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Objective: In the United Kingdom (UK), an objective structured clinical examination (OSCE) has replaced the individual patient assessment (IPA) for part 1 of the membership examination of the Royal College of Psychiatrists (MRCPsych). The authors' assessment of the OSCE was conducted., Method: Residents completed and evaluated an OSCE designed according to guidelines set by the Royal College of Psychiatrists., Results: These residents considered the OSCE fair (86%) and appropriate (89%) in assessing clinical ability. They believed that the OSCE reflected the skills required in clinical practice and found it preferable to the IPA., Conclusion: The OSCE received positive evaluation from residents.

Background: Medical education research is a maturing field of inquiry that derives theoretical perspectives from many domains. Yet while such theoretical diversity holds the promise of rich paradigmatic writing and debate, too often medical education researchers do not place their work in a historical or cultural context, giving the impression that they have somehow unearthed universal 'truths' about medical education., Methods: This paper introduces some of the key 'histories' of medical education from the contexts of Anglophone Canada and the USA following a review of major works in the history of medical education., Results: There are many and conflicting histories of medical education in North America that can be classified according to different socio-historical paradigms., Conclusions: To avoid the error of over-generalisation, a much greater effort must be made to include historical, sociological, economic and other social science perspectives in the design, interpretation and application of medical education research.

Increasing physician and patient mobility has led to a move toward internationalization of standards for physician competence. The Institute for International Medical Education proposed a set of outcome-based standards for student performance, which were then measured using three assessment tools in eight leading schools in China: a 150-item multiple-choice examination, a 15-station OSCE and a 16-item faculty observation form. The purpose of this study was to empanel a group of experts to determine whether international student-level performance standards could be set. The IIME convened an international panel of experts in student education with specialty and geographic diversity. The group was split into two, with each sub-group establishing standards independently. After a discussion of the borderline student, the sub-groups established minimally acceptable cut-off scores for performance on the multiple-choice examination (Angoff and Hofstee methods), the OSCE station and global rating performance (modified Angoff method and holistic criterion reference), and faculty observation domains (holistic criterion reference). Panelists within each group set very similar standards for performance. In addition, the two independent parallel panels generated nearly identical performance standards. Cut-off scores changed little before and after being shown pilot data but standard deviations diminished. International experts agreed on a minimum set of competences for medical student performance. In addition, they were able to set consistent performance standards with multiple examination types. This provides an initial basis against which to compare physician performance internationally.

Objective: To provide evidence-based guidelines for patient selection and to recommend the medical and nutritional aspects of multidisciplinary care required to minimize perioperative and postoperative risks in patients with severe obesity who undergo weight loss surgery (WLS)., Research Methods and Procedures: Members of the Multidisciplinary Care Task Group conducted searches of MEDLINE and PubMed for articles related to WLS in general and medical and nutritional care in particular. Pertinent abstracts and literature were reviewed for references. Multiple searches were carried out for various aspects of multidisciplinary care published between 1980 and 2004. A total of 3000 abstracts were identified; 242 were reviewed in detail., Results: We recommended multidisciplinary screening of WLS patients to ensure appropriate selection; preoperative assessment for cardiovascular, pulmonary, gastrointestinal, endocrine, and other obesity-related diseases associated with increased risk for complications or mortality; preoperative weight loss and cessation of smoking; perioperative prophylaxis for deep vein thrombosis and pulmonary embolism (PE); preoperative and postoperative education and counseling by a registered dietitian; and a well-defined postsurgical diet progression., Discussion: Obesity-related diseases are often undiagnosed before WLS, putting patients at increased risk for complications and/or early mortality. Multidisciplinary assessment and care to minimize short- and long-term risks include: comprehensive medical screening; appropriate pre-, peri-, and postoperative preparation; collaboration with multiple patient care disciplines (e.g., anesthesiology, pulmonary medicine, cardiology, and psychology); and long-term nutrition education/counseling.

Critically ill patients with alcoholism are at greater risk of morbidity and mortality from alcohol withdrawal syndrome than are patients without alcoholism. Benzodiazepines are considered the drugs of choice for the prevention and treatment of alcohol withdrawal syndrome, but some studies have suggested that intravenous ethanol may be as effective as those agents, as well as being less sedating. We evaluated the evidence regarding the use of intravenous ethanol for the prevention and treatment of alcohol withdrawal syndrome in critically ill patients in order to determine its role in this patient population. Because of the paucity of well-designed clinical trials, and because of intravenous ethanol's questionable efficacy, inconsistent pharmacokinetic profile, and relatively narrow therapeutic index, routine use of this drug is not recommended in critically ill patients who have alcohol withdrawal syndrome or are at risk for it.

The vision of the Wilson Centre for Research in Education at the University of Toronto, Ontario, Canada, is "advancing health care education and practice through research." With a core staff of eight PhD researchers, five full-time administrative staff, 150 clinical faculty members, and over a dozen fellows and visiting professors from around the world, the Wilson Centre has become an international leader in health professional education research. Diversity of ideas and research methodologies, a culture of mutual support and mentorship, and strong support from both the university and a major teaching hospital have propelled the Wilson Centre. Challenges such as focusing research priorities, involving the clinical faculty more extensively, and defining productive international collaborations are among the current issues for academic planning.

