Do we really need cadavers anymore to learn anatomy in undergraduate medicine?

With the availability of numerous adjuncts or alternatives to learning anatomy other than cadavers (medical imaging, models, body painting, interactive media, virtual reality) and the costs of maintaining cadaver laboratories, it was considered timely to have a mature debate about the need for cadavers in the teaching of undergraduate medicine. This may be particularly pertinent given the exponential growth in medical knowledge in other disciplines, which gives them valid justification for time in already busy medical curricula. In this symposium, the pros and cons of cadaver use in modern medical curricula were debated and audience participation encouraged.

Relating professionalism and conscientiousness to develop an objective, scalar, proxy measure of professionalism in anaesthetic trainees.

BACKGROUND: The concept of professionalism is complex and subjective and relies on expert judgements. Currently, there are no existing objective measures of professionalism in anaesthesia. However, it is possible that at least some elements of professionalism may be indicated by objective measures. A number of studies have suggested that conscientiousness as a trait is a significant contributor to professionalism. METHODS: A 'Conscientiousness Index' (CI) was developed by collation of routinely collected data from tasks expected to be carried out by anaesthetic trainees such as punctual submission of holiday and 'not-on-call' requests, attendance at audit meetings, timely submission of completed appraisal documentation and sickness/absence notifications. The CI consists of a sum of points deducted from a baseline of 50 for non-completion of these objective and measurable behaviours related to conscientiousness. This was correlated with consultants' formal and informal subjective measures of professionalism in those trainees. Informal, subjective measures of professionalism consisted of a 'Professionalism Index' (PI). The PI consisted of a score developed from consultants' expert, subjective views of professionalism for those trainees. Formal, subjective measures of professionalism consisted of a score derived from comments made by consultants in College Tutor feedback forms on their views on the professionalism of those trainees (College Tutor feedback; CT). The PI and CT scores were correlated against the CI using a Pearson or Spearman correlation coefficient. RESULTS: There was a negative, but not statistically significant, relationship between the CI and formal, subjective measures of professionalism; CT scores (r = -0.341, p = 0.06), but no correlation between CI and consultants informal views of trainees' professionalism; the PI scores (r s = -0.059, p = 0.759). CONCLUSIONS: This may be due the 'failure to fail' phenomenon due to the high stakes nature of raising concerns of professionalism in postgraduate healthcare professionals or may be that the precision of the tool may be insufficient to distinguish between trainees who generally show highly professional behaviour. Future development of the tool may need to include more of the sub-facets of conscientiousness. Independently of a relationship with the construct of professionalism, a measure of conscientiousness might be of interest to future employers.

Rapid plant trait evolution can alter coastal wetland resilience to sea level rise.

Rapid evolution remains a largely unrecognized factor in models that forecast the fate of ecosystems under scenarios of global change. In this work, we quantified the roles of heritable variation in plant traits and of trait evolution in explaining variability in forecasts of the state of coastal wetland ecosystems. A common garden study of genotypes of the dominant sedge Schoenoplectus americanus, "resurrected" from time-stratified seed banks, revealed that heritable variation and evolution explained key ecosystem attributes such as the allocation and distribution of belowground biomass. Incorporating heritable trait variation and evolution into an ecosystem model altered predictions of carbon accumulation and soil surface accretion (a determinant of marsh resilience to sea level rise), demonstrating the importance of accounting for evolutionary processes when forecasting ecosystem dynamics.

Toxicity associated with capecitabine plus oxaliplatin in colorectal cancer before and after an institutional policy of capecitabine dose reduction.

BACKGROUND: Capecitabine plus oxaliplatin (CAPOX) is an established treatment option in colorectal cancer, but can be associated with severe toxicities. METHODS: Following reporting of severe diarrhoea and dehydration with capecitabine 2000 mg m(-2) per day plus oxaliplatin every 3 weeks (CAPOX 2000) in 2006, we instituted a policy change to reduce capecitabine dose to 1700 mg m(-2) per day (CAPOX 1700). We undertook a retrospective analysis comparing toxicities encountered before and after this dose change. RESULTS: Of the 400 patients treated, no significant differences were seen between the CAPOX 2000 and CAPOX 1700 in grades 3 and 4 diarrhoea (21% vs 19%; P=0.80), stomatitis (0% vs 1%; P=0.50) or grades 2-4 hand foot syndrome (16% vs 11%; P=0.18). Grades 3 and 4 neutropenia (9.5% vs 3.5%; P=0.03) and all grades hyperbilirubinaemia (60% vs 40%; P<0.0001) were significantly reduced with CAPOX 1700. Rates of hospitalisation due to toxicities were not different between two groups (13% vs 11%; P=0.53). CONCLUSIONS: No clinically or statistically significant differences in gastrointestinal toxicities or hospitalisation rate were seen after reducing our routine capecitabine dose from CAPOX 2000 to CAPOX 1700.

