The influence of structural and institutional change on teaching and culture in clinical settings: an exploratory study.

OBJECTIVES: Learning in clinical settings is a function of activity, context and culture. Glasgow University's Medical School has undergone significant curricular change in recent years. This has coincided with change to National Health Service consultants' contracts, the introduction of the European Working Time Directive and the Modernising Medical Careers training initiative. We wished to explore teachers' and students' perspectives on the effects of change on our clinical teachers' capacity for teaching and on medical culture. METHODS: A qualitative approach using individual interviews with educational supervisors and focus groups with senior clinical students was used. Data were analysed using a "framework" technique. RESULTS: Curricular change has led to shorter clinical attachments in the senior clinical rotation, which combined with more centralised teaching have had adverse effects on both formal and informal teaching during attachments. Consultants' NHS contract changes the implementation of the European Working Time Directive and changes to postgraduate training have adversely affected consultants' teaching capacity, which has had a detrimental effect on their relationships with students. Medical culture has also changed as a result of these and other societal influences. CONCLUSIONS: The apprenticeship model was still felt to be relevant in clinical settings. This has to be balanced against the need for systematic teaching. Structural and institutional change affects learning. Faculty needs to be aware of the socio-historical context of their institutions.

Fetal methylmercury exposure as measured by cord blood mercury concentrations in a mother-infant cohort in Hong Kong.

This study was designed to examine newborn infants in Hong Kong prenatally exposed to levels of methylmercury considered to increase risk of neurotoxic effects and to examine subject characteristics that modify the degree of prenatal mercury exposure. Mercury concentrations in 1057 sets of maternal and cord blood samples and 96 randomly selected maternal hair samples were measured. Subject characteristics were measured or collected by questionnaire. Of the 1057 cord blood samples collected only 21.6% had mercury concentrations less than 29 nmol/L (5.8 micro g/L). Median maternal hair mercury concentration was 1.7 ppm. The geometric mean cord to maternal blood mercury ratio was 1.79 to 1. Increasing maternal fish consumption and maternal age were found to be associated with increased cord blood mercury concentrations. Marine fish consumption increased cord blood mercury concentrations more than freshwater fish (5.09%/kg vs 2.86%/kg). Female babies, maternal alcohol consumption and increasing maternal height were associated with decreased cord blood mercury concentrations. Pregnant women in Hong Kong consume large amounts of fish and as a result, most of their offspring have been prenatally exposed to moderately high levels of mercury. In this population, pregnant women should choose freshwater over marine fish and limit fish consumption.

Whose information is it anyway? Informing a 12-year-old patient of her terminal prognosis.

OBJECTIVE: To examine students' attitudes and potential behaviour towards informing a 12-year-old patient of her terminal prognosis in a situation in which her parents do not wish her to be told, as they pass through a modern medical curriculum. DESIGN: A cohort study of students entering Glasgow University's new medical curriculum in October 1996. METHODS: Students' responses obtained before year 1 and at the end of years 1, 3, and 5 to the "childhood leukaemia" vignette of the Ethics in Health Care Survey Instrument (EHCI) were examined quantitatively and qualitatively. Analysis of the students' multichoice answers enabled measurement of the movement towards professional consensus opinion. An analysis of their written justifications for their answers helped to determine whether their reasoning was consistent with professional consensus and enabled measurement of changes in knowledge content and recognition of the values inherent in the vignette. Themes on the students' reasoning behind their decision to tell the patient or not were also identified. RESULTS: Unlike other vignettes of the EHCI in which autonomy was a main theme, few students chose the consensus answer before year 1 and there was no significant movement towards consensus at any point during the course. In defence of their decision to withhold information, the students expressed strong paternalistic opinions. The patient's age was seen as a barrier to respecting her autonomy. CONCLUSIONS: It is important to identify students' perceptions on entry to medical school. Transformative learning theory may provide the basis for an approach to foster doctors who consider the rights of young people. Small-group teaching is most conducive to this approach. The importance of positive role modelling is also emphasised.

Sex and the surgery: students' attitudes and potential behaviour as they pass through a modern medical curriculum.

