This thesis is a historical study of peptic ulcer disease from the sixth decade of the eighteenth century until the end of the twentieth. Symptoms of dyspepsia or indigestion have affected more than twenty percent of the British population for most of that period and attracted the involvement of many medical practitioners and others with the provision of health care. Within this group of symptomatic dyspeptic patients were to be found gastric and duodenal ulcers which were capable of causing serious health problems. However the prevalence of stomach and duodenal peptic ulcers has declined markedly during the time course of this thesis and now they are relatively uncommon. Although peptic ulcers may still have a fatal outcome, they now are considered to be curable conditions for the majority of patients who suffer from them in the developed world. This thematic history of gastric and duodenal ulcer examines how medical practitioners worked in a changing climate of novel ideas about disease, often aided or driven by technological developments, from the nineteenth century onwards. It begins with a humoural approach to the understanding of disease, which concentrated upon a patient’s personality, lifestyle choices and circumstances but this was gradually displaced from the end of the eighteenth century by the clinico-anatomical approach, which sought to identify a specific lesion as the ‘seat’ of the disease. In the nineteenth century, the discoveries of pathology, physiology, chemistry and bacteriology became incorporated in clinical medical practice, involving the laboratory in the investigation and treatment of many diseases. In the twentieth century, medical research became rooted in experimentation using scientific technology and engineering to equip investigators with new methods which changed the ways in which diseases were understood and treated. Although there were many innovations in theoretical concepts of disease aetiology and empirical treatments, many were subsequently rejected for reasons of ineffectiveness or possible harm to the patient, sometimes after long periods of use. In its first part, the thesis draws upon publications from 1769 until 1950, mostly in the form of scientific articles and books. In the second part, the oral testimonies of health care professionals involved with the management and treatment of gastric and duodenal ulcers are added. The recorded testimonies of 28 witnesses have been preserved in written form as a supplement to this dissertation. Peptic ulcer disease was initially perceived as a whole-body ailment which was centred on the stomach as its symptomatic location and its treatment was intended to alter humoural imbalance or relieve symptoms. However after post-mortem examinations were increasingly performed from the seventeen-nineties, medical practitioners could see its complications in death and combine their findings with the clinical presentations of what was becoming recognised as a relatively common disorder. In the nineteenth century, physiologists investigated the workings of the stomach using vivisection and chemistry to analyse the stomach contents. The acid produced by the stomach was seen to play a part in ulcer genesis but there was no agreement as to what its precise contribution was for many years thereafter. Bacteriologists who found micro-organisms in the stomach assumed that they were pathogenically involved and subsequent experiments confirmed this. As a result of effective anaesthesia and antisepsis in the last decades of the nineteenth century, surgeons intervened increasingly in life-threatening complications of gastric and duodenal ulcers and their observations changed their perceptions of the diseases. In the twentieth century, opaque meal X-ray techniques began to allow doctors to see lesions inside the living stomach, as did improved endoscopes. In 1952, research suggested that stomach bacteria played no part in causing ulcers and further bacteriological research in the stomach was abandoned. By this time, surgeons had designed operations to reduce stomach acid production which healed most gastric and duodenal ulcers. Good therapeutic results were also achieved using medication and dietetic regimens, but it was recognised that only the surgeon could help patients who had failed to respond to medical treatments. In 1962 it was noted that deaths rates for gastric and duodenal ulcer were falling and fewer people were suffering from them, but they remained a serious cause of morbidity and mortality. A new acid-reducing operation was devised in 1969 that offered the hope that surgery could adequately treat ulcers without causing iatrogenic damage, and in 1976, a new drug was marketed which healed them if continuously taken. Then in 1983 it was asserted that peptic ulcers were caused by a bacterium which was later called Helicobacter pylori. In time and in the face of much opposition, it was shown that if this organism was eradicated in the stomach by medication then gastric ulcers and duodenal ulcers could be cured for the first time. This account of the history of peptic ulcer disease shows how medical practitioners adapted the theoretical basis of their medical practice as its evolved under the influence of scientific or societal changes and later abandoned concepts and therapeutic regimens which no longer were in accord with current thinking. Important issues which have arisen out of the testimonies include: medical involvement with the pharmaceutical industry, how doctors co-operate in the care of patients and how they respond to new theories and equipment and techniques as they became available. The history of peptic ulcer disease over the past two hundred years as described in this thesis follows a broadly similar course to that of other diseases such as tuberculosis, syphilis and chronic renal disease which once dominated the lives of those who suffered from them and have largely become curable in recent years. This thesis is offered as an account of an equally fascinating and complex disease.

Kidney Transplantation is the gold standard treatment for patients with end-stage renal failure. Most kidneys used for transplantation are from deceased donors and ensuring successful outcomes depends on many factors. One of these is organ storage. Hypothermic Machine Perfusion (HMP) of deceased donor organs has been shown to have several benefits. However, it has not been widely adopted and the underlying mechanism is poorly understood. The first section of this thesis examines the introduction of HMP into clinical practice. HMP outcomes were similar to those of standard storage techniques but with the additional benefit of increasing safe storage times. This was likely due to inherent benefits of the machine itself, improved recipient preparation and better peri-operative conditions. The second part of this study analysed HMP perfusate using metabolomics (Nuclear Magnetic Resonance) to identify potential predictors of graft outcome. Differences were identified in the metabolic profiles of perfusate from kidneys with immediate and delayed graft function. These may have a future role in viability assessment. Improved understanding of metabolism during storage may help target optimization strategies for deceased donor organs. The final part of this study describes the development of a porcine model of transplantation to test future hypotheses.