Alzheimer’s disease (AD) is a very complex disorder and the most common form of dementia. The two pathological hallmarks of AD are extracellular amyloid-β (Aβ) plaques in cerebral cortex, and intraneuronal neurofibrillary tangles. In the early stages of the disease it can be difficult to accurately diagnose AD, as it is difficult to distinguish from normal signs of aging. There is thus a need for sensitive non-invasive tools, able to detect pathophysiological biomarker changes. One such approach is molecular imaging of Aβ plaque load in brain, using PET (positron emission tomography) ligands. We have developed and characterized two novel Aβ plaque neuroimaging PET ligands, AZD2184 and AZD4694. The 2-pyridylbenzothiazole derivate AZD2184, is a 11C-labeled PET ligand with a higher signal-to-background ratio compared to the widely used PET ligand PIB, a 11C-labeled phenylbenzothiazole based tool. This makes it possible to detect smaller changes in Aβ plaque deposition load, and therefore theoretically, also earlier diagnosis. A drawback with 11C-labeled PET ligands is the relatively short half-life. To meet the need for PET ligands with a longer half-life, we developed the pyridylbenzofuran derivate [18F]AZD4694. Although development of fluorinated radioligands is challenging due to the lipophilic nature of aromatic fluorine, we successfully developed a 18F-labeled PET ligand with a signal-to-background ratio matching PIB, the most widely used 11C-labeled PET ligand in clinical use. 3H-labeled derivates of AZD2184, AZD4694, and PIB, showed lower binding specificity towards Aβ plaques containing ApoE. The ApoE genotype per se did not significantly affect ligand binding, instead, the amount of ApoE incorporated to the Aβ plaques appears to be of importance for the binding characteristics of these amyloid PET ligands. Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid precursor protein (APP) to Aβ peptides, making BACE1 inhibition an attractive therapeutic target in AD. We developed and characterized three novel BACE1 inhibitors, AZD3839, AZ-4217, and AZD3293. AZD3839 and AZ-4217 contains an amidine group which interacts with the catalytic aspartases Asp-32 and Asp-228 of BACE1, effectively inhibiting the enzyme. All three compounds are potent and selective inhibitors of human BACE1, with in vitro potency demonstrated in several cellular models, including primary cortical neurons. All three compound exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in several species, and two of the compounds (AZD3839 and AZD3293) were progressed into clinical trials. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Submitted.</p>

Mechanical ventilation (MV) is a life-saving therapy in acute respiratory distress syndrome (ARDS), a condition that affects 3000 patients/year in Sweden with a mortality rate of about 40%. However, MV may induce or worsen lung injury causing “ventilator-induced lung injury (VILI)”. From a mechanical perspective strain (deformation, or relative change in lung volume) and stress (tension) have been postulated as main determinants of VILI. High respiratory rate is potentially another factor that may exacerbate VILI by amplifying the total energy transmitted to the lungs during MV. In this thesis in animal ARDS models the hypotheses were that 1) lung parenchyma inhomogeneities concentrate stress and amplify lung damage and inflammation, 2) higher respiratory rates increase lung inflammation and lung edema in heterogeneous ARDS, and 3) local lung deformation is related to local inflammation. First, in a rat model the effect on inflammation and structural damage of regional lung collapse on the healthy surrounding lung tissue was assessed. Second, in porcine models the effect of respiratory rate on lung edema and inflammation was studied during two ventilatory modes; a) a permissive collapse mode and b) a homogenized lung parenchyma mode. Finally, lung deformation was correlated with lung inflammation assessed by positron emission tomography using 18F-FDG uptake. It was found that; 1) local inhomogeneities can act as stress amplifiers, increasing lung tissue inflammation and damage in the healthy surrounded lung. 2) high respiratory rate increases lung edema but decreases lung inflammation when permissive lung collapse is used and that these effects are prevented with lung parenchyma homogenization; 3) local lung deformation and inflammation are well correlated. In conclusion, lung inhomogeneities may aggravate VILI, respiratory rate may affect in different ways VILI progression depending on the ventilatory strategy, and finally, lung deformation is closely related to lung inflammation. With the caveat that the studies are performed in animal models, the results suggest that using ventilator strategies that homogenize the lungs, i.e., open collapsed lung regions and prevent re-collapse in ARDS will reduce VILI and in the end may decrease morbidity and the high mortality in this condition.

