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1.  Molecular Epidemiology and Clinical Characteristics of Drug-Resistant Mycobacterium tuberculosis in a Tuberculosis Referral Hospital in China 
PLoS ONE  2014;9(10):e110209.
Despite the large number of drug-resistant tuberculosis (TB) cases in China, few studies have comprehensively analyzed the drug resistance-associated gene mutations and genotypes in relation to the clinical characteristics of M. tuberculosis (Mtb) isolates.
Methodology/Principal Findings
We thus analyzed the phenotypic and genotypic drug resistance profiles of 115 Mtb clinical isolates recovered from a tuberculosis referral hospital in Beijing, China. We also performed genotyping by 28 loci MIRU-VNTR analysis. Socio-demographic and clinical data were retrieved from medical records and analyzed. In total, 78 types of mutations (including 42 previously reported and 36 newly identified ones) were identified in 115 Mtb clinical isolates. There was significant correlation between phenotypic and genotypic drug resistance rates for first-line anti-TB drugs (P<0.001). Genotyping revealed 101 MIRU-VNTR types, with 20 isolates (17.4%) being clustered and 95 isolates (82.6%) having unique genotypes. Higher proportion of re-treatment cases was observed among patients with clustered isolates than those with unique MIRU-VNTR genotypes (75.0% vs. 41.1%). Moreover, clinical epidemiological links were identified among patients infected by Mtb strains belonging to the same clusters, suggesting a potential of transmission among patients.
Our study provided information on novel potential drug resistance-associated mutations in Mtb. In addition, the genotyping data from our study suggested that enforcement of the implementation of genotyping in diagnostic routines would provide important information for better monitor and control of TB transmission.
PMCID: PMC4193878  PMID: 25302501
2.  Genomic and transcriptomic analysis of NDM-1 Klebsiella pneumoniae in spaceflight reveal mechanisms underlying environmental adaptability 
Scientific Reports  2014;4:6216.
The emergence and rapid spread of New Delhi Metallo-beta-lactamase-1 (NDM-1)-producing Klebsiella pneumoniae strains has caused a great concern worldwide. To better understand the mechanisms underlying environmental adaptation of those highly drug-resistant K. pneumoniae strains, we took advantage of the China's Shenzhou 10 spacecraft mission to conduct comparative genomic and transcriptomic analysis of a NDM-1 K. pneumoniae strain (ATCC BAA-2146) being cultivated under different conditions. The samples were recovered from semisolid medium placed on the ground (D strain), in simulated space condition (M strain), or in Shenzhou 10 spacecraft (T strain) for analysis. Our data revealed multiple variations underlying pathogen adaptation into different environments in terms of changes in morphology, H2O2 tolerance and biofilm formation ability, genomic stability and regulation of metabolic pathways. Additionally, we found a few non-coding RNAs to be differentially regulated. The results are helpful for better understanding the adaptive mechanisms of drug-resistant bacterial pathogens.
PMCID: PMC4147364  PMID: 25163721
3.  Insights into battles between Mycobacterium tuberculosis and macrophages 
Protein & Cell  2014;5(10):728-736.
As the first line of immune defense for Mycobacterium tuberculosis (Mtb), macrophages also provide a major habitat for Mtb to reside in the host for years. The battles between Mtb and macrophages have been constant since ancient times. Triggered upon Mtb infection, multiple cellular pathways in macrophages are activated to initiate a tailored immune response toward the invading pathogen and regulate the cellular fates of the host as well. Toll-like receptors (TLRs) expressed on macrophages can recognize pathogen-associated-molecular patterns (PAMPs) on Mtb and mediate the production of immune-regulatory cytokines such as tumor necrosis factor (TNF) and type I Interferons (IFNs). In addition, Vitamin D receptor (VDR) and Vitamin D-1-hydroxylase are up-regulated in Mtb-infected macrophages, by which Vitamin D participates in innate immune responses. The signaling pathways that involve TNF, type I IFNs and Vitamin D are inter-connected, which play critical roles in the regulation of necroptosis, apoptosis, and autophagy of the infected macrophages. This review article summarizes current knowledge about the interactions between Mtb and macrophages, focusing on cellular fates of the Mtb-infected macrophages and the regulatory molecules and cellular pathways involved in those processes.
PMCID: PMC4180456  PMID: 24938416
Mycobacterium tuberculosis; macrophages; necroptosis; apoptosis; autophagy; tumor necrosis factor (TNF); type I Interferons (IFNs)
4.  Insights into battles between Mycobacterium tuberculosis and macrophages 
Protein & Cell  2014;5(10):728-736.
