One hundred and eleven cases of heat effects are described, divided as follows: Heat exhaustion and collapse: Mild 52, Moderate 39, Severe 9 =100; Heat Hyperpvrexia: 11; Mortality: Nil; Morbidity: Average stay in hospital: 9.5 days; Average sick leave in the hills: 10 days; (This figure is not really accurate as it fails to take into account that several cases were due for routine hill leave and were sent direct from hospital with their unit parties.); Cases repatriated 3. Clinical details of all cases of hyperpyrexia and of the severe cases of heat exhaustion are given. Other cases have been treated statistically. Laboratory tests were subordinated to clinical findings and only essential investigations (examination for malarial parasites, etc.) were carried out. Cases were considered in two groups, those with considerable tropical experience, who had spent at least one hot season in India, and those with under a year's tropical service. A description of the Hospital and the facilities available is given, and of the advance preparations made to deal with the expected occurrence of cases as the hot season reached its climax. Details of the general lines of treatment of different types of case have been given in full. The medical literature on the subject has been discussed, from Haldane's pioneer research to the scientific analysis of Ladell and his colleagues in 1944 and Professor Maegraith's summary in this year's British Medical Journal. A suggestion is made of the possible value of pentothal sodium as an adjuvant to the treatment of hyperpyrexia.

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Throughout the British Isles there can be few hospitals with a ward serving so large a population as the detention ward of the Royal Infirmary of Edinburgh. Practically all cases of poisoning occurring in the South Eastern Region of Scotland pass through this ward, and it was this unique feature which prompted me to inquire more closely into the large group of patients poisoned by coal gas either by accident or by intent. With interest stimulated and reading widened, I realised that poisoning by gas still presented many problems; what was fact to one author appeared apocryphal to another; the problem as to whether the toxicity of illuminating gas was due to a pure anoxia or to a toxaemia; the frequency of sequelae and their relation to accidental and to suicidal poisoning, particularly in the subclinical types; the effective treatment and the Public Health problems associated with the subject; the known but as yet ignored increase in the accident rate due to coal gas poisoning over the last ten years, and whether some more lasting and more definite identification could not be introduced into the gas to safeguard the public. As light was shed more clearly on some problems others presented their diverse shapes, and these I attempted to clarify both by reference to experimental and clinical studies embracing the years 1938 -1948.

The purpose of this thesis was to examine; the effects of various stressors on human thermoregulation and immune function, a functional link between these two systems and the potential of novel measurement techniques. A valid, un-obtrusive measure of skin temperature was desirable for a majority of studies in this thesis. Wireless iButtons® provided such a method. Both iButtons® and conventional thermistors displayed high validity correlation (r > 0.999) and mean bias (iButtons® = +0.121°C, thernistors = +0.045°C) with a reference thermometer. A reliable measure of in vivo immunity in response to stressors, was also desirable. Contact sensitization with diphenylcyclopropenone proved a simple and robust method. Results demonstrate that exercise-induced-stress impairs both phases of in vivo T-cell-mediated immunity (oedema: induction -53%; elicitation -19%). Two-nights total sleep deprivation, with or without energy-restriction did not impair thermoregulation during cold exposure, nor appear to increase the risk of hypothermia. Core temperature, skin temperature and time to reach 35.9°C core temperature were not significantly different between trials. Three-nights sleep disruption (SDIS) did not affect core temperature at rest or during exercise-heat-stress. However, SDIS upper-body skin temperature was higher during exercise and forearm-sweating lower (-21%). Thus, alterations to heat-loss pathways were observed, but with no increase in thermal strain. Concurrent examination of the effects of SDIS, demonstrated enhanced in vivo T-cell-mediated immunity (oedema +98%). In vitro markers were unaltered by SDIS, suggesting these markers may not reveal the true effect of stressors on the co-ordinated immune response. Significant differences between sleep deprivation and control proximal and distal skin temperatures lends evidence to the functional, mechanistic coupling between circadian variations in skin temperature and skin immunity, as prolonged periods of increased skin blood flow observed during sleep disruption provides enhanced maintenance of skin immunity and thus likely to account for the observed increase in T-cell-mediated immune responses. The purpose of this thesis was to examine the effects of various stressors on thermoregulation and immune function, and to examine the functional link between these two systems, utilizing conventional, as well as examining the potential future usage of novel techniques and methods in humans.

