学校结核病暴发控制策略研究进展

结核病暴发是我国面临的严重校园公共卫生挑战之一。笔者对学校结核病疫情面临的挑战、现场流行病学调查,以及结核病暴发处置的相关问题进行了综述,重点概述了结核病潜伏感染的筛检手段与干预措施研究进展。归纳得出：肺结核患者早期发现是控制结核病暴发的基本手段;暴露关系与PPD试验相结合是评价结核潜伏感染的有效手段;预防治疗方案的短程化与全程管理是提高潜伏感染者治疗依从性的关键,等等,为制定科学的学校结核病防控技术策略提供参考。     

学校结核病集团感染控制策略的初步研究

目的 评价PPD与γ干扰素释放试验（interferon-gamma release assay,IGRA） 在结核病集团感染评价中的价值,探索控制集团感染的最佳策略。 方法 在一起结核病暴发事件中,将513名接触者按照暴露程度分为6级,由高到低（1级至6级）接触者数量依次为：47、81、110、90、122和63名,对接触者进行PPD与IGRA联合检测。采用多分类logistic回归分析统计不同Mtb感染判断标准（PPD≥10 mm、PPD≥15 mm、PPD阳转及IGRA阳性）与暴露等级的相关性;在删除40例行预防性治疗的接触者后,采用二分类logistic回归分析确定患者续发（共19例续发患者）的高风险因子;比较不同暴露等级、不同感染判断标准的发病率,同时评价各种感染控制方案的优劣。 结果 PPD≥10 mm、PPD≥15 mm、PPD阳转和IGRA阳性结果与暴露等级（6级）均密切相关,P＜0.05,OR值分别为1.78（95%CI：1.14～2.78）、1.01（95%CI：0.69～1.47）和2.84（95%CI：2.01～4.01）;IGRA阳性 (P=0.03,OR=3.63)与暴露程度 (P=0.00,OR=2.77)是患者续发的高风险因子。高密切接触等级（L1～L2）、中密切接触等级（L3～L4）和低密切接触等级（L5～L6）的续发率分别为13.3%(13/98)、3.2%(6/190)和0.0%(0/185)。高密切接触等级的续发病率显著高于低暴露等级,差异具有统计学意义,χ²=29.85,P＜0.05。IGRA阳性组发病率为8.3%（15/180）,显著高于IGRA阴性组的1.4%（4/293）,具有统计学意义,χ²=14.04,P＜0.05;对于高暴露等级（1级）无论PPD及IGRA结果如何,全部进行化学预防,对其他等级均依据IGRA阳性作为预防性治疗对象,其发病预测的敏感度为94.7%(18/19),特异度为46.1%（124/269）,阳性似然比为1.8,阴性似然比为0.1,符合最佳效益原则。 结论 IGRA在结核感染诊断和发病预测等价值方面优于PPD;暴露程度和IGRA阳性是制定集团感染控制策略的重要参考条件。     

Calpeptin provides functional neuroprotection to rat retinal ganglion cells following Ca2+ influx

Apoptosis of retinal ganglion cells (RGCs) impairs vision in glaucoma patients. RGCs are also degenerated in multiple sclerosis (MS), resulting in loss of visual perception in MS patients. We examined the involvement of calpain and caspase cascades in apoptosis of the rat retinal ganglion cell line RGC-5 following 24 h of exposure to 250 nM ionomycin (IMN) or 300 units/ml interferon-gamma (IFN-gamma) and then evaluated functional neuroprotection with 2 microM calpeptin (CP, a calpain-specific inhibitor). Morphological and biochemical features of apoptosis were detected in RGC-5 cells following exposure to IMN or IFN-gamma. Fura-2 assay determined significant increases in intracellular free [Ca2+] following exposure to IMN or IFN-gamma. Pretreatment with CP for 1 h prevented Ca2+ influx, proteolytic activities, and apoptosis in RGC-5 cells. Western blot analyses showed an increase in activities of calpain and caspase-12, upregulation of Bax:Bcl-2 ratio, release of cytochrome c from mitochondria, and increase in caspase-9 and caspase-3 activities during apoptosis. Increased caspase-3 activity was also confirmed by a colorimetric assay. Activation of caspase-8 and cleavage of Bid to tBid in RGC-5 cells following exposure to IFN-gamma indicated co-operation between extrinsic and intrinsic pathways of apoptosis. Patch-clamp recordings showed that pretreatment with CP attenuated apoptosis and maintained normal whole-cell membrane potential, indicating functional neuroprotection. Taken together, our results demonstrated that Ca2+ overload could be responsible for activation of calpain and caspase cascades leading to apoptotic death of RGC-5 cells and CP provided functional neuroprotection.     

