The steroid hormone progesterone is considered indisPensible for pregnancy - it is the 'hormone of pregnancy' as described by corner (1928). It is generally agreed that the role of progesterone in all species is to Prepare the endometrium for pregnancy and to contribute to the maintenance of myometrial quiescence from implantation to the end of Pregnancy. There is however, a conflict of opinion concerning its role in pregnancy termination. In some species, for example the sheep, there is considerable evidence that progesterone provides an important link between fetal cortisol and the control of uterine activity. But in human pregnancy the evidence is conflicting. The present study investigates the role of progesterone in the initiation of uterine activity in; - late pregnant ehtes, - early human pregnancy and - the luteal phase of the human menstrual cycIe. The study was designed following the development of a 3 B-nyaroxysteroid dehydrogenase (3 B-ttso) inhibitor (Epostane) by Sterling Winthrop Research. In vitro, Epostane acts comPetitively to inhibit the conversion of pregnenolone to Progesterone. This provides a method of investigating the role of Progesterone in the classical manner - depressing the rate of secretion.

The series of studies comprising this thesis was developed to answer a number of key inter-related questions in regard to eye banking and corneal transplantation in New Zealand. The source and management of donor tissue procured by the New Zealand National Eye Bank (NZNEB) was analysed. Significant trends were identified with respect to donor demographics, donor procurement source, improved donor tissue processing and storage, decreased biological contamination, and increased utilization of corneal tissue. Current trends and ethnicity differences in indications for penetrating keratoplasty (PKP) were investigated. Keratoconus was identified as the most common indication for PKP in New Zealand, accounting for a significantly higher proportion of PKPs than other published reports. Keratoconus was the most common indication for PKP throughout all ethnicity groups and was particularly common in the Maori and Polynesian populations. Significant trends were identified including an increase in the number of PKPs for regraft and Fuchs’ endothelial dystrophy and a decrease for aphakic or pseudophakic bullous keratopathy and viral keratitis. Survival and visual outcome following PKP in New Zealand was investigated using univariate and multivariate analysis. Several independent risk factors were identified that influenced outcome of PKP. Active inflammation at PKP, pre-existing vascularisation, pre-operative glaucoma, small or large graft size, intra-operative complications, episodes of reversible rejection and a pre-operative diagnosis of regraft, trauma or infection resulted in a significantly decreased survival rate. Advancing recipient age, active inflammation at the time of PKP, pre-existing vascularisation, pre-operative glaucoma, episodes of reversible rejection, bullous keratopathy, trauma and non-infective keratitis were associated with poor visual outcome. Patient characteristics, indications, surgical details, and outcome of paediatric keratoplasty were analysed. Acquired non-traumatic indications accounted for the majority of paediatric keratoplasties in New Zealand. This study highlighted keratoconus as a particularly common indication for paediatric keratoplasty when compared to other countries. Survival and visual outcome was better for acquired compared to congenital indications. The effects of corneal parameters on the measurement of endothelial cell density (ECD) in the normal eye were analysed. Corneal thickness appears to be negatively correlated to ECD in the normal cornea for all age groups. Corneal diameter is correlated to ECD measurement in children but not in adults. Corneal curvature was not significantly correlated to ECD measurement, but this needs further investigation. Confocal microscopy and slit scanning topography were used to analyze endothelial morphology and function in the short and long term following PKP. The results of this study are in concordance with other published reports that have identified an accelerated loss of endothelial cells and more rapid development of abnormal endothelial cells in transplanted corneas compared to normal corneas.

In New Zealand, rhegmatogenous retinal detachment (RRD) is recognised as a serious and potentially blinding disorder but little is known about the prevalence, risk factors, management and outcomes for treatment for our population. This thesis attempts to investigate these issues and part of that documentation involved a clinical review of those individuals presenting with RRD. That survey was performed over a 16 month interval enabling the annualised rate for individuals presenting with a new RRD to be determined. The prevalence was found to be 11.8 per 100,000. The risk was age-related with the incidence of RRD increasing for each decade up until the age of 70 years. Men had a slightly greater risk of RRD, and high myopes (greater than 6 dioptres) accounted for approximately 1/3 of the presentations. A history of cataract surgery was also noted to be a significant risk factor for RRD. A subsequent investigation documented in this thesis determined the rate of RRD following cataract surgery using phaco-emulsification techniques was 1%. The risk for pseudo-phakic patients was inversely related to age. The initial survey revealed approximately 2/3 of the patients presented with macula-off RRDs. While individually many of these patients did well, as a group the functional improvement following surgery was limited and less than 1/3 of eyes achieved LogMAR 0.3. It was not always apparent what factors negatively impacted on the functional prognosis but certainly those individuals requiring more than one surgery tended to fare worse. The impact of a poor visual outcome was not directly assessed in this thesis but it is likely those individuals do suffer in terms of visual functioning and quality of life issues. In New Zealand there are a number of agencies that care and support visually impaired persons but there is inadequate data to assess and benchmark treatment and rehabilitation. If this could be achieved for patients with RRD then those barriers which potentially restrict successful outcomes might provide useful insight for other individuals with visual impairment.

