This thesis is an analysis of doctors' understandings of, and responses to, changes to medicine and the doctor-patient relationship that locates them within a broader framework of socio-historical transformation. In the context of advanced modernity, adaptation to change is a key challenge facing orthodox medicine. Data on changes in the nature and context of medicine are drawn from a sample of editorials of the Australian Medical Journal, the Lancet, the Journal of the American Medical Association and the New England Journal of Medicine over the period 1965-1995. Data on the perceptions and experiences of individual doctors are drawn from semi-structured, in-depth interviews of general practitioners and specialist practitioners working in metropolitan, rural and remote regions of Tasmania and South Australia. Data from both sources are analyzed with the assistance of the qualitative analysis software package ATLAS/ti. The thesis demonstrates linkages between commodification, differentiation and rationalisation and the emergence of social processes and phenomena relevant to changing doctor-patient relationships, including the marketization of medicine and the rise of consumerism, the proliferation of knowledge and the specialisation of expertise. In contemporary social contexts (and most noticeably in metropolitan practice settings), doctor-patient relationships increasingly take the form of short-lived, 'restricted exchanges' in a market setting. Trust is becoming more problematic just as it simultaneously becomes more necessary as a mechanism for dealing with complexity and uncertainty. Five factors contribute to the 'problematization' of trust in medicine as an expert system: 1) increasing public knowledge of and access to healing systems and philosophies other than Western biomedicine, known collectively as complementary or alternative therapies; 2) growing emphasis on medicine as a 'business' and patients as 'consumers' of medical care; 3) the large and growing number of specialties and the dominance of 'high-tech' medical care; 4) greater 'visibility' of medical and scientific knowledge and particularly of the 'disputes that divide experts'; and 5) the increasingly litigious nature of wider society resulting in the new centrality of contracts, informed consent, the disclosure of diagnoses and risks and the practice of 'defensive medicine'. These factors all have implications for trust at the interpersonal level. The project indicates that, by virtue of its growing relevance to points 1) and 4), in particular, the Internet has the potential to impact upon, or even transform lay-expert relationships in a way that has only been partially realized to date. The project also finds evidence of role confusion among doctors associated with rapid social change and the diminishing public acceptance of 'paternalistic' doctor-patient relationships. It reveals considerable tension between high levels of marketization and the service-orientation and altruism central to traditional notions of professionalism. Doctors (particularly general practitioners) find themselves at the centre of a complex web of contradictory pressures and their individual and collective efforts to build and maintain trust can inadvertently contribute to its further erosion.

In guinea-pig nephrotoxic nephritis (NTN) induced by a sheep antibody there was minimal glomerular capillary deposition of C3 or accumulation of polymorphonuclear leucocytes (PMN) in the heterologous phase. The C4 deficient (C4d) strain developed the same injury as normal Dunkin-Hartley animals. Complement depletion with cobra venom factor, PMN depletion with nitrogen mustard or anti-PMN serum and treatment with antihistamines, aprotinin and indomethacin provided no protection. The relationship between the dose of nephrotoxic antibody and the proteinuria was similar for the γ1 and γ2 subclasses and the F(ab’)2 fragment of γ1 antibody. However, the F(ab’) and the F(ab) antibody fragments, though fixing on the GBM did not cause proteinuria. It is Concluded that the development of proteinuria in this system: is largely independent of the C/PMN system; is due to the fixation of the F(ab’)2 fragment of the antibody molecule; and does not depend on an intact Fc piece. In the autologous phase of NTN induced by sheep antibody to GBM in DH and C4d strain gp, <50% of animals developed proteinuria at the height of the autologous antibody response despite high anti-sheep immunoglobulin titres and fixation of the gp IgG and complement in the kidneys. Only 2 of 37 animals (5.4%) developed progressive disease. In a passive model of autologous phase injury using high titre rabbit antibody to sheep IgG, proteinuria failed to occur despite fixation of up to 95µg of rabbit antibody per kidney. Repeated injection of sheep nephrotoxic antibody caused a persisting nephritic syndrome but not the characteristic proliferative lesion of anti-GBM diseases in other species. Because antibody responses to the alternative complement pathway activator cobra venom factor, are T-dependent and B-mice therefore do not develop resistance to its action it was possible to examine whether renal injury occured under circumstances of protracted alternative pathway activation. After periods of up to three months, no evidence from measurements of blood urea or proteinuria or from examination with light microscopy, immunofluorescent or electron microscopy was obtained to indicate a direct nephrotoxic effect of this type