The physiological role of the plasma contact system still remains a partial enigma. The aim of the presented work was to expand our understanding of the plasma contact system, focusing on its physiological activation and function, principally from a hemostatic perspective. It also explored contact system activation under pathological conditions. We found that when human platelets become activated in blood, plasma proteins of the contact system bind to platelets and initiate contact activation. The platelet-triggered contact activation contributed to clot formation by shortening the clotting time and enhancing clot stability. We demonstrated that the regulation of contact activation elicited by activated platelets differed from the previously described contact activation elicited by negatively charged material surfaces. Platelet-triggered contact activation and activation propelled by clotting blood were found to be regulated by antithrombin, whereas material-induced activation was regulated by C1 inhibitor. We also showed that the fibrin fibers that are formed during the clot process further enhance and propagate the contact activation initially induced by activated platelets. Fibrin not only activated factor XII but also seemed to increase the affinity of antithrombin for the proteases of the contact system, leading to the generation of contact enzyme-antithrombin complexes during clot formation. To determine whether the contact system might be involved in the inflammation and vascular disease associated with systemic lupus erythematosus (SLE), we analyzed plasma samples from SLE patients. These patients were found to have altered levels of contact enzyme-serpin complexes, supporting the concept that the contact system may be involved in the pathophysiology of SLE. The contact enzyme-antithrombin complexes were clearly linked to platelet activation in vivo. Altered levels of both FXIIa-antithrombin and FXIIa-C1 inhibitor were found to be correlated with previous vascular disease and may therefore be potential biomarkers for assessing the risk of thrombotic events in SLE patients. These findings add to our knowledge of how the plasma contact system is activated and functions in vivo and will help us to understand the role of the contact system, not only in hemostasis but also in vascular disease and thrombotic conditions.

Fibrinogen aggregation is the last step in blood coagulation. Inhibition of fibrinogen aggregation could lead to anticoagulation effects. However, there is no good method for the ready evaluation of fibrinogen coagulation. A commonly used path method is slow and requires an expensive instrument. In this project, we have developed a microplate reader and In evaluating inhibitors of fibrinogen coagulations there is no good method. As an important process in hemostasis, fibrinogen coagulation is often detected by micro-plate reader. In our test of fibrinogen coagulation, we improved the observing and analyzing method by using photograph to see concentration-depended effect of thrombin inhibitors on the coagulation. Three known thrombin inhibitors, AEBSF, APMSF and PMSF, were applied to develop the method for detecting the fibrinogen coagulation. The results showed our method is of accuracy in determination of the amount of fibrin when compared with other types of methods.

Benzotriazole (BTAH) has been used as a corrosion inhibitor for copper and copper-, based alloys for more than 40 years. It has been successfully employed for the, prevention of both atmospheric corrosion and particularly for the protection of, copper under immersed conditions. Whilst BTAH is an excellent inhibitor in alkaline, solution its efficiency drops off markedly as the pH decreases. It was hypothesized, that a possible way to increase surface adsorption and subsequent better inhibition, over a wide pH range might be through the preparation of derivatives, particularly, carboxybenzotriazoles and alkyl esters of these compounds. In this work the following techniques: weight loss measurements, potentiodynamic, polarisation, SERS spectroscopy, electrochemical impedance spectroscopy and, coulometry were employed to investigate the inhibition efficiency of 4- and 5-, carboxybenzotriazole and their alkyl ester for copper corrosion. Molecular modelling, was also investigated as a tool for inhibitor design. Studies on 4- and 5- carboxybenzotriazole (CBT) showed that the inhibition, efficiency for copper corrosion in aerated acidic sulphate solution of each isomer was, pH, concentration and time dependant. At lower pH the 5-isomer is the better, inhibitor and this behaviour continues at higher pH. The anti-tarnishing test showed, that whilst both isomers exhibited these properties, 5-CBT was once again the, superior inhibitor. It was found that a commercial mixture of the octyl esters of 4- and 5-, carboxybenzotriazole inhibits copper corrosion in sulphate environments open to air., The inhibition efficiency of the ester mixture at the lx10-4 M level (pH - 0) is 98%, which compares very favourably with that for BTAH (- 50%). With respect to other, alkyl esters of 4- and 5-carboxybezotriazole, hexyl, butyl and methyl, it was found, that all of these inlibited copper corrosion in sulphate environments open to air. In, each case the inhibition efficiency is concentration, pH and time dependent. Both, coupon tests and EIS measurements indicate that inhibition efficiency depends on the, length of the alkyl chain. At pH - 0 the inhibition efficiency decreased in the order, octyl &gthexyl &gtbutyl &gtmethyl. At higher pH (- 8) the order is reversed. At the 1x104, M level (pH - 0) the inhibition efficiency of each of the alkyl esters is equal to or, better than that for BTAH. At higher pH (- 8) the inhibition efficiency in each case is, reduced in comparison to BTAH. but is still good enough for practical use ( 2 75%)., The inhibitive behaviour of the alkyl esters at low pH can be attributed to, chemisorption through an azole nitrogen of the protonated alkyl esters. The, hydrocarbon chain is also physically adsorbed and the increase in physical adsorption, as the chain is lengthened accounts for the improved inhibition efficiency. Dry films formed by immersing copper in solutions of alkyl esters of, carboxybenzotriazole also inhibit copper corrosion in both strongly acidic (pH - 0), and near neutral (pH - S) sulphate corrodents. The inhibition efficiency depends on, the solvents used to dissolve the esters, solution temperature and immersion time., Aqueous coating solutions furnish the most protective films. Films formed by, CBTAH-BU, CBTAH-HE and CBTAH-OE are more protective than that formed by, BTAH. The inhibition efficiency of the alkyl ester film increases as the alkyl chain is, made longer. Molecular modeling showed that the optimum crude binding energy (Eblnd), between each protonated ester molecule and the surface varied linearly with the alkyl, chain length. The resulting linear correlation between IE% and E bind for compounds, that are structurally similar suggested that the crude binding energy of a single, molecule with copper may be used to predict the inhibition performance of other, compounds constituting a series.