Cost effectiveness of high resolution computed tomography with interferon-gamma release assay for tuberculosis contact investigation

Background

Tuberculosis contact investigation is one of the important public health strategies to control tuberculosis worldwide. Recently, high resolution computed tomography (HRCT) has been reported as a more accurate radiological method with higher sensitivity and specificity than chest X-ray (CXR) to detect active tuberculosis. In this study, we assessed the cost effectiveness of HRCT compared to CXR in combination with QuantiFERON^®-TB Gold In-Tube (QFT) or the tuberculin skin test (TST) for tuberculosis contact investigation.

Methods

We constructed Markov models using a societal perspective on the lifetime horizon. The target population was a hypothetical cohort of immunocompetent 20-year-old contacts with smear-positive tuberculosis patients in developed countries. Six strategies; QFT followed by CXR, QFT followed by HRCT, TST followed by CXR, TST followed by HRCT, CXR alone and HRCT alone were modeled. All costs and clinical benefits were discounted at a fixed annual rate of 3%.

Results

In the base-case analysis, QFT followed by HRCT strategy yielded the greatest benefit at the lowest cost ($US 6308.65; 27.56045 quality-adjusted life-years [QALYs])[year 2012 values]. Cost-effectiveness was sensitive to BCG vaccination rate.

Conclusions

The QFT followed by HRCT strategy yielded the greatest benefits at the lowest cost. HRCT chest imaging, instead of CXR, is recommended as a cost effective addition to the evaluation and management of tuberculosis contacts in public health policy.     

梅毒血清固定与外周血调节性T细胞及血清IL-6、IL-10、IFN-γ的关系探讨

目的：探讨调节性T细胞的变化与白细胞介素10、6（IL-6,10）、干扰素-γ（IFN-γ）在梅毒血清固定机制中的作用。方法：流式细胞仪测定112例梅毒血清固定患者,155例梅毒血清转阴患者和58例正常人的外周血调节性T细胞及其特异性因子Foxp3的表达;酶联免疫吸附试验（ELISA）方法检测其血清IL-6,IL-10和IFN-γ的水平。结果：梅毒血清固定患者外周血CD4＋的表达为（1.95±0.66%）,而其中调节性T细胞比例为（24.5±7.63%）,较两组对照组均显著升高（P〈0.01）,CD4＋T细胞内转录因子Foxp3表达量（2272.7±876.8）明显高于两组对照组（P〈0.01）;与对照组相比,梅毒血清固定患者IL-6、IFN-γ水平较低而IL-10水平较高（P〈0.01）;血清转阴患者与健康献血者三者水平差异无显著性（P〉0.05）。结论：调节性T细胞比例的升高以及Th1/Th2比例失衡可能导致了梅毒血清固定。     

Interferon-gamma in ascites could be a predictive biomarker of outcome in ovarian carcinoma

Objective

The ovarian cancer-associated ascites is an ideal material for evaluating the interaction between the host immune system and cancer cells in the tumor micro-environment. The aim of this study was to investigate whether the selected target cytokine expression levels in ascites could serve as an immune biomarker for predicting outcomes in ovarian cancer.