Mediators of inflammation and regeneration.

Characterization of the molecular response under caries lesions requires a robust and reliable transcript isolation system, and analysis of data indicated that collection of extracted teeth in either liquid nitrogen/RNA-stabilizing solution facilitated this. Subsequent transcriptional analysis indicated higher general activity in carious pulps, while characterization of inflammatory mediators, including cytokines and S100 proteins, highlighted increasing expression levels associated with both microbial front progression and elevated cellular immune response. Analysis of the pleiotropic hormone adrenomedullin (ADM) indicated that transcript and protein levels are increased in pulpal tissue during caries, and that protein levels sequestered in dentin due to primary dentinogenesis are comparable with those of TGF-ß1. Expression analysis of a leucine-rich-repeat-containing protein (LRRC15/Lib) indicated that this highly conserved molecule was up-regulated during caries, is transcriptionally regulated by pro-inflammatory stimuli, and is relatively abundant in mineralized tissues.

Cardio-selective and non-selective beta-blockers in chronic obstructive pulmonary disease: effects on bronchodilator response and exercise.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often have co-existing cardiovascular disease and may require beta-blocker treatment. There are limited data on the effects of beta-blockers on the response to inhaled beta2-agonists and exercise capacity in patients with COPD. OBJECTIVE: To determine the effects of different doses of cardio-selective and non-selective beta-blockers on the acute bronchodilator response to beta-agonists in COPD, and to assess their effects on exercise capacity. METHODS: A double-blind, randomized, three-way cross-over (metoprolol 95 mg, propranolol 80 mg, placebo) study with a final open-label high-dose arm (metoprolol 190 mg). After 1 week of each treatment, the bronchodilator response to salbutamol was measured after first inducing bronchoconstriction using methacholine. Exercise capacity was assessed using the incremental shuttle walk test. RESULTS: Eleven patients with moderate COPD were recruited. Treatments were well-tolerated although two did not participate in the high-dose metoprolol phase. The area under the salbutamol-response curve was lower after propranolol compared with placebo (P=0.0006). The area under the curve also tended to be lower after high-dose metoprolol (P=0.076). The per cent recovery of the methacholine-induced fall was also lower after high-dose metoprolol (P=0.0018). Low-dose metoprolol did not alter the bronchodilator response. Oxygen saturation at peak exercise was lower with all beta-blocker treatments (P=0.046). CONCLUSION: Non-selective beta-blockers and high doses of cardio-selective beta-blockers may inhibit the bronchodilator response to beta2-agonists in patients with COPD. Beta-blockers were also associated with lower oxygen saturation during exercise. The clinical significance of these adverse effects is uncertain in view of the benefits of beta-blocker treatment for cardiovascular disease.

Student attitudes to peer physical examination: a qualitative study of changes in expressed willingness to participate.

BACKGROUND: A number of studies have explored student attitudes to examining each other (peer physical examination: PPE). Differences have emerged in whether students prefer to be examined by friends or strangers. Changes have been reported in how students feel about PPE if asked before or after the PPE programme commences. RESEARCH INTENTION: Since a Grounded Theory paradigm was employed, there was no formal research hypothesis: the research intention was to explore factors which might underlie changes in student willingness to undertake PPE following familiarity with the process. METHODS: Students who had completed an Examining Fellow Students Questionnaire at the beginning and end of the academic year, and who had indicated a change in willingness to participate, were invited to attend focus groups. Four focus groups were convened and transcripts were analysed for common themes. RESULTS: Surprisingly, students downplayed the significance of changes. Also unexpectedly, dichotomous views emerged on familiarity, with some students preferring friends for examination and others preferring strangers. Staff embarrassment also emerged as a factor inhibiting student participation. CONCLUSIONS: The significance of reported changes in attitudes to PPE may have been exaggerated. Proposals for increasing the willingness of students to participate in PPE are developed from the emergent themes.

