Spreading of Persistent Infections in Heterogeneous Populations

Up to now, the effects of having heterogeneous networks of contacts have been studied mostly for diseases which are not persistent in time, i.e., for diseases where the infectious period can be considered very small compared to the lifetime of an individual. Moreover, all these previous results have been obtained for closed populations, where the number of individuals does not change during the whole duration of the epidemics. Here, we go one step further and analyze, both analytically and numerically, a radically different kind of diseases: those that are persistent and can last for an individual's lifetime. To be more specific, we particularize to the case of Tuberculosis' (TB) infection dynamics, where the infection remains latent for a period of time before showing up and spreading to other individuals. We introduce an epidemiological model for TB-like persistent infections taking into account the heterogeneity inherent to the population structure. This sort of dynamics introduces new analytical and numerical challenges that we are able to sort out. Our results show that also for persistent diseases the epidemic threshold depends on the ratio of the first two moments of the degree distribution so that it goes to zero in a class of scale-free networks when the system approaches the thermodynamic limit.Comment: 12 pages and 2 figures. Revtex format. Submitted for publication

Metabolism and toxicity of arsenic in human urothelial cells expressing rat arsenic (+3 oxidation state)-methyltransferase

The enzymatic methylation of inorganic As (iAs) is catalyzed by As(+3 oxidation state)-methyltransferase (AS3MT). AS3MT is expressed in rat liver and in human hepatocytes. However, AS3MT is not expressed in UROtsa, human urothelial cells that do not methylate iAs. Thus, UROtsa cells are an ideal null background in which the role of iAs methylation in modulation of toxic and cancer-promoting effects of this metalloid can be examined. A retroviral gene delivery system was used in this study to create a clonal UROtsa cell line (UROtsa/F35) that expresses rat AS3MT. Here, we characterize the metabolism and cytotoxicity of arsenite (iAsIII) and methylated trivalent arsenicals in parental cells and clonal cells expressing AS3MT. In contrast to parental cells, UROtsa/F35 cells effectively methylated iAsIII, yielding methylarsenic (MAs) and dimethylarsenic (DMAs) containing either AsIII or AsV. When exposed to MAsIII, UROtsa/F35 cells produced DMAsIII and DMAsV. MAsIII and DMAsIII were more cytotoxic than iAsIII in UROtsa and UROtsa/F35 cells. The greater cytotoxicity of MAsIII or DMAsIII than of iAsIII was associated with greater cellular uptake and retention of each methylated trivalent arsenical. Notably, UROtsa/F35 cells were more sensitive than parental cells to the cytotoxic effects of iAsIII but were more resistant to cytotoxicity of MAsIII. The increased sensitivity of UROtsa/F35 cells to iAsIII was associated with inhibition of DMAs production and intracellular accumulation of MAs. The resistance of UROtsa/F35 cells to moderate concentrations of MAsIII was linked to its rapid conversion to DMAs and efflux of DMAs. However, concentrations of MAsIII that inhibited DMAs production by UROtsa/F35 cells were equally toxic for parental and clonal cell lines. Thus, the production and accumulation of MAsIII is a key factor contributing to the toxicity of acute iAs exposures in methylating cells

