Diagnosis of diabetes mellitus, presence of hyperglycemia, and/or insulin resistance confer cardiovascular risk, particularly for diastolic dysfunction. Diabetes is associated with elevated myocardial norepinephrine (NE) content, enhanced sympathetic nervous system (SNS) activity, altered resting heart rate, and depressed heart rate variability. Positron emission tomography (PET) using the NE analogue [11C]meta-hydroxyephedrine ([11C]HED) provides an index of myocardial sympathetic neuronal integrity at the NE reuptake transporter (NET). The hypothesis of this project is that (i) hyperglycemia imparts heightened sympathetic tone and NE release, leading to abnormal sympathetic neuronal function in the hearts of diabetic rats, and (ii) these abnormalities may be reversed or prevented by treatments to normalize glycemia. Sprague Dawley rats were rendered insulin resistant by high fat feeding and diabetic by a single dose of streptozotocin (STZ). Diabetic rats were treated for 8 weeks with insulin, metformin or rosiglitazone, starting from either 1 week (prevention) or 8 weeks (reversal) after STZ administration. Sympathetic neuronal integrity was evaluated longitudinally by [11C]HED PET. Echocardiography measures of systolic and diastolic function were completed at serial timepoints. Plasma NE levels were evaluated serially and expression of NET and β-adrenoceptors were tested at the terminal endpoints. Diabetic rats exhibited a 52-57% reduction of [11C]HED standardized uptake value (SUV) at 8 weeks after STZ, with a parallel 2.5-fold elevation of plasma NE and a 17-20% reduction in cardiac NET expression. These findings were confirmed by ex vivo biodistribution studies. Transmitral pulse wave Doppler echocardiography established an extension of mitral valve deceleration time and elevated early to atrial velocity ratio, suggesting diastolic dysfunction. Subsequent treatment with insulin but not metformin restored glycemia, reduced plasma NE by 50%, normalized NET expression, and recovered [11C]HED SUV towards non-diabetic age-matched control. Diastolic dysfunction in these rats persisted. By contrast, early treatment with insulin, metformin, or rosiglitazone delayed the progression of diastolic dysfunction, but had no effect on elevated NE and reduced [11C]HED SUV in diabetic rats, potentially owing to a latent decrease in blood glucose. In conclusion, diabetes is associated with heightened circulating and tissue NE levels which can be effectively reversed by lowering glycemia with insulin. Noninvasive interrogation of sympathetic neuronal integrity using [11C]HED PET may have added value in the stratification of cardiovascular risk among diabetic patients and in determining the myocardial effects of glycemic therapy.

Background-Pulmonary artery hypertension (PAH) is characterized by progressive vascular changes causing increased pulmonary resistance and eventual right heart failure (HF). It has been suggested that altered myocardial substrate utilization may be associated with right HF, however these changes have not yet been well characterized. The aim of this study was to evaluate in vivo right ventricular (RV) function and RV glucose and fatty acid metabolism in an experimental model of PAH using non-invasive positron emission tomography (PET) imaging and to investigate the effect of a novel endothelin receptor antagonist, Macitentan, on the development of PAH and RV energetics. Methods and Results-Severe PAH was induced in a total of 11 male Sprague-Dawley rats using a single injection of Sugen5416 followed by chronic hypoxia. The rats were then randomized to treatment or no treatment with Macitentan (30 mg/kg daily) Five and eight weeks post injection, substrate utilization was serially assessed with 2-[18F]fluoro-2-deoxyglucose (FDG) and 4-[18F]fluoro-6-thia-heptadecanoate (FTHA) PET scans for glucose and fatty acid metabolism respectively, and reported as a standardized uptake value (SUV). This data was correlated with in vivo functional measurements with echocardiography and multi gated acquisition scans. The Sugen-hypoxia (SuHx) model resulted in an increase in RV FDG uptake over 8 weeks (SUV control: 1.56 ± 0.38, week 5 SuHx: 4.06 ± 1.90, week 8 SuHx: 4.00 ± 1.60, p<0.005 between control and week 5 SuHx). RV FTHA data showed a trend towards increased uptake with onset of PAH at week 5 SuHx (SUV control: 1.50 ± 0.40, week 5 SuHx: 3.06 ± 1.10, p>0.05). Macitentan significantly decreased RV FDG uptake (SUV week 8 SuHx: 4.00 ± 1.60, week 8 SuHx +ERA: 2.54 ± 0.90, p<0.05). This was associated with improved RV ejection fraction (PAH week 8 untreated: 53.15 ± 9.9% vs PAH week 8 treated: 73.22 ± 4.8%, p<0.01) and improved pulmonary artery pressures measured by pulmonary artery acceleration time (PAH week 8 untreated: 17.32 ± 2.30 ms vs. PAH week 8 treated: 24.38 ± 3.90 ms, p<0.001). There was a strong correlation between increased pulmonary artery pressures and increased RV FDG uptake (r=0.87, p=0.001) as well as a significant inverse relationship between improved RV ejection fraction and decreased RV FDG uptake (r=-0.72, p=0.01). Conclusion-PAH is associated with metabolic changes in the RV, characterized by increased glucose uptake and a trend towards increased RV fatty acid uptake with onset of PAH. Macitentan attenuated RV FDG uptake and significantly increased RV function as well as hemodynamics compared to untreated group.

Injectable biomaterials have emerged as a treatment for myocardial infarction (MI). They can be applied either as an enhancement for cell therapy or as a stand-alone treatment for MI. The main focus of this study was to apply circulating angiogenic cells (CACs) with or without an injectable collagen matrix for MI treatment in a mouse model. Furthermore, a collagen-chitosan matrix was tested for modulating the myocardial maladaptive remodeling post-MI. First, the in vivo thermo-gelling and retention properties of the collagen matrix were validated using positron emission tomography (PET) tracer and quantum dot (Qdot) labelled matrix in MI mouse hearts. The therapeutic potential of the matrix ± CACs was then tested in a mouse MI model. The results showed that CACs-only and matrix-only treatments were associated with cardiac function preservation. However, in combination, CAC + matrix therapy had a synergistic effect and significantly improved cardiac function (echocardiography), perfusion and viability (PET scan), increased cell engraftment and arteriole density, and reduced the infarct size. CAC-matrix interaction through the integrin alpha2 receptor was essential for the observed therapeutic effect. In a third study, the addition of chitosan (a polysaccharide) to the collagen matrix was shown to reduce maladaptive remodeling post-MI by limiting cardiac fibroblast-to-myofibroblast differentiation and scar formation. In conclusion, these collagen-based hydrogels hold promise to enhance cardiac repair as a delivery scaffold for therapeutic cells, and/or as a stand-alone treatment, which can actively modulate the environment including the fibrotic process after MI.

M.Phil. (Energy Studies) / This dissertation details the radiation shielding analysis and optimization performed to design a shield for the mineral-PET (Positron Emission Tomography) facility. PET is a nuclear imaging technique currently used in diagnostic medicine. The technique is based on the detection of 511 keV coincident and co-linear photons produced from the annihilation of a positron (produced by a positron emitter) and a nearby electron. The technique is now being considered for the detection of diamonds in Kimberlite rock, in which mineral-PET technology aims to improve diamond mining through the early detection of diamond bearing rocks. High energy photons are produced via Bremsstrahlung (which occurs when electrons from an accelerator, impinge on a high density target)...

L’expérience GBAR repose sur la production d’ions antihydrogène positifs dans le but de mesurer l’accélération gravitationnelle à laquelle est soumise l’antimatière au repos. Le projet ANTION, sous-projet de GBAR, a pour but la production de ces ions d’antimatière. Il vise également à mesurer la section efficace de production d’antihydrogène dans les collisions d’antiprotons sur des atomes de positronium, ainsi que les sections efficaces correspondantes avec la matière, de production d’hydrogène et de l’ion hydrogène négatif. Ces expériences reposent sur la formation d’un nuage très dense de positronium, et nécessitent donc une grande quantité de positons qui seront implantés sur un matériau convertisseur de positons en positronium. Cette thèse décrit la construction d’un piège à “buffer gas” à trois étages, destiné à piéger et accumuler des positons pour le projet ANTION. L’association d’un piège de Penning avec une source basée sur un Linac constitue un montage expérimental unique. Le piège a été construit et optimisé, et est maintenant pleinement opérationnel. Les protocoles de piégeage ont été étudiés et les effets du gaz tampon et du gaz de refroidissement sur le taux de piégeage et la durée de vie des positons ont été quantifiés. Afin de faciliter la mesure de la section efficace de production de l’hydrogène, une simulation avec GEANT4 a été mise au point. Elle décrit l’évolution temporelle et spatiale des atomes d’ortho-positronium dans la cavité où aura lieu la production d’hydrogène. On estime que 2.7 atomes d’hydrogène sont produits pour des proton de 6 keV d’énergie incidente, en utilisant les sections efficaces calculées avec le modèle “Coulomb-Born Approximation”, et 1.6 atomes d’hydrogène pour des protons de 10 keV, si l’on utilise la méthode “two-center convergent close-coupling”. Les simulations permettent également d’estimer le bruit de fond associé aux positons et à l’annihilation du para-positronium. Cette étude amène à proposer une modification permettant d’augmenter le nombre d’atomes de positronium dans la cavité. En parallèle, une étude a porté sur l’efficacité de modération de positons d’une couche épitaxiale de carbure de silicium 4H-SiC. Une efficacité de modération de 65% a été mesurée pour des positons implantés avec une énergie de l’ordre du kilo- électronvolt. Ce résultat intéresse les expériences de physique utilisant des positons lents, car il permet d’améliorer la luminosité de faisceaux de positons; dans le cas de GBAR cela permettrait d’augmenter l’efficacité de piégeage des positons. / The GBAR experiment relies on the production of antihydrogen positive ions to achieve its goal of measuring the gravitational acceleration of antimatter at rest. The ANTION project, included in the GBAR enterprise, is responsible for the production of these antimatter ions. Moreover, it also aims to measure the cross section of antihydrogen production throughout the collision of antiprotons and positronium atoms, as well as the matter cross sections of hydrogen and the hydrogen negative ion. These experiments imply the formation of a very dense positronium cloud, thus a large amount of positrons will be implanted on a positron/positronium converter material. This thesis reports the construction of a three stage buffer gas trap with the goal of trapping and accumulating positrons for the ANTION project. The combination of the Penning-type trap with a LINAC source constitutes a unique experimental setup. The trap was commissioned and optimized and is now fully operational. Trapping protocols were studied and the effect of the buffer and cooling gases on the positron trapping rate and lifetime was assessed. In order to assist the cross section measurement of hydrogen, a GEANT4 simulation was developed. It evaluates the time and spatial evolution of the ortho-positronium atoms in a cavity, where hydrogen production will take place. It was estimated that 2.7 hydrogen atoms are produced for proton impact energy of ∼ 6 keV, according to the cross sections computed with the Coulomb-Born Approximation model, and 1.6 hydrogen atoms for a proton impact energy of ∼ 10 keV, according to the two-center convergent close-coupling method. The simulations also allow the estimation of the background associated with the positron and para-positronium decay. In addition, a suggestion is proposed to increase the number of positronium atoms in the cavity. In parallel, the positron moderation efficiency of a commercially available 4H-SiC epitaxial layer was studied. A 65% moderation efficiency was observed for kiloelectronvolt implanted positrons. This result can be of interest to slow positron physics experiments by improving the brightness of positron beams, and in particular to GBAR as it can potentially increase the efficiency of positron trapping.