The systemic delivery of [E1(-)] adenoviral (Ad) vectors encoding a transgene results in efficient viral uptake and abundant transgene expression in the liver. However, [E1(-)]Ad vector persistence is transient due to cytotoxic T lymphocyte (CTL)-mediated loss of the Ad-infected cells. Our laboratory has previously demonstrated that additional modifications to the [E1(-)]Ad vector genome, by deletion of the Ad E2b genes, significantly decreased virus-genome-derived gene expression and simultaneously improved the long-term performance of the resultant [E1(-), E2b(-)]Ad vector. In this study, we confirmed that [E1(-), E2b(-)]Ad vector genomes could persist equally well in C57Bl/6 or Balb/c mouse hepatocytes. Despite vector genome persistence, we observed a strain-dependent variability in the duration of CMV enhancer/promoter-driven transgene expression in the liver. While Balb/c mice rapidly shut down [E1(-), E2b(-)]Ad-derived transgene expression, C57Bl/6 mice allowed for prolonged transgene expression. This occurred even when both strains were crossed into a severe combined immune-deficient background, demonstrating that host adaptive immune responses are not responsible for the phenomenon. Furthermore, differential methylation of the CMV enhancer/promoter was also not demonstrated in either strain of mouse, eliminating this mechanism as causative. Thus, alternative mechanisms for this phenomenon are discussed.

Background: Referral and consultation letters ferry patients among providers, negotiating co-operative care. Our study examined how "relevance" is signalled and decoded in these letters, from the perspective of both experts and trainees in three clinical specialties., Methods: 104 letters were collected from 16 physicians representing family medicine, psychiatry and surgery. Interviews were conducted with 14 of these physicians and 13 residents from the three specialties. All documents and transcripts were analysed for emergent themes., Results: Six rhetorical factors influenced expert physicians' decisions about what material is relevant: educational, professional, audience, system-institutional, medical-legal, and evaluative. Each specialty placed different emphasis on these factors. Trainees reported having no instruction regarding how to construct rhetorically relevant letters, and they demonstrated awareness of only three of the factors identified by experts--professional, audience and evaluative. Experts and trainees differed in their understanding and application of these three factors., Conclusions: This research demonstrates that six rhetorical factors influence relevance decisions in letter writing, and that experts address these factors in tacit, dynamic and discipline-specific ways. Trainees share with experts an appreciation of the rhetorical functions of referral and consultation letters, but lack a comprehensive understanding of the influential factors and do not receive instruction in them. These findings provide a framework for instruction in this domain to equip novices to meet the expectations of their professional audiences successfully.

Direct HDL-cholesterol (HDLc) assays have several advantages over other assays that are more laborious and time-consuming. A recent College of American Pathologists (CAP) report indicates that at least 385 Beckman LX-20 analyzers use the selective detergent (homogeneous or direct) method for analyzing HDLc. There is no published evaluation of direct HDLc assays on the Beckman platform. Here we report our evaluation of a direct HDLc assay marketed by Beckman for the Beckman LX-20 analyzers. In general, the assay performed well; however, the total error was not within National Cholesterol Education Program (NCEP) guidelines. This was largely because of a significant positive bias that appeared to be due, at least in part, to triglycerides. This bias was worse at HDLc concentrations <40 mg/dL, which may make it difficult to identify a low HDLc concentration and consequently an increased risk for cardiovascular disease (CVD)., (Copyright 2004 Wiley-Liss, Inc.)

Adenoviral vectors from which the E1 region has been deleted ([E1(-)] Ad) are known to induce strong immune responses after systemic delivery. In this study we have evaluated liver toxicities in mice after intravenous injection with high doses of [E1(-)] or modified [E1(-), E2b(-)] Ad vectors (both expressing the bacterial beta-galactosidase [lacZ] marker gene) in C57BL/6, BALB/c, and SCID mice. Our data demonstrate a marked reduction in maximal liver toxicities and pathologies (typically noted at 21 days postinjection) with the use of the [E1(-), E2b(-)] modified vector in all strains of mice tested. Our data also demonstrated that despite the use of the [E1(-), E2b(-)] Ad vector, significant liver toxicities were still observed. To address this issue and the fact that the lacZ gene was perceived as a foreign antigen in the immune-competent C57BL/6 and BALB/c mice, we similarly injected mice tolerant of LacZ (lacZ-TG). In contrast to our studies in C57BL/6 and BALB/c mice, LacZ-TG mice exhibited virtually no evidence of hepatotoxicity after intravenous injection with the [E1(-), E2b(-)] vector, in contrast to use of the [E1(-)] Ad vector. Our results demonstrate that the [E1(-), E2b(-)] Ad vector class can reduce liver toxicities typically ascribed to Ad vector-mediated gene transfer after transfer of a highly immunogenic or foreign gene, whereas transfer of a transgene that is perceived as nonforeign by the host can be delivered with virtually no evidence of toxicity. On the basis of a careful review of the literature, these improvements in vector safety rival those noted with other, more significantly modified Ad vectors described to date.

Background: In 1979, Harden described the first objective structured clinical examination (OSCE). Harden's OSCE dramatically changed the assessment of professional competence because it used actors and choreographed scenarios to evaluate the performance of professional behaviours., Analysis: Because of the intense focus on performance, OSCEs have had a powerful influence on doctor training and practice. However, the immediate psychometric characteristics of OSCEs rather than their performance effects have been the subject of most research., Conclusion: The time has come to undertake a sophisticated sociological investigation of how OSCEs affect medical practice, including the ways in which they shape doctor interaction with patients, families and other health professionals.

