L'administration intraveineuse d'ADN thérapeutique rencontre de nombreux obstacles liés à sa dégradabilité, ainsi qu'à sa difficulté à pénétrer les cellules en raison de sa taille importante et de son hydrophilie. Des lipoplexes conjugués à de l'acide hyaluronique (HA) de haut poids moléculaire ont été développés afin de délivrer de l'ADN plasmidique à l'intérieur de cellules cancéreuses exprimant le récepteur membranaire CD44, récepteur clé du développement tumoral. L'emploi d'HA conjugué au phospholipide DOPE (HA-DOPE) et d'un plasmide modèle GFP a permis d'obtenir des lipoplexes d'environ 250 nm, chargés négativement, protégeant efficacement l'ADN contre les nucléases et activant peu la fraction C3 du système du complément. Dans un modèle cellulaire exprimant CD44, la transfection optimale a été obtenue par l'utilisation de lipides avec 10% d'HA-DOPE complexés à de l'ADN selon un rapport 2:1. Ces lipoplexes sont internalisés par la voie des cavéoles et de façon dépendante du récepteur CD44. Cette formulation a été appliquée à la vectorisation d'un gène thérapeutique, codant pour le récepteur des estrogènes β (ERβ), qui est un potentiel suppresseur de tumeur. Sur un modèle in vivo de xénogreffes de cellules humaines de cancer du sein estrogéno-dépendant et exprimant CD44, la diminution du volume tumoral, ainsi que de l'indice de prolifération Ki67 ont permis de montrer l'effet anticancéreux par voie intraveineuse des lipoplexes conjugués à l'HA.

The Measurement and Characterisation of Aerosol in the Urban Atmosphere (PM 10) and an Evaluation of the Sources of these Particles by Number Andrew Lindsay Dye Abstract The link between human health and the mass of fine particulate matter below 10 tm (PM10) in air is well documented. Current research suggests that the number, size and shape of particles may be of most concern and that in the urban atmosphere combustion sources of PM10, especially diesel engine sources, dominate the fine (< 1µm) and ultra-fine (<0.1 µm) particles. Despite this, the number, size and shape of particles in urban air has not been reported to any great extent or detail, and the percentage contribution to the numbers of particles from different sources is largely unknown. The objectives of this research were to characterise fine particles with respect to their morphology and thus apportion the sources of particles by number. Urban aerosol above 1 µm was initially examined to study the fluctuations in PM10 number and make retrospective analysis of periods of elevated PM10 for source identification in Plymouth, UK. Aerosol was collected via a Burkard spore trap and examined using light microscopy with image analysis between 16 March 1995 and 31 August 1996, at a background site in Plymouth, UK. Two periods, 19 Januamy-4 February and 10-25 March 1996, identified as UK wide PM 10 episodes, were retrospectively studied and compared with PM10 mass measurements. The mean number count for the whole period was 10.5 x 104 ± 7.9 x 104 particles m-3 . The two PM10 episodes had elevated average number concentrations of 13.5 x 104 ± 7.6 x 104 particles m-3 for 19 January - 4 February 1996, and 13.0 x 104 ± 9.7 x 104 particles n13 for 10-25 March 1996. During the periods of elevated PM10 the tapered element oscillating microbalance (TEOM) mass of particles had a low correlation with the particles less than 5 µm and an increased correlation to the particles greater than 5 µm in size. Outside of these peak periods the PM10 TEOM mass was most closely correlated with the number of particles less than 5 µm in size. This work shows the difference in urban aerosol during periods of air quality guideline exceedence. These findings agree with literature that an aged continental aerosol source has a key role in the generation of UK wide PM10 mass exceedances. Further analysis of the fine urban aerosol (< 1 µm) was made using direct sampling of urban aerosol on to porous carbon films (PCF) developed in this research. The efficiency of collection was low (ca 5%) but the samples were representative and enabled transmission electron microscopy (TEM) for sub-micron particle analysis. Measurement was made of the fractal dimensions and diameter of particles. This was used to identif' any ageing and ultimately the sources of aerosol. PCF were used in the simultaneous collection of urban roadside and background aerosol, on seven dates between December 1996 and August 1997 in Plymouth, UK. The average perimeter fractal dimension (PFD) of aerosol was consistently significantly greater at the roadside than the background (+ 0.02), indicative of a smoother, aged aerosol at the background site. The sampling of a variety of combustion