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1.  Added Value of IP-10 as a Read-Out of Mycobacterium tuberculosis 
Supplemental Digital Content is available in the text.
We have explored the added value of interferon-γ (IFNγ)–inducible protein 10 as a read-out of Mycobacterium tuberculosis–specific immunity in young Indian children, where the sensitivity of the IFNγ release assays for tuberculosis is poor. Reduced frequency of indeterminate results and an increased sensitivity for tuberculosis suggest a potential for fewer missed cases with a combined IFNγ/inducible protein 10 read-out in a 4th generation IFNγ release assays.
doi:10.1097/INF.0000000000001328
PMCID: PMC5108305  PMID: 27642776
tuberculosis; child; tuberculin skin test; interferon-γ release assay; cytokines; chemokines
2.  Alcoholic Beverage Preference and Dietary Habits in Elderly across Europe: Analyses within the Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES) Project 
PLoS ONE  2016;11(8):e0161603.
Introduction
The differential associations of beer, wine, and spirit consumption on cardiovascular risk found in observational studies may be confounded by diet. We described and compared dietary intake and diet quality according to alcoholic beverage preference in European elderly.
Methods
From the Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES), seven European cohorts were included, i.e. four sub-cohorts from EPIC-Elderly, the SENECA Study, the Zutphen Elderly Study, and the Rotterdam Study. Harmonized data of 29,423 elderly participants from 14 European countries were analyzed. Baseline data on consumption of beer, wine, and spirits, and dietary intake were collected with questionnaires. Diet quality was assessed using the Healthy Diet Indicator (HDI). Intakes and scores across categories of alcoholic beverage preference (beer, wine, spirit, no preference, non-consumers) were adjusted for age, sex, socio-economic status, self-reported prevalent diseases, and lifestyle factors. Cohort-specific mean intakes and scores were calculated as well as weighted means combining all cohorts.
Results
In 5 of 7 cohorts, persons with a wine preference formed the largest group. After multivariate adjustment, persons with a wine preference tended to have a higher HDI score and intake of healthy foods in most cohorts, but differences were small. The weighted estimates of all cohorts combined revealed that non-consumers had the highest fruit and vegetable intake, followed by wine consumers. Non-consumers and persons with no specific preference had a higher HDI score, spirit consumers the lowest. However, overall diet quality as measured by HDI did not differ greatly across alcoholic beverage preference categories.
Discussion
This study using harmonized data from ~30,000 elderly from 14 European countries showed that, after multivariate adjustment, dietary habits and diet quality did not differ greatly according to alcoholic beverage preference.
doi:10.1371/journal.pone.0161603
PMCID: PMC4993358  PMID: 27548323
3.  Incidence of tuberculosis among school-going adolescents in South India 
BMC Public Health  2016;16:641.
Background
Tuberculosis (TB) incidence data in vaccine target populations, particularly adolescents, are important for designing and powering vaccine clinical trials. Little is known about the incidence of tuberculosis among adolescents in India. The objective of current study is to estimate the incidence of pulmonary tuberculosis (PTB) disease among adolescents attending school in South India using two different surveillance methods (active and passive) and to compare the incidence between the two groups.
Methods
The study was a prospective cohort study with a 2-year follow-up period. The study was conducted in Palamaner, Chittoor District of Andhra Pradesh, South India from February 2007 to July 2010. A random sampling procedure was used to select a subset of schools to enable approximately 8000 subjects to be available for randomization in the study. A stratified randomization procedure was used to assign the selected schools to either active or passive surveillance. Participants who met the criteria for being exposed to TB were referred to the diagnostic ward for pulmonary tuberculosis confirmation. A total number of 3441 males and 3202 females between the ages 11 and less than 18 years were enrolled into the study.
Results
Of the 3102 participants in the active surveillance group, four subjects were diagnosed with definite tuberculosis, four subjects with probable tuberculosis, and 71 subjects had non-tuberculous Mycobacteria (NTM) isolated from their sputum. Of the 3541 participants in the passive surveillance group, four subjects were diagnosed with definite tuberculosis, two subjects with probable tuberculosis, and 48 subjects had non-tuberculosis Mycobacteria isolated from their sputum. The incidence of definite + probable TB was 147.60 / 100,000 person years in the active surveillance group and 87 / 100,000 person years in the passive surveillance group.
Conclusion
The incidence of pulmonary tuberculosis among adolescents in our study is lower than similar studies conducted in South Africa and Eastern Uganda – countries with a higher incidence of tuberculosis and human immunodeficiency virus (HIV) than India. The study data will inform sample design for vaccine efficacy trials among adolescents in India.
doi:10.1186/s12889-016-3342-0
PMCID: PMC4962501  PMID: 27461229
Pulmonary tuberculosis; TB incidence; Adolescents; South India; TB vaccine trials
4.  Quantification of the smoking-associated cancer risk with rate advancement periods: meta-analysis of individual participant data from cohorts of the CHANCES consortium 
BMC Medicine  2016;14:62.
Background
Smoking is the most important individual risk factor for many cancer sites but its association with breast and prostate cancer is not entirely clear. Rate advancement periods (RAPs) may enhance communication of smoking related risk to the general population. Thus, we estimated RAPs for the association of smoking exposure (smoking status, time since smoking cessation, smoking intensity, and duration) with total and site-specific (lung, breast, colorectal, prostate, gastric, head and neck, and pancreatic) cancer incidence and mortality.