Purpose: There are several reasons for using global ratings in addition to checklists for scoring objective structured clinical examination (OSCE) stations. However, there has been little evidence collected regarding the validity of these scales. This study assessed the construct validity of an analytic global rating with 4 component subscales: empathy, coherence, verbal and non-verbal expression., Methods: A total of 19 Year 3 and 38 Year 4 clinical clerks were scored on content checklists and these global ratings during a 10-station OSCE. T-tests were used to assess differences between groups for overall checklist and global scores, and for each of the 4 subscales., Results: The mean global rating was significantly higher for senior clerks (75.5% versus 71.3%, t55 = 2.12, P < 0.05) and there were significant differences by level of training for the coherence (t55 = 3.33, P < 0.01) and verbal communication (t55 = 2.33, P < 0.05) subscales. Interstation reliability was 0.70 for the global rating and ranged from 0.58 to 0.65 for the subscales. Checklist reliability was 0.54., Conclusion: In this study, a summated analytic global rating demonstrated construct validity, as did 2 of the 4 scales measuring specific traits. In addition, the analytic global rating showed substantially higher internal consistency than did the checklists, a finding consistent with that seen in previous studies cited in the literature. Global ratings are an important element of OSCE measurement and can have good psychometric properties. However, OSCE researchers should clearly describe the type of global ratings they use. Further research is needed to define the most effective global rating scales.

In preparation for a celebration of '30 years of OSCEs' held during the 2002 meeting of the Association for Medical Education in Europe (AMEE), I was asked to discuss the question, 'Are OSCEs valid to assess competence?". My first instinct was to review work undertaken in ay countries by famous researchers such as Harden, Colliver, Rothman, van der Vleuten, Stillman, Tamblyn and others who have studied and written about the validity of OSCEs. I could then have reviewed the extensive literature produced in Canada by the Medical Council of Canada and in the United States by the Education Commission on Foreign Medical Graduates and National Board of Medical Examiners that has demonstrated the utility of large-scale OSCEs for certification and licensure. I might have tossed in a few papers from my own research on the validity of OSCEs in psychiatry. Indeed, it would have been relatively easy to marshal the medical education literature to answer the question 'Are OSCEs valid to assess competence' strongly in the affirmative. But the more I reflected on the question, the more I confronted concerns that have troubled me for some time. Specifically, I worry that our approaches to validity may themselves not be valid. In this paper, I review what I believe to be three serious problems with our current approaches to showing that 'the OSCE is valid' Let me begin by rethinking the question. What do we mean 'Is the OSCE valid for assessing competence' There are three important problems with this question. First, validity is a property of the application of a test, not of a test itself. Second, we cannot speak of validity without giving consideration to the context in which we use the test. And finally, the concept of validity flounders because the OSCE itself is an important agent in constructing the variables of performance that it is designed to measure. I shall consider each issue in turn.

Purpose: Although expert clinicians approach interviewing in a different manner than novices, OSCE measures have not traditionally been designed to take into account levels of expertise. Creating better OSCE measures requires an understanding of how the interviewing style of experts differs objectively from novices., Methods: Fourteen clinical clerks, 14 family practice residents and 14 family physicians were videotaped during 2 15-minute standardized patient interviews. Videotapes were reviewed and every utterance coded by type including questions, empathic comments, giving information, summary statements and articulated transitions. Utterances were plotted over time and examined for characteristic patterns related to level of expertise., Results: The mean number of utterances exceeded one every 10 s for all groups. The largest proportion was questions, ranging from 76% of utterances for clerks to 67% for experts. One third of total utterances consisted of a group of 'low frequency' types, including empathic comments, information giving and summary statements. The topic was changed often by all groups. While utterance type over time appeared to show characteristic patterns reflective of expertise, the differences were not robust. Only the pattern of use of summary statements was statistically different between groups (P < 0.05)., Conclusions: Measures that are sensitive to the nature of expertise, including the sequence and organisation of questions, should be used to supplement OSCE checklists that simply count questions. Specifically, information giving, empathic comments and summary statements that occupy a third of expert interviews should be credited. However, while there appear to be patterns of utterances that characterise levels of expertise, in this study these patterns were subtle and not amenable to counting and classification.

Purpose: Process-oriented global ratings, which assess "overall performance" on one or a number of domains, have been purported to capture nuances of expert performance better than checklists. Pilot data indicate that students change behaviors depending on their perceptions of how they are being scored, while experts do not. This study examines the impact of the students' orientation to the rating system on OSCE scores and the interstation reliability of the checklist and global scores., Method: A total of 57 third- and fourth-year medical students at one school were randomly assigned to two groups and performed a ten-station OSCE. Group 1 was told that scores were based on checklists. Group 2 was informed that performance would be rated using global ratings geared toward assessing overall competence. All candidates were scored by physician-examiners who were unaware of the students' orientations to the rating system and who used both checklists and global rating forms., Results: A mixed two-factor ANOVA identified a significant interaction of rating form by group (F(1,55) = 5.5, p <.05), with Group 1 (checklist-oriented) having higher checklist scores but lower global scores than did Group 2 (oriented to global ratings). In addition, Group 1 had higher interstation alpha coefficients than did Group 2 for both global scores (0.74 versus 0.63) and checklist scores (0.63 versus 0.40)., Conclusions: The interaction effect on total exam scores suggests that students adapt their behaviors to the system of evaluation. However, the lower reliability coefficients for both forms found in the process-oriented global-rating group suggest that an individual's capacity to adapt to the system of global rating forms is relatively station-specific, possibly depending on his or her expertise in the domain represented in each station.

