Emergence of an extended-spectrum ß-lactamase-producing serotype K1 Klebsiella pneumoniae ST23 strain from Asian countries.

Extended-spectrum ß-lactamase (ESBL) production has been very rare in serotype K1 Klebsiella pneumoniae ST23 strains, which are well-known invasive community strains. Among 92 ESBL-producing strains identified in 218 isolates from nine Asian countries, serotype K1 K. pneumoniae strains were screened. Two ESBL-producing K. pneumoniae isolates from Singapore and Indonesia were determined to be serotype K1 and ST23. Their plasmids, which contain CTX-M-15 genes, are transferable rendering the effective transfer of ESBL resistance plasmids to other organisms.

Genetic variants of IL-11 associated with risk of Hirschsprung disease.

BACKGROUND: Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder characterized by the absence of enteric ganglia during enteric nervous system (ENS) development. Our recent genome-wide association study has identified a variant (rs6509940) of interleukin-11 (IL-11) as a potential susceptible locus for HSCR. As interleukins play important roles in the ENS, we further studied associations with HSCR of nine common single nucleotide polymorphisms (SNPs) on IL-11. METHODS: Biopsy specimens or surgical materials from all patients that were tested for histological examination based on the absence of the enteric ganglia were collected. A total of nine SNPs on IL-11 were genotyped in 187 HSCR patients and 283 unaffected controls using TaqMan genotyping assay. KEY RESULTS: Combined analysis revealed that several SNPs (minimum p = 1.57 × 10(-7) ) showed statistically significant associations with HSCR, even after Bonferroni correction (pcorr  = 1.73 × 10(-6) for the SNP). Moreover, the most common haplotype was strongly associated with HSCR (pcorr  = 2.20 × 10(-6) ). In further analysis among three HSCR subtypes (short segment, S-HSCR; long segment, L-HSCR; total colonic aganglionosis, TCA) based on the extent of aganglionic segment, the result showed a different association pattern depending on the subtypes (minimum pcorr  = 6.12 × 10(-5) for rs6509940 in S-HSCR; but no significant SNP in L-HSCR and TCA). CONCLUSIONS & INFERENCES: Although further replication in a larger cohort and functional evaluations are needed, our findings suggest that genetic variations of IL-11 may be associated with the risk of HSCR and/or the mechanisms related to ENS development.

No association between CCL2 gene polymorphisms and risk of inflammatory demyelinating diseases in a Korean population.

Inflammatory demyelinating disease (IDD), which includes multiple sclerosis (MS) and neuromyelitis optica (NMO), affects the central nervous system. Chemokine ligand 2 (CCL2/MCP-1) is considered an important contributor to the development or progression of IDD. However, genetic association studies of Asian populations are lacking. In this study, we investigated a possible association between CCL2 polymorphisms (rs1024611, rs28730833, and rs2857657) and a Korean population (178 IDD patients and 237 healthy controls) using multiple logistic regression models. However, we did not find any association, which was consistent with other studies in Caucasian populations. In conclusion, our results suggest that CCL2 variants may not contribute to the pathogenesis of IDD.

Predictors of uropathogens other than Escherichia coli in patients with community-onset acute pyelonephritis.

AIM: A constant reduction in the incidence of community-onset acute pyelonephritis (CO-APN) caused by Escherichia coli has been shown with a parallel increase incidence caused by other organisms. Therefore, we evaluated the risk factors and outcome of non-E. coli as uropathogens in patients with community-onset APN. METHODS: As a part of a nationwide multicentre surveillance study conducted in Korea, a total of 416 patients with CO-APN were collected with their epidemiological, antibiotic treatment and outcome data. RESULTS: The risk factors and outcomes of non-E. coli as uropathogens were evaluated in a total of 416 patients with culture-confirmed CO-APN. Non-E. coli caused 127 cases (30.5%) of CO-APN. CO-APN caused by non-E. coli resulted in higher inappropriate empirical therapy (38.6% vs. 20.1%, p < 0.001), longer hospital stay (12.6 days vs. 6.7 days, p = 0.005) and higher 30-day mortality (9.4% vs. 3.8% p = 0.020) compared with CO-APN caused by E. coli. Multivariate analyses showed that male gender (OR, 3.48; CI, 2.13-5.67; p < 0.001), underlying haematological disease (OR, 5.32; CI, 1.17-24.254; p = 0.031), underlying benign prostate hyperplasia (OR, 2.61; CI, 1.02-6.74; p = 0.046), chronic indwelling urethral catheter (OR, 6.34; CI, 1.26-31.84; p = 0.025) and admission history in the previous 6 months (OR, 2.12; CI, 1.23-3.58; p = 0.005) were predictors for CO-APN caused by a non-E. coli isolate. CONCLUSIONS: Community-onset APN caused by non-E. coli represents a distinct subset of urinary tract infections with worse outcomes. The defined risk factors related with non-E. coli should be taken into consideration when empirical antibiotic therapy is prescribed in patients with community-onset APN.