In order to assess the influence of physical stress, such as exercise and nutritional restriction, on immunity, there is a need for well-controlled field studies and use of clinically relevant and practical in vivo measures of immune competence. The broad aim of this thesis was to examine the reductive effects of physical stress on immune responses in humans. Firstly, a daily mixed nutritional supplement prevented the decrease in circulating total leukocytes, lymphocytes and monocytes and increased saliva secretory immunoglobulin-A during 8 weeks of arduous military training, compared with a comparative control group (Chapter 4). A stronger approach to investigate the effects of physical stress includes utilising a measure of in vivo immunity, such as experimental contact hypersensitivity (CHS) with the novel antigen Diphenylcyclopropenone (DPCP). Prolonged, moderate intensity exercise, but not short, high or short, moderate intensity exercise, impaired induction to DPCP, despite elevated circulating catecholamines and greater circulating cortisol following short, high intensity exercise (Chapter 5). Experimental CHS was then coupled with a suction blister technique at the site of DPCP sensitisation to measure cutaneous cytokines thought to orchestrate dendritic cell migration and successful induction of new immune memory. After demonstrating this technique to be repeatable (Chapter 6) and identifying 6 h of patch exposure as a suitable time to initiate suction blisters (Chapter 7), results showed prolonged, moderate intensity exercise had no effect on local cutaneous interleukin (IL)-1β, tumour necrosis factor (TNF)-α and IL-10 (Chapter 8), thought to be implicated in the initial events of immune induction. Therefore it is possible that prolonged, moderate intensity exercise suppresses further downstream events of immune induction, rather than local inflammatory processes at the skin. Topical application of DPCP provides an attractive tool for the assessment of in vivo immunity in future exercise stress and nutritional intervention studies. Further research is required to identify the mechanisms involved in the suppression of CHS responses to DPCP after prolonged, moderate intensity exercise.

Clonally expanded mitochondrial DNA (mtDNA) point mutations have been shown to cause mitochondrial dysfunction in the form of cytochrome c oxidase deficiency (COX deficiency) within ageing human colonic epithelium. Currently, there are a lack of robust stem cell markers within human colonic epithelium, however the detection of mitochondrial dysfunction has been shown to be a useful stem cell lineage marker, enabling the investigation of stem cell dynamics within colonic crypts. Using the most robust data set of COX deficiency frequency and mtDNA mutation number, a computational model that simulates stem cell dynamics within human colonic crypts was constructed. In silico stem cell modelling suggests: there are approximately 5 stem cells within human colonic crypts, stem cell divisions occur asymmetrically the majority of the time, and that infrequent symmetric stem cell division permits niche succession of individual stem cell clones. However, the in silico data was unable to match the biological data when a model simulating neutral drift stem cell dynamics was used, suggesting a change in stem cell biology when mitochondrial dysfunction was present. In order to assess the impact of mitochondrial dysfunction within colonic stem cells in vivo, a mouse model of mitochondrial dysfunction was crossed with a mouse model enabling the visualisation of cells expressing Lgr5 (a well-accepted stem cell marker). Double thymidine analogue labelling was used to identify cells traversing through the cell cycle, together with a marker of proliferation. This data suggests that stem cells with mitochondrial dysfunction have a small but significant increase in cell cycle progression rate compared to normal stem cells. When these data were included in the model, a better fit to the biological data was achieved. These findings suggest that mitochondrial dysfunction does significantly impact on stem cell homeostasis. As stem cells with mitochondrial dysfunction are more likely to out-compete normal stem cells over time, this may have potential implications for an increased risk of cancer propagation within the colon.

