Abstract-Recent increased adverse cardiovascular events observed with selective cyclooxygenase-2 inhibition led to the withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra), but the mechanisms underlying these atherothrombotic events remain unclear. Prostacyclin is the major end product of cyclooxygenase-2 in vascular endothelium. Using a naturally occurring mutation in the prostacyclin receptor, we report for the first time that a deficiency in prostacyclin signaling through its G protein-coupled receptor contributes to atherothrombosis in human patients. We report that a prostacyclin receptor variant (R212C) is defective in adenylyl cyclase activation in both patient blood and in an in vitro COS-1 overexpression system. This promotes increased platelet aggregation, a hallmark of atherothrombosis. Our analysis of patients in 3 separate white cohorts reveals that this dysfunctional receptor is not likely an initiating factor in cardiovascular disease but that it accelerates the course of disease in those patients with the greatest risk factors. R212C was associated with cardiovascular disease only in the high cardiovascular risk cohort (nϭ980), with no association in the low-risk cohort (nϭ2293). In those at highest cardiovascular risk, both disease severity and adverse cardiovascular events were significantly increased with R212C when compared with age-and risk factor-matched normal allele patients. We conclude that for haploinsufficient mutants, such as the R212C, the enhanced atherothrombotic phenotype is likely dependent on the presence of existing atherosclerosis or injury (high risk factors), analogous to what has been observed in the cyclooxygenase-2 inhibition studies or prostacyclin receptor knockout mice studies. [1][2][3][4] and the development of cardiovascular disease in predisposed prostacyclin receptor knockout mice, 5,6 underscores the necessity to better understand the effects of COX-2-derived metabolites on cardiovascular health. Endothelial prostacyclin synthesis requires the COX-2 enzyme 7 and may serve a role in protection from atherothrombosis. 8,9 This cardioprotective role has been supported by recent prostacyclin receptor knockout mice studies showing that the absence of the prostacyclin receptor (IP) (International Union of Pharmacology Receptor classification) leads to intimal hyperplasia, atherosclerosis, and hypercoagulability, 5,6 as well as reperfusion injury, 10 and premenopausal atherogenesis. 11 Despite such accumulating information, controversy remains as to whether prostacyclin deficiency is the etiology of the cardiovascular events observed with COX-2 inhibition, 12 particularly as no human studies have directly implicated defective prostacyclin signaling in the development of cardiovascular disease.The human prostacyclin receptor (hIP) gene (PTGIR) spans approximately 7000 bases along chromosome 19 (locus Original received October 11, 2007; revision received February 12, 2008; accepted February 21, 2008 19q13.3) and is comprised of 3 exons separated by 2 introns, 1 intron...

Background: Chondroitin sulfate (CS) and heparan sulfate (HS) are important for cartilage formation. Results: Analyses of zebrafish mutants demonstrate interplay between HS and CS biosynthesis in vivo.Conclusion: HS biosynthesis is prioritized over CS biosynthesis. The balance between extl3 and csgalnact1/csgalnact2 function determines the HS/CS ratio. Significance: Disease progression caused by HS deficiency may be affected by altered CS biosynthesis.

Objective Rituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its occurrence, consequences and contributing factors in patients with systemic lupus erythematosus (SLE). Methods Rituximab-treated patients from the Karolinska University Hospital ( n = 107) were surveyed. LON was defined as an absolute neutrophil count <1500 cells/μl, occurring four weeks to two years following rituximab treatment, or later during sustained B-cell depletion. Serum levels of B-cell-related cytokines and growth factors of the myeloid lineage were determined using enzyme-linked immunosorbent assay. Results Thirty-two patients (29.9%) developed LON after a median time of 201.5 days. Thirteen patients were admitted to the hospital; 10 due to fever. Three patients developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/ml) to the post-treatment evaluation (median: 1.16 ng/ml; p < 0.001); post-treatment levels were higher in the LON group ( p = 0.021). APRIL levels were higher in the LON group both at baseline (median: 1.54 versus 1.15 ng/ml; p = 0.027) and post-treatment (median: 2.39 versus 1.11 ng/ml; p = 0.011). IL-6 and GM-CSF levels decreased in the non-LON group ( p < 0.001), but not in LON patients. High baseline disease activity predicted LON development (OR: 4.1; 95% CI: 1.1-15.2 for SLEDAI-2K > 8). No association with neutropenia prior to rituximab treatment was documented. Conclusion Post-rituximab LON was a common complication. Although the phenomenon was predominantly self-limiting, several patients developed severe conditions. Distinct roles of BAFF and APRIL are implicated: BAFF may contribute to LON development, whereas high APRIL levels may be predictive. Rituximab-treated SLE patients should be monitored for neutrophil counts, fever and infections.