Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted. Includes bibliographical references.

A Research Report submitted to the Faculty of Medicine, University of the Witwatersrand, in part fulfilment of the requirements for the degree of Master of Medicine in the branch of Haematology Johannesburg, October 1997 / Venous thromboembolic disease is a common health problem. It contributes considerably to morbidity as well as to mortality. Thrombosis usually occurs due to an underlying risk factor which may be environmental or genetic in origin. The recently described activated Protein C (APC) resistance is the commonest cause of familial thrombophilia documented to date. The molecular lesion is a single point mutation in the factor V (FV) gene which abolishes a cleavage site whereby it is normally inactivated by APC. This defect, termed the FV Leiden mutation, is highly prevalent in normal Caucasian populations. Although it would appear to have arisen due to a founder effect, there is a paucity of data concerning non-Caucasian populations. / IT2018

Le choc septique est la principale cause de mortalité dans les services de réanimation. Les glucocorticoïdes (GC) et la protéine C activée (APC) sont deux traitements adjuvants recommandés au cours du choc septique. Ce travail a pour objectif d'évaluer l'impact de la combinaison d'APC et des GC sur les paramètres hémodynamiques et la survie. Le sepsis expérimental se caractérise par une hypotension artérielle avec acidose lactique et une hyporéactivité vasculaire. L'administration de Dexa et/ou d'APC permet de diminuer les taux de lactates, d'interleukines et de nitrate/nitrite. Chez les groupes traités, la contraction est améliorée ainsi que la relaxation vasculaire des aortes et des artères mésentériques. L'administration d'APC et de Dexa, seul ou en association, entraine une diminution de l'expression induite d'iNOS et la restauration de la voie Akt. La combinaison APC et Dexa améliore le temps de survie de façon synergique. Nos résultats suggèrent que l'APC et les GC devraient être réévalués en association dans le traitement du choc septique / Sepsis remains the major cause of death in intensive care units. International guidelines for management of severe sepsis and septic shock recommend both stress-dose steroid therapy and recombinant activated protein C (APC). The aims of the present study were to compare the effects of APC and dexamethasone (Dexa) alone as well as in combination in resuscitated septic shock on survival, hemodynamics, and vascular reactivity. Sepsis was associated with a decrease in mean arterial pressure, elevation in plasma lactate and nitrite/nitrate concentration. Administration of APC, Dexa, and their combination improve arterial pressure and decrease lactate and nitrite/nitrate concentration. Both APC and Dexa improved arterial contractility and endothelial dysfunction resulting from septic shock in rats. The expression of iNOS was significantly reduced by the administration of Dexa, APC, and combination therapy. All treatments restore the Akt pathway. Moreover, their combination increased the length of survival. These findings suggest that APC and glucocorticoids should be further re-evaluated in combination in septic shock

Severe Acute Pancreatitis (SAP) is the rapid onset of inflammation within the pancreatic organ. Unlike the milder form of this illness, SAP is associated with a high mortality and morbidity. No significant reduction in the outcomes of this disease has been made since the implementation of organ supportive management over two decades ago. This is due to difficulties in distinguishing between the milder form of the disease in the early period of the onset of symptoms when clinical intervention is most likely to prevent complications and death. Clinical equipoise exists in the management of one of these complications, namely Abdominal Compartment Syndrome (ACS) as the conventional management of surgery runs contrary to published evidence showing early abdominal surgery deteriorates clinical outcomes. Aims: Validation of the potential use of the Early Warning Score (EWS) as a predictor of SAP. Evaluation of the evidence for recombinant human protein C (Xigris™) in the early treatment of SAP. Determination of the safety profile of Xigris™ when given early in SAP. To determine if surgical management of ACS in SAP is of significant benefit compared to conventional management alone. Methods: Four studies were performed: A prospective observational study assessing the median EWS of patients admitted with acute pancreatitis; a systematic review of published evidence reporting the use of Xigris™ in SAP; a prospective cohort study using a 24 hour infusion of Xigris™ early in patients diagnosed with SAP and a pilot randomized controlled trial of targeted decompression in patients with ACS complicating SAP. Results: The highest EWS values for 130 patients with acute pancreatitis within the first 3 days of admission were not shown to have significant sensitivity and specificity in predicting an unfavourable outcome. A review of the published literature between from January 1985 to January 2011 supported the further investigation of Xigris™ as a treatment for SAP. No significant adverse events or differences in outcomes were evident in 19 patients who received a 24-hour infusion of Xigris™ early in SAP compared to matched historical controls. 22 patients were screened for the development of ACS. No patient developed ACS and consequently no randomization to either treatment arm was possible. Conclusion: With the recent advent of an updated classification system for the severity of acute pancreatitis, further prospective evaluation of the use of EWS in clinical practice is warranted. The results of the Phase 1 clinical trial of Xigris™ didnot reveal significant safety issues that might preclude the further investigation of Xigris™ as a specific therapy early in the onset of SAP. The absence of ACS inpatients with SAP lends support to a theory that ACS may be an epiphenomenon in the course of SAP.

