• Tuberculosis and Respiratory Diseases
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• 제72권1호
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• pp.30-36
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• 2012

Background: Patients with ventilator-associated pneumonia (VAP) in intensive care unit (ICU) have a high mortality rate. The routine surveillance cultures obtained previously or an ATS guideline for hospital-acquired pneumonia was used in selecting initial antimicrobials. The object of this study was to compare the respiratory samples before VAP and bronchoalveolar lavage (BAL) culture. Methods: 54 patients underwent fiberoptic bronchoscopy to obtain BAL samples. We reviewed microbiologic specimen results of prior respiratory specimens (pre-VAP) and BAL. Results: Among 51 patients with 54 VAP episodes, 52 microorganisms of pre-VAP and 56 BAL samples were isolated. Pre-VAP included 21.2% of MRSA, and 32.6% of multidrug resistant-Acinetobacter baumannii (MDR-AB). BAL samples comprised 25.0% of MRSA, 26.7% of MDR-AB, 14.3% of Stenotrophomonas maltophilia and 3.6% of Klebsiella pneumonia in order. In pre-VAP samples compared to BAL samples, only 35.2% were identical. In BAL samples compared to pre-VAP samples obtained in 5 days before the onset of VAP, only 43.6% were identical. However, among BAL samples compared to pre-VAP samples obtained after more than 5 days, 13.3% were identical (p=0.037). Conclusion: Based on these data, pre-VAP samples obtained prior to 5 day onset of VAP may help to predict the causative microorganisms and to select appropriate initial antimicrobials.

• 약학회지
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• 제53권4호
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• pp.194-200
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• 2009

Community-acquired antimicrobial resistant bacteria are an emerging problem whole world-wide. Generally, Hands are main mediator of pathogen transmission as compared with other body parts. So, the purpose of this research was to investigate the microbiological quality and antimicrobial susceptibilities of samples which were collected from the door knob and surface in public- and home-facilities, and also hand. Of total 191 samples, 71 samples (37%) were shown to be of high-level total bacterial count (>$10^8\;CFU/cm^2$). And presence of Staphylococcus and Enteric bacilli was observed in 61 samples (32%) and 76 samples (40%), respectively. Antimicrobial susceptibilities of staphylococcal isolates from the samples were tested for six different antimicrobial agents, which are in wide spread clinical use in Korea, as well as four new antimicrobials, daptomycin, linezolid, quinupristin/dalfopristin and tigecycline. Among staphylococcal isolates, antimicrobial resistance were observed in oxacillin (n=6), mupirocin (n=7), vancomycin (n=1), quinupristin/dalfopristin (n=2) and gentamicin (n=5). Fortunately, all the isolates were susceptible to new antimicrobial such as daptomycin, linezolid and tigecycline. Furthermore 4 Enterococcus faecalis were isolated from four hand samples, and all these isolates exhibited multidrug resistance to four different antimicrobial (oxacillin, quinupristin/dalfopristin, mupirocin, gentamicin). Also, 5 Escherichia coli were isolated from surface in home (n=3), door knob in public facilities (n=1) and hand (n=1). Escherichia coli isolated from hand was high-level resistant to tigecycline ($128{\mu}g$/ml) and gentamicin ($64{\mu}g$/ml).

• Bulletin of the Korean Chemical Society
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• 제33권4호
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• pp.1123-1127
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• 2012

