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The nutritional assessment of patients awaiting major abdominal surgery is important. It has been shown that malnutrition is common in such patients, but is often unrecognized. Because of the widespread availability of safe forms of nutritional therapy the task of identifying patients who warrant this therapy has become more urgent. However, current techniques used for the identification of significantly malnourished surgical patients have several important limitations. It has become increasingly evident that a fresh approach to nutritional assessement is now required. Drawing on some preliminary evidence that the loss of body protein is associated with an impairment of a range of physiologic functions, this thesis asserts that in order to improve on our ability to identify preoperative patients who are at a significantly increased risk of postoperative morbidiy and mortality because of the loss of body protein, it would be necessary to assess physiologic functions that can be easily measured, are protein dependent, and clinically relevant. Therefore, the following concept was investigated: That patients lose weight in response to disease and/or nutrient deprivation and the important component of this loss is body protein. The loss of body protein results in an impairment of important physiologic functions, which is the basis of the increased surgical risk noted in malnourished patients, and which results in the increased morbidity and mortality after major surgery. In order to investigate the inter­relationships of weight loss, protein loss, impaired function and surgical risk several objective measurement techniques had to be developed in order to measure physiologic functions (respiratory function, liver function, skeletal muscle function, wound healing reaponse and psychological function). An in vivo neutron activation analysis facility was available for the direct measurement of body protein status. In addition, techniques for the clinical assessment of nutritional status, diet, and postoperative course were developed. The fundemental conclusions of these clinical studies were: [1] that the measurement of preoperative weight loss is no longer useful in identifying patients who are at an increased risk of dying following major surgery, [2] that the preoperative loss of body protein is associated with an increased postoperative morbidity and mortality, [3] that the loss of body protein is associated with an impairment of clinically relevant physiologic functions including liver, skeletal muscle and respiratory function, [4] that a proportion (20 to 25%) of body protein can be determined and must be lost before there is an impairment of some important physiologic functions, [5] that plasma transferrin and prealbumin concentrations are sensitive to the adequacy of recent food intake, and are a measure of body protein status in the elective patients studied, [6] that plasma albumin concentration, in the elective patients studied, is sensitive to the adequacy of recent food intake, but does not reflect body protein status, [7] that voluntary grip strength is a practical and sensitive measure of the extent of body protein loss, [8] that body protein loss is an important, and hitherto unrecognized risk factor for postoperative pneumonia because of its impact on respiratory function [9] that the wound healing response is sensitive to the adequacy of recent food intake but not to body protein status, and [10] that a clinical assessment of weight loss, wasting and physiologic function can be objectively validated and can identify preoperative patients at an increased risk of postoperative morbidity and mortality. There are several important implications of these studies. The future direction of nutritional assessment will be the refinement of a clinical method that incorporates an assessment of physiologic function. Further study is required to demonstrate that nutritional therapy is able to reverse the impairment of clinically relevant physiologic functions and to demonstrate that such an improvement translates into a decrease in postoperative morbidity and mortality. It may be that specific defects due to Protein loss and responsible for the impairment of function can be identified and treated with shortterm nutritional therapy. The method of clinical assessment developed in this thesis can used be used to select preoperative patients for nutritional therapy and predict the likely efficacy of such therapy.

CI-921, an analogue of the antileukaemic agent amsacrine, was produced in an attempt to develop a cytotoxic agent with a broader spectrum of activity. CI-921 was selected for clinical trial on the basis of superior in vivo and in vitro solid tumour activity. Sixteen patients with histologically documented cancer for which there was no conventional cytotoxic treatment were entered into a phase I trial. The dose of CI-921 was escalated from 39mg/m2 to 810mg/m2 (total dose divided over 3 days) and repeated 3 weekly. Neutropenia was the major dose limiting toxicity and defined a maximum tolerated dose of 810 mg/m2. Pharmacokinetic studies revealed a biexponential pattern of drug distribution with a distribution half-life of 2.6 h. The kinetics appeared linear over the dose range tested. Less than 1% of total drug was excreted in the urine. Nineteen patients were entered into a limited phase II trial in non-small cell lung cancer using CI-921 at a dose of 648 mg/m2 in the same 3-day schedule. One of the 16 evaluable patients achieved a partial response lasting five months. Myelosuppression was the predominant toxicity as in the phase I trial, but the degree of toxicity confirmed this dose as being suitable for further phase II trials. One patient had a grand mal seizure temporally associated with three of four courses of CI-927 raising the possibility of neurotoxicity. Although drug-induced cardiotoxicity has been reported with the parent drug amsacrine, there was no evidence of this in the current study. It has been suggested that CI-921 undergoes hepatic metabolism and biliary excretion following conjugation with glutathione. There was no fall in whole blood glutathione levels in patients following CI-921 infusion, although a transient decrease in mouse hepatic GSH was demonstrated following both amsacrine and CI-921. The toxicity of CI-921 in mice was markedly increased following depletion of hepatic glutathione with BSO but was not affected by pre-treatment with morphine or the glutathione "protector" N-acetyl cysteine.

