A critical role for ATF2 transcription factor in the regulation of E-selectin expression in response to non-endotoxin components of Neisseria meningitidis

Vascular injury is a serious complication of sepsis due to the gram-negative bacterium Neisseria meningitidis. One of the critical early steps in initiating this injury is via the interaction of leucocytes, particularly neutrophils, with adhesion molecules expressed on inflamed endothelium. We have previously demonstrated that both lipopolysaccharide (LPS) and non-LPS components of meningococci can induce very high levels of expression of the vascular endothelial cell adhesion molecule E-selectin, which is critical for early tethering and capture of neutrophils onto endothelium under flow. Using an LPS-deficient strain of meningococcus, we showed that very high levels of expression can be induced in primary endothelial cells, even in the context of weak activation of the major host signal transduction factor [nuclear factor-κB (NF-κB)]. In this study, we show that the particular propensity for N. meningitidis to induce high levels of expression is regulated at a transcriptional level, and demonstrate a significant role for phosphorylation of the ATF2 transcription factor, likely via mitogen-activated protein (MAP) kinases, on the activity of the E-selectin promoter. Furthermore, inhibition of E-selectin expression in response to the lpxA- strain by a p38 inhibitor indicates a significant role of a p38-dependent MAPK signalling pathway in ATF2 activation. Collectively, these data highlight the role that LPS and other bacterial components have in modulating endothelial function and their involvement in the pathogenesis of meningococcal sepsis. Better understanding of these multiple mechanisms induced by complex stimuli such as bacteria, and the specific inflammatory pathways they activate, may lead to improved, focused interventions in both meningococcal and potentially bacterial sepsis more generally

Comparing Mutuality and Solidarity in Its Application to Disaster Ethics

Often it has been observed that in disaster situations, people (including victims) become altruistic and are very willing to listen, obey and act in a manner that would help bring an end to the situation. In this chapter, linking disaster ethics and human rights, it is argued that this indeed is how it should be, disaster or otherwise, and that we have moral duties to oneself and to others. An individual exhibiting solidarity, comradery and altruism during a disaster is indeed behaving as a reasonable Self, and exercising ethical individualism as per Gewirthian philosophy. It is the duty of the State and society to act as a supportive State and a caring society. In order to do this, we need to be conditioned for ethical rationality before any whiff of disaster arises, i.e. in our day-to-day conduct and decision-making, at a personal, institutional and transnational level. Our ethical resilience during disasters can only be as robust as our rational moral compass during ‘peace-time’. This chapter argues that Gewirthian solidarity ethics (GSE) should play a role in European policy and action in order to provide a system that conditions ethical rationality and in order to fulfil human rights. This involves addressing our current understanding of human rights as distinct categories of civil, political, economic, social and cultural rights and to effect a shift towards a more holistic understanding of human rights, whereby the hierarchy of fulfilment does not always prioritise civil and political rights.Peer reviewe

Refinement of the GINGF3 locus for hereditary gingival fibromatosis

Hereditary gingival fibromatosis (HGF) is a rare, clinically variable disorder characterized by slowly progressive fibrous overgrowth of the gingiva. Four gene loci have been mapped for autosomal dominant non-syndromic HGF (adHGF). The molecular basis of adHGF remains largely unknown, with only a single SOS1 gene mutation identified so far at the gingival fibromatosis 1 (GINGF1) locus in one family. We identified an adHGF family with ten affected individuals in whom onset of gingival fibromatosis concurred with the eruption of the primary teeth. In order to identify the molecular basis in this family, we tested for linkage of the disease to known adHGF loci. A maximal multipoint logarithm of the odds score of 3.91 was obtained with marker D2S390 (θ = 0) at the GINGF3 locus on chromosome 2p23.3–p22.3, and linkage to other known loci was excluded. Sequencing two candidate genes, ALK and C2orf18, and a single nucleotide polymorphisms array analysis did not reveal a mutation or copy number variation in a patient from the family. We refined the GINGF3 locus to a 6.56-cM, 8.27-Mb region containing 112 known and hypothetical genes, and our data and a search of the literature suggest that GINGF3 is a major adHGF locus

Carboxyhaemoglobin levels and their determinants in older British men

Background: Although there has been concern about the levels of carbon monoxide exposure, particularly among older people, little is known about COHb levels and their determinants in the general population. We examined these issues in a study of older British men.Methods: Cross-sectional study of 4252 men aged 60-79 years selected from one socially representative general practice in each of 24 British towns and who attended for examination between 1998 and 2000. Blood samples were measured for COHb and information on social, household and individual factors assessed by questionnaire. Analyses were based on 3603 men measured in or close to (< 10 miles) their place of residence.Results: The COHb distribution was positively skewed. Geometric mean COHb level was 0.46% and the median 0.50%; 9.2% of men had a COHb level of 2.5% or more and 0.1% of subjects had a level of 7.5% or more. Factors which were independently related to mean COHb level included season (highest in autumn and winter), region (highest in Northern England), gas cooking (slight increase) and central heating (slight decrease) and active smoking, the strongest determinant. Mean COHb levels were more than ten times greater in men smoking more than 20 cigarettes a day (3.29%) compared with non-smokers (0.32%); almost all subjects with COHb levels of 2.5% and above were smokers (93%). Pipe and cigar smoking was associated with more modest increases in COHb level. Passive cigarette smoking exposure had no independent association with COHb after adjustment for other factors. Active smoking accounted for 41% of variance in COHb level and all factors together for 47%.Conclusion: An appreciable proportion of men have COHb levels of 2.5% or more at which symptomatic effects may occur, though very high levels are uncommon. The results confirm that smoking (particularly cigarette smoking) is the dominant influence on COHb levels

Skin- and gut-homing molecules on human circulating gamma delta T cells and their dysregulation in inflammatory bowel disease

Changes in phenotype and function of γδ T cells have been reported in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Dysregulation of lymphocyte migration plays a key role in IBD pathogenesis; however, data on migratory properties of γδ T cells are scarce. Human circulating γδ T cells from healthy controls (n = 27), patients with active CD (n = 15), active UC (n = 14) or cutaneous manifestations of IBD (n = 2) were characterized by flow cytometry. Circulating γδ T cells in healthy controls were CD3(hi) and expressed CD45RO. They expressed gut-homing molecule β7 but not gut-homing molecule corresponding chemokine receptors (CCR)9, or skin-homing molecules cutaneous lymphocyte-associated antigen (CLA) and CCR4, despite conventional T cells containing populations expressing these molecules. CCR9 expression was increased on γδ T cells in CD and UC, while skin-homing CLA was expressed aberrantly on γδ T cells in patients with cutaneous manifestations of IBD. Lower levels of CD3 expression were found on γδ T cells in CD but not in UC, and a lower proportion of γδ T cells expressed CD45RO in CD and UC. Enhanced expression of gut-homing molecules on circulating γδ T cells in IBD and skin-homing molecules in cutaneous manifestations of IBD may be of clinical relevance