P-gp (P-glycoprotein) is a member of the ATP binding cassette (ABC) family of transporters. It transports many kinds of anticancer drugs out of the cell. It plays a major role as a cause of multidrug resistance (MDR). MDR function may be a cause of the failure of chemotherapy in cancer and influence pharmacokinetic properties of many drugs. Hence classification of candidate drugs as substrates or nonsubstrate of the P-gp is important in drug development. Therefore to identify whether a compound is a P-gp substrate or not, in silico method is promising. Recursive Partitioning (RP) method was explored for prediction of P-gp substrate. A set of 261 compounds, including 146 substrates and 115 nonsubstrates of P-gp, was used to training and validation. Using molecular descriptors that we can interpret their own meaning, we have established two models for prediction of P-gp substrates. In the first model, we chose only 6 descriptors which have simple physical meaning. In the training set, the overall predictability of our model is 78.95%. In case of test set, overall predictability is 69.23%. Second model with 2D and 3D descriptors shows a little better predictability (overall predictability of training set is 79.29%, test set is 79.37%), the second model with 2D and 3D descriptors shows better discriminating power than first model with only 2D descriptors. This approach will be used to reduce the number of compounds required to be run in the P-gp efflux assay.

• Bulletin of the Korean Chemical Society
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• 제28권6호
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• pp.947-952
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• 2007

Mycobacterium tuberculosis is a pathogen responsible for 2-3 million deaths every year worldwide. The emergence of drug-resistant and multidrug-resistant tuberculosis has increased the need to identify new antituberculosis targets. Acetohydroxy acid synthase, (AHAS, EC 2.2.1.6), an enzyme involved in branched-chain amino acid synthesis, has recently been identified as a potential anti-tuberculosis target. To assist in the search for new inhibitors and “receptor-based” design of effective inhibitors of tubercular AHAS (TbAHAS), we constructed four different structural models of TbAHAS and used one of the models as a target for virtual screening of potential inhibitors. The quality of each model was assessed stereochemically by PROCHECK and found to be reliable. Up to 89% of the amino acid residues in the structural models were located in the most favored regions of the Ramachandran plot, which indicates that the conformation of each residue in the models is good. In the models, residues at the herbicide-binding site were highly conserved across 39 AHAS sequences. The binding mode of TbAHAS with a sulfonylurea herbicide was characterized by 32 hydrophobic interactions, the majority of which were contributed by residue Trp516. The model based on the highest resolution X-ray structure of yeast AHAS was used as the target for virtual screening of a chemical database containing 8300 molecules with a heterocyclic ring. We developed a short list of molecules that were predicted to bind with high scores to TbAHAS in a conformation similar to that of sulfonylurea derivatives. Five sulfonylurea herbicides that were calculated to efficiently bind TbAHAS were experimentally verified and found to inhibit enzyme activity at micromolar concentrations. The data suggest that this time-saving and costeffective computational approach can be used to discover new TbAHAS inhibitors. The list of chemicals studied in this work is supplied to facilitate independent experimental verification of the computational approach.

• Archives of Pharmacal Research
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• 제28권7호
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• pp.823-828
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• 2005

Multidrug resistance (MDR) is one of the most significant obstacles in cancer chemotherapy. One of the mechanisms involved in the development of MDR is the over-expression of P-glycoprotein (P-gp). It is widely known that natural compounds found in vegetables, fruits, plant-derived beverages and herbal dietary supplements not only have anticancer properties, but may also modulate P-gp activity. Therefore, the purpose of this investigation was to examine the effects of naturally occurring products on P-gp function in human breast cancer cell lines, MCF-7 (sensitive) and MCF-7/ADR (resistant). The accumulation of daunomycin (DNM), a P-gp substrate, was greater in the sensitive cells compared to the resistant cells, while the efflux of DNM was higher in the resistant cells compared to the sensitive cells over a period of 2h. The $IC_{50}$ value of DNM in the resistant cells was about 22 times higher than that in the sensitive cells, indicating an over-expression of P-gp in the resistant cells, MCF-7/ADR. All of the compounds tested, with the exception of fisetin, significantly decreased the $IC_{50}$ value of DNM. Biochanin A showed the greatest increase in $[^3H]-DNM$ accumulation, increasing by $454.3{\pm}19.5%$ in the resistant cells, whereas verapamil, the positive control, increased the accumulation by $229.4{\pm}17.6%$. Also, the accumulation of $[^3H]-DNM$ was increased substantially by quercetin and silymarin while it was reduced by fisetin. Moreover, biochanin A, silymarin, and naringenin significantly decreased DNM efflux from MCF-7/ADR cells compared with the control. These results suggest that some flavonoids such as biochanin A and silymarin may reverse MDR by inhibiting the P-gp function.