Posttraumatic Stress Disorder (PTSD) is a psychiatric condition that can develop following exposure to a traumatic event involving actual or threatened death or serious injury. Responses include intense fear, helplessness or horror. Symptoms are characterised into clusters, described as re-experiencing, avoidance, and arousal. These symptoms, which are also evident in other conditions, have been associated with dysfunctions in the central acetylcholinergic system. Benefits from administering acetylcholinesterase inhibitors (AChEI) to people suffering these symptoms have been demonstrated. Donepezil hydrochloride, a reversible inhibitor of the enzyme acetylcholinesterase, is used in the treatment of conditions with difficulties in cognitive function, but has not been used in PTSD. The aim of this thesis was to determine (1) whether there was a difference in the ACh system in people with PTSD and (2) whether administration of an AChEI would change the symtomatology. IDEX (I¹ ² ³ iododexetimide) has been useful in imaging muscarinic-ACh receptors using Single Photon Emission Computerised Tomography (SPECT) and was utilised to investigate whether cholinergic activity in PTSD is altered. One hundred and sixty eight potential subjects were screened and eleven PTSD subjects were enrolled in the IDEX SPECT study. Three healthy non-PTSD control subjects also completed the study. Due to technical complications only the data obtained from eight PTSD and two control subjects was available for analysis. Imaging data for 2 further healthy non-PTSD control subjects were obtained from another study. Sixteen subjects were enrolled in the donepezil open label study (assessed at baseline, Week 2, 6 and 10). Nine PTSD subjects completed the 10-week trial and seven withdrew prematurely (at or after Week 2) due to side effects or a worsening of PTSD symptoms. For the IDEX SPECT study, a voxel-by-voxel statistical analysis of the PTSD subject group versus the control group showed both areas of reduced and increased IDEX uptake. Significant clusters in the PTSD group with a reduced IDEX uptake centred around the bilateral hippocampus, left insula and right precuneus, while increased IDEX uptake appeared in the caudate head. For the donepezil study, in the per-protocol analysis (including only the 9 subjects that completed the protocol), all psychological assessments revealed a difference between the totals obtained at the Week 10 visit compared to those at the Baseline visit and the improvement was in the order of 51%. The intention-to-treat analysis (including all 16 subjects), a repeated measures Analysis of Variance (ANOVA) with a mixed models approach showed that all psychological measures demonstrated statistically significant benefits of the treatment. All subjects who completed the protocol recounted considerable improvement in their overall PTSD symptom profile, which covered symptoms in each of the three clusters. The results of the IDEX SPECT study suggest that alterations in ACh binding in PTSD are evident and may begin to explain a part of the altered cognitive symptomatology apparent in this condition. The pilot open label donepezil trial provided some preliminary evidence that treatment with an AChEI can lessen the intrusions and distress associated with traumatic memories in people with PTSD. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1374974 / Thesis (M.Med.Sc.) -- University of Adelaide, School of Medicine, 2009

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Cornell University, January, 2009. / Vita. Includes bibliographical references (leaves 104-114).

Thesis (Ph. D.)--West Virginia University, 2008. / Title from document title page. Document formatted into pages; contains v, 42 p. : ill. (some col.). Includes abstract. Includes bibliographical references.

Thesis (Ph. D.)--University of Virginia, 2009. / Includes bibliographical references. Also available online through Digital Dissertations.