of complement activation. These studies do not support the concept that glomerular injury in patients with mesangiocapillary glomerulonephritis and hypocomplementaemia from C3 nephritic factor are due to the continued activation of the alternative pathway. The clinical course and levels of anti-GBM antibody were compared in 20 patients with Goodpasture’s syndrome treated with plasma exchange and immunosuppression (8 patients), immunosuppression alone (4patients) or no specific therapy (8 patients). There was a more rapid fall in the level of anti-GBM antibody and pulmonary haemorrhage was less protracted in the patients treated with plasma exchange and immunosuppression. In this group, one patient who presented with severe renal failure showed a marked improvement in renal function and there was no progression of disease in the four with milder renal involvement. Two of the four patients treated with immunosuppression alone and only two of the eight patients who received no specific therapy maintained normal renal function. In the group which received no specific therapy, one of the six patients who progressed to renal failure had mild renal involvement initially. There was a significant correlation between the level of anti-GBM antibody and the severity of the morphological changes seen at renal biopsy but not between the level of anti-GBM antibody and the severity of lung haemorrhage. The course and outcome of the disease in these patients not treated or treated with immunosuppression alone was better than that described in earlier reports of this disease, while those patients with plasma exchange and immunosuppression fared even better. An adequately stratified controled trial of immunosuppression in plasma exchange versus immunsuppression alone is justified. Immune complex (IC) levels were measured in normal subjects using the C1q solid phase, C1q deviation, C1q binding and polyethylene glycol precipitation assays. Significant changes in IC levels were seen in normals with each of the assays but the pattern of variation was not consistent between assays or subjects or in the same subject from day to day. There were no consistent changes with meals, time of day, exercise or the prior administration of prednisone. Low levels of IC appeared to be normal in plasma, but the variation in IC levels was not explained. Normal IC may well comprise mixtures of non-specific immunoglobulin aggregates, rheumatoid factor-immunoglobulin complexes, idiotype anti-idiotype complexes as well as specific antibody complexes with antigens from food, infective agents and other sources. Eighty-six patients with primary glomerulonephritis had circulating IC levels measured in 4 IC assays at the time of percutaneous renal biopsy. Patients with acute glomerulonephritis and type 1 mesangiocapillary glomerulonephritis showed the greatest positivity rate overall while patients with membranous glomerulonephritis had the lowest rate. overall, just over half the patients with primary glomerulonephritis were positive in any one assay and <5% in any three assays. Repeat samples taken from the same patients after an interval of some months often showed the same pattern of reactivity in the 4 assays or a return towards lower values. Thirty-one patients with proven acute myocardial infarction (MI) were studied prospectively at the time of admission to hospital and at 3, 7, and 18 days using 4 IC assays. Each assay showed an increased incidence of IC activity in MI with 76% of patients being Positive in at least one assay on one or more of the sampling days. A positive IC assay did not show a significant correlation with cardiac failure, pericarditis, post MI syndrome or previous infarction. The presence of IC was found to correlate with serum C-reactive protein (CRP), serum enzymes and ESR and suggested that complexed CRP or other acute phase proteins may account for some of the IC activity found with less specific assays. The measurement of IC levels in MI has not proved helpful in the diagnosis, management or prediction of outcome in this disorder. In recipients of cadaveric renal transplants circulating IC as detected by the C1q deviation test were found in more than two thirds of patients with recent graft. IC levels were found to rise after rejection episodes and also after episodes of infection. Low or rapidly falling IC levels soon after transplantation were associated with good graft function. Sera from 4 patients with systemic lupus erythematosis (SLE) were shown to contain abnormal lipoproteins which behaved as IC. One IC lipoprotein (ICVLDL) had the density in ultracentrifugation of very low density lipoprotein, but a markedly altered electrophoretic mobility. A second IC lipoprotein (ICIDL) had the electrophoretic mobility of very low density lipoprotein but was slightly denser than low density lipoprotein on ultracentrifugation. Both the ICVLDL and ICLDL contained IgG and behaved as IC in the C1q deviation test, platelet aggregation and rheumatoid factor inhibition assays, but not in the conglutinin and C1q binding assays and the C1q solid phase assays. These differences could be due to the low densities of the ICVLDL and ICLDL. The abnormal lipoprotein IC disappeared with clinical remission in two patients and were not present in the sera of other patients with inactive or mild SLE, type 4 hyperlipidaemia or during prednisone therapy or plasma exchange for other conditions. These IC appeared to be markers of severe and active SLE.

