Single-photon emission computed tomography (SPECT) is a nuclear-medicine imaging technique that has been shown to provide clinically useful images of radionuclide distributions within the body. The problem of quantitative determination of tomographic activity images from a projection data set leads to a mathematical inverse problem which is formulated as an integral equation. The solution of this problem then depends on an accurate mathematical model as well as a reliable and efficient inversion algorithm. The effects of attenuation and Compton scatter within the body have been incorporated into the model in the hopes of providing a more physically realistic mathematical model. The attenuated Radon transform is the mathematical basis of SPECT. In this work, the case of constant attenuation is reviewed and a new proof of the Tretiak-Metz algorithm is presented. A space-domain version of the inverse attenuated Radon transform is derived. A special case of this transform that is applicable when the object is rotationally symmetric, the attenuated Abel transform is derived, and its inverse is found. A numerical algorithm for the implementation of the inverse attenuated Radon transform with constant attenuation is described and computer simulations are performed to demonstrate the results of the inversion procedure. With the use of the single-scatter approximation and an energy-windowed detector, the effects of Compton scatter are incorporated into the model. The data is then taken to be the sum of primary photons and single-scattered photons. The scattered photons are modeled by a scatter operator acting on the original activity distribution within the object where the operator consists of convolution with a given analytic kernel followed by a boundary cut-off operation. A solution is given by first applying the inverse attenuated Radon transform to the data set. This leads to a Fredholm integral equation to which a Neumann series solution is constructed. Again simulations are performed to validate the accuracy of the assumptions within the model as well as to numerically demonstrate the reconstruction procedure.

Published Article / Rapid Manufacturing (RM) has emerged over the past few years as a potential technology to successfully produce patient-specific implants for maxilla/facial and cranial reconstructive surgeries. However, in the area of spinal implants, customization has not yet come to the forefront and with growing capabilities in both software and manufacturing technologies, these opportunities need to be investigated and developed wherever possible. The possibility of using Computed Tomography (CT) and Rapid Manufacturing (RM) technologies to design and manufacture a customized, patient-specific intervertebral implant, is investigated. Customized implants could aid in the efforts to reduce the risk of implant subsidence, which is a concern with existing standard implants. This article investigates how accurately the geometry of a customized artificial intervertebral disc (CAID) can represent the inverse geometry of a patient's vertebral endplates. The results indicate that the endplates of a customized disc implant can be manufactured to a calculated average error of 0.01mm within a confidence interval of 0.022mm, with 95% confidence, when using Direct Metal Laser Sintering.

