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Shen H.,Nanjing Medical University | Min R.,Nanjing Medical University | Tan Q.,Nanjing Medical University | Xie W.,Nanjing Medical University | And 6 more authors.
Archives of Medical Science | Year: 2015

Introduction: Multidrug-resistant tuberculosis (MDR-TB) is a hard-to-treat disease with a poor outcome of chemotherapy. In the present study, the efficacy and safety of recombinant human interleukin-2 (rhIL-2) were investigated in patients with MDR-TB. Material and methods: Fifty culture-confirmed patients with MDR-TB were included. Twenty-five patients were randomly assigned to the trial group (injection of 500 000 IU of rhIL-2 once every other day at the first, third, fifth and seventh months in addition to standard multidrug therapy) and another 25 patients to the control group with standard multidrug therapy. All patients were monitored clinically, and T-cell subsets were analyzed by flow cytometry. Results: The rates of sputum negative conversion and X-ray resolution in the trial group were higher than those of the control, and the improvements were significant by completion of treatment. In addition, CD4+CD25 + T cells in the controls rose gradually during treatment. The levels at the end of the seventh month were significantly higher than before, which were also significantly different when compared with those from the trial group at the same time. However, there were no such changes associated with treatment in the trial group. No significant differences appeared in other T cell subsets. Conclusions: Exogenous IL-2 in the present regimen improves immunity status. Adjunctive immunotherapy with a long period of rhIL-2 is a promising treatment modality for MDR-TB. Copyright © 2015 Termedia & Banach.


Dai Y.,Nanjing Medical University | Zhang X.,Nanjing Chest Hospital | Pan H.,Third Hospital of Zhenjiang City | Tang S.,Nanjing Medical University | And 2 more authors.
BMC Infectious Diseases | Year: 2011

Background: Recently, one genome-wide association study identified a susceptibility locus of rs4331426 on chromosome 18q11.2 for tuberculosis in the African population. To validate the significance of this susceptibility locus in other areas, we conducted a case-control study in the Chinese population.Methods: The present study consisted of 578 cases and 756 controls. The SNP rs4331426 and other six tag SNPs in the 100 Kbp up and down stream of rs4331426 on chromosome 18q11.2 were genotyped by using the Taqman-based allelic discrimination system.Results: As compared with the findings from the African population, genetic variation of the SNP rs4331426 was rare among the Chinese. No significant differences were observed in genotypes or allele frequencies of the tag SNPs between cases and controls either before or after adjusting for age, sex, education, smoking, and drinking history. However, we observed strong linkage disequilibrium of SNPs. Constructed haplotypes within this block were linked the altered risks of tuberculosis. For example, in comparison with the common haplotype AA (rs8087945-rs12456774), haplotypes AG (rs8087945-rs12456774)and GA (rs8087945-rs12456774)were associated with a decreased risk of tuberculosis, with the adjusted odds ratio(95% confidence interval) of 0.34(0.27-0.42) and 0.22(0.16-0.29), respectively.Conclusions: Susceptibility locus of rs4331426 discovered in the African population could not be validated in the Chinese population. None of genetic polymorphisms we genotyped were related to tuberculosis in the single-point analysis. However, haplotypes on chromosome 18q11.2 might contribute to an individual's susceptibility. More work is necessary to identify the true causative variants of tuberculosis. © 2011 Dai et al; licensee BioMed Central Ltd.


Tan Q.,Nanjing Medical University | Xie W.P.,Nanjing Medical University | Min R.,Nanjing Medical University | Dai G.Q.,Nanjing Medical University | And 6 more authors.
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2012

Multidrug-resistant tuberculosis (MDR-TB) has become a lethal global threat. Insights into the immune regulation of MDR-TB are urgently needed for the development of new treatments; however, the T cell response to an MDR-TB infection in human remains unclear. In the present study, the proportion of Th1 and Th2 cell subsets and the level of related T cell subset cytokines in peripheral blood were investigated. We detected that an MDR-TB infection resulted in suppressed Th1 and Th2 cell activation, which was more remarkable in patients with MDR-TB than that in drug-sensitive tuberculosis (DS-TB) sufferers when compared to healthy controls (HCs). In addition, MDR-TB infection down-regulated the expression of IFN-γ, IL-2, and IL-10, and up-regulated IL- 4, IL-6, and TNF-γ expression. Our data suggest that the disturbance between protective and pathogenic effects induced by the immunosuppression of Th1- and Th2-type responses is a substantial characteristic of MDR-TB infections. © Springer-Verlag 2011.