Background Nitric oxide (NO) was well known to be a component of air pollution, often in the form of nitrogen dioxide (NO2). However its importance in biological systems altered dramatically with the discovery in 1987 that it was the 'endothelial-derived relaxing factor'. Since then there has been an explosion of research on NO demonstrating that this gaseous molecule was a widespread physiological mediator and was simultaneously recognised as a vital component of immune function contributing to macrophage-mediated cytotoxicity. NO was therefore a key molecule in modulating inflammation, including airway inflammation. The aim of this thesis was: 1. To adapt a NO chemiluminscence analyser from measuring airway pollution to measuring exhaled air in human subjects. 2. To measure NO levels in exhaled air in adult subjects. 3. To evaluate whether altering measurement parameters altered the levels of NO obtained. 4. To adapt this technique from adults to measure exhaled NO in children. 5. To compare levels of NO from healthy children to groups of asthmatic children on either bronchodilator therapy only, or on regular inhaled corticosteroids. 6. To compare the levels of NO in a pilot group of asthmatic children before and after commencement of inhaled corticosteroids. Methods A Dasibi Environmental Corporation Model 2107 chemiluminescence analyser was adapted specifically requiring a reduction in response time, which was achieved by modification of the circuitry and re-routing of the analogue signal directly to a chart recorder, achieving a reduction of the response time by 80%. Addition of a number of analysers allowed the measurement of exhaled NO, carbon dioxide (CO2), mouth pressure and flow for each exhalation from total lung capacity. Twenty adult subjects (in total) were then studied looking at direct (NO, CO2, mouth pressure) versus t-piece (with the addition of flow) measurements making five exhalations from total lung capacity, at 3-minute intervals (direct/t-piece/direct or t-piece/direct/t-piece in series). The area of NO under the curve versus the peak of the NO trace was compared and the exhalation pattern of NO versus CO2 was compared. Measurement conditions were altered to evaluate the effect of individual parameters on the exhaled NO result. This included separately assessing different expiratory flows, different expiratory mouth pressures, the effect of a high versus a low background NO level and the effect of drinking water (of varying temperatures) prior to exhalation. Healthy control children were then enrolled to the study from a local school (Park Walk Primary School) and compared with asthmatic children enrolled from outpatient clinics at the Royal Brompton Hospital. The asthmatic children were further divided into those on bronchodilator treatment only and those on regular inhaled corticosteroid therapy. NO was also measured before and two weeks after commencing inhaled corticosteroid therapy in previously steroid-naive asthmatics. Results It was possible to modify a chemiluminescence analyser to enable measurement of exhaled NO. In 12 healthy subjects (mean age 32 years, 6 males) peak direct NO levels were 84.8 parts per billion (ppb) (standard error of the mean (SEM) 14.0ppb), significantly higher than 41.2ppb (SEM 10.8ppb) measured via the t-piece system. The exhaled NO rose to an early peak and plateau while the CO2 levels continued to rise to peak late in the exhalation. The mean times to peak NO levels were 32.2 seconds (s) (direct) and 23.1s (t-piece), which was significantly different from the mean times to peak CO2 levels at 50.5s (direct) and 51.4s (t-piece, p<0.001). At peak NO level, the simultaneous CO2 level of 4.9% (SEM 0.47%, direct) and 5.2% (SEM 0.18, t-piece) were significantly lower than the peak CO2 achieved of 5.8% (SEM 0.21%, direct, p<0.001) and, 6.2% (SEM 0.28, t-piece, p<0.001). There was no difference between repeat direct or t-piece measurements. With regard to varying measurement conditions, the mean peak concentrations of NO decreased by 35ppb (95% confidence intervals 25.7-43.4) from a mean of 79ppb (SEM 15.4ppb) at an expiratory flow rate of 250mls/min to 54.1ppb (SEM 10.7ppb) at 1100mls/min. The mean peak concentration of NO did not change significantly when mouth pressure was increased in eight of ten subjects, although in two it did decrease in the highest pressure. The mean NO concentration with machine and subjects sampling from a low NO reservoir was 123ppb (SEM 19.4), which was an increase from results obtained before at 81.9ppb, SEM 10.2ppb, p=0.001 95%, CI -19.9 to -62.7) and after at 94.2ppb(SEM 18.3ppb, p=0.017, 95% CI 6.0-5.18) sampling with high ambient NO levels. The mean peak NO concentration decreased from 94.4ppb (SEM 20.8) to 70.8ppb (SEM 16.5, p=0.002 95% CI 12.9 -33.1) with water consumption. In 39 healthy pre-pubertal children with a mean age of 9.9 years (range 9-11 years, 23 girls) the mean direct exhaled No level was 49.6ppb (SD 37.8ppb, range 11.5-197.2ppb) compared with mean exhaled No via t-piece sampling of 29.2ppb (SD 27.1ppb, range 5.1-141.2ppb). There was no significant difference between boys and girls for either the direct or the t-piece recordings. In comparison with normal children, 15 asthmatic children on bronchodilator therapy only had much higher levels of exhaled NO at 126.1ppb via the direct system (SD 77.1ppb, p<0.001) and 109.5ppb via the t-piece system (SD 106.8ppb, p<0.001). In 16 asthmatics on regular inhaled