Dentre as técnicas diagnósticas por imagem, em Medicina Nuclear, têm-se destacado a Tomografia por Emissão de Pósitrons (PET). O PET fornece imagens funcionais da região ou órgão de interesse, possibilitanto o diagnóstico de várias doenças e, também, um mapeamento da evolução ou regressão das mesmas. Os atuais sistemas PET apresentam blocos de cristais arranjados em geometria circular, mas a busca por novos arranjos, em geometrias diferenciadas, é pertinente, pois pode possibilitar um melhor desempenho destes tomógrafos. O objetivo deste estudo é avaliar o desempenho de um sistema PET constituído por blocos de cristais em arranjo elipsoidal. Para tal estudo, fez-se uso do GATE, ambiente de simulação para tomografia por emissão que apresentou resultados satisfatórios comparados à aparelhos utilizados na rotina clínica. Desta forma, elaborou-se dois sistemas PET, o primeiro com 46 blocos de cristais arranjados em geometria circular, no qual, os detectores opostos foram separados a uma distância de 816,4 mm na direção transaxial. No segundo caso, utilizou-se 36 blocos de cristais, arranjados em geometria elíptica, onde os detectores foram separados a uma distância de 500 mm na direção vertical e 816,4 mm na direção horizontal. Uma vez realizadas as simulações, fez-se os testes de validação para Sensibilidade, Fração de Espalhamento, NEC (Noise Equivalente Count Rate) e Resolução Espacial, para então, avaliar e comparar o desempenho do sistema PET para ambas as geometrias propostas. Estes testes foram feitos de acordo com as especificações da norma NEMA NU 2-2007. Para o teste de sensibilidade, com o phantom localizado no centro do FOV transaxial do tomógrafo, obteve-se um ganho no sistema PET, com geometria elíptica, de 28,7% em relação ao sistema convencional, de geometria circular. Para o phantom deslocado à 10 cm do centro do FOV transaxial, a sensibilidade do sistema PET elíptico foi 26,2% superior em relação ao circular. O tempo de aquisição para cada simulação neste teste foi de 400 s. Para os testes de Fração de Espalhamento e NEC foram realizadas 33 simulações, para cada geometria, variando o tempo de aquisição e a atividade. A fração de espalhamento na geometria elíptica foi de 35,5% e na circular 34,6%. Na geometria circular, a curva NEC atinge o pico máximo em 259,3 kcps a uma concentração de atividade de 34,1 kBq ml-1 , já para geometria elíptica, o pico máximo é atingido em 239,1 kcps a uma concentração de atividade de 24,8 kBq ml-1 . As medidas foram adquiridas em três posições transaxiais (x,y) no centro do FOV e, posteriormente, deslocadas em ¼ do centro do FOV, totalizando 6 medidas para cada geometria. Para cada uma destas 6 medidas, encontrou-se a FWHM (largura a meia altura) e a FWTM (largura a 10% do máximo) nos 3 eixos de coordenadas (x,y,z), assim, para cada geometria proposta obteve-se 18 valores de FWHM e 18 valores de FWTM. A geometria elíptica apresentou melhoras na resolução espacial em FWHM em 4 dos 18 valores de resolução. Já para FWTM, a geometria elíptica apresentou melhora em 8 dos 18 valores de resolução. Em relação a FWHM, onde houve melhora na resolução espacial, teve-se um ganho médio de 18,7%. Já as perdas, em resolução espacial foi em média 43,26%. Para FWTM, a melhora em resolução espacial foi em média 12,09%, mas a perda de resolução, neste caso, foi em média 45,59%. Pode-se concluir que a geometria proposta apresenta algumas vantagens em relação a geometria convencional. Na geometria elíptica há uma redução de 10 blocos de cristais em relação a geometria circular, o que possivelmente gera uma redução no custo de fabricação do tomógrafo. Em relação a sensibilidade, há uma melhora significativa para nova geometria, bem como uma redução da concentração da atividade na qual o tomógrafo alcança seu melhor desempenho, embora ocorra uma ligeira diminuição na taxa de contagens no sistema elíptico. Essa redução na concentração de atividade pode ocasionar uma redução no tempo de exame e utilização de menos material radioativo, reduzindo o risco ao paciente e o custo do exame, bem como possibilitando a realização de um maior número de exames num mesmo intervalo de tempo. A fração de espalhamento do sistema elíptico é ligeiramente maior em relação ao sistema circular. A principal perda do sistema PET elíptico está na resolução espacial, onde não houve melhoras para maior parte das medidas realizadas, necessitando de alguns ajustes que pode se dar, entre outras coisas, no arranjo dos blocos de cristais. Acredita-se que ajustes na angulação