• Tuberculosis and Respiratory Diseases
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• 제76권2호
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• pp.66-74
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• 2014

Background: The increasing number of outpatients with multidrug-resistant (MDR) pathogens has led to a new category of pneumonia, termed healthcare-associated pneumonia (HCAP). We determined the differences in etiology and outcomes between patients with HCAP and those with community-acquired pneumonia (CAP) to clarify the risk factors for HCAP mortality. Methods: A retrospective study comparing patients with HCAP and CAP at Jeju National University Hospital. The primary outcome was 30-day mortality. Results: A total of 483 patients (208 patients HCAP, 275 patients with CAP) were evaluated. Patients with HCAP were older than those with CAP (median, 74 years; interquartile range [IQR], 65-81 vs. median, 69 years; IQR, 52-78; p<0.0001). Streptococcus pneumoniae was the major pathogen in both groups, and MDR pathogens were isolated more frequently from patients with HCAP than with CAP (18.8% vs. 4.9%, p<0.0001). Initial pneumonia severity was greater in patients with HCAP than with CAP. The total 30-day mortality rate was 9.9% and was higher in patients with HCAP based on univariate analysis (16.3% vs. 5.1%; odds ratio (OR), 3.64; 95% confidence interval (CI), 1.90-6.99; p<0.0001). After adjusting for age, sex, comorbidities, and initial severity, the association between HCAP and 30-day mortality became non-significant (OR, 1.98; 95% CI, 0.94-4.18; p=0.167). Conclusion: HCAP was a common cause of hospital admissions and was associated with a high mortality rate. This increased mortality was related primarily to age and initial clinical vital signs, rather than combination antibiotic therapy or type of pneumonia.

• Genomics & Informatics
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• 제11권4호
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• pp.254-262
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• 2013

The multidrug resistance protein 2 (MRP2, ABCC2) gene may determine individual susceptibility to adverse drug reactions (ADRs) in the central nervous system (CNS) by limiting brain access of antiepileptic drugs, especially valproic acid (VPA). Our objective was to investigate the effect of ABCC2 polymorphisms on ADRs caused by VPA in Korean epileptic patients. We examined the association of ABCC2 single-nucleotide polymorphisms and haplotype frequencies with VPA related to adverse reactions. In addition, the association of the polymorphisms with the risk of VPA related to adverse reactions was estimated by logistic regression analysis. A total of 41 (24.4%) patients had shown VPA-related adverse reactions in CNS, and the most frequent symptom was tremor (78.0%). The patients with CNS ADRs were more likely to have the G allele (79.3% vs. 62.7%, p=0.0057) and the GG genotype (61.0% vs. 39.7%, p=0.019) at the g.-1774delG locus. The frequency of the haplotype containing g.-1774Gdel was significantly lower in the patients with CNS ADRs than without CNS ADRs (15.8% vs. 32.3%, p=0.0039). Lastly, in the multivariate logistic regression analysis, the presence of the GG genotype at the g.-1774delG locus was identified as a stronger risk factor for VPA related to ADRs (odds ratio, 8.53; 95% confidence interval, 1.04 to 70.17). We demonstrated that ABCC2 polymorphisms may influence VPA-related ADRs. The results above suggest the possible usefulness of ABCC2 gene polymorphisms as a marker for predicting response to VPA-related ADRs.

