Publications

BACKGROUND

The optimal strategy for the diagnosis of coronary artery disease (CAD) in women is not well defined. We compared the cost-effectiveness of several strategies for diagnosing CAD in women with chest pain.

METHODS

We performed decision and cost-effectiveness analyses with simulations of 55-year-old ambulatory women with chest pain. With a Markov model, simulations of patients underwent exercise electrocardiography, exercise testing with thallium scintigraphy, exercise echocardiography, angiography, or no workup.

RESULTS

Diagnosis with angiography cost less than $17, 000 per quality-adjusted life-year compared with exercise echocardiography if the patient had definite angina and less than $76,000 per life-year if she had probable angina. If she had nonspecific chest pain, diagnosis with exercise echocardiography increased life-years compared with no testing.

CONCLUSIONS

Cost-effectiveness of first-line diagnostic strategy for diagnosis of CAD in women varies mostly according to pretest probability of CAD. Diagnosis of coronary artery disease with angiography is cost-effective in 55-year-old women with definite angina. In 55-year-old women with probable angina, diagnosis with angiography would increase quality-adjusted life-years but significantly increase costs. Use of exercise echocardiography as a first-line diagnosis for CAD is cost effective in 55-year-old women with probable angina and nonspecific chest pain.

Hypertrophic chondrocytes in the epiphyseal growth plate express the angiogenic protein vascular endothelial growth factor (VEGF). To determine the role of VEGF in endochondral bone formation, we inactivated this factor through the systemic administration of a soluble receptor chimeric protein (Flt-(1-3)-IgG) to 24-day-old mice. Blood vessel invasion was almost completely suppressed, concomitant with impaired trabecular bone formation and expansion of hypertrophic chondrocyte zone. Recruitment and/or differentiation of chondroclasts, which express gelatinase B/matrix metalloproteinase-9, and resorption of terminal chondrocytes decreased. Although proliferation, differentiation and maturation of chondrocytes were apparently normal, resorption was inhibited. Cessation of the anti-VEGF treatment was followed by capillary invasion, restoration of bone growth, resorption of the hypertrophic cartilage and normalization of the growth plate architecture. These findings indicate that VEGF-mediated capillary invasion is an essential signal that regulates growth plate morphogenesis and triggers cartilage remodeling. Thus, VEGF is an essential coordinator of chondrocyte death, chondroclast function, extracellular matrix remodeling, angiogenesis and bone formation in the growth plate.

Initial infection of the airway by Pseudomonas aeruginosa may occur through a variety of bacterial strategies including binding to epithelial receptors present at the surface of the respiratory epithelium. In order to characterize the adherence sites for P. aeruginosa in damaged and repairing bronchial tissue, an ex vivo model of airway epithelial injury and repair was developed using primary cell cultures of nasal cells from 14 subjects with polyposis. P. aeruginosa strongly adhered to flattened dedifferentiated (FD) bronchial and nasal cytokeratin 13-positive epithelial cells in the process of migration for repair. In in vitro experiments, competitive binding inhibition assays demonstrated that alpha5beta1 integrins and cellular fibronectin, in particular the RGD sequence, are receptors involved in P. aeruginosa adherence to FD nasal epithelial cells. Fluorescent cell sorting analysis and immunofluorescence techniques revealed that the alpha5beta1 integrins are overexpressed and apically exposed in FD nasal epithelial cells. One 50 kDa outer membrane protein was identified in piliated and nonpiliated strains of P. aeruginosa that was involved in binding to cellular fibronectin and alpha5beta1 epithelial integrins. These results demonstrate that Pseudomonas aeruginosa adherence is related to the dedifferentiation of airway epithelium during the repair process which unmasks and upregulates the alpha5beta1 integrin expression and induces active synthesis of cellular fibronectin. These epithelial receptors are then used by a Pseudomonas aeruginosa 50 kDa outer membrane protein as sites of bacterial adherence.