Abstract Background The prognosis after an ischaemic stroke is determined largely by how much damage is done to the brain. Currently physicians possess only a few therapies that can improve outcome. Early changes in common physiological variables, such as blood pressure, temperature and blood glucose levels, represent a potential therapeutic target, and manipulation of these variables may eventually yield an effective and potentially widely applicable range of therapies for optimising stroke recovery. However, the natural history and determinants of physiological change require clarification before the effects of manipulating physiology can be assessed. Previous research suggests that blood pressure and glucose falls over the first few days and temperature rises over this time. Some of the determinants of this change have been identified, for example stroke severity, but their influence has not been accurately quantified. The lack of detail in previous attempts to characterise these relationships is partly due to a reliance on traditional cross-sectional statistical techniques. My aims were to use the most apposite statistical technique, namely mixed-effects modelling, to accurately characterise the temporal patterns of post-stroke blood pressure, temperature and glucose, and to identify baseline factors that represent determinants of change in these three physiological variables. Methods A cohort of ischaemic stroke patients was recruited within 48 hours of stroke onset, and their blood pressure, temperature and glucose was recorded at least every 4 hours until 48 hours post-stroke. Factors representing potential determinants of change in these physiological variables were also recorded, including stroke severity and the presence of infection. There were no protocols dictating the treatment of these physiological variables, but if this occurred, those treatments were also recorded. In each analysis, mixed-effects models were generated with serial measures of physiology as the outcome factors and the potential determinants of physiological change as the explanatory factors. These determinants included time, representing the temporal patterns of change. Patients with diabetes were excluded from the analysis of glucose, for several reasons including the excessive impact on glycaemia made by dietary intake in patients with diabetes. Results There were 157 eligible patients overall. The analysis of blood pressure (n=157) revealed a linear systolic blood pressure fall of 14.9 mmHg (95% Confidence Interval (CI) 6.2, 22.6 mmHg) and a diastolic blood pressure fall of 6.1 mmHg (95%CI 1.6, 10.5 mmHg) over the first 48 hours after stroke. Patients with post-stroke infection exhibited a slight rise in systolic blood pressure of about 4 mmHg. Higher systolic blood pressures were seen in older patients and in those with pre-existing or previously treated hypertension, previous strokes or transient ischaemic attacks, in regular alcohol users and in those with mild to moderately severe stroke. Systolic blood pressures were 4.6 mmHg (95%CI 2.35,6.85 mmHg) lower in current smokers than in non-smokers. Of the 156 patients eligible for the temperature analysis, temperature rose by 0.17 deg C in patients with mild stroke (National Institutes of Health Stroke Score (NIHSS)≤6) and 0.35 deg C in patients with moderate to severe stroke (NIHSS≥6) over the first 48 hours after stroke. Temperatures were higher in those who required paracetamol. Temperatures were 0.33 deg C (95%CI 0.07, 0.58) higher in patients with infection and the effect was fixed during the 48 hour observation period. Blood glucose remained static in the 124 patients without diabetes during the first 48 hours after stroke. Glucose levels where higher in those requiring glucose lowering therapy, and in those with more severe stroke. Conclusions I have quantified the amount by which blood pressure falls and temperature rises over the first 48 hours after stroke. In addition, I have shown that mean glucose levels remain static during this time, suggesting that previous reports of acutely resolving post-stroke hyperglycaemia may have represented misinterpretation of regression to the mean. Several determinants of change in post-stroke physiological variables were identified, with unexpected findings in several cases. Higher systolic blood pressures were seen with stroke of moderate severity but not mild or severe stroke. This relationship was fixed during the first 48 hours after stroke, but while more severe stroke was also associated with higher temperatures, the latter effect became more marked as time passed. Conversely, infection was associated with a fixed elevation in temperature, but was associated with systolic blood pressures that rose slightly during the observation period. These apparent inconsistencies require clarification in future work, for example studies of whether markers of the inflammatory or neuroendocrine stress responses evolve in parallel with the changes in physiological variables. This work provides fundamental information regarding the natural history and determinants of changes in physiological variables post-stroke, and will improve the design of future studies investigating the prognostic significance of untreated and treated physiological variables after stroke. This will ultimately lead to the refinement of clinical guidelines for the management of physiological variables post-stroke and to better outcomes for stroke patients.

