Effects of hemodialysis on circulating adrenomedullin concentrations in patients with end-stage renal disease

To characterize the determinants of circulating levels of adrenomedullin (AM), the plasma levels of this peptide were measured in 58 patients with end-stage renal disease on hemodialysis, Predialysis plasma levels of AM were more than twice as high in patients on hemodialysis as compared to controls. In hemodialysis patients with heart failure (NYHA classes II-IV) or hypertensive HD patients plasma levels of AM were significantly higher than in patients with end-stage renal disease only. Plasma levels of AM were clot altered immediately by hemodialysis but decreased significantly 14-20 h after hemodialysis, AM plasma levels before hemodialysis and 14-20 h after hemodialysis were correlated with the corresponding mean arterial pressure

Is Mycobacterium tuberculosis infection life long?

People with immunoreactivity to tuberculosis are thought to have lifelong asymptomatic infection and remain at risk for active tuberculosis. Marcel A Behr and colleagues argue that most of these people are no longer infecte

Phylogenetic detection of horizontal gene transfer during the step-wise genesis of Mycobacterium tuberculosis

<p>Abstract</p> <p>Background</p> <p>In the past decade, the availability of complete genome sequence data has greatly facilitated comparative genomic research aimed at addressing genetic variability within species. More recently, analysis across species has become feasible, especially in genera where genome sequencing projects of multiple species have been initiated. To understand the genesis of the pathogen <it>Mycobacterium tuberculosis </it>within a genus where the majority of species are harmless environmental organisms, we have used genome sequence data from 16 mycobacteria to look for evidence of horizontal gene transfer (HGT) associated with the emergence of pathogenesis. First, using multi-locus sequence analysis (MLSA) of 20 housekeeping genes across these species, we derived a phylogeny that serves as the basis for HGT assignments. Next, we performed alignment searches for the 3989 proteins of <it>M. tuberculosis </it>H37Rv against 15 other mycobacterial genomes, generating a matrix of 59835 comparisons, to look for genetic elements that were uniquely found in <it>M. tuberculosis </it>and closely-related pathogenic mycobacteria. To assign when foreign genes were likely acquired, we designed a bioinformatic program called mycoHIT (mycobacterial homologue investigation tool) to analyze these data in conjunction with the MLSA-based phylogeny.</p> <p>Results</p> <p>The bioinformatic screen predicted that 137 genes had been acquired by HGT at different phylogenetic strata; these included genes coding for metabolic functions and modification of mycobacterial lipids. For the majority of these genes, corroborating evidence of HGT was obtained, such as presence of phage or plasmid, and an aberrant GC%.</p> <p>Conclusion</p> <p><it>M. tuberculosis </it>emerged through vertical inheritance along with the step-wise addition of genes acquired via HGT events, a process that may more generally describe the evolution of other pathogens.</p

Disruption of Mycobacterium avium subsp. paratuberculosis-specific genes impairs in vivo fitness

Background: Mycobacterium avium subsp. paratuberculosis (MAP) is an obligate intracellular pathogen that infects many ruminant species. The acquisition of foreign genes via horizontal gene transfer has been postulated to contribute to its pathogenesis, as these genetic elements are absent from its putative ancestor, M. avium subsp. hominissuis (MAH), an environmental organism with lesser pathogenicity. In this study, high-throughput sequencing of MAP transposon libraries were analyzed to qualitatively and quantitatively determine the contribution of individual genes to bacterial survival during infection. Results: Out of 52384 TA dinucleotides present in the MAP K-10 genome, 12607 had a MycoMarT7 transposon in the input pool, interrupting 2443 of the 4350 genes in the MAP genome (56%). Of 96 genes situated in MAP-specific genomic islands, 82 were disrupted in the input pool, indicating that MAP-specific genomic regions are dispensable for in vitro growth (odds ratio = 0.21). Following 5 independent in vivo infections with this pool of mutants, the correlation between output pools was high for 4 of 5 (R = 0.49 to 0.61) enabling us to define genes whose disruption reproducibly reduced bacterial fitness in vivo. At three different thresholds for reduced fitness in vivo, MAP-specific genes were over-represented in the list of predicted essential genes. We also identified additional genes that were severely depleted after infection, and several of them have orthologues that are essential genes in M. tuberculosis. Conclusions: This work indicates that the genetic elements required for the in vivo survival of MAP represent a combination of conserved mycobacterial virulence genes and MAP-specific genes acquired via horizontal gene transfer. In addition, the in vitro and in vivo essential genes identified in this study may be further characterized to offer a better understanding of MAP pathogenesis, and potentially contribute to the discovery of novel therapeutic and vaccine targets. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-415) contains supplementary material, which is available to authorized users

