No description available.

No description available.

The clinical profile of Gulf War Illness (GWI) is characterized by the presence of the central nervous systems (CNS) symptoms, which include memory impairment, anxiety, widespread pain and motor problems. Now, even twenty years later, veterans with GWI continue to suffer from these persistent symptoms. Currently, there is no treatment available for treating GWI, which is largely due to the complexity of the clinical presentation of this illness and the heterogeneity of OW exposures. The main goals of this thesis were to develop and characterize GW agent exposure mouse models that recapitulate the CNS symptoms of GWI and to identify the underlying aberrant biological pathways. Three major objectives were undertaken to accomplish these goals: (1) Two mouse models of OW-agent exposure were developed using combination of the anti-nerve gas treatment pyridostigmine bromide (PB), pesticide (permethrin), an insect repellent (N,N-Diethyl-meta-toluamide) and stress. Neurobehavioral studies show that combined exposure to GW agents produced anxiety and sensorimotor deficits in one mouse model and anxiety and cognitive impairment in the other. Neuropathological studies showed a presence of astrogliosis in both models. (2) Exploratory proteomic studies suggested that lipid-metabolism and immune/inflammation were associated with GW-agent exposure. (3) As lipid dysfunction is upstream of the inflammatory pathways, a lipidomics approach was used to identify the OW-agent exposure dependent lipid profiles. Lipid profiles of mouse models of OW-agent exposure were compared with those of other neurological conditions to identify profiles that were unique to GW-agent exposure. Lipid profiles were interrogated to identify lipid-metabolism pathways that may be amenable to therapeutic targeting. Studies described in this thesis provide novel insight into the pathobiology of GWI and suggest that pathways involved in phosphatidylcholine metabolism might be of therapeutic value in treating the CNS symptoms of GWI.

An organism exposed to a stressful situation will undergo a complex array of physiological and behavioural changes aimed at the preservation of the organism during the stressful event as well as at stimulating adaptive and mnemonic processes in case the event would reoccur in the future. It is well-known that the hippocampus is highly involved in these processes. It has become clear in recent years that the processing of environmental stimuli in the hippocampus could be via changes in epigenetic state that lead to changes in neural function.

Conscientiousness exerts a protective effect on health and longevity. Recent evidence suggests that Conscientiousness may influence future health status via the experience of stress; either directly through reduction of stress exposure, and/or indirectly by buffering the negative effects of stress. Four empirical studies were conducted using multi-method approaches to explore the relationships between Conscientiousness, daily stress, and health outcomes. Daily diaries and multi-level modelling were employed to test the effects of daily stress on physical symptoms and daily mood, and whether Conscientiousness moderated these effects. Conscientiousness, and its facets, showed direct and indirect effects: Self Control was associated with experiencing fewer, less intense daily hassles; Industriousness positively predicted positive affect; Conscientiousness also moderated the relationship between appraisals and positive affect, such that stressful appraisals predicted lower positive affect for the low conscientious group on1y. These findings demonstrate multiple ways m which Conscientiousness may affect the daily experience of stress, and the relationships between stress and daily health outcomes. Relationships between Conscientiousness, daily experience and cortisol were also explored. Day-to-day changes in daily experience and cortisol were investigated, together with the influence of Conscientiousness. Conscientiousness did not have a main effect on the cortisol awakening response (CAR) or diurnal cortisol levels. However, appraisals negatively predicted the next-day CAR, and thinking about the day's schedule in the morning positively predicted the CAR. The latter effect was moderated by Conscientiousness, such that it was significant only in the low Responsibility group. A lower CAR also predicted the experience of more physical symptoms throughout the day. Therefore, daily experiences influenced cortisol levels, but cortisol also influenced daily health outcomes, and Conscientiousness moderated some of these effects. This thesis supports the suggestion that daily stress is important in explaining, in part, the relationship between Conscientiousness and health outcomes, and highlights multiple pathways between these variables.

