Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

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

Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

This thesis aims to examine Richmond's life in the context of his role as a magnate, a courtier, and the king's only son. As a much neglected subject this includes a good deal of biographical material, in order to present the duke within the context in which he lived. This also allows a re-assessment of his part in the succession crisis, with particular reference to the significance of his elevation in 1525, and the speculation regarding the king's intentions, as represented in the Succession Act of 1536. An examination of his responsibilities, not least as Lord Lieutenant in the north, of Ireland and as Lord Admiral, queries how far his extreme youth and his illegitimacy inhibited or facilitated the role Henry VIII wished him to fulfil. In tandem with this, a special study of the duke as a landlord looks at the relationship between the authority bestowed upon Richmond and the actual freedom of action allowed to the child. A view of his political importance, in matters such as marriage alliances and diplomacy, is considered alongside an appraisal of the personal standing of the duke, both in England and abroad. In order to provide a complete picture of Richmond's circumstances, there is also an account of the fortunes of his maternal relations, the Blounts of Kinlet, tracing their wealth and descent, and in particular those connections and alliances which assisted their daughter's acceptance at court. An analysis of Elizabeth Blount's relationship with Henry VIII leads into a consideration of how her royal liaison affected her life. In discussing the overall legacy left by Richmond's demise, the right and title of his widow, Mary Richmond, to her agreed jointure, and her subsequent fortunes, are weighed against the priorities of the king.

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A review of the published music for solo bassoon suggests that there is relatively little solo literature for the instrument that dates from the late eighteenth and early nineteenth centuries. This document focuses on the creation of a modern performance edition and piano reduction of a recently uncovered work for solo bassoon and orchestra by Johann Dotzauer, VIII Variations for Bassoon and Orchestra, Op. 40 (originally published by Freiderich Hoffmeister Musikverlag in 1817).A comparison of Dotzauer's work with a comparable published work by Anton Reicha, reveals that the two works are similar in their treatment of phrase structure, form, harmonic and melodic language, range, and solo passagework. This comparison has shown that Dotzauer's piece is representative of the type of writing for solo bassoon that skilled composers employed in the early nineteenth century. Through the editing process, errors and inconsistencies found in the newly-uncovered Hoffmeister Edition of VIII Variations such as corrections to pitches and notation, articulation markings, dynamic markings, and other changes have been corrected in a manner that both reflects the integrity of the Hoffmeister Edition and adds clarification for those who will perform the work. VIII Variations for Bassoon and Orchestra, Op. 40 by Johann Dotzauer, is a well-crafted composition for solo bassoon that will help fill a void in the literature for bassoon now that it is more accessible through the creation of a new performance edition and piano arrangement.

Thesis (PhD)--University of South Australia, 2000

Le facteur VIII (FVIII) est une glycoprotéine de la coagulation plasmatique, co-facteur du facteur IX activé (FIXa). Son métabolisme dépend de multiples facteurs limitant ou favorisant sa survie ou sa fonction. L’objectif de ce travail était d’analyser les différents paramètres pouvant influencer le taux de FVIII circulant et sa fonction pro-coagulante. Il a compris 4 volets : 1) Nous avons montré que la rétention intra-cellulaire connue du FVIII était en grande partie liée à son agrégation et sa dégradation par les 2 voies protéasomale et lysosomale. 2) Nous avons analysé les mutations du gène F8 responsables de l’hémophilie A dans une large cohorte de patients. Leur analyse bio-informatique a permis de démontrer leur caractère délétère pour le FVIII. L’influence de ces mutations sur la survenue d’allo-anticorps anti-FVIII a été étudiée et stratifiée, en association avec l’origine ethnique et la recherche d’antécédents familiaux d’nticorps. 3) La recherche des facteurs influençant les taux de FVIII chez les conductrices d’hémophilie A a mis en évidence des déterminants majeurs : l’existence d’une maladie génétique additionnelle responsable d’un déficit en FVIII, le taux de facteur Willebrand et l’inactivation non aléatoire du chromosome X ; et des déterminants secondaires : l’âge, la sévérité de l’hémophilie, le polymorphisme D1241E du gène F8 et 5 nouveaux polymorphismes de la LRP1 localisés dans ses sites de liaison pour le FVIII. 4) Nous avons analysé 8 FVIII recombinant mutés in vitro en alanine dans la région 1808-1818 du FVIII. Les études antérieures n’analysant que la chaîne légère, ont montré que cette région était la plus affine pour le FIXa. Nous démontrons ici que la région 1808-1818 ne paraît pas si essentielle à la fonction du FVIIIcar au sein de la molécule entière, son affinité diminue et ses mutations n’altèrent que très modérément l’activité du FVIII. / The factor VIII (FVIII) is a glucoprotein of the coagulation, being the cofactor of the activated factor IX (FIXa). Its metabolism depends on various limiting factors or enhancing its survey or function. The objective of this research’s work was to analyse different parameters that could influence the plasma FVIII level and its pro-coagulant function. It included 4 parts : 1) We showed that the known intra-cellular retention of FVIII was mainly due to its aggregation and degradation following both proteasomal and lysosomal pathways. 2) We analysed FVIII gene mutations responsible for hemophilia A in a large patients cohort. The bio-informatic analysis demonstrated its deleterious consequence. The influence of these mutations on the anti-FVIII antibodies occurrence was stratified, in association with ethnicity and familial antecedent of inhibitor. 3) The research of factors influencing FVIII levels in hemophilia A carriers showed : i) major determinants such as the presence of an additional genetic disease characterised by a FVIII deficiency, the factor Willebrad’s level and the non-random inactivation of the X chromosome; and ii) minor determinants : age, severity of hemophilia, the polymorphism D1241E of FVIII gene, and 5 new polymorphisms of LRP1 located in its binding site for FVIII.4) We analysed 8 recombinant FVIII with in vitro created mutations in its 1808-1818 region. Previous studies that analysed only the FVIII light chain, have shown that this region constituted the more affine binding site of FVIII for FIXa. We demonstrated here that the 1808-1818 region is not as essential as it was reported because within the entire molecule, its affinity decreases and mutations affecting it do alter mildly the FVIII activity.