Feng Y.,Centers for Disease Control and Prevention | Feng Y.,Nanjing Medical University | Wang F.,Nanjing Medical University | Pan H.,Third Hospital of Zhenjiang City | And 5 more authors.
BMC Infectious Diseases | Year: 2014

Background: Obesity is known to affect cell-mediated immune responses. Recent studies have revealed that genetic polymorphisms in the fat mass and obesity associated (FTO) gene are related to human obesity. We hypothesize that this gene may also play a role in the risk of immune-related infectious diseases such as tuberculosis. Methods: This case-control study included 1625 pulmonary tuberculosis cases and 1570 unaffected controls recruited from the Jiangsu province in China. Single nucleotide polymorphisms (SNPs), rs9939609 and rs8050136, in the FTO gene were genotyped using TaqMan allelic discrimination assays. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the unconditional logistic regression model. Results: We observed a significant association between the genetic polymorphism rs9939609 and tuberculosis risk. Compared with the common genotype TT, individuals carrying AA had a significantly increased risk, with an OR of 3.77 (95% CI: 2.26-6.28). After adjusting for potential confounders, the relationship remains significant. An additive model showed that carriers of an allele A had a 26% increased risk of tuberculosis compared with the T allele (OR: 1.26, 95% CI: 1.08-1.48). Compared with the common haplotype rs9939609T-rs8050136C, the haplotype rs9939609A-rs8050136C was related to an increased risk of tuberculosis (OR = 6.09, 95% CI: 3.27-12.34). Conclusions: The FTO polymorphism rs9939609 is associated with a risk of pulmonary tuberculosis in the Chinese population.


Pan H.-Q.,Third Hospital of Zhenjiang City | Pan H.-Q.,Nanjing Medical University | Bele S.,Nanjing Medical University | Feng Y.,Nanjing Medical University | And 6 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2013

SETTING: A county in Jiangsu Province, China. OBJECTIVES: To estimate the costs of the diagnosis and treatment of tuberculosis (TB) from the patient's perspective and to identify determinants of the patient's financial burden. DESIGN: In a cross-sectional survey, we interviewed 316 patients diagnosed from January 2010 to May 2011 who had already completed their anti-tuberculosis treatment. The financial burden on TB patients included out-of-pocket costs and productivity losses. RESULTS: The average per capita total out-of-pocket cost was 3024.0 Chinese yuan (CNY), with a median cost of 1086 CNY (interquartile range [IQR] 480-2456). Mean out-of-pocket medical and non-medical costs were respectively 2565.7 CNY and 458.3 CNY. Productivity lost by patients and family members was 2615.2 CNY (median 500, IQR 250-2025). Factors associated with out-of-pocket costs and productivity losses included hospitalisation, adverse drug reactions, cost of drugs to 'protect' the liver, cost of second-line anti-tuberculosis drugs and diagnostic delay. CONCLUSION: Although the government of China has implemented a 'free TB service policy', the economic burden on patients is still heavy. More patient-centred interventions are essential to reduce the financial burden on patients. © 2013 The Union.


Zhang M.,Nanjing Medical University | Ge G.,Third Hospital of Zhenjiang City | Yang Y.,Red Cross | Cai X.,Red Cross | And 3 more authors.
Virology Journal | Year: 2013

Background: Selective pressure from either the immune response or the use of nucleoside analogs in antiviral therapy could be driving the emergence of HBV mutants. Because of the overlap of the open reading frame (ORF) S for the HBsAg and ORF P for viral polymerase, rtM204I and rtM204V mutations in the polymerase would produce sI195M and sW196S in the HBsAg. The combined effects of immune-escaped mutations (sT118M, sG145K, sG145R) and drug-resistant mutations (rtM204I, rtM204V) on the antigenicity profiles of HBsAg has not been widely explored. Methods. To determine the combined effects of immune-escaped and drug-resistant mutants on the antigenicity profiles of HBsAg, recombinant plasmids encoding HBsAg double mutants were constructed using site-directed mutagenesis. The supernatant from each plasmid transfection was analyzed for HBsAg in the western-blotting and five of the most commonly used commercial ELISA kits in China. Results: Western-blotting assay showed the successful expression of each HBsAg mutant. All five ELISA kits manifested similar avidity, which were demonstrated by the slope of the curves, for the sT118M mutant, and sT118M-rtM204I (sT118M-sI195M) and sT118M-rtM204V (sT118M-sW196S) double mutants, suggesting that drug-resistant YMDD mutants caused negligible losses in the antigenicity of immune-escaped sT118M HBsAg. In contrast, the presence of the rtM204I (sI195M) mutation, but not rtM204V (sW196S) in combination with the sG145K mutation significantly reduced the avidity of sG145K HBsAg. The rtM204I (sI195M) mutation also decreased the antigenicity profiles for sG145R HBsAg. Conclusions: Drug-resistant mutations rtM204I (sI195M) and rtM204V (sW196S) caused significant reduction in antigenicity for the immune-escaped HBsAg mutants sG145K and sG145R, which may hamper HBV diagnosis and disease control from HBV blood-transfusion transmissions in China. The development of ELISA kits with a greater sensitivity for drug-resistant and immune-escaped HBsAg warrants further consideration. © 2013 Zhang et al.; licensee BioMed Central Ltd.