OBJECTIVE: To examine students' attitudes and potential behaviour to a possible intimate relationship with a patient as they pass through a modern medical curriculum. DESIGN: A cohort study of students entering Glasgow University's new learner centred, integrated medical curriculum in October 1996. METHODS: Students' pre year 1 and post year 1, post year 3, and post year 5 responses to the "attractive patient" vignette of the Ethics in Health Care Survey instrument were examined quantitatively and qualitatively. Analysis of students' multi-choice answers enabled measurement of the movement towards professional consensus opinion. Analysis of written justifications helped determine whether their reasoning was consistent with professional consensus and enabled measurement of change in knowledge content and recognition of the values inherent in the vignette. Themes on students' reasoning behind their decision to enter a relationship or not were also identified. RESULTS: No significant movement towards consensus was found at any point in the curriculum. There was little improvement in students' performance in terms of knowledge content and their abilities to recognise the values inherent in the vignette. In deciding to enter a relationship with the patient the most frequently used reasoning was that it could be justified if the patient changed their doctor. CONCLUSIONS: Teaching on the subject of sexual or improper relationships between doctors and patients, including relationships with former patients requires to be made explicit. Case based teaching would fit in with the ethos of the problem based, integrated medical curriculum.

Students' attitudes and potential behaviour to a competent patient's request for withdrawal of treatment as they pass through a modern medical curriculum.

OBJECTIVE: To examine students' attitudes and potential behaviour to a competent patient's request for withdrawal of treatment as they pass through a modern medical curriculum. DESIGN: Cohort design. SETTING: University of Glasgow Medical School, United Kingdom. SUBJECTS: A cohort of students entering Glasgow University's new learner centred, integrated medical curriculum in October 1996. METHODS: Students' responses before and after year 1, after year 3, and after year 5 to the assisted suicide vignette of the Ethics in Health Care Survey instrument, were examined quantitatively and qualitatively. Analysis of students' multichoice answers enabled measurement of the movement towards professional consensus opinion. Analysis of written justifications helped determine whether their reasoning was consistent with professional consensus and enabled measurement of change in knowledge content and recognition of the values inherent in the vignette. Themes on students' reasoning behind their decision to withdraw treatment or not were also identified. RESULTS: Students' answers were found to be consistent with professional consensus opinion precurriculum and remained so throughout the curriculum. There was an improvement in the knowledge content of the written responses following the first year of the curriculum, which was sustained postcurriculum. However, students were found to analyse the section mainly in terms of autonomy, with few responses considering the other main ethical principles or the wider ethical perspective. Students were unclear on their legal responsibilities. CONCLUSIONS: Students should be encouraged to consider all relevant ethical principles and the wider ethical perspective when deliberating ethical dilemmas. Students should have a clear understanding of their legal responsibilities.

Impact of a new course on students' potential behaviour on encountering ethical dilemmas.

OBJECTIVE: To evaluate the effectiveness of small-group ethics teaching in an integrated medical curriculum. DESIGN: A quasi-experimental, pre- and post-test, non-equivalent control group design. SETTING: University of Glasgow Medical School. SUBJECTS: 111 first-year students from Glasgow University's new learner-centred medical curriculum, with a control group of 51 students from the last year of the traditional curriculum. MAIN OUTCOME MEASURE: Student answers consistent with consensus professional judgement on the ethical dilemmas posed by the vignettes of the Ethics and Health Care Survey Instrument. RESULTS: There was a significantly greater increase in the number of post-test consensus answers in the experimental group (P=0.0048): the odds ratio for obtaining the post-test consensus answer in the experimental group compared with the control group was 1.73 (95% confidence interval 1.28-2.33). Significant movement towards consensus occurred in the areas of autonomy, confidentiality and consent. Among controls there was a significant move away from consensus in the area of "whistle blowing" on colleagues (P=0.017). CONCLUSION: Small-group ethics teaching, in an integrated medical curriculum, had a positive impact on the first-year students' potential ethical behaviour. It was more effective than a lecture and a large-group seminar-based course in developing students' normative identification with the profession of medicine.

Drug resistance in cancer: a perspective.

Drug resistance remains the thorniest obstacle in developing improved systemic therapies for disseminated cancer. The combination of genetic instability together with the great molecular heterogeneity that are displayed by malignant cells makes constructing effective, rational treatment programs difficult in the extreme. However, new insights into the action of antitumor agents at the molecular level plus greater understanding of the relationship of drug resistant states to the fundamental abnormalities that generate malignancy point the way to producing therapies that are more specific and therapeutically effective. However, a non-trival problem is the drug development system itself which is currently poorly set up to yield patient specific drug programs in a timely fashion.

Eradication of human non-Hodgkin's lymphoma in SCID mice by BCL-2 antisense oligonucleotides combined with low-dose cyclophosphamide.