As the first line of immune defense for Mycobacterium tuberculosis (Mtb), macrophages also provide a major habitat for Mtb to reside in the host for years. The battles between Mtb and macrophages have been constant since ancient times. Triggered upon Mtb infection, multiple cellular pathways in macrophages are activated to initiate a tailored immune response toward the invading pathogen and regulate the cellular fates of the host as well. Toll-like receptors (TLRs) expressed on macrophages can recognize pathogen-associated-molecular patterns (PAMPs) on Mtb and mediate the production of immune-regulatory cytokines such as tumor necrosis factor (TNF) and type I Interferons (IFNs). In addition, Vitamin D receptor (VDR) and Vitamin D-1-hydroxylase are up-regulated in Mtb-infected macrophages, by which Vitamin D participates in innate immune responses. The signaling pathways that involve TNF, type I IFNs and Vitamin D are inter-connected, which play critical roles in the regulation of necroptosis, apoptosis, and autophagy of the infected macrophages. This review article summarizes current knowledge about the interactions between Mtb and macrophages, focusing on cellular fates of the Mtb-infected macrophages and the regulatory molecules and cellular pathways involved in those processes.
PMCID: PMC4180456  PMID: 24938416
Mycobacterium tuberculosis; macrophages; necroptosis; apoptosis; autophagy; tumor necrosis factor (TNF); type I Interferons (IFNs)
5.  High expression of peroxiredoxin 4 affects the survival time of colorectal cancer patients, but is not an independent unfavorable prognostic factor 
Molecular and Clinical Oncology  2014;2(5):767-772.
Peroxiredoxin 4 (Prx4) has a number of important biological functions, such as efficient antioxidant capacity and promotion of cell proliferation and differentiation. The purpose of this study was to investigate the expression and significance of Prx4 in human colorectal cancer (CRC). Quantitative polymerase chain reaction (qPCR) was performed to detect Prx4 in 8 freshly frozen specimens of CRC and their adjacent normal tissues. In addition, immunohistochemical analysis was performed to detect Prx4 in 59 specimens of CRC and 26 of adjacent normal tissues. The immunohistochemical and qPCR results demonstrated that the expressions of the Prx4 gene and protein were higher in CRC compared to those in the adjacent normal tissues. The expression intensity of the Prx4 protein was correlated with depth of invasion (P=0.001), lymph node metastasis (P=0.006) and Dukes’ classification (P=0.004) in CRC. The Kaplan-Meier survival curves revealed that high Prx4 expression was correlated with short survival time. However, the Cox proportional hazards regression analysis did not identify Prx4 as an independent prognostic marker for CRC (P>0.05). These results suggested that Prx4 may be associated with carcinogenesis and the development of CRC and it may be a prognostic marker for postoperative CRC patients.
PMCID: PMC4106752  PMID: 25054044
peroxiredoxin; colorectal cancer; expression; prognostic marker
6.  Comparative genomic analysis of Mycobacterium tuberculosis clinical isolates 
BMC Genomics  2014;15(1):469.
Due to excessive antibiotic use, drug-resistant Mycobacterium tuberculosis has become a serious public health threat and a major obstacle to disease control in many countries. To better understand the evolution of drug-resistant M. tuberculosis strains, we performed whole genome sequencing for 7 M. tuberculosis clinical isolates with different antibiotic resistance profiles and conducted comparative genomic analysis of gene variations among them.
We observed that all 7 M. tuberculosis clinical isolates with different levels of drug resistance harbored similar numbers of SNPs, ranging from 1409–1464. The numbers of insertion/deletions (Indels) identified in the 7 isolates were also similar, ranging from 56 to 101. A total of 39 types of mutations were identified in drug resistance-associated loci, including 14 previously reported ones and 25 newly identified ones. Sixteen of the identified large Indels spanned PE-PPE-PGRS genes, which represents a major source of antigenic variability. Aside from SNPs and Indels, a CRISPR locus with varied spacers was observed in all 7 clinical isolates, suggesting that they might play an important role in plasticity of the M. tuberculosis genome. The nucleotide diversity (Л value) and selection intensity (dN/dS value) of the whole genome sequences of the 7 isolates were similar. The dN/dS values were less than 1 for all 7 isolates (range from 0.608885 to 0.637365), supporting the notion that M. tuberculosis genomes undergo purifying selection. The Л values and dN/dS values were comparable between drug-susceptible and drug-resistant strains.
In this study, we show that clinical M. tuberculosis isolates exhibit distinct variations in terms of the distribution of SNP, Indels, CRISPR-cas locus, as well as the nucleotide diversity and selection intensity, but there are no generalizable differences between drug-susceptible and drug-resistant isolates on the genomic scale. Our study provides evidence strengthening the notion that the evolution of drug resistance among clinical M. tuberculosis isolates is clearly a complex and diversified process.
Electronic supplementary material
The online version of this article (doi: 10.1186/1471-2164-15-469) contains supplementary material, which is available to authorized users.
PMCID: PMC4070564  PMID: 24923884
Mycobacterium tuberculosis; Drug resistance; Single nucleotide polymorphisms; Whole genome sequencing; Evolution
7.  Acetylation-Mediated Proteasomal Degradation of Core Histones during DNA Repair and Spermatogenesis 
Cell  2013;153(5):1012-1024.
