Clinical Research in Britain 1950-1980

Edited transcript of a Witness Seminar held at the Wellcome Institute for the History of Medicine, London, on 9 June 1998. First published by the Wellcome Trust, 2000. ©The Trustee of the Wellcome Trust, London, 2000. All volumes are freely available online at www.history.qmul.ac.uk/research/modbiomed/wellcome_witnesses/Annotated and edited transcript of a Witness Seminar held on 9 June 1998. Introduction by Dr David Gordon.Annotated and edited transcript of a Witness Seminar held on 9 June 1998. Introduction by Dr David Gordon.Annotated and edited transcript of a Witness Seminar held on 9 June 1998. Introduction by Dr David Gordon.Annotated and edited transcript of a Witness Seminar held on 9 June 1998. Introduction by Dr David Gordon.What is clinical research? The growth of clinical research in the UK since the Second World War is examined, including the 1953 Cohen Report and the subsequent creation of the Medical Research Council’s Clinical Research Board. Lord Walton of Detchant, as Chairman, guided the discussion on the inter-relationships between the MRC, the NHS, the Royal Colleges, other professional bodies and other funding organizations. Among other issues were the changes imposed by Government policy over the period, the influence of the early clinical research fellowships, growth of clinical career structures, planning of the Clinical Research Centre at Northwick Park, the tropical research units, and the effects of the Rothschild and Dainton reports on funding for clinical research and the role of the Chief Scientist. Participants include: Sir Douglas Black, Sir John Gray, Sir Raymond Hoffenberg, Dr Sheila Howarth, Professor Peter Lachmann, Sir Patrick Nairne, Professor Sir Stanley Peart and Dr Peter Williams. Reynolds L A, Tansey E M. (eds) (2000) Clinical research in Britain, 1950–1980, Wellcome Witnesses to Twentieth Century Medicine, vol. 7. London: The Wellcome Trust.The Wellcome Trust is a registered charity, no. 210183

Clinical research in Britain 1950–1980

What is clinical research? The growth of clinical research in the UK since the Second World War is examined, including the 1953 Cohen Report and the subsequent creation of the Medical Research Council’s Clinical Research Board. Lord Walton of Detchant, as Chairman, guided the discussion on the inter-relationships between the MRC, the NHS, the Royal Colleges, other professional bodies and other funding organizations. Among other issues were the changes imposed by Government policy over the period, the influence of the early clinical research fellowships, growth of clinical career structures, planning of the Clinical Research Centre at Northwick Park, the tropical research units, and the effects of the Rothschild and Dainton reports on funding for clinical research and the role of the Chief Scientist. Participants include: Sir Douglas Black, Sir John Gray, Sir Raymond Hoffenberg, Dr Sheila Howarth, Professor Peter Lachmann, Sir Patrick Nairne, Professor Sir Stanley Peart and Dr Peter Williams. Introduction by Dr David Gordon, vi, 74pp, 2 tables, subject and name index

Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy

Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC.Methods and Results - We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC.Conclusions - In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC

Clinical Genetics in Britain: Origins and development

Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.First published by the Wellcome Trust Centre for the History of Medicine at UCL, 2010.©The Trustee of the Wellcome Trust, London, 2010.All volumes are freely available online at: www.history.qmul.ac.uk/research/modbiomed/wellcome_witnesses/Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Clinical genetics has become a major medical specialty in Britain since its beginnings with Lionel Penrose’s work on mental handicap and phenylketonuria (PKU) and John Fraser Robert’s first genetic clinic in 1946. Subsequent advances in diagnosis and prediction have had key impacts on families with inherited disorders and prospective parents concerned about their unborn children. The Witness Seminar focused on the beginnings of British clinical genetics in London, Oxford, Liverpool and Manchester, the development of subspecialties, such as dysmorphology, and also the roles of the Royal College of Physicians, the Clinical Genetics Society and the Department of Health in the establishment of clinical genetics as a specialty in 1980. Specialist non-medical genetic counsellors, initially from the fields of nursing and social work, progressively became a more significant part of genetic services, while lay societies also developed an important influence on services. Prenatal diagnosis became possible with the introduction of new genetic tools in regional centres to identify fetal anomalies and chromosomal disorders. This volume complements the 2001 Witness Seminar on genetic testing which emphasizes laboratory aspects of medical genetics, with limited coverage of clinical genetics. Participants include: Ms Chris Barnes, Dr Caroline Berry, Professor Martin Bobrow (chair), Professor Sir John Burn, Dr Ian Lister Cheese, Professor Angus Clarke, Dr Clare Davison, Professor Joy Delhanty, Dr Nick Dennis, Professor Dian Donnai, Professor Alan Emery, Professor George Fraser, Mrs Margaret Fraser Roberts, Professor Peter Harper, Dr Hilary Harris, Professor Rodney Harris, Professor Shirley Hodgson, Dr Alan Johnston, Mrs Ann Kershaw, Mrs Lauren Kerzin-Storrar, Professor Michael Laurence, Professor Ursula Mittwoch, Professor Michael Modell, Professor Marcus Pembrey, Professor Sue Povey, Professor Heather Skirton, Professor Sir David Weatherall. Harper P A, Reynolds L A, Tansey E M. (eds) (2010) Clinical genetics in Britain: Origins and development. Wellcome Witnesses to Twentieth Century Medicine, vol. 39. London: The Wellcome Trust Centre for the History of Medicine at UCL.The Wellcome Trust Centre for the History of Medicine at UCL is funded by the Wellcome Trust, which is a registered charity, no. 210183

