Levels and membrane localization of the c-K-ras p21 protein in lungs of mice of different genetic strains and effects of 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and Aroclor 1254

Mutational activation of the K-ras oncogene often occurs in human and mouse lung adenocarcinomas. Since K-ras p21 functions in trans-membrane signaling, we have investigated whether the amount of this protein in lung cell membranes is a variable that could influence lung tumorigenesis, either due to genetic differences or in response to tumor promoters. The six mouse strains assessed showed little difference in the total lung K-ras p21 after immunoprecipitation and immunoblotting. However, amount of ras p21 in the membrane fraction showed significant differences, with C57BL/6 and BALB/c having 3-5-fold more than NIH Swiss, AKR and DBA mice. Interestingly, a congenic AKR strain having the Ahr(b-1) Ah receptor allele from C57BL/6 mice (designated AKR.B6Ah) had high lung membrane K-ras p21 similar to that of C57BL/6. To test for possible changes related to lung tumor promotion, mice were treated with a promotional dose of TCDD (5 nmol/kg). After 48 h C57BL/6 lungs showed an increase in p21 in both total and membrane fractions. BALB/c, DBA and Swiss mice showed an increase only in membranes. There was no change in the AKR and AKR.B6Ah. Aroclor 1254 (250 mg/kg) caused an increase in membrane/cytosol ratio in Swiss mice. Thus the membrane:cytosol K-ras p21 ratio may be influenced by the Ahr phenotype, and TCDD and PCBs can induce p21 or increase its membrane level in certain strains, but these properties are not fully dependent on Ahr receptor type. In confirmation of the relevance of these findings for the tumor target cell type, the immortalized alveolar type 2 E10 cell line presented K- ras p21 in membrane, and this was increased 4-fold by treatment with 10 nM TCDD.      

The Feasibility of Longitudinal Patient Contacts in a Large Medical School

Problem: Longitudinal patient contacts are being implemented worldwide as a way to enhance a patient-centered orientation among medical students. In large medical schools, longitudinal integrated clerkships may not be feasible, so other ways must be sought to expose students to prolonged contact with patients. Intervention: Medical students were attached to a family practice and assigned a panel of 4 patients to follow over the 3 years of their clinical training. Their role was that of companion on the patient’s medical journey. The program consisted of several encounters, joining the patient in the medical setting for significant events, and written assignments. This intervention was piloted with 35 students. We describe our experiences from the 1st pilot year of this program. Context: The intervention was performed with 3rd-year students—of a 6-year curriculum—at a large medical school in the Netherlands. Outcome: Finding enough patients per practice was feasible. On the whole, students fulfilled the program’s expectations regarding frequency of patient encounters and assignments. The most frequent problems encountered by the students were uncertainty about their role and setting boundaries in their contact with the patients. They needed more preceptor supervision and coaching than they received. Lessons Learned: For junior students, close and structured supervision led by the faculty is necessary to help them navigate and learn from a panel of patients. Students need guidance about what role they should take on and on how to manage both their own and their patient’s expectations. Guided reflection is necessary to help students give meaning to their experiences with patients.     

A collaborative, double-blind randomized study of cetiedil citrate in sickle cell crisis

We have recently completed a double-blind, placebo-controlled, noncrossover study, the goal of which was to determine whether cetiedil citrate (cetiedil) could affect the course of vaso-occlusive crises in sickle cell disease. Patients, who presented to the emergency room at least 4 but no more than 24 hours after the onset of a painful vasoocclusive crisis severe enough to require hospitalization, were considered candidates for the study. Each patient received either placebo or cetiedil at one of the following three dosages: 0.2, 0.3, or 0.4 mg/kg body weight. The assigned drug dosage was given as a 30 minute intravenous infusion every 8 hours for 4 consecutive days. A total of 67 patients was enrolled in the study. Cetiedil, at its highest dosage (0.4 mg/kg body weight), was found to be significantly superior to placebo both in reducing the number of painful sites present on all 4 treatment days and in shortening the total time in crisis. No serious adverse reactions were observed during the course of the study. We conclude that cetiedil, given at a dosage of 0.4 mg/kg body weight, is therapeutically advantageous for sickle cell crisis.