Infectious diseases that cause hemolysis are among the most threatening human diseases, because of severity and/or global distribution. In these conditions, hemeproteins and heme are released, but whether heme affects the inflammatory response to microorganism molecules remains to be characterized. Here, we show that heme increased the lethality and cytokine secretion induced by LPS in vivo and enhanced the secretion of cytokines by macrophages stimulated with various agonists of innate immune receptors. Activation of nuclear factor B (NF-B) and MAPKs and the generation of reactive oxygen species were essential to the increase in cytokine production induced by heme plus LPS. This synergistic effect of heme and LPS was blocked by a selective inhibitor of spleen tyrosine kinase (Syk) and was abrogated in dendritic cells deficient in Syk. Moreover, inhibition of Syk and the downstream molecules PKC and PI3K reduced the reactive oxygen species generation by heme. Our results highlight a mechanism by which heme amplifies the secretion of cytokines triggered by microbial molecule activation and indicates possible pathways for therapeutic intervention during hemolytic infectious diseases.A general consequence of infectious diseases that cause hemolysis, internal hemorrhage, or extensive cell damage is the release of hemeproteins. Upon oxidation, hemeproteins release heme, a potentially harmful molecule (1). Heme-binding plasma proteins, such as hemopexin or albumin, remove the intravascular free heme, subsequently degraded by heme oxygenase-1 (HO-1), generating equimolar amounts of biliverdin, carbon monoxide, and free iron (2, 3). HO-1-deficient mice (Hmox Ϫ/Ϫ ) have high plasma concentrations of heme and show increased susceptibility to LPS-induced lethality, associated with inflammation and oxidative damage (4). Accumulation of large amounts of heme might overwhelm the capacity of heme scavengers and degrading system, thus causing oxidative stress and inflammation (5, 6). In fact, recent studies suggest that heme, in combination with ROS 3 and inflammatory mediators, increase blood brain barrier leakage and hepatocyte necrosis in models of malarial infection (7,8).Hemolysis or hemoglobinemia are associated with increased mortality in septic patients (9, 10). Hemoglobin increases the secretion of TNF triggered by LPS, whereas globin has an inhibitory effect (11), suggesting that heme is responsible for the cytokine amplification. Heme has several pro-inflammatory activities, including leukocyte activation and migration, upregulation of adhesion molecules, ROS production, and induction of cytokine expression (12-14). Recently, we have shown that heme is able to activate Toll-like receptor 4 (TLR4) inducing TNF on macrophages and dendritic cells (DC) (15).Mammalian pattern recognition receptors (PRRs) recognize conserved microbial molecules from all classes of microorganisms (16,17). The activation of these receptors elicits selective intracellular signaling cascades that result in the production of cytokines, chemokin...

Conventionally optimized structures may show a tendency to be sensitive to variations, for instance in geometry and loading conditions. To avoid this, research has been carried out in the field of robust optimization where variations are taken into account in the optimization process. The overall objective is to create solutions that are optimal both in the sense of mean performance and minimum variability. This work presents an alternative approach to robust optimization, where the robustness of each design is assessed through multiple sampling of the stochastic variables at each design point. Meta models for the robust optimization are created for both the mean value and the standard deviation of the response. Furthermore, the method is demonstrated on an analytical example and an example of an aluminium extrusion with quadratic cross section subjected to axial crushing.It works well for the chosen examples and it is concluded that the method is especially well suited for problems with a large number of random variables, * Corresponding author. Tel.:+46-13-282475; fax:+46-13-282717.Email address: david.lonn@liu.se (David Lönn)Preprint submitted to International Journal of Impact Engineering July 2, 2009 M A N U S C R I P T A C C E P T E D ARTICLE IN PRESSsince the computational cost is essentially independent of the number of random variables. In addition, the presented approach makes it possible to take into consideration variations that cannot be described with a variable. This is demonstrated in this work by random geometrical perturbations described with the use of Gaussian random fields.

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A product of high quality is a product that performs well, not only in exactly the situations it was designed to handle but also in slightly different situations that arise in the usage of the product. As a specific example, the performance of a bumper system should not depend on small fluctuations in the manufacturing process or on small variations in the impact event. In this work, the robustness of an existing vehicle bumper system subjected to a crash load has been evaluated both experimentally and numerically. In the latter case, different widely used approaches to numerically assess the robustness have been utilised. A reliable numerical robustness study provides the designer with a valuable tool for improving a design, and an evaluation of these methods in this context is therefore of interest. It is concluded that for the example under study, both the Monte Carlo method and the metamodel-based Monte Carlo methods work well. Furthermore, for moderate dispersions levels, i.e. a small design space with no bifurcation in the deformation pattern, a linear response approximation is shown to have a sufficient accuracy to be used in the metamodel-based robustness analysis. The performed numerical robustness studies also point out that the performance of a nominal simulation, i.e. a simulation conducted with mean values for all variables, does not in general predict the mean performance of the finite element model. Finally, some possible design improvements for the bumper system under study are also identified.

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