We hypothesize that continuous electrical stimulation (ES) of denervated muscle using implanted electrodes and a pulse generator lessens the effects of denervation and helps to preserve muscle integrity. Ten dogs underwent sciatic nerve severance, common peroneal nerve repair, and implantation of stimulating devices. The proportion of muscle weight preserved was significantly greater in the stimulated muscle than in the untreated denervated muscle (p $<$ 0.01). There was evidence of less atrophy and degeneration in DS seen in both light and electron microscopy. Dependent t test analysis using the normal contralateral muscle groups as the control showed that twitch contraction time was maintained within normal limits by stimulation whereas in the unstimulated group prolongation of twitch time occurred (p $<$ 0.004). The electrical resistance property of the stimulated muscle was also preserved when compared to the normal control (p = 0.7) but did differ between D and N (p $<$ 0.04). Although trends in the data suggested beneficial functional effects of ES, statistical analysis failed to support differences between the stimulated and unstimulated groups in functional testing. (Abstract shortened by UMI.)

Despite the best of modern microsurgical skills, the functional result that is achieved following the repair of a severed peripheral motor nerve has usually been less than complete. In an attempt to reduce or prevent denervation atrophy we have devised a totally implantable system of electrical stimulation and have examined its effect on the target muscle of a repaired peripheral nerve. In this study, twenty New Zealand white rabbits were divided into two groups: in one group the rectus femoris muscle is electrically stimulated after microsurgical repair of the femoral nerve; whereas the control group undergoes microsurgical repair of the femoral nerve only. Comparing the muscles to their contralateral counterparts at eight weeks post-op we found that electrical stimulation resulted in (a) the retention of 79+/$-$5(SEM)% of muscle bulk (compared to 42+/$-$3% in the non-stimulated group) p $<$ 0.001, (b) a maximum force of tetanic contraction averaging 41+/$-$5% of normal (compared to 19+/$-$4% in the non-stimulated group) p $<$ 0.01, (c) less myofiber atrophy, interfascicular fibrosis, and fatty infiltration, (d) significantly less myofilamentous disruption at the ultrastructural level, and (e) a preferential atrophy of type-II fibres (p $<$ 0.001) in the absence of electrical stimulation. There was no statistical difference between the two groups in the compound action potential waveform or amplitude of evoked contractions. In conclusion, these results suggest that the electrical stimulation of skeletal muscle will improve the ultimate functional results in patients undergoing peripheral motor nerve repair.

Injured adult mammalian cardiac muscle does not respond with significant regeneration. Skeletal muscle, on the other hand, has an efficient regeneration mechanism attributable to myogenic stem (satellite) cells. This study investigated a hypothesis which states that skeletal muscle satellite cells (SCs), if grafted into an injured heart, can form muscle tissue and repair the damaged myocardium. / In the first study SCs obtained from 28 dogs were isolated, purified and cultured. Percoll density gradient and preplating methods for the purification of SC culture were investigated. Beta-galactosidase ($ beta$-Gal) labelled SCs underwent autografting into acutely cryoinjured myocardium. Three control dogs received only sham implants into the cryoinjured heart. Two (n = 6), 4 (n = 16) and 6 (n = 6) weeks after SC implantation, hearts with SC graft sites were procured and processed for histrionical examination, as well as for detection of a $ beta$-Gal marker. Control specimens were obtained at 2 (n = l), 4 (n = l), and 6 (n = l) weeks after sham implantation and were processed as described above. / In the second study on rats, SCs were obtained from donor animals (n = 30). An intramuscular bupivicaine method to increase SC yield was adopted. Purified, cultured, and $ beta$-Gal labelled SCs were implanted either into acutely cryoinjured myocardium (n = 15), or into the mature cardiac scar (n = 15) of isogenic donor animals. Myocardial specimens were obtained at 1 month after SC implantation. Techniques of rodent SC labelling in vitro with human alkaline phosphorate genes were also explored. (Abstract shortened by UMI.)

Background. A growing number of patients suffering from ischemic cardiomyopathy are not eligible for conventional revascularization. This has prompted new research in the field of angiogenesis. This study hypothesized that since inflammation is probably the mechanism behind TMR induced angiogenesis; a larger inflammatory response induced by thermal injury may lead to increased angiogenesis. / Methods. The model used for this study was coronary artery ligation in the Rat. Four groups of animals were used to compare the novel experimental approach with conventional TMR and with ischemia alone. Neovascularization was determined by immunohistochemical techniques using anti-Factor VIII antibody. Evaluation of VEGF, Ang-1 and Ang-2 expression was also carried out using immunohistochemistry. / Results. The experimental "HOT" TMR technique resulted in significantly increased angiogenesis presumably due to the thermal injury induced by the novel technique. Also a significant increase in VEGF expression was observed in all ischemic groups. Ang-1 expression was decreased in the experimental group while it was similar in the other groups. Finally Ang-2 was induced by ischemia as evidenced by increased expression among all ischemic groups. However Ang-2 expression did not significantly vary among ischemic groups. / Conclusions. The addition of thermal injury by heating of the needle led to an increased angiogenic response compared to ischemia alone and compared to conventional TMR. This increased angiogenesis was associated with increased VEGF expression at one week, however there was a significant inverse correlation between VEGF expression and angiogenesis among the ischemic groups. Also angiopoietin expression was in agreement with expression characteristics described in the literature.

Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease. Currently there is only one modestly beneficial pharmacological treatment, Riluzole, approved by the FDA. It has been documented that polyunsaturated fatty acid (PUFA) concentrations can affect the progression of neurodegenerative conditions however most interventions rely on nutritional supplementation and have limited long-term effectiveness. This thesis describes experiments using fenretinide, a synthetic retinoid capable of altering membrane PUFA concentrations, in a mouse model of ALS (SOD1(G93A)mice). Our treatment resulted in delayed onset, improved motor coordination, and increased life expectancy. Fenretinide also increased plasma levels of the ω-3 PUFA docosahexaenoic acid (DHA) while decreasing ω-6 PUFA arachidonic acid (AA) and products of lipid peroxidation malonyldialdehyde (MDA) and nitrotyrosine (NT). Spinal cord immunohistochemistry revealed a significant reduction in inflammation as assessed by the quantity of activated microglia and astrocytes. These results indicate that fenretinide represents a promising treatment strategy for ALS. / La Sclérose latérale amyotrophique (SLA) est la maladie affectant les neurones moteurs adultes la plus commune. Il n'existe qu'un seul traitement pharmacologique approuvé par la FDA ayant certains effets bénéfiques, soit le Riluzole. Il est par ailleurs documenté que des concentrations d'acides gras polyinsaturés (PUFA) peuvent affecter la progression d'un état neurodégénératif. Cependant, la plupart des interventions s'appuient sur des suppléments nutritifs et ont une efficacité à long terme plutôt limitée. Cette thèse décrit une série de traitements utilisant le fenretinide, un rétinoïde synthétique capable d'altérer la concentration de PUFA dans les membranes, dans un modèle de souris de SLA (souris SOD1(G93A)). Les traitements ont entrainé un retardement du déclenchement de la maladie avec une meilleure coordination motrice ainsi qu'une espérance de vie améliorée. Le fenretinide a également accrue les niveaux plasmatiques de l'acide docosahexaenoique tout en diminuant les niveaux d'arachidonate ainsi que les produits de peroxydation lipidiques tel que malonyldialdehye et nitrotyrosine. L'analyse immunohistochimique de la moelle épinière a révélé une réduction significative de l'inflammation déterminé par la quantité d'astrocytes et de microglies activés présentes. Ces résultats indiquent que le fenretinide représente un traitement prometteur contre la SLA.

Objectives. To study marrow stromal cells (MSCs) induced angiogenesis. To examine the possible mechanisms involved in the process. To evaluate neovascularization following implantation of MSCs in ischemic hind limb model. / Methods and result. Using murine Matrigel angiogenesis model, we compared MSCs related angiogenesis to that produced by vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We found that MSCs result in an efficient and organized angiogenesis, arteriogenesis and vasculogenesis. MSC-related angiogenesis is VEGF dependent. MSCs in vivo produce VEGF that through paracrine effect induces local angiogenesis and through an autocrine loop stimulates FLK1+MSCs to differentiate into endothelial cells. MSCs implanted into ischemic hind limb resulted in marked improvement in blood flow and collateral vessels formation. / Conclusion. MSCs spontaneously induce efficient and mature angiogenesis in ischemic/hypoxic tissues with significant arteriolar component resulting in increased blood flow. They are also capable of spontaneous differentiation into endothelium. VEGF appears to be necessary for MSC-related angiogenesis and vasculogenesis.

Limb salvage in patients with advanced peripheral vascular disease or effective nonoperative therapy for patients with limited disease still remains a challenge in modern vascular surgery. Based on recent advances in the area of angiogenesis as well as our previous studies of alternative approaches for limb ischemia, we have presented herein the step-by-step experimental investigations that are directed toward the development of a novel therapy, angiogenic stimulation, for the revascularization of ischemic limbs. An animal ischemic hindlimb model has been developed suitable for testing our hypothesis and further understanding of this potential therapy. We have demonstrated that an angiogenic factor, ECGF, when administered intramuscularly into the ischemic limb, markedly enhances revascularization of the limb in the models of unilateral as well as bilateral hindlimb ischemia. In addition, we have also demonstrated that the angiogenic effect of ECGF is dose dependent and is demonstrable only when it is administered directly into the limb in the presence of ischemia. Therefore, we conclude that angiogenic therapy may have the potential for the treatment of patients with chronic limb ischemia.

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