Methods
This is a meta-analysis of 19 population-based prospective cohort studies with individual participant data for 897,021 European and American adults. For each cohort we calculated hazard ratios (HRs) for the association of smoking exposure with cancer outcomes using Cox regression adjusted for a common set of the most important potential confounding variables. RAPs (in years) were calculated as the ratio of the logarithms of the HRs for a given smoking exposure variable and age. Meta-analyses were employed to summarize cohort-specific HRs and RAPs.
Results
Overall, 140,205 subjects had a first incident cancer, and 53,164 died from cancer, during an average follow-up of 12 years. Current smoking advanced the overall risk of developing and dying from cancer by eight and ten years, respectively, compared with never smokers. The greatest advancements in cancer risk and mortality were seen for lung cancer and the least for breast cancer. Smoking cessation was statistically significantly associated with delays in the risk of cancer development and mortality compared with continued smoking.
Conclusions
This investigation shows that smoking, even among older adults, considerably advances, and cessation delays, the risk of developing and dying from cancer. These findings may be helpful in more effectively communicating the harmful effects of smoking and the beneficial effect of smoking cessation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0607-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-016-0607-5
PMCID: PMC4820956  PMID: 27044418
Smoking; Cancer; Incidence; Mortality; Cohort; Meta-analysis
5.  Effect of major lifestyle risk factors, independent and jointly, on life expectancy with and without cardiovascular disease: results from the Consortium on Health and Ageing Network of Cohorts in Europe and the United States (CHANCES) 
Seldom have studies taken account of changes in lifestyle habits in the elderly, or investigated their impact on disease-free life expectancy (LE) and LE with cardiovascular disease (CVD). Using data on subjects aged 50+ years from three European cohorts (RCPH, ESTHER and Tromsø), we used multi-state Markov models to calculate the independent and joint effects of smoking, physical activity, obesity and alcohol consumption on LE with and without CVD. Men and women aged 50 years who have a favourable lifestyle (overweight but not obese, light/moderate drinker, non-smoker and participates in vigorous physical activity) lived between 7.4 (in Tromsø men) and 15.7 (in ESTHER women) years longer than those with an unfavourable lifestyle (overweight but not obese, light/moderate drinker, smoker and does not participate in physical activity). The greater part of the extra life years was in terms of “disease-free” years, though a healthy lifestyle was also associated with extra years lived after a CVD event. There are sizeable benefits to LE without CVD and also for survival after CVD onset when people favour a lifestyle characterized by salutary behaviours. Remaining a non-smoker yielded the greatest extra years in overall LE, when compared to the effects of routinely taking physical activity, being overweight but not obese, and drinking in moderation. The majority of the overall LE benefit is in disease free years. Therefore, it is important for policy makers and the public to know that prevention through maintaining a favourable lifestyle is “never too late”.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-015-0112-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s10654-015-0112-8
PMCID: PMC4901087  PMID: 26781655
CHANCES; Ageing; Smoking; Obesity; Cardiovascular disease; Mortality
6.  WHO guidelines for a healthy diet and mortality from cardiovascular disease in European and American elderly: the CHANCES project12 
Background: Cardiovascular disease (CVD) represents a leading cause of mortality worldwide, especially in the elderly. Lowering the number of CVD deaths requires preventive strategies targeted on the elderly.
Objective: The objective was to generate evidence on the association between WHO dietary recommendations and mortality from CVD, coronary artery disease (CAD), and stroke in the elderly aged ≥60 y.
Design: We analyzed data from 10 prospective cohort studies from Europe and the United States comprising a total sample of 281,874 men and women free from chronic diseases at baseline. Components of the Healthy Diet Indicator (HDI) included saturated fatty acids, polyunsaturated fatty acids, mono- and disaccharides, protein, cholesterol, dietary fiber, and fruit and vegetables. Cohort-specific HRs adjusted for sex, education, smoking, physical activity, and energy and alcohol intakes were pooled by using a random-effects model.
Results: During 3,322,768 person-years of follow-up, 12,492 people died of CVD. An increase of 10 HDI points (complete adherence to an additional WHO guideline) was, on average, not associated with CVD mortality (HR: 0.94; 95% CI: 0.86, 1.03), CAD mortality (HR: 0.99; 95% CI: 0.85, 1.14), or stroke mortality (HR: 0.95; 95% CI: 0.88, 1.03). However, after stratification of the data by geographic region, adherence to the HDI was associated with reduced CVD mortality in the southern European cohorts (HR: 0.87; 95% CI: 0.79, 0.96; I2 = 0%) and in the US cohort (HR: 0.85; 95% CI: 0.83, 0.87; I2 = not applicable).
Conclusion: Overall, greater adherence to the WHO dietary guidelines was not significantly associated with CVD mortality, but the results varied across regions. Clear inverse associations were observed in elderly populations in southern Europe and the United States.
doi:10.3945/ajcn.114.095117
PMCID: PMC4588736  PMID: 26354545
aging; CHANCES; cardiovascular disease; cohort; meta-analysis
7.  Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium 
Objective To investigate the impact of smoking and smoking cessation on cardiovascular mortality, acute coronary events, and stroke events in people aged 60 and older, and to calculate and report risk advancement periods for cardiovascular mortality in addition to traditional epidemiological relative risk measures.
