Mycobacterium tuberculosis Transcriptional Adaptation, Growth Arrest and Dormancy Phenotype Development Is Triggered by Vitamin C

BACKGROUND: Tubercle bacilli are thought to persist in a dormant state during latent tuberculosis (TB) infection. Although little is known about the host factors that induce and maintain Mycobacterium tuberculosis (M. tb) within latent lesions, O(2) depletion, nutrient limitation and acidification are some of the stresses implicated in bacterial dormancy development/growth arrest. Adaptation to hypoxia and exposure to NO/CO is implemented through the DevRS/DosT two-component system which induces the dormancy regulon. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that vitamin C (ascorbic acid/AA) can serve as an additional signal to induce the DevR regulon. Physiological levels of AA scavenge O(2) and rapidly induce the DevR regulon at an estimated O(2) saturation of <30%. The kinetics and magnitude of the response suggests an initial involvement of DosT and a sustained DevS-mediated response during bacterial adaptation to increasing hypoxia. In addition to inducing DevR regulon mechanisms, vitamin C induces the expression of selected genes previously shown to be responsive to low pH and oxidative stress, triggers bacterial growth arrest and promotes dormancy phenotype development in M. tb grown in axenic culture and intracellularly in THP-1 cells. CONCLUSIONS/SIGNIFICANCE: Vitamin C mimics multiple intracellular stresses and has wide-ranging regulatory effects on gene expression and physiology of M. tb which leads to growth arrest and a 'dormant' drug-tolerant phenotype, but in a manner independent of the DevRS/DosT system. The 'AA-dormancy infection model' offers a potential alternative to other models of non-replicating persistence of M. tb and may be useful for investigating host-'dormant' M. tb interactions. Our findings offer a new perspective on the role of nutritional factors in TB and suggest a possible role for vitamin C in TB

The Genome of Mycobacterium Africanum West African 2 Reveals a Lineage-Specific Locus and Genome Erosion Common to the M. tuberculosis Complex

Mycobacterium africanum, a close relative of M. tuberculosis, is studied for the following reasons: M. africanum is commonly isolated from West African patients with tuberculosis yet has not spread beyond this region, it is more common in HIV infected patients, and it is less likely to lead to tuberculosis after one is exposed to an infectious case. Understanding this organism's unique biology gets a boost from the decoding of its genome, reported in this issue. For example, genome analysis reveals that M. africanum contains a region shared with “ancient” lineages in the M. tuberculosis complex and other mycobacterial species, which was lost independently from both M. tuberculosis and M. bovis. This region encodes a protein involved in transmembrane transport. Furthermore, M. africanum has lost genes, including a known virulence gene and genes for vitamin synthesis, in addition to an intact copy of a gene that may increase its susceptibility to antibiotics that are insufficiently active against M. tuberculosis. Finally, the genome sequence and analysis reported here will aid in the development of new diagnostics and vaccines against tuberculosis, which need to take into account the differences between M. africanum and other species in order to be effective worldwide

Functional Genetic Diversity among Mycobacterium tuberculosis Complex Clinical Isolates: Delineation of Conserved Core and Lineage-Specific Transcriptomes during Intracellular Survival

Tuberculosis exerts a tremendous burden on global health, with ∼9 million new infections and ∼2 million deaths annually. The Mycobacterium tuberculosis complex (MTC) was initially regarded as a highly homogeneous population; however, recent data suggest the causative agents of tuberculosis are more genetically and functionally diverse than appreciated previously. The impact of this natural variation on the virulence and clinical manifestations of the pathogen remains largely unknown. This report examines the effect of genetic diversity among MTC clinical isolates on global gene expression and survival within macrophages. We discovered lineage-specific transcription patterns in vitro and distinct intracellular growth profiles associated with specific responses to host-derived environmental cues. Strain comparisons also facilitated delineation of a core intracellular transcriptome, including genes with highly conserved regulation across the global panel of clinical isolates. This study affords new insights into the genetic information that M. tuberculosis has conserved under selective pressure during its long-term interactions with its human host

Women's Education Level, Maternal Health Facilities, Abortion Legislation and Maternal Deaths: A Natural Experiment in Chile from 1957 to 2007