engines was made for source identification purposes. The particle morphology produced from the diesel engines showed great uniformity of particle morphology with varying speed and load; no consistent significant differences were found. The morphology results were comparable to other density fractal dimensions and penmneter fractal dimension values found in other studies for diesel. A natural log relationship between the median particle size and the median PFD was found for the diesel engine sources but not in petrol samples. This natural log trend was considered as a tentative 'fingerprint' of diesel engine combustion and was in harmony with literature values of PFD for diesel engine particles. Using the fractal measures, size and particle classification the bulk of aerosol was identified as from hydrocarbon combustion sources; ca. 88-92% of the roadside and ca. 77-86% of background. A component of carbon ceno-spheres were identified contributing ca. 6-12% of both the roadside and background aerosol. Non-combustion particles increased from ca. 1-4% of the roadside to ca. 7-9% of the background, as did the proportion of aged combustion particles, from 0-1% of roadside to 2-3% of the background aerosol. A strong correlation for the median size vs. PFD morphology curve between, the roadside and diesel sources (0.93 - 0.95) and the background and petrol sources was found (0.95). The roadside aerosol was significantly different to the petrol source in the 120-220nm size range (p=O.007) and there was a low correlation of the petrol and the roadside size vs. morphology curve (0.66). This suggests the domination of roadside aerosol by diesel engine particles. The background aerosol was similar to both diesel and petrol engine sources, especially from a dilution tunnel, thus indicative of a mixture of sources and an aged combustion aerosol. Roadside sources thus dominate the fine and ultra fine urban aerosol by number as compared to most other studies which have only apportioned the sources of particles in the air by mass.

The supply of drinking water in Gokwe District (NW Zimbabwe) is almost entirely based on groundwater drawn from boreholes and open dug wells. In certain areas of the district, the occurrence of dental fluorosis has been linked to excessive fluoride in the water supplies. A high prevalence of dental fluorosis (about 62%) was previously recorded among school children in the district. The aim of this study was to determine relationships between the spatial distribution of fluoride content in drinking water supplies in Gokwe, and lateral and vertical geological variation. A total of 224 water samples were collected from 196 water sources in the study area (a further 18 water sources just outside the study area were also sampled). All the samples were analysed for fluoride in the field using the fluoride ion selective electrode method (FISE). One hundred and fifty nine duplicate samples were analysed for fluoride and common anions and cations using High Performance Ion Chromatography (HPIC) in the laboratory. Two main groups of computer programmes were employed: (1) Geographic Information System (ArcView® GIS) was used to store, analyse and display multiple layers of surface geologic and geographic information, and (2) a three-dimensional visualisation programme (Rockworks) was used to interpret and illustrate site stratigraphy based on borehole information. Results indicated that the fluoride content of drinking water in the study area ranges from 0 to 9.65 mg/L. Forty-seven water sources (24%) yielded water containing fluoride in excess of the World Health Organisation's (WHO) health limit of 1.5 mg/L F. Of the 47 high fluoride water sources, 43 were boreholes (pumped or artesian). The shallower water sources (dug wells, streams and dams) largely yielded low-fluoride water. / The groundwater fluoride contamination is stratigraphically controlled and originates from carbonaceous material (carbonaceous shales, carbonaceous mudstones and coaly material) within the Lower Madumabisa and Middle Wankie Members of the Lower Karoo Group. It has been shown that in general the greater the proportion of carbonaceous material intersected by a borehole, the greater the fluoride concentration of the water. Probable mineral sources of fluoride within the carbonaceous material include fluorapatite, kaolinite and trona. Chemical parameters that appear to influence the concentration of dissolved F in the water supplies include total dissolved solids (TDS), NaCl and pH. In relatively low fluoride waters, F concentrations generally increase with TDS and NaCl concentrations, whereas the highest F concentrations are found in moderately