corticosteroids the mean peak exhaled levels were significantly lower at 48.7ppb via the direct method (SD 43.3ppb, p<0.001) and via the t-piece system at 45.2ppb (SD 45.9ppb, p<0.01). There was no difference between the normal children and the asthmatic children who were on regular inhaled corticosteroids (p=0.9 direct, p=0.2 t-piece).There was no significant difference in CO2, mouth pressure, duration of expiration and expiratory flows between the three groups or between the two methods (direct and t-piece). In six asthmatic children the mean peak exhaled NO levels fell from a medium peak level of 124.5ppb to 48.6ppb when measured before and two weeks after commencement of inhaled corticosteroids on treatment. Discussion This research showed it was possible to modify an NO chemiluminescence analyser to enable measurement of exhaled NO in adult and paediatric subjects. Furthermore, it was possible to measure both healthy and asthmatic children. There were significant differences between the exhalation pattern of NO and CO2 suggesting that NO was produced in the airways, not at alveolar level, unlike CO2. The measurement of exhaled NO required a standardised approach as exhaled NO levels decreased with increasing expiratory flow, when measuring at a time of high ambient NO concentration, and with consumption of either hot or cold water immediately preceding exhalation (such as might be given if a subject was coughing). The findings with expiratory mouth pressure were less certain, with a difference seen in only two of ten subjects. The levels of exhaled NO measured in children aged 9-11 years were lower than that measured in the adult subjects. There was no difference between boys and girls, or with other parameters such as having a personal history of atopy, a family history of atopy, or the presence of a smoker or furry pets within the house-hold. These findings may have altered with increased numbers in this group and could possibly be a type two statistical error. The results of exhaled NO in asthmatic children on bronchodilator therapy only were significantly elevated compared to both normal children and asthmatic children treated with regular inhaled corticosteroids. The exhaled NO level also fell significantly by two weeks following the commencement of inhaled corticosteroid treatment in steroid-naive asthmatic children. These results suggested that the methods of measuring exhaled NO required standardization and that it could potentially be a non-invasive measure of airway inflammation to follow - particularly in children with asthma who were commencing inhaled steroid treatment.

The metabolic responses to trauma are well characterized and there is growing evidence supporting an important role for cytokines in its pathogenesis. Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Tumour necrosis factor (TNF) are synthesized in the brain, and other tissues, in trauma. In order to test the hypothesis that these cytokines play an important role in the metabolic responses associated with trauma, the effects of chronic cerebroventricular and peripheral infusions of IL-1, IL-6, and TNF on protein metabolism, weight loss, anorexia, and pyrexia in Sprague-Dawley rats were examined. Specifically the aims of these investigations were: 1. To examine the effect of chronic central nervous system exposure to the proinflammatory cytokines IL-1, IL-6, and TNF. 2. To investigate the role of anorexia in the catabolic responses to centrally infused IL-1. 3. To investigate the effects of IL-1 on the hypothalamic-pituitary-adrenal axis. 4. To investigate the role of glucocorticoids in the metabolic effects produced by chronic central infusion of IL-1. 5. To examine the metabolic effects of increasing doses of chronic peripherally infused IL-1 and to distinguish between those responses mediated centrally and those mediated outside the blood-brain-barrier. The major findings of these studies were: 1. IL-1, but not IL-6 in the same dose, nor TNF in a lower dose, produced net protein catabolism, weight loss, and pyrexia in excess of that produced by anorexia alone. 2. Furthermore the loss of weight and nitrogen did not require sustained elevations of glucocorticoids, as IL-1 infusion in corticosterone-replaced, adrenalectomized rats resulted in similar losses of weight and nitrogen as observed in sham-adrenalectomized animals infused with IL-1. 3. Peripheral infusion of increasing doses of IL-1 mimicked the effects of increasing injury with low doses causing a mild acute phase response (as assessed by a fall in serum iron and albumin and a leucocytosis) and larger doses causing net protein catabolism and weight loss. An attempt was made to distinguish between the central and peripherally mediated metabolic effects of IL-1 using a novel model utilizing peripheral infusions of IL-1 and central infusions of IL-1 receptor antagonist. Using this model the data were consistent with the hypotheses that pyrexia is mediated inside and outside the blood-brain barrier and that leucocytosis is mediated by a direct peripheral effect, probably on the bone-marrow. In conclusion, centrally produced IL-1 may play an important role in the metabolic responses associated with trauma and this is in excess of the anorexia and adrenocortical activation produced by centrally acting IL-1. Peripherally produced IL-1 may play a role in various organs such as the bone-marrow and the liver to produce other features of the metabolic responses associated with injury.