Cholesterol, Atherosclerosis and Coronary Disease in the UK, 1950–2000.

Annotated and edited transcript of a Witness Seminar held on 8 March 2005. Introduction by Dr Nick Myant, Hammersmith Hospital, London.First published by the Wellcome Trust Centre for the History of Medicine at UCL, 2006. ©The Trustee of the Wellcome Trust, London, 2006. All volumes are freely available online at: www.history.qmul.ac.uk/research/modbiomed/wellcome_witnesses/Annotated and edited transcript of a Witness Seminar held on 8 March 2005. Introduction by Dr Nick Myant, Hammersmith Hospital, London.Annotated and edited transcript of a Witness Seminar held on 8 March 2005. Introduction by Dr Nick Myant, Hammersmith Hospital, London.Annotated and edited transcript of a Witness Seminar held on 8 March 2005. Introduction by Dr Nick Myant, Hammersmith Hospital, London.Annotated and edited transcript of a Witness Seminar held on 8 March 2005. Introduction by Dr Nick Myant, Hammersmith Hospital, London.Annotated and edited transcript of a Witness Seminar held on 8 March 2005. Introduction by Dr Nick Myant, Hammersmith Hospital, London.Annotated and edited transcript of a Witness Seminar held on 8 March 2005. Introduction by Dr Nick Myant, Hammersmith Hospital, London.Cholesterol began to be accepted after the Second World War as a significant cause of atherosclerosis and associated conditions such as coronary heart disease (CHD). This Witness Seminar, chaired by Professor Michael Oliver, included a discussion of the basic research on cholesterol. Early epidemiological studies demonstrated the relationship between excess saturated fat consumption and elevated levels of cholesterol, although cholesterol alone did not explain all population differences. Work on lipoprotein metabolism pointed to hypercholesterolaemia as one of, if not the major, risk factors for CHD, culminating in the development of cholesterol-lowering drugs, particularly the successful statins, available in the UK from the 1980s, and confirmed by randomized controlled trials. The role of diet in heart disease had always been controversial in the UK, and although extreme diets could reduce cholesterol, patient conformity remains difficult. Later, recommended limits on the composition of dietary fat were agreed, assisted by the food industry's introduction of functional foods such as cholesterol-lowering margarine. An introduction by Dr Nick Myant and appendices, on the diet-heart hypothesis by Professor Gerry Shaper and the development of lovastatin by Dr Jonathan Tobert, compliment the transcript. Contributors include Professor David Barker, Professor John Betteridge, Professor Gustav Born, Professor Richard Bruckdorfer, Professor George Davey Smith, Professor Paul Durrington, Professor David Galton, Dr Arthur Hollman, Professor Steve Humphries Professor Gordon Lowe, Professor Vincent Marks, Dr Paul Miller, Professor Jerry Morris, Professor Chris Packard, Professor Stuart Pocock, Professor Kalevi Pyörälä, Professor Thomas Sanders, Professor James Scott, Dr Elspeth Smith, Professor Anne Soutar, Professor Gilbert Thompson, Professor Hugh Tunstall-Pedoe, Professor Neville Woolf and Professor John S Yudkin. Reynolds L A, Tansey E M. (eds) (2006) Cholesterol, atherosclerosis and coronary disease in the UK, 1950–2000, Wellcome Witnesses to Twentieth Century Medicine, vol. 27. London: The Wellcome Trust Centre for the History of Medicine at UCL.The Wellcome Trust Centre for the History of Medicine at UCL is funded by the Wellcome Trust, which is a registered charity, no. 210183

Postconditioning protects against endothelial ischemia-reperfusion injury in the human forearm