Les tumeurs solides relèvent pour un très grand nombre de cas d’un traitement chirurgical. La réussite thérapeutique dépend de la qualité, de la précision de l’exérèse et de la capacité à « visualiser » les résidus tumoraux. Pour ce faire, différents marqueurs sont disponibles sur le marché, notamment radioactifs. Depuis peu, des émetteurs de positrons spécifiques sont disponibles, relançant l’intérêt des techniques de chirurgies radioguidées. Les objectifs de ces travaux ont été la conception, le développement et l’optimisation d’un détecteur de positons pour la localisation de la tumeur avant exérèse et des amas tumoraux résiduels après exérèse. L’avantage de la détection des positons est leur parcours dans les tissus mous, de quelques millimètres. Leur détection est donc plus précise et de meilleure sensibilité (1 à 3 ordres de grandeurs) que la détection de rayonnements gamma. Elle consiste en une technique d’imagerie de contact sur une profondeur de quelques millimètres. Nous avons donc développé 2 prototypes d’imageurs beta+ composés de photomultiplicateurs en silicone (SiPM). Le SiPM sont des photomultiplicateurs présentant les mêmes caractéristiques que les tubes photomultiplicateurs (PMT), tout en étant sensibles à une faible luminosité et de très petite dimension, ce qui est parfaitement adapté à la problématique. La tête de détection du premier prototype est l’association d’un scintillateur organique sur une matrice de SiPM. Cette configuration permet de réduire le bruit dû à la contamination du signal par des rayonnements gamma. La seconde configuration inclus une méthode de soustraction permettant d’améliorer la discrimination du bruit Gamma, sans l’éliminer totalement. Pour ce faire, un assemblage de deux scintillateurs séparés par un guide de lumière est utilisé. Le signal issu des extrémités du scintillateur sont discriminés par l’analyse des différentes distributions de lumière sur la matrice SiPM. Dans les deux cas, le détecteur a été conceptualisé de façon à positionner la tête de détection dans un boitier mécanique comprenant une électronique de lecture miniaturisée. Différents designs de la sonde Beta+, prenant en compte le matériau et l’épaisseur du scintillateur, la fenêtre de propagation lumineuse et le réflecteur optique ont été simulés avec MonteCarlo et mesurés expérimentalement. Ces paramètres ont été optimisés de façon à ce que la sonde offre les meilleures performances en termes de sensibilité de détection des positons, discrimination du bruit Gamma, résolution et distorsion spatiale et uniformité de réponse. L’influence des différents algorithmes de reconstruction sur les performances spatiales ont été étudiées et une première étude préclinique du détecteur sur fantôme a pu être réalisée avec la première configuration de détecteur. / Extent and accuracy of surgical resection is a crucial step in the therapy of operable solid tumors. The recent availability of specific tumor-seeking agents, positron labeled, renewed the interest for radioguided surgery. The detection of beta particles, due to their short range, allows a more sensitive and accurate tumor localization. Since no mechanical collimation is necessary, it is possible to design probes with a sensitivity increased by one to three orders of magnitude compared to gamma detectors. The beta particle short range also reduces the contamination from distal non-specific radiotracers uptake region, which results in a increased signal-to-noise-ratio. Conversely, beta detection requires sensors to be extremely compact in order to operate in contact with the surveyed tissues in narrow surgical cavities. This thesis takes place in that context. Its aim was to develop an intraoperative positron imaging probe based on the silicon photomultiplier technology (SiPM) and to evaluate its ability to perform in real time tumor localization and post-operative control of the surgical cavity. During this work, two prototypes of intraoperative positron imaging probe were developed. The first detector design is based on the use of a single organic scintillator coupled to an array of SiPMs. This configuration uses a small sensitive volume to reduce the contamination noise coming from the annihilation gamma rays. The second version of the probe implements a subtraction method allowing to improve gamma rejection efficiency. This configuration uses a stack of two scintillators separated by a light guide. The events interacting in the top and the bottom scintillator are discriminated by the analysis of the different light distributions on the SiPM array. Different designs of the positron imaging probes, including scintillator material and thickness, light spreading window and optical reflector, were investigated with Montecarlo simulations and measurements. Their impact on the probes performances were optimized in terms of positron sensitivity, gamma ray rejection efficiency, spatial resolution and bias and uniformity of response. The effect of different reconstruction algorithm on spatial performances was also studied. Finally, the objective of developing an intraoperative probe fully operational in the operating room has been achieved by the design of dedicated miniaturized electronic readouts and mechanical housing. In the last part of my thesis, the evaluation of the single scintillator configuration in a realistic clinical environment was performed with 18F-FDG phantoms. We showed that the low intrinsic sensitivity of this probe to gamma radiations allows to detect tumor volumes as small as 14 mg for uptake properties corresponding to currently available radiotracers and acquisition times compatible with the surgery duration.

La qualité du sommeil se modifie avec l’âge, et les troubles du sommeil seraient associés au déclin cognitif et à un risque accru de développer une maladie d’Alzheimer (MA). Cependant, les mécanismes cérébraux sous-tendant cette association restent mal compris. L’objectif de cette thèse était de contribuer à une meilleure compréhension des corrélats cérébraux structuraux, fonctionnels et moléculaires des principales modifications objectives du sommeil dans le vieillissement, et d’explorer les liens avec les performances cognitives. Nos résultats montrent que les altérations des premiers cycles de sommeil et de l’activité à ondes lentes sont associées à un hypométabolisme, une hypoperfusion et/ou une diminution du volume de substance grise au niveau des aires fronto-cingulaires et hippocampiques. De plus, la présence d’un syndrome d’apnées obstructive du sommeil et l’altération de la microstructure du sommeil paradoxal étaient significativement associés à une augmentation de la charge amyloïde, respectivement au niveau du cortex cingulaire postérieur et du précunéus, ou de manière plus diffuse. En revanche, les liens avec la cognition restaient subtils voire absents, certaines modifications cérébrales étant asymptomatiques. Ainsi, le sommeil pourrait être un facteur de résilience face aux premières altérations neuropathologiques de la MA. Ces résultats supportent la nécessité de dépister et traiter les pathologies du sommeil dans le vieillissement, avant l’apparition des premiers déficits cognitifs, dans l’espoir de ralentir le déclin cognitif. / Sleep changes are a major feature of the ageing process, and sleep disturbances are increasingly recognized as a risk factor for cognitive decline and Alzheimer’s disease (AD). However, the brain mechanisms underlying this association are still unclear. The objective of this thesis was to deepen our understanding about brain structural, functional and molecular correlates of the main objective sleep changes in ageing, and to assess the potential links with cognitive performance. Our results demonstrate that the fragmentation of the first sleep cycles and the alteration of slow wave activity, are associated with reduced gray matter metabolism, perfusion and/or volume in fronto-cingulate and hippocampal areas. Moreover, sleep-disordered breathing and rapid eye movement sleep microstructure alterations were related to increased amyloid burden respectively in the posterior cingulate cortex and precuneus, or more widespread neocortical areas. However, associations with cognitive performance remained subtle or inexistent, suggesting early and asymptomatic associations between sleep and brain changes. Therefore, sleep may contribute to resilience processes and may help to cope with early neuropathological changes in AD. These results support the need to screen and treat sleep disturbances in older adults, before the onset of the first cognitive signs, in order to slow cognitive decline.

