Proteomic Analysis of Subchronic Furan Exposure in the Liver of Male Fischer F344 Rats.

Furan is a volatile compound formed during the thermal processing of foods. Chronic exposure has been shown to cause cholangiocarcinoma and hepatocellular tumors in rodent models. We conducted a 90 day subchronic study in Fisher 344 rats exposed to various doses by gavage to determine the NOAEL. Previous reports have outlined changes in the liver using gross necropsy examination, histopathology, clinical biochemistry, hematology, immunohistochemistry, and toxicogenomics. The data revealed that males were more sensitive than females. The focus of this study was to evaluate the toxicoproteomic changes by 2-dimensional differential in gel electrophoresis followed by mass spectrometry analysis. To compliment previous studies, protein expression changes were evaluated of male animals after 90 days of exposure to doses of 0, 0.03, 0.5, and 8.0 mg/kg bw/d. Significant statistical treatment-related changes compared to the controls identified 45 protein spots containing 38 unique proteins. Proteins identified are implicated in metabolism, redox regulation, protein folding/proteolysis as well as structural and transport proteins. At lower doses, multiple cytoprotective pathways are activated to maintain a homeostasis but ultimately the loss of protein function and impairment of several pathways could lead to adverse health effects at higher doses of furan administration.

Major Loci on Chromosomes 8q and 3q Control Interferon γ Production Triggered by Bacillus Calmette-Guerin and 6-kDa Early Secretory Antigen Target, Respectively, in Various Populations.

BACKGROUND: Interferon γ (IFN-γ) release assays (IGRAs) provide an in vitro measurement of antimycobacterial immunity that is widely used as a test for Mycobacterium tuberculosis infection. IGRA outcomes are highly heritable in various populations, but the nature of the involved genetic factors remains unknown. METHODS: We conducted a genome-wide linkage analysis of IGRA phenotypes in families from a tuberculosis household contact study in France and a replication study in families from South Africa to confirm the loci identified. RESULTS: We identified a major locus on chromosome 8q controlling IFN-γ production in response to stimulation with live bacillus Calmette-Guerin (BCG; LOD score, 3.81; P = 1.40 × 10(-5)). We also detected a second locus, on chromosome 3q, that controlled IFN-γ levels in response to stimulation with 6-kDa early secretory antigen target, when accounting for the IFN-γ production shared with that induced by BCG (LOD score, 3.72; P = 1.8 × 10(-5)). Both loci were replicated in South African families, where tuberculosis is hyperendemic. These loci differ from those previously identified as controlling the response to the tuberculin skin test (TST1 and TST2) and the production of TNF-α (TNF1). CONCLUSIONS: The identification of 2 new linkage signals in populations of various ethnic origins living in different M. tuberculosis exposure settings provides new clues about the genetic control of human antimycobacterial immunity.

Tuberculin skin test negativity is under tight genetic control of chromosomal region 11p14-15 in settings with different tuberculosis endemicities.

A substantial proportion of subjects exposed to a contagious tuberculosis case display lack of tuberculin skin test (TST) reactivity. We previously mapped a major locus (TST1) controlling lack of TST reactivity in families from an area in South Africa where tuberculosis is hyperendemic. Here, we conducted a household tuberculosis contact study in a French area where the endemicity of tuberculosis is low. A genome-wide analysis of TST negativity identified a significant linkage signal (P < 3 × 10(-5)) in close vicinity of TST1. Combined analysis of the 2 samples increased evidence of linkage (P = 2.4 × 10(-6)), further implicating genetic factors located on 11p14-15. This region overlaps the TNF1 locus controlling mycobacteria-driven tumor necrosis factor α production.

Evaluation of a model for efficient screening of tuberculosis contact subjects.

RATIONALE: Contact tracing is an important component of tuberculosis (TB) control programs. Standardization of contact investigation protocols can make them more efficient. OBJECTIVES: To develop a model to select contact subjects for screening. METHODS: We prospectively collected standardized data on 325 TB index cases and their 2,009 contacts. Factors that independently influenced the risk of TB infection were included in the model, which was then validated in a second prospective cohort of 88 cases of TB and their 618 contacts. MEASUREMENTS AND MAIN RESULTS: A total of eight independent risk factors were identified (odds ratio; 95% confidence interval): age, with three subgroups: 6-14 years (3.6; 1.6-8.0); 15-29 years (3.7; 1.8-7.7); > or =30 years (4.1; 2.0-8.5); cavitation on the index case's chest radiograph (1.6; 1.1-2.2); an index case sputum smear with 100 or more acid-fast bacilli per field (1.8; 1.2-2.8); household contact at night (2.1; 1.3-3.2); first-degree family relationship with the index case (2.1; 1.3-3.3); active smoking by the contact (1.6; 1.1-2.4); free health care (2.0; 1.2-3.2); and birth in a country with TB incidence rate higher than 25 of 100,000 (2.2; 1.5-3.2). Predictive probabilities were chosen to ensure false-negative rates lower than estimated TB infection background. The number of contacts to be investigated was reduced by 26% while maintaining a false-negative rate of 8%. CONCLUSIONS: This study provides a standardized contact screening model which reduces resources required without negatively affecting disease control.