Abstract: Sunitinib (Sutent®) is a multitargeted, small molecule receptor tyrosine kinase inhibitor used as an anti-cancer drug. It has increased the overall survival rate of metastatic renal cell carcinoma patients as well as the survival time of patients with pancreatic neuroendocrine tumors. Although the clinical use of sunitinib is a significant leap forward in the therapy of those cancers, its induction of cardiac toxicity in a substantial fraction of patients remains a critical problem. Sunitinib may cause hypertension, arrhythmias, drop of the left ventricular ejection fraction and congestive heart failure, fatal in some cases. These side effects are a frequent reason for interruption of its use. The mechanism(s) underlying sunitinib cardiotoxicity are not fully understood. Similar to other receptor tyrosine kinase inhibitors, it binds to a large number of cellular kinases, thus it can affect multiple cellular processes. In vivo, the pattern of toxicity is complex and unpredictable, with symptomatic heart failure sometimes observed early during treatment. The pattern of events preceding the onset of symptomatic cardiac dysfunction during treatment is not established. This represents a significant problem for the clinical diagnosis of cardiovascular complications before they become symptomatic. The identification and early detection of those events would be highly-beneficial for the clinical management of anti-cancer therapy with sunitinib. Positron Emission Tomography (PET) is recognized for its ability to probe metabolic and functional aspects of myocardial function. Under the working concept that heart failure can occur early during sunitinib treatment, and may be sustained by early myocardial metabolic and structural alterations, we performed a study with the objective of assessing the use of PET for the early detection of sunitinib-induced ardiotoxicity. For this, we established a model of cardiotoxicity in C57BL/6 male mice given 80mg/Kg/day of sunitinib or water, orally for 4 weeks. General and cardiac toxicity were monitored by biochemical, microscopical (H&E, immunofluorescence and electron microscopy) as well as gene expression analyses and blood pressure measurements. PET scans were performed weekly using [superscript 11]C-acetate and [superscript 18]F-FDG to evaluated the myocardial blood flow (MBF), myocardial oxidative metabolism through the quantification of oxygen consumption (MVO[subscript 2]), glucose uptake (K[subscript i]), myocardial metabolic rate of glucose (MMRG) and the left ventricular ejection fractions (LVEF). We found that sunitibib was cardiotoxic as revealed by histopathology, immunostaining and electron microscopy. Signs of inflammation and tissue remodeling were found by gene expression analyses and collagen staining. No hypertension or renal damage were detected on the study. FDG-PET revealed an early decrease of the LVEF, indicative of cardiac dysfunction, which developed into grade-2 heart failure by the end of the study. However, no signs of alterations in cardiac metabolism were uncovered by FDG- or [superscript 11]C-acetate-PET. Our results hint that the onset of sunitinib-induced contractile dysfunction may occur in the absence of hypertension or overt metabolic damage and call for further studies with longer treatments to clearly mark the onset of metabolic cardiotoxicity. // Résumé: Le sunitinib est un inhibiteur de tyrosine kinase qui est utilisée comme agent anticancéreux. Bien que l'utilisation clinique du sunitinib représente une percée significative pour le traitement de certains cancers, ce médicament s’avère cardiotoxique chez plusieurs patients, une situation qui est problématique. Le sunitinib peut provoquer une hypertension, des arythmies, une chute de la fraction d'éjection ventriculaire gauche et une insuffisance cardiaque congestive qui peut être fatale. Le mécanisme responsable de la cardiotoxicité de sunitinib n’est pas encore bien compris. Comme plusieurs autres inhibiteurs des récepteurs de la tyrosine kinase, il se lie à un grand nombre de kinases et peut affecter de nombreux processus cellulaires. In vivo, les mécanismes responsables de la toxicité sont complexes et imprévisibles et une insuffisance cardiaque est parfois observée tôt pendant le traitement. La séquence des évènements menant à l'apparition d’une dysfonction cardiaque pendant le traitement n’est pas connue. Cela pose un problème important pour le diagnostic de complications cardiovasculaires avant qu'elles ne deviennent symptomatiques. Une identification précoce de ces événements néfastes serait très bénéfique pour le suivi du traitement au sunitinib. La tomographie d'émission par positrons (TEP) est une méthode reconnue pour l’évaluation du métabolisme et de la fonctionnalité du myocarde. Selon notre hypothèse de travail, une insuffisance cardiaque peut survenir rapidement pendant le traitement au sunitinib, elle est l’expression d’altérations structurelles et métaboliques au niveau du myocarde; ces modifications se produisent tôt pendant le traitement. Nous avons effectué une étude pour évaluer la faisabilité d’utiliser l’imagerie TEP pour la détection précoce de la cardiotoxicité induite par le sunitinib. La première étape a été de développer un modèle de cardiotoxicité chez des souris. L’induction de la cardiotoxicité s’est faite par administration orale pour une période de quatre semaines, soit de sunitinib 80mg/Kg/jour ou d'eau pour les souris contrôles. Le suivi inclut la mesure de la pression sanguine, l’évaluation des altérations biochimiques, l’expression de certains gènes et un examen histologique du myocarde. Un suivi par imagerie TEP a été effectué chaque semaine avec du [indice supérieur 11]C-acétate et du [indice supérieur 18]F-FDG afin d'évaluer le flux sanguin myocardique (MBF), le métabolisme oxydatif du myocarde incluant la consommation d'oxygène (MVO2), l'absorption du glucose (K[indice inférieur i]), le taux métabolique oxydatif du glucose (MMRG) ainsi que la fraction d'éjection ventriculaire gauche (FEVG). Les résultats que nous avons obtenus par histopathologie, immunocoloration et microscopie électronique montrent que notre modèle est capable d’induire une cardiotoxicité. Nous avons également observé des évidences d'inflammation et de remodelage tissulaire à partir de l’étude de l'expression de certains gènes et de l’analyse de l’accumulation de collagène. Nous n’avons pas observé d’hypertension ni de lésions rénales. La TEP avec [indice supérieur 18]FDG a montré une diminution rapide de la FEVG, une indication d’une dysfonction cardiaque qui a été classée comme insuffisance cardiaque de grade 2 à la fin de l'étude. Cependant, aucun signe de modifications du métabolisme cardiaque n’a été mis en évidence par TEP/[indice supérieur 18]FDG- ou TEP/[indice supérieur 11]C-acétate. Nos résultats laissent penser que l'apparition de la dysfonction contractile induite par sunitinib peut se produire en l'absence d'hypertension ou de dommages métaboliques manifestes. De nouvelles études avec des traitements plus longs permettraient peut être de mieux définir le début de la cardiotoxicité métabolique.