alkaline (pH 7.8-9) waters. Based on ranges of fluoride concentration in drinking water, fluorosis-risk zones were identified and have been illustrated on a fluorosis-risk map. The zones are: No Risk Zone (0-1.5 mg/L F), Moderate Risk Zone (1.5-3.0 mg/L F), High Risk Zone (3.0-6.0 mg/L F) and the Very High Risk Zone (6.0-10.0 mg/L F). The map suggests that groundwater available to people occupying 3650 km z (60.8%) of the study area potentially contains excessive fluoride (F>1.5 mg/L), presaging the occurrence of dental fluorosis, skeletal fluorosis and crippling skeletal fluorosis in the area. Different strategies may be employed to ameliorate the fluoride problem in Gokwe. / These include sinking new boreholes to optimal depths and in appropriate locations, promoting the use of surface water and shallow groundwater, resettlement and defluoridation. However in order to fully understand the problem and to prescribe these or other solutions more comprehensively, multi-disciplinary studies may be required. Such studies may consider isotopic dating of water to investigate any relationships between fluoride concentration and residence time of water, geochemical analyses of rocks and soils, detailed fluorosis epidemiology studies and test-scale defluoridation investigations.

La pathologie Tau est une lésion commune à plus d'une vingtaine de maladies neurodégénératives, regroupées sous le terme de Tauopathies. Elle correspond à l'accumulation intracellulaire de matériel fibrillaire constitué de protéines Tau hyper- et anormalement phosphorylées. Dans la maladie d'Alzheimer (MA), démence la plus courante chez la personne âgée, la progression et la distribution topographique de ces agrégats évoluent au cours du temps et sont corrélés aux déficits cognitifs observés. A ce jour, les traitements sont principalement symptomatiques. Cependant, plusieurs stratégies thérapeutiques sont étudiées parmi lesquelles l'immunothérapie. Les travaux présentés dans cette thèse ont pour objectif d'étudier les effets de l'immunothérapie Tau, active et passive, dans un modèle transgénique murin mimant la pathologie Tau de type Alzheimer. Les souris THY-Tau22, surexpriment une isoforme de Tau humaine mutée sur deux sites et sous contrôle d'un promoteur neuronal. Ce modèle présente dès l'âge de trois mois des altérations progressives de l'apprentissage et de la mémoire en parallèle d'une accumulation de protéine Tau principalement au niveau hippocampique, sans perte neuronale majeure, ce qui lui confère les caractéristiques d'un stade précoce de MA. Au sein du modèle THY-Tau22, on retrouve la protéine Tau phosphorylée en Ser422, un épitope particulièrement pertinent pour l'immunothérapie. En effet, la pSer422 est un épitope de phosphorylation anormale unique, présent dans la plupart des Tauopathies. Dans ces travaux de thèse, nous montrons que la vaccination précoce contre la Ser422 phosphorylée de la protéine Tau peut prévenir l'altération de mémoire spatiale mesurée par le test du labyrinthe en Y. Cette diminution de l'atteinte cognitive est associée à une diminution de la phosphorylation anormale de Tau au niveau de l'hippocampe et à une réduction significative des espèces insolubles de Tau. Les résultats de cette vaccination nous ont amenés à générer un anticorps monoclonal dirigé contre la pSer422 (2H9) afin d'évaluer les effets de l'immunothérapie passive. Selon la même cinétique d'âge, nous avons injecté, chaque semaine, par voie intrapéritonéale, des souris THY-Tau22 avec 5mg/kg et 10mg/kg de 2H9 ou une solution saline. Cette approche prévient l'apparition de déficits de mémoire spatiale mesurée par les tests du labyrinthe en Y et de la piscine de Morris. Les analyses immunohistochimiques révèlent également une réduction des protéines Tau anormalement phosphorylées au niveau de l'hippocampe. Afin d'étudier les mécanismes sous-jacents à l'immunothérapie anti Tau, nous avons injecté des anticorps anti-phosphoTau par stéréotaxie au niveau de l'hippocampe de souris THY-Tau22. Nous montrons, qu'une fois au sein du cerveau, ils sont capables d'entrer dans les neurones contrairement au contrôle isotypique. Plusieurs études récentes d'immunothérapie, suggèrent une implication de la macroautophagie dans la dégradation médiée par les anticorps. Nous montrons que les anticorps internalisés dans les neurones colocalisent avec différents marqueurs de la voie lysosomiale (NPC1, Lamp2) confirmant l'hypothèse d'une dégradation par le lysosome. Cependant, la barrière hémato encéphalique étant très sélective, il est fort probable que les anticorps générés restent en périphérie. Nous montrons, que l'administration périphérique de 250µg d'anticorps 2H9 génère une augmentation significative de la protéine Tau au niveau plasmatique suggérant un mécanisme de siphon périphérique comme dans l'immunothérapie Aβ. La vaccination, qui génère une réponse polyclonale, conduit à une augmentation plus importante de la Tau plasmatique qui confirme l'hypothèse d'une dégradation périphérique de la protéine Tau. L'ensemble des résultats de cette thèse confirme le potentiel de l'immunothérapie Tau dans le traitement de la maladie d'Alzheimer et des autres Tauopathies. Il propose une nouvelle hypothèse quant à la dégradation de la protéine Tau médiée par les anticorps: l'effet siphon périphérique.

