The effects of cyclosporin on the collagenolytic activity of gingival fibroblasts.

BACKGROUND: The immunosuppressive agent cyclosporin is associated with a number of major side-effects including the development of gingival overgrowth. Although the pathogenesis of cyclosporin-induced gingival overgrowth remains unclear, it has been suggested that the finely regulated balance between extracellular matrix synthesis and degradation may be disturbed, resulting in an accumulation of excess connective tissue components within the gingival tissue. The aim of this study was to investigate the effect of cyclosporin on matrix metalloproteinases (MMP)-1 and tissue inhibitors of MMP (TIMP)-1 expression at the mRNA, protein, and enzyme activity levels. METHODS: Gingival fibroblasts were grown to confluence and then cultured in serum-free medium supplemented with cyclosporin over the concentration range of 0 to 2000 ng/ml. MMP-1 and TIMP-1 mRNA levels in cultures were determined by reverse transcription polymerase chain reaction (RT-PCR), protein levels in whole conditioned medium were assessed by enzyme-linked immunosorbent assay (ELISA), and collagenolytic activity determined using a 3H-acetylated type I collagen degradation assay. Tissue mRNA levels in normal and overgrown gingiva were also determined by RT-PCR. RESULTS: Results indicated that cyclosporin inhibited MMP-1 expression at both the mRNA and protein level in a dose- and time-dependent fashion. The effects on TIMP-1 expression were less clear, cyclosporin inhibiting mRNA expression, but having no effect on TIMP-1 protein levels at any concentration studied. Addition of the drug resulted in reduced levels of collagenolytic activity in the culture medium. MMP-1 mRNA expression was significantly reduced in overgrown compared to normal tissue. CONCLUSIONS: These results add support to the hypothesis that the accumulation of collagen seen in gingival overgrowth can be explained by a cyclosporin-induced inhibition of collagenolytic activity within the gingival tissues.

Hospital performance with myocardial reperfusion therapy: are hospitals capable of meeting established guidelines?

OBJECTIVES: To determine whether hospitals are capable of delivering myocardial reperfusion therapy in a manner consistent with the American College of Cardiology/American Heart Association guidelines. DATA SOURCE AND STUDY SETTING: Data from the National Registry of Myocardial Infarction (NRMI)-2 and NRMI-3 were used. NRMI is an observational study, sponsored by Genentech, conducted from June 1994 through June 2000 and involving 1876 hospitals and 1,310,030 patients across the United States. The protocol calls for collecting data on all patients with a diagnosis of acute myocardial infarction. The setting was community and tertiary hospitals in the United States. STUDY DESIGN: This observational study used process capability analysis. PRINCIPAL FINDINGS: Overall, no hospital was deemed capable of delivering myocardial reperfusion therapy consistent with the American College of Cardiology/American Heart Association guidelines. The highest thrombolytic and angioplasty CPUs were 0.44 and 0.52, respectively-well below the traditional value of 1.0 signifying minimum capability. In addition, among the hospitals examined, there remained a wide degree of variability in process capability, ranging from -0.69 to 0.52. CONCLUSIONS: Myocardial reperfusion therapy performance measurement systems relying solely on mean time-to-reperfusion conceal true process performance, thereby obscuring quality improvement opportunities and strategies for improvement. Health care providers, purchasers, regulators, and other organizations interested in measuring and improving health care quality are encouraged to incorporate process capability analysis into their myocardial reperfusion therapy performance measurement and quality management systems.