Publications

Cyclosporin A (CsA) is a potent immunosuppressive agent, now gaining wide application in human organ transplantation. The immunosuppressive activity of CsA is at least in part due to inhibition of lymphokine production by activated T lymphocytes. Specifically, inhibition of T-cell growth factor (TCGF; also designated interleukin 2) production appears to be an important pathway by which CsA impairs T-cell function. To define further both the specificity of CsA and the level at which it interferes with lymphokine gene expression, we have studied its effects on TCGF mRNA accumulation as well as TCGF gene transcription. These studies were performed with a cloned human leukemic T-cell line (Jurkat, subclone 32), which can be induced with phytohemagglutinin and phorbol 12-myristate 13-acetate to produce large amounts of TCGF. In these cells, high levels of TCGF mRNA were present in induced but not in uninduced Jurkat cells as judged by hybridization to a cloned human TCGF cDNA probe. CsA completely inhibited induced TCGF mRNA accumulation at concentrations of 0.3-1.0 microgram/ml, whereas low levels of appropriately sized TCGF mRNA were present at 0.01 microgram/ml. In nuclear transcription experiments, CsA inhibited the synthesis of TCGF transcripts in a dose-dependent manner with complete inhibition at a concentration of 1 microgram/ml. In contrast, CsA did not inhibit the expression of two other inducible genes, TCGF receptor and HT-3. Further, HLA gene expression was also less affected than TCGF in CsA-treated cells. These data suggest a relatively selective action of CsA on TCGF gene transcription.

To determine whether sulfur dioxide and airway cooling and drying interact in causing bronchoconstriction in persons who have asthma, we measured specific airway resistance in seven asthmatic subjects before and after they performed voluntary eucapnic hyperpnea for 3 min breathing four different gas mixtures. The mixtures, which the subjects breathed through a mouthpiece in random order on 4 different days, were 1) humidified room-temperature air, 2) humidified room-temperature air containing 0.5 ppm SO2, 3) cold dry air, and 4) cold dry air containing 0.5 ppm SO2. Each subject breathed at a rate and depth known from preliminary studies to cause little or no bronchoconstriction when that subject inhaled 0.5 ppm SO2 in humidified room-temperature air or cold dry air. When given independently in the blinded study, 0.5 ppm SO2 or cold dry air again caused insignificant bronchoconstriction, but when given together the two stimuli caused significant bronchoconstriction, as indicated by an increase in specific airway resistance from 6.94 +/- 2.85 to 22.35 +/- 10.28 l X cmH2O X l-1 X s (mean +/- SD) (P less than 0.001). thus airway cooling and/or drying increases the bronchoconstriction induced by inhaled SO2 in persons who have asthma. This increase suggests that persons who have asthma may be more sensitive to the bronchoconstrictor effects of ambient SO2 in cold dry environments than in warm moist environments.

In order to determine the relative efficacy and dose equivalency of propranolol four times a day and nadolol once daily for the treatment of stable angina pectoris, ten patients were studied in a double blind randomized placebo controlled crossover study. Total daily doses of propranolol and nadolol were determined by titrating until an equivalent degree of reduction in the heart rate response to exercise was achieved. At these doses, the treadmill exercise time to 0.1 mV of electrocardiographic ST-segment depression was increased from 248 +/- 75 seconds on placebo to 405 +/- 56 seconds on propranolol (p less than 0.05) and 471 +/- 46 seconds on nadolol (p less than 0.01). Also, the mean frequency of angina decreased from eight attacks per week on placebo to three on propranolol and nadolol (both p less than 0.05). In six of the ten patients, the effective total daily dose of propranolol and nadolol was identical, and the dose ratio for all ten patients was 1.17:1, propranolol to nadolol. However, individual dose titration is recommended when switching from propranolol four times a day to nadolol once daily because of the dosage variability noted in 40 percent of the patients.

To test the hypothesis that physician education is an effective strategy to reduce total hospital costs, we evaluated three educational interventions at a large university hospital. This prospective controlled study spanned two academic years and involved 1,663 patients and 226 house staff. In the first year, weekly lectures on cost containment (medicine and surgery) and audit with feedback (medicine only) both failed to produce a significant change in total hospital charges. The "dose" of the intervention was increased on medicine in the second year by combining the lecture and audit strategies. Again, total charges did not change significantly. While decreased use occurred for certain selected services, the impact was not great enough to affect total hospital charges significantly. We conclude that, in the absence of other cost containing incentives, physician education alone is not an effective hospital cost containment strategy.