Design Individual participant meta-analysis using data from 25 cohorts participating in the CHANCES consortium. Data were harmonised, analysed separately employing Cox proportional hazard regression models, and combined by meta-analysis.
Results Overall, 503 905 participants aged 60 and older were included in this study, of whom 37 952 died from cardiovascular disease. Random effects meta-analysis of the association of smoking status with cardiovascular mortality yielded a summary hazard ratio of 2.07 (95% CI 1.82 to 2.36) for current smokers and 1.37 (1.25 to 1.49) for former smokers compared with never smokers. Corresponding summary estimates for risk advancement periods were 5.50 years (4.25 to 6.75) for current smokers and 2.16 years (1.38 to 2.39) for former smokers. The excess risk in smokers increased with cigarette consumption in a dose-response manner, and decreased continuously with time since smoking cessation in former smokers. Relative risk estimates for acute coronary events and for stroke events were somewhat lower than for cardiovascular mortality, but patterns were similar.
Conclusions Our study corroborates and expands evidence from previous studies in showing that smoking is a strong independent risk factor of cardiovascular events and mortality even at older age, advancing cardiovascular mortality by more than five years, and demonstrating that smoking cessation in these age groups is still beneficial in reducing the excess risk.
doi:10.1136/bmj.h1551
PMCID: PMC4413837  PMID: 25896935
8.  Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium 
The BMJ  2015;350:h1551.
Objective To investigate the impact of smoking and smoking cessation on cardiovascular mortality, acute coronary events, and stroke events in people aged 60 and older, and to calculate and report risk advancement periods for cardiovascular mortality in addition to traditional epidemiological relative risk measures.
Design Individual participant meta-analysis using data from 25 cohorts participating in the CHANCES consortium. Data were harmonised, analysed separately employing Cox proportional hazard regression models, and combined by meta-analysis.
Results Overall, 503 905 participants aged 60 and older were included in this study, of whom 37 952 died from cardiovascular disease. Random effects meta-analysis of the association of smoking status with cardiovascular mortality yielded a summary hazard ratio of 2.07 (95% CI 1.82 to 2.36) for current smokers and 1.37 (1.25 to 1.49) for former smokers compared with never smokers. Corresponding summary estimates for risk advancement periods were 5.50 years (4.25 to 6.75) for current smokers and 2.16 years (1.38 to 2.39) for former smokers. The excess risk in smokers increased with cigarette consumption in a dose-response manner, and decreased continuously with time since smoking cessation in former smokers. Relative risk estimates for acute coronary events and for stroke events were somewhat lower than for cardiovascular mortality, but patterns were similar.
Conclusions Our study corroborates and expands evidence from previous studies in showing that smoking is a strong independent risk factor of cardiovascular events and mortality even at older age, advancing cardiovascular mortality by more than five years, and demonstrating that smoking cessation in these age groups is still beneficial in reducing the excess risk.
doi:10.1136/bmj.h1551
PMCID: PMC4413837  PMID: 25896935
9.  Effect of Non-tuberculous Mycobacteria on Host Biomarkers Potentially Relevant for Tuberculosis Management 
Background
Non-tuberculous mycobacteria (NTM) are different from Mycobacterium tuberculosis (MTB) both in their ubiquitous environmental distribution and in their reduced capacity to cause disease. While often neglected in favour of other infectious diseases, NTM may interfere with important aspects of TB control and management, namely the efficacy of new anti-tuberculosis (TB) vaccines; the immuno-diagnostic Tuberculin skin test (TST) and QuantiFERON TB Gold In Tube assay (QFTGIT); and immune biomarkers explored for their diagnostic and/or predictive potential. Our objective was therefore to explore host immune biomarkers in children who had NTM isolated from respiratory and/or gastric specimens.
Methodology and Principle Findings
The present study was nested within a prospective cohort study of BCG-vaccinated neonates in Southern India. In this setting, immune biomarkers from peripheral blood were analyzed in 210 children aged <3 years evaluated for TB using dual-colour-Reverse-Transcriptase-Multiple-Ligation-dependent-Probe-Amplification (dcRT-MLPA) and Bio-Plex assays. The children were classified based on clinical examination, chest X-rays and mycobacterial culture reports as either: 1) TB disease, 2) NTM present and 3) controls. The study shows a down-regulation of RAB33A (p<0.001) and up-regulation of TGFβ1, IL-2 and IL-6 (all p<0.05) in children with TB disease, and that RAB33A, TGFBR2 and IL-10 (all p<0.05) were differentially expressed in children with NTM present when compared to children that were culture negative for MTB and NTM (controls).
Conclusions and Significance
Carriage of NTM may reduce the specificity of future diagnostic and predictive immune biomarkers relevant to TB management.
Author Summary
Non-tuberculous mycobacteria (NTM) are a ubiquitous group of mycobacteria found in the environment. They are opportunistic pathogens causing human disease, especially in immunocompromised individuals. Differentiation between NTM infection and tuberculosis (TB) can be difficult. Data on incidence of NTM in TB endemic countries is limited due to resource intensive methods required for identification and a considerable workload due to other diseases. The present study was based on children investigated for TB and classified according to chest X-rays and mycobacterial culture reports. We explored host immune biomarkers which are potentially relevant to TB management, in children with confirmed NTM exposure. The findings from the present study suggest that NTM exposure modulates TB-relevant immune biomarkers in the host by eliciting some of the same immune responses as MTB infection. This is may be of importance when evaluating immunological correlates of protection in the setting of TB vaccine trials and potential TB diagnostic biomarkers.
doi:10.1371/journal.pntd.0003243
PMCID: PMC4199571  PMID: 25329719
10.  Combination of Cytokine Responses Indicative of Latent TB and Active TB in Malawian Adults 
PLoS ONE  2013;8(11):e79742.