Since the introduction of immersive virtual reality (VR) equipment, a number of studies have found that users can experience unpleasant side effects. A major focus of VR research and development has been on head-mounted display (HMD) based systems. Incorporation of an HMD provides the user with a sensation of immersion and presence in the virtual environment (VE), and it has been these systems that have attracted the most attention from both the media and human factors researchers over the last ten to fifteen years. Health and safety concerns associated with the use of this technology include symptoms experienced by users which resemble those of motion sickness (for example, disorientation, pallor, stomach awareness and nausea) and reports of visual discomfort, particularly eyestrain. The motion sickness-like symptoms have been referred to as virtual simulation sickness (VSS), and VSS is considered to be a form of visually-induced motion sickness. Susceptibility to motion sickness varies immensely, however females are generally regarded as being more susceptible than males to all forms of motion sickness, and it has been suggested that this heightened susceptibility in females could be attributed to the functioning of the female endocrine system. Changes to many of the body's systems have been reported to occur over the menstrual cycle, and it is reasonable to suggest that changes in susceptibility to nauseogenic visual stimuli may also occur. The first piece of research conducted in this thesis examined the influence of the menstrual cycle on susceptibility to VSS. 16 naturally cycling females were immersed in a nauseogenic YE on specific days (5, 12, 19 and 26) of their menstrual cycle, these days were chosen because they fall in line with peaks and troughs of ovarian hormone levels. The menstrual cycle phase of participants was confirmed by the measurement of salivary oestradiol and progesterone levels. The responses from the naturally cycling females (the experimental group) were compared to those from two control groups, consisting of 16 pre-menopausal females taking a combined monophasic oral contraceptive, and 16 men. Susceptibility to VSS did vary over the menstrual cycle, with susceptibility increasing on day 12, this was seen as both an increase in symptom severity and a decrease in symptom onset time. No consistent variation was seen in the females taking a combined monophasic oral contraceptive. In addition to susceptibility to VSS changing over the menstrual cycle, variations in reports of visual discomfort were also apparent, with visual discomfort also increasing on day 12. As no previous research has investigated the influence of the menstrual cycle on susceptibility to visual discomfort, two studies were conducted to determine whether such a relationship exists in other situations. The first was a laboratory based experiment whereby visual discomfort was induced by prolonged accommodative effort, and the second was a field study whereby reports of visual discomfort were examined in individuals performing intensive VDU work. Unlike the changes in visual discomfort seen over the menstrual cycle in females viewing a nauseogenic VE through an HMD, no changes in visual discomfort were found over the menstruaJ cycle when visual discomfort was induced by prolonged accommodative effort, or by intensive VDU work. It was concluded from this research that the previously seen changes in susceptibility to visual discomfort over the cycle, in females viewing a nauseogenic VE, were not a consequence of susceptibility to visual discomfort changing over the cycle. In the first experiment, susceptibility to VSS was seen to increase on day 12, as manifest by an increase in the severity of nausea reported on this day, and increases in general bodily discomfort. It is suggested that the change in visual discomfort reported over the cycle is a consequence of these general changes rather than having a specific ocular origin. This idea was supported in a fourth experiment which examined symptom reports collected from 88 participants immersed in a nauseogenic virtual environment at weekly intervals. A relationship was found between the severity of symptoms of VSS reported and the amount of visual discomfort reported.

