Radiosurgery is a radiation treatment modality in which a high radiation dose (few 1000 cGy) is given to a small volume (few cm$ sp3$) within the patient's brain during a single treatment. The main physical characteristics of radiosurgery are narrow circular radiation beams, stringent requirements on the numerical ($ pm$2%) and spatial ($ pm$1 mm) accuracy of dose delivery to the target and the need for sharp dose fall-offs outside the target volume. / Physical aspects of radiosurgery based on isocentric linear accelerators (linacs) are presented. The equipment and techniques used in the measurement of various radiosurgical beam parameters are discussed. Also discussed is the accuracy of radiation beam delivery to the target, the calculation and measurement of 3-dimensional isodose distributions obtained from circular beams, and the production of cylindrical dose distributions with rectangular beams. It is shown from the physics point-of-view that linac-based radiosurgery is a viable alternative to radiosurgery with the commercially available Gamma unit.

Recently, an important role has been attributed to endothelin-1 (ET-1), a potent vasoconstrictor and a mitogenic factor. The prostate and the vascular endothelium, including that of the penis, are known to produce ET-1. Furthermore, it has been shown that there are two receptor subtypes in the penis, ETa and ETb. Radiation treatment is known to cause an increase in ET-1 and may be a fundamental cause of radiation-associated impotence (RAI). / The aim of the present study was to evaluate the role of ET-1 in RAI. In the first part of our study, rats were divided into groups according to a different radiation dose. A ET-1 time course in tissue and serum was established. Markedly higher ET-1 levels were found in a high radiation dose compared with a lower dose and in the control group. / In the second part of the study, rats underwent evaluation of erectile function after radiation therapy. Subsequently, rats were given an antagonist of ETa (BQ-123) to assess whether the erectile response could be potentiated. Our results show that the use of this specific antagonist results in an improved erectile activity in a rat animal model. (Abstract shortened by UMI.)

Neurogenic impotence is a clinical situation commonly resulting from major pelvic surgery. A detailed description of the neural pathways mediating erection has been lacking and this has been implicated as a major cause for the high incidence of post-operative impotence. Nitric oxide (NO) is a gaseous molecule believed to be an important mediator of erection. The synthesis of nitric oxide is regulated by the enzyme nitric oxide synthase. / In the first part of this work, we studied the neuroanatomical pathways responsible for erection in the male lower urogenital tract. Using a histochemical staining technique able to localize a co-factor of nitric oxide synthase, NADPH, we traced the course of the cavernous nerve and its microscopic branch fibers from the pelvic plexus distally until the penile crura. Studies in a rat model and in man demonstrated multiple small nitric oxide releasing nerve fibers located on the anterior and lateral surfaces of the prostatic capsule. The physiologic importance of these fibers was shown in a rat model. Transection of these fibers resulted in a significant loss of intracavernosal pressure rise following cavernous nerve stimulation. / The nitric oxide synthase enzyme is found in three isoforms: neuronal, endothelial, and inducible forms. The neuronal form is believed to be important in the neural regulation of erection as has been demonstrated in histological studies. Using a specific inhibitor of the neuronal form of nitric oxide synthase, 7-nitroindazole, we evaluated and showed the importance of the neuronal form in regulating erection in an animal model.