Histone acetylation plays critical roles in chromatin remodeling, DNA repair, and epigenetic regulation of gene expression, but the underlying mechanisms are unclear. Proteasomes usually catalyze ATP- and polyubiquitin-dependent proteolysis. Here we show that the proteasomes containing the activator PA200 catalyze the polyubiquitin-independent degradation of histones. Most proteasomes in mammalian testes (“spermatoproteasomes”) contain a spermatid/sperm-specific α-subunit α4s/PSMA8 and/or the catalytic β-subunits of immunoproteasomes in addition to PA200. Deletion of PA200 in mice abolishes acetylation-dependent degradation of somatic core histones during DNA double-strand breaks, and delays core histone disappearance in elongated spermatids. Purified PA200 greatly promotes ATP-independent proteasomal degradation of the acetylated core histones, but not polyubiquitinated proteins. Furthermore, acetylation on histones is required for their binding to the bromodomain-like regions in PA200 and its yeast ortholog, Blm10. Thus, PA200/Blm10 specifically targets the core histones for acetylation-mediated degradation by proteasomes, providing mechanisms by which acetylation regulates histone degradation, DNA repair, and spermatogenesis.
PMCID: PMC3983474  PMID: 23706739
8.  Association of Hepatitis B Virus Pre-S Deletions with the Development of Hepatocellular Carcinoma in Qidong, China 
PLoS ONE  2014;9(5):e98257.
To investigate the roles of mutations in pre-S and S regions of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China.
We conducted an age matched case-control study within a cohort of 2387 male HBV carriers who were recruited from August, 1996. The HBV DNA sequence in pre-S/S regions was successfully determined in 96 HCC cases and 97 control subjects. In addition, a consecutive series of samples from 11 HCC cases were employed to evaluate the pre-S deletion patterns before and after the occurrence of HCC.
After adjustment for age, history of cigarette smoking and alcohol consumption, HBeAg positivity, pre-S deletions, pre-S2 start codon mutations, and T53C mutation were significantly associated with HCC, showing adjusted odds ratios (ORs) from 1.914 to 3.199. HCC patients also had a lower frequency of T31C mutation in pre-S2 gene, compared with control subjects (0.524; 95% CI 0.280-0.982). HBV pre-S deletions were clustered mainly in the 5′ end of pre-S2 region. Multivariate analysis showed that pre-S deletions and pre-S2 start codon mutations were independent risk factors for HCC. The OR (95% CI) were 2.434 (1.063–5.573) and 3.065 (1.099–8.547), respectively. The longitudinal observation indicated that the pre-S deletion mutations were not acquired at the beginning of HBV infection, but that the mutations occurred during the long course of liver disease.
Pre-S deletions and pre-S2 start codon mutations were independently associated with the development of HCC. The results also provided direct evidence that pre-S deletion mutations were not acquired from the beginning of infection but arose de novo during the progression of liver disease.
PMCID: PMC4029943  PMID: 24849936
9.  Structural Diversity of Class 1 Integrons and Their Associated Gene Cassettes in Klebsiella pneumoniae Isolates from a Hospital in China 
PLoS ONE  2013;8(9):e75805.
Klebsiella pneumoniae strains carrying class 1 integrons are becoming more common worldwide, and their role in the dissemination of drug resistance is significant. The aim of this study was to characterize the structural diversity of class 1 integrons and their associated gene cassettes in K. pneumoniae isolates from hospital settings.
Methodology/Principal Findings
We analyzed a total of 176 K. pneumoniae isolates in a tertiary-care hospital in Beijing, China for the period of November 1, 2010-October 31, 2011. The presence of class 1 integrons and gene cassettes was analyzed by PCR and sequencing. The prevalence of class 1 integrons was 51.1% (90/176). Fourteen different gene cassettes and 10 different gene cassette arrays were detected. dfrA and aadA cassettes were predominant and cassette combination dfrA1-orfC was most frequently found (13.6%, 24/176). Strong association between resistance to a variety of drugs (both phenotypes and the associated genes) and the presence of class 1 integrons was observed. In addition, we also identified an association between some previously identified prevalent sequence types (such as ST11, ST15, ST147, ST562, and ST716) and the presence of class 1 integrons.
Data from this study demonstrated that class 1 integrons are highly diverse and are associated with a variety of drug resistance phenotypes, drug resistance genes, as well as genotypes among K. pneumoniae isolates. Continuous monitoring of gene cassettes in class 1 integrons is warranted to improve the understanding and control of drug resistance among hospital settings.
PMCID: PMC3786929  PMID: 24098729
10.  Impact of beta2-agonists, beta-blockers, and their combination on cardiac function in elderly male patients with chronic obstructive pulmonary disease 
This study was undertaken to determine the association between cardiac function and therapy with beta2-adrenoceptor agonists (β2-agonists), β-blockers, or β-blocker–β-agonist combination therapy in elderly male patients with chronic obstructive pulmonary disease (COPD).
Patients and methods
This was a retrospective cohort study of 220 elderly male COPD patients (mean age 84.1 ± 6.9 years). The patients were divided into four groups on the basis of the use of β-blockers and β2-agonists. N-terminal fragment pro-B-type natriuretic peptide (NT pro-BNP), left ventricular ejection fraction (LVEF), and other relevant parameters were measured and recorded. At follow-up, the primary end point was all-cause mortality.