This thesis develops statistical methodology for an important area of environmental epidemiology, that of the relationship between short-term exposure to air pollution and mortality or morbidity which has been a public health concern for over fifty years. The majority of studies investigating this relationship are based on ecological data, and estimate a group level association between ambient pollution levels and population aggregated mortality. This association is typically estimated with Poisson regression models, which make a number of simplifying assumptions about the underlying processes that generate the data. The work presented in this thesis extends the standard approaches to modelling these data in three main ways, the first proposing the use of autoregressive processes rather than smooth functions to remove any long-term trends and temporal correlation in the daily mortality series. The second extension relates to the pollution-mortality relationship, and investigates whether it changes over time rather than being constant or a dose-response curve. The remainder of this thesis investigates the importance of correctly estimating pollution exposures, and how mis-estimating them affects the resulting health risk. These extensions are implemented using Bayesian hierarchical models with estimation achieved via Markov chain monte carlo simulation. For the first two extensions likelihood based alternatives are also presented, using a combination of maximum likelihood and least squares methods. The thesis ends with a concluding discussion.

No description available.

Οι ομάδες των ορμονών που επηρεάζουν σημαντικά την αύξηση και την ανάπτυξη των παιδιών και των εφήβων, ανήκουν κυρίως στον άξονα της αύξησης και της αναπαραγωγής, στο σύστημα του stress και στο αναοσολογικό σύστημα. Η κορτιλόλη, η λεπτίνη και η IL-6 αποτελούν στρεσογόνους παράγοντες οι οποίοι συνδέονται με τη δυναμική της ανάπτυξης και ενηβωσης του ανθρώπινου οργανισμού. Εκτός από την επίδραση τον ορμονών, η ενήβωση και η αναπαραγωγή του φύλου μπορεί να επηρεαστεί από φαρμακολογικούς παράγοντες, όπως είναι η υδροκορτιζόνη, τα αναβολικά στεροειδή και τα οιστρογόνα. Η φυσική άσκηση είναι ένας τύπος φυσικού stress που προκαλεί πλήθος ορμονικών, μεταβολικών και ανοσολογικών αλλαγών ενώ οι αθλητές και οι αθλήτριες ρυθμικής και ενόργανης γυμναστικής εκτίθονται σε έντονους φυσικούς και ψυχολογικούς στρεσογόνους παράγοντες. Τα τελευταία χρόνια οι προσδιορισμοί στο σίελο προσελκύουν τεράστιο ενδιαφέρον (λόγω του ανώδυνου τρόπου συλλογής του σιέλου) και κυρίως χρησιμοποιούνται στην Ενδοκρινολογία για την παρακολούθηση των επιπέδων των στεροειδών ορμονών. Υλικά και Μέθοδοι: Μελετήθηκαν 142 αθλήτριες και 97 αθηλτές της ενόργανης γυμναστικής υψηλού αγωνιστικού επιπέδου καθώς και 107 αθλήτριες της ρυθμικής γυμναστικής. Ως ομάδα ελέγχου μελετήθηκαν 73 κορίτσια και 68 αγόρια, τα οποία δεν αθλούνταν. Η συλλογή των δειγμάτων έγινε χρησιμοποιώντας μια ειδικά σχεδιασμένη συσκευή συλλογής σιέλου (Salivette). Για τον προσδιορισμό της λεπτίνης στο σίελο χρησιμοποιήθηκε ραδιοανοσολογική μέθοδος ενώ για τον προσδιορισμό της κορτιζόλης η μέθοδος ηλεκτροχημειοφωταύγειας. Για την μέτρηση της IL-6 στο σίελο αναπτύχθηκε και επικυρώθηκε μέθοδος Elisa υψηλής ευαισθησίας. Αποτελέσματα: Οι αθήτριες της ρυθμικής και της ενόργανης γυμναστικής χαρακτηρίζονται από υψηλότερα επίπεδα κορτιζόλης στο σίελο (p<0,01) συγκριτικά με τους μάρτυρες και τους αθλητές της ενόργανης. Τόσο στους αθλητές όσο και στις αθλήτριες της ενόργανης γυμναστικής, οι απογευματινές τιμές κορτιζόλης (μετά από άσκηση) παραμένουν στα ίδια επίπεδα με τις πρωινές τιμές. Στις αθλήτριες της ενόργανης τα επίπεδα της IL-6 παρουσιάζουν τάση αύξησης και της λεπτίνης τάση μείωσης μετά από άσκηση, αν και οι μεταβολές αυτές δεν είναι στατιστικά σημαντικές. Συμπεράσματα: Η συλλογή του σιέλου είναι μια μη επεμβατική, ανώδυνη τεχνική που επιτρέπει την επαναλαμβανόμενη δειγματοληψία. Η ραδιοανοσολογικής μέθοδος είναι απλή και εύκολη για τον προσδιορισμό της λεπτίνης στο σίελο, ενώ η μέθοδος της ηλεκτροχημειοφωταύγειας αποτελεί αξιόπιστη επιλογή για τη μέτρηση της κορτιζόλης στο σίελο. Για τον προσδιορισμό της IL-6 στο σίελο απαιτείται η ανάπτυξη και η επικύρωση μεθόδου Elisa, λόγω του ότι ο σίελος επηρεάζει τη μέτρηση της συγκεκριμένης κυταροκίνης. Τόσο στις αθλήτριες όσο και στους αθλητές της ενόργανης γυμναστικής υψηλού αγωνιστικού επιπέδου, ο νυχθημερήσιος ρυθμός έκκρισης της κορτιζόλης καταργείται. Επίσης οι αθλήτριες της ενόργανης γυμναστικής χαρακτηρίζονται από υψηλότερες τιμές δεικτών stress συγκριτικά με τους αθλητές. / -