This thesis presents an investigation of statistical analytical methods applied to the analysis of the shape of the arterial pressure waveform. The arterial pulse is analysed by a selection of both supervised and unsupervised methods of learning. Supervised learning methods are generally better known as regression. Unsupervised learning methods seek patterns in data without the specification of a target variable. The theoretical relationship between arterial pressure and wave shape is first investigated by study of a transmission line model of the arterial tree. A meta-database of pulse waveforms obtained by the SphygmoCor"??" device is then analysed by the unsupervised learning technique of Self Organising Maps (SOM). The map patterns indicate that the observed arterial pressures affect the wave shape in a similar way as predicted by the theoretical model. A database of continuous arterial pressure obtained by catheter line during sleep is used to derive supervised models that enable estimation of arterial pressures, based on the measured wave shapes. Independent component analysis (ICA) is also used in a supervised learning methodology to show the theoretical plausibility of separating the pressure signals from unwanted noise components. The accuracy and repeatability of the SphygmoCor?? device is measured and discussed. Alternative regression models are introduced that improve on the existing models in the estimation of central cardiovascular parameters from peripheral arterial wave shapes. Results of this investigation show that from the information in the wave shape, it is possible, in theory, to estimate the continuous underlying pressures within the artery to a degree of accuracy acceptable to the Association for the Advancement of Medical Instrumentation. This could facilitate a new role for non-invasive sphygmographic devices, to be used not only for feature estimation but as alternatives to invasive arterial pressure sensors in the measurement of continuous blood pressure.

Bibliography: leaves 192-212. / xv, 212 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The present study investigates the relationships between fetal growth, as manifest in size and shape at birth, and later blood pressure and blood lipids, in an Australian cohort. Data on these outcomes for cohort members at age 8 years are available from a previous study. Birth details (body weight, placental weight, head circumference, chest circumference and length) are abstracted from hospital records. In addition, a follow up of cohort members is undertaken to collect new data pertaining to the two cardiovascular risk factors at 20 years of age. Socio-economic circumstances are characterised at birth, age 8 and age 20. / Thesis (Ph.D.)--University of Adelaide, Dept. of Public Health, 1997?

Doctor of Philosophy(PhD) / This thesis addresses the neurochemistry and function of specific nuclei in the autonomic nervous system that are crucial mediators of cardiorespiratory regulation. The primary aim is to build on previous knowledge about muscarinic cholinergic mechanisms within cardiorespiratory nuclei located in the ventrolateral medulla oblongata. The general focus is characterisation of gene expression patterns of specific muscarinic receptor subtypes in central nuclei involved in blood pressure control and respiratory control in normal rats. The findings were subsequently extended by characterisation of muscarinic receptor gene expression patterns in 1) a rat model of abnormal blood pressure control (hypertension) (Chapter 3) 2) a rat model of cholinergic sensitivity (Chapter 5) 3) the rat ventral respiratory group (Chapter 6) The results of a series of related investigations that ensued from the initial aims more finely characterise the neurocircuitry of the ventrolateral medulla, from a specifically cholinoceptive approach. All five muscarinic receptor subtypes are globally expressed in the ventrolateral medulla but only the M2R mRNA was significantly elevated in the VLM of hypertensive animals compared to their normotensive controls and in the VLM of animals displaying cholinergic hypersensitivity compared to their resistant controls. Surprisingly, M2R mRNA is absent in catecholaminergic cell groups but abundant in certain respiratory nuclei. Two smaller projects involving gene expression of other neurotransmitter / neuromodulators expressed in cardiorespiratory nuclei were also completed during my candidature. Firstly, the neurochemical characterisation of enkephalinergic neurons in the RVLM, and their relationship with bulbospinal, catecholaminergic neurons in hypertensive compared to normotensive animals was carried out (Chapter 4). A substantial proportion of sympathoexcitatory neurons located in the RVLM were enkephalinergic in nature. However, there was no significant difference in preproenkephalin expression in the RVLM in hypertensive compared to normotensive animals. Secondly, the identification and distribution of components of the renin-angiotensin aldosterone system (RAAS) within the brainstem, and differences in gene expression levels between hypertensive and normotensive animals was also investigated. The RAAS data was not included in this thesis, since the topic digresses substantially from other chapters and since it is published (Kumar et al., 2006). The mRNA expression aldosterone synthase, mineralocorticoid receptor (MR1), 12-lipoxygenase (12-LO), serum- and glucocorticoid- inducible kinase and K-ras) were found to be present at all rostrocaudal levels of the ventrolateral medulla. Expression of MR1 mRNA was lower in the RVLM of SHR compared with WKY rats and 12-LO mRNA levels were lower in the CVLM in SHR compared with WKY rats. Otherwise, there was no difference in gene expression level, or the method of detection was not sensitive enough to detect differences in low copy transcripts between hypertensive and normotensive animals.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.