Multiple linear regression analysis revealed no significant associations between NT pro-BNP and the use of β2-agonists (β = 35.502, P = 0.905), β-blockers (β = 3.533, P = 0.989), or combination therapy (β = 298.635, P = 0.325). LVEF was not significantly associated with the use of β2-agonists (β = −0.360, P = 0.475), β-blockers (β = −0.411, P = 0.284), or combination therapy (β = −0.397, P = 0.435). Over the follow-up period, 52 patients died, but there was no significant difference in mortality among the four groups (P = 0.357). Kaplan–Meier analysis showed no significant difference among the study groups (log-rank test, P = 0.362). After further multivariate adjustment, use of β2-agonists (hazard ratio [HR] 0.711, 95% confidence interval [CI] 0.287–1.759; P = 0.460), β-blockers (HR 0.962, 95% CI 0.405–2.285; P = 0.930), or combination therapy (HR 0.638, 95% CI 0.241–1.689; P < 0.366) were likewise not correlated with mortality.
There was no association between the use of β2-agonists, β-blockers, or β-blocker-β2-agonist combination therapy with cardiac function and all-cause mortality in elderly male COPD patients, which indicated that they may be used safely in this population.
PMCID: PMC3783502  PMID: 24072964
β2-agonists; β-blockers; β-blocker; β2-agonist combination; elderly COPD patients; cardiac function; mortality
11.  Serum GP73 is complementary to AFP and GGT-II for the diagnosis of hepatocellular carcinoma 
Oncology Letters  2013;6(4):1152-1158.
Golgi protein 73 (GP73) is a resident Golgi type II transmembrane protein that has been reported to markedly increase in chronic liver disease, particularly in hepatocellular carcinoma (HCC). However, it remains unclear as to whether serum GP73 represents a reliable serum marker for the diagnosis of HCC. The aim of the present study was to evaluate the diagnostic value of serum GP73 in patients with HCC and to determine the diagnostic accuracy of measuring serum GP73 in combination with α-fetoprotein (AFP) and γ-glutamyl transferase isoenzyme II (GGT-II) in HCC. Serum GP73 was detected using a time-resolved fluorescence immunological assay (TRFIA) and enzyme-linked immunosorbent assay (ELISA) in 79 HCC cases, including 16 liver cirrhosis, 30 chronic hepatitis and 28 healthy individuals. The correlation between serum GP73 and tumor size and HCC grading was analyzed and the complementary diagnostic value of serum GP73, AFP and GGT-II was evaluated. TRFIA was established for the detection of serum GP73 and was sensitive and reproducible. The expression levels of serum GP73 were markedly higher in the patients with HCC when compared with those of the individuals with liver cirrhosis and chronic hepatitis or the healthy individuals. According to the receiver operating characteristic (ROC) curve, diagnostic sensitivity and specificity for HCC with a cut-off value of 78.1 ng/l were 73.4 and 79.0%, respectively. However, no correlation was identified among serum GP73 and tumor size or grading, and no correlations were identified among serum GP73, AFP and GGT-II. The diagnostic sensitivities for HCC, as detected by TRFIA of GP73, AFP and GGT-II, were 73.4, 55.6 and 68.4%, respectively, and the specificities were 80.0, 86.7 and 97.1%, respectively. The combined determination of these markers increased the diagnostic sensitivity to 96.3% for HCC. TRFIA functions as a sensitive and replicable assay for the detection of serum GP73. The levels of serum GP73 were significantly higher in the HCC group when compared with the individuals with benign liver diseases. Serum GP73 may serve as a potential independent diagnostic candidate for HCC and the combined determination of serum GP73, AFP and GGT-II may increase the diagnostic efficiency of HCC.
PMCID: PMC3796428  PMID: 24137480
time-resolved fluorescence immunological assay; golgi protein 73; hepatocellular carcinoma
12.  Lack of Association of MiR-34b/c Polymorphism (rs4938723) with Hepatocellular Carcinoma: A Meta-Analysis 
PLoS ONE  2013;8(7):e68588.
Previous studies have focused on the association of miR-34 family members with carcinogenesis of many cancers, including hepatocellular carcinoma (HCC). It has been suggested that miR-34b/c polymorphism (rs4938723) is associated with susceptibility to HCC. In the present study, we performed a meta-analysis to systematically summarize the possible association between rs4938723 and the risk for HCC.
Methodology/Principal Findings
We conducted a search of case-control studies on the associations of rs4938723 with susceptibility to HCC in PubMed, EMBASE, ISI Web of Science, Cochrane Central Register of Controlled Trials, ScienceDirect, Wiley Online Library, Wangfang database in China, and Chinese National Knowledge Infrastructure databases. Data from eligible studies were extracted for meta-analysis. HCC risk associated with rs4938723 was estimated by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). 3 studies on rs4938723 were included in our meta-analysis. Our results showed that neither allele frequency nor genotype distribution of the rs4938723 was associated with risk for HCC in all genetic models.