Background
An IFN-γ response to M. tuberculosis-specific antigens is an effective biomarker for M. tuberculosis infection but it cannot discriminate between latent TB infection and active TB disease. Combining a number of cytokine/chemokine responses to M. tuberculosis antigens may enable differentiation of latent TB from active disease.
Methods
Asymptomatic recently-exposed individuals (spouses of TB patients) were recruited and tuberculin skin tested, bled and followed-up for two years. Culture supernatants, from a six-day culture of diluted whole blood samples stimulated with M. tuberculosis-derived PPD or ESAT-6, were measured for IFN-γ, IL-10, IL-13, IL-17, TNF-α and CXCL10 using cytokine ELISAs. In addition, 15 patients with sputum smear-positive pulmonary TB were recruited and tested.
Results
Spouses with positive IFN-γ responses to M. tuberculosis ESAT-6 (>62.5 pg/mL) and TB patients showed high production of IL-17, CXCL10 and TNF-α. Higher production of IL-10 and IL-17 in response to ESAT-6 was observed in the spouses compared with TB patients while the ratios of IFN-γ/IL-10 and IFN-γ/IL-17 in response to M. tuberculosis-derived PPD were significantly higher in TB patients compared with the spouses. Tuberculin skin test results did not correlate with cytokine responses.
Conclusions
CXCL10 and TNF-α may be used as adjunct markers alongside an IFN-γ release assay to diagnose M. tuberculosis infection, and IL-17 and IL-10 production may differentiate individuals with LTBI from active TB.
doi:10.1371/journal.pone.0079742
PMCID: PMC3832606  PMID: 24260295
11.  Association of dietary fat intakes with risk of esophageal and gastric cancer in the NIH-AARP Diet and Health study 
The aim of this study was to investigate whether intakes of total fat and fat subtypes were associated with esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastric cardia or gastric non-cardia adenocarcinoma. From 1995–1996, dietary intake data was reported by 494,978 participants of the NIH-AARP cohort. 630 EAC, 215 ESCC, 454 gastric cardia and 501 gastric non-cardia adenocarcinomas accrued to the cohort. Cox proportional hazards regression was used to examine the association between the dietary fat intakes, whilst adjusting for potential confounders. Though apparent associations were observed in energy-adjusted models, multivariate adjustment attenuated results to null (e.g. EAC energy adjusted hazard ratio (HR) and 95% confidence interval (95%CI) 1.66 (1.27–2.18) P for trend <0.01; EAC multivariate adjusted HR (95%CI) 1.17 (0.84–1.64) P for trend=0.58). Similar patterns were also observed for fat subtypes (e.g. EAC saturated fat, energy adjusted HR (95%CI) 1.79 (1.37–2.33) P for trend <0.01; EAC saturated fat, multivariate adjusted HR (95%CI) 1.27 (0.91–1.78) P for trend=0.28). However, in multivariate models an inverse association for polyunsaturated fat (continuous) was seen for EAC in subjects with a body mass index (BMI) in the normal range (18.5–<25 kg/m2) (HR (95%CI) 0.76 (0.63–0.92)), that was not present in overweight subjects (HR (95%CI) 1.04 (0.96–1.14)), or in unstratified analysis (HR (95%CI) 0.97 (0.90–1.05)). P for interaction=0.02. Overall, we found null associations between the dietary fat intakes with esophageal or gastric cancer risk; though a protective effect of polyunsaturated fat intake was seen for EAC in subjects with a normal BMI.
doi:10.1002/ijc.27366
PMCID: PMC3346853  PMID: 22116732
cohort; dietary fat; esophageal neoplasms; stomach neoplasms; prospective
12.  Two-Step Tuberculin Skin Testing in School-Going Adolescents with Initial 0-4 Millimeter Responses in a High Tuberculosis Prevalence Setting in South India 
PLoS ONE  2013;8(9):e71470.
Background
The utility of two-step tuberculin skin testing among adolescents in high tuberculosis prevalence settings is not well established.
Objectives
To determine the proportion and determinants of a 0-4 mm response to an initial standard tuberculin skin test (TST) and evaluating 'boosting' with repeat testing.
Methods
Adolescents between 11 and 18 years attending schools/colleges underwent a TST; those with a response of between 0–4 mm had a repeat TST 1-4 weeks later.
Results
Initial TST was done for 6608/6643 participants; 1257 (19%) developed a 0-4 mm response to the initial TST. Younger age and under-nutrition were more likely to be associated with a 0-4 mm response, while the presence of BCG (Bacillus Calmette Guerin) scar and higher socio-economic class were less likely to be associated with a 0-4 mm response. On repeat testing boosting was seen in 13.2% (145/1098; ≥ 6 mm over the initial test) while 4.3% showed boosting using a more conservative cutoff of a repeat TST ≥ 10 mm with an increment of at least 6 mm (47/1098). History of exposure to a tuberculosis (TB) case was associated with enhanced response.