Tomography in soft X-ray microscopy is an emerging technique for obtaining quantitative 3D structural information about cells. One of its strengths, compared with other techniques, is that it can image intact cells in their near-native state at a few 10 nm’s resolution, without staining. However, the methods for reconstructing 3D-data rely on algorithms that assume projection data, which the images are generally not due to the imaging systems’ limited depth of focus. To bring out the full potential of tomography in soft X-ray microscopy an improved understanding of the image formation is desired. This Thesis reviews zone plate-based X-ray microscopy for biological imaging and the theory necessary for a numerical implementation of a 3D image formation model. Furthermore, a novel reconstruction approach is proposed that improves the overall resolution in a reconstruction of a tomographically imaged object. This is demonstrated by simulations and experiments. Finally, this Thesis covers work on the Stockholm X-ray microscope, including an upgrade of the X-ray source yielding unprecedented brightness for a compact system. With this upgrade it was possible to do high-quality imaging of cells in their near-native state with only 10 second exposures. / Tomografi i mjukröntgenmikroskopi är en ny teknik för att få ut kvantitativ strukturell 3D information om celler. Dess styrka jämfört med andra tekniker är att den kan avbilda intakta celler i deras nära naturliga tillstånd med ett par 10 nm upplösning, utan omfattande preparering. Dock är metoderna för att rekonstruera 3D-data beroende av algoritmer som antar projektionsdata, vilket bilderna i allmänhet inte är på grund av avbildningsystemens begränsade skärpedjup. För att få ut den fulla potentialen av tomografi i röntgenmikroskopi behövs en ökad förståelse för avbildningsprocessen. Denna avhandling behandlar zonplatte-baserad röntgenmikroskopi för biologisk avbildning och den nödvändiga teorin för en numerisk implementering av en avbildningsmodell i 3D. En ny rekonstruktionsmetod föreslås som förbättrar upplösningen i rekonstruktionen för ett tomografiskt avbildat objekt. Detta visas i simuleringar och experiment. Slutligen omfattar denna avhandling arbete på Stockholms mjukröntgenmikroskop, inklusive en uppgradering av röntgenkällan som ger oöverträffad ljusstyrka för ett kompakt system. Denna uppgradering möjliggör högkvalitativ avbildning av celler i deras nästan naturliga tillstånd med endast 10 sekunders exponering. / <p>QC 20160324</p>

Analyzing the structure of a single cell based on its refractive index (RI) distribution is a common and valued approach, because it does not require any artificial markers. The RI is an inherent structural marker that can be quantified in three dimensions with optical diffraction tomography (ODT), an inverse scattering technique. This work reviews the theory of ODT and its implementation with an emphasis on single-cell analysis, identifying the Rytov approximation as the most efficient descriptor for light propagation. The accuracy of the reconstruction method is verified with in silico data and imaging artifacts associated with the inverse scattering approach are addressed. Furthermore, an experimental ODT setup is presented that consists of a bright-field microscope, a phase-imaging camera, and an optical trap combined with a microfluidic chip. A novel image analysis pipeline is proposed that addresses image corrections and frame alignment of the recorded data prior to the RI reconstruction. In addition, for a rotational axis that is tilted with respect to the image plane, an improved reconstruction algorithm is introduced and applied to single, suspended cells in vitro, achieving sub-cellular resolution.

Reflection seismic and seismic tomography methods can be used to image the upper kilometer of hard bedrock and the loose unconsolidated sediments covering it. Developments of these two methods and their application, as well as identifying issues concerning their usage, are the main focus of the thesis. Data used for this development were acquired at three different sites in Sweden, in Forsmark 140 km north of Stockholm, in the Oskarshamn area in southern Sweden, and in the northern part of the Siljan Ring impact crater area. The reflection seismic data were acquired with long source-receiver offsets relative to some of the targeted depths to be imaged. In the initial processing standard steps were applied, but the uppermost part of the sections were not always clear. The longer offsets imply that pre-stack migration is necessary in order to image the uppermost bedrock as clearly as possible. Careful choice of filters and velocity functions improve the pre-stack migrated image, allowing better correlation with near-surface geological information. The seismic tomography method has been enhanced to calculate, simultaneously with the velocity inversion, optimal corrections to the picked first break travel times in order to compensate for the delays due to the seismic waves passing through the loose sediments covering the bedrock. The reflection seismic processing used in this thesis has produced high-quality images of the upper kilometers, and in one example from the Forsmark site, the image of the uppermost 250 meters of the bedrock has been improved. The three-dimensional orientation of reflections has been determined at the Oskarshamn site. Correlation with borehole data shows that many of these reflections originate from fracture zones. The developed seismic tomography method produces high-detail velocity models for the site in the Siljan impact area and for the Forsmark site. In Forsmark, detailed estimates of the bedrock topography were calculated with the use of the developed tomography method.

Teleseismic data recorded by broad-band seismic stations in the Swedish National Seismic Network (SNSN) have been used in a suite of studies of seismic wave conversion in order to assess the structure of the crust and upper mantle beneath the Baltic Shield. Signals of seismic waves converted between P and S at seismic discontinuities within the Earth carry information on the velocity contrast at the converting interface, on the depth of conversion and on P and S velocities above this depth. The conversion from P to S at the crust-mantle boundary (the Moho) provides a robust tool to constrain crustal thicknesses. Results of such analysis for the Baltic Shield show considerable variation of Moho depths and significantly improve the Moho depth map. Analysis of waves converted from S to P in the upper mantle reveals a layered lithosphere with alternating high and low velocity bodies. It also detects clear signals of a sharp velocity contrast at the lithosphere-asthenosphere boundary at depths around 200 km. Delay times of P410s, the conversion from P to S at the upper mantle discontinuity at 410 km depth, were used in a tomographic inversion to simultaneously determine P and S velocities in the upper mantle. The polarisation of P410s was also used to study anisotropy of the upper mantle. Results of these analyses are found to be in close agreement with independently derived results from arrival time tomography and shear-wave splitting analysis of SKS. The results presented in this thesis demonstrate the ability of converted wave analysis as a tool to detect and image geological boundaries that involve sharp contrasts in seismic properties. The results also show that this analysis can provide means of studying aspects of Earth’s structure that are conventionally studied using other types of seismic data.

Seismic traveltime inversion, traveltime tomography and seismic reflection techniques have been applied for two dimensional (2D) and three dimensional (3D) data acquired in conjunction with site characterization and monitoring aspects at a carbon dioxide (CO2) geological storage site at Ketzin, Germany (the CO2SINK project). Conventional seismic methods that focused on investigating the CO2 storage and caprock formations showed a poor or no image of the upper 150 m. In order to fill this information gap, an effort on imaging the shallow subsurface at a potentially risky area at the site is the principal goal of this thesis. Beside this objective, a seismic source comparison from a 2D pilot study for acquisition parameter testing at the site found a weight drop source suitable with respect to the signal penetration, frequency content of the data and minimizing time and cost for 3D data acquisition. For the Ketzin seismic data, the ability to obtain high-quality images is limited by the acquisition geometry, source-generated noise and time shifts due to near-surface effects producing severe distortions in the data. Moreover, these time shifts are comparable to the dominant periods of the reflections and to the size of structures to be imaged. Therefore, a combination of seismic refraction and state-of-the-art processing techniques, including careful static corrections and more accurate velocity analysis, resulted in key improvements of the images and allowed new information to be extracted. The results from these studies together with borehole information, hydrogeologic models and seismic modeling have been combined into an integrated interpretation. The boundary between the Quaternary and Tertiary unit has been mapped. The internal structure of the Quaternary sediments is likely to be complicated due to the shallow aquifer/aquitard complex, whereas the heterogeneity in the Tertiary unit is due to rock alteration associated with fault zones. Some of the major faults appear to project into the Tertiary unit. These findings are important for understanding the potentially risky anticline crest and can be used as a database for the future monitoring program at the site.