This meta-analysis suggests that rs4938723 is not associated with the risk of HCC. Well-designed studies with larger sample size and more ethnic groups are required to further validate the results.
PMCID: PMC3729562  PMID: 23935875
13.  Genotypic Analysis of Klebsiella pneumoniae Isolates in a Beijing Hospital Reveals High Genetic Diversity and Clonal Population Structure of Drug-Resistant Isolates 
PLoS ONE  2013;8(2):e57091.
The genetic diversity and the clinical relevance of the drug-resistant Klebsiella pneumoniae isolates from hospital settings are largely unknown. We thus conducted this prospective study to analyze the molecular epidemiology of K. pneumoniae isolates from patients being treated in the 306 Hospital in Beijing, China for the period of November 1, 2010–October 31, 2011.
Methodology/Principal Findings
Antibiotic susceptibility testing, PCR amplification and sequencing of the drug resistance-associated genes, and multilocus sequence typing (MLST) were conducted. A total of 163 isolates were analyzed. The percentage of MDR, XDR and PDR isolates were 63.8% (104), 20.9 (34), and 1.8% (3), respectively. MLST results showed that 60 sequence types (STs) were identified, which were further separated by eBURST into 13 clonal complexes and 18 singletons. The most dominant ST was ST15 (10.4%). Seven new alleles and 24 new STs were first identified in this study. Multiple logistic regression analysis revealed that certain clinical characteristics were associated with those prevalent STs such as: from ICU, from medical ward, from community acquired infection, from patients without heart disease, from patients with treatment success, susceptible to extended spectrum cephalosporin, susceptible to cephamycins, susceptible to fluoroquinolones, and with MDR.
Our data indicate that certain drug-resistant K. pneumoniae clones are highly prevalent and are associated with certain clinical characteristics in hospital settings. Our study provides evidence demonstrating that intensive nosocomial infection control measures are urgently needed.
PMCID: PMC3578803  PMID: 23437318
14.  Combined analysis of serum γ-glutamyl transferase isoenzyme II, α-L-fucosidase and α-fetoprotein detected using a commercial kit in the diagnosis of hepatocellular carcinoma 
γ-glutamyl transferase isoenzyme II (GGT-II) is a sensitive biomarker of hepatocellular carcinoma (HCC). However, numerous disadvantages of the traditional manual method affected its application. The commercial kit provided a convenient and fast method for the determination of GGT-II levels. The purposes of the present study were to compare the reproducibility and sensitivity between the manual and commercial kit methods and to evaluate the diagnostic efficiency for HCC with the combined analysis of GGT-II, α-L-fucosidase (AFU) and α-fetoprotein (AFP). In patients with various liver diseases (HCC, liver cirrhosis and chronic hepatitis) and normal subjects, GGT-II was detected by manual and commercial polyacrylamide gel electrophoresis (PAGE). The levels of AFU and AFP were assayed by colorimetry and a chemiluminescence immunoassay, respectively. The commercial PAGE had equal diagnostic efficiency with traditional manual PAGE and no significant differences were observed in intra- and average-gel reproducibility and GGT-II sensitivities between the manual and commercial PAGE (P>0.05). The incidence of GGT-II detected by commercial PAGE in HCC patients was 84.1% and <8% in benign liver disease. The levels of AFU and AFP in the benign liver diseases and normal subjects were lower than those in HCC. According to the cut-off value obtained by receiver operating characteristic curves, a total of 56.6 and 59.3% of HCC patients (64 out of 113 and 67 out of 113) had AFU >636.5 μmol/l h and AFP >44.0 μg/l, respectively. There were no significant correlations between GGT-II and AFU or AFP. Combined detection of GGT-II with AFU or AFP increased the diagnostic sensitivity to 92.9 and 93.8%, respectively. These results suggest that commercial PAGE provides a simple and reproducible method for GGT-II detection. Combined determination of GGT-II with AFU or AFP exhibited superior sensitivity and specificity for the diagnosis of HCC.
PMCID: PMC3524245  PMID: 23251247
γ-glutamyl transferase isoenzyme II; α-L-fucosidase; α-fetoprotein; hepatocellular carcinoma; diagnosis
15.  Ionic liquid-stabilized non-spherical gold nanofluids synthesized using a one-step method 
Nanoscale Research Letters  2012;7(1):583.
Ionic liquid (IL)-stabilized non-spherical gold nanofluids have been synthesized by a one-step method in aqueous solution. The whole reaction proceeded in room temperature. In the presence of amino-functionalized ionic liquids, gold nanofluids with long-wave surface plasmon resonance (SPR) absorption (>600 nm) could be obtained by adopting tannic acid as the reductant. The specific SPR absorption was related to the non-spherical gold nanoparticles including gold triangle, decahedra, and icosahedra nanocrystals. All the nanocrystals were observed by transmission electron microscopy. It was deduced that the formation of non-spherical gold nanofluids was related to the hydroxyls in tannic acid while IL acted as the synthesis template.
