Long-term outcomes of elderly patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists.

Unlabelled: Essentials The long-term effects of VKORC1 and CYP2C9 variants on clinical outcomes remains unclear. We followed 774 patients ≥65 years with venous thromboembolism for a median duration of 30 months. Patients with CYP2C9 variants are at increased risk of death and non-major bleeding.

Lipid raft adhesion receptors and Syk regulate selectin-dependent rolling under flow conditions.

Selectins and their ligand P-selectin glycoprotein ligand-1 (PSGL-1) mediate leukocyte rolling along inflamed vessels. Cell rolling is modulated by selectin interactions with their ligands and by topographic requirements including L-selectin and PSGL-1 clustering on tips of leukocyte microvilli. Lipid rafts are cell membrane microdomains reported to function as signaling platforms.

Molecular basis of leukocyte rolling on PSGL-1. Predominant role of core-2 O-glycans and of tyrosine sulfate residue 51.

Interactions between the leukocyte adhesion receptor L-selectin and P-selectin glycoprotein ligand-1 play an important role in regulating the inflammatory response by mediating leukocyte tethering and rolling on adherent leukocytes. In this study, we have examined the effect of post-translational modifications of PSGL-1 including Tyr sulfation and presentation of sialylated and fucosylated O-glycans for L-selectin binding. The functional importance of these modifications was determined by analyzing soluble L-selectin binding and leukocyte rolling on CHO cells expressing various glycoforms of PSGL-1 or mutant PSGL-1 targeted at N-terminal Thr or Tyr residues.

TCR-mediated activation of allergen-specific CD45RO(+) memory T lymphocytes results in down-regulation of cell-surface CXCR4 expression and a strongly reduced capacity to migrate in response to stromal cell-derived factor-1.

The selective migration of functional T(h) lymphocyte subsets with different cytokine production profiles into inflamed tissue is likely to depend on the state of activation of the cells, as well as on the differential expression of various adhesion molecules and chemokine receptors. In this study, we have analyzed the effect of allergen-specific activation on the expression of the chemokine receptor CXCR4 on T lymphocytes. We show that stimulation of peripheral blood mononuclear cells from atopic patients with the allergen Der p results in down-regulation of CXCR4 surface expression on Der p-activated CD25(+)CD45RO(+) antigen-specific memory cells which was caused by a decrease in CXCR4 gene transcription and did not seem to be mediated by endogenous cytokines, such as IFN-gamma.

The role of IgE in asthma.

Asthma is a multifactorial and complex disease in which allergic factors and non-allergic triggers interact and result in bronchial obstruction and inflammation. Allergenic sensitization is important in the development of asthma and, although links between inhalant allergy and asthma have been known for many years, they have recently been re-emphasized. Indoor allergens are associated with asthma prevalence, severity and exacerbations whereas outdoor allergens such as pollens are associated with exacerbations.

Effect of bronchial allergen challenge on in vitro cytokine release by peripheral blood mononuclear cells of atopic patients.

Background: During the pollen season, peripheral blood mononuclear cells (PBMC) from allergic patients produce increased levels of Th2 cytokines after stimulation with allergen in vitro. We have studied the effect of a single bronchial provocation test (BPT) of allergic patients to determine whether allergen challenge in vivo modulates cytokine production by PBMC, after subsequent stimulation with the same allergen in vitro.

Methods: Twelve atopic asthmatic patients were challenged with the relevant allergen, and their PBMC, isolated before (T0) or 6 (T6) or 24 h (T24) after BPT, respectively, were cultured for 120 h in the presence or absence of the same allergen, after which cytokine production was measured by ELISA.

IL-4 induces functional cell-surface expression of CXCR4 on human T cells.

Here we report that IL-4 specifically enhances cell surface expression of CXCR4 on resting peripheral and cord blood T cells. Whereas polarized Th2 clones express variable levels of CXCR4, expression of this receptor is undetectable on polarized Th1 clones but can be induced on the latter cells as well, following short-term culture in the presence of IL-4. The IL-4-induced CXCR4 is functional since interaction with its ligand, stromal-derived factor (SDF)-1, activates the p42 MAP-kinase ERK-2.