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1.
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.  相似文献   

2.
A tuberculosis model which incorporates treatment of infectives and chemoprophylaxis is presented. The model assumes that latently infected individuals develop active disease as a result of endogenous re-activation, exogenous re-infection and disease relapse, though a small fraction is assumed to develop active disease soon after infection. We start by formulating and analyzing a TB model without any intervention strategy that we extend to incorporate chemoprophylaxis and treatment of infectives. The epidemic thresholds known as reproduction numbers and equilibria for the models are determined, and stabilities analyzed. The reproduction numbers for the models are compared to assess the possible community benefits achieved by treatment of infectives, chemoprophylaxis and a holistic approach of these intervention strategies. The study shows that treatment of infectives is more effective in the first years of implementation (≈ 10 years) as treatment results in clearing active TB immediately and there after chemoprophylaxis will do better in controlling the number of infectives due to reduced progression to active TB.  相似文献   

3.
Evidence for linkage between tuberculosis and human chromosomal region Xq26 has previously been described. The costimulatory molecule CD40 ligand, encoded by TNFSF5 and located at Xq26.3, is a promising positional candidate. Interactions between CD40 ligand and CD40 are involved in the development of humoral- and cell-mediated immunity, as well as the activation of macrophages, which are the primary host and effector cells for Mycobacterium tuberculosis. We hypothesised that common variation within TNFSF5 might affect susceptibility to tuberculosis disease and, thus, might be responsible for the observed linkage to Xq26. Sequencing 32 chromosomes from a Gambian population identified nine common polymorphisms within the coding, 3 and 5 regulatory sequences of the gene. Six single nucleotide polymorphisms (SNPs) and a 3 microsatellite were genotyped in 121 tuberculosis patients and their available parents. No association with tuberculosis was detected for these variants using a transmission disequilibrium test, although one SNP at –726 showed some evidence of association in males. This finding, however, did not replicate in a separate case control study of over 1,200 West African individuals. We conclude that common genetic variation in TNFSF5 is not likely to affect tuberculosis susceptibility in West Africa and the linkage observed in this region is not due to variation in TNFSF5.Sadly, Professor Steve Bennett passed away in March 2003  相似文献   

4.
The nucleotide oligomerization binding domain 2 gene (NOD2) encodes an intracellular receptor for bacterial components, which is expressed in monocytes and is associated with Crohn's Disease (CD). This finding, along with epidemiological evidence, supports a role for infection in the pathogenesis of CD. Speculation that mycobacteria are involved in CD led us to investigate NOD2 in susceptibility to tuberculosis (TB), a global public health problem caused by Mycobacterium tuberculosis. CD-associated NOD2 variants were absent in a case-control study of 640 Gambians, where CD is rare. Novel NOD2 promoter polymorphisms were identified but showed no association with TB in this African population sample.  相似文献   

5.
目的 探讨老年人、儿童、营养不良及合并其他慢性疾病等特殊人群肺结核患者在抗结核治疗期间药物不良反应情况,为其临床调整用药提供相关依据,以降低特殊人群肺结核治疗中不良反应发生.方法 由结核科专业医师查阅2007年1月至2012年12月病例资料,包括住院病历、病程记录、服药记录、实验室检查等,回顾性分析特殊人群肺结核患者药物所致不良反应的发生情况.结果 特殊人群肺结核患者抗结核治疗药物不良反应发生率达43.1%,显著高于非特殊人群的29.7%(P<0.05),特殊人群组不良反应出现的时间平均为24.3d,显著早于非特殊人群组的33.7d(P<0.05).特殊人群97.7%的不良反应发生在服药后2个月内,而非特殊人群服药2个月内发生不良反应率为83.5%(P<0.05).结论 特殊人群肺结核患者抗结核治疗期间药物不良反应发生时间较早、发生率较高,特殊人群要加强不良反应监测.  相似文献   

6.
Heterogeneity is an important property of any population experiencing a disease. Here we apply general methods of the theory of heterogeneous populations to the simplest mathematical models in epidemiology. In particular, an SIR (susceptible-infective-removed) model is formulated and analyzed when susceptibility to or infectivity of a particular disease is distributed. It is shown that a heterogeneous model can be reduced to a homogeneous model with a nonlinear transmission function, which is given in explicit form. The widely used power transmission function is deduced from the model with distributed susceptibility and infectivity with the initial gamma-distribution of the disease parameters. Therefore, a mechanistic derivation of the phenomenological model, which is believed to mimic reality with high accuracy, is provided. The equation for the final size of an epidemic for an arbitrary initial distribution of susceptibility is found. The implications of population heterogeneity are discussed, in particular, it is pointed out that usual moment-closure methods can lead to erroneous conclusions if applied for the study of the long-term behavior of the models.  相似文献   