Methods

Eighty-eight specimens of ovarian cancer-associated ascites were evaluated to select the target cytokine by a cytokine profiling kit. The 144 total samples were subsequently analyzed for this target cytokine. The correlation between the target cytokine and clinical characteristics was analyzed.

Results

Interferon-gamma (IFN-γ) was identified as the target cytokine. Higher levels of IFN-γ in the ascites of the tumor micro-environment were associated with advanced disease (p = 0.012), higher tumor histological grading (p = 0.004), and sub-optimal surgical status (p = 0.040). By multivariate analysis, the adjusted hazard ratios (HRs) were 2.74 (95% confidence interval (CI) 1.85–4.05, p < 0.001) for disease-free survival (DFS) and 1.72 (95% CI 1.01–2.93, p = 0.048) for overall survival (OS) for a 10-fold increase in IFN-γ concentration in the ascites. An inverse dose–response relationship between IFN-γ level and survival was also noted (P_trend < 0.001 for DFS and P_trend < 0.042 for OS).

Conclusions

Patients with ovarian cancer and higher IFN-γ expression levels in cancer-associated ascites will have shorter DFS and OS. IFN-γ levels in the ascites may be a prognostic marker and a potential reference for immunotherapy targeting IFN-γ.     

Induction of mRNA for HLA-DRβ in human keratinocytes cocultured with interferon-gamma

Summary Explanted human keratinocytes exposed in vitro to recombinant interferon-gamma (IFN-) were investigated for the appearance of mRNA for HLA-DR. Using in situ hybridization with a (³⁵S)UTP-labelled HLA-DR cRNA probe, mRNA-positive cells were detected already within 6 h with maximal numbers of positive cells as well as the amount of mRNA per cell after 48 h. The corresponding protein HLA-DR, as analysed by immunoperoxidase staining, was detected on 20%–40% of the cells after 24 h and on almost all cells within 48 h. The expression of HLA-DQ and-DP antigens were always exceeded by that of HLA-DR. Whereas an increase in the concentration of IFN- above 50 U/ml did not affect the maximal level of HLA-DR reactive cells, there was a fourfold increase in the frequency of cells reactive with HLA-DQ and a twofold increase for HLA-DP when the IFN- concentration was raised from 50 to 500 U/ml. When IFN- was withdrawn from the cultures, HLA-DR mRNA and protein synthesis ceased — indicating the continuous need for IFN- to maintain the HLA-DR synthesis in keratinocytes.     

Interleukin-18 and interleukin-12 synergistically inhibit osteoclastic bone-resorbing activity

The effect of interleukin (IL)-18 on osteoclastic bone-resorbing activity was investigated in vitro. Osteoclast-enriched cells, about 70% of which were tartrate-resistant acid phosphatase (TRAP)-positive, were cultured on dentine slices, and then the total volume of resorption pits on each dentine slice was measured as bone-resorbing activity. When the effects of IL-18 alone at 1, 10, 100, and 1000 ng/mL were examined, bone-resorbing activity was significantly reduced only at 1000 ng/mL, by about 50%. However, IL-18 plus IL-12 (10 ng/mL each) reduced bone-resorbing activity by about 70%, whereas IL-12 alone had no significant effect. When the concentration of interferon (IFN)-γ in the medium was measured, IL-18 or IL-12 was found to increase it slightly, and the combination of these two cytokines synergistically increased it. The inhibitory effect of the combination of the two cytokines was completely abolished by the addition of an anti-IFN-γ neutralizing antibody to the medium, but IFN-γ by itself did not inhibit osteoclastic bone resorption. IL-18 alone or in combination with IL-12 did not affect the number of TRAP-positive cells in culture of osteoclast-enriched cells. Osteoclasts prepared from osteoclast-enriched cells expressed mRNAs of IL-18 receptor, MyD88, and cathepsin K. Furthermore, IL-18 receptor protein was detected on the cell surface of osteoclasts. The present results indicate that the combination of IL-18 and IL-12 synergistically inhibits osteoclastic bone-resorbing activity, suggesting that IFN-γ participates in the mechanism underlying this inhibition.