Les recommandations de bonne pratique, issues de la médecine des preuves, s'insèrent dans un processus ancien visant à asseoir la légitimité médicale sur la science et se sont déployées en tant qu'instrument politique de rationalisation des pratiques.Comment rencontrent-elles les valeurs professionnelles et l'exercice de la médecine ?La question est traitée dans le cadre de la médecine générale et de l'hypertension artérielle (HTA) dont la mise en recommandations est exemplaire de la construction d'un risque en santé publique.La première partie s'intéresse à l'origine de la médecine des preuves et en quoi ce mouvement est porteur de continuité et de modification dans les relations entre Médecine et État, au sein de la profession, entre médecin et patient.La seconde partie, centrée sur une microsociologie des consultations de patients hypertendus, montre que les recommandations constituent un appui pour le travail médical de prise de conscience par le patient de la réalité pathologique de l'HTA et des risques cardiovasculaires associés. Mais le généraliste inscrit son action dans la durée et, sous influence du patient, négocie et fait des compromis voire déroge aux " bonnes pratiques ", considérant que ce qui n'est pas réalisable aujourd'hui le sera demain.Les recommandations sont intégrées dans les pratiques sous forme d'un modèle hybride associant la référence aux données scientifiques et l'adaptation à la singularité de la situation. La figure du patient statistique porté par la médecine des preuves est confrontée à la réalité sociale de l'individu plus ou moins doté d'autonomie et de ressources dont il s'agit pour le médecin d'acquérir la confiance et de la conserver.

Le cancer de la prostate est la troisième cause de mortalité par cancer chez l'homme après les cancers colorectaux et broncho-pulmonaires avec, en 2010, près de 150 000 décès. On voit donc tout l'intérêt d'élaborer de nouvelles stratégies thérapeutiques en essayant de prendre en compte à la fois : i) la métabolisation qui peut modifier in vivo l'efficacité de la molécule initiale et ii) les différences individuelles intervenant à ce niveau du fait de la nature de l'environnement du patient.Nous avons porté notre étude, en collaboration avec l'Ecole HEI de Lille, sur l'intérêt de la Phenstatine (molécule en développement pré-clinique) et de ses métabolites puisque qu'au cours de ces dernières années des résultats thérapeutiques prometteurs ont été obtenus, dans les cancers prostatiques hormono-résistants avec les taxanes, dont le rôle est de stabiliser les microtubules en inhibant leur dépolymérisation.L'objectif de ce travail de thèse a donc été dans un premier temps d'étudier l'effet pharmacologique de la Phenstatine et de ses métabolites issus de sa biotransformation par des microsomes hépatiques humains sur la polymérisation de la tubuline ainsi que sur la prolifération de la lignée cancéreuse prostatique humaine PC3. Nous avons ensuite essayé de déterminer les CYPs responsables de la formation des métabolites identifiés et quantifiés. Enfin, nous avons abordé l'influence de certaines conditions environnementales, plus particulièrement la présence de cadmium, sur le métabolisme de ces composés originaux et donc sur leur activité vis-à-vis de cellules cancéreuses prostatiques. Pour tenter de comprendre la réponse ou la non réponse à ces différents traitements, nous avons suivi les profils d'expression de gènes impliqués dans la prise en charge cellulaire des xénobiotiques en utilisant une technologie fonctionnant à haut débit et basée sur le principe de la PCR quantitative en temps réel (TaqmanTM Low Density Arrays). Un modèle d'étude a pu ainsi être élaboré afin de montrer l'implication de l'environnement sur l'efficacité d'une molécule à visée anticancéreuse. Ce modèle devrait par la suite pouvoir être élargi à d'autres agents participant à la métabolisation des xénobiotiques et déboucher sur la mise en évidence des mécanismes génétiques ou épigénétiques responsables de ces réponses particulières aux traitements anticancéreux.

