Drug-Induced Liver Injury: Clinical and Etiologic Features at a Large Tertiary Teaching Hospital in China.

BACKGROUND Since the epidemiological profile of drug-induced liver injury (DILI) in China, especially the western of China, it has rarely been studied. The aim of this study was to analyze the characteristics of DILI patients in a large tertiary teaching hospital at Chongqing, a municipality in western China. MATERIAL AND METHODS The medical records of hospitalized patients which diagnosed with DILI between January 2011 and December 2016 were searched retrospectively, and demographic, clinical data, and laboratory data were retrieved for analysis. RESULTS A total of 1811 patients had been diagnosed with DILI, accounting for 0.248% of the total admissions during the same period. Among the 1096 patients included in our analysis, DILI was caused by "medications" in 462 cases (42.15%), "herbs" in 391 cases (35.68%), and combined medications in 189 cases (17.24%). The profiles for each etiology were distinctive for age, sex, clinical features, laboratory features, and types and severity of DILI. CONCLUSIONS Our study provides a systematic etiological profile of DILI in Chinese patients, which can represent references for prevention, diagnosis and treatment, supporting and promoting efforts to ease the burden of this liver disease in China.

Hyperoside attenuates hydrogen peroxide-induced L02 cell damage via MAPK-dependent Keap1-Nrf2-ARE signaling pathway.

The flavonoid hyperoside has been reported to elicit cytoprotection against oxidative stress partly by increasing the activity of antioxidant enzymes, such as glutathione peroxidase, superoxide dismutase and catalase. However, the cellular and molecular mechanisms underlying this effect remain unclear. Here, hepatic L02 cells exposed to H(2)O(2) (100 µM) were used to demonstrate that hyperoside protected cells by significantly inhibiting overproduction of intracellular ROS, depletion of the mitochondrial membrane potential and leakage of lactate dehydrogenase. Hyperoside further enhanced the cellular antioxidant defense system through increasing the activity of heme oxygenase-1 (HO-1), and by up-regulating HO-1 expression. Meanwhile, real time PCR, western blot and immunofluorescence studies revealed that hyperoside stimulated nuclear translocation of the Nrf(2) transcription factor in a dose-dependent manner, and this effect was significantly suppressed by pharmacological inhibition of the mitogen-activated protein kinases (MAPK) p38 and ERK. Collectively, our data provide the first description of the mechanism underlying hyperoside's ability to attenuate H(2)O(2)-induced cell damage, namely this compound interacts with the MAPK-dependent Keap(1)-Nrf(2)-ARE signaling pathway to up-regulate HO-1 expression and enhance intracellular antioxidant activity.

Enhancement of biofilm formation by subinhibitory concentrations of macrolides in icaADBC-positive and -negative clinical isolates of Staphylococcus epidermidis.

Biofilm formation in Staphylococcus epidermidis is mediated by icaADBC-dependent and -independent pathways. Subinhibitory concentrations of erythromycin, azithromycin, and clarithromycin enhanced, in a dose-dependent manner, the level of biofilm formation by 20% (21/105 isolates) by macrolide-resistant ica-positive and -negative isolates tested in vitro. The presence of ica, however, apparently produced an enhanced effect on biofilm formation. The levels of expression of the biofilm-related genes icaA, atlE, fruA, pyrR, sarA, and sigB were increased in response to erythromycin. The results likely underscore the potential clinical relevance of macrolide-induced biofilm growth.

Scorpion primer PCR analysis for genotyping of allele variants of thiopurine s­methyltransferase*3.

Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. Mutations in the TPMT gene can affect drug activity, which may have adverse effects in humans. Thus, genotyping can help elucidate genetic determinants of drug response to thiopurines and optimize the selection of drug therapies for individual patients, effectively avoiding palindromia during maintenance treatment caused by insufficient dosing and the serious side effects caused by excessive doses. The current available detection methods used for TPMT*3B and TPMT*3C are complex, costly and time­consuming. Therefore, innovative detection methods for TPMT genotyping are urgently required. The aim of the present study was to establish and optimize a simple, specific and timesaving TPMT genotyping method. Using the principles of Web­based Allele­Specific PCR and competitive real­time fluorescent allele­specific PCR (CRAS­PCR), two pairs of Scorpion primers were designed for the detection of TPMT*3B and *3C, respectively, and a mutation in TPMT*3A was inferred based on data from TPMT*3B and *3C. In total, 226 samples from volunteers living in Chongqing were used for CRAS­PCR to detect TPMT*3 mutations. Results showed that nine (3.98%) were mutant (MT) heterozygotes and none were MT homozygotes for TPMT*3C, and no TPMT*3A and TPMT*3B mutations were found. Three TPMT*3C MT heterozygotes were randomly selected for DNA sequencing, and CRAS­PCR results were consistent with the sequencing results. In conclusion, in order to improve simplicity, specificity and efficiency, the present study established and optimized CRAS­PCR assays for commonly found mutant alleles of TPMT*3A (G460A and A719G), TPMT*3B (G460A), and TPMT*3C (A719G).