Heat shock or stress proteins (HSPs), are a large family of phylogenetically conserved molecules that can be constitutively expressed at high levels under normal physiological conditions. These proteins are selectively synthesized following metabolic and environmental insult. This study was designed to determine whether cognate and/or inducible HSP production are altered in CD4-expressing lymphocytic cell lines concomitant with acute and chronic human immunodeficiency virus type 1 (HIV-l) infection. Our findings indicate that in CEM.NKR cells, HSP27 production is selectively altered at early stages of acute HIV-infection (6-24h post-infection), subsequent to virus internalization but prior to synthesis of viral progeny. Levels of HSP27 induction were viral dose-dependent and were not accompanied by any alterations in cellular proliferation. In contrast, acute HIV-infection was not associated with significant quantitative changes in the constitutive expression of HSP60, HSP70, or HSP90. Nevertheless, a transient, marked induction of select HSP70 subspecies was evident at early stages of infection, finally disappearing by 48-72h. Acute-infection of Jurkat cells resulted in similar patterns of de novo induction of HSP27 and HSP70 isoforms. Uninfected and chronically-infected CEM extracts showed little detectable constitutive HSP27. However, synthesis of select HSP27 and HSP70 homologues in chronically-infected cells was observed following exposure to a mild heat shock and doses of TNF$ alpha$. Similar HSP70 homologues arose in chronically-infected cells treated with heat-shock and TNF$ alpha$. These findings indicate that HSP pathways are uniquely modulated in CD4+ cells as a consequence of acute and chronic HIV-1 infection.

Skeletal muscle fatigue and insufficient power output were two biological constraints impeding the application of this endogenous energy source for support of the failing ventricle. Our ability to manipulate muscle phenotypic expression by a transforming and continuous low frequency electrical stimulation and the development of synchronizable pulse-train stimulators have overcome these historical obstacles. / This thesis addresses the hypothesis that fatigue-resistant transformed skeletal muscle can support the failing circulation. The work is divided into two major sections involving animal laboratory and clinical human experimentation. / In acute dog models of heart failure we have demonstrated the feasibility of transformed latissimus dorsi muscle assisting the heart in various configurations: (1) to power a potentially implantable pericardiovascular mechanical assist device and (2) in hybrid union for biventricular failure with cardiomyoplasty and mechanical support for the right and left ventricles respectively. / In another series of experiments using coronary sinus drainage as a surrogate marker for epicardial coronary flow we did not witness any compromise of epicardial coronary flow by the overlying muscle graft. / In our clinical series of 5 patients with chronic heart failure, who were all rejected for transplantation and underwent dynamic cardiomyoplasty, our follow-up investigations have revealed insights into appropriate patient selection criteria and the potential underlying pathophysiologic mechanisms of this new surgical technique in the palliation of refractory heart failure.

A multimodality image fusion and localisation system for radiosurgery treatments of arteriovenous malformations (AVM) has been developed and validated. Within this system, three-dimensional magnetic resonance angiography (MRA) and two-dimensional digital subtraction angiography (DSA) vasculature information is combined with three-dimensional magnetic resonance (MR) and/or computed tomography (CT) anatomical information in order to benefit from the functionality of all modalities. MRA/MR/CT datasets are fused, and linked to the DSA images. The consistency of the linking procedure is verified by correlation of the DSA images with two-dimensional ray-traced projections of the MRA datasets. Organ contours are drawn on the MRA images, simultaneously visualised on their MR/CT counterparts, and projected onto the DSA images for visual feedback. This procedure allows users to incorporate both vascular and anatomical information in the three-dimensional target localisation and delineation process. Patient examples illustrating the utility of the system are presented.

The purpose of this study was to provide evidence for a field defect around colorectal carcinomas using c-fos, mutant p53 and statin markers. Tissue from ten colorectal carcinomas and mucosa at 1, 5 and 10 cm from the primary lesion was obtained from surgical specimens and frozen in liquid nitrogen. Detergent-extracted protein was separated by electrophoresis through polyacrylamide gells and western blots performed using monoclonal antibodies against c-fos, mutant p53 and statin. Expression of c-fos within the carcinoma was increased relative to its expression at 1 cm, which was increased relative to 5 or 10 cm. The reverse results were obtained for statin with the lowest expression detected in the carcinoma, intermediate expression at 1 cm, and highest values at 5 and 10 cm. Increased mutant p53 expression was detected only within the carcinoma. These results indicate that c-fos gain and statin loss may occur before p53 mutation and be initial steps in oncogenesis.