The formation of a pelvic ileal reservoir or pouch for patients requiring a proctocolectomy for ulcerative colitis or familial adenomatous polyposis (FAP) has gained rapid favour over recent years. The operation has evolved by empiric practice with the progressive refinement of operative technique. There is still debate over whether to retain or remove the anal transitional zone (ATZ). This debate relates to concern about the neoplastic and inflammatory potential of diseased mucosa if retained in the anal canal. Similarly the chronic inflammatory changes observed in ileal pouch mucosa have raised the possibility that neoplasia may be a long term consequence of forming the ileum into a pouch. This thesis investigates these issues. The work begins with a review of the literature on the ATZ and its importance in restorative proctocolectomy. Following this a detailed study of the micro anatomy of the anal canal is carried out on 28 anal canals. The median span of the ATZ was found to be only 4.5 millimetres and it contains almost no columnar epithelium. However an important area termed the columnar cuff was identified. In a patient who does not have a mucosectomy, the columnar cuff constitutes a span of diseased Columnar epithelium extending over 1 5 to 2.5 cm in the upper anal canal. Long term concerns need to focus on the columnar cuff rather than the ATZ. The columnar cuff and ATZ in 113 patients with an ileal pouch has been studied. These patients had an examination with the intention of biopsying the anal canal and ileal pouch to study the ATZ and columnar cuff. It was possible to obtain a successful biopsy of the columnar cuff in 72% of cases. The technique of staining for the small bowel brush border enzyme sucrase isomaltase has been developed and shown to reliably distinguish between pouch mucosa with villous atrophy and columnar cuff mucosa. The same group of patients was followed over a 2.5 year period and 9% were shown to have symptomatic ‘cuffitis’. A histological scoring system is described and a diagnostic triad of symptoms, endoscopic inflammation and acute inflammation on histology is put forward as a way to diagnose cuffitis. The same 113 patients had columnar cuff biopsies examined for dysplasia and aneuploidy at a mean of 2.5 years after pouch formation and 10.1 years after the diagnosis of ulcerative colitis. No dysplasia was found but one patient had aneuploidy in the columnar cuff. The final part of the work focuses on investigating the risk of neoplasia in ileal pouches. This work draws on a large cohort of 1221 patients with an ileal pouch and selects out a potentially higher risk group for pouch neoplasia. 106 patients who had a pouch for ulcerative colitis were selected, including 34 with chronic pouchitis. In addition 33 patients who had a pouch for FAP were studied. In the ulcerative colitis group one patient was found to have low grade dysplasia and aneuploidy and a further two patients aneuploidy. The risk of neoplasia in an ileal pouch for ulcerative colitis appears low and chronic pouchitis was not identified as a particular risk factor. In contrast adenomatous polyps were found in the ileal pouch of 42% of patients with FAP. It appears that forming the terminal ileum into a reservoir promotes the formation of ileal polyps. In conclusion forming the ileum into a pelvic reservoir to maintain continence appears to be a safe procedure with medium term follow up. It will be important to continue to gather data to establish the natural history of an ileal pouch. In the interim a level of follow up and surveillance for some groups of patients may be wise. / Whole document restricted, but available by request, use the feedback form to request access.