PMCID: PMC3484079  PMID: 23092303
Ionic liquid; Gold; Nanofluid; One-step method; Non-spherical
16.  Analysis of Drug Resistance Determinants in Klebsiella pneumoniae Isolates from a Tertiary-Care Hospital in Beijing, China 
PLoS ONE  2012;7(7):e42280.
The rates of multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) isolates among Enterobacteriaceae isolates, particularly Klebsiella pneumoniae, have risen substantially worldwide.
Methodology/Principal Findings
To better understand the molecular mechanisms of drug resistance in K. pneumoniae, we analyzed the drug resistance determinants for K. pneumoniae isolates collected from the 306 Hospital, a tertiary-care hospital in Beijing, China, for the period of September 1, 2010-October 31, 2011. Drug susceptibility testing, PCR amplification and sequencing of the drug resistance determinants were performed. Conjugation experiments were conducted to examine the natural ability of drug resistance to disseminate among Enterobacteriaceae strains using a sodium azide-resistant Escherichia coli J53 strain as a recipient. Among the 223 consecutive non-repetitive K. pneumoniae isolates included in this study, 101 (45.3%) were extended-spectrum beta-lactamases (ESBLs) positive. The rates of MDR, XDR, and PDR isolates were 61.4% (n = 137), 22.0% (n = 49), and 1.8% (n = 4), respectively. Among the tested drug resistance-associated genes, the following ones were detected at relatively high rates blaCTX-M-10 (80, 35.9%), aacC2 (73, 32.7%), dhfr (62, 27.8%), qnrS (58, 26.0%), aacA4 (57, 25.6%), aadA1 (56, 25.1%). Results from conjugation experiments indicate that many of the drug resistance genes were transmissible.
Our data give a “snapshot” of the complex genetic background responsible for drug resistance in K. pneumoniae in China and demonstrate that a high degree of awareness and monitoring of those drug resistance determinants are urgently needed in order to better control the emergence and transmission of drug-resistant K. pneumoniae isolates in hospital settings.
PMCID: PMC3409176  PMID: 22860106
17.  Association of cardiac and renal function with extreme N-terminal fragment Pro-B-type natriuretic peptide levels in elderly patients 
The data are inconsistent regarding whether extreme N-terminal fragment pro-B-type natriuretic peptide (NT pro-BNP) levels are associated with impaired renal function. Furthermore, the relationship between extreme NT pro-BNP levels and cardiac and renal function in elderly patients has not been reported. The aim of the present study was to examine a hypothesis that extreme NT pro-BNP levels may be associated with impaired cardiac and renal function in elderly patients.
We retrospectively analyzed the data of demographic, clinical, and echocardiographic features on 152 consecutive elderly patients aged more than 80 years old (average age, 83.65 ± 3.58 years) with NT pro-BNP levels ≥ 3000 pg/ml. The participants were divided into two categories according to their NT pro-BNP levels: (1) 3000–10000 pg/mL and (2) >10000 pg /mL.
The number of patients with impaired renal function (P = 0.019) and the mortality (P < 0.001) in the period of inpatient was higher in the group with NT pro-BNP > 10000 pg /mL. The levels of serum creatinine and creatine kinase MB (CK-MB) in the group of NT pro-BNP > 10000 pg / mL were higher than those in the group of NT pro-BNP = 3000-10000 pg/mL (P = 0.001 and P = 0.023, respectively). Furthermore, no significant difference in the distribution by NYHA class in different NT pro-BNP levels was observed. Multiple linear regression analyses demonstrated that with NT pro-BNP levels as the dependent variable, NT pro-BNP levels were positively correlated with CK-MB (β = 0.182, P = 0.024) and creatinine levels (β = 0.281, P = 0.001). The area under the receiver-operating characteristic (ROC) curve of NT pro-BNP levels and clinical diagnosis of impaired renal function was 0.596 and reached significant difference (95%CI:0.503-0.688, P = 0.044).
These data suggest that the extreme elevation of NT pro-BNP levels (≥3000 pg/ml) is mainly determined by impaired renal function in elderly patients above 80 years. Extreme NT pro-BNP levels may be useful for assessing the severity of impaired renal function.
PMCID: PMC3422193  PMID: 22834778
NT pro-BNP; Factors; Elderly; Impaired renal function
18.  2-Amino-4,6-dimeth­oxy­pyrimidin-1-ium 2,2-dichloro­acetate 
In the title salt, C6H10N3O2 +·C2HCl2O2 −, two cations and two anions are linked by N—H⋯O hydrogen bonds, forming chains along the c axis.
