candida auris isolates) were analyzed. Of the 18 C. haemulonii and C. pseudohaemulonii isolates, 18, 15, 18, 10, and 9 exhibited AMB MICs of >1 μg/ml by the Etest-MH, Etest-RPG, Vitek-2, CLSI, and EUCAST methods, respectively. All 20 C. auris isolates showed AMB MICs of ≤1 μg/ml by all five methods. Of the methods, the Etest-MH generated the broadest distribution of AMB MICs for all 38 isolates and showed the best discrimination between the C. haemulonii and C. pseudohaemulonii isolates (4 to 32 μg/ml) and those of C. auris (0.125 to 0.5 μg/ml). Taking the Etest-MH as the reference method, the essential agreements (within two dilutions) for the Etest-RPG, Vitek-2, CLSI, and EUCAST methods were 84, 92, 55, and 55%, respectively; the categorical agreements were 92, 92, 79, and 76%, respectively. This study provides the first data on the efficacy of the Etest-MH and its excellent agreement with Vitek-2 for discriminating AMB-resistant from AMB-susceptible isolates of these Candida species.
doi:10.1128/JCM.06440-11
PMCID: PMC3372122  PMID: 22442324

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