The need to strengthen the role of environmental and health considerations in decision-making processes is increasingly recognized by the Canadian government and industry-based organizations. Integrating human health into environmental assessments (EAs) at the earliest stage is critical for identifying and managing potentially adverse effects. The World Health Organization states health depends on our ability to understand and manage the interaction between human activities and the physical and biological environment. We have the knowledge for this but have failed to act on it. In light of this shortfall, the primary objectives of this research are to evaluate the scope of health within EA, and to evaluate the state-of-practice with regard to the incorporation of human health impacts into the EA process within Canadas Northern natural resource sector. The adopted methodology combines both a mail-out questionnaire survey of practitioner and administrator experiences with EA across the North, as well as semi-structured interviews with health professionals. The results confirm the importance of human health integration in northern EA; however, in practice, human health or human health impacts are receiving inconsistent and superficial treatment with very little agreement as to the scope of health issues in EA. Project-based assessments are often limited to the investigation of the biophysical impacts and neglect to consider the social and cultural effects, and broader determinants of health. In cases where broader social health issues are addressed, attention seems to be limited to those impacts for which the proponents have direct control over, notably employment and business opportunities. Subsequently, the performance of northern EAs is often less than satisfactory, and improvements are required in the EA process to correct this. Barriers to effective integration were found to include an incomplete understanding of the scope of health in EA; difficulties identifying causal links between project actions, environmental change and human health; the absence of standardized procedures; as well as economic and temporal barriers. Adapting the EA process to the specific needs of the North, including local culture and customs, and diverse knowledge systems is therefore necessary for EA practice to be successful. The research results contribute to a larger project to increase the understanding and effectiveness of health and EA systems, with specific attention on the Canadian North.

Since 1970, vehicle’s exhaust pollutions have received increasing attention as a source of air pollution at both local (human health concerns) and global (global warming) scales. This study mainly discusses diesel and gasoline vehicles because, today, over 90% of vehicles on the road use gasoline and diesel fuels. The major concerns of gasoline exhaust contaminants are carbon monoxide (CO), hydrocarbon (HC), carbon dioxide (CO2) and polycyclic aromatic hydrocarbons (PAHs); the major concerns of diesel exhaust emissions contaminants are nitrogen oxides (NOX) and particulate matter (PM). The aim of this study is mainly to compare gasoline and diesel fuels, and to determine which fuel and its developed forms are less harmful to humans, and which are most suitable for the natural environment at both a local and global level. The results show that burning gasoline fuels will emit less PM and NOX emissions than burning diesel fuels, but it will generate about 50% more CO2 than diesel fuels, and it also emit about ten times more CO, PAHs and around five times more HC than diesel fuels; burning diesel fuels will produce less CO2 emissions than gasoline fuels, but will emit around ten times more NOX and PM than gasoline fuels. Consequently using a gasoline car in urban areas might help to reduce the human health effects; using a diesel car on motorways or in rural areas might help to reduce the greenhouse gas (GHG) emissions and minimize the global warming effects. Biofuels, biodiesel and ethanol, have the potential to minimize the vehicle exhaust emissions and adverse effects. Nonetheless, there are still many debatable issues around biodiesel, such as insufficient fuel supply and health concerns (especially, ultrafine particles (UFPs)). In the future, there remains a need to continue the further studies of vehicle exhaust emissions, and to improve the understanding of all vehicle exhaust emissions and all of their impacts, especially the vehicle exhaust health research.