The formation of a pelvic ileal reservoir or pouch for patients requiring a proctocolectomy for ulcerative colitis or familial adenomatous polyposis (FAP) has gained rapid favour over recent years. The operation has evolved by empiric practice with the progressive refinement of operative technique. There is still debate over whether to retain or remove the anal transitional zone (ATZ). This debate relates to concern about the neoplastic and inflammatory potential of diseased mucosa if retained in the anal canal. Similarly the chronic inflammatory changes observed in ileal pouch mucosa have raised the possibility that neoplasia may be a long term consequence of forming the ileum into a pouch. This thesis investigates these issues. The work begins with a review of the literature on the ATZ and its importance in restorative proctocolectomy. Following this a detailed study of the micro anatomy of the anal canal is carried out on 28 anal canals. The median span of the ATZ was found to be only 4.5 millimetres and it contains almost no columnar epithelium. However an important area termed the columnar cuff was identified. In a patient who does not have a mucosectomy, the columnar cuff constitutes a span of diseased Columnar epithelium extending over 1 5 to 2.5 cm in the upper anal canal. Long term concerns need to focus on the columnar cuff rather than the ATZ. The columnar cuff and ATZ in 113 patients with an ileal pouch has been studied. These patients had an examination with the intention of biopsying the anal canal and ileal pouch to study the ATZ and columnar cuff. It was possible to obtain a successful biopsy of the columnar cuff in 72% of cases. The technique of staining for the small bowel brush border enzyme sucrase isomaltase has been developed and shown to reliably distinguish between pouch mucosa with villous atrophy and columnar cuff mucosa. The same group of patients was followed over a 2.5 year period and 9% were shown to have symptomatic ‘cuffitis’. A histological scoring system is described and a diagnostic triad of symptoms, endoscopic inflammation and acute inflammation on histology is put forward as a way to diagnose cuffitis. The same 113 patients had columnar cuff biopsies examined for dysplasia and aneuploidy at a mean of 2.5 years after pouch formation and 10.1 years after the diagnosis of ulcerative colitis. No dysplasia was found but one patient had aneuploidy in the columnar cuff. The final part of the work focuses on investigating the risk of neoplasia in ileal pouches. This work draws on a large cohort of 1221 patients with an ileal pouch and selects out a potentially higher risk group for pouch neoplasia. 106 patients who had a pouch for ulcerative colitis were selected, including 34 with chronic pouchitis. In addition 33 patients who had a pouch for FAP were studied. In the ulcerative colitis group one patient was found to have low grade dysplasia and aneuploidy and a further two patients aneuploidy. The risk of neoplasia in an ileal pouch for ulcerative colitis appears low and chronic pouchitis was not identified as a particular risk factor. In contrast adenomatous polyps were found in the ileal pouch of 42% of patients with FAP. It appears that forming the terminal ileum into a reservoir promotes the formation of ileal polyps. In conclusion forming the ileum into a pelvic reservoir to maintain continence appears to be a safe procedure with medium term follow up. It will be important to continue to gather data to establish the natural history of an ileal pouch. In the interim a level of follow up and surveillance for some groups of patients may be wise. / Whole document restricted, but available by request, use the feedback form to request access.

Recent studies have demonstrated that 84% of women suffering from unexplained pelvic pain have dilated pelvic veins. Such appearances are generally considered to be evidence of ‘pelvic congestion’. Venographic studies of women without pain did not show these appearances. Management of pelvic congestion is considered difficult as there are few therapies currently available. Psychotherapy has been previously shown to be successful in the management of a number of painful conditions including women with chronic pelvic pain. Ovarian suppression with medroxyprogesterone acetate (MPA) has also been shown to reduce both venogram and pain scores. The first hypothesis of this thesis was that women with chronic pelvic pain in association with venographic evidence of pelvic congestion could be treated with medroxyprogesterone acetate and that longer term benefit could be obtained with the concurrent use of psychotherapy. The second hypothesis was that treatment with MPA will lower levels of pituitary gonadotrophins, the ovarian hormones, the karyopyknotic index (vaginal cytology) and reduce the dimensions of the uterus, endometrium, ovaries and pelvic veins. This thesis presents the results of a randomised controlled trial comparing two different treatment approaches; psychotherapy and ovarian suppression using MPA. One hundred and two women with pelvic congestion were randomly allocated to one of four treatment groups; MPA, MPA and psychotherapy, placebo, and placebo and psychotherapy. Women were treated for four months and thereafter followed up regularly for 9 months with pain assessments, pelvic ultrasound scanning and hormone measurements. Women treated with MPA showed a significant benefit in terms of a reduction in pain scores, with 73% of women reporting an improvement compared with 33% of those in the non-MPA groups. After 9 months therapy no clear drug effect emerged. Fifty percent of women in the placebo group were improved at the end of follow up. Those women who received MPA had significant reductions in the uterine cross-sectionnal area, endometrial thickness, oestradiol, testosterone and luteinising hormone levels. Medical therapy with MPA was shown to be a useful first line therapy for women with pain associated with demonstrable pelvic congestion.