7.
We have developed a dynamic model for tuberculosis (TB) transmission in South Korea using a SEIR model with the time-dependent parameters. South Korea ranked the highest TB incidence among members of the Organization for Economic Cooperation and Development (OECD) in 2005 yr. The observed data from the Korea Center for Disease Control and Prevention (KCDC) shows a certain rise of active-TB incidence individuals after 2001 yr. Because of this sudden jump, we have considered two different periods for best fitting the model: prior to 2001 yr and posterior to 2001 yr. The least-squares fitting has been used for estimating model parameters to the observed data of active-TB incidence. Our model agrees well with the observed data. In this work, we also propose optimal treatment strategies of TB model in South Korea for the future. We have considered three control mechanisms representing distancing, case finding and case holding efforts. Optimal control programs have been proposed in various scenarios, in order to minimize the number of exposed and infectious individuals and the cost of implementing the control treatment.  相似文献   

8.
It is well known that the rate of aging is constant for populations described by the Gompertz law of mortality. However, this is true only when a population is homogeneous. In this note, we consider the multiplicative frailty model with the baseline distribution that follows the Gompertz law and study the impact of heterogeneity on the rate of aging in this population. We show that the rate of aging in this case is a function of age and that it increases in (calendar) time when the baseline mortality rate decreases.  相似文献   

9.
Summary Accurate prediction of the cumulated genetic gain requires predicting genetic variance over time under the joint effects of selection and limited population size. An algorithm is proposed to quantify at each generation the effects of these factors on average coefficient of inbreeding, genetic variance, and genetic mean, under a purely additive polygenic model, with no mutation, and under the assumption of absence of inbreeding depression on viability affecting selection differentials. This algorithm is relevant to populations where mating is at random and generations do not overlap. It was tested via Monte Carlo simulation on a population of 3 males and 25 females mass selected out of 50 candidates of each sex, over 30 generations. For two values of the initial heritability of the selected trait, 0.5 and 0.9 (to represent high accuracy in index selection), predicted values of the genetic variance are in agreement with observed results up to the 12th and 19th generations, respectively. Beyond these generations, the variance is overestimated, due to an underestimation of the effect of selection on the rate of inbreeding. Finally, the algorithm provides predictions of the cumulated responses close to the observed values in both selected populations. It is concluded that, as regards the hypotheses of the study, the proposed algorithm is satisfactory, and could be used to optimize selection methods with respect to the cumulated genetic gain in the mid- or long-term. Possible extensions of the algorithm to more realistic situations are discussed.  相似文献   

10.
Genebank seed accessions of predominantly self-pollinating species may be stored either as bulked (mixed) seed lines or as pure line cultivars. If seed lines are bulked in storage then when considered over several regeneration cycles, loss of genetic diversity within heterogeneous self pollinating genebank accessions is shown to be severe. This within-accession loss of diversity represents opportunities foregone through the random loss of individual genotypes. Amongst working collections, the utility and repeatability of genebank accessions is paramount in the justification of the germ plasm resource. Therefore, the only practical solution to the management of predominantly self-pollinating species is to preserve individual accessions as pure lines.  相似文献   

11.
Summary The adequacy of an expression for the withinfamily genetic variance under pure random drift in an additive infinitesimal model was tested via simulation in populations undergoing mass selection. Two hundred or one thousand unlinked loci with two alleles at initial frequencies of 1/2 were considered. The size of the population was 100 (50 males and 50 females). Full-sib matings were carried out for 15 generations with only one male and one female chosen as parents each generation, either randomly or on an individual phenotypic value. In the unselected population, results obtained from 200 replicates were in agreement with predictions. With mass selection, within-family genetic variance was overpredicted by theory from the 12th and 4th generations for the 1,000 and 200 loci cases, respectively. Taking into account the observed change in gene frequencies in the algorithm led to a much better agreement with observed values. Results for the distribution of gene frequencies and the withinlocus genetic covariance are presented. It is concluded that the expression for the within-family genetic variance derived for pure random drift holds well for mass selection within the limits of an additive infinitesimal model.  相似文献   