Controlled source seismic methods were employed in this study to investigate the reflectivity and velocity structure of two Hercynian orogens – the Uralides and Variscides. Conventional common depth point (CDP) sections from five reflection seismic campaigns and a velocity model obtained from tomographic inversion of wide-angle observations were the main datasets studied from the Middle Urals. These were complemented with the near-vertical seismic sections and velocity models from the Southern Urals. In the Variscides, conventional CDP processing, along with non-standard processing and synthetic data modeling, were used to obtain and interpret reflection seismic images of the Southwestern Iberian crust. Although, the Uralian and Variscan belts were formed in Late Paleozoic time in apparently similar plate collisional settings, a comparison of the seismic results show that the crust of these two orogens looks quite different at depth. In the Urals, collision of Baltica with Asian terranes (Siberia and Kazakhstan) resulted in a highly diversely reflective crust of 40-45 km thickness. The axial zone of the orogen is characterized by a high velocity crustal root of diffuse reflectivity and an imbricated Moho, with a crustal thickness reaching 55-60 km. The Moho discontinuity is marked by a sharp decrease in reflectivity and is well imaged in most locations except in the crustal root zone. The Southwestern Iberian Variscan crust is 30-35 km thick and is characterized by a highly reflective two-layered structure that resulted from collision of Luarussia and Gondwana, including terranes in-between them. This type of crustal structure is very similar to those imaged in other regions of the Variscan belt in the Europe. The Moho discontinuity is flat and appears to be the deepest reflection. This thesis compares the deep structure of the two orogens and interprets mountain building processes related to late Paleozoic plate movements.

The Big Clifty (Jackson) Sandstone Member of the Golconda Formation is the most important of the Mississippian (Chesterian) heavy-oil reservoirs in the southeastern Illinois Basin. Heavy oil reservoirs, or asphalt rock deposits, have been studied extensively in south central and western Kentucky, and ~2 billion barrels of original oil in place (OOIP) have been proposed to occur in the Big Clifty Sandstone. Despite high OOIP estimates, heterogeneities in the reservoir negatively impact the production of heavy oil deposits. Heterogeneities related to depositional facies changes are poorly understood in the Big Clifty Sandstone of Kentucky, where it has been mostly described as a 60-120 feet thick sandstone unit. In some locations, the Big Clifty occurs as two distinct sand bodies with intercalated mud-rich units and, most typically, with the greatest clay- and silt-rich units present between sandstone bodies. Questions exist as to how such muddy facies occur in the reservoir. This study couples sedimentary facies analysis with sequence stratigraphy to assess how lithological factors affect the occurrence of petroleum in Big Clifty reservoirs. Multiple datasets were integrated to develop a depositional model for lithologic facies observed in this study. Datasets include core, exposure descriptions, petrographic analysis, bitumen concentrations, electrical resistivity tomography (ERT), and borehole geophysical analysis. This study occurred in Logan, Warren, and Butler counties, with emphasis on an active asphalt-rock mine in Logan County. Surface geophysical methods aided in demarcating Chesterian limestones, sandstone bodies and, in particular, highly resistive heavy-oil laden Big Clifty channel bodies. In Warren County, located E-NE of the Stampede Mine, the Big Clifty coalesces into a single amalgamated sandstone channel or a series of superimposed stacked channels as observed in outcrop along Indian Creek at McChesney Field Station and at Jackson’s Orchard. In these locations, the tidal influence is subtle with large-scale trough cross bedding dominating, and the contact on the Beech Creek Limestone is sharp. Facies changes related to the environment of deposition greatly impact the quality of heavy-oil reservoirs and must be taken into consideration during exploration and siting of asphalt rock mines.