'10% of your medical students will cause 90% of your problems': a prospective correlational study.

OBJECTIVES: Our aim was to explore the relationship between medical student Conscientiousness Index scores and indicators of later clinical performance held in the UK Medical Education Database (UKMED). Objectives were to determine whether conscientiousness in first-year and second-year medical students predicts later performance in medical school and in early practice. Policy implications would permit targeted remediation where necessary or aid in selection. DESIGN: A prospective correlational study. SETTING: A single UK medical school and early years of practice, 2005-2018. PARTICIPANTS: The data were obtained from the UKMED on 858 students. Full outcome data was available for variable numbers of participants, as described in the text. MAIN OUTCOME MEASURES: Scores on the UK Foundation Programme Office's Situational Judgement Test (SJT) and Educational Performance Measure (EPM), the Prescribing Safety Assessment (PSA) and Annual Review of Competency Progression (ARCP) outcomes. RESULTS: Linear regression analysis shows Conscientiousness Index scores significantly correlate with pregraduate and postgraduate performance variables: SJT scores (R=0.373, R2=0.139, B=0.066, p<0.001, n=539); PSA scores (R=0.249, R2=0.062, B=0.343, p<0.001, n=462); EPM decile scores for the first (lowest) decile are significantly lower than the remaining 90% (p=0.003, n=539), as are PSA scores (p<0.001, n=463), and ARCP year 2 scores (p=0.019, n=517). The OR that students in the first decile fail to achieve the optimum ARCP outcome is 1.6126 (CI: 1.1400 to 2.2809, p=0.0069, n=618). CONCLUSIONS: Conscientiousness Index scores in years 1 and 2 of medical school have predictive value for later performance in knowledge, skills and clinical practice. This trait could be used either for selection or for targeted remediation to avoid potential problems in the future.

Reproductive tract lesions in male mice exposed prenatally to diethylstilbestrol.

Sixty percent of the male offspring from pregnant mice treated with diethylstilbestrol during gestation were sterile. The affected animals had gonadal changes which included intra-abdominal or fibrotic testes, or both. Additionally, nodular masses in the ampullary region of the reproductive tract were observed in 6 of 24 animals; one of these appeared to be preneoplastic.

Diethylstilbestrol induces neoplastic transformation without measurable gene mutation at two loci.

The frequency with which diethylstilbestrol induces neoplastic transformation and somatic mutation was measured concomitantly in Syrian hamster embryo cells. While diethylstilbestrol was as active as benzo[a]pyrene in inducing transformation, it failed to induce mutations at two conventionally studied loci. These results suggest that diethylstilbestrol may transform cells in the absence of gene mutations.

A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA.

The 21-nucleotide small temporal RNA (stRNA) let-7 regulates developmental timing in Caenorhabditis elegans and probably in other bilateral animals. We present in vivo and in vitro evidence that in Drosophila melanogaster a developmentally regulated precursor RNA is cleaved by an RNA interference-like mechanism to produce mature let-7 stRNA. Targeted destruction in cultured human cells of the messenger RNA encoding the enzyme Dicer, which acts in the RNA interference pathway, leads to accumulation of the let-7 precursor. Thus, the RNA interference and stRNA pathways intersect. Both pathways require the RNA-processing enzyme Dicer to produce the active small-RNA component that represses gene expression.

Synergistic activation of estrogen receptor with combinations of environmental chemicals.

Certain chemicals in the environment are estrogenic. The low potencies of these compounds, when studied singly, suggest that they may have little effect on biological systems. The estrogenic potencies of combinations of such chemicals were screened in a simple yeast estrogen system (YES) containing human estrogen receptor (hER). Combinations of two weak environmental estrogens, such as dieldrin, endosulfan, or toxaphene, were 1000 times as potent in hER-mediated transactivation as any chemical alone. Hydroxylated polychlorinated biphenyls shown previously to synergistically alter sexual development in turtles also synergized in the YES. The synergistic interaction of chemical mixtures with the estrogen receptor may have profound environmental implications. These results may represent a previously uncharacterized level of regulation of estrogen-associated responses.

Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals.

The term "endocrine disrupting chemicals" is commonly used to describe environmental agents that alter the endocrine system. Laboratories working in this emerging field-environmental endocrine research-have looked at chemicals that mimic or block endogenous vertebrate steroid hormones by interacting with the hormone's receptor. Environmental chemicals known to do this do so most often with receptors derived from the steroid/thyroid/retinoid gene family. They include ubiquitous and persistent organochlorines, as well as plasticizers, pharmaceuticals, and natural hormones. These chemicals function as estrogens, antiestrogens, and antiandrogens but have few, if any, structural similarities. Therefore, receptor-based or functional assays have the best chance of detecting putative biological activity of environmental chemicals. Three nuclear estrogen receptor forms-alpha, beta, and gamma-as well as multiple membrane forms and a possible mitochondrial form have been reported, suggesting a previously unknown diversity of signaling pathways available to estrogenic chemicals. Examples of environmental or ambient estrogenization occur in laboratory experiments, zoo animals, domestic animals, wildlife, and humans. Environmentally estrogenized phenotypes may differ depending upon the time of exposure-i.e., whether the exposure occurred at a developmental (organizational and irreversible) or postdevelopmental (activational and reversible) stage. The term "estrogen" must be defined in each case, since steroidal estrogens differ among themselves and from synthetic or plant-derived chemicals. An "estrogen-like function" seems to be an evolutionarily ancient signal that has been retained in a number of chemicals, some of which are vertebrate hormones. Signaling, required for symbiosis between plants and bacteria, may be viewed, therefore, as an early example of hormone cross-talk. Developmental feminization at the structural or functional level is an emerging theme in species exposed, during embryonic or fetal life, to estrogenic compounds. Human experience as well as studies in experimental animals with the potent estrogen diethylstilbestrol provide informative models. Advances in the molecular genetics of sex differentiation in vertebrates facilitate mechanistic understanding. Experiments addressing the concept of gene imprinting or induction of epigenetic memory by estrogen or other hormones suggest a link to persistent, heritable phenotypic changes seen after developmental estrogenization, independent of mutagenesis. Environmental endocrine science provides a new context in which to examine the informational content of ecosystem-wide communication networks. As common features come to light, this research may allow us to predict environmentally induced alterations in internal signaling systems of vertebrates and some invertebrates and eventually to explicate environmental contributions to human reproductive and developmental health.

Adjuvant selection regulates gut migration and phenotypic diversity of antigen-specific CD4+ T cells following parenteral immunization.

Infectious diarrheal diseases are the second leading cause of death in children under 5 years, making vaccines against these diseases a high priority. It is known that certain vaccine adjuvants, chiefly bacterial ADP-ribosylating enterotoxins, can induce mucosal antibodies when delivered parenterally. Based on this, we reasoned vaccine-specific mucosal cellular immunity could be induced via parenteral immunization with these adjuvants. Here, we show that, in contrast to the Toll-like receptor-9 agonist CpG, intradermal immunization with non-toxic double-mutant heat-labile toxin (dmLT) from enterotoxigenic Escherichia coli drove endogenous, antigen-specific CD4+ T cells to expand and upregulate the gut-homing integrin α4ß7. This was followed by T-cell migration into gut-draining lymph nodes and both small and large intestines. We also found that dmLT produces a balanced T-helper 1 and 17 (Th1 and Th17) response, whereas T cells from CpG immunized mice were predominantly Th1. Immunization with dmLT preferentially engaged CD103+ dendritic cells (DCs) compared with CpG, and mice deficient in CD103+ DCs were unable to fully license antigen-specific T-cell migration to the intestinal mucosae following parenteral immunization. This work has the potential to redirect the design of existing and next generation vaccines to elicit pathogen-specific immunity in the intestinal tract with non-mucosal immunization.

Audit of acute admissions of chronic obstructive pulmonary disease: inpatient management and outcome.

