A new initiative with multiple sponsors to help prepare medical students to be safe and effective prescribers.

Most medical schools in the US, and in other countries as well, continue to struggle to teach their medical students to be safe and effective prescribers before they graduate and set off for their residency programs. We describe a new initiative supported by several national organizations to help medical schools address this need by producing and making available online learning modules that can be used by medical students at any US medical school.

Two cases of rapid onset Parkinson's syndrome following toxic ingestion of ethylene glycol and methanol.

Ethylene glycol and methanol are toxic alcohols commonly found in a variety of commercial products. We report two cases, one associated with ethylene glycol and one with methanol poisoning, which both led to acute hemorrhagic necrosis of the basal ganglia and resulted in acute Parkinson's syndrome. It is unlikely that oxalate crystal deposition is the only mechanism for such basal ganglia necrosis, because similar findings were seen following methanol intoxication. We discuss other possible mechanisms that may contribute towards this unusual neurotoxicity. Both of our patients survived their toxic ingestions, but then developed acute Parkinson's syndrome within 10 days of the ingestion. However, the patient who ingested methanol developed respiratory muscle stiffness/weakness, which responded poorly to anti-Parkinsonian drug therapy. Treatment with carbidopa/levodopa improved cogwheel rigidity and bradykinesia in both patients. We conclude that acute Parkinsonism is one of the lesser-recognized devastating complications of both ethylene glycol and methanol poisoning.

American Board of Clinical Pharmacology fellowship training and certification in clinical pharmacology: educational value and future needs for the discipline.

Currently, the training and education of young clinical pharmacologist who represent the future of our discipline rest almost entirely on institutions/organizations with established and productive fellowship training programs. Here, we discuss the role of the American Board of Clinical Pharmacology (ABCP) in accrediting fellowship training programs and certifying individual clinical pharmacologists. We also explore how ABCP certification adds value to both individual trainees and the discipline in the evolving world of clinical therapeutics and research in human pharmacology.

Non-melanoma skin cancers and glucocorticoid therapy.

Non-melanoma skin cancer (NMSC) is an important cause of morbidity and long-term mortality in organ transplant recipients receiving immunosuppressive drugs such as azathioprine and cyclosporin, often combined with adrenocortical steroids (glucocorticoids). At lower doses, glucocorticoids alone are prescribed for other conditions including musculoskeletal, connective tissue and respiratory disorders. Presently, it is unknown whether patients taking glucocorticoids are at an increased risk of skin malignancies. In a population-based case-control study in New Hampshire, USA, we compared use of glucocorticoids in 592 basal cell carcinoma (BCC) and 281 squamous cell carcinoma (SCC) cases and in 532 age and gender matched controls; neither cases nor controls had a history of organ transplantation. Participants underwent a structured personal interview regarding history of medication use and skin cancer risk factors. We used unconditional logistic regression analysis to compute odds ratios associated with glucocorticoid use for 1 month or longer while controlling for potential confounding factors. Risk of SCC was increased among users of oral glucocorticoids (adjusted odds ratio = 2.31; 95% CI = 1.27, 4.18), and risk of BCC was elevated modestly (adjusted odds ratio = 1.49; 95% CI = 0.90, 2.47). In contrast, risk of both SCC and BCC were unrelated to use of inhaled steroids. Our data suggest that use of oral glucocorticoids may increase risk of NMSC, and SCC in particular, among patients other than organ transplant recipients. We hypothesize that immunosuppression induced by oral glucocorticoids may allow these cancers to emerge from immunosurveillance.

Fatal poisoning from liquid dimethylmercury: a neuropathologic study.

Since ancient times, mercury has been recognized as a toxic substance. Dimethylmercury, a volatile liquid organic mercury compound, is used by a small number of chemistry laboratories as a reference material in nuclear magnetic resonance spectroscopy. To our knowledge, dimethylmercury has been reported in only three cases of human poisoning, each proving fatal. Very small amounts of this highly toxic chemical can result in devastating neurological damage and death. We report the neuropathologic findings in a fatal case of dimethylmercury intoxication occurring in a laboratory researcher that resulted from a small accidental spill. We compare these findings to those reported in one previously reported fatal case of dimethylmercury poisoning, and to earlier reports of monomethylmercury poisoning, and discuss the clinicopathologic correlation.

