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Autotransporters represent a large superfamily of known and putative virulence factors produced by Gram-negative bacteria. They consist of an N-terminal “passenger domain” responsible for the specific effector functions of the molecule and a C-terminal “β domain” responsible for translocation of the passenger across the bacterial outer membrane. The serine protease autotransporters of Enterobacteriaceae (SPATEs) represent those autotransporters produced by Enterobacteriaceae where, as the name suggests, the passenger domain functions as a serine protease. Members of this family of autotransporters include among others the extracellular serine protease EspP produced by enterohemorrhagic Escherichia coli (EHEC) O157:H7. EHEC, especially those of serotype O157:H7, have been implicated as causative agents of hemorrhagic colitis and hemolytic-uremic syndrome, both of which include disruption of the normal processes in human blood responsible for maintaining good health. EspP has previously been shown to cleave human coagulation factors V and VIII and has been hypothesized to possibly contribute to the mucosal hemorrhage in patients infected with EHEC. This thesis aims to better understand the functional significance of EspP in EHEC pathogenesis by analyzing the crystallographic structure of the mature passenger domain of EspP and by investigating, in vitro, its effects on the coagulation and fibrinolytic processes in human blood. Like the previously determined autotransporter passenger domains, the EspP passenger domain is found to contain an extended right-handed parallel β-helix preceded by an N-terminal globular domain housing the catalytic function of the protease. Of note, however, is the absence of a second globular domain protruding from this β-helix. Furthermore, EspP is found to alter hemostasis in vitro by drastically decreasing the activities of human blood coagulation factors V, VII, VIII and XII, by enhancing platelet-fibrin clot formation, and by accelerating fibrinolysis. These results provide compelling evidence for a pathogenic role played by EspP during EHEC infection.

Autotransporters represent a large superfamily of known and putative virulence factors produced by Gram-negative bacteria. They consist of an N-terminal “passenger domain” responsible for the specific effector functions of the molecule and a C-terminal “β domain” responsible for translocation of the passenger across the bacterial outer membrane. The serine protease autotransporters of Enterobacteriaceae (SPATEs) represent those autotransporters produced by Enterobacteriaceae where, as the name suggests, the passenger domain functions as a serine protease. Members of this family of autotransporters include among others the extracellular serine protease EspP produced by enterohemorrhagic Escherichia coli (EHEC) O157:H7. EHEC, especially those of serotype O157:H7, have been implicated as causative agents of hemorrhagic colitis and hemolytic-uremic syndrome, both of which include disruption of the normal processes in human blood responsible for maintaining good health. EspP has previously been shown to cleave human coagulation factors V and VIII and has been hypothesized to possibly contribute to the mucosal hemorrhage in patients infected with EHEC. This thesis aims to better understand the functional significance of EspP in EHEC pathogenesis by analyzing the crystallographic structure of the mature passenger domain of EspP and by investigating, in vitro, its effects on the coagulation and fibrinolytic processes in human blood. Like the previously determined autotransporter passenger domains, the EspP passenger domain is found to contain an extended right-handed parallel β-helix preceded by an N-terminal globular domain housing the catalytic function of the protease. Of note, however, is the absence of a second globular domain protruding from this β-helix. Furthermore, EspP is found to alter hemostasis in vitro by drastically decreasing the activities of human blood coagulation factors V, VII, VIII and XII, by enhancing platelet-fibrin clot formation, and by accelerating fibrinolysis. These results provide compelling evidence for a pathogenic role played by EspP during EHEC infection.