BACKGROUND: Despite the publication of several management guidelines for exacerbations of chronic obstructive pulmonary disease (COPD), there is little information on standards of care in clinical practice. The aim of this audit was to examine the assessment, management and outcome of COPD admissions to a secondary and tertiary referring New Zealand hospital during two different seasons. Compliance to current recommendations was examined and compared with the available international published work. METHODS: All COPD-related admissions to Waikato Hospital during the months of May and October 2004 were reviewed. Ninety-four cases (from 84 patients) were audited. RESULTS: General characteristics, clinical features and lung function tests were similar to that of other cohorts. Twenty-three per cent of the admissions were Maori and the mean age of Maori admissions were significantly less than that of the non-Maori admissions (57 and 72 years, respectively; P = 0.0001). The geometric mean length of stay was 3.4 days, which is significantly less than most other reported hospital lengths of stays related to exacerbations of COPD. Fifty-five per cent of the cohort was admitted more than once to the hospital for COPD in the 12 months before the index admission. Thirteen per cent of all admissions received assisted ventilation. Overall 30-day mortality was 8% and the 12-month mortality was 31%. Decreased body mass index was a risk factor for death as was an increased CURB-65 (confusion, urea, respiratory rate, blood pressure age) score--a simple bedside assessment score, which has previously been used to predict mortality in patients with community-acquired pneumonia. CONCLUSION: This audit documented the general characteristics, assessment, management and outcome of the COPD admissions to a secondary New Zealand hospital. Further investigations into factors contributing to shorter length of stay and predictors of mortality are needed.

The Impact of Systemic Therapy Beyond First-line Treatment for Advanced Cervical Cancer.

AIMS: Despite recent advances in the primary and secondary prevention of cervical cancer, a significant number of women present with or develop metastatic disease. There is currently no consensus on the standard of care for second-line systemic treatment of recurrent/metastatic cervical cancer. The purpose of this study was to evaluate the second-line systemic therapy used and the associated outcomes in a single cancer centre. MATERIALS AND METHODS: A retrospective review of patients with cervical cancer who received one or more lines of treatment for recurrent or metastatic cervical cancer at the Royal Marsden Hospital between 2004 and 2014 was carried out. The primary objective was to establish the types of second-line systemic treatment used. Secondary end points included objective response rate, progression-free survival and overall survival after second-line therapy. RESULTS: In total, 75 patients were included in the study; 53 patients (70.7%) received second-line therapy for recurrent/metastatic disease. The most common second-line therapy was weekly paclitaxel (28.3%). Carboplatin-based chemotherapy (24.5%), targeted agent monotherapy within clinical trials (22.6%), docetaxel-based chemotherapy (13.2%), topotecan (9.4%) and gemcitabine (1.9%) were also used. The objective response rate to second-line therapy was 13.2%, which included three partial responses to carboplatin and paclitaxel, two partial responses to docetaxel-based chemotherapy, one partial response to weekly paclitaxel and one partial response to cediranib. Twenty-two patients (41.5%) achieved stable disease at 4 months. The median progression-free survival for women treated with second-line therapy was 3.2 months (95% confidence interval 2.1-4.3) and median overall survival was 9.3 months (95% confidence interval 6.4-12.5). Thirty-nine per cent of patients received third-line therapy. CONCLUSION: Seventy per cent of patients treated with first-line systemic therapy for recurrent/metastatic cervical cancer subsequently received second-line treatment but response rates were poor. There remains no standard of care for second-line systemic therapy for advanced cervical cancer. Patients should be considered for clinical trials whenever feasible, including novel targeted agents and immunotherapy.

Studies of the multifaceted mast cell response to bacteria.

The concept of mast cells as playing a critical and multifaceted role in immune defense against pathogens is new, and effective ways to study and validate this notion are required. Recently, a number of approaches have been described that can be used to study the molecular aspects of mast cell recognition of pathogens, and of specific mast cell responses, such as mediator release, bacterial endocytosis and mast cell migration, to pathogens.

Vaginal adenosis and adenocarcinoma in mice exposed prenatally or neonatally to diethylstilbestrol.