Towards probabilistic decision support in public health practice: Predicting recent transmission of tuberculosis from patient attributes

AbstractObjectiveInvestigating the contacts of a newly diagnosed tuberculosis (TB) case to prevent TB transmission is a core public health activity. In the context of limited resources, it is often necessary to prioritize investigation when multiple cases are reported. Public health personnel currently prioritize contact investigation intuitively based on past experience. Decision-support software using patient attributes to predict the probability of a TB case being involved in recent transmission could aid in this prioritization, but a prediction model is needed to drive such software.MethodsWe developed a logistic regression model using the clinical and demographic information of TB cases reported to Montreal Public Health between 1997 and 2007. The reference standard for transmission was DNA fingerprint analysis. We measured the predictive performance, in terms of sensitivity, specificity, negative predictive value, positive predictive value, the Receiver Operating Characteristic (ROC) curve and the Area Under the ROC (AUC).ResultsAmong 1552 TB cases enrolled in the study, 314 (20.2%) were involved in recent transmission. The AUC of the model was 0.65 (95% confidence interval: 0.61–0.68), which is significantly better than random prediction. The maximized values of sensitivity and specificity on the ROC were 0.53 and 0.67, respectively.ConclusionsThe characteristics of a TB patient reported to public health can be used to predict whether the newly diagnosed case is associated with recent transmission as opposed to reactivation of latent infection

Effect of dibutyryl cyclic AMP and isoproterenol on 7β-hydroxycholesterol cytotoxicity and esterification in spontaneous transformed cell lines derived from astrocyte primary cultures

AbstractIncubation of spontaneous transformed cells derived from astrocyte primary cultures with 30 μM 7β-hydroxycholesterol (7β-OH-CH) which is lethal to the cells or with 150 μM isoproterenol reduces the intracellular level of cAMP (4- and 2-fold respectively). Treatment of the cultures with 0.5 mM dibutyryl (db)-cAMP and 7β-OH-CH increases 3-fold the intracellular level of cAMP and both, db-cAMP and isoproterenol, raise the lethal effect of 7β-OH-CH and its esterification on C-3-OH by naturally occurring fatty acids (metabolite). Kinetics studies of net steryl-3-esters hydrolysis revealed that db-cAMP and isoproterenol lower that of cholesteryl-3-esters (2-fold) whereas the opposite is found for the metabolite. These data demonstrate that (i) high cAMP intracellular levels modulate differently the net hydrolysis of cholesteryl-3-esters and metabolite, (ii) isoproterenol acts otherwise than cAMP on 7β-OH-CH esterification, (iii) the cytotoxicity of 7β-OH-CH is linked to its own esterification. The accumulation of metabolite subsequent to db-cAMP or isoproterenol treatment as a result of acyl-CoA:cholesterol acyl transferase activation is discussed

Drivers of Tuberculosis Transmission.

Measuring tuberculosis transmission is exceedingly difficult, given the remarkable variability in the timing of clinical disease after Mycobacterium tuberculosis infection; incident disease can result from either a recent (ie, weeks to months) or a remote (ie, several years to decades) infection event. Although we cannot identify with certainty the timing and location of tuberculosis transmission for individuals, approaches for estimating the individual probability of recent transmission and for estimating the fraction of tuberculosis cases due to recent transmission in populations have been developed. Data used to estimate the probable burden of recent transmission include tuberculosis case notifications in young children and trends in tuberculin skin test and interferon γ-release assays. More recently, M. tuberculosis whole-genome sequencing has been used to estimate population levels of recent transmission, identify the distribution of specific strains within communities, and decipher chains of transmission among culture-positive tuberculosis cases. The factors that drive the transmission of tuberculosis in communities depend on the burden of prevalent tuberculosis; the ways in which individuals live, work, and interact (eg, congregate settings); and the capacity of healthcare and public health systems to identify and effectively treat individuals with infectious forms of tuberculosis. Here we provide an overview of these factors, describe tools for measurement of ongoing transmission, and highlight knowledge gaps that must be addressed