Development of discrimination SNP markers for Hanwoo (Korean native cattle).

In the Korean meat market, the native cattle, Hanwoo beef, are preferred over imported beef and domestic Holstein beef despite its relatively high price. In order to hold the beef industry accountable and support consumers' right to know, correct beef-origin labeling is required. For this purpose, we developed 90 single-nucleotide polymorphism markers to discriminate between Hanwoo and other breeds including Holstein using 1602 cattle DNAs. The probability of discrimination was found to be 100% in a subsequent validation set consisting of 632 DNAs. Our study suggests that improved beef-origin discrimination can be achieved by using a combined genetic model that takes into account small genetic differences among a large number of markers. These markers could be useful for discriminating between Hanwoo and imported breeds including domestic Holsteins, and would contribute to the prevention of falsified beef origin.

Associations of CD6, TNFRSF1A and IRF8 polymorphisms with risk of inflammatory demyelinating diseases.

AIMS: Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory autoimmune diseases that affect the central nervous system. Several genome-wide and candidate gene studies have identified genetic polymorphisms associated with the risk of MS or NMO. In particular, two recently published studies of meta-analysis in European-origin populations have suggested associations of single-nucleotide polymorphisms (SNPs) in CD6, TNFRSF1A and IRF8 with MS. The aim of our study was to assess the associations between SNPs in these three genes and the risk of inflammatory demyelinating disease (IDD) including MS and NMO. To the best of our knowledge, this is the first time such a study has been performed in an Asian population. METHODS: A total of 21 SNPs of CD6, TNFRSF1A and IRF8 were genotyped in 178 IDD cases (79 MS and 99 NMO patients) and 237 normal controls in a Korean population. RESULTS: Logistic analyses revealed that one SNP in CD6 (rs12288280, P = 0.04) and three SNPs in TNFRSF1A (rs767455, rs4149577 and rs1800693, P = 0.01-0.03) were associated with NMO. However, there was no association of IRF8 polymorphisms with IDD, including MS and NMO. Using further information from the SNP Function Prediction website, two exonic splicing enhancers (ESEs), including the polymorphic site of rs767455, were predicted to be binding sites for splicing factors (SRp55, SF2/ASF2 and SF2/ASF1). CONCLUSION: Although additional studies are needed, our findings could provide information regarding the genetic aetiology of IDD in the Korean population.

A possible association between ZNRD1 and aspirin-induced airway bronchoconstriction in a Korean population.

BACKGROUND: The etiology of aspirin-exacerbated respiratory disease (AERD) has been attributed to the combination of environmental and genetic risk factors. Although widely investigated in various diseases associated with immune dysfunction, the human zinc ribbon domain containing 1 (ZNRD1) gene is thought to play a role in the pathogenesis of AERD by altering the mechanisms involved in disease development. METHODS: We selected 6 single-nucleotide polymorphisms (SNPs) for genotyping from the International HapMap database in order to analyze the association between polymorphisms in ZNRD1 and AERD in a Korean asthma cohort. Genotyping was carried out using the TaqMan assay, and differences in genotype frequency distributions were analyzed using logistic regression models. RESULTS: Nominal associations were found between ZNRD1 rs1150740 and risk ofAERD via codominant and dominant genetic inheritance (P=.03; odds ratio, 1.14 [1.14-10.16]). The same polymorphism was found to be significantly associated with a decrease in forced expiratory volume in the first second of expiration, an important diagnostic marker of AERD, even after multiple testing corrections (P=.006, P(corr)=.03 in codominant and dominant models). CONCLUSIONS: These preliminary findings suggest a possible relationship between ZNRD1 and aspirin-induced respiratory dysfunctions in a Korean population and provide essential information on the etiology of AERD.