The operation of extrafascial excision dissects directly on the rectal fascia propria to remove the rectum and mesorectum within an intact fascial envelope. The studies contained in this thesis revolve around the recent finding that if a rectal cancer is contained within the fascia propria and the rectum is removed by extrafascial excision then local recurrence of the cancer will be exceptional. The thesis is presented in 4 parts as anatomical, radiological, clinical and operative sections. Gross and microscopic examination of surgical specimens, post-mortem dissections and axial cross sectional anatomy images were used to define the anatomy of the fascia propria. It is shown to be a 150μm thick, collagen membrane completely surrounding the mesorectum. The hypogastric nerves and pelvic plexuses are embedded in the parietal fascia separated from the mesorectum and fascia propria by a loose areolar layer. A computerised three-dimensional model of the rectum and mesorectum has been generated based on 1mm axial cross sections of the anatomy of the area and axial MR scans offering the potential to visualise the rectum in its mesorectum preoperatively. A systematic review of preoperative radiological staging has been reported comparing endorectal ultrasound, CT and MR imaging. The ability to determine the relation of the tumour to the fascia propria preoperatively has, however, not been previously explored. Cadaveric studies in this thesis have demonstrated that the fascia propria can be identified by axial CT and MR imaging. In a consecutive series of 43 patients with rectal cancer preoperative MR accurately predicted the relation of the deepest tumour invasion to this fascia. In the third section extrafascial excision has been compared with conventional surgery at a single institution over a 16 year period. In a study population of 262 rectal cancer patients operated on with curative intent, extrafascial excision had a significantly lower local recurrence rate and prolonged cancer-free survival without an increase in cost or complication rates. Based on these studies a new description of the operation of extrafascial excision of the rectum is presented in the fourth section with emphasis on preventing complications. This thesis has provided a new understanding of the surgical anatomy of the rectum and a novel management protocol for rectal cancer based on the relationship of the tumour to the fascia propria as detected by preoperative MR imaging.

Short-term variability in cerebral blood flow velocity (CBFV) in the VLBW infant largely relates to respiratory influence. Extreme variability may be a poor prognostic indicator. Few have studied cohorts of babies in this regard. I sequentially studied a consecutive cohort of unselected VLBW infants, to determine the frequency of respiratory influence on CBFVV and to identify factors associated with its occurrence. Doppler CBFV, arterial BP and respiratory signals were recorded simultaneously and spectral analysis was applied to identify a respiratory signal in BP and CBFV traces. Respiratory associated variability was present in the cerebral circulation at some time in more than half of the infants studied and was most likely in those of lowest gestational age who were hypotensive. Mortality, and cerebral morbidity as assessed by cerebral ultrasound were more common in those demonstrating a respiratory influence in CBFV. There was a strong correlation between the coefficient of variation(CV%) of BP and that of CBFV. Babies demonstrating hypotension had higher CV%s in CBFV; those who did not survive showed higher variability than survivors, but there was a wide spread of values in both groups. where the variability in CBFV was high, correlation between CBFV and BP was greater. However, no significant association was found between CV% of CBFV and brain injury, ductal patency, or sedation. Although exaggerated beat-to-beat variability in CBFV was an adverse prognostic indicator, absence of variability carried the worst prognosis. Slow variations of cerebral blood flow velocity at a frequency of 1-5 cycles per minute, previously described as a normal phenomenon, were also examined. Evolution of this variability was studied amongst those present for a month or more. Slow variations diminished with both increasing postnatal and postconceptional age, perhaps representing maturation of the balance between the two components of the autonomic nervous system. The cycle length of the slow variations was variable suggesting the presence of several low frequency components; longer recordings would be needed to resolve these. Addition of serial Doppler measurements of CBFV performed in the first week of life, did not improve prediction of an 18-month outcome obtained from ultrasound imaging alone.

In guinea-pig nephrotoxic nephritis (NTN) induced by a sheep antibody there was minimal glomerular capillary deposition of C3 or accumulation of polymorphonuclear leucocytes (PMN) in the heterologous phase. The C4 deficient (C4d) strain developed the same injury as normal Dunkin-Hartley animals. Complement depletion with cobra venom factor, PMN depletion with nitrogen mustard or anti-PMN serum and treatment with antihistamines, aprotinin and indomethacin provided no protection. The relationship between the dose of nephrotoxic antibody and the proteinuria was similar for the γ1 and γ2 subclasses and the F(ab’)2 fragment of γ1 antibody. However, the F(ab’) and the F(ab) antibody fragments, though fixing on the GBM did not cause proteinuria. It is Concluded that the development of proteinuria in this system: is largely independent of the C/PMN system; is due to the fixation of the F(ab’)2 fragment of the antibody molecule; and does not depend on an intact Fc piece. In the autologous phase of NTN induced by sheep antibody to GBM in DH and C4d strain gp, <50% of animals developed proteinuria at the height of the autologous antibody response despite high anti-sheep immunoglobulin titres and fixation of the gp IgG and complement in the kidneys. Only 2 of 37 animals (5.4%) developed progressive disease. In a passive model of autologous phase injury using high titre rabbit antibody to sheep IgG, proteinuria failed to occur despite fixation