Tuberculosis and homelessness in Montreal: a retrospective cohort study

BACKGROUND: Montreal is Canada's second-largest city, where mean annual tuberculosis (TB) incidence from 1996 to 2007 was 8.9/100,000. The objectives of this study were to describe the epidemiology of TB among homeless persons in Montreal and assess patterns of transmission and sharing of key locations. METHODS: We reviewed demographic, clinical, and microbiologic data for all active TB cases reported in Montreal from 1996 to 2007 and identified persons who were homeless in the year prior to TB diagnosis. We genotyped all available Mycobacterium tuberculosis isolates by IS6110 restriction fragment length polymorphism (IS6110-RFLP) and spoligotyping, and used a geographic information system to identify potential locations for transmission between persons with matching isolates. RESULTS: There were 20 cases of TB in homeless persons, out of 1823 total reported from 1996-2007. 17/20 were Canadian-born, including 5 Aboriginals. Homeless persons were more likely than non-homeless persons to have pulmonary TB (20/20), smear-positive disease (17/20, odds ratio (OR) = 5.7, 95% confidence interval (CI): 1.7-20), HIV co-infection (12/20, OR = 14, 95%CI: 4.8-40), and a history of substance use. The median duration from symptom onset to diagnosis was 61 days for homeless persons vs. 28 days for non-homeless persons (P = 0.022). Eleven homeless persons with TB belonged to genotype-defined clusters (OR = 5.4, 95%CI: 2.2-13), and ten potential locations for transmission were identified, including health care facilities, homeless shelters/drop-in centres, and an Aboriginal community centre. CONCLUSIONS: TB cases among homeless persons in Montreal raise concerns about delayed diagnosis and ongoing local transmission

Heterologous Production of 1-Tuberculosinyladenosine in Mycobacterium kansasii Models Pathoevolution towards the Transcellular Lifestyle of Mycobacterium tuberculosis

ABSTRACT Mycobacterium kansasii is an environmental nontuberculous mycobacterium that causes opportunistic tuberculosis-like disease. It is one of the most closely related species to the Mycobacterium tuberculosis complex. Using M. kansasii as a proxy for the M. kansasii-M. tuberculosis common ancestor, we asked whether introducing the M. tuberculosis-specific gene pair Rv3377c-Rv3378c into M. kansasii affects the course of experimental infection. Expression of these genes resulted in the production of an adenosine-linked lipid species, known as 1-tuberculosinyladenosine (1-TbAd), but did not alter growth in vitro under standard conditions. Production of 1-TbAd enhanced growth of M. kansasii under acidic conditions through a bacterial cell-intrinsic mechanism independent of controlling pH in the bulk extracellular and intracellular spaces. Production of 1-TbAd led to greater burden of M. kansasii in the lungs of C57BL/6 mice during the first 24 h after infection, and ex vivo infections of alveolar macrophages recapitulated this phenotype within the same time frame. However, in long-term infections, production of 1-TbAd resulted in impaired bacterial survival in both C57BL/6 mice and Ccr2−/− mice. We have demonstrated that M. kansasii is a valid surrogate of M. tuberculosis to study virulence factors acquired by the latter organism, yet shown the challenge inherent to studying the complex evolution of mycobacterial pathogenicity with isolated gene complementation. IMPORTANCE This work sheds light on the role of the lipid 1-tuberculosinyladenosine in the evolution of an environmental ancestor to M. tuberculosis. On a larger scale, it reinforces the importance of horizontal gene transfer in bacterial evolution and examines novel models and methods to provide a better understanding of the subtle effects of individual M. tuberculosis-specific virulence factors in infection settings that are relevant to the pathogen

The BCG World Atlas: A Database of Global BCG Vaccination Policies and Practices

Madhu Pai and colleagues introduce the BCG World Atlas, an open access, user friendly Web site for TB clinicians to discern global BCG vaccination policies and practices and improve the care of their patients