The lung has been satisfactorily modelled as a fractal, and change in lung structure due to disease is assumed to change the fractal dimensionality of the lung. It is hypothesized that those changes in fractal dimension affect perceptually relevant elements (perceived texture) of the lung, and therefore the fractal dimension may prove to be a predictor of diagnosis. If the fractal dimensionality reflects structure in ways more accurately reflecting changes in lung structure than can be achieved by nuclear medicine physicians, then it may also prove useful as a diagnostic tool. Fractal dimension is linearly related to the slope of the power spectrum (SPS) as plotted on log-log paper, and the SPS was used as the metric reflecting the fractal dimension. Seventy-two cases were selected that were either normal, had congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), or pulmonary embolism (PE). Five of the cases had both CHF and COPD. The lung scans from these cases were digitized, with appropriate corrections for linearization, edge artifacts, target nonuniformities and film gamma. Fast Fourier Transforms provided the power spectrum from which the SPS was calculated. Four nuclear medicine physicians read the original lung scans and rated their certainty about the presence of two texture elements, the extensiveness of disease involvement, and presence of the three diseases used (CHF, COPD, and PE). The results found the SPS to be significantly related to both texture ratings and diagnostic certainty, but inferior as a predictor of disease to either texture rating or diagnostic certainty. This study reveals the SPS to be a promising but incomplete candidate for machine-algorithm generated diagnosis.

A new method is presented to identify and clone novel transforming genes from radiation-induced tumors. This method involves the creation of a cDNA expression library from radiation-induced tumors. The library is transfected into non-transformed cells, and the nude mouse tumorigenicity assay functionally defines the acquisition of a transformed phenotype. cDNA clones responsible for transformation are rescued by PCR amplification. This method is applicable to a variety of mammalian systems. The only requirement is a functional assay with which to measure the acquisition of an altered phenotype following transfection of a cDNA library. While this method has not yet been applied to a radiation-induced tumor, it has identified a cDNA for the 16 kD subunit of v-H⁺-ATPase, which has been associated with cellular transformation. Two protocols were used to generate radiation-induced tumors. One experiment utilizing fractionated doses of ionizing radiation had a much greater tumor yield than the second protocol using a single dose of 11.25 Gy. To determine if the mechanism of gene activation is different in radiation- and chemically-induced tumors, the expression pattern of five tumor-associated genes was analyzed. The expression patterns of mals 1-4 were not significantly different in tumors generated by the two carcinogens. However, transin, a secreted protease, was overexpressed in radiation-induced papillomas and undetectable in chemically-induced papillomas. This observation supports previous studies indicating a higher conversion rate of radiation-initiated benign papillomas to malignant squamous cell carcinomas when compared to their chemically-initiated counterparts. Transin degrades basement membrane proteins and may be involved in the progression of benign, encapsulated tumors to malignant, invasive squamous cell carcinomas. Isolation and characterization of genes with dominant transforming activity from radiation-induced tumors will provide information to bridge the gap between the initial ionizing radiation event and the subsequent development of malignant tumors. The function of these genes may also provide information about the development of human malignancies. An understanding the natural biology of cells will help elucidate the pathogenesis cancer and other diseases.