Conclusion
The proportion of adolescents who demonstrated boosting on two-step TST testing in our study was relatively low. As a result repeat testing did not greatly alter the prevalence of TST positivity. However, the two-step TST helps identify individuals who can potentially boost their immune response to a second test, and thus, prevents them from being misclassified as those with newly acquired infection, or tuberculin converters. While two-step tuberculin skin testing may have a limited role in population- level TST surveys, it may be useful where serial tuberculin testing needs to be performed to distinguish those who show an enhanced response or boosters from those who indeed have a new infection, or converters.
doi:10.1371/journal.pone.0071470
PMCID: PMC3765300  PMID: 24039716
13.  Parasitic infection may be associated with discordant responses to QuantiFERON and tuberculin skin test in apparently healthy children and adolescents in a tuberculosis endemic setting, Ethiopia 
BMC Infectious Diseases  2013;13:265.
Background
M. tuberculosis remains one of the world’s deadliest pathogens in part because of its ability to establish persistent, latent infections, which can later reactivate to cause disease. In regions of the globe where disease is endemic, as much as 50% of the population is thought to be latently infected, complicating diagnosis and tuberculosis control. The tools most commonly used for diagnosis of latent M. tuberculosis infection are the tuberculin skin test and the newer interferon-gamma release assays, both of which rely on an antigen-specific memory response as an indicator of infection. It is clear that the two tests, do not always give concordant results, but the factors leading to this are only partially understood.
Methods
In this study we examined 245 healthy school children aged from 12 to 20 years from Addis Ababa, a tuberculosis-endemic region, characterised them with regard to response in the tuberculin skin test and QuantIFERON™ test and assessed factors that might contribute to discordant responses.
Results
Although concordance between the tests was generally fair (90% concordance), there was a subset of children who had a positive QuantIFERON™ result but a negative tuberculin skin test. After analysis of multiple parameters the data suggest that discordance was most strongly associated with the presence of parasites in the stool.
Conclusions
Parasitic gut infections are frequent in most regions where M. tuberculosis is endemic. This study, while preliminary, suggests that the tuberculin skin test should be interpreted with caution where this may be the case.
doi:10.1186/1471-2334-13-265
PMCID: PMC3674899  PMID: 23738853
Latent tuberculosis; QuantiFERON; TST; Adolescents; Children; Parasites
14.  Hazardous alcohol consumption is associated with increased levels of B-type natriuretic peptide: evidence from two population-based studies 
European Journal of Epidemiology  2013;28(5):393-404.
Russia has very high mortality from cardiovascular disease (CVD), with evidence that heavy drinking may play a role. To throw further light on this association we have studied the association of alcohol with predictors of CVD risk including B-type natriuretic peptide (BNP). Levels of BNP increase primarily in response to abnormal cardiac chamber wall stretch which can occur both as a result of atherosclerosis as well as due to other types of damage to the myocardium. No previous population-based studies have investigated the association with alcohol. We analysed cross-sectional data on drinking behaviour in 993 men aged 25–60 years from the Izhevsk Family Study 2 (IFS2), conducted in the Russian city of Izhevsk in 2008–2009. Relative to non-drinkers, men who drank hazardously had an odds ratio (OR) of being in the top 20 % of the BNP distribution of 4.66 (95 % CI 2.13, 10.19) adjusted for age, obesity, waist–hip ratio, and smoking. Further adjustment for class of hypertension resulted in only slight attenuation of the effect, suggesting that this effect was not secondary to the influence of alcohol on blood pressure. In contrast hazardous drinking was associated with markedly raised ApoA1 and HDL cholesterol levels, but had little impact on levels of ApoB and LDL cholesterol. Similar but less pronounced associations were found in the Belfast (UK) component of the PRIME study conducted in 1991. These findings suggest that the association of heavy drinking with increased risk of cardiovascular disease may be partly due to alcohol-induced non-atherosclerotic damage to the myocardium.
doi:10.1007/s10654-013-9808-9
PMCID: PMC3672507  PMID: 23645505
Alcohol; B-type natriuretic peptide; Russia; Cardiovascular disease
15.  Expression of TNF-Alpha-Dependent Apoptosis-Related Genes in the Peripheral Blood of Malagasy Subjects with Tuberculosis 
PLoS ONE  2013;8(4):e61154.
The majority of Mycobacterium tuberculosis (Mtb) infections remain asymptomatic with only up to 10% progressing to clinical tuberculosis. However, the constituents of the effective “protective immunity” against tuberculosis responsible for containing most infections remain unknown. Evaluating gene transcriptional profiles in tuberculosis clinical cohorts is one approach to understanding the spectrum of tuberculosis progression. It is clear that apoptosis plays a role in the control of tuberculosis but the utility of apoptosis-related genes as surrogate markers of protection against tuberculosis has not been well investigated. To characterize potential surrogate markers that could discriminate different phases of the clinical tuberculosis spectrum, we investigated gene expression of several TNF-alpha dependent apoptotic genes (TNFR1, TNFR2, FLICE, FLIPs) by real-time RT-PCR of peripheral blood cells from cohorts of individuals with active tuberculosis or potential exposure to tuberculosis.
Newly diagnosed tuberculosis patients (n = 23), their close household contacts (n = 80), and community controls (n = 46) were tested at intervals over a period of up to two years. Latent infection or previous Mtb contact was assessed by ELISPOT and TST and complete blood counts were performed during the follow up.