Highly-dispersive transparency at optical frequencies in planar metamaterials based on two-bright-mode coupling.

Using a planar metamaterial, which consists of two silver strips, we theoretically demonstrate the plasmonic electromagnetically-induced transparency (EIT)-like spectral response at optical frequencies. The two silver strips serve as the bright modes, and are excited strongly by the incident wave. Based on the weak hybridization between the two bright modes, a highly-dispersive plasmonic EIT-like spectral response appears in our scheme. Moreover, the group index is higher than that of another scheme which utilizes the strong coupling between the bright and dark modes.

Variations in the STK10 gene and possible associations with aspirin-intolerant asthma in a Korean population.

BACKGROUND AND OBJECTIVE: Lymphocyte-oriented kinase deficiency encoded by the serine/threonine kinase 10 (STK10) gene correlates with the intracellular adhesion molecule 1 (ICAM-1)/lymphocyte function associated antigen 1 (LFA-1) complex in aspirin hypersensitivity. This study investigated the association between single nucleotide polymorphisms (SNPs) of STK10 and aspirin-intolerant asthma (AIA). METHODS: A total of 54 SNPs were genotyped in 163 AIA patients and 429 aspirin-tolerant asthma (ATA) controls. RESULTS: Logistic regression revealed that a synonymous variant (rs2306961G>A) had the most significant association with AIA (P = .008 under the codominant model; P = .004 under the dominant model), suggesting that tissue-specific codon usage between Lys_TTT and Lys_CTT could play a role in regulating expression of STK10 in airway epithelium. Haplotype analysis revealed that 4 haplotypes, including STK10_BL4-ht1, which is unique to rs2306961G>A, were significantly associated with aspirin hypersensitivity in asthmatics (P < .05). CONCLUSIONS: Although replications in independent cohorts and further functional evaluations are needed, our preliminary findings suggest that STK10 polymorphisms might be susceptible genetic markers of AIA and that gene expression could be mediated by tissue-specific codon usage.

Neuregulin 3 does not confer risk for schizophrenia and smooth pursuit eye movement abnormality in a Korean population.

Located on chromosome 10q22-q23, the human neuregulin3 (NRG3) is considered to be a strong positional and functional candidate gene for schizophrenia pathogenesis. Several case-control studies examining the association of polymorphisms in NRG3 with schizophrenia and/or related traits such as delusion have been reported recently in cohorts of Han Chinese, Ashkenazi Jews, Australians and white Americans of Western European ancestry. Thus, this study aimed to comprehensively investigate the association of NRG3 genetic variations with the risk of schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. Using TaqMan assay, six single-nucleotide polymorphisms (SNPs) in the intronic region of NRG3 were genotyped and two major haplotypes were identified in 435 patients with schizophrenia as cases and 393 unrelated healthy individuals as controls. A total of 113 schizophrenia patients underwent an eye tracking task, and degree of SPEM abnormality was measured using the logarithmic values of the signal/noise (Ln S/N) ratio. Differences in frequency distributions were analyzed using logistic and regression models following various modes of genetic inheritance and controlling for age and sex as covariates. Subsequent analysis revealed that the frequency distributions of NRG3 polymorphisms and haplotypes were similar between schizophrenia patients and healthy controls of Korean ethnicity. Furthermore, no significant differences were observed between the genetic variants tested for SPEM abnormality. By elucidating a lack of association in a Korean population, findings from this study may contribute to the understanding of the genetic etiology focusing on the role of NRG3 in schizophrenia pathogenesis.

Genome-wide methylation profile of nasal polyps: relation to aspirin hypersensitivity in asthmatics.

