Thesis (M. Soc. Sc.)--University of Hong Kong, 1989.

Lübeck, University, Thesis (doctoral), 2001.

Shigella flexneri is a bacterial pathogen which causes dysentery by invading the epithelial cells of the colon. In order to survive and replicate inside the host, S. flexneri requires many genes present on both its chromosome and the large virulence plasmid it carries. This study examines which genes are required for infection of cultured epithelial cells in order to understand which processes are used by S. flexneri during the infection process. This analysis pinpointed genes involved in metabolism, LPS synthesis, protein homeostasis and virulence effector proteins. The role of Elongation factor P (EF-P) in S. flexneri virulence is also investigated in this study. EF-P is a bacterial translation factor that is post-translationally modified with a [Beta]-lysine by the action of PoxA. Here it is shown that both EF-P and PoxA are necessary for virulence of S. flexneri. Loss of either EF-P or PoxA leads to an impaired ability of S. flexneri to invade epithelial cells. Proteomic analysis of efp and poxA deletion mutants revealed decreased levels of several virulence effector proteins, as well as proteins for the biosynthesis of the siderophore aerobactin. Virulence proteins were affected due to decreased levels of the master virulence regulator VirF. Reduction in VirF transcription is likely due to decreased levels of CpxA, which activates virF through the response regulator CpxR. The role of CpxAR in reduced synthesis of VirF and its downstream effectors was confirmed by showing increased invasion when a mutation resulting in constitutively vii activated CpxR was introduced into the efp mutant. Thus, modified EF-P is one of the chromosomal factor necessary for the virulence of this bacterial pathogen. / text

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Two points of view exist at present on how inference about the true number of factors should be made. In the older classical statistical approach the N individuals are considered as a sample from a population of individuals and an attempt is made to make inferences about this population from the characteristics of the sample. The proponents of the newer, psychometric approach consider the n variables as a sample from a universe of content and attempt to make inferences about this universe. [...]

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

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Evidence that an instrument measures what it purports to measure is essential to empirically study the given construct. Despite this fact, little attention has been made to investigate the validity of the Inventory of Childhood Memories and Imaginings (ICMI) and the Creative Experiences Questionnaires (CEQ) - instruments that purport to measure the fantasy proneness construct. In assessing the validity of fantasy proneness measures, the aim of the current study was unique, in that, no known study had conducted a factor analysis of scores on the ICMI, CEQ and Dissociative Experiences Scale (DES) separately and simultaneously in the same study. Undergraduate psychology students (N = 223) from a large New Zealand University completed six questionnaires measuring fantasy proneness, imagery, dissociation, personality and desirable responding. Separate factor analysis results suggested a three factor solution for ICMI scores accounting for 22.60% of the total variance, a six factor solution for CEQ scores accounting for 42.93% of the total variance, and a three factor solution for DES scores accounting for 81.31% of the total variance. Simultaneous factor analysis results on factor scores of the ICMI, CEQ and DES revealed that dimensions of fantasy proneness loaded on two factors, whereas dimensions of dissociation loaded distinctively on a separate factor. The findings from this study suggest that there is less dimensional overlap between fantasy proneness and dissociation than has been suggested in the recent literature. Findings of this study also suggest that conclusions based on the overall scales of fantasy proneness may be limited and potentially misleading.

Dimuon yields of the decays η → µ + µ − γ, ω → µ + µ − π 0 and ρ → µ + µ − withcalculated form factors by Terschlüsen and Leupold (2010) and Schneider etal. (2012) were numerically fitted to NA60 data and compared to the resultby Arnaldi et al. (2009). The calculated form factors are theoretically moresound and are an alternative to the previously used pole approximation. Inaddition, the ρ production temperature was reviewed theoretically usingthe ratio of η and ω yields. Several fits were made and the best results wereachieved by using Terschlüsen’s form factor for the ω decay and Schneider’sfor the ρ using two fit parameters less than Arnaldi et al. In addition, theassumption that the yield is the result of only three sources could not bedisproved.

Background and Aims Acute Pancreatitis is an inflammatory disorder of varied aetiology and outcome. Tumour necrosis factor (TNF) and interleukin-10 are important mediators of disease pathogenesis. To investigate if the TNF and IL-10 gene loci influence susceptibility to and severity of acute pancreatitis, 135 patients with acute pancreatitis, ethnically matched normal controls, and alcoholics without pancreatic disease were studied. Methods Aetiology was classified as being secondary to alcohol, gallstones, or idiopathic. Patients were stratified into groups according to disease severity by assigning an organ failure score. Three TNF microsatellite loci (TNFa, TNFb, and TNFc), the -308 polymorphism within the TNF gene, the IL-10.G microsatellite locus, and 3 hi-allelic polymorphisms in the 5' flanking region of the IL-l 0 gene were typed using the polymerase chain reaction. Results There was no difference in allelic frequency of any of the cytokine gene loci between groups stratified according to disease severity. When patients were stratified according to aetiology of disease there was a decrease in the frequency of the TNFa2 allele in those patients with alcoholic acute pancreatitis compared to controls (14.3 vs. 35.5%, χ²=7.24, p=0.007). There was also a reduction in the frequency of the IL-10.Gl3 allele in patients with alcoholic pancreatitis compared to controls (4.8 vs. 21.3%, χ² =6.46, p=0.011). Data is also presented showing that a number of haplotypes exist as well as linkage disequilibrium across all 4 loci of the IL-10 gene, which contrasts with findings from previous work. The 3 locus haplotypes GCC and ATA are in strongest linkage disequilibrium, as is the microsatellite allele G9 and -1117.A and G9 with the 3-locus haplotype ATA. Conclusions This work has identified an allele within the TNF gene locus, and an allele within the IL-1 0.G locus which have different frequencies in patients with alcohol induced acute pancreatitis compared to other aetiologies. This finding may in part explain individuals' differing susceptibility to the development of acute pancreatitis after excessive alcohol consumption. Haplotypes not previously described exist across the IL-10 locus.