The somatotrophic axis plays a vital role in the hormonal regulation of growth and intermediary metabolism. It encompasses the regulation of pituitary growth hormone (GH) secretion from the pituitary gland, the actions of GH on peripheral tissues via interactions with specific growth hormone receptors (GHR) and subsequent endocrine, paracrine and autocrine events, many of which are mediated via the insulin-like growth factor (IGF) system and its regulators. There are multiple effectors and points of regulation within the axis, including feedback loops, functioning to maintain homeostasis of the organism in physiological and pathophysiological situations. This thesis focuses on a number of studies of GH action and the GH receptor and its regulation, and subsequent processes mediated via the IGF system. Specific aims include further understanding the role of GH and the GHR in fetal and early life, exploring the interaction of other hormones (particularly placental lactogen and somatostatin) with the somatotrophic axis and examining the somatotrophic axis in a rapidly growing tissue (the antler) which does not appear to express the GHR. The ontogenic and GH regulation of the hepatic GHR (as reflected by hepatic bovine GH (bGH) specific binding) and serum GH binding protein (GHBP) were studied in the pig. Marked age-related increases were seen in serum GHBP and hepatic bGH binding, and both were increased by recombinant porcine GH treatment in infant and pubertal animals. Serum IGF-I correlated significantly with serum GHBP and hepatic bGH specific binding. Serum GHBP levels reflected major changes in the hepatic GHR, but not closely in pubertal animals, suggesting some differential regulation. Also, the low levels of hepatic GHR in the infant pig were inducible by GH, suggesting GH responsiveness and a role for GH in early life. In further exploring the role of GH in early life, GH (but not IGF-I) administration to neonatal dwarf rats was found to have small but significant somatogenic effects on growth, serum IGF-I and body composition, with an associated decrease in hepatic bGH specific binding. These studies support a role for GH and GH responsiveness in the neonatal rat. This concept was able to be explored indirectly in the human by studying birth weight and early growth in GH-deficient infants. These infants were short at birth with relative adiposity, and had impaired longitudinal growth in the first year of life, suggesting some GH-dependence of growth in fetal life and early infancy. In investigating the perinatal changes in the GHR and serum IGF-I levels, post-mature fetuses were found to have much lower hepatic bGH specific binding than neonatal lambs of the same post-conceptional age, suggesting that these increases relate to events at parturition, and not to post-conceptional age or intrinsic timing. Thus, while evidence is emerging for a significant role of GH and the GHR in fetal life, major induction of these somatotrophic axis components appears to be inhibited until after birth. Since placental lactogen (PL) has been suggested as having an important role in fetal growth and metabolism, the binding properties and somatogenic properties of ovine PL (oPL) were explored. Studies in dwarf rats demonstrated somatogenic effects of oPL which were in some instances greater than those of bGH. Receptor binding studies in rat and sheep livers consistently showed greater potency of oPL, although with detailed displacement studies in sheep showing parallel changes in oPL and bGH binding over a range of developmental stages. This and other supporting evidence suggest that oPL may interact with the GHR or a closely related receptor, although the possibility of a distinct oPL receptor cannot be conclusively discounted. While the GHR is clearly of major importance in the regulation of growth in many tissues, no GHRs were demonstrated in deer antler by autoradiography or radioreceptor assays. Specific binding sites were identified for IGF-I and IGF-II, with properties suggestive of the type 1 and type 2 IGF receptors. Thus, endocrine IGF-I is proposed to have a prominent role in antler growth, although local IGF production and action is also likely to be important. Finally, in exploring other potential regulators of the GHR, the possibility of direct effects of somatostatin on the GHR was examined, since somatostatin has been suggested to influence the peripheral somatotrophic axis by reducing GH-induced IGF-I expression. Octreotide administration was associated with decreased IGF-I expression, yet with increases in hepatic GHR expression, suggesting that the suppressive effects of octreotide on IGF-I metabolism are not mediated via downregulation of GHR expression, but more likely by direct effects on IGF-I expression. The studies in this thesis have furthered the understanding of some aspects of the role and regulation of GH and the GHR in the somatotrophic axis. Many questions remain to be answered on the complicated role played by these systems in the regulation of growth and metabolism. / Whole document restricted, but available by request, use the feedback form to request access.

This thesis explores whether low birth weight affects glucose homeostasis and other aspects of the metabolic syndrome in twin children. The key parameter studied is insulin resistance, and whether insulin resistance is also associated with abnormalities in blood pressure or other aspects of the metabolic syndrome. This thesis is a comparison of twins to singletons, rather than being a study of these traits within twin pairs. The fetal origins hypothesis suggests that low birth weight ultimately is associated with adult onset diseases namely coronary heart disease, glucose intolerance and hypertension. All twins to a degree are born prematurely and with low birth weight. It is unclear whether their metabolism in later life reflects this, or alternatively reflects their uniqueness as twins irrespective of birth weight. This thesis reviews how adaptation for their unique fetal life has affected in particular, glucose homeostasis in twins. Insulin resistance has been consistently identified prior to the onset of both type 2 diabetes mellitus and hypertension and is also the primary metabolic abnormality persisting from programming of the undernourished fetus. Both small-for-gestational-age and prematurely born infants are insulin resistant when examined in mid-childhood. It has been postulated that this represents an attempt of the fetus to salvage itself from a state of inadequate nutrition. Twins when examined in this thesis are also shown to be insulin resistant, or to have a reduction in insulin sensitivity. This insulin resistance was independent of low birth weight and prematurity, and reflected a unique twin effect. Examing blood pressure precisely revealed that twins had increased night-time blood pressure, a feature also seen in a variety of pre-hypertensive states. However, there was no association between low birth weight and any 24 hour blood pressure monitoring parameter in twins. Twins also had elevated leptin levels but reduced TNF-alpha levels in twins irrespective of birth weight or prematurity. Twins have unique metabolic profiles which are not correlated with low birth weight, and twins should be considered an exception to the fetal origins hypothesis. / 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.