• Journal of Pharmaceutical Investigation
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• 제37권6호
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• pp.369-376
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• 2007

Cyclosporine (CsA) and tacrolimus (FK506) have a narrow therapeutic range, and their pharmacokinetic (PK) characteristic varies among individual. They are also substrates for cytochrome P450 (CYP) 3A4, 3A5 genes, and P-glycoprotein, the product of the multidrug resistance 1 (MDR1). The aims were to investigate the relationship between CYP3A and MDR1 genotypes and their PK parameters among healthy subjects. We investigated the genotype for CYP3A and MDR1 gene in human using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. After oral administration of CsA and FK506 (100 mg and 1 mg, respectively), whole blood samples were taken up to 24 hours. Blood CsA and FK506 concentrations were measured by LC/MS/MS. Each PK parameters were compared using Kruskal-Wallis test according to the CYP3A and MDR1 genotype. We found that the values of AVC for CsA were significantly different among CYP3A5 and MDR1 exon 26 (C3435T) genotypes (P=0.037 and P=0.049). On the other hand, the AUC for FK506 was significantly different only among CYP3A5 genotypes (P=0.013). The results clearly demonstrate the effects of CYP3A5 and MDR1 exon 26 on Cys and FK506 disposition.

• Journal of Microbiology and Biotechnology
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• 제27권9호
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• pp.1716-1723
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• 2017

The rapid dissemination of extended-spectrum ${\beta}$-lactamase (ESBL)-producing Escherichia coli has significantly contributed to public health hazard globally. A total of 281 E. coli strains recovered from pigs and chickens between 2009 and 2015 in South Korea were analyzed for ESBL production. ESBL phenotypes were recognized in 14 E. coli isolates; ten and three ESBL-producing isolates carried only $bla_{CTX-M}$ and $bla_{CMY}$ genes, respectively, and one isolate harbored both genes. The predominant CTX-M and CMY types were CTX-M-15 (n = 8) and CMY-2 (n = 3). We also detected ESBL-producing isolates harboring $bla_{CTX-M-65}$, $bla_{CTX-M-14}$, $bla_{CMY-6}$, $bla_{DHA-1}$, and $bla_{TEM-1}$ genes. All ESBL-producing isolates showed resistance to the extent of the fourth generation cephalosporins, along with multidrug resistance. CTX-M-15-producing isolates showed higher MIC values than CTX-M-14- and CTX-M-65-producing isolates. The $bla_{CTX-M}$ and $bla_{CMY}$ genes have the potential to be transferable. The spreading of $bla_{CMY}$ and $bla_{CTX-M}$ genes was arbitrated mainly via Frep and IncI1 plasmids. Our isolates showed clonal diversity in PFGE analysis. This is the first report of E. coli isolates carrying $bla_{CMY-6}$ in chicken from South Korea. The emergence of CMY-6 ESBLs in a population of poultry suggests that extensive screening with long-term surveillance is necessary to prevent the dissemination of ESBL from chicken to human.

• Restorative Dentistry and Endodontics
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• 제28권6호
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• pp.435-448
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• 2003

This study was performed to observe the antibacterial effect of polyphosphate (polyP) with various chain lengths (P3~P75) on virulent. invasive strains of P. gingivalis A7A1-28 and W50, and multidrug resistant E. faecalis ATCC29212. P. gingivalis strains were grown in brain-heart infusion broth (BHI) containing hemin and vitamin K with or without polyP. PolyP was added at the very beginning of the culture or during the exponential growth phase of the culture. Inhibition of the growth of P. gingivalis was determined by measuring the absorbancy at 540nm of the grown cells. Viable cell counts of the culture and release of intracellular nucleotide from P. gingivalis were measured. E. faecalis was grown in plain BHI with antibiotics alone or in combination with polyP(calgon: 0.1~1.0%) and the bacterial absorbancy was measured. The overall results suggest that polyP has a strong antibacterial effect on the growth of the virulent strains of P. gingivalis and the antibacterial activity of polyP seems largely bactericidal. accompanying bacteriolysis in which chelation phenomenon is not involved. Although polyP does not exert antibacterial activity against E. faecalis, it appears to increase antibacterial effect of erythromycin and tetracycline on the bacterium. Therefore, polyP alone or in combination with antibiotics may be developed as a candidate for the agent controlling oral infections including endodontic infection.