Sepsis has been defined as a systemic response to an infection. With an incidence of 3 per 1000 population per year or about 750 000 cases a year, this syndrome ranks as the 10th leading cause of death in the United States (1). Increasing severity of sepsis correlates with increasing mortality, which rises from 30-40% for severe sepsis up to 40-60% for septic shock. This thesis examines the effectiveness of adjunctive therapies, including activated protein C, hypercapnia and acidosis, and sodium selenite, in a clinically relevant ovine model of septic shock. The results from these studies can provide valuable information for future clinical trials on sepsis.<p>This thesis is divided into four sections: 1) sepsis overview; 2) an autologous fecal peritonitis model in sheep and its evaluation; 3) the series of studies on adjunctive therapeutics; and 4) ongoing studies and future perspective.<p>In the first section, a broad overview gives a rough introduction to delineate many aspects of sepsis syndrome such as terminology, etiology, epidemiology, pathophysiology and current guidelines for management. Hemodynamics in sepsis are especially elaborated since these are major observations throughout the studies presented later.<p>In the second section, the general characteristics of the sepsis models used in this thesis are elucidated. Data on hemodynamics, lung mechanics, gas exchange, etc. are presented to feature the ovine peritonitis model. The results of laboratory examinations for hematology, coagulation, bacteriology, biochemistry and hormonology are also presented. And then, I review currently used sepsis models with regards to their advantages and disadvantages.<p>The third section discusses three studies with their objectives, the methods used, the major findings, and the potential clinical implications.<p>9<p>1) Beneficial effects of recombinant human activated protein C in experimental septic shock. Activated protein C has a multitude of beneficial effects in severe sepsis and septic shock, including anti-inflammation, anti-coagulation, profibrinolysis, anti-apoptosis and endothelial protection. A clinical Phase III trial demonstrated that the administration of recombinant human activated protein C improved survival in patients with severe sepsis. However, doubts on the protective effects of activated protein C have persisted and been refueled by the recently published negative trials in less severely ill patients and in children. In the light of these ambiguities and uncertainties, we reinvestigated the effects of activated protein C in experimental septic shock.<p>2) Acute hypercapnia improves indices of tissue oxygenation more than dobutamine in septic shock. Hepercapnia has been found to possess beneficial effects in diverse acute inflammatory states independent of protective lung mechanics. To prove the hypothesis that acute hypercapnia has similar or superior hemodynamic effects to those of a dobutamine infusion, which may be particularly relevant in the presence of hemodynamic instability associated with respiratory failure, we investigated the effects of hypercapnia, which induced by inspiring extrinsic carbon dioxide in experimental septic shock.<p>3) High bolus dose of sodium selenite prolongs survival in an ovine model of septic shock. Selenite has both pro- and anti-oxidant effects. The administration of high dose sodium selenite may improve survival in septic shock patients. The benefit may be greater with the administration of a bolus (to achieve higher concentrations) rather than a continuous infusion. To test this hypothesis, we examined the effects of a high dose bolus administration of sodium selenite in experimental septic shock.<p>The fourth and final section talks about currently ongoing studies and offers some perspective on future direction. / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Effective management of acute pancreatitis has for centuries eluded mankind. The disease has a wide spectrum of presentation; the milder form is usually a self limiting condition, whereas the severe form presents as a highly morbid and frequently lethal attack. The ability to predict disease progression on admission would aid in the comprehensive and multidisciplinary management of patients. The perfect predictor of disease progression has been an elusive factor hindering the management of the disease. On systematically reviewing literature and identifying appropriate biochemical markers in predicting progression of acute pancreatitis, the ideal predictor would be a combination of biochemical, clinical and contemporary organ dysfunction scoring systems. Early prediction of disease progression however, is important in the better management of the disease. The pathophysiological changes of acinar cell injury and death are the earliest events that occur in acute pancreatitis. Identification of potential pharmacological interventions offered through valuable insight in to experimental and clinical acute pancreatitis may lead on to the development of various natural and synthetic potential disease modifiers. Green Tea Extracts (GTE) consumed in many parts of the world has been examined as a potential therapeutic medication. Experimental results have demonstrated the effect of GTE on the oxidative pathway significantly ameliorating the effects of pancreatic injury. The various green tea catechins especially Epigallocatechin-3- gallate (EGCG) can perhaps be useful lead compounds for new drug discovery. With no specific targeted therapy for severe acute pancreatitis at present, various medications have been tested. The possibility of targeting initial acinar cell injury may not be a feasible option as patient presentation and management would usually be after this phase. As the disease progresses, severe acute pancreatitis is characterised by inflammation and necrosis. The hypothesis of preserving pancreatic parenchymal microvascular patency and thus ameliorating pancreatic injury through the early administration of recombinant human Activated Protein C (rhAPC) has identified a potential treatment for acute pancreatitis. rhAPC converted from its inactive precursor, protein C, by thrombin acts through fibrinolysis and inhibition of thrombosis. Studies on rhAPC in experimental acute pancreatitis examined the modulation of rhAPC on inflammatory markers, morphology, microvascular thrombosis and apoptosis. The encouraging results from initial experimental work helped set up the Phase 2 clinical trial of administering rhAPC early on in severe acute pancreatitis. Prior to taking this significant step from bench to bed side, the variation in functional protein C levels with the severity of the disease was examined as a precursor to the Phase 2 trial.