The impact of early clinical training in medical education: a multi-institutional assessment.

With funding from The Robert Wood Johnson Foundation's Generalist Physician Initiative, Dartmouth Medical School (DMS), New York Medical College (NYMC), and Virginia Commonwealth University School of Medicine (VCU-SOM) adopted early community-based training models for longitudinal clinical experiences. These schools developed different evaluation strategies to assess these models. This paper describes each program, the method used to evaluate an aspect of the program, lessons learned about early clinical teaching and learning, and challenges encountered. Each program used cross-sectional evaluation, and the analysis methods included descriptive statistics, chi-square, t-tests, analysis of variance, and generalized linear models. Dartmouth determined that the type of preceptor does not greatly influence the development of clinical skills, although case-specific differences were discovered. NYMC learned that students taught clinical skills in community-based settings performed as well as or better than their peers who received early patient experience on hospital wards. Virginia Commonwealth discovered that community experiences contributed positively to students' education, critical thinking, and problem-solving skills. Students value early clinical experiences and make important achievements in clinical skills and knowledge development, although logistic challenges exist in conducting these courses. Evaluations are critical to ensure competency, and faculty development must be linked to the evaluation process.

The use of "vertical integration groups" to help define and update course/clerkship content.

Faculty at many medical schools are working hard to improve the quality of their curricula. While the world "curriculum" means different things to different people, curricular change often includes improving the structure of the teaching/learning environment (e.g., seminars or problem-based learning groups vs lectures), the content of courses and clerkships (the core set of knowledge, skills, and attitudes that should be learned), and the manner in which student learning of knowledge and skills is evaluated (the sense that evaluation can help "drive" the curriculum). The author describes how "vertical integration groups" have been used over four years at Dartmouth Medical School to improve and modernize the content of courses and clerkships. In this approach, students and faculty work together to address and improve content areas that normally are not associated with traditional, discipline-centered courses or clerkships. The author discusses the advantages of this approach, the challenges encountered during implementation, and examples of how the approach has been put into action.

The challenge of "teaching" large groups of learners: strategies to increase active participation and learning.

While teaching in a tutorial, seminar, or problem-based learning group format may be the most fun and most active/interactive for both learner and faculty mentor, there are situations in medical student education in which various constraints require the use of the "lecture" format. Similar constraints may occur in the field of continuing medical education, or graduate medical education, as well. When this occurs, the faculty mentor can increase the active participation of the learners in the audience by continuously stressing seven key pedagogical (androgogical) principles. These include: 1) begin the learning exercise with a clinical example or anecdote to show the relevance of the material to the student; 2) frequently ask the students whether they have ever seen examples of what you describe in their previous experience with patients, personal experience, experience with relatives, etc.; 3) ask students frequently whether they have heard similar material presented differently in other courses; 4) recruit students to help solve "mystery cases"; 5) show examples of similar material from real life (e.g., patient descriptions, or even excerpts from favorite TV shows); 6) ask students to help summarize key points at the end of the session; and 7) allow, or even encourage, whispering during the class. Using some or all of these techniques can help turn a "lecture format" into a much more fun, interactive, and valuable session that emphasizes "learning" rather than "teaching."

Olsalazine and 6-mercaptopurine-related bone marrow suppression: a possible drug-drug interaction.

A patient with refractory Crohn's disease had two separate episodes of bone marrow suppression while receiving 50 to 75 mg 6-mercaptopurine a day and 1000 to 1750 mg olsalazine a day. This adverse reaction necessitated dose reduction of 6-mercaptopurine on the first occasion and withdrawal of 6-mercaptopurine and olsalazine on the second occasion. The patient's red blood cell thiopurine methyltransferase (TPMT) activity was 1.2 U per milliliter red blood cells (low normal range) and her TPMT genotype was wild-type sequence for all known alleles of TPMT that result in low TPMT enzyme activity. In vitro enzyme kinetic studies confirmed the hypothesis that olsalazine and olsalazine-O-sulfate are potent noncompetitive inhibitors of recombinant human TPMT. We suggest that the patient's relatively low baseline level of TPMT activity was inhibited by olsalazine and olsalazine-O-sulfate, leading to decreased clearance of 6-mercaptopurine and its accumulation. This ultimately increased intracellular 6-thiopurine nucleotide levels to toxic concentrations, which caused bone marrow suppression.