BACKGROUND: In addition to the dysregulation of arachidonic acid metabolism in aspirin-intolerant asthma (AIA), aspirin acetylsalicylic acid (ASA) exerts effects on inflammation and immunity; however, many of these effects are unknown. OBJECTIVE: The aim of the study was to evaluate the methylation status of whole genome in blood and polyp tissues with and without aspirin hypersensitivity. METHODS: Genome-wide DNA methylation levels in nasal polyps and peripheral blood cells were examined by microarray analysis using five subjects with AIA and four subjects with aspirin-tolerant asthma (ATA). RESULTS: In the nasal polyps of the patients with AIA, hypermethylation was detected at 332 loci in 296 genes, while hypomethylation was detected at 158 loci in 141 genes. Gene ontologic and pathway enrichment analyses revealed that genes involved in lymphocyte proliferation, cell proliferation, leukocyte activation, cytokine biosynthesis, cytokine secretion, immune responses, inflammation, and immunoglobulin binding were hypomethylated, while genes involved in ectoderm development, hemostasis, wound healing, calcium ion binding, and oxidoreductase activity were hypermethylated. In the arachidonate pathway, PGDS, ALOX5AP, and LTB4R were hypomethylated, whereas PTGES was hypermethylated. CONCLUSION: The nasal polyps of patients with AIA have characteristic methylation patterns affecting 337 genes. The genes and pathways identified in this study may be associated with the presence of aspirin hypersensitivity in asthmatics and are therefore attractive targets for future research.

Changing etiology of community-acquired bacterial meningitis in adults: a nationwide multicenter study in Korea.

Epidemiologic data on the etiologic organisms is important for appropriate empirical antibiotic treatment of bacterial meningitis. We identified the etiologies of community-acquired bacterial meningitis in Korean adults and the associated epidemiological factors. A retrospective, multicenter nationwide study was carried out. Patients 18 years of age or older with community-acquired bacterial meningitis with a confirmed pathogen were enrolled. Demographic, clinical, and microbiological data were collected. One hundred and ninety-five cases were collected. Streptococcus pneumoniae was the most common pathogen (50.8%), followed by Staphylococcus aureus (10.3%), Klebsiella pneumoniae (7.7%), Listeria monocytogenes (6.7%), and group B Streptococcus (3.1%). The penicillin resistance rate of the S. pneumoniae was 60.3%; 40.0% of the organisms were not susceptible to third-generation cephalosporins. The combination of third-generation cephalosporin with vancomycin was used in 76.3% of cases. Steroids were given before or with the first dose of antibiotics in 37.4% of patients. The 30-day mortality rate was 20.5% and neurological sequelae developed in 15.6% of cases. S. pneumoniae was the most common organism identified in community-acquired bacterial meningitis among Korean adults. S. aureus, K. pneumoniae, L. monocytogenes, and group B Streptococcus were also common. S. pneumoniae had high rates of resistance to penicillin and third-generation cephalosporins.

Identification of genetic polymorphisms in bovine mitochondrial deoxyribonucleic acid.

In this study, the intent was to identify genetic polymorphisms of mitochondrial (mt) DNA in Korean cattle (Bos taurus coreana) and to analyze the genetic relationship between Korean cattle and other breeds. Whole mtDNA genomes (16,338 bp) of 26 animals (16 Korean cattle and 10 Holsteins) were directly sequenced. Multiple alignments, including 26 whole-mtDNA sequences obtained by direct sequencing and 10 mtDNA sequences from a public database (National Center for Biotechnology Information), revealed 393 mtDNA polymorphisms (382 SNP, 3 heteroplasmies, and 8 insertion-deletion polymorphisms). Estimated gene diversity of mtDNA was 0.00198 among these 36 animals. Phylogenic analysis with mtDNA polymorphisms revealed a distinct genetic difference between Bos taurus (Korean, Japanese Black, Holstein, and Fleckvieh breeds) and Bos indicus (Nellore and Zwergzebu breeds). The genetic information regarding mtDNA polymorphisms identified in this study would be useful for further investigation of mtDNA in other breeds.

Putative association of transforming growth factor-alpha polymorphisms with clearance of hepatitis B virus and occurrence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection.

