Combined inhibition of complement C5 and CD14 markedly attenuates inflammation, thrombogenicity, and hemodynamic changes in porcine sepsis

Complement and the TLR family constitute two important branches of innate immunity. We previously showed attenuating effects on inflammation and thromogenicity by inhibiting the TLR coreceptor CD14 in porcine sepsis. In the present study, we explored the effect of the C5 and leukotriene B4 inhibitor Ornithodoros moubata complement inhibitor (OmCI; also known as coversin) alone and combined with anti-CD14 on the early inflammatory, hemostatic, and hemodynamic responses in porcine Escherichia coli-induced sepsis. Pigs were randomly allocated to negative controls (n = 6), positive controls (n = 8), intervention with OmCI (n = 8), or with OmCI and anti-CD14 (n = 8). OmCI ablated C5 activation and formation of the terminal complement complex and significantly decreased leukotriene B4 levels in septic pigs. Granulocyte tissue factor expression, formation of thrombin-antithrombin complexes (p < 0.001), and formation of TNF-α and IL-6 (p < 0.05) were efficiently inhibited by OmCI alone and abolished or strongly attenuated by the combination of OmCI and anti-CD14 (p < 0.001 for all). Additionally, the combined therapy attenuated the formation of plasminogen activator inhibitor-1 (p < 0.05), IL-1β, and IL-8, increased the formation of IL-10, and abolished the expression of wCD11R3 (CD11b) and the fall in neutrophil cell count (p < 0.001 for all). Finally, OmCI combined with anti-CD14 delayed increases in heart rate by 60 min (p < 0.05) and mean pulmonary artery pressure by 30 min (p < 0.01). Ex vivo studies confirmed the additional effect of combining anti-CD14 with OmCI. In conclusion, upstream inhibition of the key innate immunity molecules, C5 and CD14, is a potential broad-acting treatment regimen in sepsis as it efficiently attenuated inflammation and thrombogenicity and delayed hemodynamic changes.

The heatwaves in Switzerland in summer 1947

In 1947, Switzerland was affected by a heat period of large spatial and temporal extent and rare occurrence. The heatwaves of 1947 can be compared with the events of 2003 in terms of intensity and duration. The summer of 1947 is studied based on the analysis of MeteoSwiss station data as well as the “Twentieth Century Reanalysis” (20CR) data set. Heatwaves were defined as six consecutive exceedances of the local 90th percentile of temperature. Five different heatwaves were identified which struck Switzerland during the summer of 1947. The most intense heatwave event is analysed in more detail. The meteorological situation was characterized by a high-pressure bridge over Central Europe. Based on a comparison with literature and with observations, the applicability of the 20CR dataset for the meteorological analysis of heatwave events could be demonstrated. The representation of the heat period in summer 1947 in 20CR is satisfactory when compared with station data, albeit with a temperature bias due to differences in topography. Hence, heatwaves cannot be defined using an absolute threshold. We conclude that 20CR is applicable for an overview of the meteorological patterns characterizing a heat wave but may not reproduce local details.

Refugee Settlement in Australia: Policy, Scholarship and the Production of Knowledge, 1952 − 2013

Since 1947, Australia has formally resettled more than 750,000 refugees. During that time, researchers have successfully completed more than 150 Masters and doctoral theses and published more than 900 articles, books and reports about issues of refugee settlement in Australia, with about half of them being published in the past 10 years. In this paper, we discuss the development of the production of knowledge about refugee resettlement. We identify trends in the literature, such as the emergence of an ethno-specific focus, and the concern with settlement's psychological and emotional impact, and relate them to policy changes. We suggest that scholars need critically to take stock of the knowledge produced so far and be more cognisant of the international scholarly debate.