dos detectores e na formação das coincidências seja possível melhorias nas resoluções, e NEC. / Among the diagnostic imaging techniques, in Nuclear Medicine, have been prominent in Positron Emission Tomography (PET). PET provides functional images of the region or organ of interest, allowing diagnostic of various diseases and also a mapping of the development or regression of the same. Current PET systems feature blocks arranged in circular geometry crystals, but the search for new arrangements, in different geometries, is relevant because it can provide a better performance of these scanners. The objective of this study is to evaluate the performance of a PET system consisting of blocks of crystals ellipsoidal arrangement. For this study, we used the GATE simulation environment for emission tomography that presented satisfactory results compared to the devices used in the clinical routine. This way we prepared two PET systems, the first one containing 46 blocks of crystals arranged in a circular geometry, where the opposite detectors were separated by a distance of 816.4 mm in the transaxial direction. In the second case, we used 36 blocks of crystals arranged in an elliptical geometry, where the detectors are separated a distance of 500 mm in the vertical direction and 816.4 mm in the horizontal direction. After the simulations were performed, the validation tests for sensitivity, scatter fraction, NEC (Noise Equivalent Count Rate) and Spatial Resolution were made, to finally evaluate and compare the performance of the PET system for both proposed geometries. The tests were made accordingly to specified NEMA NU 2-2007 standard. For the sensitivity test, with the phantom located in the center of FOV transaxial of the tomography, we obtained a gain in PET system with elliptical geometry of 28.7% compared to the conventional system, the circular geometry. For the phantom shifted to 10 cm from the center of the transaxial FOV, the sensitivity of PET elliptical system was 26.2% higher than in the circular. The acquisition time for each simulation in this test was 400 s. For Scatter Fraction test and NEC, were made 33 simulations for each geometry, varying the time of acquisition and activity. The scatter fraction in the elliptical geometry was 35,5% and 34,6% in the circular geometry. In the circular geometry, NEC curve reaches its peak in 259.3 kcps at an activity concentration of 34.1 kBq ml-1, for the elliptical geometry, the maximum peak is reached at 239.1 kcps at an activity concentration of 24.8 kBq ml-1. For the spatial resolution test we used a point source containing 18F with 4 MBq activity and acquisition time of 200 s. The measurements were acquired in three transaxials positions (x,y) in the center of FOV and, shifted in ¼ of the center of the FOV, summarizing 6 measurements for each geometry. For each one of these 6 measurements, we found the FWHM (Full width at half-maximum amplitude) and the FWTM (Full width at tenth-maximum amplitude) in the three axis (x,y,z), in this way, for each proposed geometry, we obtained 18 values of FWHM and 18 values of FWTM. The elliptical geometry showed improvement in the spatial resolution in FWHM in 4 of the 18 resolution values. For the FWTM, the elliptical geometry showed improvement in 8 of 18 resolution values. Regarding the FWHM, where there was an improvement in spatial resolution, we obtained the average gain of 18,7%. For the losses, in spatial resolution was an average of 43,26%. For the FWTM, the improvement in spatial resolution was an average percentage of 12,09%, while the loss of resolution had the average percentage of 45,59%. It can be concluded that the proposed geometry showed some advantages regarding the traditional geometry. In the elliptical geometry there is one reduction of 10 blocks of crystals in relation to the circular geometry, which possibly can cut fabrication costs of the tomography. Regarding to sensibility, there is a significant improvement for the new geometry, as well as one reduction of the activity concentration in which the tomography reaches the best performance, although the occurrence of a slight fall in the counts in the elliptical system. This reduction in the activity concentration can help to reduce the test time and the use less radioactive material, reducing the risk for the patients and the test costs, as well as improving the number of tests in the same period of time. The scattering fraction in the elliptical system is slight higher to the circular system. The major loss in the elliptical PET system is the spatial resolution, where there was not improvement for the great fraction of the obtained measurements, requiring some modifications that can be made, in special, in the crystal blocks arrangement. It is believed that some modifications to the angle of the detectors and in the formation of the coincidences can improve the resolutions and NEC.