The aim of this study was to assess the main factors related to maternal mortality reduction in large time series available in Chile in context of the United Nations' Millennium Development Goals (MDGs).Time series of maternal mortality ratio (MMR) from official data (National Institute of Statistics, 1957-2007) along with parallel time series of education years, income per capita, fertility rate (TFR), birth order, clean water, sanitary sewer, and delivery by skilled attendants were analysed using autoregressive models (ARIMA). Historical changes on the mortality trend including the effect of different educational and maternal health policies implemented in 1965, and legislation that prohibited abortion in 1989 were assessed utilizing segmented regression techniques.During the 50-year study period, the MMR decreased from 293.7 to 18.2/100,000 live births, a decrease of 93.8%. Women's education level modulated the effects of TFR, birth order, delivery by skilled attendants, clean water, and sanitary sewer access. In the fully adjusted model, for every additional year of maternal education there was a corresponding decrease in the MMR of 29.3/100,000 live births. A rapid phase of decline between 1965 and 1981 (-13.29/100,000 live births each year) and a slow phase between 1981 and 2007 (-1.59/100,000 live births each year) were identified. After abortion was prohibited, the MMR decreased from 41.3 to 12.7 per 100,000 live births (-69.2%). The slope of the MMR did not appear to be altered by the change in abortion law.Increasing education level appears to favourably impact the downward trend in the MMR, modulating other key factors such as access and utilization of maternal health facilities, changes in women's reproductive behaviour and improvements of the sanitary system. Consequently, different MDGs can act synergistically to improve maternal health. The reduction in the MMR is not related to the legal status of abortion

Síndrome de Burnout em graduandos de Odontologia Burnout syndrome among dental students

A Síndrome de Burnout caracteriza-se por esgotamento profissional e tem sido relatada em estudantes universitários. O objetivo desse estudo foi estimar a prevalência da Síndrome de Burnout em estudantes de Odontologia de uma universidade pública e sua relação com características sociodemográficas. Todos os estudantes (n = 300) foram convidados a participar. Utilizou-se o Inventário de Burnout de Maslach - versão estudantes (MBI-SS). Realizou-se análise das propriedades psicométricas do MBI-SS. Para comparação entre os escores médios das dimensões do Burnout realizou-se Análise de Variância Multivariada (MANOVA) seguida de Análise de Variância (ANOVA) e testes post-hoc de Tukey. Dos 235 participantes, 72,8% eram mulheres e a média de idade era de 21,0 ± 1,8 anos. O MBI-SS mostrou-se confiável e válido. Dos estudantes, 17,0% apresentaram a Síndrome de Burnout. Verificou-se relação significativa entre a Síndrome de Burnout e o desempenho do estudante no curso (F = 4,433, p < 0,001), o consumo de medicação devido aos estudos (F = 7,721, p < 0,001) e o pensamento de desistir do curso (F = 16,168, p < 0,001). Foram mais acometidos aqueles com desempenho ruim no curso, que consomem medicações devido aos estudos e que já pensaram em desistir do curso. Conclui-se que a prevalência da Síndrome entre os estudantes de Odontologia foi alta, sendo significativa a relação entre a Síndrome e o desempenho do estudante no curso, o consumo de medicação devido aos estudos e o pensamento de desistir do curso.<br>The burnout syndrome is characterized by professional exhaustion and has been reported in college students. The aim of this study was to estimate the prevalence of Burnout Syndrome among dentistry students from a public university, and its relationship to socio-demographic characteristics. All students (n = 300) were invited to participate. We used the Maslach Burnout Inventory - Student Version (MBI-SS). We carried out an analysis of the MBI-SS' psychometric properties. Multivariate Analysis of Variance (MANOVA) was performed, followed by Analysis of Variance (ANOVA) and Tukey's post-hoc tests to compare the mean scores of burnout dimensions. Of the 235 participants, 72.8% were women and the mean age was 21.0 ± 1.8 years. The MBI-SS was reliable and valid. Of the students, 17.0% had Burnout Syndrome. There was a significant relation between Burnout Syndrome and a student's performance during the course (F = 4.433, p < 0.001), medication intake because of studies (F = 7.721, p < 0.001), and the thought of dropping the course (F = 16.168, p < 0.001). The students most affected were those with poor performance, those who took medication because of studies, and those with thoughts of dropping the course. We concluded that the prevalence of the syndrome among dentistry students was high, with a significant relation between the syndrome and a student's academic performance, use of medication because of studies, and thoughts of dropping the course