The purpose of the work contained in this thesis was to investigate whether experimental paradigms based on the system identification approach are an effective clinical assessment tool. This was accomplished by conducting two companion studies: a reliability study on a group of fifteen control subjects and a case study of an individual who had sustained a unilateral undisplaced ankle fracture. The data collected in both studies included ankle angular position, torque, and Tibialis Anterior and Triceps Surae electromyograms. From these data, measures of both static (e.g. range of motion) and dynamic (e.g. estimated elastic stiffness) joint function, were obtained. / A number of clinically relevant variables (plantarflexion MVC, dorsiflexion MVC, range of motion, passive torque, K offset, low K region, and the intercept of the K-absolute torque relation) were shown to be reliable. In addition, the results of the case study demonstrated that it would be feasible to use these experimental procedures and analytic methods on individuals who have sustained orthopedic trauma. Finally, certain variables (the K offset, the slope and intercept of the K-torque relation, and a low stiffness region) appeared to be sensitive to the clinical changes associated with orthopedic pathology.

The role of nerve growth factor (NGF), a neurotrophic molecule, and its high-affinity receptor in intact and injured adult rat lumbar sensory neurons was examined at a cellular level using quantitative receptor radioautography to localize the NGF high-affinity receptor-positive subpopulation, in conjunction with histochemistry on adjacent sections. The 40-50% of sensory neurons displaying NGF receptors were characterized. Virtually all neurons containing substance P or CGRP were NGF receptor-positive, but not those with somatostatin or thiamine monophosphatase activity. The ability of a neuron to bind NGF with high-affinity correlates positively with growth-associated protein (GAP43) expression but not with neurofilament (NFM) expression. Following injury, sensory neurons atrophy, lose NGF receptors, decrease NFM expression, while GAP43 expression is elevated in all neurons irrespective of their ability to bind NGF. Infusion of NGF for 1 week, at the time of injury or 3 weeks following injury counteracts NGF receptor loss, cell atrophy, and decreased NFM expression, but only in those neurons bearing NGF receptors. GAP43 expression remained high in all neurons despite infusion. NGF's function in normal sensory neurons appears to be modulatory, permitting regulation of intrinsic properties. Injury disrupts this permissive state, which can be restored with exogenous NGF.

Liver xenotransplantation could eliminate the liver donor shortage, but currently it is not possible because of a lack of understanding of liver xenograft rejection. Hyperacute xenograft rejection is initiated by the binding of preformed naturally occurring xenoreactive antibodies (XNA) to the xenograft endothelium. The XNA bind to the xenograft endothelium, leading to complement-mediated endothelial injury. / Liver xenotransplantation will be initially offered to patients with severe liver failure as a bridge to a human liver transplantation. The hypothesis tested in this thesis is that hyperacute rejection of liver xenografts placed into recipients with liver failure will be diminished because of the complement deficiency that accompanies liver failure. The experiments described in this thesis detail the development of an in vitro pig-to-human liver xenotransplant model incubating cultured pig hepatic endothelial cells (PHEC) and human serum in culture. We showed that either classical or alternative complement pathways could initiate endothelial injury. Next we developed the dog-to-pig liver xenograft model and characterized the lethal coagulopathy that results from hyperacute rejection. The coagulopathy results from the lack of function of platelets as well as their disappearance from the circulation. We then used the galactosamine induced liver injury model in porcine recipients of canine liver xenografts to demonstrate that hyperacute rejection in the setting of liver failure is diminished. We showed that; tissue injury, coagulopathy and platelet defect, and endothelial injury were diminished. Our experiments suggested that the cause of the decreased injury was the lack of complement in the pigs with galactosamine induced liver injury since the XNA levels were no different than in control animals. Our final experiments evaluated serum from patients with liver failure and compared the injury caused by incubation with PHEC. Serum from the liver failure patients had similar levels of XNA when compared with normal subjects, but had less complement activity, and less C3 and C4. Incubation of liver failure serum with PHEC caused much less injury and complement activation than serum from control subjects. The results in this thesis suggest that liver failure will have a significant impact on liver xenograft rejection, helping to diminish hyperacut