PREFACE iii
Preface
The following manuscript is the product of my efforts to understand a fraction of themind of God.From the beginning, I had the great fortune of adopting one of my predecessor’s finalprojects 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 anadept NMR scientist. The preliminary hypothesis of this study was to observe changes inmurine tumor oxygenation with radiotherapy. In preceding works, it was shown that thespin-lattice relaxation rate of perfluorocarbons was directly proportional to the dissolvedoxygen tension. This relationship between fluorine relaxation and oxygenation, alongwith NMR imaging techniques, allowed for evaluation of therapeutic interventions usingperfluorocarbons.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 hadshown that there was a highly positive correlation between tumor oxygenation and theapparent diffusion coefficient (ADC) of water in the tumor. These findings weretroubling because intuitively, if there were any correlation between tumor oxygenationand ADC, we would expect to see a negative rather than a positive correlation. To
PREFACE iv
resolve this issue, we undertook the project of experimentally correlating tumoroxygenation using
19
F imaging and
1
H ADC mapping techniques. This proved to be arewarding experiment because our intuition served us correctly. Despite the findings byother groups, our studies showed that no apparent correlation existed between ADCvalues and tumor oxygenation.Studies in animals brought up questions about the behavior of water in the brainfollowing the onset of stroke. During cerebral ischemia, ionic imbalances in the brainresult 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 swellingof cells, it was difficult to understand the intricacies behind the relationship of water to itssurroundings. The answer to this basic question of what is happening to the water in acomplicated two-compartment system has been one of the motivating factors for mystudy of water in a model system of yeast cells. Studies of two-compartment systems byothers have shown non-monoexponential diffusion signal attenuation, which has beenassumed to be because of the different compartmental contributions. Although this maybe a possibility, previous works have shown that even in single compartment systems,non-monoexponential behavior could be observed simply as a result of the tortuousdiffusion pathways of water in the interstitial space. This observation in singlecompartment systems cast doubt on the interpretation of the data from the two-compartment system. Not only are there compartmental effects on diffusion, but thediffusion behavior is also confounded by restriction effects. One of the premises behind
PREFACE v
the work done in yeast-cell suspensions was that a deconvolution of the compartmentaleffects could provide valuable information on the behavior of water. With this goal inmind, a majority of my research efforts was devoted to investigating model systems forunderstanding the diffusion behavior of water in a two-compartment system. Fortunately,a well-characterized system was available in yeast-cell suspensions. The yeastexperiments should serve merely as a stepping stone to other experiments which furthercharacterize the model system and, ultimately, carry over to
in vivo
experiments tounderstand the behavior of water during ischemic brain injury.The last experiment in this dissertation deals with diffusion of water in excised rabbitAchilles tendon. The initial set of experiments on tendon gave very promising results andeventually led to a Master’s thesis for one of my colleagues. Unfortunately, furtherinvestigation into the behavior of the tendon revealed that these observed effects were nomore than an artifact of the storage medium. The initial discovery of this fact wasdisappointing, but at the same time opened up another avenue for the direction of theseexperiments. 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 notcompletely revealing, we are still of the belief that the viscoelastic properties of tendonschange with tensile load. Whether this phenomenon is observable
via
NMR is still to bedetermined.
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