The need to strengthen the role of environmental and health considerations in decision-making processes is increasingly recognized by the Canadian government and industry-based organizations. Integrating human health into environmental assessments (EAs) at the earliest stage is critical for identifying and managing potentially adverse effects. The World Health Organization states health depends on our ability to understand and manage the interaction between human activities and the physical and biological environment. We have the knowledge for this but have failed to act on it. In light of this shortfall, the primary objectives of this research are to evaluate the scope of health within EA, and to evaluate the state-of-practice with regard to the incorporation of human health impacts into the EA process within Canadas Northern natural resource sector. The adopted methodology combines both a mail-out questionnaire survey of practitioner and administrator experiences with EA across the North, as well as semi-structured interviews with health professionals. The results confirm the importance of human health integration in northern EA; however, in practice, human health or human health impacts are receiving inconsistent and superficial treatment with very little agreement as to the scope of health issues in EA. Project-based assessments are often limited to the investigation of the biophysical impacts and neglect to consider the social and cultural effects, and broader determinants of health. In cases where broader social health issues are addressed, attention seems to be limited to those impacts for which the proponents have direct control over, notably employment and business opportunities. Subsequently, the performance of northern EAs is often less than satisfactory, and improvements are required in the EA process to correct this. Barriers to effective integration were found to include an incomplete understanding of the scope of health in EA; difficulties identifying causal links between project actions, environmental change and human health; the absence of standardized procedures; as well as economic and temporal barriers. Adapting the EA process to the specific needs of the North, including local culture and customs, and diverse knowledge systems is therefore necessary for EA practice to be successful. The research results contribute to a larger project to increase the understanding and effectiveness of health and EA systems, with specific attention on the Canadian North.

Shellfish are an important food source however they are known to harbour bacteria, viruses and toxic chemicals that can be detrimental to their human consumers. Oysters have been associated with the gastroenteritis virus Norovirus. New Zealand has some of the highest cases of foodborne illness in the western world. This study investigated a possible link between periods of high rainfall and reported Norovirus outbreaks in four major cities in New Zealand (Auckland, Wellington, Christchurch and Dunedin) as well as national data. Norovirus is a highly infectious foodborne illness. Outbreaks of norovirus have been linked to the consumption of shellfish, and in particular oysters. Norovirus virions can enter the aquatic environment via sewage as a result of human shedding of the virus. This investigation into rainfall and Norovirus outbreaks found no statistically significant relationship, in a monthly or season setting. In addition the relationship between environmental cadmium levels and exposure levels in New Zealand was investigated through meta-analysis. Cadmium is a heavy metal commonly associated with the mining of copper and zinc ores. It is found naturally in the environment, in air land and oceans Increased exposure to cadmium is known to have a number of serious detrimental health effects, in particular this study investigates cadmiums immunosuppressive properties. Concentrations in New Zealand were compared with Canada, Italy and the UK to determine if New Zealand has a relatively high cadmium intake. Interestingly environmental levels (soil and oceanic) in New Zealand were low. Cadmium levels were higher in oysters than in mussels, with New Zealand oysters containing the highest concentration of cadmium presented. New Zealanders also had the highest cadmium burdens in the kidneys and the highest daily intakes. A No Observable Effect Level (NOEL) was calculated from mice data and compared to the daily intakes of the four countries. Both Canada and New Zealand were above this level. Shellfish are a common mechanism for exposure to both Norovirus and cadmium. The levels of cadmium present in the diet of New Zealanders may be sufficiently high to suppress the immune system, making it more vulnerable to infections of enteric diseases such as Norovirus.