Patients suffering from Inflammatory Bowel Disease (IBD) as a group uniformly suffer from nutritional problems. Nevertheless the extent, severity and clinical significance of Protein Energy Malnutrition (PEM) in the various clinical presentations of these diseases remains unclear. In particular little is known of the nutritional status of the ambulatory patient with IBD. Confusion still exists over the long term nutritional changes following colectomy for colitis. Whether intravenous nutrition (IVN) should be prescribed in patients admitted to hospital for acute exacerbations of IBD still remains contentious. Recent work suggests that the significance of PEM relates to the associated impairments seen in various organ systems eg., impaired respiratory muscle function. Furthermore, there is other data to suggest that nutritional therapy may result in improvement in some of these physiological functions long before there is any measured change in the patient’s nutritional status. Through direct measurements of Body Composition (by neutron activation analysis in conjunction with tritium dilution) together with tests of physiological function (hepatosecretory proteins, skeletal muscle function, respiratory muscle function, wound healing and psychological function) work has been directed to clarify the following clinical questions:- 1. How extensive is the problem of protein depletion in the various clinical presentations of IBD? 2. What are the long term changes in body composition following surgery for colitis? and what is the nature of this restorative process. Is there a return to normal body composition? and if so, What is the duration of this recovery process? 3. What are the effects of a short course of IVN in patients suffering severe exacerbations of IBD? The results of these clinical studies have reaffirmed the high incidence of PEM in patients suffering from acute exacerbations of IBD, furthermore this work has established the existence of persisting protein deficits in the ambulatory patient with IBD who is in clinical remission. Contrary to previous reports, fully convalescent patients following surgery for colitis, were found to have normal body stores of protein and water. The timing of this restorative process was found however to take many months. A 2 week course of IVN was found not only to prevent further loss of body protein in a group of patients presenting with severe exacerbations of IBD, but also within a few days (4 days) lead to a significant improvement in hepatosecretory function, respiratory muscle function, skeletal muscle function, wound healing and psychological function. The magnitudes of these improvements although not complete was probably significant clinically. Following these early improvements, subsequent improvement was slow over many months and was dependent on an increase in body stores of protein.

1. Motility of Treponema pallidum is mediated by endoflagella located within the periplasmic space. The endoflagella comprise a core surrounded by a sheath, with the sheath being composed of a 37-kD antigen (FlaA). 2. Treponemal endoflagella were isolated and component proteins were purified by reverse-phase high pressure liquid chromatography (HPLC). N-terminal amino acid sequence analysis was performed using the sheath protein and two core proteins from T. pallidum subsp. pallidum, T. pallidum subsp. pertenue, and T. phagedenis. For all three proteins, the N-terminal sequences found for T. pallidum and T. pertenue were identical but differed from the sequence of T. phagedenis. The sheath proteins from the three treponemes were also compared by HPLC tryptic peptide maps: maps for T. pallidum and T. pertenue were very similar but differed from T. phagedenis. 3. A λgt11 clone, λA34, that expressed a portion of FlaA was selected from a T. pallidum genomic library using a murine monoclonal antibody. The insert from λA34 provided a probe with which a chimeric plasmid, pRI4, encoding all but the nine N-terminal amino acids of FlaA was selected from a pBR322 T. pallidum genomic library. 4. The nucleotide sequence of flaA upstream of amino acid 10 could not be determined by routine cloning strategies. Instead, the remaining sequence was determined using the inverse- and asymmetric-polymerase chain reaction methods. flaA contains a consensus Escherichia coli promoter and a ribosome binding site. A single open reading frame encodes a precursor protein, pre-FlaA, of 350 amino acids with a calculated Mr 38,860. A 20 amino acid signal sequence with a typical signal peptidase I cleavage site immediately precedes the known N-terminus of FlaA. Twenty six per cent (91/350) of the DNA-derived amino acid sequence was confirmed by N-terminal sequence analysis of ten tryptic peptides derived from native FlaA. 5. Polymerase chain reaction-derived constructs lacking the native