La radiothérapie induit des séquelles aigues puis tardives affectant les tissus sains inclus dans le volume irradié. D'une façon générale, le processus lésionnel se caractérise par une ischémie vasculaire, une apoptose cellulaire et une fibrose cicatricielle. Dans ce contexte, la thérapie cellulaire à l'aide de cellules souches mésenchymateuses médullaires CSMM pourrait constituer une nouvelle approche thérapeutique séduisante, les CSMM ayant une capacité intrinsèque à promouvoir l'angiogenèse et une implication dans les processus naturels de réparation tissulaire. La première partie de ce travail a consisté à la mise au point de modèles murins présentant un processus de dégénérescence tissulaire similaire à celui survenant après radiothérapie. L'objectif étant d'affiner la compréhension des mécanismes physiopathologiques des lésions tissulaires radio-induites et de déterminer une stratégie thérapeutique la plus adaptée possible. La seconde partie de ce travail a été consacrée à l'évaluation de la faisabilité d'une autogreffe de CSMM dans le modèle murin d'irradiation précédemment établi en répondant à deux pré-requis : la rétention des cellules injectées au niveau du tissu cible et l'évaluation de la greffe sur le métabolisme osseux. Cette investigation préclinique sur un modèle murin a permis de réaliser une étape essentielle dans l'évaluation du traitement des lésions tissulaires radio-induites par thérapie cellulaire. Les données issues de ces travaux pourraient à terme permettre la mise en place d'études cliniques. / Radiation therapy induced acute and late sequelae within healthy tissue included in the irradiated area. In general, lesions are characterized by ischemia, cell apoptosis and fibrosis. In this context, cell therapy using bone marrow mesenchymal stem cells (BMSC) might represent an attractive new therapeutic approach, based partly on their angiogenic ability and their involvement in the natural processes of tissue repair. The first part of this work consisted in the development of experimental mouse model of radio-induced tissue degeneration similar to that occurring after radiotherapy. The aim was to better understand the physiopathological mechanisms of radiation-induced tissue damage and to determine the best treatment strategy. The second part of this work investigated the feasibility of autologous BMSC therapy on the murine model of radiation previously established with emphasis on two pre-requisites : the retention of the injected cells within the target tissue and the evaluation of the graft on bone metabolism. This preclinical investigation in a mouse model constitutes an essential step allowing an evaluation of the benefit of cell therapy for the treatment of radiation-induced tissue injury. Data from these studies could allow the proposal of clinical studies.