An In Silico Modeling Approach to Understanding the Dynamics of Sarcoidosis

BACKGROUND: Sarcoidosis is a polygenic disease with diverse phenotypic presentations characterized by an abnormal antigen-mediated Th1 type immune response. At present, progress towards understanding sarcoidosis disease mechanisms and the development of novel treatments is limited by constraints attendant to conducting human research in a rare disease in the absence of relevant animal models. We sought to develop a computational model to enhance our understanding of the pathological mechanisms of and predict potential treatments of sarcoidosis. METHODOLOGY/RESULTS: Based upon the literature, we developed a computational model of known interactions between essential immune cells (antigen-presenting macrophages, effector and regulatory T cells) and cytokine mediators (IL-2, TNFα, IFNγ) of granulomatous inflammation during sarcoidosis. The dynamics of these interactions are described by a set of ordinary differential equations. The model predicts bistable switching behavior which is consistent with normal (self-limited) and "sarcoidosis-like" (sustained) activation of the inflammatory components of the system following a single antigen challenge. By perturbing the influence of model components using inhibitors of the cytokine mediators, distinct clinically relevant disease phenotypes were represented. Finally, the model was shown to be useful for pre-clinical testing of therapies based upon molecular targets and dose-effect relationships. CONCLUSIONS/SIGNIFICANCE: Our work illustrates a dynamic computer simulation of granulomatous inflammation scenarios that is useful for the investigation of disease mechanisms and for pre-clinical therapeutic testing. In lieu of relevant in vitro or animal surrogates, our model may provide for the screening of potential therapies for specific sarcoidosis disease phenotypes in advance of expensive clinical trials

Linkage of Type I Interferon Activity and TNF-Alpha Levels in Serum with Sarcoidosis Manifestations and Ancestry

BACKGROUND: Both type I interferon (IFN), also known as IFN-α and tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis of sarcoidosis. We investigated serum levels of these cytokines in a large multi-ancestral sarcoidosis population to determine correlations between cytokine levels and disease phenotypes. METHODS: We studied serum samples from 98 patients with sarcoidosis, including 71 patients of African-American ancestry and 27 patients of European-American ancestry. Serum type I IFN was measured using a sensitive reporter cell assay and serum TNF-α was measured using a commercial ELISA kit. Clinical data including presence or absence of neurologic, cardiac, and severe pulmonary manifestations of sarcoidosis were abstracted from medical records. Twenty age-matched non-autoimmune controls were also studied from each ancestral background. Differences in cytokine levels between groups were analyzed with Mann-Whitney U test, and correlations were assessed using Spearman's rho. Multivariate logistic regression models were used to detect associations between cytokines and clinical manifestations. RESULTS: Significant differences in cytokine levels were observed between African- and European-American patients with sarcoidosis. In African-Americans, serum TNF-α levels were significantly higher relative to matched controls (P = 0.039), and patients with neurologic disease had significantly higher TNF-α than patients lacking this manifestation (P = 0.022). In European-Americans, serum type I IFN activity was higher in sarcoidosis cases as compared to matched controls, and patients with extra-pulmonary disease represented a high serum IFN subgroup (P = 0.0032). None of the associations observed were shared between the two ancestral groups. CONCLUSIONS: Our data indicate that significant associations between serum levels of TNF-α and type I IFN and clinical manifestations exist in a sarcoidosis cohort that differ significantly by self-reported ancestry. In each ancestral background, the cytokine elevated in patients with sarcoidosis was also associated with a particular disease phenotype. These findings may relate to ancestral differences in the molecular pathogenesis of this heterogeneous disease

Technique et rentabilité des dièdres à houle

Technique and profitability of converging wave channels. An examination of numerous arrangements put forward for the recovery of wave energy brings us to the conclusion that only strong structures having, as it were, no moving mechanical parts, are suitable for the harnessing of wave energy without risk of rapid destruction. An investigation of converging channels to supply a basin, constituting a fore bay for a conventional low head power station, has brought us to the conclusion that their output is considerably superior to any other arrangement that we know of. At the same time it should be stated that the output is highly variable according to the characteristics of the wave and the tide. In spite of the remarkable results, from the technical point of view, the economic calculations indicate that a converging channel power station would not be profitable at the present time, and this in spite of the possible use of modern generator units of the axial, bulb or well type.L'examen de très nombreux dispositifs proposés pour la récupération de l'énergie de la houle nous a fait conclure que seuls de puissants ouvrages ne comportant pour ainsi dire pas de pièces mécaniques mobiles pouvaient être susceptibles de capter l'énergie de la houle sans risques de destruction rapide. L'étude de dièdres qui alimentent un bassin constituant la chambre d'eau d'une usine à basse chute classique a permis de constater que le rendement énergétique du dispositif était très supérieur à celui de tous les autres dispositifs dont nous avions pu avoir connaissance. En même temps, on constatait que ce rendement était fortement variable avec les caractéristiques de la houle et de la marée. Malgré des résultats remarquables du point de vue technique, les calculs économiques indiquent qu'une usine à dièdres ne serait actuellement pas rentable, malgré l'emploi éventuel de groupes générateurs modernes des types axiaux, bulbes ou puits.Dhaille R. Technique et rentabilité des dièdres à houle. In: Les énergies de la mer. Compte rendu des quatrièmes journées de l'hydraulique, Paris, 13, 14 et 15 juin 1956. Tome 2, 1957