Allan Cumming

Endothelin-A Receptor Antagonism Reduces Blood Pressure and Increases Renal Blood Flow in Hypertensive Patients With Chronic Renal Failure A Comparison of Selective and Combined Endothelin Receptor Blockade

Background—Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade. Methods and Results—We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls −4±2%, CRF −13±2%, P <0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8±23.9%, P <0.01 versus placebo) and reduced renal vascular resistance (−44.5±11.3%, P <0.01 versus placebo) when given alone but not when combined with BQ-788. These changes were accompanied by a reduction in effective filtration fraction. BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls, and BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls. Conclusions—ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension. In addition, there were effects consistent with a renoprotective action. However, because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits.

The Tuning Project for Medicine – learning outcomes for undergraduate medical education in Europe

The Tuning Project is an initiative funded by the European Commission to develop learning outcomes/competences for degree programmes in Europe and to promote harmonisation in the Higher Education sector. It is closely linked to the Bologna Declaration and subsequent developments. Under the auspices of the MEDINE Thematic Network for Medical Education in Europe, the Tuning (Medicine) Task Force has generated a draft set of learning outcomes for primary medical degree qualifications in Europe. These take account of previous work on learning outcomes in medicine, have been generated through an iterative process of expert review and development, and have been the subject of a Europe-wide internet-based opinion survey and subsequent analysis. They have been approved by the MEDINE Network and validated (subject to some additional analysis) by an Expert Panel of the European Commission.

Endothelin A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Are Synergistic via an Endothelin B Receptor–Mediated and Nitric Oxide–Dependent Mechanism

Animal studies suggest that endothelin A (ETA) receptor antagonism and angiotensin-converting enzyme (ACE) inhibition may be synergistic. This interaction and the role of ETB receptors and endothelial mediators were investigated in terms of systemic and renal effects in humans in two studies. In one study, six subjects received placebo, the ETA receptor antagonist BQ-123 alone, and BQ-123 in combination with the ETB receptor antagonist BQ-788 after pretreatment with the ACE inhibitor enalapril (E) or placebo. In the other, six subjects who were pretreated with E received placebo, BQ-123, and BQ-123 with concomitant inhibition of nitric oxide (NO) synthase or cyclo-oxygenase (COX). Both were randomized, double-blind, crossover studies. Mean arterial pressure was reduced by BQ-123, an effect that was doubled during ACE inhibition (mean area under curve +/- SEM; BQ-123, -2.3 +/- 1.8%; BQ-123+E, -5.1 +/- 1.1%; P < 0.05 versus placebo). BQ-123 increased effective renal blood flow (BQ-123, -0.1 +/- 2.4%; BQ-123+E, 10.9 +/- 4.2%; P < 0.01 versus BQ-123), reduced effective renal vascular resistance (BQ-123, -1.2 +/- 3.1%; BQ-123+E, -12.8 +/- 3.0%; P < 0.01 versus placebo and versus BQ-123), and increased urinary sodium excretion markedly (BQ-123, 2.6 +/- 12.8%; BQ-123+E, 25.2 +/- 12.6%; P < 0.05 versus BQ-123, P < 0.01 versus placebo and versus E) only during ACE inhibition. These effects were abolished by both ETB receptor blockade and NO synthase inhibition, whereas COX inhibition had no effect. In conclusion, the combination of ETA receptor antagonism and ACE inhibition is synergistic via an ETB receptor-mediated, NO-dependent, COX-independent mechanism. The reduction of BP and renal vascular resistance and associated substantial natriuresis make this a potentially attractive therapeutic combination in renal disease.

Cross-referencing the Scottish Doctor and Tomorrow's Doctors learning outcome frameworks

Learning outcomes, organised into systems or frameworks which describe and define the output of an educational programme, are being created and used in healthcare education with increasing frequency (Harden , 2002). Medical schools may be required to conform to more than one such outcome framework. For example, both the UK General Medical Council (GMC) and the Scottish Deans’ Medical Curriculum Group (SDMCG) have created and published a systematic learning outcome framework for medical graduates. Although both of these publications are concerned with undergraduate medical education, they differ in their aims, and structure. In order to use, evaluate and validate them, a cross-referencing system which relates each learning outcome statement, term or groups of terms is required.  This paper describes the cross-referencing exercise undertaken by the SDMCG, the philosophy behind it, the practical steps taken, the findings, the lessons learnt and reflections upon how this work may be taken forward. It will be of interest to all those who are involved in curriculum development using outcomes, and especially those who use the GMCs Tomorrows Doctors or the SDMCGs Scottish Doctor frameworks and those who are interested in education informatics in general.

Performance-based assessment in undergraduate medical education

P ostgraduate medical education in the UK is currently undergoing major reform – Modernising Medical Careers (MMC). At the heart of these changes is the adoption of an assessment strategy that aims to make an accurate measure of a doctor’s performance in his or her workplace. There has been a dramatic move recently towards competency-based assessment in undergraduate medical education, stimulated initially by the innovative work on objective structured clinical examinations (OSCEs) by Harden et al., and the publication of Tomorrow’s Doctors in 1993. Competencies have been assessed through clinically relevant tasks, though these were often simulated and on occasion distant from the workplace. The limitations of this practice have led us to explore the concept of performance based assessment (PBA). There has been a dramatic move recently towards competencybased assessment Practical assessment

The Bologna process, medical education and integrated learning

The Bologna Declaration, signed in 1999 by all European Ministers of Education and currently in a phase of active implementation in Europe, specifies a three-cycle degree structure – Bachelors, Masters, Doctorate – for all disciplines in Higher Education. The application of this model to medical education has been opposed on various grounds. In particular, a ‘Ba/Ma’ model for undergraduate medical degrees has been viewed as undoing recent progress towards fully integrated learning of basic and clinical medical sciences. However, this can be overcome by the use of a learning outcomes framework, agreed at European level, that reinforces the primarily medical nature of both degrees and which requires integrated teaching, learning and assessment at every stage. With this proviso, application of the Bologna principles to medicine can help to drive educational development and quality enhancement in European medical education.