Cancers overexpressing Bcl-2 protein, which prevents programmed cell death (apoptosis), are less sensitive to stresses that produce cellular damage, including chemotherapy. If the level of Bcl-2 protein can be reduced sufficiently using antisense oligonucleotides (ASOs) targeting the gene message, then cytotoxic agents may be rendered more effective in eliminating disease and increasing cure rate. Preclinical studies in SCID mice bearing Bcl-2 overexpressing systemic human B-cell lymphoma (DoHH2) were undertaken to support development of a clinical trial. These data confirm that a combination of an ASO (5 mg/kg) targeting bcl-2 and a low dose of cyclophosphamide (35 mg/kg) was an effective strategy, leading to the eradication of the DoHH2 cells in vivo and cure of the animals. When mice deficient in natural killer cell activity were treated with an ASO, similar results were observed, suggesting that ASO stimulation of the host immune system was not a significant factor in elimination of lymphoma cells. These studies indicate that therapeutic strategies involving the use of an ASO targeting bcl-2 in combination with a cytotoxic agent may improve clinical outcomes.

A process evaluation of medical ethics education in the first year of a new medical curriculum.

BACKGROUND: Despite the recent increase in activity in the field of medical ethics education, few evaluative studies have been carried out. Most studies have taken place in North America, in curricula where teaching is discipline-based, and have concentrated on outcome rather than on the curricular processes adopted. AIM: To evaluate the process of medical ethics education in the first year of a new learner-centred, problem-based, integrated medical curriculum. METHOD: A qualitative, multi-method approach was adopted using open questionnaires, focus groups and tutor evaluation rating scales. The study involved all 238 students in the first year of the new medical curriculum, and the 30 clinical tutors who facilitated ethics learning. A stratified sampling technique was used to choose focus group participants. RESULTS: Small group teaching proved highly acceptable to both students and tutors. Tutors' teaching skills were central to its effectiveness. Tutors played an important role in promoting students' appreciation of the relevance of medical ethics to clinical practice, and in establishing a climate where constructive criticism of colleagues' actions is acceptable. Course integration, including the provision for students of clinical experiences on which to reflect, was an important aid to learning. Students and tutors were noted to be driving the ethics curriculum towards having a contextual rather than theoretical base. CONCLUSION: This evaluation identified those aspects of the medical ethics course which contributed to its effectiveness and those which detracted from it. This information will be used to inform future development.

Review of ethics curricula in undergraduate medical education.

Medical ethics education, it has been said, has 'come of age' in recent years in terms of its formal inclusion in undergraduate medical curricula. This review article examines the background to its inclusion in undergraduate curricula and goes on to examine the consensus that has arisen on the design of ethics curricula, using Harden's curriculum and S.P.I.C.E.S models as templates. While there is consensus on content for undergraduate medical ethics education, there is still significant debate on learning and teaching methods. Despite the broad agreement on the need to apply adult education principles to ethics teaching, there would appear to be some tension between balancing the need for experiential learning and achieving the 'core curriculum'. There are also as yet unresolved difficulties with regards to resources for delivery, academic expertise, curriculum integration and consolidation of learning. Assessment methods also remain contentious. Although there is consensus that the ultimate goal of medical ethics, and indeed of medical education as a whole, is to create 'good doctors', the influence of the 'hidden curriculum' on students' development is only beginning to be recognized, and strategies to counteract its effects are in their infancy. The need for proper evaluation studies is recognized. It is suggested that the areas of debate appearing in the literature could be used as a starting point for evaluation studies, which would form the empirical basis of future curriculum development.

Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides.

Bcl-2 expression is upregulated in prostate cancer cells after androgen withdrawal and is associated with the development of androgen independence and chemoresistance. Induction of apoptotic cell death after androgen ablation, or chemotherapy, may be enhanced through functional inhibition of bcl-2. In this report, we tested the effects of antisense bcl-2 oligodeoxynucleotides (ODN) with androgen ablation and taxane therapy on time to androgen-independent (Al) progression in the androgen-dependent Shionogi tumor model. Treatment of Shionogi tumor cells in vitro with 500 nmol/L antisense bcl-2 ODN decreased bcl-2 mRNA by 85%, compared with treatment with 500 nmol/L mismatch control ODN. Although bcl-2 expression levels in Shionogi cells were not changed by docetaxel treatment, docetaxel treatment induced bcl-2 phosphorylation. Consequently, the formation of bcl-2/Bax heterodimer formation was inhibited in a dose-dependent manner. Treatment of Shionogi tumors in vitro with either 500 nmol/L antisense bcl-2 ODN or 10 nmol/L docetaxel alone did not induce apoptosis or reduce growth rates. However, combined treatment reduced the concentration that reduces cell viability by 50% (IC50) of docetaxel from 100 nmol/L to 10 nmol/L and induced characteristic apoptotic DNA laddering and cleavage of the poly(ADP-ribose)polymerase (PARP) protein. Adjuvant in vivo administration of antisense bcl-2 ODN and polymeric micellar paclitaxel after castration resulted in a significant delay in time to Al recurrence when compared with administration of either agent alone. Furthermore, combined treatment of mice bearing Al recurrent Shionogi tumors with antisense bcl-2 ODN and micellar paclitaxel synergistically induced tumor regression and growth inhibition when compared with treatment with either agent alone. These findings suggest that down-regulation of bcl-2 by antisense ODN chemosensitizes Al Shionogi tumors to taxanes, over and above the effects of taxane-induced phosphorylation of bcl-2. Antisense bcl-2 ODN combined with taxanes may be a novel approach to the treatment of both established and emerging Al disease.

