C-X-C motif receptor 2 (CXCR2) is a G-protein coupled receptor normally expressed on granulocytes, in particular CD11b +, Gr1+, Ly6G+ bone marrow derived suppressor cells (BMDCs) and once differentiated neutrophils.

Colorectal cancer is the second most common cause of cancer death in the UK. It is accepted that both tumour and host factors are important determinants of disease progression and survival. While systemic and local inflammatory responses are increasingly recognized to be of particular importance the understanding of the mechanisms linking these important inflammatory processes remains unclear. This thesis examines the prognostic importance of measures of systemic and local inflammation and proposes a hypothesis for a link between tumour necrosis, systemic and local inflammatory responses in patients with colorectal cancer. Chapter 3 reports the comparison of the prognostic value of longitudinal measurements of systemic inflammation in patients undergoing curative resection of colorectal cancer. In Chapter 3 the results demonstrate that there was no significant overall change in either mGPS or NLR from pre- to post- operatively. This study highlighted the associations between pre- and post- operative mGPS and NLR and T-stage (p<0.001), TNM stage (p<0.005) and cancer-specific survival. The relationships between pre-operative measurements were examined using multivariate analysis. For pre-operative measurement both mGPS and NLR were associated with cancer-specific survival while when post-operative measures were examined only mGPS was specifically associated with cancer-specific survival (HR 4.81, CI 2.13-10.83, P<0.001). Chapter 4 examines the prognostic value of the Klintrup-Makinen scoring method and the existing limitations with regard to its clinical utility. An automated scoring method using commercially available image analysis software was developed and compared with manual scoring of tumour inflammatory infiltrates. This study demonstrated that both manual K-M scoring (p<0.001) and automated K-M scoring (p<0.05) had prognostic value in patients who had undergone potentially curative resection of colorectal cancer, and that the novel automated method may provide an objective method of assessment of tumour inflammatory infiltrates using routinely stained haematoxylin and eosin sections of tumour samples. In chapter 5 a hypothesis was proposed that Interleukin-6 may link tumour necrosis and systemic and local inflammatory responses in patients with colorectal cancer. This chapter examined the basis for this hypothesis, which is presented in figure 5.1. In addition, in chapter 5 the importance of this potential link is examined. In chapter 6, the hypothesis outlined in chapter 5 was examined in a cohort of patients who had undergone attempted curative resection of colorectal cancer. This study examined the inter-relationships between circulating mediators, in particular IL-6, tumour necrosis and systemic and local inflammatory responses. This results of this study demonstrated that IL-6 was associated with tumour necrosis (<0.001) and mGPS (<0.001) independent of T-stage. Thus adding weight to the hypothesis that elevated circulating concentrations of IL-6 may play a role in modulating both the systemic and local inflammatory responses in patients with cancer. Chapter 7 further develops the hypothesis that IL-6 signalling may be important in modulating systemic and local inflammatory responses in patients with colorectal cancer. Further, in chapter 7 the basis for the role of trans-signalling in this signaling pathway was examined. In this study, we reported that neither expression of the soluble IL-6 receptor or soluble gp130 were associated with systemic or local inflammatory responses. As a result the possible reasons for these findings were explored and future work suggested. A prospective database of patients undergoing attempted curative resection of colorectal cancer in Glasgow Royal Infirmary was used throughout this thesis. This database was created and is maintained regularly by successive research fellows at the Royal Infirmary. The work presented in this thesis highlights the importance of the host response in the form of systemic and local inflammation in patients with colorectal cancer and proposes a link between these responses and tumour necrosis. In addition, this work adds weight to the body of evidence suggesting that assessment of these host responses may improve stratification to treatment for patients with colorectal cancer. Further, this work proposes a mechanistic link, between tumour necrosis, systemic and local inflammatory responses through Interleukin-6, that merits further investigation.

Total joint replacement is one of the most common elective surgical procedures performed worldwide, with an estimate of 1.5 million operations performed annually. It has long been recognised that wear analysis of total joint replacements is an important means in determining failure mechanisms, functionality and improving longevity of these devices. The standardised method for assessing wear volumes in such joints is through gravimetric means and it has been shown that this method is a useful tool for indicating simulated wear volumes. This method is, however, of little value when considering the case of a clinically explanted bearing surface for which, by definition, there is no ‘pre-wear’ data. The purpose of this thesis is to present a co-ordinate measuring machine (CMM) based technique for assessing the volumetric material loss in total joint replacement joints and to establish its effectiveness. To this end uncertainty calculations are completed for the specific case of orthopaedic component measurement. In this thesis methods have been developed in this thesis for measurement of in vitro wear of total knee replacement bearings and a number of knee joint simulator tests have been completed and their results discussed. An initial test investigating the possible use of metal-on-metal bearings for total knee replacement is described. A test profile for simulation of deep squat is developed, a simulator test completed and the results discussed. An adapted version of the developed CMM measurement method is further adapted and developed for measurement of clinical wear from retrieved bearings and the implications of this capability are examined and discussed. In tandem with this methods are developed for the mapping of wear location and component form deviation and the implications that this has for manufacturing control and wear potential is discussed at length. Overall future developments and work are explored.