This thesis was about the relationship of the Factor V Leiden mutation and activated protein C resistance. I looked up patients with Leiden mutation and activated protein C resistance. I monitored the frequency of thromboembolism and miscarriages in the personal and family case history of patients. Subsequently, I looked up if other risk factors which affect clinical manifestations in patients with this mutation can be found.

Diabetes mellitus is hallmarked by accelerated atherosclerosis, a major cause of mortality among patients with diabetes. Efficient therapies for diabetes-associated atherosclerosis are absent. Accelerated atherosclerosis in diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Here, we directly compared the effects of high glucose and oxidized LDL, revealing that high glucose induced more pronounced responses in regard to maladaptive unfolded protein response (UPR), senescence, and vascular endothelial cell barrier disruption. Ex vivo, diabetic ApoE mice displayed increased levels of senescence and UPR markers within atherosclerotic lesions compared with nondiabetic ApoE mice. Activated protein C pretreatment maintained barrier permeability and prevented glucose-induced expression of senescence and UPR markers in vitro. These data suggest that high glucose-induced maladaptive UPR and associated senescence promote vascular endothelial cell dysfunction, which—however—can be reversed by aPC. Taken together, current data suggest that reversal of glucose-induced vascular endothelial cell dysfunction is feasible.

Diabetes mellitus, which is largely driven by nutritional and behavioral factors, is characterized by accelerated atherosclerosis with impaired plaque stability. Atherosclerosis and associated complications are the major cause of mortality in diabetic patients. Efficient therapeutic concepts for diabetes-associated atherosclerosis are lacking. Atherosclerosis among diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Here, we demonstrate that atherosclerotic plaque stability is reduced in hyperglycemic mice expressing dysfunctional TM (TMPro/Pro mice), which have a pro-coagulant phenotype due to impaired thrombin inhibition and markedly reduced aPC generation. The vessel lumen and plaque size of atherosclerotic lesions in the truncus brachiocephalic were decreased in diabetic TMPro/Pro ApoE-/- mice compared to diabetic ApoE-/- mice. While lipid accumulation in lesions of diabetic TMPro/Pro ApoE-/- mice was lower than that in diabetic ApoE-/- mice, morphometric analyses revealed more prominent signs of instable plaques, such as a larger necrotic core area and decreased fibrous cap thickness in diabetic TMPro/Pro ApoE-/- mice. Congruently, more macrophages and fewer smooth muscle cells were observed within lesions of diabetic TMPro/Pro ApoE-/- mice. Thus, impaired TM function reduces plaque stability, a characteristic of hyperglycemia-associated plaques, thus suggesting the crucial role of impaired TM function in mediating diabetes-associated atherosclerosis.