Background: Hypoxic cell death follows interruption of blood supply to tissues. Although successful restoration of blood flow is mandatory for salvage of ischemic tissues, reperfusion can paradoxically place tissues at risk of further injury. Brief periods of ischemia applied at the onset of reperfusion have been shown to reduce ischemia-reperfusion (IR) injury, a phenomenon called postconditioning. The aim of this study was to determine whether postconditioning protects against endothelial IR injury in humans, in vivo. Methods and Results: Brachial artery endothelial function was assessed by vascular ultrasound to measure flow-mediated dilation (FMD) in response to forearm reactive hyperemia. FMD was measured before and after IR (20 minutes of arm ischemia followed by 20 minutes of reperfusion) in healthy volunteers. To test the protective effects of postconditioning, 3 cycles of reperfusion followed by ischemia (each lasting 10 or 30 seconds) were applied immediately after 20 minutes of arm ischemia. To determine whether postconditioning needs to be applied at the onset of reperfusion, a 1-minute period of arm reperfusion was allowed before the application of the 10-second postconditioning stimulus. IR caused endothelial dysfunction (FMD 9.1±1.2% pre-IR, 3.6±0.7% post-IR, P<0.001; n=11), which was prevented by postconditioning applied as 10-second cycles of reperfusion/ischemia (FMD 9.9±1.7% pre-IR, 8.3±1.4% post-IR, P=NS; n=11) and 30-second cycles of reperfusion/ischemia (FMD 10.8±1.7% pre-IR, 9.5±1.5% post-IR, P=NS; n=10) immediately at the onset of reperfusion. No protection was observed when the application of the 10-second postconditioning stimulus was delayed for 1 minute after the onset of reperfusion (FMD 9.8±1.2% pre-IR, 4.0±0.9% post-IR, P<0.001; n=8). Conclusions: This study demonstrates for the first time that postconditioning can protect against endothelial IR injury in humans. Postconditioning might reduce tissue injury when applied at the onset of reperfusion by modifying the reperfusion phase of IR

Improving specialised care for neuromuscular patients reduces the frequency of preventable emergency hospital admissions

Two retrospective audits were undertaken across several hospitals to understand the frequency and preventability of emergency admissions in people with neuromuscular disease (NMD). Following audit 1 (A1), a number of preventable themes emerged on the basis of which recommendations were made to improve quality and co-ordination of care and a network approach was developed to improve awareness and education amongst patients and non-expert professionals. Audit 2 (A2) was undertaken to determine the effect of these measures. The central NHS IT database identified emergency NMD admissions. Case notes were reviewed and audited against pre-agreed criteria. A1 included 576 admissions (395 patients) A2 included 361 admissions (314 patients). Preventable admissions (where an NMD was known) accounted for 63% in A1 and 33% in A2, with more patients followed up at a specialized neuromuscular centre in A2. There were fewer re-admissions in A2 (12%) compared with A1 (25%) and lower mortality (A1: 4.5%, A2: 0.3%). A2 showed a significant rise in patients admitted under the care of neuroscience during the acute admission and fewer preventable ITU admissions. These audits demonstrate a significant impact for both patient care and potential for financial savings following the implementation of recommendations made after A1

Collaborative working within UK NHS secondary care and across sectors for COPD and the impact of peer review : qualitative findings from the UK National COPD Resources and Outcomes Project

Introduction: We investigated the effects on collaborative work within the UK National Health Service (NHS) of an intervention for service quality improvement: informal, structured, reciprocated, multidisciplinary peer review with feedback and action plans. The setting was care for chronic obstructive pulmonary disease (COPD). Theory and methods: We analysed semi-structured interviews with 43 hospital respiratory consultants, nurses and general managers at 24 intervention and 11 control sites, as part of a UK randomised controlled study, the National COPD Resources and Outcomes Project (NCROP), using Scott’s conceptual framework for action (inter-organisational, intra-organisational, inter-professional and inter-individual). Three areas of care targeted by NCROP involved collaboration across primary and secondary care. Results: Hospital respiratory department collaborations with commissioners and hospital managers varied. Analysis suggested that this is related to team responses to barriers. Clinicians in unsuccessful collaborations told ‘atrocity stories’ of organisational, structural and professional barriers to service improvement. The others removed barriers by working with government and commissioner agendas to ensure continued involvement in patients’ care. Multidisciplinary peer review facilitated collaboration between participants, enabling them to meet, reconcile differences and exchange ideas across boundaries. Conclusions: The data come from the first randomised controlled trial of organisational peer review, adding to research into UK health service collaborative work, which has had a more restricted focus on inter-professional relations. NCROP peer review may only modestly improve collaboration but these data suggest it might be more effective than top-down exhortations to change when collaboration both across and within organisations is required

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients

In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype

The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1–0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes