The metabolite 1 alpha,25-dihydroxyvitamin D3 enhances lymphokine- mediated activation of the oxidative metabolism of the U937 cell line and phosphorylation of a 48-kD respiratory burst-associated protein

U937 cells respond to a variety of stimuli with increased differentiation as manifested by reduced growth, increased adherence, increased expression of several surface receptors, and increased capacity for phagocytosis and formation of reactive oxygen intermediates. In the present study the effects of lymphocyte conditioned media, recombinant interferon-gamma (IFN-gamma), and 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the ability to form reactive oxygen intermediates by U937 cells were measured by using the luminol-dependent luminescence (LDL) assay. Neither 1,25(OH)2D3 alone nor IFN-gamma alone enhanced competence for phorbol myristate acetate- stimulated LDL. Cells were capable of moderate LDL after exposure to lymphocyte conditioned media, and this was enhanced by 1,25(OH)2D3 (10(- 8) mol/L) and other vitamin D metabolites at higher concentrations. This effect was not secondary to accelerated production of myeloperoxidase, which is important in the LDL assay. Enhanced phorbol myristate acetate-stimulated phosphorylation of a 48-kd substrate was observed in 32P-labeled intact cells treated with 1,25(OH)2D3 alone or in combination with IFN-gamma. Treatment of cells with IFN-gamma or lymphocyte conditioned media did not alter phosphorylation. These results support the concept that 1,25(OH)2D3 plays a role in phagocyte differentiation and activation beyond the effects of lymphokines. Protein kinase C-mediated phosphorylation reactions may be necessary for the ability of U937 cells to reduce O2 and required for maximal activity under some conditions of incubation.     

The management of stage I--II Hodgkin's disease with irradiation alone or combined modality therapy: the Stanford experience

At Stanford University, between 1968 and 1978, 230 patients with pathologic stage I--II Hodgkin's disease were treated on prospective clinical trials with either irradiation alone or irradiation followed by 6 cycles of adjuvant combination chemotherapy. The actuarial survival at 10 yr was 84% for patients in either treatment group. Freedom from relapse at 10 yr was 77% among patients treated with irradiation alone and 84% after treatment with combined modality therapy [p(Gehan) = 0.09]. Freedom from second relapse at 10 yr was 89% and 94%, respectively [p(Gehan) = 0.56]. Several prognostic factors were evaluated in order to identify patients at high risk for relapse or with poor ultimate survival after initial treatment with irradiation alone. Systemic symptoms, histologic subtype, age, and limited extranodal involvement (E-lesions) did not affect the prognosis of patients and failed to identify patients whose survival could be improved by the routine use of combined modality therapy. Patients with large mediastinal masses (mediastinal mass ratio greater than or equal to 1/3) had a significantly poorer freedom from relapse when treated with irradiation alone than when treated initially with combined modality therapy [45% versus 81% at 10 yr, p(Gehan) = 0.03). The 10-yr survival of these patients, however, was not significantly different (84% versus 74%). The implications of these observations on the management of patient with early stage Hodgkin's disease are discussed.     

The pharmacokinetics of cyclosporine. I. Single dose and constant rate infusion studies in the rabbit

A two-part study was conducted to characterize the pharmacokinetics of cyclosporine in rabbits. First, cyclosporine was given iv as boluses to nine rabbits in doses of 5, 10, and 20 mg/kg. At each dose level, three rabbits were used. Analysis of blood samples collected was performed by HPLC. The data indicate an increase in the half-life of the terminal phase (255 to 550 min), and in the volume of distribution at steady state (3.16 to 7.82 liters/kg) with increasing dose (5 to 20 mg/kg). Cyclosporine was then administered to three rabbits by constant rate iv infusion. The infusion rate was altered to provide three different steady states within 36 hr in each animal. Infusion rates in two rabbits were increased from 16.8 to 65.4 micrograms/min, and in the third rabbit they were decreased from 65.4 to 16.8 micrograms/min. Blood samples were collected during and postinfusion. Doubling the infusion rate within each animal produced less than double the steady state concentration. All three rabbits showed the same trend. Thus, the total body clearance of cyclosporine increased with increasing infusion rate, indicating nonlinear pharmacokinetic behavior of cyclosporine in rabbits.     

In vitro-in vivo correlation and dissolution studies with oral theophylline dosage forms

The dissolution rates of theophylline from six commercially available products (three uncoated and three sustained-release formulations) were determined in distilled water using the USP and rotating-filter dissolution apparatus. The effect of pH on the dissolution of these products was also examined by both methods. In addition, the effect of stirring rate on the dissolution of theophylline from these products was studied using the rotating-filter apparatus. The data obtained under all conditions were reproducible and well-described by a first-order equation. There was no significant difference between the percent of labeled content dissolved in 30 min (D30) and in 60 min (D60) obtained by the USP method and those obtained by the rotating-filter apparatus. The product-to-product variation in D30 and D60 was significant (p less than 0.001) for both the sustained-release and uncoated dosage forms. The pH of the dissolution fluid had a significant effect on the dissolution of theophylline from the products. The data obtained from the dissolution and absolute bioavailability studies in the rabbit were subjected to linear least-squares regression analysis, and good correlations were obtained between the dose-normalized peak serum level, time-to-peak, percent of the dose absorbed at 1 h and at 6 h, or the dose-normalized area under the curve from t = 0 to t = 00 and from t = 0 to t = 6 h and D30, D60, or the rate constant for dissolution. The linear relationship assumed for two of the products was used to predict bioavailability parameters from dissolution variables. The values predicted by this method were not statistically different from the actual values of these parameters.     

ROLE OF NITRIC OXIDE IN THE DEVELOPMENT OF CORTICOTROPIN-INDUCED HYPERTENSION IN SHEEP

1. The possibility that altered synthesis of vascular nitric oxide (NO) plays a role in the development of corticotropin-induced hypertension in sheep was examined by determining the effect of concomitant infusion of L-arginine, a precursor of NO, on the development of the hypertension. 2. Corticotropin (5 μg/kg per h) infused over 2 days increased mean arterial pressure (MAP) from 83 ± 4 to 99 ± 4 mmHg in five conscious sheep. Concomitant infusion of L-arginine (60 mg/kg per h) did not alter this response; infusion of L-arginine alone had no effect on blood pressure. 3. The dose of L-arginine (60 mg/kg per h) used blocked the rise in MAP (+16 mmHg) in response to a 5 h infusion of N-nitro-L-arginine (1 mg/kg per h). 4. These findings suggest that disruption of NO synthesis does not play a role in the development of corticotropin hypertension in sheep.     

Images in Anesthesia: Transesophageal echocardiogram (TEE) images of an anomalous left circumflex coronary artery

Canadian Journal of Anesthesia/Journal canadien d'anesthésie -     

Withdrawing versus not offering cardiopulmonary resuscitation: Is there a difference?

Conflict between substitute decision makers (SDMs) and health care providers in the intensive care unit is commonly related to goals of treatment at the end of life. Based on recent court decisions, even medical consensus that ongoing treatment is not clinically indicated cannot justify withdrawal of mechanical ventilation without consent from the SDM. Cardiopulmonary resuscitation (CPR), similar to mechanical ventilation, is a life-sustaining therapy that can result in disagreement between SDMs and clinicians. In contrast to mechanical ventilation, in cases for which CPR is judged by the medical team to not be clinically indicated, there is no explicit or case law in Canada that dictates that withholding/not offering of CPR requires the consent of SDMs. In such cases, physicians can ethically and legally not offer CPR, even against SDM or patient wishes. To ensure that nonclinically indicated CPR is not inappropriately performed, hospitals should consider developing ‘scope of treatment’ forms that make it clear that even if CPR is desired, the individual components of resuscitation to be offered, if any, will be dictated by the medical team’s clinical assessment.