Publications

The effects of single doses of intravenous (IV) ciprofloxacin and rifampin and of multiple doses of rifampin on glyburide exposure and blood glucose levels were investigated in nine healthy volunteers. A single IV dose of rifampin significantly increased the area under the concentration-time curve (AUC) of glyburide and its metabolite. Blood glucose levels were significantly lower than those observed after dosing with glyburide alone. Multiple doses of rifampin induced an increase in liver enzyme levels, leading to a marked decrease in glyburide exposure and blood glucose levels. When IV rifampin was administered after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect; however, the relative changes in AUC for glyburide and its hydroxyl metabolite were similar to those seen under noninduced conditions. The studies reported here demonstrate how measurements of the levels of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug-drug induction and inhibition effects and in characterizing enzymatic vs. transporter mechanisms.

OBJECTIVES

To compare tympanostomy tube insertion for children with otitis media in 2002 with the recommendations of two sets of expert guidelines.

DESIGN

Retrospective cohort study.

SETTING

New York metropolitan area practices associated with five diverse hospitals.

PARTICIPANTS

682 of 1046 children who received tympanostomy tubes in the five hospitals for whom charts from the hospital, primary care physician, and otolaryngologist could be accessed.

RESULTS

The mean age was 3.8 years. On average, children with acute otitis media had fewer than four infections in the year before surgery. Children with otitis media with effusion had less than 30 consecutive days of effusion at the time of surgery. Concordance with recommendations was very low: 30.3% (n=207) of all tympanostomies were concordant with the explicit criteria developed for this study and 7.5% (n=13) with the 1994 guideline from the American Academy of Pediatrics, American Academy of Family Medicine, and American Academy of Otolaryngology-Head and Neck Surgery. Children who had previously had tympanostomy tube surgery, who were having a concomitant procedure, or who had "at risk conditions" were more likely to be discordant.

CONCLUSIONS

A significant majority of tympanostomy tube insertions in the largest and most populous metropolitan area in the United States were inappropriate according to the explicit criteria and not recommended according to both guidelines. Regardless of whether current practice represents a substantial overuse of surgery or the guidelines are overly restrictive, the persistent discrepancy between guidelines and practice cannot be good for children or for people interested in improving their health care.

We examined a novel human feeder cell layer of mesenchymal stem cells harvested from human adipose tissues. Gene expression analyses and colony-forming assay with human primary epithelial cells showed that the adipose tissue-derived mesenchymal stem cells produced various factors to support epithelial stem/progenitor maintenance and cell growth. Using the mesenchymal stem cells as novel feeder layers, transplantable epithelial cell sheets could be effectively generated ex vivo on temperature-responsive cell-culture surfaces.

INTRODUCTION

Myxomatous mitral valve "degeneration" with prolapse (MVP) is the most frequent form of nonischemic mitral valve disease. In myxomatous valves, interstitial cells express extracellular matrix-degrading enzymes and it has been postulated that matrix metalloproteinases (MMPs) contribute to these changes.

METHODS

We generated mice with cardiac-specific expression of constitutively active MMP-2 under the control of the alpha-myosin heavy chain promoter.

RESULTS

These mice are normal at 4-6 months of age; at 12-14 months the mitral valves and chordae tendineae exhibit severe myxomatous change with echocardiographic MVP. Myxomatous change was also evident to a lesser extent in the aortic valves. Myxomatous changes were heterogeneous and limited to the left side of the heart with major disorganization of collagen bundles within the lamina fibrosa. Alcian blue/PAS-stained valves revealed massive accumulation of acidic glycosoaminoglycans within the lamina spongiosa, consistent with valvular interstitial cell differentiation to a chondrocytic phenotype. Cells with the histologic features of hypertrophied chondrocytes were found within the chordae tendineae and the tips of the mitral papillary muscles.

CONCLUSION

This report demonstrates that increased activity of a single enzyme, MMP-2, within a transgenic context reproduces many of the features of the human MVP syndrome. The cardiac-specific MMP-2 transgenic mouse potentially provides a unique experimental platform for the evaluation of nonsurgical therapies based on the underlying pathophysiology of this disease.