Results showed significant upregulation of FLIPs expression by infected individuals regardless of clinical status at entry to the study. A higher percentage of lymphocytes was found in the infected household contacts that remained healthy. In contrast, in individuals with active TB, a significant upregulation of TNFR2 expression, a significantly higher percentage of monocytes and a significantly decreased lymphocyte count were seen, compared to subjects that remained healthy. Moreover, the household contacts who subsequently developed signs of TB also had a significantly high number of monocytes.
These data suggest tuberculosis may be associated with decreased T-cell survival (perhaps due to apoptosis) while inhibition of apoptosis in monocytes could lead to a relative increase in these cells: a situation predicted to favour Mtb.
doi:10.1371/journal.pone.0061154
PMCID: PMC3625145  PMID: 23593415
16.  A prospective cohort study of obesity and risk of esophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health study 
Gut  2011;61(9):1261-1268.
Objective
Incidence of esophageal adenocarcinoma (EAC) has increased rapidly over the past forty years and accumulating evidence suggests that obesity, as measured by body mass index (BMI), is a major risk factor. However, it remains unclear whether abdominal obesity is associated with esophageal and gastric adenocarcinoma.
Design
Cox proportional hazards regression was used to examine associations between overall and abdominal obesity with EAC and gastric adenocarcinoma among 218,854 participants in the prospective NIH-AARP cohort.
Results
253 incident EAC, 191 gastric cardia adenocarcinomas, and 125 gastric non-cardia adenocarcinomas accrued to the cohort. Overall obesity (BMI) was positively associated with EAC and gastric cardia adenocarcinoma risk (highest [≥35 kg/m2] versus referent [18.5–<25 kg/m2]; hazard ratio (HR) 95% confidence interval (95% CI); 2.11 (1.09–4.09) and 3.67 (2.00–6.71), respectively). Waist circumference was also positively associated with EAC and gastric cardia adenocarcinoma risk, (highest versus referent; HR (95% CI) 2.01 (1.35–3.00) and 2.22 (1.43–3.47), respectively), whereas waist-to-hip ratio (WHR) was positively associated with EAC risk only (highest versus referent; HR (95% CI) 1.81 (1.24–2.64)); persisted in patients with normal BMI (18.5–<25 kg/m2). Mutual adjustment of WHR and BMI attenuated both, but did not eliminate the positive associations for either with risk of EAC. In contrast, the majority of the anthropometric variables were not associated with adenocarcinomas of the gastric non-cardia.
Conclusion
Overall obesity was associated with a higher risk of EAC and gastric cardia adenocarcinoma, whereas abdominal obesity was found to be associated with increased EAC risk; even in people with normal BMI.
doi:10.1136/gutjnl-2011-300551
PMCID: PMC3504700  PMID: 22174193
adenocarcinoma; epidemiology; esophageal cancer; gastric adenocarcinoma; obesity
17.  Dietary fat and meat intakes and risk of reflux esophagitis, Barrett’s esophagus and esophageal adenocarcinoma 
The aim of this study was to investigate whether dietary fat and meat intakes are associated with reflux esophagitis (RE), Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). In this all-Ireland case-control study, dietary intake data was collected using a food frequency questionnaire in 219 RE patients, 220 BE patients, 224 EAC patients, and 256 frequency-matched controls between 2002 and 2005. Unconditional multiple logistic regression analysis was used to examine the association between dietary variables and disease risk using quartiles of intake, to attain odds ratios (OR) and 95% confidence intervals (95%CI), while adjusting for potential confounders. Patients in the highest quartile of total fat intake had a higher risk of RE (OR=3.54; 95%CI=1.32–9.46) and EAC (OR=5.44; 95%CI=2.08–14.27). A higher risk of RE and EAC was also reported for patients in the highest quartile of saturated fat intake (OR=2.79; 95%CI=1.11–7.04; OR=2.41; 95%CI=1.14–5.08, respectively) and monounsaturated fat intake (OR=2.63; 95%CI=1.01–6.86; OR=5.35; 95%CI=2.14–13.34, respectively). Patients in the highest quartile of fresh red meat intake had a higher risk of EAC (OR=3.15; 95%CI=1.38–7.20). Patients in the highest category of processed meat intake had a higher risk of RE (OR=4.67; 95%CI=1.71–12.74). No consistent associations were seen for BE with either fat or meat intakes. Further studies, investigating the association between dietary fat and food sources of fat are needed to confirm these results.
doi:10.1002/ijc.26108
PMCID: PMC3144995  PMID: 21455992
adenocarcinoma; Barrett’s esophagus; dietary fat; epidemiology; meat
18.  Iron intake and markers of iron status and risk of Barrett’s esophagus and esophageal adenocarcinoma 
Cancer causes & control : CCC  2010;21(12):2269-2279.
Objective
To investigate the association between iron intake and iron status with Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC).
Methods
220 BE patients, 224 EAC patients, and 256 frequency-matched controls completed a lifestyle and food frequency questionnaire, and provided serum and toenail samples between 2002 and 2005. Using multiple logistic regression, odds ratios (OR) and 95% confidence intervals (95%CI) were calculated within quartiles of intake/status.
