This overview reviews seventeen publications between 1995 and 2005. CHE Imray was the first author of eleven of the papers, the senior author of four and a major contributor to two of the publications. The overview should be read in conjunction with the full copies of the seventeen publications (Appendix 2). The brain is exquisitely sensitive to oxygen requiring a constant supply of adequately oxygenated blood to function normally. Cerebral oxygen delivery is dynamic, and alters rapidly in response to changes in physiological and pathological stimuli. Interference with cerebral oxygen delivery, either as a result of decreased cerebral blood flow, decreased arterial oxygenation or particulate matter (cerebral microemboli) within the blood can all rapidly result in temporary or permanent loss of function within minutes. The author has used non-invasive cerebral perfusion imaging techniques, initially in the clinical setting (in clinic, at the bedside and in the operating theatre) and later transferring these methods to the field setting at high altitude. As a result of these studies, new insights into cerebral perfusion have been gained. Novel concepts such as 'virtual altitude' and 'partitioning of arterial and venous volumes' have been developed. New equipment has been designed and developed, such as the recumbent, collapsible, portable exercise bike. Finally new clinical treatments have been developed, including an apparently safe way to treat the high-risk group of patients with crescendo transient ischaemic attacks or mini-strokes, greatly reducing the risk of developing a subsequent major stroke. The work submitted for consideration for a PhD by publication represents ten years of investigation in two closely inter-related fields. The aim of the submission is to provide a background to the seventeen publications (Appendix 2) allowing them to be seen in context to existing knowledge. Appendix 3 contains twelve additional communications that have either been published, or accepted for publication after the original list of seventeen publications was submitted to the University of Glamorgan. They confirm the author's ongoing interest and contributions to this field of research.

La carbamazépine est une molécule antiépileptique très largement utilisée au point de devenir un marqueur environnemental de l'activité humaine. Elle donne lieu à des réactions d'hypersensibilité particulières, rares mais potentiellement létales, associant manifestations cutanées, hyperéosinophilie et atteintes multi-organiques (DRESS syndrome). Les hypothèses physiopathologiques font principalement appel aux métabolites de la carbamazépine mais la voie métabolique minoritaire des dérivés acridiniques est peu explorée. Les résultats obtenus à partir de stimulations ex vivo en laboratoire indiquent d'une part que l'acridine stimule la sécrétion d'interleukine-5 (facteur de croissance principal des éosinophiles), et d'autre part que la formation d'acridine et d'acridone est possible dans le sang à partir de métabolites primaires (époxyde et iminostilbène). Les données cliniques montrent une diminution des taux sanguins du 9-hydroxyméthyl-10-carbamoylacridan et du rapport acridine/acridone au cours de l'état de DRESS. Le co-traitement par l'acide valproïque majore le taux basal d'IL-5 et oriente en partie le profil métabolique vers celui du DRESS. L'étude de l'action des procédés oxydatifs environnementaux indique que les lits bactériens et le lagunage augmentent le rejet d'acridine. Nos travaux en pharmacologie humaine positionnent l'acridine et l'acridone comme des métabolites sanguins, a minima marqueurs et a maxima acteurs de la physiopathologie du DRESS. L'établissement d'un profil métabolique apparaît justifié lors d'une co-thérapie avec l'acide valproïque chez des patients à terrain atopique. L'acridine semble également être un marqueur environnemental d'intérêt. / Carbamazepine is a very usefull antiepileptic drug, widely used at the point of becoming an environmental marker of human activity. It is giving rise to rare but potentially lethal hypersensitivity reactions, with specific combination of skin manifestations, eosinophilia and multi-organ damage (DRESS syndrome). The pathophysiological hypotheses rely primarily to metabolites of carbamazepine, but the minor pathway of acridinic derivatives is little explored.The results obtained from ex vivo stimulation in our laboratory suggest both that acridine stimulates the secretion of interleukin-5 (main growth factor of eosinophils), and that the formation of acridine and acridone is possible in blood from primary metabolites (epoxide and iminostilbene). Clinical data show a decrease in blood levels of 9-hydroxymethyl-10-carbamoylacridan and in the ratio (acridine / acridone) during the state of DRESS. Co-treatment with valproic acid increases the basal rate of IL-5 and diverts, at least in part, to the metabolic profile of DRESS. The study of the action of environmental oxidative processes indicates that the purification processes by trickling filters and stabilization ponds increase the release of acridine, while activated sludge systems have little impact.Our work in human pharmacology positions acridine and acridone as regular blood metabolites, involved as markers or actors of the pathophysiology of DRESS. The determination of the metabolic profile appears warranted for atopic patients requiring co-therapy with valproic acid. Acridine also appears to be a marker of environmental interest.

The relevance of preconceptional and prenatal toxicant exposures for genomic stability in offspring is difficult to analyze in human populations, because gestational exposures usually cannot be separated from preconceptional exposures. To analyze the roles of exposures during gestation and conception on genomic stability in the offspring, stability was assessed via the Comet assay and highly sensitive, semiautomated confocal laser scans of gammaH2AX foci in cord, maternal, and paternal blood as well as spermatozoa from 39 families in Crete, Greece, and the United Kingdom. With use of multivariate linear regression analysis with backward selection, preconceptional paternal smoking (% tail DNA: P>0.032; gammaH2AX foci: P>0.018) and gestational maternal (% tail DNA: P>0.033) smoking were found to statistically significantly predict DNA damage in the cord blood of F1 offspring. Maternal passive smoke exposure was not identified as a predictor of DNA damage in cord blood, indicating that the effect of paternal smoking may be transmitted via the spermatozoal genome. Taken together, these studies reveal a role for cigarette smoke in the induction of DNA alterations in human F1 offspring via exposures of the fetus in utero or the paternal germline. Moreover, the identification of transgenerational DNA alterations in the unexposed F1 offspring of smoking-exposed fathers supports the claim that cigarette smoke is a human germ cell mutagen.