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Preface The following manuscript is the product of my efforts to understand a fraction of the mind of God.

From the beginning, I had the great fortune of adopting one of my predecessor’s final projects as my first project. Working on this project became a milestone in my studies, not only as an initial project, but more so because of the experience of working with an adept NMR scientist. The preliminary hypothesis of this study was to observe changes in murine tumor oxygenation with radiotherapy. In preceding works, it was shown that the spin-lattice relaxation rate of perfluorocarbons was directly proportional to the dissolved oxygen tension. This relationship between fluorine relaxation and oxygenation, along with NMR imaging techniques, allowed for evaluation of therapeutic interventions using perfluorocarbons.

During this time, a parallel experiment was in progress to observe the effects of oxygenation on the diffusion of water molecules in murine tumors. Other groups had shown that there was a highly positive correlation between tumor oxygenation and the apparent diffusion coefficient (ADC) of water in the tumor.

These findings were

troubling because intuitively, if there were any correlation between tumor oxygenation and ADC, we would expect to see a negative rather than a positive correlation. To

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resolve this issue, we undertook the project of experimentally correlating tumor oxygenation using

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F imaging and 1H ADC mapping techniques. This proved to be a

rewarding experiment because our intuition served us correctly. Despite the findings by other groups, our studies showed that no apparent correlation existed between ADC values and tumor oxygenation.

Studies in animals brought up questions about the behavior of water in the brain following the onset of stroke. During cerebral ischemia, ionic imbalances in the brain result in changes in cellular water distribution and give rise to edema (cellular swelling). Although it is clear that the properties of diffusing water are correlated with the swelling of cells, it was difficult to understand the intricacies behind the relationship of water to its surroundings. The answer to this basic question of what is happening to the water in a complicated two-compartment system has been one of the motivating factors for my study of water in a model system of yeast cells. Studies of two-compartment systems by others have shown non-monoexponential diffusion signal attenuation, which has been assumed to be because of the different compartmental contributions. Although this may be a possibility, previous works have shown that even in single compartment systems, non-monoexponential behavior could be observed simply as a result of the tortuous diffusion pathways of water in the interstitial space.

This observation in single

compartment systems cast doubt on the interpretation of the data from the twocompartment system. Not only are there compartmental effects on diffusion, but the diffusion behavior is also confounded by restriction effects. One of the premises behind

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the work done in yeast-cell suspensions was that a deconvolution of the compartmental effects could provide valuable information on the behavior of water. With this goal in mind, a majority of my research efforts was devoted to investigating model systems for understanding the diffusion behavior of water in a two-compartment system. Fortunately, a well-characterized system was available in yeast-cell suspensions.

The yeast

experiments should serve merely as a stepping stone to other experiments which further characterize the model system and, ultimately, carry over to in vivo experiments to understand the behavior of water during ischemic brain injury.

The last experiment in this dissertation deals with diffusion of water in excised rabbit Achilles tendon. The initial set of experiments on tendon gave very promising results and eventually led to a Master’s thesis for one of my colleagues. Unfortunately, further investigation into the behavior of the tendon revealed that these observed effects were no more than an artifact of the storage medium. The initial discovery of this fact was disappointing, but at the same time opened up another avenue for the direction of these experiments. In wrestling with the logistics of measuring NMR properties of tendons, most of the groundwork has been laid for future studies. Although these results are not completely revealing, we are still of the belief that the viscoelastic properties of tendons change with tensile load. Whether this phenomenon is observable via NMR is still to be determined.

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Although diverse in nature, all of these experiments have taught one common lesson. Ask the good question and seek the right answer. I hope that the writings herein will be a reflection of the work done to seek the right answer.

May God bless the reading of this dissertation.