Results
Comparing the fourth to the first quartile, ferritin (OR 0.47; 95%CI: 0.23, 0.97) and transferrin saturation (OR 0.41; 95%CI: 0.20, 0.82) were negatively associated with BE; whilst total iron binding capacity was positively associated per 50 µg/dl increment (OR 1.47; 95%CI: 1.12, 1.92). Comparing the fourth to the first quartile, iron intake (OR 0.50; 95%CI: 0.25, 0.98), non-heme iron intake per 10 mg/day increment (OR 0.29; 95%CI: 0.08, 0.99), and toenail iron (OR 0.40; 95%CI: 0.17, 0.93) were negatively associated with EAC; whilst heme iron intake was positively associated (OR 3.11 95%CI: 1.46, 6.61).
Principal conclusion
In contrast to the hypothesis that increased iron intakes and higher iron stores are a risk factor for BE and EAC, this study suggests that higher iron intakes and stores may have a protective association with BE and EAC, with the exception of what was found for heme iron intake.
doi:10.1007/s10552-010-9652-0
PMCID: PMC3438890  PMID: 20936528
adenocarcinoma; Barrett's esophagus; epidemiology; ferritin; iron
19.  Risk Stratification of Latent Tuberculosis Defined by Combined Interferon Gamma Release Assays 
PLoS ONE  2012;7(8):e43285.
Background
Most individuals infected with Mycobacterium tuberculosis develop latent tuberculosis infection (LTBI). Some may progress to active disease and would benefit from preventive treatment yet no means currently exists to predict who will reactivate. Here, we provide an approach to stratify LTBI based on IFN-γ responses to two antigens, the recombinant Early-Secreted Antigen Target-6 (rESAT-6) and the latency antigen Heparin-Binding Haemagglutinin (HBHA).
Methods
We retrospectively analyzed results from in-house IFN-γ-release assays with HBHA (HBHA-IGRA) and rESAT-6 (rESAT-6-IGRA) performed during a 12-year period on serial blood samples (3 to 9) collected from 23 LTBI subjects in a low-TB incidence country. Both the kinetics of the absolute IFN-γ concentrations secreted in response to each antigen and the dynamics of HBHA/rESAT-6-induced IFN-γ concentrations ratios were examined.
Results
This analysis allowed the identification among the LTBI subjects of three major groups. Group A featured stable HBHA and rESAT-6-IGRA profiles with an HBHA/rESAT-6 ratio persistently higher than 1, and with high HBHA- and usually negative rESAT-6-IGRA responses throughout the study. Group B had changing HBHA/rESAT-6 ratios fluctuating from 0.0001 to 10,000, with both HBHA and rESAT-6 responses varying over time at least once during the follow-up. Group C was characterized by a progressive disappearance of all responses.
Conclusions
By combining the measures of IFN-γ concentrations secreted in response to an early and a latency antigens, LTBI subjects can be stratified into different risk groups. We propose that disappearing responses indicate cure, that persistent responses to HBHA with HBHA/rESAT-6 ratios ≥1 represent stable LTBI subjects, whereas subjects with ratios varying from >1 to <1 should be closely monitored as they may represent the highest-risk group, as illustrated by a case report, and should therefore be prioritized for preventive treatment.
doi:10.1371/journal.pone.0043285
PMCID: PMC3422279  PMID: 22912846
20.  Diagnosis of latent tuberculosis infection in healthy young adults in a country with high tuberculosis burden and BCG vaccination at birth 
BMC Research Notes  2012;5:415.
Background
One third of the world’s population is thought to have latent tuberculosis infection (LTBI) with the potential for subsequent reactivation of disease. To better characterize this important population, studies comparing Tuberculin Skin Test (TST) and the new interferon-γ release assays including QuantiFERON®-TB Gold In-Tube (QFT-GIT) have been conducted in different parts of the world, but most of these have been in countries with a low incidence of tuberculosis (TB). The aim of this study was therefore to evaluate the use of QFT-GIT assay as compared with TST in the diagnosis of LTBI in Ethiopia, a country with a high burden of TB and routine BCG vaccination at birth.
Methods
Healthy medical and paramedical male students at the Faculty of Medicine, Addis Ababa University, Ethiopia were enrolled into the study from December 2008 to February 2009. The TST and QFTG-IT assay were performed using standard methods.
Results
The mean age of the study participants was 20.9 years. From a total of 107 study participants, 46.7% (95%CI: 37.0% to 56.6%) had a positive TST result (TST≥10 mm), 43.9% (95%CI: 34.3% to 53.9%) had a positive QFT-GIT assay result and 44.9% (95%CI: 35.2% to 54.8%) had BCG scar. There was strong agreement between TST (TST ≥10mm) and QFT-GIT assay (Kappa = 0.83, p value = 0.000).
Conclusion
The TST and QFT-GIT assay show similar efficacy for the diagnosis of LTBI in healthy young adults residing in Ethiopia, a country with high TB incidence.
doi:10.1186/1756-0500-5-415
PMCID: PMC3478185  PMID: 22870897
Tuberculosis; Latent; BCG; Tuberculin skin test; Interferon-γ release assay; Ethiopia
21.  TB case detection: can we remain passive while the process is active? 
TB remains a major public health problem despite all the efforts that have been made since it was declared a global emergency in 1993. Different strategies have been implemented to curb the spread of the epidemic. Early case detection and treatment is one of the pillars of the TB control program. In 1991, WHO set targets for increasing case detection and treatment success rates to 70% and 85% respectively. Although the target of treatment success rate has been achieved, the case detection rate remains far below target at currently less than 50%. It is high time that control programs move from simple passive to a more systematic active case finding in order to accelerate TB control.