The src family kinases are key cellular regulators of acute neutrophilic inflammation. When uncontrolled, this causes numerous inflammatory disorders, including the acute respiratory distress syndrome (ARDS). This is associated with an unacceptably high 90-day mortality and prolonged hospital admissions. ARDS currently has no effective pharmacological treatment. The work contained in this thesis aimed to characterise the anti-inflammatory, pro-resolutionary effects of src kinase inhibition on various neutrophil functions, using novel in vitro and in vivo models of acute inflammation and resolution. Results show that the src kinase inhibitors, PP1 and dasatinib, attenuate in vitro neutrophil extracellular degranulation in response to stimulation with formylated peptide, lipopolysaccharide and live bacteria. They also exert additional effects on integrin-dependent neutrophil functions, but have no effect on neutrophil fate or bacterial killing efficiency. Src kinase inhibition of neutrophils also attenuates in vitro epithelial cell damage and promotes a pro-resolutionary environment, with improved macrophage efferocytosis of apoptotic neutrophils, by inhibiting the release of an unidentified soluble factor believed to be a product of neutrophil degranulation. Extending these findings to in vivo murine models of bacteria- and acid-induced experimental lung inflammation, dasatinib exerts an inhibitory effect on markers of neutrophil degranulation in each model, at doses of 1mg/kg and 5mg/kg, respectively. At 10mg/kg, a detrimental effect is observed, as evidenced by reduced bacterial clearance, increased alveolar leak and extrapulmonary toxicity in the infection model and increased neutrophil influx, degranulation and alveolar haemorrhage in the acid model. These findings highlight a possible therapeutic role of src kinase inhibition in inflammatory conditions driven by neutrophil influx and degranulation that is worthy of further study in other models of lung inflammation. Future work should focus on developing more specific inhibitors to offer selective control over neutrophil granule processing, and careful dosing to avoid undesired effects on bacterial killing mechanisms.

Deactivation of blood monocytes during sepsis is associated with increased mortality and susceptibility to secondary infections. Septic monocytes may also have mitochondrial DNA (mtDNA) depletion and mitochondrial respiratory dysfunction. Two principal approaches explored the link between these phenomena in THP-1 cells, a human leukaemia cell line resembling monocytes, to test the hypothesis that mtDNA depletion is important in the pathophysiology of monocytic cell immune deactivation. Firstly, the consequences of immune deactivation for mitochondria was assessed using an endotoxin tolerance model in which repeated exposures to lipopolysaccharide (LPS) trigger diminishing inflammatory responses. In parallel with the induction of endotoxin tolerance, LPS treatment lead to increased mitochondrial respiration due to the activation of mitochondrial biogenesis. These results could not be confirmed in healthy volunteers following inhalation of LPS as this model failed to induce endotoxin tolerance in blood monocytes. Secondly, the effects of depleting mtDNA, by treatment with ethidium bromide or transfection with short-interfering RNA targeted against mitochondrial transcription factor A, on immunity were measured. THP-1 cells with mtDNA depletion displayed the key phenotypic feature of deactivated septic monocytes, a decreased LPS-induced release of the pro-inflammatory cytokine tumour necrosis factor-α. Furthermore, there were significant alterations in the nuclear transcriptome of mtDNA-depleted THP-1 cells, with a particular inhibition of key innate immune signalling pathways and a marked blunting of the transcriptomic response to LPS. These investigations confirm that there are complex but vital links between mitochondria and innate immunity. Compensatory responses following an inflammatory insult include the simultaneous induction of mitochondrial biogenesis and shift to an anti-inflammatory phenotype. Moreover, when sepsis disrupts mitochondrial homeostasis the negative effects of mtDNA depletion on innate immunity may exacerbate monocyte immune deactivation. Further investigations should focus on exploring the fundamental processes coupling mitochondria with immunity and confirming these findings in blood monocytes during sepsis.