An individual who is diagnosed with an inherited bleeding disorder is expected to manage his or her condition on a daily basis. This chronic situation can totally disrupt psychosocial functioning and make it more difficult to adjust to the illness. Other researchers have studied this phenomenon in various other chronic illnesses; however, not in individuals with inherited bleeding disorders (Akkasilpa, et al, 2000, Pollack, 1989a, 1989b). Psychosocial problems are not restricted to individuals with one chronic illness and clinically, it is noted that some individuals adjust to chronic diseases better than others. Individuals living with inherited bleeding disorders may also have other chronic illnesses such as hypertension, asthma, diabetes mellitus (DM), congestive heart failure (CHF), arthritis, and hepatitis A, B, C and/or HN. The aims of this study are to describe health stressors, health related hardiness, perception of illness impact, self perception of health status and psychosocial adjustment to illness in individuals living with an inherited bleeding disorder; to determine relationships between demographic and illness variables, health stressors, health related hardiness, perception of illness impact, self­ perception of health status and psychosocial adjustment to illness; and to determine if perception of illness impact has a direct and/or mediating effect on the relationship between health stressors, health related hardiness, and self-perception ofhealth status and psychosocial adjustment to illness. A cross sectional survey design was used in this study. Sixty individuals of predominantly Asian Pacific Islander ethnicity diagnosed with hemophilia, von Willebrand's Disease, Factor V or as hemophilia carriers comprised the sample which was drawn from the Hemophilia Treatment Center of Hawaii. All participants were asked to complete five questionnaires: Demographic form and illness information, health related hardiness scale (Pollock, 1990), perception of illness impact scale, self-perception of health status and psychosocial adjustment to illness scale (Derogatis, 1990). Higher health stressors were associated with higher perception of illness impact, lower perception of health status and poorer psychosocial adjustment to illness. Individuals with higher hardiness were better adjusted to their illness. Higher perception of illness impact was associated with lower self-perception of health status and poorer psychosocial adjustment to illness. Higher self-perception of health status was associated with better psychosocial adjustment to illness. Perception of illness impact did mediate the relationship between health related hardiness and psychosocial adjustment to illness. Perception of illness impact did not mediate the relationship between health stressors and psychosocial adjustment to illness, between health stressors and self-perception of health status, and between health related hardiness and self-perception of health status. The knowledge generated from this study has the potential to impact the existing practices in improving evidence-based nursing practice in caring for individuals with inherited bleeding disorders. Future research is indicated with a large sample to determine differences between diagnosed individuals and carriers, between various Asian Pacific Islander cultural groups, and to determine replicability of the findings from this smaller study sample.

Thesis (M.Med.Sc.) -- University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 2000. / Bibliography: leaves 115-125.

Thesis (Ph. D.)--University of Texas at Austin, 1998. / Vita. Includes bibliographical references (leaves 176-183). Available also in a digital version from Dissertation Abstracts.

Th. 3e cycle--Biochim.--Nancy--I.N.P.L., 1979.

Made available in DSpace on 2014-06-11T19:23:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-04-12Bitstream added on 2014-06-13T18:50:41Z : No. of bitstreams: 1 santos_jm_me_bauru.pdf: 549067 bytes, checksum: 7489ebe71b862060486033eb00f03299 (MD5) / Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico do Maranhão (FAPEMA) / Esse estudo investigou a cinética de coagulação floculação do TiO2 em suspensão aquosa de baixa força iônica (água destilada)e força iônica média (água de abastecime to público),em função do pH e da adição de sulfato de alumínio. A coagulação floculação do TiO2 ocorre quando o pH é ajustado próximo ao pH do potencial isoelétrico, pela compressão da camada de difusão ou pela adsorção hidrólise com íons Al 3+ . Em suspensões de TiO2 com baixa força iônica,a coagulação ocorre a um determinado pH (4,0 e 7,0), uma vez que ele depende basicamente da superfície do óxido. Com adição de um coadjuvante de sedimentação (por ex. sulfato de alumínio), a qual a força iônica é alta,a coagulação floculação ocorre muito rápido. O tempo de decantação do material em suspensão foi de 2:00 h, foi comparada a cinética de sedimentação da decantação simples com a realizada em Jar Test sob a influência de agitação rápida (eletrocinético) e lenta (ortocinético) antes de permitir a sedimentação. O melhor desempenho foi em Jar Test,turbidez final de 10 NTU. / This study investigated the coagulation-flocculation kinetics of TiO2 in an aqueous Suspension of low-strength ionic solution (distilled water) and a medium strength ionic solution (tap water) as a function of pH and of the addition of aluminum sulfate. Coagulation-flocculation of TiO2 occurs when the pH is adjusted close to the isoelectric potential (iep), by compression of the diffusion layer or by adsorption-hydrolysis with Al 3+ ions. In TiO2 suspensions with low electric strength,coagulation takes place at certain pH (4,0 a d 7,0) since it depends basically on the oxide surface.With the addition of sedimentation aid (e.g.,aluminum sulfate), in which the ionic strength is high, coagulation-flocculation, takes place very fast. The decantation time of the material in suspension was of 2h. The sedimentation kinetic of the simple decantation was compared to that carried out in Jar Test under influence of fast stirring (electrokinetic) and slow stirring (ortokinetic) before sedimentation set up.The best performance was in Jar Test,final turbidez of 10 NTU.

Made available in DSpace on 2014-10-09T12:52:03Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:57:51Z (GMT). No. of bitstreams: 0 / Dissertação (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP