Thesis (Ph.D.)--Texas Christian University, 2006. / Title from dissertation title page (viewed Jan. 5, 2007). Includes abstract. Includes bibliographical references.

Techn. Hochsch., Diss., 2002--Aachen.

Humboldt-University, Diss., 2003--Berlin.

Techn. Hochsch., Diss., 1997--Aachen.

University, Diss., 2004--Bonn.

Techn. Hochsch., Diss., 2005--Aachen.

Background: Mounting evidence suggests that inflammation is involved in the pathophysiology of both Major Depressive Disorder (MDD) and schizophrenia. The presence of inflammation in the brain, however, is less clear. Microglial activation, a measure of neuroinflammation, can be quantified using PET ligands that bind to the Translocator Protein (TSPO) which is overexpressed by activated microglia. Previous PET studies using TSPO radioligands have shown some evidence for neuroinflammation in both MDD and schizophrenia. However some of these studies have been confounded by antidepressant/antipsychotic medication, low numbers and mild severity. We aimed to address some of these issues and investigate the relationship between neuroinflammation and peripheral inflammation, medication status, symptom severity and cognitive function. Method: Fourteen patients in a Major Depressive Episode (MDE) of at least moderate severity, sixteen patients with a diagnosis of schizophrenia of at least moderate severity and a total of eighteen age and gender-matched healthy volunteers underwent a 60 minute dynamic PET scan with the TSPO radioligand [11C](R)-PK11195 on the High Resolution Research Tomograph (HRRT). Parametric maps of binding potential (BPND) were generated using the simplified reference tissue model and a grey matter cerebellum input function. All of the MDD patients were antidepressant-free for at least eight months prior to scanning. Of the sixteen schizophrenia patients, eight were antipsychotic-free (for at least twelve months) and eight were on a long-acting injection of risperidone or paliperidone. All patients and healthy volunteers were medically healthy and had drug or alcohol abuse within the previous year. Results: We found a 26% mean increase in BPND values, indicative of microglial activation, in MDD patients compared to healthy volunteers. Exploratory analysis revealed significantly higher [11C](R)-PK11195 binding in the anterior cingulate cortex (ACC). We found no significant correlations between [11C](R)-PK11195 binding and peripheral markers of inflammation or with symptom severity. We also found a mean 27% increase in BPND values in the schizophrenia patients compared to healthy volunteers. There were significant correlations between [11C](R)-PK11195 and negative symptoms across multiple brain regions. When breaking the cohort down according to medication status, there was no difference between antipsychotic-free patients and healthy volunteers. However, mean BPND values were 30% higher in the ACC. The medicated patients exhibited higher BPND values than healthy volunteers, with a mean increase of 48%. Exploratory t-tests revealed significant increases in dorsolateral prefrontal cortex and ACC.Conclusions: Our findings are largely consistent with previous PET findings of increased microglial activation in a sample of antidepressant-free patients in a moderate-to-severe MDE, suggesting that neuroinflammation is present in MDD. We also investigated neuroinflammation in antipsychotic-free patients for the first time and found no evidence of microglial activation. However it is likely that the subgroup sample was underpowered. The medicated patients exhibited a 48% increase in [11C](R)-PK11195 binding compared to controls, suggesting that either medication or duration of illness might potentiate microglial activation. Our findings also point to an association between neuroinflammation and the negative symptoms of schizophrenia. The PET findings from both cohorts are largely overlapping, suggesting that neuroinflammation is not specific to either disorder but rather a common mechanism. This could reflect a common aetiology and/or an overlap in symptoms. Our findings suggest that inflammation could be used as a potential biomarker as well as a target for novel treatment strategies in both MDD and schizophrenia.

In recent years tumour hypoxia has been extensively investigated, mainly because it is a source of resistance to the common radio and chemo therapies. In fact, the low levels and heterogeneous distribution of oxygen in hypoxic microenvironment render ionizing radiation ineffective in treating cell proliferation. Furthermore, a low oxygen concentration promotes the activation of HIF-1 transcription factor, which favours the development of a more malignant and resistant cancer cell phenotype often associated with poor prognosis. Positron Emission Tomography (PET) imaging is a valuable diagnostic tool for investigating hypoxia in vivo by means of radiotracers, which incorporates both a radioisotope and a hypoxia-sensitive function. The aim of this multidisciplinary project was to develop small libraries of radiolabelled compounds starting from the biological and chemical features of the two gold standard hypoxia PET tracers [18F]FMISO and [18F]FAZA as well as those of the promising new tracer [18F]HX4. These new radiocompounds display the following peculiar structural characteristics: a 2-nitroimidazole hypoxia-sensitive moiety, different spacers to modulate steric constraint, lipophilicity and metabolic stability and a fluorinated aldopentose sugar as prosthetic group (e.g. [18F]FDR). Two series of compounds were designed and developed based on the conjugation method used to introduce the prosthetic group, namely the oxime bond formation and the thiazolidine ring closure. Six radiotracers belonging to the oxime-derivatives series were tested in vitro on MCF7 breast cancer cell lines in hypoxic conditions and a lead radiocompound incorporating a cyclopropyl group was identified. This new hypoxia tracer showed a better kinetic profile than both [18F]FMISO and [18F]FAZA in MCF7 cancer cell lines and comparable uptake values on a panel of different cancer cell lines, up to 120 min post administration at 1% of O2. These promising results will pave the way for futures in vivo studies.

A search for evidence that fundamental particles are made of smaller subconstituents is performed. The existence of excited states of fundamental particles would be an unambiguous indication of their composite nature. Experimental signatures compatible with the production of excited states of charged leptons in electron-positron collisions are studied. The data analysed were collected by the OPAL detector at the LEP collider. No evidence for the existence of excited states of charged leptons was found. Upper limits on the product of the cross-section and the electromagnetic branching fraction are inferred. Using results from the search for singly produced excited leptons, upper limits on the ratio of the excited lepton coupling constant to the compositeness scale are calculated. From pair production searches, 95% confidence level lower limits on the masses of excited electrons, muons and taus are determined to be 103.2 GeV. / Graduate

Le carbure de silicium est un des materiaux envisages pour des applications nucleaires tels que les reacteurs a fission de 4eme generation et les reacteurs a fusion. Dans ce cadre, le SiC serait soumis a des conditions extremes de temperatures et d’irradiation ainsi qu’a la presence de gaz issus des produits de fission ou d’activation qui necessitent de comprendre comment les proprietes physiques du SiC pourraient evoluer. Dans le present travail nous nous sommes attaches a etudier les phenomenes se deroulant a l’echelle atomique qui modifient la microstructure et peuvent degrader les proprietes macroscopiques. La premiere partie de cette these est consacree a la caracterisation de l’endommagement et notamment des defauts lacunaires crees dans le SiC par irradiation avec des ions lourds a differentes energies et differentes fluences au moyen de la spectroscopie d’annihilation de positons (PAS) complete par la spectrometrie Raman. Les resultats de cette etude mettent en evidence que l’importante perte d’energie electronique associee aux irradiations avec des ions lourds modifie la nature et la distribution des defauts en-dessous de 0.2 dpa. Au-dela, l’impact n’est pas visible. Pour un endommagement a fort dpa en regime de collisions elastiques, l’amorphisation peut etre atteinte. Elle se caracterise par la formation de volumes libres equivalents a l’hexalacune. La deuxieme partie est consacree a l’etude de l’interaction de l’helium avec les defauts lacunaires dans des echantillons de SiC implantes He 50 keV a deux fluences. La distribution des defauts lacunaires etudiee par PAS evolue avec la temperature et deux stades d’evolution majeurs ont ete mis en evidence, celui a plus haute temperature depend de la fluence. Des mesures de thermodesorption ont montre que le second stade coincidait avec la desorption de l’helium. Enfin, des mesures de RBS et NRA en mode canalisee ont permis de localiser l’helium dans la maille cristalline et d’observer qu’une fraction migrait en quittant des sites interstitiels tetraedriques a une temperature correspondante au premier stade. / Silicon carbide is one of the envisaged materials for nuclear applications such as GEN IV fission reactor and fusion reactor. In this framework, SiC will be exposed to extreme temperature and radiation conditions and gas presence coming from activation and fission products. It is needed to better understand how the SiC physical properties will evolve under these conditions. In this work, we have specially focused our studies on the phenomena occurring at atomic scale and which modify the microstructure leading to the degradation of the macroscopic properties. The first part of this thesis is devoted to the damage characterization and especially to the vacancy-type defects created in SiC by heavy ion irradiation at various energies and fluences by using positron annihilation spectroscopy and Raman spectroscopy. The results highlight that the important electronic loss energy associated to high energy heavy ion irradiations modify the defect nature and distribution below 0.2 dpa. Beyond this value, the impact is not visible. For a damage induced at high dpa in the elastic collision regime, the SiC is amorphised and this structure is characterized by the formation of free volume similar to the hexa-vacancy. The second part is focused on the study of helium interaction with vacancy-type defects in SiC samples implanted with 50 keV-He ions at two fluences. First, the defect distribution evolution as a function of the temperature has been studied by PAS and has evidenced two evolution stages depending on the fluence. Then, thermodesorption measurements have shown that the second stage coincide with the helium desorption. Finally, RBS and NRA measurements in channeling mode have allowed us to localize helium atom in crystal structure and to observe that a part of helium migrates from tetrahedral interstitial sites at a temperature corresponding to the first stage one.