Cardiovascular disease remains the commonest cause of death worldwide. The majority of deaths are caused by atherosclerotic plaque rupture with resultant myocardial infarction or stroke, or rupture of abdominal aortic aneurysms. Conventional imaging modalities have consistently failed to identify atherosclerotic plaques or aneurysms with high-risk pathological features that are at highest risk of rupture or progression. The development of modern molecular imaging techniques targeted at these features could lead to the identification of such high-risk plaques and aneurysms in vivo and guide the development of novel treatment strategies. The aim of this thesis was to evaluate whether novel molecular modalities have a role in providing new insights into biological disease processes, and identify high-risk plaques and aneurysms. Using positron emission tomography-computed tomography (PET-CT), 18F-fluorodeoxyglucose and 18F-fluoride were utilised as markers of metabolic inflammation and active calcification. Cellular inflammation was assessed using ultrasmall superparamagnetic particles of iron oxide (USPIO) enhanced magnetic resonance imaging (MRI). In a prospective trial, 80 patients with myocardial infarction (n=40) and stable angina (n=40) underwent 18F-fluoride and 18F-fluorodeoxyglucose PET-CT, and invasive coronary angiography (Chapter 3). Intense 18F-fluoride uptake localised to recently ruptured plaque in patients with acute myocardial infarction. In patients with stable coronary artery disease, 18F-fluoride uptake identified coronary plaques with high-risk features on intravascular ultrasound. 18F-fluoride PET-CT is the first noninvasive imaging method to identify and localise ruptured and high-risk coronary plaques. Aortic vascular uptake of 18F- fluorodeoxyglucose was studied in patients with myocardial infarction and stable angina (Chapter 4). In a separate outcome of 1,003 patients enrolled in the Global Registry of Acute Coronary Events, we further evaluated whether infarct size predicted recurrent coronary events. Patients with myocardial infarction had higher remote atherosclerotic tracer uptake that correlated with the degree of myocardial necrosis, and exceeded that observed in patients with stable coronary disease. The outcome cohort demonstrated that patients with higher degree of myocardial necrosis had the highest risk of early recurrent myocardial infarction. This supports the hypothesis that acute myocardial infarction exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: myocardial infarction begets myocardial infarction. In a prospective imaging cohort, the role inflammation and calcification was assessed in 63 patients with abdominal aortic aneurysms and 19 age and sex matched patients with atherosclerosis (Chapter 5). Compared to non-aneurysmal segments, enhanced inflammation and calcification was observed within the wall of aortic aneurysmal segments. In comparison to matched controls with atherosclerosis, the entire aorta in those with aortic aneurysm appears more highly inflamed, suggesting presence of a global aortopathy rather than a disease confined only to the abdominal region of the aorta. Aortic aneurysms have greater active inflammation and calcification than atherosclerotic controls suggesting a more intense, destructive and transmural pathological process. A subgroup of fifteen patients with aortic aneurysms underwent imaging with both PET-CT with 18F-fluorodeoxyglucose, and T2*- weighted MRI before and 24 h after administration of USPIO (Chapter 6). Whilst there was a moderate correlation between the two tracers, there were distinct differences in the pattern and distribution of uptake suggesting a differential detection of macrophage glycolytic and phagocytic activity respectively. These studies provide novel insights into vascular biological processes involved in the initiation, progression and rupture of atherosclerotic plaques and aortic aneurysms. Future longitudinal studies are needed to establish whether these techniques have a role in improving the clinical management and treatment of patients with coronary artery disease and aortic aneurysms.