Previous studies showed that several genetic polymorphisms might influence the clinical outcome of chronic hepatitis B virus (HBV) infection, including HBV clearance or development of hepatocellular carcinoma (HCC). The aim of this study was to determine whether polymorphisms of the transforming growth factor-alpha (TGF-alpha) gene are associated with clinical outcome of HBV infection. A total of 1096 Korean subjects having either present or past evidence of HBV infection were prospectively enrolled between January 2001 and August 2003. Among 16 genetic variants in TGFA gene, nine variants were genotyped using TaqMan assay and the genetic association with HBV clearance and HCC occurrence was analysed. Statistical analyses revealed that TGFA+103461T>C, TGFA+106151C>G and TGFA-ht2 were marginally associated with clearance of HBV infection. However, only TGFA-ht2 retained significance after multiple correction (OR = 0.39, P(corr) = 0.007 in recessive model). Although no variants were significant after multiple correction, TGFA+88344G>A and TGFA+103461T>C were weakly associated in recessive model in the analysis of HCC occurrence. In addition, Cox relative hazards model also revealed that TGFA+88344G>A was associated with onset age of HCC occurrence in subjects (RH = 1.46, P(corr) = 0.04). TGF-alpha polymorphisms might be an important factor in immunity, progression of inflammatory process and carcinogenesis, which explains the variable outcome of HBV infection at least in part. Further biological evidence is warranted in the future to support these suggestive associations.

Inappropriate initial antimicrobial therapy as a risk factor for mortality in patients with community-onset Pseudomonas aeruginosa bacteraemia.

This study was performed to identify the risk factors for mortality and evaluate the effect of inappropriate initial antimicrobial therapy on the outcomes of patients with community-onset Pseudomonas aeruginosa bacteraemia in an emergency department (ER) setting. All cases with P. aeruginosa bacteraemia occurring within 48 h after ER visit from January 2000 to December 2005 were retrospectively analysed. A total of 106 community-onset P. aeruginosa bacteraemia cases in the ER were included (mean age, 57.61 +/- 14.44 years old; M:F, 58:48). Although P. aeruginosa bacteraemia was diagnosed in the ER, most of the cases of P. aeruginosa bacteraemia were healthcare-associated (88.7%). Malignancy (n = 83, 78.3%) was the most common underlying disorder. Fifty patients (47.2%) were neutropaenic and 56 patients (52.8%) had septic shock. The overall 30-day mortality rate was 26.4% (28/106). In the univariate analysis, underlying malignancy, high Charlson's weighted index of comorbidity (> or = 3), high Pitt bacteraemia score (> or = 4), indwelling central venous catheter and inappropriate initial therapy were significantly associated with 30-day mortality (all P < 0.05). In the multivariate analysis, high Pitt bacteraemia score (OR, 17.03; 95% CI, 4.60-63.15; P < 0.001) and inappropriate initial antimicrobial therapy (OR, 4.29; 95% CI, 1.39-13.24; P = 0.011) were found to be significant risk factors for 30-day mortality. The 30-day mortality rate was significantly higher in the inappropriate therapy group (18/51, 35.3%) than in the appropriate therapy group (10/55, 18.2%) (P = 0.046). This study demonstrated that inappropriate initial antimicrobial therapy was significantly associated with unfavourable outcomes in patients with community-onset P. aeruginosa bacteraemia. As P. aeruginosa bacteraemia can be a fatal infection, even when community-onset, inappropriate antimicrobial therapy should be avoided in suspected cases of P. aeruginosa bacteraemia.

Associations of DNase IV polymorphisms with autoantibodies in patients with systemic lupus erythematosus.

OBJECTIVES: The aim of this study was to investigate genetic polymorphisms of DNase IV and their relationship with SLE and various autoantibodies present in SLE patients. METHODS: A total of 532 SLE patients and 521 healthy controls belonging to the Korean population were enrolled into this study. Sequencing of the entire coding region of the DNase IV gene (including the promoter region) was carried out using a DNA analyser. Autoantibodies including anti-Sm, anti-Ro, anti-La, anti-RNP and anti-dsDNA were determined either by indirect immunofluorescence or double immunodiffusion methods. Multiple logistic regression analysis was performed to examine the genetic association with SLE and autoantibodies. RESULTS: We found three single-nucleotide polymorphisms (SNPs): -2753G-->A, +147T-->G (Gly49Gly) and +1466G-->T. The -2753G-->A and +147T-->G (Gly49Gly) SNPs were selected for larger scale genotyping based on linkage disequilibria and haplotype-tagging status. Although the -2753G-->A SNP was more common than the +147T-->G (Gly49Gly) SNP (frequencies: 0.330 and 0.002, respectively), its association with the risk of SLE was not statistically significant. However, -2753G-->A SNP was significantly associated with the production of anti-Sm antibody [odds ratio (95% CI): co-dominant model, 1.89 (1.28-2.79); dominant model, 2.17 (1.20-3.90) and recessive model, 2.62 (1.33-5.17)]. CONCLUSIONS: We did not find significant relationships between DNase IV polymorphisms and the risk of SLE, but the association of the common -2753G-->A allele in the promoter region with the production of anti-Sm antibody implicates DNase IV as a putative candidate gene of SLE.

