[Show abstract][Hide abstract] ABSTRACT: Some common childhood infections appear to prevent the development of atopy and asthma. In some Mycobacterium bovis BCG-vaccinated populations, strong delayed-type hypersensitivity responses to mycobacterial antigens are associated with
a reduced risk of atopy. Although BCG exposure decreases allergen-induced lung eosinophilia in animal models, little attention
has been given to the effect of immunity to BCG on responses against live pathogens. We used the murine Cryptococcus neoformans infection model to investigate whether prior BCG infection can alter such responses. The present study shows that persistent
pulmonary BCG infection of C57BL/6 mice induced an increase in gamma interferon, a reduction in interleukin-5, and a decrease
in lung eosinophilia during subsequent Cryptococcus infection. This effect was long lasting, depended on the presence of live bacteria, and required persistence of mycobacterial
infection in the lung. Reduction of eosinophilia was less prominent after infection with a mutant BCG strain (ΔhspR), which
was rapidly cleared from the lungs. These observations have important implications for the development of vaccines designed
to prevent Th2-mediated disease and indicate that prior lung BCG vaccination can alter the pattern of subsequent host inflammation.
Infection and Immunity 07/2003; 71(6):3384-91. DOI:10.1128/IAI.71.6.3384-3391.2003 · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: With a view to exploring the role of transforming growth factor β (TGF-β) during mycobacterial infection, recombinant clones
of bacillus Calmette-Guérin (BCG) were engineered to express the natural antagonist of TGF-β, latency-activated peptide (LAP).
Induction of TGF-β activity was reduced when macrophages were infected with BCG expressing the LAP construct (LAP-BCG). There
was a significant reduction in the growth of LAP-BCG in comparison to that of control BCG following intravenous infection
in a mouse model. The enhanced control of mycobacterial replication was associated with an increase in the production of gamma
interferon by splenocytes challenged during the acute stage of infection but with a diminished recall response assessed after
13 weeks. Organ weight and hydroxyproline content, representing tissue pathology, were also lower in mice infected with LAP-BCG.
The results are consistent with the hypothesis that TGF-β has a detrimental effect on mycobacterial immunity. While a reduction
in TGF-β activity augments the initial response to BCG vaccination, early bacterial clearance may adversely affect the induction
of a long-term memory response by LAP-BCG.
Infection and Immunity 12/2001; 69(11):6676-82. DOI:10.1128/IAI.69.11.6676-6682.2001 · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cerebral intracellular energy production (cerebral bioenergetics) via oxidative phosphorylation and the production of adenosine triphosphate (ATP) is critical to cerebral function. To test the hypothesis that patients with chronic stable hypoxia also generate neuronal ATP via an anaerobic metabolism, we studied the changes in cerebral (31)P magnetic resonance spectra ((31)P MRS) in patients with stable chronic obstructive pulmonary disease (COPD), and compared the results with MR spectra from similar areas of the brain in control subjects. Ten patients with stable COPD (age: 65 +/- 9 yr [mean +/- SD]; Pa(O(2)): 8.8 +/- 1.2 kPa; Pa(CO(2)): 6.1 +/- 0.8 kPa; pH 7.42 +/- 0.03, and FEV(1): 41 +/- 20% predicted) and five healthy volunteers underwent cerebral (31)P MRS (TR-5,000 ms) at 1.5 T. When COPD patients were compared with controls, the percentage MR signal with respect to total MR-detectable phosphorus-containing metabolites was increased from inorganic phosphate (Pi) (7.1 +/- 1. 3% versus 3.9 +/- 0.7%, p = 0.0001) and phosphomonoesters (PMEs) (9. 4 +/- 1.2% versus 6.9 +/- 0.3%, p = 0.0001), whereas the signal from phosphodiesters was reduced (34.8 +/- 3.2 versus 40.4 +/- 3.3%, p = 0.015). The ratios of Pi to betaATP (0.8 +/- 0.2 versus 0.4 +/- 0.1, p = 0.001) and of PME to betaATP (1.0 +/- 0.2 versus 0.7 +/- 0.1, p = 0.015) were increased, but the phosphocreatine-to-Pi ratio (2.1 +/- 0.6 versus 3.2 +/- 0.6, p = 0.01) was reduced in patients as compared with controls. This alteration in phosphorus-containing metabolites within cerebral cells provides evidence of extensive use of anaerobic metabolism in hypoxic COPD patients.
American Journal of Respiratory and Critical Care Medicine 01/2000; 160(6):1994-9. DOI:10.1164/ajrccm.160.6.9810069 · 13.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since 1987 there has been an increase in tuberculosis notifications in the U.K., with this increase disproportionately affecting London. A recent national survey suggests that co-infection with HIV occurs in less than 5% of tuberculosis patients. This study asked if local co-infection rates in Inner London differed from the national results.
157 consecutive patients starting antituberculous chemotherapy were venesected 2 weeks into treatment. Anonymized blood samples were screened for antibodies for HIV-1 and HIV-2 by enzyme-linked immunosorbent assay (ELISA). Epidemiological data were collected on each patient which was also coded before HIV test results were known.
Of 157 patients commencing antituberculous therapy, 39 patients (24.8%) were found to be co-infected with HIV-1. HIV-negative and positive patients were similar in terms of age and sex. When 98 patients giving their country of origin as other than Europe were considered there were 22 co-infected with HIV (22.4%). Of the 39 HIV-positive identified in this study, 37 were also identified by our voluntary HIV testing programme.
This study has shown that there may be very different rates of co-infection at a local level in the U.K. The local variation may be missed by national surveys and diverse local testing procedures. Anonymous testing identified only two patients with tuberculosis and HIV infection who were not identified by our voluntary HIV testing programme and this suggests that offering HIV tests to patients with tuberculosis is largely taken up by those at risk of HIV infection. Surveillance studies of this type are important in identifying marked local variation from the national pattern of HIV and Mycobacterium tuberculosis infection.
Journal of Infection 06/1999; 38(3):162-6. DOI:10.1016/S0163-4453(99)90244-X · 4.44 Impact Factor