Positron emission tomography (PET) is a quantitative and non-invasive investigative tool, which permits the identification of pivotal biomarkers and their role in disease onset, transformation and progression. Quantitative detection of these disease biomarkers has qualified PET as a pioneering approach to rapid diagnosis. The tool is a powerful approach to patient diagnosis and investigation of inter- and intra- patient disease heterogeneity thereby supporting patient stratification and forging a truly personalised medicine approach. The sensitivity of PET is complemented by use of highly selective radiopharmaceuticals; this has fuelled the popularity of radiolabelled affinity peptides and proteins (APPs). Inspired by the high selectivity and affinity of biological protein-protein interactions, APP-based radiotracers are an increasingly popular class of radiotracer. Monoclonal antibodies (mAbs) are an important category of APP-based radiotracer; their prevalence in the field is attributed to their high target selectivity and affinity characteristics, which, will likely, uphold their popularity in the field. Yet, advancements in protein engineering has transformed the landscape of APP-based radiotracers, indicated by a preference for small radiolabelled APPs which exhibit rapid pharmacokinetics whilst retaining high target specificity and affinity. Their fast pharmacokinetics is matched by the half-life of 18F which has been defined as an ideal PET radionuclide. 18F APP radiolabelling hasn't yet met its full potential due to its inherent challenges; many approaches have been adopted, ranging from non-site specific radiolabelling with amine reactive prosthetic groups to site-specific methods including oxime bond formation. The radiochemistry of 18F APP radiolabelling is diverse and evolving; yet ideal goals are apparent including site-specificity, fast reaction kinetics, mild labelling conditions and applicability to automation. Automation is challenging for multi-step 18F APP radiolabelling methods, but is a key developmental step. Automation helps with conformance to good manufacturing practice (GMP) by enhancing process robustness, consistency and reliability. It also permits the radiosynthesis of clinically relevant radiotracer doses. The development of an automated generic platform, or a method that adopts a general approach, for APP radiolabelling with 18F would assist in [18F]APPs meeting their potential in PET and, importantly, aid their translation from bench-to-bedside.

No description available.