No description available.

Total hip replacement is one of the most common surgical procedures performed both in the UK and worldwide, with aseptic loosening cited as the primary reason for revision. Aseptic loosening is attributed to the wear debris generated by wear of the components. Recently, as great progress has been achieved in reducing wear at the head–cup interface, there has been a shift of research interest to other load bearing surfaces. The main purpose of this thesis is to study fretting wear mechanisms at the polished femoral stem–bone cement interface. The initial studies have investigated the bond strength at the stem–cement interface using seven brands of bone cement and femoral stems with different surface finishes. It can be confirmed that debonding at this interface is inevitable, which subsequently facilitates generation of fretting wear on the stem surface. A new test methodology has been developed to reproduce fretting wear clinically seen on polished stems through in vitro wear simulations, and it shows great success in comparison with previous attempts. In addition, migration of the stem within the cement mantle has been investigated, and it has been indicated that the simulation setup more realistically mimics clinical situations. The influence of two factors on generation of fretting wear, i.e. the duration of in vivo service of the hip implant and bone cement brand, has been studied. A potential fretting wear initiator that is concerned with polymerisation of bone cement has been identified, with both experimental (the results of wear simulations) and theoretical (finite element analysis) evidence being provided. In summary, the overall contribution of this research is that it has gained a deep insight into the fretting wear mechanism between polished femoral stem and bone cement.

An attempt to reproduce tendon sheaths using autologous venous grafts has been undertaken in Cercopithecus aethiops (Blue Vervet Monkey). Ten venous grafts were tested. Five were placed around sutured tendons in paratenon, and the remainder around tendons in sheath formation. In no instance did synovial-like sheaths form. In the latter series, the experiment was controlled, and the results obtained expressed in terms of function. The functional results of the venous ensheathed tendons were worse than those of the controlled tendons.The controlled experiment was confined to the digital sheath, an area notoriously liable to adhesion formation, and the one which offered the most critical test of operative technique.A method for the evaluation of function, following the repair of divided tendons in the experimental animal has been presented. Voluntary movement of joints in the experimental animal was obviously impossible, but the method employed in this experiment, namely, the electrical stimulation of muscles, and the photographic recording of the range of joint movement, presented no disadvantages.The experimental animal used in this study was ideal, in that anatomical studies of the hand of this species, revealed features both structurally and functionally comparable to those in man.The anatomical and physiological aspects of tendon action, the mechanics of tendon gliding, and the healing processes in divided tendons have been studied.The fate of human autologous venous grafts has been investigated.A review of previous methods employed to prevent peritendinous adhesions has been presented.

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.

The ability to quantify kinematic parameters of the knee is crucial in understanding normal biomechanics, recognising the presence of pathology and its severity, planning treatment and evaluation of outcomes. Current methods of quantifying lower limb kinematics remain limited in allowing accurate dynamic assessment. Computer assisted surgery systems have been validated in quantifying kinematic parameters, but remain limited to the operative setting. Recently, image-free computer assisted surgery technology has been adapted for non-invasive use and validated in terms of repeatability in measuring coronal and sagittal femorotibial mechanical alignment in extension. The aim of this thesis was to develop and implement a set of validation protocols to quantify the reliability, precision and accuracy of this non-invasive technology in quantifying lower limb coronal and sagittal femorotibial mechanical alignment, anteroposterior and rotatory laxity of the knee by comparison with a validated, commercially available image-free computer assisted surgery system. Pilot study confirmed feasibility of further experimental work and revealed that the noninvasive method measured with satisfactory precision and accuracy: coronal mechanical femorotibial alignment (MFTA) from extension to 30° knee flexion, anteroposterior translation in extension and tibial rotatory laxity during flexion. Further experiments using 12 fresh cadaveric limbs revealed that the non-invasive method gave satisfactory precision and agreement with the invasive system measuring MFTA without stress from extension to 40° knee flexion, and with 15Nm coronal stress from extension to 30° knee flexion. Using 100N of anterior force on the tibia, the non-invasive system was acceptably precise and accurate in measuring sagittal tibial displacement from extension to 40° flexion. End of range apprehension, such as has been proven repeatable in measuring tibial rotatory laxity was used and the non-invasive method gave superior 3 precision and accuracy to most reported non-invasive devices in quantifying tibial rotatory range of motion. Non-invasive optical tracking systems provide a means to quantify important kinematic parameters in health and disease, and could allow standardisation of knee examination increasing communicability and translation of findings from the out-patient to operative setting. This technology therefore could allow restoration of individual specific kinematics in knee arthroplasty and soft-tissue reconstruction.

