This thesis explores the late-Henrican polity through the archive and perspective of William Paget, Henry VIII's secretary at the end of his reign. Paget's papers as secretary (1543-1547), that form the basis of the thesis, are an extensive, unique and relatively under-used source. From this starting-point Paget's role as secretary is explored and he is revealed as the personal servant of the king, whose natural environment was the court. As such he was an influential source of counsel and perhaps the key patronage-broker at court. In this context Paget also had a significant influence over the operation of the dry stamp at the end of the reign. Equally, Paget's role in shaping the function of the secretary and his relations with the recently formed privy council was of considerable importance, providing the template for later Tudor secretaries. Diplomacy in the uncertain world of the 1540s was one of Paget's primary concerns and his priorities can be seen as trying to provide security and stability for the realm. This is revealed not only in his 'Consultation' of August 1546 but also in his diplomacy with the French, the Schmalkaldic League and the Papacy. In this he sometimes found himself at odds with the king and leading a privy council united in a desire for peace. Politically Paget has traditionally been cast as an ambitious politique, the 'master of practices' and part of the earl of Hertford's reform party. Whilst acknowledging Paget's close relations with Hertford this thesis questions the factional interpretation of the last years of the reign and argues that the predominant concern of Paget and his fellow privy councillors was a peaceful succession in which unanimity rather than conflict was the key-note.

La Maladie Thrombo-Embolique Veineuse (MTEV) est une maladie dont les facteurs de risque sont à la fois environnementaux et génétiques. Les facteurs de risque génétiques bien établis sont les déficits en anti-thrombine, en protéine S, en protéine C, la mutation du Facteur V de Leiden (FVL), la mutation du Facteur (F) II G20210A, ainsi que le gène ABO dont les allèles A1 et B augmentent le risque de MTEV par rapport aux allèles A2 et O. Alors qu'une part importante de l'héritabilité de la MTEV reste inexpliquée, les études contemporaines se heurtent à un manque de puissance pour découvrir de nouveaux facteurs génétiques dont les effets sont de plus en plus faibles. En vue d'augmenter la puissance de détection de nouveaux gènes de susceptibilité à la MTEV, j'ai recherché les déterminismes génétiques de deux de ses phénotypes intermédiaires : les taux d'activité plasmatique du FVIII et les taux d'antigénémie de sa protéine de transport, le Facteur de von Willebrand (vWF). Dans un premier temps, j'ai réalisé une analyse de liaison des taux de FVIII et de vWF à partir d'un échantillon de cinq grandes familles franco-canadiennes (totalisant 255 personnes) recrutées via un cas de MTEV avec mutation FVL. Quatre régions liées aux taux de FVIII et/ou vWF ont été identifiées. L'une de ces régions correspondait au locus du gène ABO déjà connu pour influencer les taux de FVIII et vWF. La recherche de gènes candidats au sein des autres signaux de liaison s'est effectuée par l'étude in silico d'une analyse d'association pangénomique de la MTEV incluant 419 cas et 1228 témoins. Deux gènes candidats ont été identifiés : STAB2 et BAI3. J'ai ensuite réalisé des études d'associations de cinq polymorphismes de BAI3. L'un d'entre eux était d'une part associé à une élévation des taux de vWF (résultat obtenu dans un échantillon de 108 familles nucléaires en bonne santé et reproduit dans un échantillon de 916 patients non apparentés atteints de MTEV), et d'autre part associé au risque de survenue de MTEV parmi les sujets non porteurs de mutations FVL et FII de deux échantillons cas-témoins (respectivement 916 cas et 801 témoins, et 250 cas et 607 témoins). Quant à STAB2, durant le courant de ma thèse, deux de ces polymorphismes ont été décrits comme associés aux taux de FVIII et vWF au cours d'une vaste étude d'association pangénomique (GWAS) menée par le consortium CHARGE rassemblant 23 600 personnes. Dans un second temps, j'ai réalisé une méta-analyse de trois GWAS des taux de FVIII et vWF. Ces analyses avaient été conduites avec l'échantillon des cinq grandes familles franco-canadiennes et deux échantillons de 972 et 570 patients atteints de MTEV. Elles étaient ajustées sur les polymorphismes du gène ABO permettant de distinguer les allèles A1, A2, B et O, dans l'optique d'augmenter la puissance des analyses en diminuant la variance résiduelle des phénotypes. Aucun polymorphisme n'était associé ni aux taux de vWF ni à ceux de FVIII après prise en compte de la correction de Bonferroni pour tests multiples (p<10-7). Cependant, parmi les onze gènes qui présentaient des polymorphismes associés aux taux de vWF ou de FVIII avec une significativité p<10-5, de manière intéressante se trouvait STAB2. Cette étude a de plus permis de confirmer les associations nouvellement découvertes de polymorphismes situés dans les gènes VWF, STXBP5 et STX2.