Effects of 4 y of oral supplementation with beta-carotene on serum concentrations of retinol, tocopherol, and five carotenoids.

beta-Carotene has been studied widely as a potential cancer-preventing agent. Recent studies found that subjects who took beta-carotene supplements orally had increases in their serum concentrations of alpha-carotene and lycopene that were large (> 150% increase) and significantly greater than such increases in subjects who received placebo and that similar supplementation was associated with a decrease of approximately 37% in plasma lutein concentrations. A biologic interaction between beta-carotene and other carotenoids was suggested. We measured concentrations of retinol, alpha-tocopherol, and five carotenoids in serum specimens from a random sample of subjects enrolled in a clinical trial of the use of antioxidant vitamins in preventing colonic adenomas. We used serum specimens obtained at enrollment and after the subjects took placebo (n = 54) or 25 mg beta-carotene/d (n = 54) orally for 4 y. In a multivariate analysis, baseline serum concentrations of the analytes, sex, body mass index, diet, smoking status, and age were associated with variable changes in some analytes over the 4-y period but supplementation with beta-carotene was related only to a mean increase in serum beta-carotene itself of 151%. We excluded with 95% confidence an increase in lycopene > 4.9%, an increase in alpha-carotene > 17.6%, and a decrease in lutein > 14.7% in subjects given beta-carotene. These results confirm previous findings that supplementation with beta-carotene given orally does not alter serum concentrations of retinol or alpha-tocopherol. The findings also indicate that beta-carotene supplementation, which results in a moderate increase in serum beta-carotene concentration, does not significantly change serum concentrations of other carotenoids.

Risk of squamous cell carcinoma of the skin in relation to plasma selenium, alpha-tocopherol, beta-carotene, and retinol: a nested case-control study.

We conducted a nested case-control study of squamous cell skin cancer (SCC) to determine whether risk was related to plasma concentrations of selenium, alpha-tocopherol, beta-carotene, and retinol. We derived the study sample from participants in our Skin Cancer Prevention Study, all of whom had at least one basal cell or squamous cell skin cancer before study entry. Those who developed a new squamous cell skin cancer during the 3-5-year follow-up period were selected as cases (n = 132). Controls (n = 264) were chosen at random, with matching by age, sex, and study center, from among those who did not develop SCC but were being followed actively at the time the SCC case was diagnosed. Prediagnostic plasma samples were analyzed for alpha-tocopherol, beta-carotene, and retinol using high-performance liquid chromatography. Selenium determinations were made using instrumental neutron activation analysis. Odds ratios were computed using conditional logistic regression for matched samples. We found no consistent pattern of SCC risk associated with any of the nutrients examined. The odds ratios (95% confidence intervals) for the highest versus the lowest quartiles of beta-carotene, retinol, alpha-tocopherol, and selenium were 0.73 (0.38-1.41), 1.43 (0.77-2.64), 0.89 (0.43-1.85), and 0.86 (0.47-1.58), respectively. Thus, our data add to the growing body of evidence that these nutrients, at the concentrations we evaluated, are not related strongly to SCC risk.

Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation.

OBJECTIVE: To examine the relationship between beta carotene plasma concentration and beta carotene supplementation and risk of death from major disease causes. DESIGN: Cohort study of plasma concentrations; randomized, controlled clinical trial of supplementation. SETTING: Medical school-affiliated dermatology practices. PATIENTS: A total of 1188 men and 532 women with mean age of 63.2 years, who had enrolled in a randomized clinical trial of beta carotene supplementation to prevent nonmelanoma skin cancer. INTERVENTION: Oral beta carotene, 50 mg per day for a median of 4.3 years. MAIN OUTCOME MEASURES: All-cause mortality and mortality from cardiovascular disease and cancer. RESULTS: During a median follow-up period of 8.2 years, there were 285 deaths. Persons whose initial plasma beta carotene concentrations were in the highest quartile (>0.52 micromol/L [27.7 microg/dL]) had a lower risk of death from all causes (adjusted relative rate [RR], 0.52; 95% confidence interval [CI] 0.44 to 0.87) and from cardiovascular diseases (adjusted RR, 0.57; 95% CI, 0.34 to 0.95) compared with persons with initial concentrations in the lowest quartile (<0.21 micromol/L [11.2 microg/dL]). Patients randomly assigned to beta carotene supplementation showed no reduction in relative mortality rates from all causes (adjusted RR, 1.03; 95% CI, 0.82 to 1.30) or from cardiovascular disease (adjusted RR, 1.16; 95% CI, 0.82 to 1.64). There was no evidence of lower mortality following supplementation among patients with initial beta carotene concentrations below the median for the study group. CONCLUSIONS: These analyses provide no support for a strong effect of supplemental beta carotene in reducing mortality from cardiovascular disease or other causes. Although the possibility exists that beta carotene supplementation produces benefits that are too small or too delayed to have been detected in this study, noncausal explanations should be sought for the association between plasma concentrations of beta carotene and diminished risk of death.