12.
There is a critical need for improved and shorter tuberculosis (TB) treatment. Current in vitro models of TB, while valuable, are poor predictors of the antibacterial effect of drugs in vivo. Mathematical models may be useful to overcome the limitations of traditional approaches in TB research. The objective of this study was to set up a prototype mathematical model of TB treatment by rifampin, based on pharmacokinetic, pharmacodynamic and disease submodels.The full mathematical model can simulate the time-course of tuberculous disease from the first day of infection to the last day of therapy. Therapeutic simulations were performed with the full model to study the antibacterial effect of various dosage regimens of rifampin in lungs.The model reproduced some qualitative and quantitative properties of the bactericidal activity of rifampin observed in clinical data. The kill curves simulated with the model showed a typical biphasic decline in the number of extracellular bacteria consistent with observations in TB patients. Simulations performed with more simple pharmacokinetic/pharmacodynamic models indicated a possible role of a protected intracellular bacterial compartment in such a biphasic decline.This modeling effort strongly suggests that current dosage regimens of RIF may be further optimized. In addition, it suggests a new hypothesis for bacterial persistence during TB treatment.  相似文献   

13.
This paper presents qualitative and quantitative study of a TB mathematical model to test results from a survey carried out in Benin City, Nigeria. The purpose of the survey was to determine factors that could enhance the case detection rate of tuberculosis. Results from the survey identified four key factors that must be combined for an effective control of TB and increase the case detection rate: effective awareness programme, active cough identification, associated cost factor for treatment of identified cases and effective treatment. The overall effect of these factors on the basic reproduction number under treatment, RT, of the TB model was considered. In all, a serious concentration on tuberculosis awareness programmes and active cough identification as a marker for someone having TB was shown to significantly reduce the value of the reproduction number, hereby reducing the severity of the disease in the presence of treatment.  相似文献   

14.
A method for reconstructing allele frequencies characteristic of an original ethnically homogeneous population before the start of migration processes is described. Information on both the ethnic group studied and offspring of interethnic marriages is used to estimate the allele frequencies. This makes it possible to increase the informativeness of the sample, which, in the case of ethnic heterogeneity, depends not only on allele frequencies and the total sample size, but also on the ethnic structure of the sample. The problem of estimating allele frequency in an ethnically heterogeneous sample has been solved analytically for diallelic loci. It has been demonstrated that, if offspring of interethnic marriages with the same degree of outbreeding is added to a sample of the ethnic group studied, the sample informativeness does not change. To utilize the information contained in the phenotypes of the offspring of interethnic marriages, representatives of the population from which migration occurs should be included into the sample. The size of the sample ensuring the preassigned accuracy of estimation is minimized at a certain ratio between the numbers of the offspring of interethnic marriages and the "immigrants." To analyze polyallelic loci, a software package has been developed that allows estimating allele frequencies, determining the errors of these estimates, and planning the sample ensuring the preassigned accuracy of estimation. The package is available free at http://mga.bionet.bionet.nsc.ru/PopMixed/PopMixed.html.  相似文献   

15.
结核病是一种棘手的重大传染病.虽然存在一些有一定疗效的治疗药物,亦有预防性疫苗--卡介苗(BCG);但结核病仍在世界范围流行,且发病率和病死率居高不下.结核病的免疫病理机制及疫苗研究近年来取得了一定的进展.结核分枝杆菌通过Toll样受体(TLR)等模式识别受体,激活巨噬细胞的天然免疫反应,清除细菌和调节获得性免疫反应....  相似文献   

16.
结核分枝杆菌感染动物模型的研究进展   总被引:1,自引:0,他引:1  
人类结核病位居单一病原引起死亡的严重传染病之首,结核分枝杆菌是其主要病原.尽管结核分枝杆菌可引起许多种动物感染并患病,但人类是其主要宿主.动物模型作为研究人类疾病的标准化工具,虽然不能完全模拟人类结核病的整个过程,但可成为研究结核病的有用工具,有助于研究其发病机制、治疗过程及宿主对病原的免疫病理学反应.由于不同种类动物对结核分枝杆菌的敏感性不同,因此根据研究需要选择合适的动物模型非常必要.本文综述了结核病研究中最常用的动物模型,包括豚鼠、小鼠、兔、非人灵长类和鱼类等模型,归纳了结核病各种动物模型的特点和研究概况.  相似文献   