Progression to androgen independence is delayed by adjuvant treatment with antisense Bcl-2 oligodeoxynucleotides after castration in the LNCaP prostate tumor model.

Bcl-2 has emerged as a critical regulator of apoptosis in a variety of cell systems and is up-regulated during progression to androgen independence in prostate cancer cells. The objectives of this study were to characterize changes in Bcl-2 after androgen withdrawal and during progression to androgen independence in the human prostate LNCaP tumor model and determine whether adjuvant use of antisense Bcl-2 oligodeoxynucleotides (ODNs) with androgen ablation delays progression to androgen independence. Bcl-2 expression in LNCaP cells is down-regulated to undetectable levels by androgen in vitro and up-regulated after castration in vivo. Antisense Bcl-2 ODN treatment reduced LNCaP cell Bcl-2 messenger RNA and protein levels by >90% in a sequence-specific and dose-dependent manner at concentrations >50 nM. Bcl-2 mRNA levels returned to pretreatment levels by 48 h after discontinuing treatment. Athymic male mice bearing SQ LNCaP tumors were castrated and injected i.p. with 12.5 mg/kg/day with two-base mismatch ODN control, reverse polarity ODN control, or antisense Bcl-2 ODN. Tumor volume in control mice gradually increased 5-fold (range, 3-6) by 12 weeks after castration compared to a 10-50% decrease in precastrate tumor volume in mice treated with antisense Bcl-2 ODN. Changes in serum PSA paralleled changes in tumor volume, increasing 4-fold faster above nadir in controls than in mice treated with antisense Bcl-2 ODN. After decreasing 70% by 1 week after castration, PSA increased 1.6-fold above precastrate levels by 11 weeks in controls while staying 30% below precastrate levels in antisense-treated mice. In a second group of experiments, LNCaP tumor growth and serum PSA levels were 90% lower (P<0.01) in mice treated with antisense Bcl-2 ODN compared with mismatch or reverse polarity ODN controls. These results support the hypothesis that Bcl-2 helps mediate progression to androgen independence and is an appropriate target for antisense therapy.

The use of conventional salvage chemotherapy before dose-intensive cytotoxic therapy and autologous transplantation for aggressive-histology lymphoma: a case for re-evaluation.

The use of CSCT to judge suitability for DIT and AHSCT in patients with aggressive-histology lymphoma who recur after primary chemotherapy is a widespread practice that excludes many NHL patients from this potentially curative therapy. Surprisingly, little direct evidence exists to suggest that CSCT used in this way is a useful strategy. On the other hand, it is clear that many of these patients undergoing DIT and AHSCT will not be cured using any currently available strategy or technique, and a method to identify such patients would be most helpful. CSCT may or may not be the best way to do so. This is an important question, but currently there are insufficient data to give us a definitive answer. Clinical trials are needed to resolve the issue. If the utility of CSCT is not validated, it should be abandoned. If it is validated, however, we may begin to address ways in which CSCT may be given more effectively.

Toxicity studies in thymidine kinase-deficient herpes simplex virus therapy for malignant astrocytoma.