Objective: To evaluate the role of intravenous valproate sodium (IV VPA) in the treatment of status epilepticus (SE)., Data Sources: A literature search of the English language was performed (MEDLINE 1966-July 2000). Search terms included valproate, valproic acid, and status epilepticus. Bibliographies of articles chosen were reviewed to identify other possible sources., Data Synthesis: A review of the medical literature was conducted to evaluate the safety and efficacy of IV VPA in the treatment of SE., Conclusions: Experience with IV VPA in the treatment of SE is too limited to recommend its use as a first-line agent. IV VPA may represent a third- or fourth-line option in cases of SE when other agents are ineffective or contraindicated.

Objective: The authors reviewed the literature on mental health education for primary care physicians and made recommendations for the design of educational programs and research., Method: They searched the MEDLINE and PsycLIT databases from 1950 to 2000 by using a variety of key words and subjects., Results: More than 400 articles were identified, ranging from empirical studies to philosophical articles. Many identified a perceptual gap between primary care and psychiatry as the basis for problems of contextual relevance in psychiatric education for primary care practitioners. There were few empirical studies; most reported only results of satisfaction surveys or simple tests of knowledge. Long-term outcomes were less positive; there were important negative findings., Conclusions: An extensive literature published over five decades identified a strong need for ongoing mental health training for primary care physicians. Helpful recommendations exist related to objectives, methods, and evaluation. However, there are organizational and attitudinal issues that may be equally or more important for educators to consider than the selection of educational methods.

Objective: To assess the current evidence of the value of cycling of antimicrobials to control the emergence of resistance or to reverse existing resistance to antimicrobials., Data Sources: Articles were obtained through a MEDLiNE search of the English-language literature from 1966 to January 2000. Additionally, references from retrieved publications were reviewed to identify further articles., Study Selection and Data Extraction: All investigations of switching between or cycling among antimicrobials were evaluated. Studies switching between or cycling among specific drugs or classes of drugs within institutional settings were included in this review., Data Synthesis: Studies involving cycling among different aminoglycosides suggest that, although temporary decreases in resistance can be documented, resistance usually rebounds rapidly on completion of the cycle and return to the original agent. Switching between classes of antimicrobials has produced inconsistent results and has been shown to replace resistance to one agent with resistance to another. Mathematical models using both in vitro and clinical data have suggested that, due to residual resistance in the population, cycling among drug classes is unlikely to yield long-term reductions in antimicrobial resistance, especially if a high level of antimicrobial resistance exists., Conclusions: Cycling among different antimicrobials to reverse resistance trends is currently not supported by published literature. Cycling to prevent the emergence of resistance may ultimately be more useful; however, no studies have evaluated this concept. Well-designed prospective studies are needed to evaluate the potential clinical value of antimicrobialcycling.

Context: Problem based learning (PBL) has become an integral component of medical curricula around the world. In Ontario, Canada, PBL has been implemented in all five Ontario medical schools for several years. Although proper and timely feedback is an essential component of medical education, the types of feedback that students receive in PBL have not been systematically investigated., Objectives: In the first multischool study of PBL in Canada, we sought to determine the types of feedback (grades, written comments, group feedback from tutor, individual feedback from tutor, peer feedback, self-assessment, no feedback) that students receive as well as their satisfaction with these different feedback modalities., Subjects and Methods: We surveyed a sample of 103 final year medical students at the five Ontario schools (University of Toronto, McMaster University, Queens University, University of Ottawa and University of Western Ontario). Subjects were recruited via E-mail and were asked to fill out a questionnaire., Results: Many students felt that the most helpful type of feedback in PBL was individual feedback from the tutor, and indeed, individual feedback was one of the more common types of feedback provided. However, although students also indicated a strong preference for peer and group feedback, these forms of feedback were not widely reported. There were significant differences between schools in the use of grades, written comments, self-assessment and peer feedback, as well as the immediacy of the feedback given., Conclusions: Across Ontario, students do receive frequent feedback in PBL. However, significant differences exist in the types of feedback students receive, as well as the timing. Although rated highly by students at all schools, the use of peer feedback and self-assessment is limited at most, but not all, medical schools.

Glycogen storage disease type II (GSD-II) is a lethal, autosomal recessive metabolic myopathy caused by a lack of acid-alpha-glucosidase (GAA) activity in the cardiac and skeletal muscles. Absence of adequate intralysosomal GAA activity results in massive amounts of glycogen accumulation in multiple muscle groups, resulting in morbidity and mortality secondary to respiratory embarrassment and/or cardiomyopathy. In a mouse model of GSD-II, we demonstrate that infection of the murine liver with a modified adenovirus (Ad) vector encoding human GAA (hGAA) resulted in long-term persistence of the vector in liver tissues for at least 6 months. Despite both a rapid shutdown of hGAA mRNA expression from the vector, as well as the elicitation of anti-hGAA antibody responses (hGAA is a foreign antigen in this model), the hGAA secreted by the liver was taken up by all muscle groups analyzed and, remarkably, persisted in them for at least 6 months. The persistence of the protein also correlated with long-term correction of pathologic intramuscular glycogen accumulations in all muscle groups tested, but most notably the cardiac tissues, which demonstrated a significantly decreased glycogen content for at least 190 days after a single vector injection. The results suggest that gene therapy strategies may have the potential to significantly improve the clinical course for GSD-II patients.