Pan H.,Third Hospital of Zhenjiang City | Dai Y.,Nanjing Medical University | Tang S.,Nanjing Medical University | Wang J.,Nanjing Medical University
International Journal of Immunogenetics | Year: 2012

A genome-wide association study (GWAS) of leprosy reported four specific genetic polymorphisms of NOD2 that were associated with susceptibility to Mycobacterium leprae in China. Considering the role of NOD2 in innate immune defence, we performed a study in a Chinese population to determine whether the same SNPs of NOD2 that were associated with disease caused by M. leprae were also associated with disease caused by Mycobacterium tuberculosis. We performed a frequency-matched case-control study in 1043 patients with pulmonary tuberculosis and 808 unaffected controls. All subjects were >15years old and were Han Chinese from Jiangsu Province. We extracted DNA from a blood sample from each study participant. SNPs of rs3135499, rs7194886, rs8057341 and rs9302752 in the NOD2 gene were genotyped using a TaqMan-based allelic discrimination system. Using all possible patients with tuberculosis as cases, no significant association was found between the four specific SNPs and the risk of tuberculosis. In a subgroup analysis restricted to cases with bacteriologically confirmed tuberculosis (sputum culture positive), the variant genotype of rs7194886 was significantly associated with an altered risk of tuberculosis. Compared with the CC genotype, individuals carrying the CT/TT genotype of rs7194886 had an increased risk [odds ratio (OR) 1.35, 95% confidence interval (CI) (1.05-1.72)]. The association was stronger among tobacco smokers and males. By haplotype analysis, rs9302752C-rs7194886T was associated with an increased risk of bacteriologically confirmed tuberculosis (sputum culture positive) (P=0.039), but it was not significant after correcting for multiple comparisons. In summary, genetic polymorphisms of the SNP rs7194886 in the NOD2 gene, which were discovered in the GWAS of leprosy, might also be associated with the pulmonary tuberculosis in the Chinese population. © 2012 Blackwell Publishing Ltd.


Lu J.,Nanjing Medical University | Pan H.,Nanjing Medical University | Pan H.,Third Hospital of Zhenjiang City | Chen Y.,Third Hospital of Zhenjiang City | And 9 more authors.
Gene | Year: 2014

Objective: Genetic host factors play an important role in controlling individual's susceptibility to the pathogen. This study aims to explore the single and joint effect of genetic polymorphisms of interferon-gamma (IFNG) and its receptor (IFNGR1) in association with the pulmonary tuberculosis in a Chinese Han population. Methods: This population-based case control study consisted of 1434 pulmonary tuberculosis patients and 1412 healthy controls. Six tag SNPs in IFNG/IFNGR1 were genotyped using TaqMan allelic discrimination technology. The logistic regression model was carried out to analyze the associations between the genotypes and haplotypes and the risk of tuberculosis by calculating the odds ratio (OR) and 95% confidence interval (CI). Results: After the Bonferroni correction for multiple comparisons, three SNPs (rs2234711, rs1327475 and rs7749390) in IFNGR1 gene were observed to be significantly associated with the altered risks of tuberculosis. For the SNP rs2234711, individuals carrying C allele (vs. T) showed a decreased risk, with the adjusted OR(95% CI) of 0.82(0.76-0.91). The additive model revealed that each additional allele contributed about 14% decreased risk (OR: 0.86, 95% CI: 0.77-0.95). Moreover, we observed a strong linkage disequilibrium between rs2234711 and rs3799488. Compared with the common rs2234711C-rs3799488C haplotype, the haplotype rs2234711T-rs3799488C contributed to a significant increase in the risk of tuberculosis (adjusted OR: 1.24, 95% CI: 1.09-1.41). Conclusions: Our results suggest that genetic polymorphisms in IFNGR1 gene are involved in the risk of tuberculosis in the Chinese population. Future studies should include a comprehensive sequencing analysis to identify the specific causative sequence variants underlying the observed associations. © 2014 Elsevier B.V.