Previous studies have shown that genetically engineered thymidine kinase (tk)-defective herpes simplex virus type 1 (HSV-1) can effectively and selectively destroy gliomas in animal models. The consequences of viral infection and tumor regression must be characterized before this therapy can be applied in human trials. To study the potential for long-term toxicity, immunocompetent rats harboring 9L gliosarcomas were injected intratumorally with a tk-defective HSV-1, KOS-SB, at titers that previously have been demonstrated to cause tumor regression. In animals surviving 3 months or longer following viral treatment, there was no evidence of persistent infection or inflammation in peritumoral brain tissue or in remote systemic organs studied with routine histological and immunocytochemical analyses. Polymerase chain reaction using primers specific for HSV-1 detected HSV-1 DNA in peritumoral tissue only in animals sacrificed within 3 months of viral injection. There was no evidence of HSV-1 DNA in systemic tissues at any time after treatment. We conclude that stereotactic intratumoral injection of tk-deficient HSV can be attempted for the treatment of brain tumors without risk of systemic infection or significant toxicity to normal brain or remote proliferating tissues.

Modulation of doxorubicin resistance in P388/ADR cells by Ro44-5912, a tiapamil derivative.

We describe here investigations into the ability of a tiapamil derivative, Ro44-5912 to overcome multidrug resistance (MDR) in doxorubicin (ADR)-resistant murine leukemic P388 cells. This compound has the formula: C27H39NO4S2.1:2C6H8O6, a M. W. of 858 and is structurally similar to verapamil, an established inhibitor of P-glycoprotein (PGP). We have compared the MDR modulating properties of Ro44-5912 with verapamil in P388ADR cells. Doxorubicin concentration required to achieve 50% inhibition of growth (IC50) for P388ADR cells was found to be 24 microM. In contrast, treatment of P388ADR cells with Doxorubicin and 3 microM verapamil decreased the IC50 value to 2.5 microM. A further decrease was observed with 3 microM Ro44-5912 treatment, where an IC50 value of 1.1 microM was obtained. Doxorubicin accumulation was also determined by flow cytometry in order to determine whether the increased levels of chemosensitivity observed for Ro44-5912 were reflected by increased cellular drug uptake. The results revealed that Ro44-5912, at equivalent concentration, increased doxorubicin accumulation in P388ADR cells beyond that obtained with verapamil whereas no effects were seen with the parental P388 cells. The effect of Ro44-5912 on the binding of C219 monoclonal antibody to PGP in MDR cells was also studied and found not to decrease C219 expression on P388ADR cells.

Selective destruction of gliomas in immunocompetent rats by thymidine kinase-defective herpes simplex virus type 1.

BACKGROUND: Thymidine kinase-deficient herpes simplex virus type 1 [tk(-) HSV-1] replicates well in dividing cells but not in nondividing cells such as neurons, suggesting a potential use in the treatment of brain tumors. PURPOSE: We attempted to examine the efficacy of using tk(-) HSV-1 for treating brain tumors in immunocompetent animals. METHODS: 9L glioma cells were cultured and subsequently implanted intracerebrally in immunocompetent, adult male Long-Evans rats. A thymidine kinase-defective HSV-1 virus, KOS-SB, was used to infect 9L cells in culture, and the viability of the infected cells was compared with that of mock-infected (i.e., uninfected) cells. We also injected the virus intratumorally and determined the mortality of the tumor-bearing animals. Tumor regression and viral spread following virus injection were examined by histologic and immunocytochemical assays. RESULTS: In vitro, the tk(-) virus destroyed cultured 9L cell monolayers at multiplicities of infection of 0.1 and 1.0 within 48 hours. With the same quantity of virus, no remarkable difference in survival of neural cells was found. Foscarnet, an antiviral drug that acts independently of tk activity, blocked viral replication by greater than 99% at a concentration of 100 micrograms/mL. The mortality of animals bearing tumors declined with an increase in the amount of virus injected. Histologic examination showed that the HSV-1 treatment caused severe tumor regression. Immunocytochemistry using an anti-HSV-1 antibody revealed only a weak staining within the regressing tumors, and few immunopositive neurons were evident in the surrounding brain tissue. CONCLUSIONS: The results indicate that tk(-) HSV-1 mutants can selectively and effectively destroy glioma cells both in vitro and in vivo in normal, immunocompetent animals. IMPLICATIONS: Our failure to detect viral spread associated with regressing tumors suggests that some other cytopathic factors might be involved in the tumor regression. Regardless of the precise mode of tumor cell killing, HSV-1 may be useful for treating brain tumors.

Modelling the process of drug resistance.

Modelling the process of drug resistance can provide insight into such issues as the difference between intrinsic and acquired drug resistance. Other important biological questions such as whether resistance arises through selective or inducible events can also be addressed by reference to appropriate models. If drug resistant cells are produced by some type of inducible up regulation step then this has a number of qualifications for cancer chemotherapy. Selection theories of drug resistance imply that certain sequences of drugs will be superior to others something which can be tested by experiment.