The association of intrauterine exposure to diethylstilbestrol (DES) and the subsequent development of reproductive tract abnormalities in young women has been well documented. Although the incidence of vaginal adenocarcinoma was low in the exposed population, vaginal adenosis, a nonmalignant abnormality, was quite common. In order to study the pathogenesis of adenocarcinoma and to determine the frequency of adenosis following prenatal exposure to DES, timed pregnant CD-1 mice were treated s.c. with DES (dose range, 5 to 100 micrograms/kg/day) on Days 9 though 16 of gestation. This period corresponds to major organogenesis of the reproductive tract in the mouse. Female offspring were sacrificed between 1 and 18 months of age. In addition to nonmalignant abnormalities, some of which have been described in women exposed prenatally to DES, two cases of vaginal adenocarcinoma (2%) were observed in 91 prenatally DES-treated animals. No comparable epithelial lesions were seen in 158 control female mice. One other case of adenocarcinoma of the vagina was reported previously by this laboratory using the prenatally exposed animal model. In another series of mice treated prenatally with DES, 100 micrograms/kg/day, 3 of 20 (15%) 1-month-old animals and one of 10 (10%) 18-month-old treated offspring had glandular epithelium abnormally located in the vaginal fornices (adenosis). Other cervicovaginal abnormalities observed after prenatal DES exposure included structural alterations, cervical enlargement, squamous metaplasia in the endocervical canal, excess keratinization of the ectocervix and vagina, transverse folds and basal cell hyperplasia in the upper vagina, and prominent Wolffian duct remnants. Thus, vaginal adenosis in the mouse does not appear to be a common abnormality following treatment with DES in utero. Neonatal exposure to DES on Days 1 to 5, on the other hand, resulted in six of eight (75%) animals with adenosis at 35 days of age. Since perinatal mouse studies have reported high incidences of vaginal adenosis, but, to our knowledge, no cases of vaginal adenocarcinoma, the results presented in this report suggest that the stage of cellular differentiation at the time of DES exposure may be critical in the final expression of these abnormalities.

Oxidative metabolism of diethylstilbestrol by prostaglandin synthetase.

The cooxidative metabolism of the transplacental carcinogen, diethylstilbestrol (DES), was examined using ram seminal vesicle microsomes. The major extractable metabolite was beta-dienestrol (Z,Z-DIES) and represented about 35% of the added DES in 3-min incubations supplemented with arachidonic acid. Its formation was dependent upon the presence of arachidonic acid, whereas reduced nicotinamide adenine dinucleotide phosphate failed to elicit Z,Z-DIES above background. Indomethacin and 1-phenyl-3-pyrazolidone, known inhibitors of prostaglandin synthetase, blocked Z,Z-DIES formation, probably by inhibiting the cyclooxygenase and the hydroperoxidase activities, respectively. Hydrogen peroxide and 15-hydroperoxyarachidonic acid (cosubstrates of the prostaglandin synthetase-hydroperoxidase), when replacing arachidonic acid in incubations, also supported oxidative metabolism of DES catalyzed by ram seminal vesicle microsomes. 1-Phenyl-3-pyrazolidone, but not indomethacin, inhibited the 15-hydroxyperoxyarachidonic acid-dependent formation of Z,Z-DIES. Incubation conditions which supported efficient Z,Z-DIES formation also resulted in the formation of 3,3-di(p-hydroxyphenyl)hexan-4-one and the cis-isomer of DES as well as nonextractable, protein-associated radioactivity indicating the presence of reactive intermediates. The implications of the peroxidative metabolism of DES for its toxic activity are obvious.

Visualization by light and scanning electron microscopy of reproductive tract lesions in female mice treated transplacentally with diethylstilbestrol.

Pregnant female mice were exposed to diethylstilbestrol or 11 beta-methoxy-17 beta-estradiol on Days 9 to 16 of gestation. The female offspring of these animals were then examined for reproductive tract abnormalities. Scanning electron microscopic and histological evaluation of these specimens demonstrated reproductive tract lesions in all treatment groups when compared to matched control mice. These lesions included apparent displacement of the squamocolumnar junction, uterine squamous metaplasia, atypical uterine cell surface specializations, protrusions of uterine cells, vaginal and cervical papillary growths, enlarged uterine cervix, abnormal vaginal and uterine folding patterns, female hypospadias, and the presence of vaginal concretions. Scanning electron microscopic observations proved particularly useful in studying lesions which involved the disruption of the normal structure and shape of the reproductive tract and the displacement of cell types.