Polyethylene Terephthalate (PET) has become the preferred material of choice for many packaging applications. A preference over glass due to its low weight, similar transparency to glass and cost consideration, including the availability of recycled PET feedstock via kerbside collection has provided newer opportunities for hot-fill applications. Ostensibly, this material is used for beverage markets requiring cold and hot filling (85 oC) of liquid foods. However due to the poor thermal stability of PET - due to its low glass transition temperature - an increase in elevated temperatures limits the number of market segments the material can be utilised. Current practices incorporate the heat-set process, aimed at improving the crystallisation kinetics within the amorphous and crystalline region. This body of work incorporates a single stage Injection Stretch Blow Moulding machine (ISBM). Modifications to conventional carbonated soft drink (CSD) beverage containers to include heat-set capabilities are incorporated. The current research study investigates the potential benefits of RPET blends for improving thermal stability at elevated temperatures. This study investigates changes in mechanical properties which include • Youngs modulus, • top load strength, • burst strength, • Thermal analysis specifically investigating changes in • Glass transition temperature, • enthalpy changes due to heat-set conditions • Percentage crystallinity changes as a function of heat-set conditions Rheological characteristics to all materials used were investigates. Furthermore, changes in the physical properties to each PET beverage container were investigated which include; • process shrinkage (S1), • hot-fill shrinkage (S2) • Density changes via optimised DoE parameters. A combination of cold (80 oC) and hot moulds (150 oC) as measured via Forward Looking Infrared (FLIR) at the exterior to the blow mould and their affect on percentage crystallinity was studied. Preform surface temperature (PST) and strain induced crystallinity, assisting in molecular relaxation is analysed. Upon completion to an exhaustive experimental ISBM trial, a DoE software package - in this case Echip - was used to analyse and predict optimised hot-fill shrinkage values of 2.5 percent with a maximum constrained RPET blend value totalling 40 percent. ISBM optimised conditions demonstrated advantages when combining an increased preform surface temperature, RPET blends and optimised ISBM process conditions as indicated via the DoE at low heat-set temperatures.

Molecular imaging is becoming an important contributor to the development of personalized medicine. Positron Emission Tomography (PET) is a technology that enables molecular imaging by allowing a physician to detect and map the location of various physiological processes. The purpose of this work is to design, fabricate and test a mechanism that would make the production of the PET isotope, copper-64 practical for both researchers and commercial suppliers. In order to have the maximum usefulness, the design needs to fit and operate within several constraints. A one dimensional thermal analysis indicated that operation of the system under existing cooling conditions would be a reasonable solution. Based on the design specifications, a detailed design was completed and fabricated. The design was functionally and operationally tested with the performance meeting expectations. The design was utilized to produce copper-64 isotope with a typical one hour bombardment producing 30 mCi of isotope. The design could be optimized if future isotope demand exceeded current production capacity or if research required the production of other radioisotopes with varying thermal characteristics.

A telephone questionnaire was developed to collect information on pet owners, cat ownership patterns, and people's opinions about homeless pets. A 7-day observation log was also developed to gather information about free-roaming cats in Caldwell, TX. The objectives of this research were: (1) to evaluate the reliability of the telephone questionnaire, (2) to assess general cat ownership patterns, (3) to evaluate attachment level of pet owners to their pets, (4) to determine general opinions about free-roaming cats, (5) to determine if demographics were associated with opinions about free-roaming cat and dog problems and (6) to investigate free-roaming cat activity in a community. Telephone questionnaire information collected from 100 subjects was tested for reliability. Reliability was fair to good for cat level questions (sex, age, breed, length of time owned, indoor/outdoor status, litter, number of vet visits, vaccinated). Reliability was good for questions concerning subjects' knowledge of cat and dog behavior and levels of attachment to their pets. Reliability was excellent for all household level (demographic) variables. Reliability was moderate for questions regarding subjects' opinions about homeless animals. Telephone questionnaire responses collected from 441 subjects were checked for associations using exploratory logistic and linear regression models. A cat's role as a pet, vaccination status, and the length of time owned were associated with a cat's sterilization status. A cat's role as a pet was associated with the cat's indoor/outdoor status. Household size, education level and ethnicity of the owner were associated with cat ownership. Having children was associated with a negative opinion about homeless cats. Education level was associated with subjects' knowledge about dog and cat behavior. Gender, household size, and knowledge score were associated with subjects' attachment to their pets. Descriptive information on free-roaming cat activity was collected from 21 subjects using the 7-day observation log. Subjects made 382 cat sightings during the study period. Slightly more cat sightings were made during the morning than in the evening and afternoon. Most cats were spotted in neighborhoods and were resting or eating. Most of these cats that were eating were seen during the morning or evening hours.