The Objective Structured Clinical Examination and student collusion: marks do not tell the whole truth

Objective: To determine whether the marks in the third year Objective Structured Clinical Examination (OSCE) were affected by the collusion reported by the students themselves on an electronic discussion board. Design: A review of the student discussion, examiners’ feedback and a comparison of the marks obtained on the 2 days of the OSCE. Participants: 255 third year medical students. Setting: An OSCE consisting of 15 stations, administered on three sites over 2 days at a UK medical school. Results: 40 students contributed to the discussion on the electronic discussion board. The main points raised were perceived inequity between students who did, or did not, have prior knowledge of the station content, and the lack of honesty and professionalism of their peers. Most contributors claimed to have received, or knew of others receiving, prior knowledge, but none confessed to passing on information. No significant difference (p = 0.16) was observed in the overall mark for the OSCE on day 1 (mean 390 (SD 37)) and day 2 (mean 397 (38)). On day 2, marks were considerably greater for four stations and markedly lower for three stations. It was not obvious why collusion should affect these station marks. A clear indication of the effects of collusion could only be obtained from a single subsection of an individual station (pathology) where 82 students on day 2 incorrectly gave the diagnosis from day 1. Conclusion: Marks do not provide a sound inference of student collusion in an OSCE and may mask the aspects of professional development of students.

The Kallikrein-Kinin and Renin-Angiotensin Systems in Nephrotic Syndrome

We previously found that virtually all patients with nephrotic syndrome (NS) excrete supranormal amounts of urinary kallikrein; it is known that activity of the renin-angiotensin system (RAS) is increased in some such patients. We therefore studied the relationship between urinary kallikrein excretion (UKa) and plasma renin activity (PRA) in 16 patients with NS. Compared with healthy controls, PRA was normal in 8 subjects and elevated in 8; UKa was elevated in the high-renin group (40.4 +/- 5.2 nkat/24 h, normals 12.0 +/- 1.1). UKa was also elevated in the normal renin group (25.7 +/- 2.4 nkat/24 h) but to a significantly lesser degree. Significant activity in plasma against a specific substrate of glandular and renal kallikreins was observed in 8 of 10 patients with NS. Such activity was not found in plasma of 17 patients with glomerulonephritis without NS, or in 10 healthy controls. The results are in keeping with previous suggestions of a functional link between the renal kallikrein-kinin system (KKS) and the RAS, but indicate that the renal KKS is activated in NS, in some cases independently of the RAS. It is possible that renal kallikrein reaches the systemic circulation in some patients with NS.

Report of the MEDINE2 Bachelor of Medicine (Bologna First Cycle) Tuning Project

Abstract Background: European Higher Education institutions are expected to adopt a three-cycle system of Bachelor, Master and Doctor degrees as part of the Bologna Process. Tuning methodology was previously used by the MEDINE Thematic Network to gain consensus on core learning outcomes (LO) for primary medical degrees (Master of Medicine) across Europe. Aims: The current study, undertaken by the MEDINE2 Thematic Network, sought to explore stakeholder opinions on core LO for Bachelor of Medicine degrees. Method: Key stakeholders were invited to indicate, on a Likert scale, to what extent they thought students should have achieved each of the Master of Medicine LO upon successful completion of the first three years of university education in medicine (Bachelor of Medicine). Results: There were 560 responses to the online survey, representing medical students, academics, graduates, employers, patients, and virtually all EU countries. There was broad consensus between respondents that all LO previously defined for primary medical degrees should be achieved to some extent by the end of the first three years. Conclusions: The findings promote integration of undergraduate medical curricula, and also offer a common framework and terminology for discussing what a European Bachelor of Medicine graduate can and cannot do, promoting mobility, graduate employability and patient safety.

Renal alterations in the septic patient

Considering the fact that sepsis, in varying guises, accounts wholly or in part, for more than 50% of cases of acute renal failure 11, 2], surprisingly little is known about the pathogenesis of this type of renal dysfunction. Many different experimental models have been studied in an attempt to understand the mechanisms involved. However, some of these experimental manoeuvres are of doubtful relevance to clinical practice, and do not reproduce the typical features of sepsis in patients. For example, although it seems clear that bacterial endotoxin, by activating a cascade of mediator systems, is focal to development of clinical sepsis, infusion of endotoxin alone into the isolated perfused kidney has no consistent effect on renal function or structure [3, 4]. This emphasises the extent to which secondary events, triggered by sepsis, are critical to the development of organ dysfunction. Understanding these mechanisms is crucial to the effective diagnosis and treatment of this type of acute renal failure [5, 6]. Many of the observations made in experimental models have still to be tested in clinical studies, and this remains a challenging area in terms of current management and future research.