PMCID: PMC3379456  PMID: 22719654
19.  Diagnosis Analysis of 4 TCM Patterns in Suboptimal Health Status: A Structural Equation Modelling Approach 
Background. We illustrated an example of structure equation modelling (SEM) in the research on SHS to explore the diagnosis of the Sub optimal health status (SHS) and provide evidence for the standardization of traditional Chinese medicine (TCM) patterns in SHS. And the diagnosis of 4 TCM patterns in SHS was evaluated in this analysis. Methods. This study assessed data on 2807 adults (aged 18 to 49) with SHS from 6 clinical centres. SEM was used to analyze the patterns of SHS in TCM. Parameters in the introduced model were estimated by the maximum likelihood method. Results. The discussed model fits the SHS data well with CFI = 0.851 and RMSEA = 0.075. The direct effect of Qi deficiency pattern on dampness pattern had the highest magnitude (value of estimate is 0.822). With regard to the construct of “Qi deficiency pattern”, “fire pattern”, “stagnation pattern” and “dampness pattern”, the indicators with the highest load were myasthenia of limbs, vexation, deprementia, and dizziness, respectively. It had been shown that estimate factor should indicate the important degree of different symptoms in pattern. Conclusions. The weights of symptoms in the respective pattern can be statistical significant and theoretical meaningful for the 4 TCM patterns identification in SHS research. The study contributed to a theoretical framework, which has implications for the diagnosis points of SHS.
PMCID: PMC3329144  PMID: 22550544
20.  Prevalence of cardiovascular disease in subjects hospitalized due to chronic obstructive pulmonary disease in Beijing from 2000 to 2010 
To investigate the overall prevalence of cardiovascular disease (CVD) in subjects hospitalized for chronic obstructive pulmonary disease (COPD), and explore the prevalence of the major CVD complications and trends in patients with COPD over a 10-year period.
Medical records in the PLA General Hospital, Beijing Union Medical College Hospital, and Beijing Hospital from 2000/01/01 to 2010/03/03 were retrospectively reviewed. A total of 4960 patients with COPD were reviewed in the study (3570 males, mean age, 72.2 ± 10.5 years; 1390 females, mean age, 72.0 ± 10.4 years).
The prevalence of CVD in COPD patients was 51.7%. The three most prevalent CVDs were ischemic heart disease (28.9%), heart failure (19.6%), and arrhythmia (12.6%). During the 10-year study period, the prevalence of various CVDs in COPD patients showed a gradual increasing trend with increasing age. There was higher morbidity due to ischemic heart disease (P < 0.01) in male COPD patients than in the female counterparts. However, heart failure (P < 0.01) and hypertension (P < 0.01) occurred less frequently in male COPD patients than in female COPD patients. Furthermore, the prevalence of ischemic heart disease decreased year by year. In addition to heart failure, various types of CVD complications in COPD patients tended to occur in younger subjects. The prevalence of all major types of CVD in women tended to increase year by year.
The prevalence of CVD in patients hospitalized for COPD in Beijing was high. Age, sex and CVD trends, as well as life style changes, should be considered when prevention and control strategies are formulated.
PMCID: PMC3390099  PMID: 22783317
Prevalence; Cross-sectional investigation; Chronic obstructive pulmonary disease; Cardiovascular disease
21.  μ-4,4′-Bipyridine-bis­[aqua­(4-hy­droxy­pyridine-2,6-dicarboxyl­ato)copper(II)] 
The title compound, [Cu2(C7H3NO5)2(C10H8N2)(H2O)2], exhibits a centrosymmetric binuclear molecule. Each completely deprotonated 4-hy­droxy­pyridine-2,6-dicarb­oxy­lic acid mol­ecule assumes a tridentate chelating coordination mode. The square-pyramidal coordination geometry around the CuII ion is completed by the bridging bipyridine ligand and an apical water molecule. Adjacent complexes are connected via O—H⋯O and C—H⋯O hydrogen bonds to generate a three-dimensional supra­molecular structure.
PMCID: PMC3297272  PMID: 22412462
22.  R-848 triggers the expression of TLR7/8 and suppresses HIV replication in monocytes 
Toll-like receptors (TLR) 7 and 8 are important in single-stranded viral RNA recognition and may play a role in HIV infection and disease progression. We analyzed TLR7/8 expression and signaling in monocytes from HIV-infected and uninfected subjects to investigate a pathway with new potential for the suppression of HIV replication.
Eighty-one HIV-infected and uninfected subjects from Liaoning and Henan provinces in China participated in this study. Monocytes were isolated from subjects' peripheral blood mononuclear cells by magnetic bead selection. TLR7 and TLR8 mRNA was measured using quantitative real-time reverse transcriptase PCR. R-848 (resiquimod) was used as a ligand for TLR7 and TLR8 in order to 1) assess TLR7/8-mediated monocyte responsiveness as indicated by IL-12 p40 and TNF-α secretion and 2) to examine HIV replication in cultured monocytes in the presence of R-848.
We found that expression of TLR7/8 mRNA in peripheral blood monocytes decreased with disease progression. TLR7 expression was decreased with stimulation with the TLR7/8 agonist, R-848, in vitro, whereas TLR8 expression was unaffected. Following R-848 stimulation, monocytes from HIV-infected subjects produced significantly less TNF-α than those from uninfected subjects, but trended towards greater production of IL-12 than stimulated monocytes from uninfected subjects. R-848 stimulation also suppressed HIV replication in cultured monocytes.
