175 leaves ; ill. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Surgery, 1972

Two thousand years elapsed before man could unravel several of the problems and implications of disturbed glucose tolerance. As far back as 30 years B.C. gross manifestations of the disease now known as Diabetes Mellitus were recognized. Despite great advances, however, there is much that is still unknown. The history of many a malady begins with the observation of the illness in its most grotesque form. As medical science gathers more and more knowledge the less severe symptoms and signs come to be recognized. Gradually special tests are evolved, by means of which the disorder can be diagnosed inits earliest stages. And thereafter, the tendency to develop the condition is seen before it becomes manifest. The long history of disturbed glucose tolerance follows this pattern. Many centuries have passed in the gradual evolvement of the various stages. With the passing of the years improved diagnostic methods were discovered, so that mild rooms of the disorder could be detected. In the past few decades the concept of mildly impaired glucose and "pre-diabetes" has been formulated. One of the most interesting of recent developments, for example, has been the conclusion that the birth of overlarge babies may be a sign of predisposition to this metabolic disturbance.

No description available.

Between August 1979 and September 1982, acute variceal haemorrhage has been managed in the University Department of Surgery, Glasgow Royal Infirmary by a policy of oesophageal tamponade and injection sclerotherapy. Haemorrhage was controlled in 90% of admissions with an admission mortality of 28%. Recurrent haemorrhage occurred in half the patients surviving their first admission to hospital despite entering a programme of elective sclerotherapy. The results of this management policy are reviewed and the means of selecting patients for more aggressive therapy discussed. The deficiencies of a modified Child's classification in selection of patients are highlighted and overcome by the development of a prognostic index obtained by regression analysis on data collected on patients managed over this 3 year period. The admission prognostic index clearly defines 'high' and 'low' risk groups and 'predicts' outcome following admission in 90% of patients. The use of this index is validated in a further group of patients managed by a similar policy. Further regression analysis is used to obtain a prognostic index for alcohol cirrhotic patients alone and to determine the factors associated with one year survival. These indices are used to audit the management policy. Prothrombin, creatinine and encephalopathy are shown to have a clear association with outcome when measured at the time of variceal haemorrhage whereas other factors such as albumin and haemoglobin emerge as having prognostic value when measured one month following the acute episode. The possible applications of these prognostic indices are investigated in a prospective two centre study assessing the efficacy of propranolol in preventing recurrent variceal haemorrhage. It is shown that they can be used to exclude patients from entry into a study assessing the longterm benefit of propranolol when the prospects of short-term survival are limited. Their value in auditing management and their possible use in withdrawing treatment are shown. The prognostic indices are used to compare results of treatment at the two hospitals and are shown to be of value in analysing the results of the trial. These prognostic indices provide an objective means of evaluating patient management and may allow selection of patients for consideration of other treatment options.

Thesis MSc.(Med)(Virology)-- University of Limpopo, 2011 / Background: Intraventricular hemorrhage (IVH) is a known complication occurring in the first week of life in premature neonates. The exact time of its occurrence and the ideal time to perform diagnostic imaging investigation remain controversial. Objectives: 1. To determine the incidence of intraventicular hemorrhage in premature babies at Dr George Mukhari Hospital, Pretoria. 2. To determine the timing at which bleeding occurs. 3. To determine if the rate of diagnosing intraventicular hemorrhage improves when performing ultrasound via the posterior fontanelle. 4. To determine the risk factors for intraventricular haemorrhage Materials and methods: The study included 60 premature babies of gestational age of less than 32 weeks that were admitted to our neonatal Intensive Care Unit over a two months period and screened for IVH. They were grouped into three categories according to their weight at birth, and according to their gestational age. All babies had a cranial ultrasound on day 1, 3 and 7. Results: We found that the overall incidence of IVH among premature babies was 28%. Although it did not reach statistical significance, the incidence was found to be inversely related to the birth weight and gestational age. The majority of the bleeds occurred within the first day of life and were mostly grade I and II according to Papile’s classification. The use of inotropes was found to be significantly associated with development of IVH. We also found that scanning through the posterior fontanelle did not significantly increase the rate of diagnosis for IVH.

No description available.

Spontaneous (non-traumatic) intracerebral haemorrhage accounts for ~10% of all strokes in Western populations. Investigations may identify intracerebral haemorrhage (ICH) as ‘secondary’ to underlying causes such as tumours or aneurysms, but ~80% of ICHs which have no apparent underlying cause (so-called ‘primary’ ICH) tend to be attributed to small vessel vasculopathies such as arteriolosclerosis or cerebral amyloid angiopathy (CAA), on the basis of an adult’s risk factors and clinical and radiographic features of the ICH. The commonly accepted hypothesis is that CAA contributes to lobar ICH and arteriolosclerosis causes non-lobar ICH. In the following thesis, I set out to explore whether (a) the baseline demographic, clinical features and apolipoprotein E genotype of adults with lobar and non-lobar ICH differ, (b) the prognosis of adults with lobar and non-lobar ICH differ and (c) the neuroimaging correlates of small vessel disease in adults with lobar and non-lobar ICH differ since this might provide clues to the vasculopathies underlying lobar and non-lobar ICH. I explored (d) the strength of the association between CAA and ICH by systematically reviewing neuropathological case control studies and (e) the radiological and pathological features of lobar ICH to examine the nature of CAA in persons with lobar ICH and whether any computed tomography (CT) features of ICH are associated with CAA-related lobar ICH. I set up a prospective, community-based inception cohort study of adults with ICH in South East Scotland. Adults with spontaneous primary definite ICH had the opportunity to consent to participate in the Lothian Study of IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN), an ethically-approved, prospective community-based research study examining the causes of ICH using apolipoprotein E genotyping, brain MRI and research autopsy in case of death. Of 128 adults with first-ever spontaneous primary definite ICH diagnosed during 2010- 2011, age and pre-morbid hypertension did not differ by ICH location but a history of dementia was more common in adults with lobar ICH. The proportion of adults with one or more non-lobar brain microbleed (BMB) was significantly higher in adults with non-lobar ICH but I did not find any other differences in the severity or distribution of other neuroimaging correlates of small vessel disease between lobar and non-lobar ICH. The apolipoprotein e4 allele was more common in participants with lobar ICH in comparison to those with non-lobar ICH but the frequency of the e2 allele did not differ by ICH location. Adults with lobar ICH were significantly more likely to survive one year after their ICH in comparison to those with non-lobar ICH after adjustment for other known predictors of outcome. From a systematic review of neuropathological case control studies of CAA and ICH, stratified by ICH location, I found a significant association between CAA and lobar ICH but not with ICH in other locations. I examined the radiological and pathological features of 33 adults with first-ever lobar ICH. The presence of CAA or vasculopathy and the severity of CAA in a lobe affected by ICH was concordant with that of the corresponding contralateral unaffected lobe. Capillary CAA was associated with severe CAA. Subarachnoid extension of the ICH tended to be more frequent in those with CAA-related strictly lobar ICH. Having explored the incidence, risk factors and prognosis of lobar and non-lobar ICH, in future work I would aim to establish the strength of the association between CAA and ICH in different brain locations in a neuropathological case control study. Future work should examine the radiopathological features of lobar ICH in a larger cohort and the coexistence of other small vessel diseases, in particular arteriolosclerosis in persons with ICH.

No description available.