Erythromycin resistance features and biofilm formation affected by subinhibitory erythromycin in clinical isolates of Staphylococcus epidermidis.

BACKGROUND/PURPOSE: Subminimal inhibitory concentration (sub-MIC) of antibiotics can modify the phenotype of biofilm formation in bacteria. However, the relationship between resistance phenotypes, genotypes, and the biofilm formation phenotype in response to sub-MIC antibiotics remains unclear. METHODS: Here, we collected 96 clinical isolates of Staphylococcus epidermidis (S. epidermidis) and investigated the erythromycin (ERY) susceptibility, the biofilm formation in respond to sub-MIC ERY, the presence and transcription expression of erm genes. Serial passage of induction resistance was used against ERY-susceptible isolates and biofilm formation in response to their new sub-MIC ERY was determined. RESULTS: The incidence of biofilm phenotype modification in ERY-resistant isolates was significantly higher than that of ERY-susceptible isolates [27/85 (31.8%) vs. 0/11 (0%), p = 0.031]. Yet, ERY-susceptible isolates displayed the phenomenon of biofilm phenotype modification (7/11), after induction of resistance to ERY. The ermC gene was absolutely dominant among the three macrolide resistant genes including erm (A, B, C) [6/96 (6.2%), 6/96 (6.2%), and 91/96 (94.8%), respectively]. With statistic stratification analysis, a linear and positive correlation was identified between the two factors in the biofilm-enhanced strains, a linear and negative correlation in biofilm-inhibited strains, and a weakly positive correlation in biofilm-unaffected strains (R(2) = 0.4992, 0.3686, and 0.0512, respectively). CONCLUSION: The results suggest that the ERY resistance phenotype and the transcription expression of ermC gene could be considered as important signs to estimate whether the biofilm formation phenotype in S. epidermidis clinical isolates can be easily affected by sub-MIC ERY.

Opposite effects of cefoperazone and ceftazidime on S­ribosylhomocysteine lyase/autoinducer-2 quorum sensing and biofilm formation by an Escherichia coli clinical isolate.

To investigate the effects of subminimum inhibitory concentrations of cephalosporins on bacterial biofilm formation, the biofilm production of 52 Escherichia (E.) coli strains was examined following treatment with cephalosporin compounds at 1/4 minimum inhibitory concentrations (MICs). Ceftazidime (CAZ) inhibited biofilm formation in seven isolates, while cefoperazone (CFP) enhanced biofilm formation in 18 isolates. Biofilm formation of E. coli E42 was inhibited by CAZ and induced by CFP. Therefore, using reverse transcription­polymerase chain reaction, the expression of the biofilm­modulating genes of this isolate was investigated. To monitor the production of the autoinducer of quorum sensing in E. coli, autoinducer­2 (AI­2) production was detected by measuring the bioluminescence response of Vibrio harveyi BB170. Antisense oligonucleotides (AS­ODNs) targeting S­ribosylhomocysteine lyase (luxS) inhibited the expression of the luxS gene in E. coli. CAZ at 1/4 MIC reduced luxS mRNA levels and the production of AI­2, whereas CFP at 1/4 MIC had the opposite effect. AS­ODNs targeting luxS significantly decreased the aforementioned inhibitory effects of CAZ and the induction effects of CFP on E. coli biofilm formation. Therefore, biofilm formation by the E. coli clinical isolate E42 was evoked by CFP but attenuated by CAZ at sub­MICs, via a luxS/AI­2­based quorum sensing system.

The epidemiology and resistance mechanisms of Acinetobacter baumannii isolates from the respiratory department ICU of a hospital in China.

Acinetobacter baumannii is an important nosocomial pathogen able to cause severe infections in an intensive care unit (ICU). However, there is a lack of analysis regarding the epidemiology and resistance of A. baumannii in respiratory department ICUs. In this study, clinical isolates were collected from the respiratory department ICU of Southwest Hospital from January 2009 to December 2010, and the social and demographic information of the patients from whom the isolates were taken was obtained from the Southwest Hospital information system. The minimal inhibitory concentration (MIC) of the isolates was determined by the agar dilution method. The carbapenemase-encoding resistance genes of these isolates were amplified using PCR. The clonal relationship of isolates was analyzed by pulsed-field gel electrophoresis (PFGE). Forty-six isolates were collected from the respiratory department ICU, and the antibiotics minocycline and quinolone had higher drug sensitivity against these isolates. The OXA-51, OXA-23, and IMP-4 genes were present at rates of 100% (46/46), 67.4% (31/46), and 41.3% (19/46), respectively. Forty-six isolates had 12 different PFGE genotypes. The results above suggested that the hospital environment and patients contributed to nosocomial infections, and the spread of resistance genes in the hospital was common.