PMCID: PMC3343678  PMID: 22593786
Case detection; Tuberculosis; DOTS
22.  Potential of novel Mycobacterium tuberculosis infection phase-dependent antigens in the diagnosis of TB disease in a high burden setting 
Background
Confirming tuberculosis (TB) disease in suspects in resource limited settings is challenging and calls for the development of more suitable diagnostic tools. Different Mycobacterium tuberculosis (M.tb) infection phase-dependent antigens may be differentially recognized in infected and diseased individuals and therefore useful as diagnostic tools for differentiating between M.tb infection states. In this study, we assessed the diagnostic potential of 118 different M.tb infection phase-dependent antigens in TB patients and household contacts (HHCs) in a high-burden setting.
Methods
Antigens were evaluated using the 7-day whole blood culture technique in 23 pulmonary TB patients and in 19 to 21 HHCs (total n = 101), who were recruited from a high-TB incidence community in Cape Town, South Africa. Interferon-gamma (IFN-γ) levels in culture supernatants were determined by ELISA.
Results
Eight classical TB vaccine candidate antigens, 51 DosR regulon encoded antigens, 23 TB reactivation antigens, 5 TB resuscitation promoting factors (rpfs), 6 starvation and 24 other stress response-associated TB antigens were evaluated in the study. The most promising antigens for ascertaining active TB were the rpfs (Rv0867c, Rv2389c, Rv2450c, Rv1009 and Rv1884c), with Areas under the receiver operating characteristics curves (AUCs) between 0.72 and 0.80. A combination of M.tb specific ESAT-6/CFP-10 fusion protein, Rv2624c and Rv0867c accurately predicted 73% of the TB patients and 80% of the non-TB cases after cross validation.
Conclusions
IFN-γ responses to TB rpfs show promise as TB diagnostic candidates and should be evaluated further for discrimination between M.tb infection states.
doi:10.1186/1471-2334-12-10
PMCID: PMC3282638  PMID: 22260319
24.  Modulation of Transcriptional and Inflammatory Responses in Murine Macrophages by the Mycobacterium tuberculosis Mammalian Cell Entry (Mce) 1 Complex 
PLoS ONE  2011;6(10):e26295.
The outcome of many infections depends on the initial interactions between agent and host. Aiming at elucidating the effect of the M. tuberculosis Mce1 protein complex on host transcriptional and immunological responses to infection with M. tuberculosis, RNA from murine macrophages at 15, 30, 60 min, 4 and 10 hrs post-infection with M. tuberculosis H37Rv or Δ-mce1 H37Rv was analyzed by whole-genome microarrays and RT-QPCR. Immunological responses were measured using a 23-plex cytokine assay. Compared to uninfected controls, 524 versus 64 genes were up-regulated by 15 min post H37Rv- and Δ-mce1 H37Rv-infection, respectively. By 15 min post-H37Rv infection, a decline of 17 cytokines combined with up-regulation of Ccl24 (26.5-fold), Clec4a2 (23.2-fold) and Pparγ (10.5-fold) indicated an anti-inflammatory response initiated by IL-13. Down-regulation of Il13ra1 combined with up-regulation of Il12b (30.2-fold), suggested switch to a pro-inflammatory response by 4 hrs post H37Rv-infection. Whereas no significant change in cytokine concentration or transcription was observed during the first hour post Δ-mce1 H37Rv-infection, a significant decline of IL-1b, IL-9, IL-13, Eotaxin and GM-CSF combined with increased transcription of Il12b (25.1-fold) and Inb1 (17.9-fold) by 4 hrs, indicated a pro-inflammatory response. The balance between pro-and anti-inflammatory responses during the early stages of infection may have significant bearing on outcome.
doi:10.1371/journal.pone.0026295
PMCID: PMC3200323  PMID: 22039457
25.  Modulation of Cell Death by M. tuberculosis as a Strategy for Pathogen Survival 
It has been clearly demonstrated that in vitro, virulent M. tuberculosis can favor necrosis over apoptosis in infected macrophages, and this has been suggested as a mechanism for evading the host immune response. We recently reported that an effect consistent with this hypothesis could be observed in cells from the blood of TB patients, and in this paper, we review what is known about evasion strategies employed by M. tuberculosis and in particular consider the possible interaction of the apoptosis-inhibiting effects of M. tuberculosis infection with another factor (IL-4) whose expression is thought to play a role in the failure to control M. tuberculosis infection. It has been noted that IL-4 may exacerbate TNF-α-induced pathology, though the mechanism remains unexplained. Since pathology in TB typically involves inflammatory aggregates around infected cells, where TNF-α plays an important role, we predicted that IL-4 would inhibit the ability of cells to remove M. tuberculosis by apoptosis of infected cells, through the extrinsic pathway, which is activated by TNF-α. Infection of human monocytic cells with mycobacteria in vitro, in the presence of IL-4, appears to promote necrosis over apoptosis in infected cells—a finding consistent with its suggested role as a factor in pathology during M. tuberculosis infection.
doi:10.1155/2011/678570
PMCID: PMC3022200  PMID: 21253484

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