The correlation of vacancy concentration with microhardness of Fe-Al alloys was studied on samples quenched from 1000 řC and subsequently annealed at lower temperatures. Using X-ray diffraction the lattice parameter and crystal structure were determined for samples of Fe-Al alloys. By measurements of positron lifetime was revealed the high concentration of vacancies in quenched samples and subsequent annealing caused significant decrease in vacancy concentration while in samples with Al content above 39% also the decrease of microhardness was measured. Measurements of coincidence Doppler broadening of annihilation peak helped to distinguish the annihilations coming from positron trapped or delocalized annihilated by electrons of both atoms, Fe and Al. Comparison of measured results with theoretical quantum-mechanics calculations performed in this diploma thesis determined the most probable defect type as a vacancy on A-sublatice of B2 structure.

Název práce: Studium defekt· v kvazikrystalech Autor: Marián Vlček Katedra: Katedra fyziky nízkých teplot Vedoucí disertační práce: doc. Mgr. Jakub ížek, Ph.D., Katedra fyziky nízkých teplot Abstrakt: V predloženej práci boli pomocou spektroskopie doby života poz- itrónov a koincidenčnej spektroskopie Dopplerovského rozšírenia anihilačného píku študované zliatiny WE43 s prídavkom zinku a ternárne zliatiny Mg-Zn-Y. V týchto zliatinách bola nedávno zistená prítomnos' ikosahedrálnej fázy Mg3Zn6Y1 s kvázikryštalickou štruktúrou, čo pritiahlo pozornos' výskumníkov. Spektroskopia doby života pozitrónov preukázala prítomnos' unikátnych vakanciám podobných defektov na rozhraní ikosahedrálnej fázy a horčíkovej matrice, ktoré sú charakter- istické pre horčíkové zliatiny obsahujúce ikosahedrálnu fázu. Tepelné spracovanie skúmaných zliatin vedie k významným zmenám morfológie hraničných fáz. Ke¤že vakanciám podobné defekty spojené s ikosahedrálnou fázou sa vyskytujú na jej rozhraní s horčíkovou matricou, zmeny v morfológii ikosahedrálnej fázy vedú k výrazným zmenám koncentrácie týchto defektov. "alej boli skúmané vzorky pripravené uhlovým pretláčaním kanálom rovnakého prierezu. Typy defektov prítomné v týchto zliatinách a ich teplotná stabilita bola určená pomocou spektroskopie doby života pozitrónov a merania tvrdosti...

Title: Investigation of vacancies in Fe-Al alloys Author: RNDr. František Lukáč Department: Department of Low Temperature Physics Supervisor: doc. Mgr. Jakub Čížek, Ph.D., Department of Low Temperature Physics, Faculty of Mathematics and Physics Abstract: Fe-Al alloys exhibit relatively high vacancy concentrations, which significantly influence the mechanical properties of these alloys. Positron annihi- lation spectroscopy was employed for investigations of vacancies in this work and the vacancy concentrations in Fe-Al alloys were determined by positron lifetime spectroscopy and measurements of positron diffusion length of implanted mono- genergetic positrons. The correlation of hardness with the vacancy concentration was characterized by determination of the vacancy hardening coefficient in Fe- Al alloys. The thermal evolutions of hardness and the vacancy concentration were compared during the annealing of the Fe-Al alloys with various composi- tions. Coincidence Doppler broadening of annihilation peak was employed for determination of the chemical composition of quenched-in vacancies in Fe-Al al- loys. Increased concentration of Al atoms in surrounding vacancies in Fe-Al alloys was related to the attractive interaction between the Al atoms and the vacancy. Quantum mechanical ab initio calculations were...