An eQTL variant of ZXDC is associated with IFN-γ production following Mycobacterium tuberculosis antigen-specific stimulation.

There is a large inter-individual variability in the response to Mycobacterium tuberculosis infection. In previous linkage analyses, we identified a major locus on chromosome region 8q controlling IFN-γ production after stimulation with live BCG (Bacillus Calmette-Guérin), and a second locus on chromosome region 3q affecting IFN-γ production triggered by the 6-kDa early secretory antigen target (ESAT-6), taking into account the IFN-γ production induced by BCG (IFNγ-ESAT6BCG). High-density genotyping and imputation identified ~100,000 variants within each linkage region, which we tested for association with the corresponding IFN-γ phenotype in families from a tuberculosis household contact study in France. Significant associations were replicated in a South African familial sample. The most convincing association observed was that between the IFNγ-ESAT6BCG phenotype and rs9828868 on chromosome 3q (p = 9.8 × 10-6 in the French sample). This variant made a significant contribution to the linkage signal (p < 0.001), and a trend towards the same association was observed in the South African sample. This variant was reported to be an eQTL of the ZXDC gene, biologically linked to monocyte IL-12 production through CCL2/MCP1. The identification of rs9828868 as a genetic driver of IFNγ production in response to mycobacterial antigens provides new insights into human anti-tuberculosis immunity.

Transmission of tuberculosis from adults to children in a Paris suburb.

Tuberculosis in children is often acquired by contact with a family or household member. The aim of our study was to evaluate risk factors for latent infection and active disease in exposed children in a suburb of Paris. We examined medical records for the period 1997-2000 at six departmental centers for medical prevention in Val de Marne. Thirty-nine patients aged 18 years or more with M. tuberculosis-positive sputum samples, and living with children or adolescents, were identified. Ninety-one children, aged 3 months-17 years, were exposed to these index cases. All the children initially underwent a tuberculin skin test and chest radiography, and children with no criteria for latent infection or active disease at time of initial evaluation were asked to attend a second evaluation 3 months later. Overall, 20 of the 91 (22%) children were infected, including 4 children identified only at the second evaluation. Eight (40%) of the 20 infected children had active disease, including 2 of the 4 children identified at the second evaluation. The risk of infection was not influenced by the children's age, but was significantly associated with three characteristics of the adult cases, i.e., age younger than 40 years, presence of cavitary lesions, and smears with more than 100 bacilli per microscopic field. In conclusion, our results call for early examination of all exposed children, in order to prevent infection and progression to active disease, and for a routine second evaluation after the adult contact has ended.

Gluten contamination of naturally gluten-free flours and starches used by Canadians with celiac disease.

A large national investigation into the extent of gluten cross-contamination of naturally gluten-free ingredients (flours and starches) sold in Canada was performed. Samples (n = 640) were purchased from eight Canadian cities and via the internet during the period 2010-2012 and analysed for gluten contamination. The results showed that 61 of the 640 (9.5%) samples were contaminated above the Codex-recommended maximum level for gluten-free products (20 mg kg⁻¹) with a range of 5-7995 mg kg⁻¹. For the ingredients that were labelled gluten-free the contamination range (5-141 mg kg⁻¹) and number of samples were lower (3 of 268). This picture was consistent over time, with approximately the same percentage of samples above 20 mg kg⁻¹ in both the initial set and the subsequent lot. Looking at the total mean (composite) contamination for specific ingredients the largest and most consistent contaminations come from higher fibre ingredients such as soy (902 mg kg⁻¹), millet (272 mg kg⁻¹) and buckwheat (153 mg kg⁻¹). Of the naturally gluten-free flours and starches tested that do not contain a gluten-free label, the higher fibre ingredients would constitute the greatest probability of being contaminated with gluten above 20 mg kg⁻¹.