Sphingosine 1-phosphate (S1P), a bioactive lipid mediator and ligand of 5 G-protein coupled receptors, is involved in many cellular processes including cell survival and proliferation, lymphocyte migration, and endothelial barrier function. As neutrophils are major mediators of inflammation, neutrophil trans-endothelial migration could be the target of therapeutic approaches to many inflammatory conditions. The aim of this project was to assess whether S1P can protect against inflammation by affecting neutrophil trans-endothelial migration, either by acting on neutrophils directly or indirectly through the endothelial cells. The direct effects of S1P on isolated human neutrophils from healthy volunteers were assessed. It was shown that S1P signals in neutrophils mainly through the receptors S1PR1 and S1PR4 and it induces phosphorylation of ERK1/2. Moreover, S1P pretreatment enhances IL-8 induced phosphorylation. However, in chemotaxis assays, S1P pre-treated neutrophils showed no altered migration towards IL-8 in comparison to untreated neutrophils. Additionally, in an in vitro flow-based adhesion assay, S1P pretreatment did not have a significant effect on IL-8 induced neutrophil adhesion to VCAM-1 and ICAM-1. Next, the effects of S1P on endothelial cells were measured. When HMEC-1 endothelial cell line and HUVEC primary endothelial cells were treated with S1P or S1P receptor agonists CYM5442 and CYM5541, the production of the chemokine IL-8 was induced. On the other hand, this treatment inhibited neutrophil trans-endothelial migration through HMEC-1 and HUVEC endothelial cells. This indicates S1P enhances endothelial barrier integrity, with a mechanism involving reduction of VE-cadherin phosphorylation. Finally, S1P treatment caused upregulation of the adhesion molecules VCAM-1 and ICAM-1, but inhibition of TNF-α induced upregulation, also shown as reduced neutrophil adhesion to endothelial cells under in vitro flow conditions. To investigate the in vivo effects of S1P, two mouse models of cell recruitment were used, the peritoneum cell recruitment and the air pouch model. In the peritoneum cell recruitment model, S1P administration could successfully inhibit neutrophil recruitment at the peritoneum induced by IL-8. In conclusion, functional assays indicated no direct effect of S1P on neutrophil migration, although S1P receptor signalling in neutrophils can activate MAPK/ERK iii signalling pathways and enhance IL-8 signalling. However, S1P can affect neutrophil migration indirectly, either by inducing IL-8 and adhesion molecules expression by endothelial cells, or by enhancing endothelial barrier integrity leading to inhibition of trans-endothelial migration of neutrophils. The latter effect appears to be more pronounced in vivo.

This thesis addresses the possibility of applying the compressed sensing (CS) framework to Functional Magnetic Resonance Imaging (fMRI) acquisition. The fMRI is one of the non-invasive neuroimaging technique that allows the brain activity to be captured and analysed in a living body. One disadvantage of fMRI is the trade-off between the spatial and temporal resolution of the data. To keep the experiments within a reasonable length of time, the current acquisition technique sacrifices the spatial resolution in favour of the temporal resolution. It is possible to improve this trade-off using compressed sensing. The main contribution of this thesis is to propose a novel reconstruction method, named Referenced Compressed Sensing, which exploits the redundancy between a signal and a correlated reference by using their distance as an objective function. The compressed video sequences reconstructed using Referenced CS have at least 50% higher in terms of Peak Signal-to-Noise Ratio (PSNR) compared to state-of-the-art conventional reconstruction methods. This thesis also addresses two issues related to Referenced CS. Firstly, the relationship between the reference and the reconstruction performance is studied. To maintain the high-quality references, the Running Gaussian Average (RGA) reference estimator is proposed. The reconstructed results have at least 3dB better PSNR performance with the use of RGA references. Secondly, the Referenced CS with Least Squares is proposed. This study shows that by incorporating the correlated reference, it is possible to perform a linear reconstruction as opposed to the iterative reconstruction commonly used in CS. This approach gives at least 19% improvement in PSNR compared to the state of the art, while reduces the computation time by at most 1200 times. The proposed method is applied to the fMRI data. This study shows that, using the same amount of samples, the data reconstructed using Referenced CS has higher resolution than the conventional acquisition technique and has on average 50% higher PSNR than state-of-the-art reconstructions. Lastly, to enhance the feature of interest in the fMRI data, the baseline independent (BI) analysis is proposed. Using the BI analysis shows up to 25% improvement in the accuracy of the Referenced CS feature.