Non-compressible haemorrhage from within the torso and junctional regions constitutes the leading cause of potentially preventable death on the battlefield. It can be defined as haemorrhagic shock arising from injury to named torso vessels, pulmonary parenchyma, high grade solid organ injury and/or disruption of the bony pelvis. Data from the US Department of Defence Trauma Registry demonstrate a torso injury rate of 12.7% with 17.1% of casualties exhibiting torso injury and shock. The overall mortality is 18.7%, with major arterial injury and pulmonary injury identified as independent predictors of mortality on multivariate analysis. The UK Joint Theatre Trauma Registry reports similar findings with the greatest burden of mortality occurring prior to hospital admission (75.0%), a rate that has remained unchanged over a decade of war. Injury from improvised explosive devices (IEDs) in particular are associated with non-compressible haemorrhage, frequently causing traumatic lower extremity amputation in combination with torso injury. Contemporary surgical strategy relates to early operative haemorrhage control in patients presenting with shock. In patients sustaining a circulatory arrest, resuscitative thoracotomy and aortic cross clamping can be used to control inflow and increase cardiac afterload. The UK experience over 5 years at Camp Bastion demonstrated a mortality of 78.5%, with greatest survival observed in patients with the shortest time to thoracotomy. In patients sustaining lower extremity amputation following IED injury, 1 in 5 require a laparotomy for proximal vascular control, with less than half requiring further intra-abdominal intervention. There is a pressing need for a haemorrhage control and resuscitation adjunct in non-compressible haemorrhage that can be deployed prior to or as an adjunct to operative haemorrhage control. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a technique that can occlude the aorta without the need for an operating theatre. It is an experimental technique, so its effect on survival and physiology is unknown. In a porcine model of uncontrolled pelvic haemorrhage, infra-renal REBOA was shown to be as effective as chitosan gauze in the setting of normal coagulation. However, REBOA was associated with a significantly greater survival in a coagulopathic setting. Similar results were obtained when using a porcine model of abdominal haemorrhage in conjunction with thoracic REBOA. In both studies, balloon occlusion demonstrated a significant improvement in systolic blood pressure and other haemodynamic measures compared to the no-occlusion control groups. Having demonstrated a survival and haemodynamic benefit in uncontrolled haemorrhage models, the metabolic and inflammatory consequences of thoracic REBOA were characterised in further detail using a porcine model of controlled hypovolaemic shock. Occlusion for 30 and 90 minutes was associated with a significant lactate burden when compared to animals undergoing shock alone. However, following resuscitation with blood and intravenous fluid, normal physiology was restored within 6 hours. The inflammatory sequelae were studied following 30, 60 and 90 minutes of shock and occlusion. Increasing occlusion time resulted in an escalating release of interleukin-6 which manifest clinically as an increase in ARDS and need for vassopressor support. In order to develop a fluoroscopy free REBOA system, a series of human studies were undertaken to examine the relationship between an external measure of torso height and aortic length in order to guide insertion length. A retrospective examination of computed tomography in male trauma patients demonstrated a correlation between torso height and aortic length. This was confirmed by a prospective study which was also used linear regression to develop equations predictive of insertion length. Finally, the UK Joint Theatre Trauma Registry was used to determine the need for REBOA in a population of UK military personnel injured over 10 years of conflict. Of 1317 severely injured patients 70.2% had no indication, 11.2% had a contra-indication and 18.5% had an injury pattern indication for REBOA. Of those with an indication for REBOA, 66 (27.0%) patients died en-route to hospital and 29 (11.9%) died in-hospital. In conclusion, non-compressible haemorrhage constitutes a significant burden of potentially preventable battlefield mortality. REBOA is a technique that can be used in the thoracic or infra-renal aorta as a haemorrhage control and resuscitation adjunct, prior to operative haemorrhage control. While associated with a significant survival advantage in models of uncontrolled haemorrhage, it is associated with a significant metabolic penalty, although with resuscitation this can be ameliorated successfully.

The aim of this study was to examine patients’ experiences of day surgery from a sociological perspective. Although there has been massive expansion in day surgery provision, both internationally and in the United Kingdom, there has been surprisingly little sociological research concerning this development. Within the space of three hours a patient is admitted to hospital, undergoes a general anaesthetic, followed by a significant surgical intervention and is then discharged home where responsibility for their care, which was previously performed by health service professionals, is now undertaken by the patient and their families. A study was devised to gain an understanding of the patients’ experiences within a sociological framework of analysis. One-hundred and forty-five patients and their relatives, from two different day surgery units within the United Kingdom, were recruited to the study. A qualitative framework, utilizing the grounded theory approach, enabled the researcher to gain deep insights into the patient experience. Fieldwork comprised semi-structured interviews and observation, as well as extensive use of field notes and memos. During a two-year span in the field, patients were interviewed on three occasions. The first interview took place in the pre-operative assessment clinic, where fitness for day surgery was assessed. The second and third interviews were carried out by telephone, at forty-eight hours and four weeks post-operatively. Data was simultaneously analyzed alongside data collection. Line by line analysis of the transcribed interview was undertaken whereby keywords and phrases were identified. Codes were then clustered into groups from which emerged core concepts. The core concepts which emerged from this study were: Time, the ambiguities of the Sick Role, Control, the importance of therapeutic relationships and formal communication. Recommendations include improved educational preparation for day surgery patients and their families as well as for the day surgery and community staff who are called upon to support the patient following discharge.