T. pallidum promoter were cloned downstream of a T7 promoter. T7 polymerase transcription was under the control of a PL λ promoter. When the λ repressor was inactivated at 42°C, FlaA was expressed at relatively low levels in E. coli. Native and recombinant FlaA were identical as assessed by antibody reactivity and electrophoretic mobility in both sodium dodecyl sulphate- and two dimensional-polyacrylamide gels. 6. Although some pre-FlaA is processed to FlaA in E. coli, pre-FlaA is accumulated indicating inefficient processing of pre-FlaA in E. coli. Soluble FlaA was not detected in either the cytoplasmic or the periplasmic fractions of E. coli transformants. Fractionation of E. coli cell envelopes unexpectedly revealed that pre-FlaA and FlaA were associated with both the inner and outer membranes. 7. Two gene fusions, cro-lacZ-flaA and lacZ’-flaA, were constructed in an attempt to increase expression of the recombinant antigen; a bovine protease Xa site was engineered into the hybrid proteins immediately upstream of the N-terminus of FlaA to allow for subsequent proteolytic cleavage of the purified hybrid proteins. The LacZ’-FlaA protein was expressed in E. coli in increased amounts as compared with FlaA, but like recombinant FlaA, associated with both the inner and outer bacterial membranes. LacZ’-FlaA can be released from the membranes by treatment with 1% [wt/vol] sarkosyl, 6 M urea, or 6 M guanidine hydrochloride.

The continued loss of protein from patients with severe sepsis, trauma or cancer cachexia, which occurs despite the provision of adequate calories and nitrogen, remains a challenge for surgeons and intensivists involved in their care. Prolonged loss of protein may impair cardiopulmonary and immune function and wound healing, and so its effective treatment may represent a considerable clinical advance. In this thesis, studies have been performed in both Patients and laboratory animals which investigate the potential of human growth hormone and insulin-like growth factors to slow or reverse the accelerated protein catabolism associated with severe surgical illness. In the patient studies, the following issues have been addressed: i) The effects of a short course of recombinant human growth hormone (rhGH) on the rate of net protein loss, whole body protein turnover, glucose kinetics, free fatty acid and glycerol concentrations and total carbohydrate and fat oxidation have been measured in septic and injured patients in both postabsorptive and parenterally fed states. ii) The effects of a short course of recombinant human growth hormone on the rate of protein synthesis has been determined in tissues removed from patients with cancer. In the animal studies the following issues have been addressed; i)The effects of acute infusions of recombinant human insulin-like growth factor I (rhIGF-I) on the rate of net protein loss, whole body protein turnover, tissue protein synthesis, glucose kinetics and free fatty acid and glycerol concentrations have been measured. The actions of rhIGF-I infusion were then compared to those of an insulin infusion of equivalent hypoglycaemic potential and to an equimolar infusion of recombinant human insulin-like growth factor II (rhIGF-II). ii) The difficulty in achieving nitrogen accretion in patients with critical surgical illness or cancer cachexia may result from metabolic derangements caused by release of inflammatory mediators such as tumour necrosis factor (TNF). In order to determine whether recombinant human insulin-like growth factor I (rhIGF-I) preserved its protein sparing effects in the face of high plasma TNF concentrations, rhIGF-I was infused into lambs which were simultaneously receiving infusions of recombinant human tumour necrosis factor (rhTNF), and the change in the rate of net protein loss compared to control animals who received rhIGF-I alone. The major findings of the human studies were as follows: i) In parenterally fed patients, rhGH treatment almost halved the rate of net protein loss, although a positive nitrogen balance was not achieved. The rate of whole body protein turnover was not altered, suggesting that the reduction in net protein loss was due to an increase in the rate of protein synthesis rather than reduced catabolism. In the post absorptive group, rhGH treatment increased the rate of appearance and oxidation of free fatty acids and reduced the rate of protein oxidation, from which it was concluded that fat was being oxidized in preference to protein. ii) The rate of protein synthesis in skeletal muscle tissue removed from patients with cancer undergoing resection to whom a short course of rhGH had been administered was significantly greater than that of a matched group of control patients, however the rate of protein synthesis in the tumour per se was not increased. It appears that rhGH favourably alters host tissue protein