Our study provides evidence that the TLR7 and TLR8 triggering can suppress HIV replication in monocytes and lead to postpone HIV disease progression, thereby offering novel targets for immunomodulatory therapy.
PMCID: PMC3274444  PMID: 22243920
Toll-like receptor; HIV; Monocytes; R-848
23.  ABO Blood Group and the Risk of Hepatocellular Carcinoma: A Case-Control Study in Patients with Chronic Hepatitis B 
PLoS ONE  2012;7(1):e29928.
Studies have observed an association between the ABO blood group and risk of certain malignancies. However, no studies of the association with hepatocellular carcinoma (HCC) risk are available. We conducted this hospital-based case-control study to examine the association with HCC in patients with chronic hepatitis B (CHB).
From January 2004 to December 2008, a total of 6275 consecutive eligible patients with chronic hepatitis B virus (HBV) infection were recruited. 1105 of them were patients with HBV-related HCC and 5,170 patients were CHB without HCC. Multivariate logistic regression models were used to investigate the association between the ABO blood group and HCC risk.
Compared with subjects with blood type O, the adjusted odds ratio (AOR) for the association of those with blood type A and HCC risk was 1.39 [95% confidence interval (CI), 1.05–1.83] after adjusting for age, sex, type 2 diabetes, cirrhosis, hepatitis B e antigen, and HBV DNA. The associations were only statistically significant [AOR (95%CI) = 1.56(1.14–2.13)] for men, for being hepatitis B e antigen positive [AOR (95%CI) = 4.92(2.83–8.57)], for those with cirrhosis [AOR (95%CI), 1.57(1.12–2.20)], and for those with HBV DNA≤105copies/mL [AOR (95%CI), 1.58(1.04–2.42)]. Stratified analysis by sex indicated that compared with those with blood type O, those with blood type B also had a significantly high risk of HCC among men, whereas, those with blood type AB or B had a low risk of HCC among women.
The ABO blood type was associated with the risk of HCC in Chinese patients with CHB. The association was gender-related.
PMCID: PMC3250489  PMID: 22235351
24.  Characteristics and Treatment Outcomes of Patients with MDR and XDR Tuberculosis in a TB Referral Hospital in Beijing: A 13-Year Experience 
PLoS ONE  2011;6(4):e19399.
Information on treatment outcomes among hospitalized patients with multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are scarce in China.
Methodology/Principal Findings
We conducted this retrospective study to analyze the characteristics and treatment outcomes in MDR- and XDR-TB patients in the 309 Hospital in Beijing, China during 1996–2009. Socio-demographic and clinical data were retrieved from medical records and analyzed. Logistic regression analysis was performed to identify risk factors associated with poor treatment outcomes and Cox proportional hazards regression model was further used to determine risk factors associated with death in TB patients. Among the 3,551 non-repetitive hospitalized TB patients who had drug susceptibility testing (DST) results, 716 (20.2%) had MDR-TB and 51 (1.4%) had XDR-TB. A total of 3,270 patients who had medical records available were used for further analyses. Treatment success rates (cured and treatment completed) were 90.9%, 53.4% and 29.2% for patients with non-MDR-TB, patients with MDR-TB excluding XDR-TB and patients with XDR-TB, respectively. Independent risk factors associated with poor treatment outcomes in MDR-TB patients included being a migrant (adjusted OR = 1.77), smear-positivity at treatment onset (adjusted OR = 1.94) and not receiving 3 or more potentially effective drugs (adjusted OR = 3.87). Independent risk factors associated with poor treatment outcomes in XDR-TB patients were smear-positivity at treatment onset (adjusted OR = 10.42) and not receiving 3 or more potentially effective drugs (adjusted OR = 14.90). The independent risk factors associated with death in TB patients were having chronic obstructive pulmonary disease (adjusted HR = 5.25) and having hypertension (adjusted HR = 4.31).
While overall satisfactory treatment success for non-MDR-TB patients was achieved, more intensive efforts should be made to better manage MDR- and XDR-TB cases in order to improve their treatment outcomes and to minimize further emergence of so-called totally drug-resistant TB cases.
PMCID: PMC3084844  PMID: 21559362
25.  5-Amino-7-(4-bromo­phen­yl)-3,7-di­hydro-2H-thieno[3,2-b]pyran-6-carbo­nitrile 1,1-dioxide 
In the title compound, C14H11BrN2O3S, the 2,3-dihydro­thio­phene ring is almost planar [maximum deviation = 0.006 (1) Å]. The pyran ring is in an envelope conformation [puckering parameters Q = 0.115 (2) Å, θ = 77.5 (10), ϕ = 172.9 (10)°]. The pyran and phenyl rings are approximately perpendicular, making a dihedral angle of −76.4 (2)°. The crystal packing is stabilized by inter­molecular N—H⋯O hydrogen bonds, with the sulfone O atoms acting as acceptors.
PMCID: PMC2979727  PMID: 21579705

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