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Ever since the inception of Diffusion Tensor Imaging (DTI), unabated advancements in its capabilities and applications have been spearheaded by a vibrant research effort to devise dedicated acquisition sequences, protocols and hardware. In translational research, however, the transition of these innovations into the arenas of biomedical research, and ultimately clinical practice is frequently hampered by practical considerations. These include the availability of appropriate expertise, time and resources for their implementation, and considerations of compatibility with established techniques and results reported in literature. Such concerns provide the impetus to maximize the utility of existing protocols before attempting the development of novel dedicated techniques. In this thesis, three investigations, each targeting a different DTI application, are presented. The strategy implemented throughout involves assessing the suitability of existing sequences for the intended task, and determining any limiting factors, evaluating whether appropriate modifications of the acquisition protocols used are capable of alleviating limitations, and developing novel, dedicated protocols wherever necessary. The value and, importantly, the wide scope of this approach in answering important research questions is exemplified through the breadth of the studies presented. The first study presents, for the first time, a quantitative evaluation of the effects of cardiac pulsation on prevalent DTI metrics acquired with a specific acquisition protocol used routinely in clinical practice. Findings inform the on-going debate on whether the investment in cardiac gating is merited by improvements in data quality. Effects were observed during only 6 % of the cardiac cycle, and not 20 % as previously reported. The impact of cardiac pulsation on selected diffusion Tensor indices was minimal in group studies, but of potential practical relevance in individual cases. Methods to predict which individuals may benefit from gating have also been suggested. Secondly, the feasibility of post-mortem DTI was established through the successful acquisition, also for the first time, of DTI data on a chemically fixed whole human post-mortem brain using a clinical sequence. Previous failed attempts have been attributed to insufficient SNR. In this study scanner stability and distortion are found to be the main limiting factors, and mitigated using appropriate averaging and co-registration strategies. The third study assessed the potential of ultra-high field strength DTI by identifying and optimizing the potential strengths of DTI at 7T. Subsequent to optimization with respect to SNR, the main sources of artefact were found to be B1 inhomogeneity and inadequate fat suppression. Both were alleviated by modification of the available acquisition protocol, resulting in higher SNR and data quality than previously reported. Finally, in developing appropriate data quality measures, the ‘Difference method’, commonly used for the quantification of SNR, was found to be unsuitable for in vivo DTI acquisitions at 7 T, leading to the proposal, and successful implementation and validation of an alternative.

Time-series analysis designs strengthen before and after studies and are regarded as easy and cheap to use. These designs have recently become more popular in guideline implementation studies but there is suspicion that time series analysis designs are used inappropriately or without sufficient understanding or the underlying methodology. In this thesis, we attempt to evaluate their use by means of a systematic review of published studies, and by actively using time series analysis to evaluate the effect of dissemination of the 3rd edition of the Royal College of Radiologists' guidelines on imaging referral patterns from primary care in the North East of Scotland. The systematic review established that indeed many time series studies are conducted inappropriately with key issues such as the use of adequate number of data points and adjustment for trends not taken into consideration. Often results are tested using non-statistical analyses. Our findings suggest that there should be an increased awareness among investigators of the correct statistical technique for performing and analysing time series analyses. From the guideline evaluation study, it was found that the passive dissemination of the imaging guideline in the North East of Scotland did not affect GPs' imaging referral patterns. This may suggest the need for reinforcement with more active dissemination strategies. It was also established that time series analysis can be complex, requiring a clear understanding before use if researchers are to achieve the best from them. Compared to time series analysis before and after studies were shown to be unreliable with the potential of giving misleading results.

Hyperpolarized (hp) gases such 129Xe and 83Kr (spin I = 1/2 and I = 9/2 respectively) can allow for significantly enhanced signal in a number of magnetic resonance applications. As a result there has been a growing interest in recent years to advance hp noble gas technology to non-invasively image the airspace of lungs, with the goal of developing a helpful probe for lung pathologies. 83Kr longitudinal relaxation (T1) has been shown to be sensitive to various surface properties, and may prove to be an interesting for identifying certain diseases including those that change surface chemistry (such as cystic fibrosis) or the surface-to-volume ratio in the lung (like in emphysema). This thesis contains several studies furthering 83Kr lung imaging, while also exploring methods for 129Xe imaging. A major focus has been on increasing spin polarization of the noble gases, as an increased polarization yields a greater MR signal strength. A novel low-pressure spin-exchange optical pumping technique has been utilized in this work allowing for 83Kr polarizations exceeding 17.5 %; as opposed to 4.4 % previously reported in literature. Gas produced in this fashion must be pressurized to above ambient before it is possible for it to be delivered to a lung. Two methodologies for pressurizing the noble gas via compression are explored and optimized for hp gas delivery to excised lungs with 83Kr polarizations as high as 13.8 % achievable after compression. This ultimately allowed for the first ever coronal 83Kr lung images in an ex vivo lung model. Further work repeated with isotopically enriched 83Kr achieved a surface-sensitive T1 relaxation map in this system. Finally gas handling techniques where created to allow for efficient and thorough mixing of the hp noble gases and O2 while minimizing relaxation effects. This is vital for any future in vivo studies.

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