Burn injury initiates a shift in superantigen-induced T cell responses and host survival

Severe injury induces a temporal shift in immune reactivity that can cause serious complications or even death. We previously reported that mice exposed to bacterial superantigen (SAg) early after injury undergo a strong SAg response with lethal consequences. This study compares the early and late effects of burn injury on SAg reactivity in vivo to establish how injury influences adaptive immune responses. We found that mice challenged with ordinarily sublethal doses of staphylococcal enterotoxin A or staphylococcal enterotoxin B at 1 day after burn injury exhibited high mortality, whereas no mortality occurred at 7 days after injury. This shift in mortality correlated with higher Th2-type cytokines (IL-4 and IL-10) being expressed by CD4(+) and CD8(+) T cells from burn as opposed to sham mice at 7 days after injury. Lymph node cells from burn-injured mice also produced higher levels of Th2-type cytokines at 7 days after injury. The results of cell-mixing studies using CD4(+) and CD8(+) T cells mixed with APCs from sham or burn mice suggested that changes in both T cells and APCs are involved in the altered SAg response. Finally, the biological significance of altered SAg reactivity following injury was shown by demonstrating that blocking IL-10 activity in vivo caused higher SAg-induced mortality at 7 days after injury. These findings support the idea that injury promotes a Th2-type shift in adaptive immune reactivity. Although prior studies link this counterinflammatory-type response to lowered resistance to infection, the present results suggest it may sometimes benefit the injured host.     

Establishment of national diagnostic reference levels (DRLs) for radiotherapy localisation computer tomography of the head and neck

Aim

The aim of this research is to establish if variation exists in the dose delivered for head and neck (HN) localisation computed tomography (CT) imaging in radiation therapy (RT); to propose a national diagnostic reference levels (DRLs) for this procedure and to make a comparison between the national DRL and a DRL of a European sample.

Efflux Pumps Represent Possible Evolutionary Convergence onto the β-Barrel Fold

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Role of arterial hypoxemia and pulmonary mechanics in exercise limitation in adults with cystic fibrosis.

We tested the hypothesis that maximal exercise performance in adults with cystic fibrosis is limited by arterial hypoxemia. In study 1, patients completed two maximal exercise tests, a control and a test with 400 ml of added dead space. Maximal O2 consumption was significantly lower in the added dead space study vs. control (1.04 +/- 0.15 vs. 1.20 +/- 0.11 l/min; P < 0.05), with no difference in peak ventilation. There was significant O2 desaturation during exercise that was equal in both control and added dead space studies. The decrease in maximal O2 consumption with added dead space suggests that maximal exercise in cystic fibrosis is limited by respiratory factors. We subsequently examined whether pulmonary mechanics or arterial hypoxemia limits maximal exercise performance. In study 2, patients completed two maximal exercise tests, a control and a test with 400 ml of added dead space while also breathing 38% O2. Added dead space was used to overcome the suppressive effects of hyperoxia on minute ventilation. Maximal O2 consumption was significantly higher with added dead space and 38% O2 vs. control (1.62 +/- 0.16 vs. 1.43 +/- 0.14 l/min; P < 0.05). Peak ventilation and O2 saturation were significantly greater in the added dead space and 38% O2 test vs. control. The increase in maximal O2 consumption and peak ventilation with added dead space and 38% O2 suggests that maximal exercise in cystic fibrosis is limited by arterial hypoxemia.     

Local Modelling Techniques for Assessing Micro-Level Impacts of Risk Factors in Complex Data: Understanding Health and Socioeconomic Inequalities in Childhood Educational Attainments

Although inequalities in health and socioeconomic status have an important influence on childhood educational performance, the interactions between these multiple factors relating to variation in educational outcomes at micro-level is unknown, and how to evaluate the many possible interactions of these factors is not well established. This paper aims to examine multi-dimensional deprivation factors and their impact on childhood educational outcomes at micro-level, focusing on geographic areas having widely different disparity patterns, in which each area is characterised by six deprivation domains (Income, Health, Geographical Access to Services, Housing, Physical Environment, and Community Safety). Traditional health statistical studies tend to use one global model to describe the whole population for macro-analysis. In this paper, we combine linked educational and deprivation data across small areas (median population of 1500), then use a local modelling technique, the Takagi-Sugeno fuzzy system, to predict area educational outcomes at ages 7 and 11. We define two new metrics, “Micro-impact of Domain” and “Contribution of Domain”, to quantify the variations of local impacts of multidimensional factors on educational outcomes across small areas. The two metrics highlight differing priorities. Our study reveals complex multi-way interactions between the deprivation domains, which could not be provided by traditional health statistical methods based on single global model. We demonstrate that although Income has an expected central role, all domains contribute, and in some areas Health, Environment, Access to Services, Housing and Community Safety each could be the dominant factor. Thus the relative importance of health and socioeconomic factors varies considerably for different areas, depending on the levels of each of the other factors, and therefore each component of deprivation must be considered as part of a wider system. Childhood educational achievement could benefit from policies and intervention strategies that are tailored to the local geographic areas'' profiles.     

A Coding IRAK2 Protein Variant Compromises Toll-like receptor (TLR) Signaling and Is Associated with Colorectal Cancer Survival

Within innate immune signaling pathways, interleukin-1 receptor-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors and the interleukin-1 receptor. Although human IRAK4 deficiency was shown to lead to severe immunodeficiency in response to pyogenic bacterial infection during childhood, little is known about the role of human IRAK2. We here identified a non-synonymous IRAK2 variant, rs35060588 (coding R214G), as hypofunctional in terms of NF-κB signaling and Toll-like receptor-mediated cytokine induction. This was due to reduced ubiquitination of TRAF6, a key step in signal transduction. IRAK2 rs35060588 occurs in 3–9% of individuals in different ethnic groups, and our studies suggested a genetic association of rs35060588 with colorectal cancer survival. This for the first time implicates human IRAK2 in a human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point.