Cerebral ischaemia, or stroke, is a leading cause of death and disability worldwide. Ischaemic stroke, as a result of arterial occlusion, and subarachnoid haemorrhage (SAH), as a consequence of arterial rupture in the subarachnoid space, are major subtypes of stroke. Treatment options for both are limited, and many therapeutic strategies have failed. In ischaemic stroke, lack of evidence of brain penetration of treatments has been cited as a major weakness and contributing factor to failed clinical trials. In SAH, animal models do not always mimic key pathophysiological hallmarks of the disease, hindering development of new therapeutics. Inflammation is strongly associated with brain injury after cerebral ischaemia and inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1) represents apossible therapeutic target. Therefore, the key objectives of this thesis were; (1) to improve preclinical data on a promising stroke treatment, interleukin-1 receptor antagonist (IL-1Ra), by investigating its pharmacokinetic profile and brain penetration in a rat model of ischaemic stroke, (2) to investigate the endovascular perforation model of SAH in rat, as a tool for the investigation of neuroprotectants, and (3) to examine the role of the inflammatory response in the SAH model and the effects of IL-1Ra. The neuroprotective effect, pharmacokinetic profile and brain penetration of IL-1Ra were assessed after a single subcutaneous (s.c.) dose (100mg/kg) in rats, after transient (90 min) middle cerebral artery occlusion (MCAo). A single s.c. dose of IL-1Ra reduced neuronal damage, resulted in sustained, high concentrations of IL-1Ra in plasma and cerebrospinal fluid and also penetrated brain tissue exclusively in areas of blood brain-barrier (BBB) breakdown. An endovascular perforation model of SAH in rat was investigated and produced widespread multifocal infarcts. In this model, administration of IL-1Ra (s.c.) reduced BBB breakdown, which correlated with injury at 48 h. IL-1_ was expressed in the brain early after SAH in areas associated with haem oxygenase-1 (HO-1) expression, indicating the presence of free haem. Stimulation of primary mouse mixed glial cells in vitro with haem induced expression and release of IL-1 alpha but not IL-1 beta. These data, after MCAo in rat, are the first to show that a single s.c. dose of IL-1Ra rapidly reaches salvageable brain tissue and is neuroprotective. This allows confidence that IL-1Ra is able to confer its protective actions both peripherally and centrally. After experimental SAH, we suggest that haem, a breakdown product of haemoglobin, released from lysed red blood cells in the subarachnoid space, acts as a danger associated molecular pattern (DAMP) driving IL-1- dependent inflammation. These data provide new insights into inflammation after SAH-induced brain injury and suggest IL-1Ra as a candidate treatment for the disease. Overall, these findings strengthen preclinical data supporting IL-1Ra as a neuroprotective therapy for ischaemic stroke, and identify SAH as a new indication for treatment with IL-1Ra.

Delayed control of haemorrhage or blood loss has been recognised as a major contributor to preventable trauma deaths, but early detection of internal bleeding is difficult due to unreliability of heart rate (HR) and blood pressure (BP) as markers of volume status. This thesis explores a novel method of early blood loss detection using a noninvasive finger photoplethysmographic (PPG) pulse oximetry waveform that is normally utilised in pulse oximeters for estimating arterial oxygen saturation. Graded head-up tilt (n = 13) and blood donation (n = 43) in human volunteers were selected as experimental models of mild to moderate blood loss. From the tilt study, a novel method for automatically detecting left ventricular ejection time (LVET) from the finger PPG waveform has been developed and verified by comparison with the LVET measured from aortic flow velocity. PPG waveform derived LVET (LVETp) and pulse transit time (PTT) were strongly correlated with aortic LVET and pre-ejection period respectively (median r = 0.954 and 0.964) and with the decrease in central blood volume indicated by the sine of the tilt angle (median r = -0.985 and 0.938), outperforming R-R interval (RRI) and BP in detecting mild central hypovolaemia. In the blood donation study, progressive blood loss was characterised by falling LVETp and rising PTT (p < 0.01). A new way of identifying haemorrhagic phases by monitoring changes and trends in LVETp, PTT and RRI has been proposed based on the results from the two studies. The utility of frequency spectrum analysis of PPG waveform variability (PPGV) in characterising blood loss has also been examined. A new technique of PPGV analysis by computing the coherence-weighted cross-spectrum has been proposed. It has been shown that the spectral measures of finger PPGV exhibited significant changes (p < 0.01) with blood donation and were mildly correlated with systemic vascular resistance in intensive care unit patients (r from 0.53 to 0.59, p < 0.0001), therefore may be useful for identification of different haemorrhagic phases. In conclusion, this thesis has established finger PPG waveform as a potentially useful noninvasive tool for early detection of blood loss.