Publications

To control G protein signaling in vivo, we have modified G protein-coupled receptors to respond exclusively to synthetic small molecule agonists and not to their natural agonist(s). These engineered receptors are designated RASSLs (receptor activated solely by a synthetic ligand). A prototype RASSL (Ro1) based on the Gi-coupled K opioid receptor was expressed in transgenic mice under the control of the tetracycline transactivator (tet) system. Activation of Ro1 expressed in the heart decreased heart rate by up to 80%, an expected effect of increased Gi signaling. Maximal heart rate changes occurred in less than 1 min, demonstrating the speed of this inducible signaling system. This Ro1-mediated slowing of heart rate was also subject to desensitization, which lasted more than 24 h. Both the initial effect on heart rate and the desensitization occurred, even though Ro1 is derived from a human opioid receptor not normally involved in heart rate control. In addition, the tet system was used to induce Ro1 expression in hepatocytes and salivary gland, where Gi signaling is known to control physiologic events such as proliferation and secretion. These studies demonstrate that a RASSL can be inducibly expressed in several mouse tissues and used in vivo to activate G protein signaling in a controllable fashion.

To explore the role of patient preferences in explaining gender differences in the use of invasive cardiac procedures, we surveyed 174 patients presenting for cardiac stress testing at a university hospital. Controlling for sociodemographic factors, health status, symptom severity, and history of prior procedures, women expressed greater willingness than men to accept a physician's recommendation of cardiac catheterization (odds ratio 7.1; 95% confidence interval 1.1, 45.3) and similar willingness to accept a recommendation for coronary angioplasty or coronary artery bypass graft surgery. We conclude that patient preferences are unlikely to explain gender disparities in the use of invasive cardiac procedures.

STUDY OBJECTIVES

To evaluate whether findings from surveillance bronchoscopy predict survival following lung transplantation.

DESIGN

Retrospective review and analysis of 498 bronchoscopies with transbronchial biopsy (TBB) and BAL performed in 34 patients after lung transplantation.

SETTING

University-based, tertiary referral medical center.

PATIENTS

Thirty-four patients after lung transplantation. The mean age at transplantation was 49+/-9 years; 20 (59%) were female. Twenty-four (71%) underwent single and 10 (29%) underwent bilateral lung transplantation. The most common pretransplantation diagnostic groups were emphysema/COPD without concomitant alpha1-antiprotease deficiency (n = 13) and other obstructive disease processes (n = 10).

INTERVENTIONS

Over follow-up, subjects underwent multiple bronchoscopies with TBB and BAL. The median number per subject was 15 (25 to 75% range 13 to 17).

MEASUREMENTS AND RESULTS

We calculated the overall median BAL WBCs and median percent neutrophils (polymorphonuclear leukocytes [PMNs]) among all of the BALs performed for each subject. We then calculated the mean +/- SD of those median values. We used Cox proportionate hazards to assess mortality risk. The median overall follow-up observation period for the cohort was 560 days. There were 11 deaths during this period. Twenty-four subjects (71%) had acute rejection (AR) grades 2 to 4 (mild to severe), and nine (27%) had obliterative bronchiolitis (OB) diagnosed by TBB at any point. The mean value for BAL WBCs was 366+/-145 x 10(3) per milliliter; for percentage PMNs, the mean was 7+/-10%. Adjusting for age, gender, single vs bilateral lung transplantation, pretransplantation diagnostic group, presence of AR, presence of OB, BAL WBC concentration, and lymphocyte CD4/CD8 ratio, PMN percent was a significant predictor of mortality (p = 0.02).

CONCLUSIONS

Ongoing inflammation manifested by an increased percentage PMNs over repeated bronchoscopies predicts mortality following lung transplantation. Biopsy data alone may be insufficient to identify posttransplantation patients at risk of poor outcome.