MyD88 is an important signaling adaptor for both TLR and IL-1R family members. Here, we evaluated the role of TLR2/MyD88 and IL-1R/MyD88 signaling in host defense against S. aureus by using a cutaneous infection model in conjunction with bioluminescent bacteria. We found that lesions of S. aureus-infected MyD88- and IL-1R-deficient mice were substantially larger with higher bacterial counts compared with wild-type mice. In contrast, TLR2-deficient mice had lesions that were only moderately larger with minimally higher bacterial counts. In addition, MyD88- and IL-1R- but not TLR2-deficient mice had severely decreased recruitment of neutrophils to the site of infection. This neutrophil recruitment was not dependent upon IL-1R/MyD88 signaling by recruited bone marrow-derived cells, suggesting that resident skin cells utilize IL-1R/MyD88 signaling to promote neutrophil recruitment.

Intracellular pathogens survive by evading the host immune system and accessing host metabolic pathways to obtain nutrients for their growth. Mycobacterium leprae, the causative agent of leprosy, is thought to be the mycobacterium most dependent on host metabolic pathways, including host-derived lipids. Although fatty acids and phospholipids accumulate in the lesions of individuals with the lepromatous (also known as disseminated) form of human leprosy (L-lep), the origin and significance of these lipids remains unclear. Here we show that in human L-lep lesions, there was preferential expression of host lipid metabolism genes, including a group of phospholipases, and that these genes were virtually absent from the mycobacterial genome. Hostderived oxidized phospholipids were detected in macrophages within L-lep lesions, and 1 specific oxidized phospholipid, 1-palmitoyl-2-(5,6-epoxyisoprostane E 2 )-sn-glycero-3-phosphorylcholine (PEIPC), accumulated in macrophages infected with live mycobacteria. Mycobacterial infection and host-derived oxidized phospholipids both inhibited innate immune responses, and this inhibition was reversed by the addition of normal HDL, a scavenger of oxidized phospholipids, but not by HDL from patients with L-lep. The accumulation of host-derived oxidized phospholipids in L-lep lesions is strikingly similar to observations in atherosclerosis, which suggests that the link between host lipid metabolism and innate immunity contributes to the pathogenesis of both microbial infection and metabolic disease.

SUMMARYA computational multiscale framework is proposed that incorporates microstructural behaviour in a macroscale discrete fracture model. Homogenisation procedures are derived for both adhesive and cohesive failure on the macroscale and are implemented in an FE 2 -setting. The most important feature of the homogenisation procedure is that it implicitly defines a traction-opening relation for the macroscale fracture model. The representativeness of the micro models is studied using a onedimensional example, which shows that in the softening regime the proposed multiscale scheme behaves different from a bulk homogenisation scheme. These results are also observed in a numerical simulation for a micro model with a periodic microstructure. Numerical simulations further demonstrate the applicability of the method.

SUMMARYA path-following constraint is developed which is based on the energy release during failure. This makes it applicable to the simulation of quasi-brittle materials when no previous knowledge is available on the failure behaviour of a body and, consequently, indirect displacement control methods like CMOD cannot be applied. The constraint is derived from the ÿrst principle of thermodynamics for a ÿnite-element discretization of a solid with a continuum damage model. The performance of the constraint is demonstrated by means of a bending test on a single-edge-notched beam.

The aim of the study was to compare clinical manifestations, disease activity, functional capacity, spinal mobility, and radiological findings between men and women from a multicenter, multiethnic Ibero-American cohort of patients with Spondyloarthritis (SpA).This observational cross-section study included 1264 consecutive SpA patients who fulfilled the modified New York criteria for ankylosing spondylitis (AS). Demographic, clinical, and radiologic data were evaluated. Categorical data were compared by X2 or Fisher's exact tests and continuous variables by ANOVA with post-hoc tests.Primary AS was diagnosed in 1072 patients, psoriatic spondylitis in 147, and spondylitis associated to inflammatory bowel disease (IBD) in 45 patients. Overall, male patients were significantly younger, had longer diagnostic delay, lower disease activity, worse spinal mobility, better quality of life, and more severe radiologic damage. Dactylitis and enthesitis, as well as swollen joint count, were significantly more common among women. In primary AS, there was a marked male predominance (76.2%). Among patients with psoriatic spondylitis, male predominance was lower (57.8%), but was also associated with worse spinal mobility and more severe radiologic damage. In the total population, male patients with primary AS referred higher permanent work disability (13.2% vs 6.9%; P < 0.05), although no difference was observed in psoriatic or IBD spondylitis according to the gender.Among Ibero-American SpA patients, there are some differences in clinical and radiological manifestations, men showing more structural damage, whereas women more active disease. These data suggest that the phenotype of SpA differs between genders. This can influence the subsequent diagnostic approach and therapeutic decisions.

