SUMMARY The investigation work “Optimal tolerance count in unconnected dimensions chains” consist of optimal cost institution. Subject of investigation is optimal tolerance count. I‘m doing in my work research, which could help me to reach the optimum result at the manufacturing cost rate. At first we take a look at the dimension chains, next we come to the count. Composing tolerance chains, from them I‘m counting the optimum rapport. To find the rapports need to rate the costs. At last we set the least cost from the project interval.

The development of inhibitory antibodies to the factor VIII (FVIII) protein is the greatest complication in the management of hemophilia A patients. These antibodies, which form in approximately 25% of patients, neutralize the procoagulant activity of FVIII. There are limited treatment options to manage FVIII “inhibitors”, and this significantly increases morbidity within the hemophilia population. Therefore, understanding the immunobiology of FVIII, and developing safe, efficacious therapies to induce immunological tolerance to FVIII is a clinical priority. In 2010, there is no therapy available to prevent the formation of FVIII inhibitors in boys with hemophilia. Therefore, we evaluated the efficacy of anti-CD3 to induce tolerance to FVIII in a prophylactic setting. Low-dose anti-CD3 significantly increased the level CD4+CD25+ T regulatory cells, and prevented formation of inhibitors in >80% in hemophilia A mice. Depleting CD4+CD25+ cells in vivo completely abrogated tolerance. Furthermore, cytokine production by splenocytes from tolerant mice were shifted toward a Th1 response. Anti-CD3 therefore represents one of the most efficacious pre-clinical therapies for FVIII tolerance induction. Surgery is widely regarded in the hemophilia community as a trigger for inducing de novo inhibitor formation. There is, however, only conflicting clinical evidence, and no basic science data to lend support to this clinical hypothesis. Therefore, we developed a novel surgical procedure in hemophilia A mice to study the influence of surgery on FVIII immunogenicity. We found that surgery induced a systemic proinflammatory response (upregulated plasma IL-1 and IL-6), but surprisingly the immunogenicity of FVIII was not enhanced when infused at the perioperative time. These results are significant, however, because they suggest that surgery is not as important for de novo inhibitor formation as previously thought. Finally, it is unknown whether central tolerance to FVIII shapes the peripheral T cell repertoire. Therefore, we studied the murine thymus for evidence of FVIII expression. Whole thymus expressed FVIII mRNA but not protein. FVIII mRNA expression in the thymus was due, at least in part, by the thymic epithelium (CD45-/loEpCAM+). In FVIII-/-AIRE+/-, the immunogenicity of FVIII appeared to be unaltered. This study is the first to investigate a possible role for central tolerance to FVIII. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2010-09-23 10:22:07.39

Organic nitrates such as glyceryl trinitrate (GTN) are commonly used to treat cardiovascular disease. They are prodrugs that require bioactivation for pharmacological activity. Currently, there are two proposed pathways of organic nitrate activation: a high-affinity pathway for high-potency nitrates (GTN and pentaerythrityl tetranitate) and a low-affinity pathway for low-potency nitrates (isosorbide dinitrate (ISDN) and isosorbide mononitrate). A major limitation in the utility of organic nitrates is the rapid onset of tolerance during chronic treatment. Inhibition of the enzymes responsible for bioactivation has been put forward as the major cause of tolerance, and aldehyde dehydrogenase 2 (ALDH2) has been proposed as the primary enzyme responsible for bioactivation in the high-affinity pathway. ALDH2 activity is decreased in GTN-tolerant tissues and it has been suggested that ALDH2 inactivation is the underlying cause of GTN tolerance. However, several aspects of this hypothesis are problematic. My objective was to develop an in vivo model of ISDN tolerance and to use this model to examine the effects of chronic ISDN treatment on ALDH2 activity and on organic nitrate-induced vasodilation. The hypothesis of my research is that the reduced potency of GTN caused by ISDN tolerance is mediated by a mechanism independent of ALDH2 inactivation. ISDN tolerance was induced in rats using an in vivo model in which animals were exposed to 0.8 mg/hr ISDN for 24-96 hr. ALDH2 activity was measured in liver mitochondrial fractions and tolerance was assessed in isolated aortic preparations. There was no inhibition of mitochondrial ALDH2 activity in ISDN-treated animals. However, chronic treatment with ISDN resulted in parallel rightward shifts of both the ISDN and GTN concentration-response curves, which increased with increased duration of exposure iii to ISDN. Concentration-response curves for acetylcholine (ACh), sodium nitroprusside (SNP), and diethylamine NONOate were unchanged in ISDN-treated animals. The model of chronic ISDN treatment results in cross tolerance to GTN but does not affect ALDH activity. The data presented in this study indicate no role for ALDH2 in the development of nitrate tolerance. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2011-05-30 12:06:05.785

Hypoxic condition is a naturally occurring environmental stressor in aquatic ecosystems. However, due to modern anthropocentric activities, hypoxia has been increasing in prevalence and severity. Rainbow trout, a keystone species in many North American lakes, is hypoxia intolerant. As a result, this species is of particular concern when studying the effects of hypoxia on an organism’s physiological functioning. Chronic starvation was used as a tool to induce metabolic depression to determine the effect that depressed metabolic rate had on hypoxia tolerance. Juvenile rainbow trout were deprived of food for five weeks at 15oC. Each week, routine metabolic rate (RMR) and critical oxygen tension (Pcrit) were measured. Concomitantly, resting and post-hypoxia fish (8 h at ~50% air saturation) were sampled to measure metabolites in blood, liver and muscle, as well as enzyme activities in select tissues. Food deprivation resulted in a decrease in routine metabolic rate (RMR) and shift towards an increased reliance on aerobic metabolism. Pcrit decreased significantly following four weeks of food deprivation respectively, indicating that metabolic depression induced by food deprivation may confer an increased tolerance to low environmental oxygen concentration ([O2]). However, marginal metabolic scope (MMS), another indicator of hypoxia tolerance, did not change in response to metabolic depression. Furthermore, subjecting trout to O2 limitation resulted in mobilization of carbohydrates from the liver subsequently leading to hyperglycemia. This was likely a survival technique ensuring that if severe hypoxia ensues, anaerobic substrates are ready for transport to the necessary tissues. / Thesis (Master, Biology) -- Queen's University, 2011-10-12 23:21:04.517

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.