Mathematical model insights into arsenic detoxification

<p>Abstract</p> <p>Background</p> <p>Arsenic in drinking water, a major health hazard to millions of people in South and East Asia and in other parts of the world, is ingested primarily as trivalent inorganic arsenic (iAs), which then undergoes hepatic methylation to methylarsonic acid (MMAs) and a second methylation to dimethylarsinic acid (DMAs). Although MMAs and DMAs are also known to be toxic, DMAs is more easily excreted in the urine and therefore methylation has generally been considered a detoxification pathway. A collaborative modeling project between epidemiologists, biologists, and mathematicians has the purpose of explaining existing data on methylation in human studies in Bangladesh and also testing, by mathematical modeling, effects of nutritional supplements that could increase As methylation.</p> <p>Methods</p> <p>We develop a whole body mathematical model of arsenic metabolism including arsenic absorption, storage, methylation, and excretion. The parameters for arsenic methylation in the liver were taken from the biochemical literature. The transport parameters between compartments are largely unknown, so we adjust them so that the model accurately predicts the urine excretion rates of time for the iAs, MMAs, and DMAs in single dose experiments on human subjects.</p> <p>Results</p> <p>We test the model by showing that, with no changes in parameters, it predicts accurately the time courses of urinary excretion in mutiple dose experiments conducted on human subjects. Our main purpose is to use the model to study and interpret the data on the effects of folate supplementation on arsenic methylation and excretion in clinical trials in Bangladesh. Folate supplementation of folate-deficient individuals resulted in a 14% decrease in arsenicals in the blood. This is confirmed by the model and the model predicts that arsenicals in the liver will decrease by 19% and arsenicals in other body stores by 26% in these same individuals. In addition, the model predicts that arsenic methyltransferase has been upregulated by a factor of two in this population. Finally, we also show that a modification of the model gives excellent fits to the data on arsenic metabolism in human cultured hepatocytes.</p> <p>Conclusions</p> <p>The analysis of the Bangladesh data using the model suggests that folate supplementation may be more effective at reducing whole body arsenic than previously expected. There is almost no data on the upregulation of arsenic methyltransferase in populations chronically exposed to arsenic. Our model predicts upregulation by a factor of two in the Bangladesh population studied. This prediction should be verified since it could have important public health consequences both for treatment strategies and for setting appropriate limits on arsenic in drinking water. Our model has compartments for the binding of arsenicals to proteins inside of cells and we show that these comparments are necessary to obtain good fits to data. Protein-binding of arsenicals should be explored in future biochemical studies.</p

The Association of Arsenic Exposure and Metabolism With Type 1 and Type 2 Diabetes in Youth: The SEARCH Case-Control Study

Little is known about arsenic and diabetes in youth. We examined the association of arsenic with type 1 and type 2 diabetes in the SEARCH for Diabetes in Youth Case-Control (SEARCH-CC) study. Because one-carbon metabolism can influence arsenic metabolism, we also evaluated the potential interaction of folate and vitamin B12 with arsenic metabolism on the odds of diabetes

Monomethylarsonous Acid (MMAIII) Has an Adverse Effect on the Innate Immune Response of Human Bronchial Epithelial Cells to Pseudomonas Aeruginosa

Arsenic is the number one contaminant of concern with regard to human health according to the World Health Organization. Epidemiological studies on Asian and South American populations have linked arsenic exposure with an increased incidence of lung disease, including pneumonia, and chronic obstructive pulmonary disease, both of which are associated with bacterial infection. However, little is known about the effects of low dose arsenic exposure, or the contributions of organic arsenic to the innate immune response to bacterial infection. This study examined the effects on Pseudomonas aeruginosa (P. aeruginosa) induced cytokine secretion by human bronchial epithelial cells (HBEC) by inorganic sodium arsenite (iAsIII) and two major metabolites, monomethylarsonous acid (MMAIII) and dimethylarsenic acid (DMAV), at concentrations relevant to the U.S. population. Neither iAsIII nor DMAV altered P. aeruginosa induced cytokine secretion. By contrast, MMAIII increased P. aeruginosa induced secretion of IL-8, IL-6 and CXCL2. A combination of iAsIII, MMAIII and DMAV (10 pbb total) reduced IL-8 and CXCL1 secretion. These data demonstrate for the first time that exposure to MMAIII alone, and a combination of iAsIII, MMAIII and DMAV at levels relevant to the U.S. may have negative effects on the innate immune response of human bronchial epithelial cells to P. aeruginosa

Analysis of latent tuberculosis and mycobacterium avium infection data using mixture models

