Effects of a p38 MAP kinase inhibitor on bone ingrowth and tissue differentiation in rabbit chambers.

The effects of an oral p38 mitogen-activated protein kinase (MAPK) inhibitor and polyethylene particles separately and together on tissue differentiation in the bone harvest chamber (BHC) in rabbits over a 3-week treatment period were investigated. The harvested tissue was analyzed histomorphometrically for markers of bone formation (percentage of bone area), osteoblasts (alkaline phosphatase staining), and osteoclasts (CD51, the alpha chain of the vitronectin receptor). Polyethylene particles decreased the percentage of bone ingrowth and staining for alkaline phosphatase. The p38 MAPK inhibitor alone decreased alkaline phosphatase staining. When the oral p38 MAPK inhibitor was given and the chamber contained polyethylene particles, there was a suppression of bone ingrowth and alkaline phosphatase staining. In contrast to oral non-steroidal anti-inflammatory drugs (NSAIDs) and local Interleukin-1 receptor antagonist (IL-1ra) administration, the oral p38 MAPK inhibitor alone did not suppress bone formation when given during the initial phase of tissue differentiation. Particle-induced inflammation and the foreign body reaction were not curtailed when the p38 MAPK inhibitor was given simultaneously with particles. Additional experiments are needed to establish the efficacy of p38 MAPK inhibitor administration on mitigating an established inflammatory and foreign body reaction that parallels the clinical situation more closely.

Comparison of VEGF-producing cells in periprosthetic osteolysis.

The pro-angiogenic cytokine vascular endothelial growth factor (VEGF) has been implicated in periprosthetic osteolysis and subsequent aseptic loosening of implants following total hip arthroplasty (THA). The goal of this study was to investigate whether increased VEGF at the bone-implant interface is secondary to a greater number of VEGF-producing cells or to increased VEGF production by individual cells. Real time polymerase chain reaction (RT-PCR) techniques were used to assess the expression of VEGF mRNA (isoforms 121, 165, 189) in periprosthetic tissues from revision THAs. Immunofluorescence was used to determine both differences in overall cellularity and in VEGF-producing cell type (macrophages, fibroblasts, endothelial cells) between patients with periprosthetic osteolysis (OL) and a control group undergoing primary THA for osteoarthritis (OA). Quantitative analysis of VEGF release in periprosthetic membranes via RT-PCR demonstrated no significant difference in the per-cell mRNA production of VEGF isoforms 121 165, or 189 between OL and OA patient groups. Immunofluorescence showed both higher cellularity and higher overall VEGF expression in the OL group. Immunofluorescence also showed a significant increase in macrophages in the OL group, but no significant difference in the proportion of fibroblasts or endothelial cells between the OL and OA groups. Co-localization of CD68+ and CD11b+ macrophage fluorescent signals with VEGF signal was greater in the OL group than in the OA group. Our results demonstrate that increased VEGF in OL periprosthetic tissue compared to OA synovium is correlated to increased numbers of VEGF-producing CD68+ and CD11b+ macrophages. Impact statement: Aseptic loosening, caused in large part by OL, remains the major cause of failed THAs leading to revision surgery. At the bone-implant interface, we found increased numbers of macrophages-cellular mediators of OL-and increased VEGF expression. VEGF may be a possible target for therapeutic intervention in mitigating OL.

Healthcare ethics committees and managed care.

OBJECTIVES: Healthcare ethics committees (HECs) play an important role in medical decision making in US hospitals, but no study has determined whether HECs deal with managed care, in any form. This pilot study was performed to evaluate the activities and perceptions of HECs about managed care. STUDY DESIGN: Forty-five hospitals in the Philadelphia area were selected at random, and comprised 36.6% of area institutions and 47% of area inpatient beds. Surveys were administered to ethics committee representatives by the authors in 1998. PATIENTS AND METHODS: Survey responses were coded, and both tabulated responses and analyzed data are presented. Correlations were analyzed with the unpaired 2-tailed t test. RESULTS: HECs devoted 7.6% of committee time to managed care issues, and the remainder to education, policy development, and case consultation. Time spent on managed care issues depended on the size of the institution (small hospitals spent twice the time on managed care as did large institutions); composition of the committee (presence of clergy and retirees on HECs correlated with the likelihood that HECs would address managed care issues); and whether the HEC was requested to help with managed care issues. Of the HECs surveyed, 18% had formal but disparging discussions of ethical concerns in managed care. The impact of changing insurance programs on the hospital and HECs was a concern. CONCLUSIONS: HECs arbitrate ethical conflicts in managed care when asked. As the presence of managed care increases, ethics committees will increasingly be called on to resolve the resulting ethical dilemmas. To be effective in this role, HECs must become knowledgeable about managed care principles and policies.

A national study of ethics committees.

Conceived as a solution to clinical dilemmas, and now required by organizations for hospital accreditation, ethics committees have been subject only to small-scale studies. The wide use of ethics committees and the diverse roles they have played compel study. In 1999 the University of Pennsylvania Ethics Committee Research Group (ECRG) completed the first national survey of the presence, composition, and activities of U.S. healthcare ethics committees (HECs). Ethics committees are relatively young, on average seven years in operation. Eighty-six percent of ethics committees report that they played a role in ongoing clinical decision making through clinical ethics consultation. All are engaged in developing institutional clinical policy. Although 4.5% of HECs write policy on managed care, 50% of HEC chairs feel inadequately prepared to address managed care. The power and activity of ethics committees parallels the composition of those committees and the relationship of members to their institutions. The role of ethics committees across the nation in making policies about clinical care is greater than was known, and ethics committees will likely continue to play an important role in the debate and resolution of clinical cases and clinical policies.