The psychodynamic life narrative is a statement that is made to the patient that gives current emotional reaction meaning in the context of his life history, and shows it to be a logical and inevitable product of previous life experiences. Because the patient in crisis characteristically present feeling overwhelmed, confused and needy, there is a sense of urgency and helplessness which impacts on the resident therapist's intervention. Common countertransference reactions which can result are assuming omnipotent control, a grandiose rescue fantasy or passivity. The authors present a clinical vignette to illustrate the supervisory process and its vicissitudes in the use of the psychodynamic life narrative in supervision of crisis work. The early identification of the "rescuing" response led to the rapid formulation of the psychodynamic life narrative and a successful outcome.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by the lack of expression of the dystrophin protein in muscle tissues. We genetically engineered a mouse model (mdx) of DMD that allowed for the high level and inducible transcription of a dystrophin mini-gene. This was achieved via the tetracycline-responsive transactivator (tTA) system. Multiple analyses confirmed that dystrophin expression in the mice was: (i) tTA dependent; (ii) correctly localized to the sarcolemmal membranes; (iii) capable of preventing the onset of dystrophy; and (iv) effectively blocked by the oral administration of tetracyclines. The model allowed us to somatically extinguish or induce dystrophin gene transcription. Somatic induction of dystrophin transcription prevented the onset of muscular dystrophy in some muscle groups. The levels of phenotypic rescue were influenced, however, by the age of the animals at the time of dystrophin induction. We also found that despite somatic termination of dystrophin gene transcription, the dystrophin protein was found to be associated with the sarcolemmal membrane for at least 26 weeks. Persistent detection of dystrophin was also accompanied by a prolonged protection of the muscle cells from the onset of dystrophy. The findings demonstrated that somatic transfer of the dystrophin gene not only may allow for the prevention of muscular dystrophy in multiple muscle groups, but also may be accompanied by persistent efficacy, secondary to the long-term functional stability of the dystrophin protein in vivo. This model should be useful in future studies concerning the potential of genetic therapy for DMD, as well as other muscle disorders.

Background: The inherent limitations of [E1-]Ad vectors as gene therapy vehicles suggest that further modifications may improve their overall performance profiles. However, Ad vector modifications can have untoward effects on their basic biology, e.g., some helper-virus dependent Ad vectors have been found to be unstable without the presence of preterminal protein (pTP) activities. Despite this concern, we generated a new class of helper-virus independent Ad vector that was multiply deleted for the E1, polymerase, and pTP genes, and investigated the ramifications of these deletions upon several vector performance parameters., Methods: The construction and propagation of an [E1-, polymerase-, pTP-]Ad vector was achieved with the use of trans-complementing cells co-expressing the Ad E1, polymerase and pTP genes., Results: High titer production of the [E1-, polymerase-, pTP-]Ad vector was successfully accomplished via conventional Ad purification techniques. This unique class of Ad vector was capable of long-term gene transfer in vivo (despite lacking pTP functions) that was concomitant with a significantly decreased hepatic toxicity., Conclusions: Previous studies had suggested that Ad genome persistence in vivo may be dependent upon the presence of low level vector genome replication and/or pTP functions. Our results suggest that [E1-, polymerase-, pTP-]Ad vectors can overcome these barriers. The further benefits afforded by the use of this class of Ad vector (increased cloning capacity, high level growth, decreased propensity to generate replication competent Ad (RCA), decreased toxicity) suggests that they will be highly beneficial for use in several aspects of human gene therapy.

The ganglioside GM1 is a glycosphingolipid which enhances process formation of several neuronal lines and potentiates some growth factor-mediated responses. Previously we have shown that 24 h exposure of Neuro 2a cells to GM1 mobilized the neuron-specific microtubule-associated protein, MAP2, away from microtubule-rich areas to areas of neurite sprouting where MAP2 was more closely associated with the subcortical actin network. To examine the role of GM1 in fostering the shift of the association of MAP2 from tubulin to actin, NIH 3T3 cells were co-transfected with pHook-1, which expresses a surface antigen, and a construct expressing MAP2. Transfected cells were selected with magnetic beads coated with a hapten that binds to the expressed surface antigen and treated with 150 microg/ml GM1 for 18-24 h. Actin and MAP2 or tubulin and MAP2 were immunolocalized and examined with confocal microscopy. MAP2 was found throughout the cytoplasm as well as associated with actin filaments. As observed previously with Neuro 2a, GM1 treatment of transfected fibroblasts redistributed the MAP2 away from direct association with microtubules to peripheral areas where the association of MAP2 with actin was enhanced. GM1 did not induce neurite-like processes in MAP2-transfected cells. Treatment with cytochalasin B, which is reported to result in process formation, also did not induce neurite-like processes. These studies suggest that GM1's ability to mobilize MAP2 and promote its association with actin is not restricted to neurons.

The clustering of acetylcholine receptors (AChR) on skeletal muscle fibers is an early event in the formation of neuromuscular junctions. Recent studies show that laminin as well as agrin can induce AChR clustering. Since the alpha7beta1 integrin is a major laminin receptor in skeletal muscle, we determined if this integrin participates in laminin and/or agrin-induced AChR clustering. The alternative cytoplasmic domain variants, alpha7A and alpha7B, and the extracellular spliced forms, alpha7X1 and alpha7X2, were studied for their ability to engage in AChR clustering. Immunofluorescence microscopy of C2C12 myofibers shows that the alpha7beta1 integrin colocalizes with laminin-induced AChR clusters and to a much lesser extent with agrin-induced AChR clusters. However, together laminin and agrin promote a synergistic response and all AChR colocalize with the integrin. Laminin also induces the physical association of the integrin and AChR. High concentrations of anti-alpha7 antibodies inhibit colocalization of the integrin with AChR clusters as well as the enhanced response promoted by both laminin and agrin. Engaging the integrin with low concentrations of anti-alpha7 antibody initiates cluster formation in the absence of agrin or laminin. Whereas both the alpha7A and alpha7B cytoplasmic domain variants cluster with AChR, only those isoforms containing the alpha7X2 extracellular domain were active. These results demonstrate that the alpha7beta1 integrin has a physiologic role in laminin-induced AChR clustering, that alternative splicing is integral to this function of the alpha7 chain, and that laminin, agrin, and the alpha7beta1 integrin interact in a common or convergent pathway in the formation of neuromuscular junctions.

