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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The combination of pretransplant donor specific transfusion (DST) and cyclosporin (Cys) has proven to be an effective mode of immunomodulation in numerous allograft models. Our experiments were designed to study the effect of clinically applicable protocols using DST and low-dose cyclosporin in an heterotopic, fully allogenic model of small bowel transplantation in the rat. / A 1 ml systemic DST 24 hours pretransplant with Cys (10 mg/kg day $-$1, 5 mg/kg POD 0 to 7, 2.5 mg/kg POD 8 to 14) was shown to be more effective than DST or Cys alone in prolonging graft survival (p $<$ 0.05). Adding successive post-transplant DST (POD 7,14,21) had no effect on graft survival. Portal transfusion and Cys was the most effective mode of antigen presentation (p = 0.01 vs systemic DST), with 33% of the animals having prolonged survival. Adding successive post-transplant DST was deleterious to the portal DST effect. The adjunct of anti-lymphocyte serum to the DST-Cys combination was ineffective.

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The effects of ischemia/reperfusion injury on humoral changes in canines that underwent left lung allotransplantation was compared to autotransplantation (n = 10 each). Cytokines IL-2, TNF-a and IFN-g were measured in bronchoalveolar lavage (BAL) and plasma samples at 1, 4, 24 hours and 1 week postoperatively. In the allograft there was an early postoperative increase in all cytokines in BAL which decreased after 24 hours. The same trend was seen for IL-2 in the autograft. In contrast, TNF-a and IFN-g levels in the autograft remained unchanged. Using immunohistochemical staining techniques, MHC II antigen expression was observed on lung allograft bronchial epithelium which was less intense in the autograft. Hematoxylin and eosin staining of lung biopsies revealed early evidence of lung injury and also grade 1-2 rejection after 1 week in the allograft. Injury was not as severe in the autograft. We conclude that a temporary elevation of cytokines early after allotransplantation is partly due to ischemia/reperfusion injury and graft allogenicity. This early cytokine release may play an important role in the development of early graft dysfunction and rejection.

('125)I-tonin injected intravenously to rats dissappeared from plasma with a bi-exponential decline. The label accumulated in the liver, adrenal glands, spleen and kidney. In renal hypertensive rats no important changes in tissue dispostion were found, but the apparent volume of distribution of ('125)I-tonin was reduced. ('125)I-PMS-tonin, a modified protein which does not bind to the tonin-inhibitor in plasma, had a significantly different disposition, accumulating in the kidneys, while much less was found in the adrenal glands. When unlabeled tonin was co-injected with ('125)I-tonin, survival of tonin radioactivity in the circulation was prolonged and liver, spleen and adrenal uptake significantly reduced. Co-injection with trypsin produced similar effects, but associated with important hemodynamic changes which might explain the findings. Taken together, these facts suggest that tissue uptake of the tonin-inhibitor complex may be mediated by recognition sites specific for the complex. Radioautography after injection of ('125)I-tonin to rats showed greater accumulation in the adrenal glomerulosa and reticularis. The grains seemed to associate with adrenal cells and not with endothelial cells lining the sinusoids. In the liver the radioautographic reaction was found to concentrate in Kupffer cells. In the kidney grains predominated in the lumenal pole of cells of the proximal convoluted tubule. / A pressor effect of tonin, absent in normal rats or rabbits, was found in bilaterally nephrectomized animals. No important change in vascular reactivity or in the inhibitory power of plasma could be detected. The response was produced by generation of angiotensin II in plasma. A role of substrate levels in the modulation of tonin activity in vivo even in the presence of the tonin inhibitor was suggested. / The infusion of tonin into conscious seemingly unstressed rats produced an increase in plasma aldosterone and corticosterone, and a decrease in plasma renin activity. Plasma angiotensin II concentration was not different from controls, but the plasma renin/angiotensin II ratio was decreased. Plasma electrolytes were unchanged. The angiotensin III antagonist blocked the response of the adrenal. Of angiotensin II antagonists, sar('1)ala('8)angiotensin II was ineffective and sar('1)thr('8)angiotensin II blocked the effect partially. No significant response could be found in sodium depleted rats. The plasma aldosterone concentration in these rats, however, presented a wide dispersion of values. No adrenal response was seen in chronically hypophysectomized rats. Tonin stimulated aldosterone biosynthesis by isolated rat adrenal glomerulosa cells only in the presence of plasma, when large amounts of angiotensin II were generated in the incubate. These results suggest that tonin does not act in vivo directly on adrenal cells. The lack of effect in hypophysectomized rats indicates that the response may be mediated by a pituitary peptide, unless this finding is caused by the reduction of the concentration of substrate in plasma and tissues observed in this experimental situation. / The elevated blood pressure of one-kidney one-clip hypertensive rabbits was reduced when active immunization against tonin was successful. Together with previous evidence, this suggests an involvement of the tonin-angiotensin II system in this form of experimental hypertension.

Introduction. The Carotid Endarterectomy (CEA) is used for stroke prophylaxis in asymptomatic carotid stenosis and in patients with previous strokes or transient ischemic attacks. / Objective. To audit the operative results of the CEA in the province of Quebec between 1996 and 1999. / Methods. The Quebec Medical Discharge Summary Database provided demographics and surgical complications following all CEAs performed between 1996--1999. / Results. The CEA was performed at a rate of 42 procedures/100 000 persons aged greater than 40 however this rate appears to be declining over the study span. Being operated on by a neurosurgeon was an independent risk factor for peri-operative stroke (OR 1.55, 95%CI 1.12--2.12). There was no difference in outcomes between teaching and non-teaching centres. / Conclusion. The CEA is being used less frequently recently and is being performed fewer times than in the United States. Neurosurgeons have poorer outcomes which might be due to surgeon factors or poorly controlled counfounders.

Transmyocardial Revascularization (TMR), a procedure for enhancing myocardial perfusion, is used to treat patients with refractory angina. The mechanism remains elusive. We tested the hypotheses that (a) needle TMR induces nitric oxide synthase (NOS) enzyme, which is potentially capable of causing vasodilatation to augment blood flow; (b) that needle TMR can recruit smooth muscle cells for vessel development (arteriogenesis) in the late phase of TMR; and (c) that needle TMR improves myocardial regional blood flow in the early and late phases of TMR under either rest or stress conditions. We conclude that, both experimentally and clinically, the validity of TMR as an effective therapy for myocardial ischemia remains questionable and that the placebo effect in TMR treatment cannot be excluded.