17.
Electrohoretically detectable enetic variation for 29 kinds of blood protein encoded by 33 loci was analyzed for 78 Asian eletants (Elephas maximus) which were collected from its four local populations: Sri Lanka, Souti India, Thailand and Nepal. Elehants in Sri Lanka are classified into the subspecies E.m. maximus, and those from the other tlree localities into the subspecies E. m. indicus. Six variable loci were detected, and one of them, the tetrazolium oxidase locus, was observed to show a complete allele substitution between the subspecies. Average heterozgosity within local populations were in a range of 0.0152 ? 0.0303. Whereas the Nei's genetic distance among three local populations of the subspecies indicus were 0.0013 ? 0.0031, the distance between the subspecies indicus and maximus were 0.0328 ? 0.0370, indicating that the two subspecies were well differentiated genetically.  相似文献   

18.
目的 模拟自然感染方式建立结核病小鼠模型,并对其病理变化进行综合评价.方法 通过气雾攻击方式将结核分枝杆菌H37Rv接种至C57BL/6J小鼠体内.在感染后的4周、6周、8周对小鼠进行micro-CT活体动态扫描,无菌分离肺脏和脾脏,肉眼观察病变情况,活菌菌落计数,组织病理检测(HE和抗酸染色).结果 肉眼观察和micro-CT扫描发现,不同时间小鼠肺部感染情况逐渐加重,至感染后第8周时病变弥漫至整个肺部;HE染色肺组织出现弥漫性肉芽肿样实变;抗酸染色可见结核分枝杆菌.结论 通过大体病变、病理、影像、菌落计数几个方面对建立的小鼠模型进行综合分析,证明利用气雾攻击法感染的结核病小鼠模型建立成功;该模型在形成病变时与结核患者的情况存在一定差异,对其完善的综合评价有助于在相关研究中对该小鼠模型的合理应用.  相似文献   

19.
One-third of the world population (approximately 2 billion individuals) is currently infected with Mycobacterium tuberculosis, the vast majority harboring a latent infection. As the risk of reactivation is around 10% in a lifetime, it follows that 200 million of these will eventually develop active pulmonary disease. Only therapeutic or post-exposure interventions can tame this vast reservoir of infection. Treatment of latent infections can reduce the risk of reactivation, and there is accumulating evidence that combination with post-exposure vaccines can reduce the risk of reinfection. Here we develop mathematical models to explore the potential of these post-exposure interventions to control tuberculosis on a global scale. Intensive programs targeting recent infections appear generally effective, but the benefit is potentially greater in intermediate prevalence scenarios. Extending these strategies to longer-term persistent infections appears more beneficial where prevalence is low. Finally, we consider that susceptibility to reinfection is altered by therapy, and explore its epidemiological consequences. When we assume that therapy reduces susceptibility to subsequent reinfection, catastrophic dynamics are observed. Thus, a bipolar outcome is obtained, where either small or large reductions in prevalence levels result, depending on the rate of detection and treatment of latent infections. By contrast, increased susceptibility after therapy may induce an increase in disease prevalence and does not lead to catastrophic dynamics. These potential outcomes are silent unless a widespread intervention is implemented.  相似文献   

20.
Epidemic control strategies alter the spread of the disease in the host population. In this paper, we describe and discuss mathematical models that can be used to explore the potential of pre-exposure and post-exposure vaccines currently under development in the control of tuberculosis. A model with bacille Calmette-Guerin (BCG) vaccination for the susceptibles and treatment for the infectives is first presented. The epidemic thresholds known as the basic reproduction numbers and equilibria for the models are determined and stabilities are investigated. The reproduction numbers for the models are compared to assess the impact of the vaccines currently under development. The centre manifold theory is used to show the existence of backward bifurcation when the associated reproduction number is less than unity and that the unique endemic equilibrium is locally asymptotically stable when the associated reproduction number is greater than unity. From the study we conclude that the pre-exposure vaccine currently under development coupled with chemoprophylaxis for the latently infected and treatment of infectives is more effective when compared to the post-exposure vaccine currently under development for the latently infected coupled with treatment of the infectives.  相似文献   

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