Analysis of within-subject variation of caffeine metabolism when used to determine cytochrome P4501A2 and N-acetyltransferase-2 activities.

Cytochrome P4501A2 (CYP1A2) and N-acetyltransferase-2 (NAT2) are hepatic enzymes that may activate some procarcinogens. Previous reports have determined CYP1A2 and NAT2 phenotypes by quantitating relative amounts of urinary caffeine and metabolites. However, a number of experimental issues with this approach remain. To address these, we measured caffeine and 4 metabolites in urine samples from 20 healthy volunteers on 3 separate occasions at 7-day intervals. Two additional volunteers were studied to measure the pattern of excretion of these analytes in urine over time. The molar ratio of two compounds (1,7-dimethylxanthine/1,3,7-trimethylxanthine) was used to phenotype CYP1A2, while the molar ratio of two other compounds (5-acetylamino-6-formylamino-3-methyluracil/1-methylxanthine) served to phenotype NAT2. Within-subject variation was less than 25% for most participants. In instances when within-subject variation of the metabolic ratio was > 25%, metabolite peaks were usually present in one or more control urine samples. Some caffeine metabolites were observed in urine samples at detectable levels up to 48 h after caffeine ingestion. We conclude that: (a) this assay for determining CYP1A2 and NAT2 activities (phenotyping) has an acceptably low within-subject variation over 3 consecutive weeks for most subjects who were caffeine-free for 36 h prior to study; (b) collecting and analyzing urine samples prior to testing can indicate if subjects are excreting caffeine metabolites and will aid in locating metabolite peaks on chromatograms; (c) refraining from caffeine for 48 h before testing is the best compromise between convenience for the subject and obtaining reproducible results; (d) determining metabolite molar ratios in urine collected 4-5 h after ingesting caffeine provides an acceptable time for the measurement; and (e) different ratios of metabolites for determining CYP1A2 phenotype have different advantages.

Steady-state serum concentration of alpha tocopherol not altered by supplementation with oral beta carotene. The Polyp Prevention Study 1 Group.

BACKGROUND: The antioxidants beta carotene and vitamin E may play a role in cancer prevention. However, some studies have suggested that oral supplements of beta carotene may cause a decrease in serum levels of alpha tocopherol (vitamin E). PURPOSE: We conducted this study to determine if beta carotene supplements affect serum levels of vitamin E and vice versa. METHODS: Five hundred five patients in a clinical trial of antioxidant vitamins, used to prevent recurrences of colonic polyps, received either a placebo, 25 mg of beta carotene per day, 1 g ascorbic acid plus 400 mg alpha tocopherol per day, or all three agents combined. Serum levels of beta carotene and vitamin E were measured before and after 9 months of supplementation, using high-performance liquid chromatography. RESULTS: Vitamin E levels changed very little among the groups receiving placebo or beta carotene and went up substantially and equally in the groups receiving vitamin E plus ascorbic acid or all three agents together. Conversely, beta carotene levels changed very little for the groups receiving placebo or ascorbic acid plus vitamin E but went up substantially and equally for the groups receiving beta carotene alone or all three agents. CONCLUSIONS: We conclude that oral supplementation with beta carotene for 9 months does not alter serum concentration of vitamin E and that supplementation with vitamin E plus ascorbic acid does not alter serum beta carotene levels.