of up to 95µg of rabbit antibody per kidney. Repeated injection of sheep nephrotoxic antibody caused a persisting nephritic syndrome but not the characteristic proliferative lesion of anti-GBM diseases in other species. Because antibody responses to the alternative complement pathway activator cobra venom factor, are T-dependent and B-mice therefore do not develop resistance to its action it was possible to examine whether renal injury occured under circumstances of protracted alternative pathway activation. After periods of up to three months, no evidence from measurements of blood urea or proteinuria or from examination with light microscopy, immunofluorescent or electron microscopy was obtained to indicate a direct nephrotoxic effect of this type of complement activation. These studies do not support the concept that glomerular injury in patients with mesangiocapillary glomerulonephritis and hypocomplementaemia from C3 nephritic factor are due to the continued activation of the alternative pathway. The clinical course and levels of anti-GBM antibody were compared in 20 patients with Goodpasture’s syndrome treated with plasma exchange and immunosuppression (8 patients), immunosuppression alone (4patients) or no specific therapy (8 patients). There was a more rapid fall in the level of anti-GBM antibody and pulmonary haemorrhage was less protracted in the patients treated with plasma exchange and immunosuppression. In this group, one patient who presented with severe renal failure showed a marked improvement in renal function and there was no progression of disease in the four with milder renal involvement. Two of the four patients treated with immunosuppression alone and only two of the eight patients who received no specific therapy maintained normal renal function. In the group which received no specific therapy, one of the six patients who progressed to renal failure had mild renal involvement initially. There was a significant correlation between the level of anti-GBM antibody and the severity of the morphological changes seen at renal biopsy but not between the level of anti-GBM antibody and the severity of lung haemorrhage. The course and outcome of the disease in these patients not treated or treated with immunosuppression alone was better than that described in earlier reports of this disease, while those patients with plasma exchange and immunosuppression fared even better. An adequately stratified controled trial of immunosuppression in plasma exchange versus immunsuppression alone is justified. Immune complex (IC) levels were measured in normal subjects using the C1q solid phase, C1q deviation, C1q binding and polyethylene glycol precipitation assays. Significant changes in IC levels were seen in normals with each of the assays but the pattern of variation was not consistent between assays or subjects or in the same subject from day to day. There were no consistent changes with meals, time of day, exercise or the prior administration of prednisone. Low levels of IC appeared to be normal in plasma, but the variation in IC levels was not explained. Normal IC may well comprise mixtures of non-specific immunoglobulin aggregates, rheumatoid factor-immunoglobulin complexes, idiotype anti-idiotype complexes as well as specific antibody complexes with antigens from food, infective agents and other sources. Eighty-six patients with primary glomerulonephritis had circulating IC levels measured in 4 IC assays at the time of percutaneous renal biopsy. Patients with acute glomerulonephritis and type 1 mesangiocapillary glomerulonephritis showed the greatest positivity rate overall while patients with membranous glomerulonephritis had the lowest rate. overall, just over half the patients with primary glomerulonephritis were positive in any one assay and <5% in any three assays. Repeat samples taken from the same patients after an interval of some months often showed the same pattern of reactivity in the 4 assays or a return towards lower values. Thirty-one patients with proven acute myocardial infarction (MI) were studied prospectively at the time of admission to hospital and at 3, 7, and 18 days using 4 IC assays. Each assay showed an increased incidence of IC activity in MI with 76% of patients being Positive in at least one assay on one or more of the sampling days. A positive IC assay did not show a significant correlation with cardiac failure, pericarditis, post MI syndrome or previous infarction. The presence of IC was found to correlate with serum C-reactive protein (CRP), serum enzymes and ESR and suggested that complexed CRP or other acute phase proteins may account for some of the IC activity found with less specific assays. The measurement of IC levels in MI has not proved helpful in the diagnosis, management or prediction of outcome in this disorder. In recipients of cadaveric renal transplants circulating IC as detected by the C1q deviation test were found in more than two thirds of patients with recent graft. IC levels were found to rise after rejection episodes and also after episodes of infection. Low or rapidly falling IC levels soon after transplantation were associated with good graft function. Sera from 4 patients with systemic lupus erythematosis (SLE) were shown to contain abnormal lipoproteins which behaved as IC. One IC lipoprotein (ICVLDL) had the density in ultracentrifugation of very low density lipoprotein, but a markedly altered electrophoretic mobility. A second IC lipoprotein (ICIDL) had the electrophoretic mobility of very low density lipoprotein but was slightly denser than low density lipoprotein on ultracentrifugation. Both the ICVLDL and ICLDL contained IgG and behaved as IC in the C1q deviation test, platelet aggregation and rheumatoid factor inhibition assays, but not in the conglutinin and C1q binding assays and the C1q solid phase assays. These differences could be due to the low densities of the ICVLDL and ICLDL. The abnormal lipoprotein IC disappeared with clinical remission in two patients and were not present in the sera of other patients with inactive or mild SLE, type 4 hyperlipidaemia or during prednisone therapy or plasma exchange for other conditions. These IC appeared to be markers of severe and active SLE.