kinetics without accelerating the rate of tumour protein synthesis. The important results from the animal studies were as follows: i) Infusion of rhIGF-I reduced the rate of net protein loss by both increasing the rate of protein synthesis and reducing the rate of protein catabolism. The rate of protein synthesis was increased by a greater extent in the heart and in the diaphragm than in other skeletal muscles. High rates of rhIGF-I infusion which saturated the plasma IGF-I binding capacity lowered the blood glucose concentration by enhancing peripheral glucose uptake. Infusion of an equimolar dose of rhIGF-II did not influence protein kinetics but did result in a small increase in the rate of glucose clearance. Insulin infused at a dose which resulted in the same degree of hypoglycaemia as the rhIGF-I infusion caused a similar reduction in the rate of net protein loss but did not accelerate the rate of protein synthesis in any of the tissues examined. ii) Recombinant human TNF infusion resulted in pyrexia and increased the plasma glucose, cortisol, glucagon and insulin concentrations. The reduction in the rate of net protein loss following rhIGF-I infusion in rhTNF infused lambs was identical to that seen in control animals infused with rhIGF-I alone. We conclude that as rhIGF-I preserves its protein anabolic action in the face of high rhTNF levels, further investigation into a possible clinical role for rhIGF-I in severe surgical illness is warranted. In general terms, these studies demonstrate that rhGH administration to septic or injured patients significantly reduces their rate of loss of protein, and that rhIGF-I infusion similarly conserves protein in an animal model of sepsis. These findings present the challenge to determine whether the favourable changes in protein kinetics brought about by the administration of anabolic peptide hormones will realize tangible improvements in the clinical course of severely ill surgical patients.

Morphine is an effective potent analgesic. However the side effects of nausea, constipation and sedation are seen frequently. Respiratory depression is not such a common problem clinically but is the most potentially dangerous toxicity. An analgesic inducing equivalent analgesic potency without these toxicities would be particularly valuable. Morphine 6-glucuronide (M6G), one of the major metabolites of morphine, has analgesic activity in animals and animal studies have suggested an improved therapeutic index. The initial study in this thesis confirms the analgesic activity of M6G in man and the pharmacokinetic profile after intravenous and oral administration has been determined. The elimination half life is approximately 1.6 hours with the rate of clearance closely correlating with creatinine clearance. Oral bioavailability at approximately 5%, however, is poor due to its hydrophilic nature. In an effort to more critically examine the comparative emetic potency of M6G and morphine, both compounds were administered to the ferret, a known emetic model for man. Surprisingly M6G had a greater emetic potency in this model. A pilot pharmacokinetic study performed on the ferret revealed that M6G is only a very minor metabolite accounting for approximately only 1% of the metabolic product of morphine compared to 10% in man. It is possible that other aspects of opiate handling are also different, and reminds us of the importance in studying the drug handling of any animal model used for the testing of any drug, particularly when metabolites are thought to play a role in clinical effect. No patients or volunteers in the initial open studies in man experienced any nausea or sedation. This observation prompted a double-blind randomized study comparing the analgesic potency, respiratory depression, nausea and sedation induced by morphine and M6G in normal volunteers. This study confirmed that M6G has an increased analgesic potency in man when compared to morphine and causes significanctly less respiratory depression, nausea and sedation. It has been previously hypothesized that the µ opioid receptor with lower affinity for morphine, the µ2 receptor, is responsible for the majority of morphine toxic side-effects, including respiratory depression. The last study presented in this thesis utilises radioligand binding studies to determine the opioid receptor binding affinities of morphine and M6G at the µ1, µ2, total µ and delta opioid receptors. This reveals that M6G has a 5-fold lower binding affinity to the putative µ2 opioid receptor and hence provides a possible explanation for the decreased toxicity seen compared to morphine. In light of the findings in man above, further investigation of this active morphine metabolite is therefore indicated as M6G could prove particularly beneficial to those patients with severe underlying pulmonary disease and for obstetric use.