La pathologie pleurale est fréquente dans la pratique médicale. Dans certaines séries, une effusion pleurale est retrouvée chez 10 % des patients hospitalisés en médecine interne. Les épanchements pleuraux peuvent refléter tant une pathologie pleurale princeps que les manifestations dun grand nombre de pathologies pulmonaires et extra-thoraciques. La recherche étiologique de ces pleurésies impose un diagnostic différentiel vaste sous-tendu par des processus physiopathologiques très différents. En particulier, il est de première importance didentifier une pathologie pleurale maligne eu égard à sa prise en charge spécifique et à son pronostic extrêmement réservé. Comme nous lavons rappelé dans une revue de littérature explicitant lexploration pleurale actuellement admise, limagerie conventionnelle ne présente pas de critère spécifique pour le diagnostic différentiel bénin vs malin dune pathologie pleurale. De même, la rentabilité de la thoracocentèse et de la biopsie pleurale percutanée demeure relativement faible et justifie fréquemment le recours à la thoracoscopie médicale. Dans notre travail, nous avons poursuivi trois objectifs. Notre premier objectif a été dévaluer lintérêt de la tomographie à émission de positrons (TEP) utilisant pour traceur le 18F-fluorodéoxyglucose (18FDG) dans le diagnostic étiologique de la pathologie pleurale et, en particulier, dans lidentification des effusions malignes. Dans ce cadre, nous avons aussi évalué la faisabilité dune mesure semi-quatitative de lhyperfixation du 18FDG dans le diagnostic différentiel bénin vs malin dune pleurésie, ainsi que dans la localisation thoracique vs extra-thoracique des pleurésies métastatiques. Nous avons pu établir deux valeurs seuils distinguant ces groupes respectifs. Notre deuxième objectif a été dévaluer la valeur pronostique de lintensité de lhyperfixation pleurale du 18FDG. Nous avons ainsi démontré que la quantification de lhyperfixation du 18FDG au niveau de la pleurésie présentait une valeur pronostique chez des patients présentant une néoplasie pulmonaire non à petites cellules avec pleurésie métastatique. Fort de ces données, nous avons positionné limagerie métabolique dans lapproche diagnostique de la pathologie pleurale et précisé ses indications cliniques. Enfin, notre troisième objectif a été dévaluer la valeur de lanalyse biochimique, en particulier de cytokines ou de facteurs de croissance dans le diagnostic étiologique des épanchements pleuraux. Nous avons étudié lintérêt du dosage pleural de 3 cytokines/facteurs de croissance (Interleukine-6 (IL-6)), Transforming growth factor-β1 (TGF-β1) et Vascular endothial growth factor (VEGF)) dans les pleurésies malignes. Nous avons démontré que, contrairement à lIL-6 et au TGF-β1, seul le VEGF présentait un taux significativement plus élevé dans les pleurésies malignes comparativement aux bénignes. Nous avons montré que le taux de VEGF pleural était corrélé à des marqueurs de lagressivité de la pleurésie (taille de lépanchement, nombre de globules rouges au sein de la pleurésie, taux pleural de glucose et de lactate déshydrogénase (LDH)). Toutefois, malgré ses taux pleuraux accru dans les pleurésies malignes, le dosage du VEGF dans le liquide pleural revêtait une rentabilité diagnostique modeste dans la distinction entre une pleurésie maligne et une bénigne. En outre, nous avons démontré que dans le diagnostic bénin vs malin dune pleurésie, la combinaison des trois critères classiques de Light, définissant un exsudat (rapport des taux pleuraux/sanguins des protéines, des LDH et la valeur absolue du taux de LDH pleuraux supérieur au 2/3 de la norme supérieur), présentait une sensibilité et une rentabilité diagnostiques similaires à celles du VEGF voisine de 60%. En conclusion, limagerie métabolique par TEP est discriminante pour affirmer la malignité dune pathologie pleurale et constitue un facteur pronostique indépendant de survie des patients atteints de pleurésies métastatiques de tumeur pulmonaire non à petite cellule. Dès lors la TEP sintègre dans lalgorithme décisionnel du diagnostic, et de la prise en charge dune pathologie pleurale et permet déviter de recourir systématiquement à une technique dinvestigation pleurale invasive. Quoique significativement plus élevés dans les pleurésies malignes, le taux pleural de VEGF présente un pouvoir discriminant modeste dans le diagnostic