M. J. Pippard

In vivo studies on the relationship between intestinal iron (Fe3+) absorption, hypoxia and erythropoiesis in the mouse

Summary The effect of hypoxia and changes in erythropoiesis on the absorption of 59Fe3+ from in situ tied‐off duodenal segments was studied in the mouse. Hypoxia led to an increase in mucosal uptake within 6 h, whilst mucosal transfer was unaffected for about 20 h, suggesting independent regulation of these two processes. Hypoxia (3 d) stimulated erythropoiesis and resulted in a 2–3‐fold increase in the total mucosal uptake of 59Fe. Conversely, hyperoxia (100% O2) caused a decrease in reticulocyte counts and the total mucosal uptake. The changes in the transfer of 59Fe from the mucosa to the body were more marked than changes in uptake in both hypoxia and hyperoxia.

Integration of e-learning resources into a medical school curriculum

Background: E-learning has the potential to make important contributions to medical education, but there has been limited study of a blended approach in which the digital resources are introduced alongside traditional teaching methods such as lectures. Methods: We describe the successful embedding of an e-learning resource into 3 of the 5 weeks of cardiovascular system teaching for 164 first-year medical students by providing scheduled slots in the timetables. A questionnaire completed by the students at the end of the 5 weeks had a response rate of 66%. Students varied in how they made use of the resource, some systematically working through it and others browsing and studying sections felt to be personally most relevant. Results: Almost all (96%) rated the e-learning resources as probably or definitely of value: they particularly valued interactive activities, animations, video demonstrations, video clips of experts and self-assessment exercises. Graduate students had a significantly more favourable assessment of the e-learning resources than their undergraduate colleagues, while female students felt the value in supporting existing learning opportunities more strongly than male students. Conclusions: It should not be assumed that all students will choose to use an e-learning resource in the same way and instructional design should enable alternative approaches. The sequence in which the e-learning resource is used in relation to the other learning opportunities, such as lectures and PBL group discussions, may be important and merits further consideration. The experiences reported in this study provide encouragement and pointers for others engaged in the integration of e-learning in their curriculum.

Relationship between erythropoiesis and the enhanced intestinal uptake of ferric iron in hypoxia in the mouse

Summary. An in vitro technique was used to determine the unidirectional Fe3+ uptake rates in mouse duodenal fragments. In animals in which erythropoiesis had been stimulated by hypoxia, Fe3+ uptake by the duodenal fragments was enhanced due to an increase in Vappmax However, when erythropoiesis was increased by injections of erythropoietin, intestinal Fe3+ uptake rates were unaffected. Mice subjected to sub‐total nephrectomy showed an increased Vappmax for Fe3+ after exposure to hypoxia, despite the absence of an erythropoietic response. When the bone marrow was obliterated by treatment with 89Sr, a small increase in Vappmax for Fe3+ was found: permeability studies and morpho‐metric analyses demonstrated no apparent irradiation damage to the duodenal mucosa of these animals. Exposure of 89Sr‐treated mice to hypoxia caused a further significant increase in Vappmax. These results indicate that the increase in intestinal mucosal iron uptake which follows hypoxia is not mediated by erythropoietin or other factors associated with increased erythropoiesis.

Haemochromatosis mutations in North‐East Scotland

The HFE gene and its mutations C282Y and H63D cause hereditary haemochromatosis (HH). Among 54 affected individuals from North‐East Scotland, 91% were homozygous for C282Y and 5.5% were compound heterozygotes for C282Y and H63D. The general population allele frequencies were high (8% and 15.7% for C282Y and H63D respectively). Although it is likely that HH is under diagnosed, these figures suggest that disease expression is variable, and many of those with the genetic predisposition HH will never develop the clinical consequences of iron overload. This has implications for diagnosis and predictive testing.

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.

Regulation of iron absorption in iron loaded subjects with end stage renal disease : effects of treatment with recombinant human erythropoietin and reduction of iron stores

Summary. The effects on iron absorption of variation in erythroid activity, haemoglobin and iron stores were studied in six anaemic dialysis‐dependent subjects in whom iron stores were increased from previous red cell transfusions. Gastrointestinal mucosal uptake and whole body retention of oral iron were measured at the beginning of the study, after starting treatment with recombinant erythropoietin (but before significant increase in haemoglobin), after partial correction of anaemia, after further reduction of iron stores by repeated phlebotomy, and when erythropoiesis decreased from the discontinuation of treatment with erythropoietin. Between successive measurements, valid comparisons were made in five subjects.

Deferiprone for thalassaemia

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Comparison of opinions and profiles of late or non-responding medical students with initial responders to a course evaluation questionnaire

This study examined whether students requiring prompting to evaluate an educational module differed from initial responders in their rating of the experience and their profile (academic ability, age and gender). At the end of a 4th year induction Module, medical students completed an evaluation questionnaire. Those who did not respond were followed-up. Fifty-nine percent responded immediately, 34% after first or second prompts (late responders) and 7% were non-responders. Late responders rated the module significantly lower than initial responders. Late and non-responders were academically weaker than initial responders, but were similar in age and gender. Academically weaker students in the non- or late responders groups, may be less willing to reflect on their experience, and may require new strategies to encourage a response.