Association of polymorphisms in the insulin-degrading enzyme gene with type 2 diabetes in the Korean population.

Insulin-degrading enzyme (IDE) is a metalloproteinase which degrades insulin and terminates its action. Homologous deletion of IDE gene resulted in hyperinsulinemia and glucose intolerance in a rat model of type 2 diabetes mellitus. Several genetic association studies examined IDE as a susceptibility gene for type 2 diabetes in European descents. Here we investigated the genetic association of IDE polymorphisms with the risk of type 2 diabetes and its related phenotypes in the Korean population. Among six single nucleotide polymorphisms analyzed, g.-179T>C (OR=1.73, P=0.04), and g.IVS18+99G>A (OR=1.23, P=0.02) revealed borderline association with increased risk of type 2 diabetes. Combining our results with previous data obtained from the European population, g.-179T>C (OR=1.11, P=0.03), and g.IVS24-64A>T (OR=1.18, P=0.005) showed significant association with type 2 diabetes. Haplotype consisting of common alleles of the six polymorphisms was associated with decreased risk of type 2 diabetes (OR=0.82, P=0.02). However, none of the polymorphisms was significantly associated with metabolic phenotypes. We can conclude that variations in IDE might contribute to diabetes susceptibility in the Korean population.

Clinical features and outcome of community-onset bloodstream infections caused by extended-spectrum beta-lactamase-producing Escherichia coli.

This study was conducted to evaluate the epidemiology and clinical features of bloodstream infections caused by extended-spectrum beta-lactamase-producing E. coli (ESBL-EC) in community-onset bacteremia. Of 929 episodes of community-onset E. coli bacteremia, 4.1% (38/929) had bacteremia with ESBL producers. Of these, 63.2% (24/38) were further classified as healthcare-associated infections. Although most patients had risk factors for infection due to ESBL producers, three patients with urinary tract infection, four patients with cholangitis, and one patient with a liver abscess had no identified predisposing risk factors. The 30-day mortality was 21.1% (8/38). ESBL-EC is a significant cause of bloodstream infection, even in patients with community-onset infection.

A promoter nucleotide variant of the dendritic cell-specific DCNP1 associates with serum IgE levels specific for dust mite allergens among the Korean asthmatics.

Dendritic cells (DCs), the most abundant antigen-presenting cells in the lung, have been drawing attention for their roles in specific allergic responses to aeroallergens with support of Th lymphocytes, and in persistent inflammatory changes in allergic asthma. To identify genetic factors that may be involved in the asthma susceptibility and development of the disease phenotypes, we examined association of DC-specific DCNP1 polymorphisms with the disease risk. The case-control study revealed association of the nucleotide variants with serum immunoglobulin E (IgE) levels specific for Dermatophagoides farinae (Der f 1) and Dermatophagoides pteronyssinus (Der p 1), major aeroallergens of dust mites, among subjects with asthma. In particular, the T-allele-carrying genotype frequencies for one of the variants (c.-1289C>T) located in the promoter region were found increased in the asthmatic group with low levels of the mite-specific IgE (odds ratio (OR)=0.63 (0.48-0.83) for Der p 1). Results from functional analyses indicated that the promoter variant would affect the gene expression by modulating DNA-protein interaction. We propose that the genetic polymorphism of DCNP1 may influence production of specific IgE by altering DC functions in the mite allergen presenting and/or processing. The functional relevance of the genetic variation would provide an important insight into the genetic basis of allergic response to the mite antigens.