IL-8 is one of the major mediators of the transendothelial migration of neutrophils from the circulation to the site of injury and infection. In this work we demonstrate that the CXC or alpha-chemokines, IL-8 and melanoma growth stimulatory activity (MGSA) induce myeloid suppression via direct action on progenitor cells, mediated by activation of the murine homologue of the CXC chemokine receptor-2 (CXCR2) or IL-8R B. We first show that proliferation of the IL-3-dependent murine myeloid progenitor cell line 32D is suppressed by human IL-8 and the functionally and structurally related peptide, MGSA. Second, we show for the first time the high endogenous expression of the murine CXCR2 in 32D cells, as demonstrated by Northern blot analysis, binding to [125I]macrophage inflammatory protein-2, and macrophage inflammatory protein-2-induced calcium responses in 32D cells. Third, we demonstrate that IL-8 and MGSA induce a rise in intracellular calcium in 32D cells. The IL-8-induced Ca2+ response is desensitizing, since a second dose of IL-8 did not trigger a second calcium response. Other chemokines, including neutrophil-activating protein-2, platelet factor-4, RANTES, and macrophage chemotactic protein-1, neither suppressed the proliferation of 32D cells nor induced a rise in intracellular calcium. Finally, the IC50 of IL-8- and MGSA-dependent suppression of proliferation of 32D cells is in good agreement with the EC50 of IL-8- and MGSA-dependent activation of neutrophil Mac-1 up-regulation and chemotaxis. Our studies are consistent with the idea that IL-8 and MGSA suppress the proliferation of 32D cells by activation of murine CXCR2.

Although objective structured clinical examinations (OSCEs) are well-accepted performance-based assessments with good reliability, psychiatric educators have been slow to adopt this evaluation method, opting for oral exams that often have inferior psychometric properties. A 4-station "mini-OSCE" was developed and used to test 42 clinical clerks in psychiatry. The examination mean score and standard deviation were 74% and 8.08, respectively, while individual scores ranged from 56% to 86%. Interstation reliability was 0.61. Student and faculty satisfaction was high. A "mini-OSCE" for psychiatric clinical clerks confers the benefits of acceptable reliability and a high degree of acceptance without incurring the high costs usually associated with OSCE evaluation.

Many aspects of myogenesis are believed to be regulated by myoblast interactions with specific components of the extracellular matrix. For example, laminin has been found to promote adhesion, migration, and proliferation of mammalian myoblasts. Based on affinity chromatography, the alpha7beta1 integrin has been presumed to be the major receptor mediating myoblast interactions with laminin. We have prepared a monoclonal antibody, O26, that specifically reacts with both the X1 and the X2 extracellular splice variants of the alpha7 integrin chain. This antibody completely and selectively blocks adhesion and migration of rat L8E63 myoblasts on laminin-1, but not on fibronectin. In contrast, a polyclonal antibody to the fibronectin receptor, alpha5beta1 integrin, blocks myoblast adhesion on fibronectin, but not on laminin-1. The alpha7beta1 integrin also binds to a mixture of laminin-2 and laminin-4, the major laminin isoforms in developing and adult skeletal muscle, but O26 is a much less potent inhibitor of myoblast adhesion on the laminin-2/4 mixture than on laminin-1. Based on affinity chromatography, we suggest that this may be due to higher affinity binding of alpha7X1 to laminin-2/4 than to laminin-1.

Purpose: To assess the feasibility, reliability, and validity of an objective structured clinical examination (OSCE) for psychiatric clinical clerks., Method: In 1995 two parallel forms of a ten-station OSCE (eight clinical stations, two writing stations) were developed at the University of Toronto Faculty of Medicine Each 12-minute performance-based clinical station was assessed by a faculty psychiatrist using both a checklist for each student's performance content and a global-rating scale of the performance process. The students' clinical-station scores were calculated as the average of their content and process scores (expressed as percentages). Examiners also recorded an overall judgment of each students' performance (pass, borderline, or fail) and wrote [in collaboration with the standardized patient (SP) at that station] comments on each student's performance. There were two criteria for a passing grade: a total mark of 60% or higher across all ten stations and a "pass" or "borderline" mark in at least five of the eight clinical stations. Each OSCE form was administered three times., Results: The first form was used to examine 94 clerks, the second form to examine 98 clerks. The students' mean scores for the two forms were 70.47% (SD, 6.33%) and 67.66% (SD, 7.05%), respectively. In addition to the standard evaluation information collected on the students, several critical incidents occurred (e.g., a student's loss of control of emotions) that may identify potential problems in professional conduct. The direct cost for one administration of the examination was approximately Can$3,300: the largest portion of this was for the SPs' time spent in training and performing their roles., Conclusion: Preliminary evidence suggests that a psychiatry OSCE is feasible for assessing complex psychiatric skills. However, careful attention must be paid to SP training, examination monitoring, detection of critical incidents, and provision of feedback to students, faculty, and SPs. The university's previous system of oral examinations required approximately 600 faculty hours per year. The OSCE requires approximately 450 faculty hours, and the 150 hours saved almost cover the Can$20,000 that the examination costs each year. In all, the OSCE is an evaluation system that has demonstrable reliability and is more enjoyable for both the faculty and the students.