PubMed | Nanjing Medical University and Third Hospital of Zhenjiang City
Type: Comparative Study | Journal: PloS one | Year: 2015

China has implemented a free-service policy for tuberculosis. However, patients still have to pay a substantial proportion of their annual income for treatment of this disease. This study describes the economic burden on patients with tuberculosis; identifies related factors by comparing two areas with different management models; and provides policy recommendation for tuberculosis control reform in China.There are three tuberculosis management models in China: the tuberculosis dispensary model, specialist model and integrated model. We selected Zhangjiagang (ZJG) and Taixing (TX) as the study sites, which correspond to areas implementing the integrated model and dispensary model, respectively. Patients diagnosed and treated for tuberculosis since January 2010 were recruited as study subjects. A total of 590 patients (316 patients from ZJG and 274 patients from TX) were interviewed with a response rate of 81%. The economic burden attributed to tuberculosis, including direct costs and indirect costs, was estimated and compared between the two study sites. The Mann-Whitney U Test was used to compare the cost differences between the two groups. Potential factors related to the total out-of-pocket costs were analyzed based on a step-by-step multivariate linear regression model after the logarithmic transformation of the costs.The average (median, interquartile range) total cost was 18793.33 (9965, 3200-24400) CNY for patients in ZJG, which was significantly higher than for patients in TX (mean: 6598.33, median: 2263, interquartile range: 983-6688) (Z = 10.42, P < 0.001). After excluding expenses covered by health insurance, the average out-of-pocket costs were 14304.4 CNY in ZJG and 5639.2 CNY in TX. Based on the multivariable linear regression analysis, factors related to the total out-of-pocket costs were study site, age, number of clinical visits, residence, diagnosis delay, hospitalization, intake of liver protective drugs and use of the second-line drugs.Under the current free of diagnosis and treatment policy, the financial burden remains heavy on tuberculosis patients. Policy makers need to consider appropriate steps to lessen the burden of out-of-pocket costs for tuberculosis patients in China and how best to improve service delivery for poor patients.


PubMed | Third Hospital of Zhenjiang City
Type: Journal Article | Journal: International journal of immunogenetics | Year: 2012

A genome-wide association study (GWAS) of leprosy reported four specific genetic polymorphisms of NOD2 that were associated with susceptibility to Mycobacterium leprae in China. Considering the role of NOD2 in innate immune defence, we performed a study in a Chinese population to determine whether the same SNPs of NOD2 that were associated with disease caused by M. leprae were also associated with disease caused by Mycobacterium tuberculosis. We performed a frequency-matched case-control study in 1043 patients with pulmonary tuberculosis and 808 unaffected controls. All subjects were >15 years old and were Han Chinese from Jiangsu Province. We extracted DNA from a blood sample from each study participant. SNPs of rs3135499, rs7194886, rs8057341 and rs9302752 in the NOD2 gene were genotyped using a TaqMan-based allelic discrimination system. Using all possible patients with tuberculosis as cases, no significant association was found between the four specific SNPs and the risk of tuberculosis. In a subgroup analysis restricted to cases with bacteriologically confirmed tuberculosis (sputum culture positive), the variant genotype of rs7194886 was significantly associated with an altered risk of tuberculosis. Compared with the CC genotype, individuals carrying the CT/TT genotype of rs7194886 had an increased risk [odds ratio (OR) 1.35, 95% confidence interval (CI) (1.05-1.72)]. The association was stronger among tobacco smokers and males. By haplotype analysis, rs9302752C-rs7194886T was associated with an increased risk of bacteriologically confirmed tuberculosis (sputum culture positive) (P = 0.039), but it was not significant after correcting for multiple comparisons. In summary, genetic polymorphisms of the SNP rs7194886 in the NOD2 gene, which were discovered in the GWAS of leprosy, might also be associated with the pulmonary tuberculosis in the Chinese population.

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