Dynamic relationship between IFN-gamma and IL-2 profile of Mycobacterium tuberculosis-specific T cells and antigen load

Distinct IFN-gamma and IL-2 profiles of Ag-specific CD4(+) T cells have recently been associated with different clinical disease states and Ag loads in viral infections. We assessed the kinetics and functional profile of Mycobacterium tuberculosis Ag-specific T cells secreting IFN-gamma and IL-2 in 23 patients with untreated active tuberculosis when bacterial and Ag loads are high and after curative treatment, when Ag load is reduced. The frequencies of M. tuberculosis Ag-specific IFN-gamma-secreting T cells declined during 28 mo of follow-up with an average percentage decline of 5.8% per year (p = 0.005), while the frequencies of Ag-specific IL-2-secreting T cells increased during treatment (p = 0.02). These contrasting dynamics for the two cytokines led to a progressive convergence of the frequencies of IFN-gamma- and IL-2-secreting cells over 28 mo. Simultaneous measurement of IFN-gamma and IL-2 secretion at the single-cell level revealed a codominance of IFN-gamma-only secreting and IFN-gamma/IL-2 dual secreting CD4(+) T cells in active disease that shifted to dominance of IFN-gamma/IL-2-secreting CD4(+) T cells and newly detectable IL-2-only secreting CD4(+) T cells during and after treatment. These distinct T cell functional signatures before and after treatment suggest a novel immunological marker of mycobacterial load and clinical status in tuberculosis that now requires validation in larger prospective studies

Improved diagnostic evaluation of suspected tuberculosis

Background: The role of new T-cell–based blood tests for tuberculosis in the diagnosis of active tuberculosis is unclear.Objective: To compare the performance of 2 interferon-? assays and tuberculin skin testing in adults with suspected tuberculosis.Design: Prospective study conducted in routine practice.Setting: 2 urban hospitals in the United Kingdom.Patients: 389 adults, predominantly of South Asian and black ethnicity, with moderate to high clinical suspicion of active tuberculosis.Intervention: Tuberculin skin testing, the enzyme-linked immunospot assay (ELISpot) incorporating early secretory antigenic target-6 and culture filtrate protein-10 (standard ELISpot), and ELISpot incorporating a novel antigen, Rv3879c (ELISpotPLUS) were performed during diagnostic assessment by independent persons who were blinded to results of the other test.Measurements: Sensitivity, specificity, predictive values, and likelihood ratios.Results: 194 patients had a final diagnosis of active tuberculosis, of which 79% were culture-confirmed. Sensitivity for culture confirmed and highly probable tuberculosis was 89% (95% CI, 84% to 93%) with ELISpotPLUS, 85% (CI, 79% to 90%) with standard ELISpot, 79% (CI, 72% to 85%) with 15-mm threshold tuberculin skin testing, and 83% (CI, 77% to 89%) with stratified thresholds of 15 and 10 mm in vaccinated and unvaccinated patients, respectively. The ELISpotPLUS assay was more sensitive than tuberculin skin testing with 15-mm cutoff points (P = 0.01) but not with stratified cutoff points (P = 0.10). The ELISpotPLUS assay had 4% higher diagnostic sensitivity than standard ELISpot (P = 0.02). Combined sensitivity of ELISpotPLUS and tuberculin skin testing was 99% (CI, 95% to 100%), conferring a negative likelihood ratio of 0.02 (CI, 0 to 0.06) when both test results were negative.Limitations: Local standards for tuberculin skin testing differed from others used internationally. The study sample included few immunosuppressed patients.Conclusion: The ELISpotPLUS assay is more sensitive than standard ELISpot and, when used in combination with tuberculin skin testing, enables rapid exclusion of active infection in patients with moderate to high pretest probability of tuberculosis

Evolutionary algorithms for practical sensor fault tolerant control

The Shaky Hand is a multi-input, multi-output laboratory demonstrator which is modelled on a village fete game. In the original, the aim is to guide, by hand, a wire loop along a wire which has been bent to form a meandering track, 'without touching the loop to the wire. In the original game, touching the hand-held loop against the wire track sets off a loud warning bell and the player loses. The thesis presents the research work associated with the quest for practical solutions to a generic problem: the correct operation of a fallible system. The work covers three distinct areas: modelling of the demonstrator, design and construction of a physical system, and evoiution of algorithms for control of the demonstrator in practice in the presence of sensor faults, using Cartesian Genetic Programming (CGP). The third area forms the core of the thesis. The key challenges in creating the virtual environment to train for generic sensor fault tolerant algorithms are considered and addressed. The evolved algorithms are analysed and then verified using the demonstrator in practice. The practical results showed that sensor fault tolerant control was successfully achieved