In most objective structured clinical examinations (OSCEs), communication skills are assessed as an 'add-on' to history-taking stations, rather than in stations designed to assess communication skills in the broadest sense. This study investigated the feasibility of developing such stations. In part one, 60 clinical clerks and 36 residents were rated in four 10-min emotionally charged situations portrayed by standardized patients. Inter-rater reliability was demonstrated (r = 0.59-0.63) and a highly significant effect of educational level was found. Generalizability between communication stations was low (0.17-0.20). Several explanations for poor generalizability, including poor discrimination as a result of low score variance and the confounding effect of content knowledge, were addressed in part 2. Ninety-five final-year medical students participated in an OSCE in which six 10-min encounters examined the students' ability to manage difficult emotional situations such as fear, anxiety, mania, sadness, confusion and anger. Half the students encountered a patient with moderate emotional symptoms and half an extreme emotional state. For difficult stations, students' scores were lower and standard deviation higher, suggesting that manipulating difficulty increases score variance and potentially discrimination. However, a strong interaction was found between difficulty and station content, and communication scores were highly correlated with content. Scenarios which created major communication difficulties (such as mania) resulted in much larger differences in scores between the easy and difficult versions. Communication OSCE stations can be created with acceptable reliability including difficult cases which address communication skills beyond simple history taking. Nevertheless, a generalizable set of communication skills remains elusive.

Objective: To examine the type and number of interactions of psychiatry residents, interns and clerks with sales representatives of pharmaceutical companies and the attitudes of physicians-in-training toward these interactions., Design: Survey conducted with the use of a self-report questionnaire., Setting: Seven teaching hospitals affiliated with the Department of Psychiatry, University of Toronto., Participants: All 105 residents, interns and clerks training in psychiatry at the seven teaching hospitals between October 1993 and February 1994 were eligible; 74 completed questionnaires, for a response rate of 70%. One respondent was excluded from the analysis., Outcome Measures: Number of personal meetings and "drug lunches" attended, number of drug samples and promotional items received and estimated value of gifts received by each physician-in-training during a 1-year period as well as attitudes of residents, interns and clerks about interactions with pharmaceutical representatives., Results: Median number of personal meetings reported was 1 (range 0 to 35), of drug lunches attended was 10 (range 0 to 70), of promotional items received was 2 (range 0 to 75) and of drug samples received was 1 (range 0 to 20). Trainees' median estimate of the value of gifts received was $20 (range $0 to $800 Fewer than one third felt that pharmaceutical representatives were a source of accurate information about drugs; however, 71% (52/73) disagreed with the statement that representatives should be banned from making presentations. Although only 15% (11/73) felt they had sufficient training about meeting with pharmaceutical representatives, 34% (25/73) felt that discussions with representatives would have no impact on their prescribing practices, and 56% (41/73) felt that receiving gifts would have no impact on prescribing. Fewer than half said they would maintain the same degree of contact with representatives if they did not receive promotional gifts. The more money and promotional items a physician-in-training had received, the more likely he or she was to believe that discussions with representatives did not affect prescribing (p < 0.05). Clerks, interns and junior (first-year and second-year) residents attended two to three times more drug lunches than senior (third-year and fourth-year) residents, and significantly more junior than senior residents felt that pharmaceutical representatives have a valuable teaching role. Junior residents were three times more likely than senior residents to have received drug samples., Conclusions: Interactions between pharmaceutical representatives and psychiatry residents, interns and clerks are common. The physicians-in-training perceive little educational value in these contacts and many, especially clerks, interns and junior residents, disavow the potential of these interactions to influence prescribing. Therefore, supervisors of postgraduate medical training programs may wish to provide instruction concerning potential conflicts of interest inherent in these types of interactions.

Thirty-six lung transplant candidates (n = 16), recipients (n = 11), and support people (n = 9) were examined for psychological distress, coping style, and orientation to independent learning before and after receiving a self-help book in a program designed to alleviate psychosocial distress and bolster adaptive coping. The subjects rated the book as highly acceptable, and none reported increased psychological distress. A further six subjects completed initial psychological measures but elected not to us the book. These subjects were compared with study completers and found to have significantly higher disengagement scores on the Coping Strategies Inventory. Although uncontrolled, significant changes were observed in coping strategies used by the completer group. The relevance of these findings to the use of bibliotherapy in medically ill populations is discussed.

The analgesic property of the anesthetic gas N2O has long been known and used to treat pain in clinical medicine and dentistry. The present study was conducted to identify by subtype and possible location the brain opioid receptors that mediate N2O antinociception in rats. A 5-min exposure to 70% N2O consistently evoked an antinociceptive effect in the hot plate test. This drug effect was partly antagonized in dose-related fashion by i.c.v. pretreatment with naltrexone, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 and beta-endorphin, which block multiple, mu and epsilon opioid receptors, respectively. However, the N2O-evoked antinociception was unaffected by i.c.v. pretreatment with either the delta opioid antagonist naltrindole or the kappa opioid antagonist nor-binaltorphimine. When D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 was administered intracerebrally directly into the periaqueductal gray, N2O antinociception was partly antagonized in a dose-dependent manner. The antinociceptive response to N2O was uninfluenced by beta-endorphin administered into the periaqueductal gray. The findings of these pharmacological antagonism studies are consistent with the hypothesis that exposure to N2O causes a neuronal release of beta-endorphin. These results indicate that supraspinal mu and epsilon opioid receptors mediate N2O antinociception in the rat hot plate paradigm and that one central site of such mu but not epsilon opioid receptors is the periaqueductal gray.