Restricted Item. Print thesis available in the University of Auckland Library or available through Inter-Library Loan. In New Zealand (NZ) asthma mortality rates are higher than in any other developed country studied, and hospital admission rates for asthma are among the highest. Within NZ, both mortality and hospital admission rates for asthma are higher among Polynesians than among Europeans. To investigate the possibility that these differences were due to differences in asthma prevalence, a study was initiated to measure the prevalence and severity of asthma among both Europeans and Polynesians in Auckland using methods identical to those used in an overseas study. From all primary schools in the Auckland Urban Area, classes were sampled by two-stage, random, stratified sampling. In the winter of 1985, the children in the sampled classes were studied employing a questionnaire and a rapid, portable method of bronchial challenge testing with histamine which had been used to study schoolchildren aged 8 to 10 years in two areas in New South Wales (NSW), Australia. Participation was 83%, the participants comprising 1084 European, 509 Maori, and 460 Pacific Island children, who were closely matched in gender and age to the NSW children. Prevalence of various items was compared including asthma symptoms, diagnosed asthma, and bronchial hyperresponsiveness (BHR), defined as a 20% fall in the one-second forced expiratory volume (FEV1), on or before the administration of a cumulative dose of 7.8 µmol histamine. The prevalence rates of respiratory symptoms, BHR, severe BHR and BHR combined with symptoms were similar among the 1084 Auckland European children and 769 inland NSW children, but lower among 718 coastal NSW children than the other two sites. In Auckland, the prevalence of respiratory symptoms was higher in Maoris than among Europeans or Pacific Islanders, whereas prevalence of diagnosed asthma was similar in all three groups. Europeans had the highest rate of BHR and severe BHR followed by Maoris then Pacific Islanders. Maori and Pacific Island children reporting symptoms were less likely to receive prophylactic medication than European children. The study design also enabled assessment of the epidemiological correlates of BHR, which had been little studied in random populations before 1985. Among the Auckland children, bronchial responsiveness was found to be unimodally distributed, with no clear separation between children with a diagnosis or symptoms of asthma and those without. The presence or absence of BHR did not accurately identify children with a diagnosis or symptoms of asthma. A l4-variable multiple logistic regression model was developed which explained 27% of the variability in BHR rates. The main variables independently increasing BHR risk were: low baseline FEV1, a history of wheeze, diagnosed asthma, atopic conditions, or bronchodilator treatment, and European (as opposed to Polynesian) ethnicity. Climatic conditions at the time of the test were less strongly associated. In summary, neither the international nor the inter-ethnic differences in asthma mortality and asthma admission rates were adequately explained by differences in the prevalence of asthma symptoms, diagnosed asthma or BHR; however, differences in asthma severity and in the management of asthma may be contributory. In this large population-based study of children, BHR was associated independently with a number of different variables but did not precisely identify children reporting asthma symptoms or a diagnosis of asthma. Thus a single bronchial challenge test is not an ideal tool on its own for diagnosing asthma or measuring asthma prevalence.

Chapter 1 The part that 19th century Edinburgh medicine played in formulating the early concepts of motor neuron disease as a nosological entity is described, including some hitherto unrecognized descriptions by graduates of Edinburgh Medical School, including the first description of progressive bulbar palsy. Credit is given to the great European neurologists, especially charcot’s landmark contribution of the definitive clinico-pathological correlations. Terminology relating to MND is discussed and the problems which have arisen over the nosology relating to diseases of motor neurons. The requirement for a clearly defined classification system and the importance of measuring incidence in this disease are outlined. Chapter 2 A comprehensive review of previous studies of incidence, mortality and distribution is presented. It is suggested that the value of previous clinical descriptions and epidemiological studies of motor neuron disease (MND) have been limited by methodological problems. There appears to have been a real increase in mortality from MND over recent decades. Comparison of incidence in different places is complicated by non standardised methods of case-ascertainment and diagnosis but evidence is presented which challenges the traditional concept that the distribution of MND in developed countries is uniform and static. It remains uncertain, from the evidence available, if age specific incidence continues to rise into old age and the apparent “peak” in late-middle life is due to ascertainment bias. This is an important consideration on which to base aetiological hypotheses. In the northern hemisphere there is a weak positive correlation between standardised, age specific incidence and distance from the equator. There is a high prevalence focus of an atypical MND/ALS on Guam, and while an environmental factor is probably responsible, its nature is uncertain. The relevance of other reported clusters of MND is discussed and the requirements for the ideal study of MND incidence are outlined, which acted as the impetus for the Scottish Motor Neuron Disease Register (SMNDR). Chapter 3 The methodology of the SMNDR is described. This is the first collaborative, population based, prospective, epidemiological study of MND and illustrates the feasibility of such a study and the way in which Scotland is suited (in terms of size and National Health service structure) to such a project. Diagnostic criteria are outlined for application to this and other large scale studies. Of 257 patients registered with the SMNDR as possible MND diagnosed in 1989 and 1990 in Scotland, 229 with proven (by autopsy), clinically definite or probable, sporadic or familial MND, form the basis of the description of incidence, distribution, clinical features and natural history contained in this chapter. The crude incidence was 2.24/100,000/year and age specific incidence continued to rise steeply with age into the very elderly age bands. No evidence for clustering on the basis of Scottish regions was found. 5% of patients had a family history of MND; the clinical pattern varied according to sex and age, with elderly women most likely to present with, or develop, progressive bulbar palsy. Chapter 4 The utility of the 1989-90 Scottish Hospital In-patient statistics (SHIPS) and 1989-90 death certificate coding (Registrar General for Scotland) by International classification of Diseases (ICD)-9, 335 (MND) are analysed as a tool for epidemiological studies and heath care planning. Coded hospital discharge data were an inaccurate record of a diagnosis of MND with a positive predictive value of a diagnosis of MND as determined by SHIPS of 70%. Such data cannot, in their present form, be used as a reliable measure of incidence in Scotland. Greater care is required in the preparation of summaries and coding if these data are to be useful care planning and epidemiological research. However, as an important source of case notification for the SMNDR to achieve a complete sample of patients. There was also a problematic false positive rate (10%) for mortality data but this source more closely approximated true incidence. Chapter 5 A review of previous case control studies of environmental risks for MND is presented. In order to test the hypothesis that certain environmental factors may play a role in the aetiology of MND, a case control study of 103 incident patients (diagnosis date May 1990-october 1991; 57 from the above cohort (as described in chapter 3) and 46 diagnosed in 1991, age and sex matched with community controls was conducted and is described. Measures were taken to minimise potential sources of bias and these are discussed. Fractures were more common in patients than controls especially in the in the five years prior to symptom onset (odds ratio = 15 (95% CI, 2.3-654). Manual workers were over represented and a number of environmental exposures of potential toxicity including exposure to lead (OR = 5.3, 95% CI, 1.5-11) and solvents or chemicals (OR = 3.8, 95% CI 1.5-11) were found. The limited extent of these associations favours a multifactorial aetiology for MND. No relationship to social class, poliovirus infection or to factors which might increase the risk of enteroviral infection in childhood (home space and domestic amenities) was found. Chapter 6 A comprehensive review of previous prognostic studies in MND is presented. An actuarial analysis of the survival of the cohort of 229 incident patients (57 seen in person) in Scotland in 1989-90, with complete follow up for a mean of two years from diagnosis, is calculated on the basis of the SMNDR clinical classification system. The overall 50% survival from diagnosis was 1.2 years (95% CI, 1.0-1.4) and from symptom onset, 2.5 years (95% CI, 2.2-3.0 years). There were significant differences in survival with a poorer prognosis for: progressive bulbar palsy (PBP), female sex and age > 65 years. The presence of PBP and old age were the strongest predictors of outcome, the difference in survival between the sexes was due to the higher frequency of PBP in females. The overall five year survival from symptom onset was 27.7% (95% CI, 19.9-36.0%) but for patients with PBP as the presenting feature was only 3.5% (95% CI, 0.0-15%). These results suggest that, in well defined cohorts, survival can be predicted with some confidence and are useful for the planning of treatment trials. Chapter 7 In this concluding chapter I consider the work contained in this thesis.

Preeclampsia is a serious disorder of pregnancy. The syndrome is the leading cause of maternal mortality in the United Kingdom and it also contributes significantly to perinatal morbidity and mortality. Maternal mortality is primarily due to cerebral complications. Despite continued research, the aetiology of preeclampsia remains unknown. This has limited the development of screening, preventive and therapeutic measures to control the syndrome. Present management is based on basic screening to detect early signs of the syndrome, observation of its progress and occasionally therapeutic intervention to control hypertension. Delivery is timed to prevent maternal and fetal complications, while simultaneously aiming to gain fetal maturity. Unfortunately, in many situations this control is not possible. Owing to an increasing understanding of the pathogenesis of the disease, a new option for prophylaxis - low-dose aspirin - may soon be available. If prevention of preeclampsia becomes a reality, a simple but sensitive screening test will be required to select those women who will benefit from treatment. This thesis is focused on the prevention of preeclampsia and its complications. It will involve examination of screening tests, the preventive therapy low-dose aspirin, and the preliminary assessment of a new technique to detect women at risk for developing cerebral complications from the disease.