Increased IL-8 production in human bronchial epithelial cells after exposure to azithromycin-pretreated Pseudomonas aeruginosa in vitro.

Although Pseudomonas aeruginosa is not typically susceptible to azithromycin (AZM) in in vitro tests, AZM improves the clinical outcome in patients with chronic respiratory infections, in which both the modulation of the host immune system and of bacterial virulence by AZM are thought to play an important role. However, there is currently little direct evidence showing the impact of bacteria pretreated with AZM on epithelial cells, which represents the first barrier to infecting P. aeruginosa. In this study, we pretreated P. aeruginosa with AZM and subsequently infected human bronchial epithelial cells (HBEs) in the absence of AZM. The results showed that AZM-pretreated P. aeruginosa (PAO1 and six different clinical isolates) significantly stimulated HBE cells to release IL-8, a crucial pro-inflammatory cytokine. This effect was not observed in a P. aeruginosa PAO1 mutant strain unable to produce the type III secretion system effector gene pcrV (strain PW4017). Our results suggest that AZM-pretreated P. aeruginosa could indirectly exacerbate pro-inflammation by inducing IL-8 production in HBEs.

Detection of carbapenemase-encoding genes among clinical isolates of Pseudomonas aeruginosa in a Chinese burn unit.

The carbapenemases have recently emerged as molecules implicated in one of the most feared bacterial resistance mechanisms because of their ability to hydrolyze virtually all lactamase agents and their highly mobile genes. This study aimed to investigate the prevalence of carbapenemase and antimicrobial susceptibilities of Pseudomonas aeruginosa isolated from burn patients in Chongqing, China. Antimicrobial susceptibility of 111 isolates was determined by the disc agar diffusion test and the agar dilution method. Random Amplification of Polymorphic DNA polymerase chain reaction analysis revealed 111 P. aeruginosa 42 genotypes. Carbapenemase genes were amplified by polymerase chain reaction and the sequence verified by blast. Ninety-three of 111 (83.8%) isolates were resistant to imipenem; all of them had developed multidrug resistance and exhibited higher resistant rates compared with the imipenem-susceptible Pseudomonas. Ciprofloxacin was the most effective antipseudomonal agent. Thirty-three of the isolates were identified to contain the metallo-ß-lactamase blaIMP-4 gene and belong to different Random Amplification of Polymorphic DNA polymerase chain reactiongenotypes. In conclusion, the high prevalence of multidrug resistance (94.6%) and the production of blaIMP-4 genes in P. aeruginosa isolates in burn patients highlight the necessity of considering these issues in burn hospitals.

Retrospective analysis of epidemiology and prognostic factors for candidemia at a hospital in China, 2000-2009.

The incidence of candidemia has increased in recent years. This paper reports a retrospective analysis of 270 cases of candidemia occurring from January 2000 to December 2009 at a teaching hospital in China. Demographic and clinical data were collected from patient medical records and the hospital's laboratory database. Candida albicans (35.9%) was the most prevalent species isolated, followed by C. tropicalis (21.8%) and C. glabrata (13.0%). Antifungal susceptibilities to fluconazole, flucytosine, and amphotericin B tended to decline over the study period. The most common risk factors were the presence of central venous catheters, endotracheal intubation, hypoproteinemia, renal failure, and concurrent bacteremia. In the 181 (67.0%) patients who died during hospitalization, endotracheal intubation, hypoproteinemia, and C. albicans were the major factors associated with mortality. This study highlights the importance of considering the possibility of invasive Candida infection in patients exposed to these risk factors.

Spectrum and drug resistance of pathogens from patients with burns.

Microbial infection is an obstacle of burn treatment. However, little is known on what types of microbial infection dominate in the burn center and how the dynamic change of those microorganisms occurs during the past several years in China. We conducted a retrospective study of nosocomial infection (NI) in a large burn center to analyze the spectrum and antimicrobial resistance of microbial isolates from January 2003 to December 2010. We studied 989 isolates from 677 patients who had signs and symptoms of infection 48h after admission. The number of NIs per 100 admissions was 10.9. The commonest isolates were Pseudomonas aeruginosa (23.1%), Staphylococcus aureus (18.7%), and Candida (11.4%). The result indicated that the numbers of patients with Acinetobacter sp. infection increased (P=0.004), but with Proteus mirabilis infection decreased (P=0.004). The isolated Acinetobacter sp. and P. aeruginosa were consistently highly resistant to almost all antibiotics tested. Notably, more frequent Acinetobacter sp. isolates appeared to be resistant to amikacin, gentamicin, tobramycin, ceftazidim, piperacillin, tazobactam, levofloxacin, and ciprofloxacin and more frequent Escherichia coli isolates were resistant to ceftazidime and aztreonam at the late time period although the P. aeruginosa and E. coli isolates were sensitive to less used ciprofloxacin and piperacillin/tazobactam. The increased rates of drug-resistant isolates in the later period might be associated with regular prophylactic therapy with antibiotics.