Strong inhibition of TNF-α production and inhibition of IL-8 and COX-2 mRNA expression in monocyte-derived macrophages by RWJ 67657, a p38 mitogen-activated protein kinase (MAPK) inhibitor

In inflammatory processes, the p38 mitogen-activated protein kinase (MAPK) signal transduction route regulates production and expression of cytokines and other inflammatory mediators. Tumor necrosis factor α (TNF-α) is a pivotal cytokine in rheumatoid arthritis and its production in macrophages is under control of the p38 MAPK route. Inhibition of the p38 MAPK route may inhibit production not only of TNF-α, but also of other inflammatory mediators produced by macrophages, and indirectly of inflammatory mediators by other cells induced by TNF-α stimulation. Here we investigate the effects of RWJ 67657, a p38 MAPK inhibitor, on mRNA expression and protein production of TNF-α and other inflammatory mediators, in monocyte-derived macrophages. A strong inhibition of TNF-α was seen at pharmacologically relevant concentrations of RWJ 67657, but also inhibition of mRNA expression of IL-1β, IL-8, and cyclooxygenase-2 was shown. Furthermore, it was shown that monocyte-derived macrophages have a high constitutive production of matrix metalloproteinase 9, which is not affected by p38 MAPK inhibition. The results presented here may have important implications for the treatment of rheumatoid arthritis

Chronic limb-threatening ischemia: when is enough enough?

Vascular Surger

Adherence to Guidelines for Adult (Non-GIST) Soft Tissue Sarcoma in the Netherlands: A Plea for Dedicated Sarcoma Centers

Introduction: Optimal management of soft tissue sarcoma (STS) remains a challenge. A nationwide survey assessed the quality of STS care in the Netherlands, thereby aiming to identify potentialities for improvement through more centralized disease management. Methods: From the Netherlands Cancer Registry (NCR), data were obtained on 3317 adult STS patients (excluding gastrointestinal stromal tumor, GIST) diagnosed in 2006–2011. Logistic regression models were employed to compare outcomes on selected clinical indicators reflecting prevailing STS guidelines between high-volume (≥10 resections annually) and low-volume (<10 resections) hospitals, between academic and general hospitals, and between sarcoma research centers and other hospitals, adjusted for case mix. Analyses were performed on imputed datasets (m = 50), generated through multiple imputations by chained equations. Results: Overall, 89% of patients underwent surgical resection. Resection status remained unknown in 24% (excluding those with metastasized disease), and grade was not documented for one-third of tumors. Microscopic residual disease was detected in 20% with an increased risk for older patients, larger and deeply located tumors, and those located in the (retro)peritoneum or upper extremity. Almost half of patients with an R1 resection re