différentiel bénin vs malin dune pleurésie exsudative. Toutefois, ces observations aident à la compréhension physiopathologique des pleurésies tumorales et ouvrent la porte à de nouvelles thérapeutiques. Summary: Pleural involvements are common in various respiratory diseases including inflammatory, infectious, occupational or neoplastic pathological entities and pleural thickening and pleurisy are usual radiological presentation. Pleural pathology is found in 10 % of the patients hospitalized in a department of internal medicine. Pleural effusions can be induced both by primary pleural disease and by lung and extra-thoracic pathologies. Finding their etiology imposes a vast and sometimes difficult differential diagnosis as different physiopathological processes may be involved in thickening and effusions. In particular, its of first importance to identify malignant pleural disease in consideration of its specific treatment and its dire prognosis. Here we review the currently accepted pleural diseases investigation methods. There are no specific diagnosis criteria for malignancy with conventional pleural imaging by radiology, ultrasound, scanning and nuclear magnetic resonance. The analysis of chemistry, bacteriology and cytology of pleural fluid obtained by thoracocentesis makes a significant contribution to the diagnostic approach even though its diagnostic sensitivity does not exceed 62 %. Similarly, although allowing tissue examination, the sensitivity of closed-needle pleural biopsies does not exceed 51 %. Therefore the invasive thoracoscopy is often justified to find out the accurate diagnosis of pleural diseases, achieving a diagnostic sensitivity greater than 95%. Our goals in this thesis were threefold. Our first objective was to study the accuracy of positron emission tomography (TEP) using the 18F-fluorodeoxyglucose (18FDG) to distinguish between benign and malignant disease in exudative lymphocytic pleural effusions and pleural thickening. We evaluated the diagnostic performance of 18FDG TEP imaging with semi-quantitative analysis for differentiating benign from malignant pleural effusions and for guiding the search for the primary tumor (extra-thoracic vs thoracic location) of pleural metastases. We established two threshold values distinguishing benign from malignant pleural lesions on the one hand and extra-thoracic from thoracic malignant pleurisies on the other hand. Our second objective was to estimate the value of the pleural 18FDG uptake intensity as an independent survival prognosis factor in non small cell lung cancer with pleural extension (T4 NSCLC). We showed an inverse relationship between survival and pleural metabolic activity while there was no relationship between survival and the primary tumor metabolic activity. Finally, our third objective was to assess the value of biochemical analysis and in particular the value of cytokine (IL-6) and growth factors ((TGF-ß 1, VEGF) in differentiating benign from malignant pleural effusions. No significant difference was found between malignant and benign effusions with respect to IL-6 and TGF- pleural levels. In contrast to IL-6 and TGF-pleural VEGF concentrations were significantly higher in malignant than in benign effusions. Furthermore VEGF levels correlated with the effusion volume, pleural LDH and glucose levels and red cell counts. Nevertheless, although being greater in malignant pleural effusions, pleural VEGF levels are of a rather limited clinical interest in distinguishing between malignant and benign pleural effusions. VEGF levels did not perform better than the use the 3 combined Lights criteria in this attempt with a quite similar sensitivity around 60%. In conclusion, the metabolic imaging by TEP is an accurate method for differentiating benign from malignant pleural diseases and the intensity of the pleural 18FDG uptake seems to be an independent survival prognostic factor in non small cell lung cancer with pleural malignant effusion. Our results suggest TEP could be integrated in the investigation algorithm of pleural diseases and facilitate decision-making as to when begin invasive procedures. Raised pleural VEGF levels in malignant effusions are related to the aggressiveness of the tumors and, although of limited diagnostic value, should prompt the evaluation in the near future of new treatment strategy using anti-VEGF.