CISH基因多态性与结核病易感性的相关性研究

目的:寻找肺结核的易感位点,探索宿主遗传因素差异对肺结核发病的影响,为肺结核的预防和药物研发提供理论依据。方法:对1218名汉族居民进行病例对照研究,其中病例组600例,对照组618例,进行流行病学调查和生化指标检查。运用限制性片段长度多态性聚合酶链反应(PCR-RFLP)技术检测CISH基因rs2239751和rs622502的基因型分布,探讨CISH基因多态性与中国汉族人群肺结核易感性的关联性。结果:CISH基因的rs2239751和rs622502等位基因分布均符合Hardy-Weinberg(H-W)遗传平衡定律(P0.05)。rs2239751位点基因型和等位基因分布在两组间差异有统计学意义,P值分别为0.013和0.01,并且携带C等位基因个体患肺结核的风险是携带A等位基因的个体1.16倍(95%CI=1.03-1.29,P=0.01)。rs2239751基因分型结果在女性病例组和对照组中差异有统计学意义,P值为0.007,OR(95%CI)为1.51(1.12-2.03)。rs2239751基因分型结果在45岁人群病例组和对照组中差异有统计学意义,P值为0.010,OR(95%CI)为1.32(1.07-1.64)。rs622502位点基因型和等位基因分布在两组间差异均无统计学意义(P0.05)。结论:在汉族人群中,rs2239751位点多态性可能是肺结核的危险因素之一,C等位基因为风险等位基因。rs2239751基因多态性与肺结核的关联性仅限于于女性和45岁人群。rs622502位点多态性可能与肺结核无关。     

Comparing epidemic tuberculosis in demographically distinct heterogeneous populations

There is wide variation in endemic tuberculosis (TB) levels between countries and we seek to identify possible causes of these differences. In this study we present an epidemiological model of Mycobacterium tuberculosis infection to investigate the effects of host genetics and demographic factors on epidemic TB. We discuss the general framework for this approach and present analytical results to identify important parameters affecting steady-state prevalence and incidence rates of TB disease. We then use numerical simulations of our model to observe the effects of a genetically susceptible subpopulation on TB disease dynamics at the population level. Finally, we simulate infection within a genetically heterogeneous population in two demographic settings: India (a typical population with high TB prevalence) and the USA (a typical population with low TB prevalence). Results show that changes in transmission parameters, the fraction of the population genetically susceptible to infection, and demographic factors strongly affect TB prevalence and incidence rates.     

Vitamin D supplementation promotes macrophages' anti-mycobacterial activity in type 2 diabetes mellitus patients with low vitamin D receptor expression

The increasing number of people with type 2 diabetes (DM2) is alarming and if it is taken into account that the relative odds of developing tuberculosis in diabetic patients ranges from 2.44 to 8.33 compared with non-diabetic patients, thus in developing countries where these two diseases are encountering face to face, there is a need for prophylaxis strategies. The role of vitamin D has been widely implicated in growth control of Mycobacterium tuberculosis (Mtb) during primary infection mainly through the induction of certain antimicrobial peptides (AMPs). In this study we evaluated the vitamin D serum levels, CYP27B1-hydroxylase enzyme, vitamin D receptor (VDR) and AMPs gene expression in Healthy donors, DM2 and TB patients. Results showed that DM2 group has lower VDR and AMPs expression levels. When Monocytes Derived Macrophages (MDM) from DM2 patients with low VDR expression were supplemented with vitamin D, MDMs eliminate efficiently M. tuberculosis. This preliminary study suggests the use of vitamin D as prophylaxis for tuberculosis in high DM2 endemic countries.     

A medicinal chemists’ guide to the unique difficulties of lead optimization for tuberculosis

Tuberculosis is a bacterial disease that predominantly affects the lungs and results in extensive tissue pathology. This pathology contributes to the complexity of drug development as it presents discrete microenvironments within which the bacterium resides, often under conditions where replication is limited and intrinsic drug susceptibility is low. This consolidated pathology also results in impaired vascularization that limits access of potential lead molecules to the site of infection. Translating these considerations into a target-product profile to guide lead optimization programs involves implementing unique in vitro and in vivo assays to maximize the likelihood of developing clinically meaningful candidates.     

Modelling local and global effects on the risk of contracting Tuberculosis using stochastic Markov-chain models

For some diseases, the transmission of infection can cause spatial clustering of disease cases. This clustering has an impact on how one estimates the rate of the spread of the disease and on the design of control strategies. It is, however, difficult to assess such clustering, (local effects on transmission), using traditional statistical methods. A stochastic Markov-chain model that takes into account possible local or more dispersed global effects on the risk of contracting disease is introduced in the context of the transmission dynamics of tuberculosis. The model is used to analyse TB notifications collected in the Asembo and Gem Divisions of Nyanza Province in western Kenya by the Kenya Ministry of Health/National Leprosy and Tuberculosis Program and the Centers for Disease Control and Prevention. The model shows evidence of a pronounced local effect that is significantly greater than the global effect. We discuss a number of variations of the model which identify how this local effect depends on factors such as age and gender. Zoning/clustering of villages is used to identify the influence that zone size has on the model’s ability to distinguish local and global effects. An important possible use of the model is in the design of a community randomised trial where geographical clusters of people are divided into two groups and the effectiveness of an intervention policy is assessed by applying it to one group but not the other. Here the model can be used to take the effect of case clustering into consideration in calculating the minimum difference in an outcome variable (e.g. disease prevalence) that can be detected with statistical significance. It thereby gauges the potential effectiveness of such a trial. Such a possible application is illustrated with the given time/spatial TB data set.     

