Mycobacterium tuberculosis-specific CD4+ and CD8+ T cells differ in their capacity to recognize infected macrophages.

Containment of Mycobacterium tuberculosis (Mtb) infection requires T cell recognition of infected macrophages. Mtb has evolved to tolerate, evade, and subvert host immunity. Despite a vigorous and sustained CD8+ T cell response during Mtb infection, CD8+ T cells make limited contribution to protection. Here, we ask whether the ability of Mtb-specific T cells to restrict Mtb growth is related to their capacity to recognize Mtb-infected macrophages. We derived CD8+ T cell lines that recognized the Mtb immunodominant epitope TB10.44-11 and compared them to CD4+ T cell lines that recognized Ag85b240-254 or ESAT63-17. While the CD4+ T cells recognized Mtb-infected macrophages and inhibited Mtb growth in vitro, the TB10.4-specific CD8+ T cells neither recognized Mtb-infected macrophages nor restricted Mtb growth. TB10.4-specific CD8+ T cells recognized macrophages infected with Listeria monocytogenes expressing TB10.4. However, over-expression of TB10.4 in Mtb did not confer recognition by TB10.4-specific CD8+ T cells. CD8+ T cells recognized macrophages pulsed with irradiated Mtb, indicating that macrophages can efficiently cross-present the TB10.4 protein and raising the possibility that viable bacilli might suppress cross-presentation. Importantly, polyclonal CD8+ T cells specific for Mtb antigens other than TB10.4 recognized Mtb-infected macrophages in a MHC-restricted manner. As TB10.4 elicits a dominant CD8+ T cell response that poorly recognizes Mtb-infected macrophages, we propose that TB10.4 acts as a decoy antigen. Moreover, it appears that this response overshadows subdominant CD8+ T cell response that can recognize Mtb-infected macrophages. The ability of Mtb to subvert the CD8+ T cell response may explain why CD8+ T cells make a disproportionately small contribution to host defense compared to CD4+ T cells. The selection of Mtb antigens for vaccines has focused on antigens that generate immunodominant responses. We propose that establishing whether vaccine-elicited, Mtb-specific T cells recognize Mtb-infected macrophages could be a useful criterion for preclinical vaccine development.

Prevalence of HIV-1 drug resistance after failure of a first highly active antiretroviral therapy regimen in KwaZulu Natal, South Africa.

BACKGROUND: Emergence of human immunodeficiency virus type 1 (HIV-1) drug resistance may limit the benefits of antiretroviral therapy in resource-limited settings. The prevalence of resistance was assessed among patients from KwaZulu Natal, South Africa, following failure of their first highly active antiretroviral therapy (HAART) regimen. METHODS: Genotypic resistance testing was performed on plasma virus samples from patients who experienced virologic failure of their first HAART regimen at 2 clinics in KwaZulu Natal. Clinical and demographic data were obtained from medical records. Regression analysis was performed to determine factors associated with > or =1 significant drug resistance mutation. RESULTS: From January 2005 through August 2006, a total of 124 antiretroviral-treated adults who experienced virologic failure were enrolled. The predominant subtype was HIV-1C. Virus samples from 83.5% of participants carried > or =1 significant drug resistance mutation. Dual-class drug-resistant virus was present in 64.3% of participants, and 2.6% had virus with triple-class drug resistance. The most common mutation was M184V/I (64.3% of patients); K103N was present in virus from 51.3%, and V106M was present in virus from 19.1%. Thymidine analog resistance mutations were found in virus from 32.2% of patients, and protease resistance mutations were found in virus from 4.4%. CONCLUSIONS: Antiretroviral drug-resistant virus was detected in >80% of South African patients who experienced failure of a first HAART regimen. Patterns of drug resistance reflected drugs used in first-line regimens and viral subtype. Continued surveillance of resistance patterns is warranted to guide selection of second-line regimens.

Resilience and sustainable development: building adaptive capacity in a world of transformations.

Emerging recognition of two fundamental errors underpinning past polices for natural resource issues heralds awareness of the need for a worldwide fundamental change in thinking and in practice of environmental management. The first error has been an implicit assumption that ecosystem responses to human use are linear, predictable and controllable. The second has been an assumption that human and natural systems can be treated independently. However, evidence that has been accumulating in diverse regions all over the world suggests that natural and social systems behave in nonlinear ways, exhibit marked thresholds in their dynamics, and that social-ecological systems act as strongly coupled, complex and evolving integrated systems. This article is a summary of a report prepared on behalf of the Environmental Advisory Council to the Swedish Government, as input to the process of the World Summit on Sustainable Development (WSSD) in Johannesburg, South Africa in 26 August 4 September 2002. We use the concept of resilience--the capacity to buffer change, learn and develop--as a framework for understanding how to sustain and enhance adaptive capacity in a complex world of rapid transformations. Two useful tools for resilience-building in social-ecological systems are structured scenarios and active adaptive management. These tools require and facilitate a social context with flexible and open institutions and multi-level governance systems that allow for learning and increase adaptive capacity without foreclosing future development options.

Gastroenterologists should read CT colonography.

Screening for colorectal neoplasms has become the standard of care in advanced medical settings worldwide. Identifying asymptomatic colorectal neoplastic lesions has been shown to reduce colorectal cancer incidence and the overall cost of medical care. Clinicians have several alternatives at their disposal as they consider screening for their respective patient population. Two important methods to consider are optical colonoscopy and computed tomographic colonography (CTC). The purpose of this article is to make the case that gastroenterologists should read CTC. Central to the argument that gastroenterologists read CTC is the benefit of experience with video-assisted colonic imaging and the physician-patient relationship.

Parts per billion doping and characterization of uranium distribution in an epoxy polymer matrix.

Formulating an epoxy polymer provides a broadly applicable method for homogeneously doping a chemically stable, particulate-resistant, and radiation-hardened matrix with virtually any trace elements of interest. In the example reported, control of uranium levels over the range, 15 microg/g-15 ng/g, is demonstrated. Fission track density determinations, referenced to NIST SRMs, indicate +/-5% variations in lateral uranium distributions. Determinations of levels of uranium impurities in commercially available high-purity samples of graphite, fused silica, and aluminum show respective nanogram per gram ranges of 3 +/- 0.1-5 +/- 0.3, 3 +/- 0.8-27 +/- 2, and 113 +/- 11-546 +/- 11. The prepared polymer materials cover 3 orders of magnitude of uranium levels in an ideal matrix. This accomplishes the prerequisite for subsequent investigations of the chemistry occurring at fission fragment-induced damage sites of selected track registering materials as a function of controlled reactive site densities. The matrix also serves as a source of swift heavy ions for creating nanoscale features in dielectric materials.

Cascading effects of over-fishing marine systems.

Profound indirect ecosystem effects of over-fishing have been shown for coastal systems such as coral reefs and kelp forests. A new study from the ecosystem off the Canadian east coast now reveals that the elimination of large predatory fish can also cause marked cascading effects on the pelagic food web. Overall, the view emerges that, in a range of marine ecosystems, the effects of fisheries extend well beyond the collapse of fish exploited stocks.