Autoimmune disorders develop as a result of deregulated immune responses that target self-antigens and cause destruction of healthy host tissues. Because dendritic cells (DCs) play an important role in the maintenance of peripheral immune tolerance, we are interested in identifying means of enhancing their therapeutic potential in autoimmune diseases. It is thought that during steady state, DCs are able to anergize potentially harmful T cells bearing T cell receptors that recognize selfpeptide-major histocompatibility complexes. The tolerogenic capacity of DCs requires an immature phenotype, which is characterized by a reduced expression of costimulatory molecules. On the contrary, activation of antigen-specific naive T cells is enhanced by DC maturation, a process that involves expression of genes controlled by the transcription factor nuclear factor (NF)-B. We evaluated the capacity of drugs that inhibit NF-B to enhance the tolerogenic properties of immature DCs in the experimental autoimmune encephalomyelitis (EAE) model. We show that andrographolide, a bicyclic diterpenoid lactone, and rosiglitazone, a peroxisome proliferatoractivated receptor ␥ agonist, were able to interfere with NF-B activation in murine DCs. As a result, treated DCs showed impaired maturation and a reduced capacity to activate antigen-specific T cells. Furthermore, NF-B-blocked DCs had an enhanced tolerogenic capacity and were able to prevent EAE development in mice. The tolerogenic feature was specific for myelin antigens and involved the expansion of regulatory T cells. These data suggest that NF-B blockade is a potential pharmacological approach that can be used to enhance the tolerogenic ability of immature DCs to prevent detrimental autoimmune responses.

SUMMARYA concise overview is given of various numerical methods that can be used to analyse localization and failure in engineering materials. The importance of the cohesive-zone approach is emphasized and various ways to incorporate the cohesive-zone methodology in discretization methods are discussed. Numerical representations of cohesive-zone models suffer from a certain mesh bias. For discrete representations this is caused by the initial mesh design, while for smeared representations it is rooted in the ill-posedness of the rate boundary value problem that arises upon the introduction of decohesion. A proper representation of the discrete character of cohesive-zone formulations which avoids any mesh bias can be obtained elegantly when exploiting the partition-of-unity property of finite element shape functions. The effectiveness of the approach is demonstrated for some examples at different scales. Moreover, examples are shown how this concept can be used to obtain a proper transition from a plastifying or damaging continuum to a shear band with gross sliding or to a fully open crack (true discontinuum). When adhering to a continuum description of failure, higher-order continuum models must be used. Meshless methods are ideally suited to assess the importance of the higher-order gradient terms, as will be shown. Finally, regularized strain-softening models are used in finite element reliability analyses to quantify the probability of the emergence of various possible failure modes.

BackgroundRupture of the cap of a vulnerable plaque present in a coronary vessel may cause myocardial infarction and death. Cap rupture occurs when the peak cap stress exceeds the cap strength. The mechanical stress within a cap depends on the plaque morphology and the material characteristics of the plaque components. A parametric study was conducted to assess the effect of intima stiffness and plaque morphology on peak cap stress.MethodsModels with idealized geometries based on histology images of human coronary arteries were generated by varying geometric plaque features. The constructed multi-layer models contained adventitia, media, intima, and necrotic core sections. For adventitia and media layers, anisotropic hyperelastic material models were used. For necrotic core and intima sections, isotropic hyperelastic material models were employed. Three different intima stiffness values were used to cover the wide range reported in literature. According to the intima stiffness, the models were classified as stiff, intermediate and soft intima models. Finite element method was used to compute peak cap stress.ResultsThe intima stiffness was an essential determinant of cap stresses. The computed peak cap stresses for the soft intima models were much lower than for stiff and intermediate intima models. Intima stiffness also affected the influence of morphological parameters on cap stresses. For the stiff and intermediate intima models, the cap thickness and necrotic core thickness were the most important determinants of cap stresses. The peak cap stress increased three-fold when the cap thickness was reduced from 0.25 mm to 0.05 mm for both stiff and intermediate intima models. Doubling the thickness of the necrotic core elevated the peak cap stress by 60% for the stiff intima models and by 90% for the intermediate intima models. Two-fold increase in the intima thickness behind the necrotic core reduced the peak cap stress by approximately 25% for both intima models. For the soft intima models, cap thickness was less critical and changed the peak cap stress by 55%. However, the necrotic core thickness was more influential and changed the peak cap stress by 100%. The necrotic core angle emerged as a critical determinant of cap stresses where a larger angle lowered the cap stresses. Contrary to the stiff and intermediate intima models, a thicker intima behind the necrotic core increased the peak cap stress by approximately 25% for the soft intima models. Adventitia thickness and local media regression had limited effects for all three intima models.ConclusionsFor the stiff and intermediate intima models, the cap thickness was the most important morphological risk factor. However for soft intima models, the necrotic core thickness and necrotic core angle had a bigger impact on the peak cap stress. We therefore need to enhance our knowledge of intima material properties if we want to derive critical morphological plaque features for risk evaluation.