BACKGROUND: Estimation of the frequency of latent tuberculosis infection (LTBI) is difficult in areas with low tuberculosis infection rates and high exposure to non-tuberculous mycobacteria (NTM), including BCG vaccination. The objective was to assess LTBI and M avium infection and to estimate their probability based on skin tests responses in an infant population from a region with the aforementioned characteristics. METHODS: A population-based tuberculin skin test (TST) and sensitin (M avium) survey was conducted on seven years old infants in Biscay, a province from The Basque Country (Spain). 2268 schoolchildren received sensitin and 5277 TST. Participation rate was 89%. Commonly used estimation methods were compared with a method based on the fit of mixture models using the Expectation Maximization algorithm. Functions estimating the probabilities of LTBI and M avium infection given the observed skin tests responses were developed for vaccinated and unvaccinated children. RESULTS: LTBI prevalences varied widely according to the estimation method. The mixture model provided prevalences higher than expected although intermediates between those obtained by currently recommended approaches. Exposure to previous BCG vaccine produces an upward shift of an average of about 3 mm on the induration size to attain the same probability of infection. CONCLUSION: Our results confirm the commonplace exposure to NTM which effect should be taken into account when performing and assessing tuberculin surveys. The use of mixture analysis under the empirical Bayes framework allows to better estimate the probability of LTBI in settings with presence of other NTM and high BCG-vaccination coverage. An estimation of the average effect of BCG vaccination on TST induration is also provided. These models maximise information coming from classical tuberculin surveys and could be used together with the newly developed blood tests to improve survey's specificity and cost-effectiveness

Reduced Transmissibility of East African Indian Strains of Mycobacterium tuberculosis

BACKGROUND: Mycobacterium tuberculosis (MTB) has been classified into 4 main lineages. Some reports have associated certain lineages with particular clinical phenotypes, but there is still insufficient information regarding the clinical and epidemiologic implications of MTB lineage variation. METHODS: Using large sequence polymorphisms we classified MTB isolates from a population-based study in Montreal, Canada into the 4 major lineages, and identified the associated clinical and epidemiologic features. In addition, IS6110-RFLP and spoligotyping were used as indicators of recent TB transmission. The study population was divided into a derivation cohort, diagnosed between 2001 and 2007, and a separate validation cohort, diagnosed between 1996 and 2000. RESULTS: In the derivation cohort, when compared to the other MTB lineages, the East African-Indian (EAI) lineage was associated with lower rates of TB transmission, as measured by: positive TST among close contacts of pulmonary TB cases (adjusted odds ratio 0.6: [95% confidence interval 0.4-0.9]), and clustered TB cases (0.3: [<0.001-0.6]). Severe forms of TB were also less likely among the EAI group (0.4: [<0.001-0.8]). There were no significant differences when comparing patients with the other MTB lineages. In the validation cohort, the EAI lineage was associated with lower rates of positive TST among contacts (0.5: [0.3-0.9]) and a trend towards less clustered TB cases (0.5: [0.1-1.8]) when compared to the other lineages. Disease severity among the different groups was not significantly different in the validation cohort. CONCLUSIONS: We conclude that in Montreal, EAI strains were associated with reduced transmission compared to other MTB lineages

The benefits and risks of bacille Calmette-Guérin vaccination among infants at high risk for both tuberculosis and severe combined immunodeficiency: assessment by Markov model

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccine is given to Canadian Aboriginal neonates in selected communities. Severe reactions and deaths associated with BCG have been reported among infants born with immunodeficiency syndromes. The main objective of this study was to estimate threshold values for severe combined immunodeficiency (SCID) incidence, above which BCG is associated with greater risk than benefit. METHODS: A Markov model was developed to simulate the natural histories of tuberculosis (TB) and SCID in children from birth to 14 years. The annual risk of tuberculous infection (ARI) and SCID incidence were varied in analyses. The model compared a scenario of no vaccination to intervention with BCG. Appropriate variability and uncertainty analyses were conducted. Outcomes included TB incidence and quality-adjusted life years (QALYs). RESULTS: In sensitivity analyses, QALYs were lower among vaccinated infants if the ARI was 0.1% and the rate of SCID was higher than 4.2 per 100,000. Assuming an ARI of 1%, this threshold increased to 41 per 100,000. In uncertainty analyses (Monte Carlo simulations) which assumed an ARI of 0.1%, QALYs were not significantly increased by BCG unless SCID incidence is 0. With this ARI, QALYs were significantly decreased among vaccinated children if SCID incidence exceeds 23 per 100,000. BCG is associated with a significant increase in QALYs if the ARI is 1%, and SCID incidence is below 5 per 100,000. CONCLUSION: The possibility that Canadian Aboriginal children are at increased risk for SCID has serious implications for continued BCG use in this population. In this context, enhanced TB Control – including early detection and treatment of infection – may be a safer, more effective alternative