Administration of the anesthetic gas N2O evoked an antinociceptive effect in two rodent antinociception paradigms. In the mouse abdominal constriction test, pretreatment with the nitric oxide synthase (NOS) inhibitor L-NG-nitroarginine (L-NOARG) caused dose-related antagonism of the antinociceptive effect of N2O but not of either morphine or trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide methane sulfonate. This antinociceptive effect was also antagonized by systemic pretreatment with the NOS inhibitors L-NG-nitroarginine methyl ester (L-NAME) and L-NG-monomethylnitroarginine. The antagonism of N2O by L-NOARG and L-NAME was completely reversed by i.c.v. administration of L-arginine but not D-arginine. In the absence of NOS inhibition, N2O antinociception was potentiated by i.c.v. treatment with L-arginine but not D-arginine. The i.c.v. pretreatment with L-NAME also reduced N2O antinociception; this antagonism was also stereospecifically reversed by L-arginine. In the rat hot plate test, the antinociceptive response to 70% N2O was antagonized in dose-related manner by i.c.v. pretreatment with L-NOARG or L-NAME. N2O antinociception was restored by i.c.v. treatment with L-arginine but not D-arginine. However, neither L-arginine nor D-arginine alone affected N2O antinociception. These results implicate a key role for NO in the mediation of the antinociceptive effects of N2O in both mice and rats.

The present study was conducted to ascertain whether an anxiolytic effect of nitrous oxide was demonstrable in rats using the social interaction test and whether this drug effect might be mediated by benzodiazepine receptors. Compared to behavior of vehicle-pretreated, room air-exposed rats, rat pairs exposed to nitrous oxide showed a generally inverted U-shaped dose-response curve with the maximum increase in social interaction encounters occurring at 25% and significant increase in time of active social interaction at 15-35%; higher concentrations produced a sedative effect that reduced social interaction. Treatment with 5.0 mg/kg of the anxiolytic benzodiazepine chlordiazepoxide also increased social interaction. Pretreatment with 10 mg/kg of the benzodiazepine receptor blocker flumazenil, which alone had no effect, significantly antagonized the social interaction-increasing effects of both nitrous oxide and chlordiazepoxide. In summary, these findings suggest that nitrous oxide produces a flumazenil-sensitive effect comparable to that of chlordiazepoxide and implicate central benzodiazepine mechanisms in mediation of the anxiolytic effect of nitrous oxide.

The seroprevalence of antibodies to HIV-1, HTLV-I, and HCV was evaluated in three populations from northern rural Haiti: 1,727 patients attending the hospital for symptoms suggestive of HIV disease, 228 consecutive surgical patients, and 500 pregnant women were tested. HIV-1 seroprevalence was 6.1 and 4.0% in the last two groups, respectively, and 39.3% in the symptomatic population. Associated symptoms of wasting, cough, and diarrhea and a clinical diagnosis of AIDS were significantly predictive of HIV-1 seropositivity. Antibody to HTLV-I seroprevalence ranged from 2.2-5.3% in pregnant women, surgical patients, and HIV-seronegative symptomatic patients and was similar among the three groups when stratified by age. In contrast, HIV-1 seropositivity and HTLV-I seropositivity were significantly associated. The prevalence of confirmed antibody to HCV was low and not associated with either HIV-1 or HTLV-I seropositivity.

This secondary analysis from the National Adolescent Student Health Survey (NASHS) examined relationships between adolescents' personal and perceived peer attitudes toward condom use with gender and self-reported ethnic background. Descriptive results revealed general personal support and perceived peer support for condom use. Results from multivariate analysis of variance (MANOVAs) demonstrated significant interaction effects for the eighth grade sample [F = (4, 2383228) = 3530.01 p = .000], and the 10th grade sample [F = (4, 2636878) = 2594.41073, p = .000]. Contrasts revealed significant differences among all ethnic groups for both belief variables for the entire sample, eighth grade students, and 10th grade students. Though general support exists for condom use among U.S. eighth and 10th grade students, conviction varies among groups perhaps indicating a need for tailored messages about condom use, especially for Hispanic students. Implications for health education include the need for cultural-sensitive and gender-sensitive STD education.

The penetration of ceftazidime, a new broad-spectrum cephalosporin, into fluids from subcutaneous threads, suction blisters, and cantharidin blisters was studied in eight healthy male volunteers. A pharmacokinetic analysis showed fundamental differences between the models. The results obtained with the subcutaneous thread technique were similar to those of the peripheral compartment and were characteristic of a rapidly equilibrating compartment. The results obtained with the suction and cantharidin blister techniques were characteristic of slowly equilibrating compartments. We concluded that although one model will not accurately predict the penetration of an antibiotic in all clinical situations, each model will have its own particular application.

A conventional method of bacteriological examination of removed cerebrospinal fluid shunts was compared with another method which relies on microscopic and cultural examination of intraluminal fluid. Fifty-five shunts were tested. All eight cases of clinical shunt infection gave positive results with the latter method, whereas a further 23 shunts yielded positive cultures by the conventional method in the absence of clinical infection. The consequences of missed infections due to omission of microscopic examination and overdiagnosis using the conventional culture method are discussed.