Design, implementation and evaluation of a medical education programme using the ambulatory diagnostic and treatment centre

Background: In the UK a central government initiative is seeking to transfer aspects of specialist NHS care to community settings using ambulatory diagnostic and treatment centres (ADTCs). Aims: Following the redevelopment of a district general hospital as an ADTC, we were interested in the feasibility of using this new facility to deliver a structured programme for undergraduate medical students. Method: Twenty self-selected fifth year medical students at the University of Dundee, together with teaching and administration staff in the ADTC, took part in the study during the academic year 2005–2006. Results: One hundred percent of students and 73% of staff responded to a questionnaire pitched at the level of reaction to the course. The key findings were that the students found the teaching venues useful, the general environment conducive to learning, and the content appropriate to their needs. Staff felt that patients were not unhappy or disturbed by having students present and did not think the presence of students inhibited their clinical work. They appreciated the new opportunity to teach. Conclusions: An ADTC is a viable setting for structured teaching of undergraduate medical students. It provides a context for medical student leaning away from the main teaching hospital.

Microcytic anaemias in childhood and iron‐refractory iron deficiency anaemia

In this issue, Bhatia et al (2017) report a study from India in which iron deficiency anaemia was found to be resistant to oral iron therapy in over 10% of 550 young children: those resistant were subsequently investigated for the phenotype of iron refractory iron deficiency anaemia (IRIDA) and, where this was present, whether TMPRSS6 gene variations might explain this finding. Their work draws attention to the approach to the diagnosis of microcytic anaemias, and how new understanding of the molecular pathways involved in systemic and cellular iron metabolism (comprehensively reviewed by Hentze et al, 2010) may change this. Microcytic anaemias accompany reduced haemoglobin production in developing red cells. This in turn results from failure of either haem synthesis (most commonly from lack of availability of iron but rarely from failure of protoporphyrin synthesis or of iron incorporation into the porphyrin ring in sideroblastic anaemias), or of globin synthesis in the thalassaemia disorders. Many young children have minimal or no iron stores as assessed by low serum ferritin concentrations and are at particular risk of developing iron deficiency anaemia, by far the commonest cause of childhood anaemia: in the UK National Diet and Nutrition Surveys, up to a third of children aged 1 5–4 5 years had serum ferritin values below the World Health Organization cut off values (Scientific Advisory Committee on Nutrition, 2010). Iron deficiency in such children is usually the result of a combination of the increased iron requirements of growth and limited availability of iron in the diet, particularly if the latter is predominantly vegetarian, though chronic blood loss (e.g. from intestinal hookworm infestation) and exposure to cow’s milk may be important in many parts of the world. Chronic disease may also give rise to microcytic red cells as a result of iron malutilisation rather than any reduction in total body iron and may impair the response to iron therapy. Contributions from multiple causes in a single patient may sometimes cause diagnostic difficulty, and interpretations of individual laboratory measures of iron status need to consider whether they are appropriate to the overall clinical context. For example, a ‘normal’ plasma ferritin in the presence of anaemia may be inappropriate in the sense that, together, the measures imply an overall reduction of total body iron, as may a ‘normal’ plasma hepcidin in the presence of iron deficiency (Girelli et al, 2016). In most cases iron deficiency anaemia responds rapidly to oral iron, but less common alternative diagnoses must be considered, especially if there is an inadequate response. Such refractoriness may result from failure of absorption: mucosal damage in coeliac disease has long been recognised as a potential cause for this, and more recently has been joined by Helicobacter pylori infection, at least in adults, where it is most probably the result of reduction in the gastric acid secretion needed to solubilise dietary iron (Hershko & Camaschella, 2014). However, rarer inherited defects may lead to impaired iron availability or utilisation and inappropriately low amounts of iron absorption (Donker et al, 2014). Foremost among inherited defects leading to impaired iron absorption are those resulting in loss of function of the TMPRSS6 gene and of the ferroportin gene, SLC40A1, though the latter leads to macrophage iron retention and loading rather than a microcytic anaemia. TMPRSS6 codes for the serine protease, matriptase-2 (also termed transmembrane protease, serine 6, TMPRSS6), which inhibits the transcription of hepcidin within hepatocytes. Hepcidin is the major systemic regulator of internal iron exchange, downregulating iron release via the membrane transporter, ferroportin, from cells (enterocytes, macrophages and hepatocytes) that donate iron to circulating transferrin and thus make it available for incorporation into haemoglobin by developing erythroblasts (Hentze et al, 2010). Matriptase-2 modulates hepcidin synthesis by interrupting the main iron-responsive signal transduction pathway. It cleaves the membrane protein haemojuvelin (HJV), one of several coreceptors, including transferrin receptor 2 (TFR2) and haemochromatosis (HFE) protein, for the bone morphogenetic protein (BMP) receptor. The BMP receptor complex initiates signal transduction after interaction with BMPs, particularly BMP6: the production of BMP6 is regulated at mRNA level by iron (Meynard et al, 2009) and is therefore related to intracellular iron levels, particularly in liver nonparenchymal cells (Rausa et al, 2015). Diferric (iron Correspondence: Professor Martin J. Pippard, University of Dundee School of Medicine, Ninewells Hospital, Dundee DD1 9SY, UK. E-mail: m.j.pippard@dundee.ac.uk editorial comment