Bioarcheological and biocultural evidence for the New England vampire folk belief

Folk beliefs associated with death and disease can impact on the bioarcheological record. Unusual postmortem actions by humans and distinctive paleopathological evidence may be clues to these beliefs. This report presents bioarcheological and paleopathological evidence in support of a 19th century New England folk belief in vampires with a particular reference to a colonial period burial. The New England folk belief in vampires revolves around the ability of a deceased tuberculosis victim to return from the dead as a vampire and cause the “wasting away” of the surviving relatives. To stop the actions of the vampire, the body of the consumptive was exhumed and disrupted in various ways. Twelve historic accounts of this activity indicate that the belief was not uncommon in 19th century New England. This creative interpretation of contagion is consistent with the etiology of tuberculosis. Three pieces of evidence are important in this case. The skeleton of a 50- to 55-year-old male from a mid-19th century Connecticut cemetery exhibiting pulmonary tuberculosis rib lesions are discussed. In addition, certain bones in the skeleton were rearranged after decomposition was complete. A historic vampire account from the same time period and geographical location place the belief within the parameters of the cemetery. © 1994 Wiley-Liss, Inc.     

ATP synthase in mycobacteria: Special features and implications for a function as drug target

ATP synthase is a ubiquitous enzyme that is largely conserved across the kingdoms of life. This conservation is in accordance with its central role in chemiosmotic energy conversion, a pathway utilized by far by most living cells. On the other hand, in particular pathogenic bacteria whilst employing ATP synthase have to deal with energetically unfavorable conditions such as low oxygen tensions in the human host, e.g. Mycobacterium tuberculosis can survive in human macrophages for an extended time. It is well conceivable that such ATP synthases may carry idiosyncratic features that contribute to efficient ATP production. In this review genetic and biochemical data on mycobacterial ATP synthase are discussed in terms of rotary catalysis, stator composition, and regulation of activity. ATP synthase in mycobacteria is of particular interest as this enzyme has been validated as a target for promising new antibacterial drugs. A deeper understanding of the working of mycobacterial ATP synthase and its atypical features can provide insight in adaptations of bacterial energy metabolism. Moreover, pinpointing and understanding critical differences as compared with human ATP synthase may provide input for the design and development of selective ATP synthase inhibitors as antibacterials. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.     

Syndecan-4 assists Mycobacterium tuberculosis entry into lung epithelial cells by regulating the Cdc42, N-WASP,and Arp2/3 signaling pathways

Syndecan-4 (SDC4) is a transmembrane heparin sulfate proteoglycan that regulates inflammatory responses, cell motility, cell adhesion and intracellular signaling. In this study, we found that overexpression of SDC4 promoted the infection efficiency of Mycobacterium tuberculosis (Mtb), whereas knockdown of SDC4 reduced the infection efficiency, suggesting that SDC4 assisted Mtb infection of epithelial cells. We also observed that Mtb infection affected the F-actin/G-actin ratio, which was also correlated with SDC4 expression levels. Analysis of the Cdc42, N-WASP, and Arp2/3 signaling pathways during Mtb infection revealed that knockdown of Cdc42 and N-WASP or the addition of ZCL278, Wiskostatin or CK636 (blockers of Cdc42, N-WASP, and Arp2/3, respectively) significantly exacerbated Mtb infection in lung epithelial cells. Taken together, our data indicate that SDC4 assists Mtb infection of epithelial cells by regulating the Cdc42, N-WASP, and Arp2/3 signaling pathways, which regulate the polymerization of the actin cytoskeleton.     

Evaluation of Diagnostic Value of Mediastinum for Differentiation of Drug Sensitive,Multi and Extensively Drug Resistant Tuberculosis Using Chest X-Rays

Background and ObjectiveThe rise of Drug Resistant Tuberculosis (DR TB), particularly Multi DR (MDR), and Extensively DR (XDR) has reduced the rate of control of the disease. Computer aided diagnosis using Chest X-rays (CXRs) can help in mass screening and timely diagnosis of DR TB, which is essential to administer proper treatment regimens. In CXRs, lungs and mediastinum are two significant regions which contain the information about the likelihood of DR TB. The objective of this work is to analyze the shape characteristics of lungs and mediastinum to improve the diagnostics accuracy for differentiation of Drug Sensitive (DS), MDR and XDR TB using computer aided diagnostics system.MethodsThe CXR images of DS and DR TB patients are obtained from a public database. The lung fields are segmented from the CXRs using Reaction Diffusion Level Set Evolution. Mediastinum is segmented from the delineated lung masks using Chan Vese model. The shape features from each lung and mediastinum masks are extracted and analysed. The discriminative power of individual and combination of both lung and mediastinum features are evaluated using machine learning techniques for classification of DS vs MDR, MDR vs XDR and DS vs XDR TB images. The performances of classifiers are compared using standard metrics.ResultsThe proposed segmentation methods are able to delineate lungs and mediastinum from the CXR images. The extracted lung and mediastinum features are found to be statistically significant (p < 0.05) for differentiation of DS and DR TB conditions. Using the combination of both lung and mediastinum features, Multi-Layer Perceptron classifier achieves maximum F-measure of 82.4%, 81.0% and 87.0% for differentiation of DS vs MDR, MDR vs XDR and DS vs XDR, respectively.ConclusionAnalysis of mediastinum along with the lungs in chest X-rays could improve the diagnostic performance for differentiation of drug sensitive and resistant TB conditions. The proposed methodology is able to differentiate DS, MDR and XDR TB, and found to be clinically relevant. Hence, this work is useful for computer-based early detection of DS and DR TB conditions.