Cardiovascular disease (CVD) is a major cause of adult morbidity and mortality in developed as well as in developing countries. In black population groups, stroke is more prominent than ischaemic heart disease. This may be attributed to a combination of risk factors seen in this population group inter alia raised haemostatic markers, which favour the development of stroke since it is well known that a disturbance in the haemostatic balance (a hypercoagulable and a hypofibrinolytic state) predisposes to CVD. It is generally accepted that childhood genetic, environmental and behavioural factors lay the groundwork for the manifestation of adult CVD. Therefore, one of the studies that form part of this dissertation was a cross-sectional study to determine whether haemostatic abnormalities are already present in black African adolescents and to determine whether high risk groups exist [in relation to the following haemostatic markers: fibrinogen, factor VIII (FVIII), plasminogen activator inhibitor type 1 activity (PAI-Iact), and thrombin anti-thrombin complex (TAT)] for the development of CVD later in life. The population subdivisions were made according to gender, body fat %, maturity status, height for age Z-score, and habitual PA levels. Since behavioural factors [diet, physical activity (PA), smoking and drinking habits] are controllable determinants, it could be possible to improve CVD risk to a certain degree. Therefore, the second study that forms part of this dissertation attempted to establish whether a PA programme will successfully reduce haemostatic variables in a subset of the study population used in the first study. The reader is referred to the abstracts at the beginning of each separate study manuscript (Chapters 3 and 4), for a description of the subjects, study design and methods used in each study. The results of the cross-sectional study showed that in African adolescents (a) gender independently contributed to the variability in PAI-Iact, but that the gender difference in fibrinogen and TAT could be explained by the significant differences in fat mass and PA levels observed between the genders; (b) fibrinogen was significantly higher in the stunted compared to the non-stunted children indicating that childhood chronic malnutrition may possibly predispose independently to CVD; (c) fitness influences TAT concentrations positively and that (d) no significant differences in FVIII could be found between any of the subdivisions. As these determinants seem to be modifiable through behavioural changes and optimal nutrition status through early life, it raises a sense of urgency to develop strategies for the prevention and treatment of these risk factors. The results of the intervention study showed that an 11-week outdoor PA intervention programme had no significant effect on the haemostatic markers of African adolescents, but the results of this study should be interpreted with caution since (a) seasonal variations could have clouded the effect of the PA intervention as baseline measurements were taken in the summer and end measurements in the winter; (b) attendance of the PA sessions does not necessarily implicate compliance to the exercises given; (c) baseline values seem to play a prominent role in the changes that could be expected during an intervention and, therefore, improvements in the haemostatic profile would most likely be more significant in individuals with raised baseline levels. Similar research on African children is warranted since studies investigating PA's effect on haemostatic variables remain a topic of debate and speculation and data on African population groups are scanty. / Thesis (M.Sc. (Nutrition))--North-West University, Potchefstroom Campus, 2007

Le facteur VIII (FVIII) joue un rôle essentiel dans la coagulation sanguine. Lorsque le FVIII fait génétiquement défaut, une pathologie hémorragique grave survient: l'hémophilie A (HA) congénitale. La complication majeure de la prise en charge de ces patients est l'apparition d'allo-anticorps (alloAcs) dirigés contre le FVIII thérapeutique administré. Dès lors, la seule thérapeutique efficace est l'induction de tolérance immune (ITI) qui vise à les éradiquer. Cependant, ce traitement échoue dans 30% des cas, sans qu'aucun facteur ne permette actuellement de prédire l'échec de ce traitement contraignant et coûteux. des facteurs immunologiques prédictifs de l'efficacité de l'ITI ont été recherchés chez 25 patients par analyse du répertoire épitopique et isotypique des Acs anti-FVIII à l'aide de la technologie x-MAP. Des biomarqueurs individuels (Acs anti-A2 et -A1 du FVIII), et des combinaisons originales ont été identifiés (0,841 < AUC < 0,946). Des manifestations hémorragiques peuvent apparaitre chez des patients non hémophiles, dues à des autoAcs anti-FVIII (HA acquise). Dans certains cas, les autoAcs se développent au moment du postpartum. peu de données sont disponibles sur cette réponse immune. Dans une seconde étude portant sur 73 cas, nous avons découvert un profil immunologique (autoAcs anti-A1) différenciant les HA du postpartum et les autres HA acquises. Les profils d'IgG anti-FVIII que nous avons établis s'avèrent prometteurs pour prédire l'efficacité de l'ITI et engendrer une cartographie précise de la réponse autoimmune chez les patients atteints d'HA acquise. / Factor VIII (FVIII) plays a critical role in blood coagulation. When FVIII s genetically defective, a serious hemorrhagic disease occurs: congenital hemophilia A (HA). The main complication of the management of these patients is the appearance of alloantibodies (alloAbs) directed against administred therapeutic FVIII. therefore, the only effective treatment is the immune tolerance induction (ITI), which aims to eradicate these alloAbs. However, this treatment fails in up to 30% of cases, without any factor currently able to predict the failure of this constraining and expensive treatment. Immunological factors predictive to the efficacy of ITI were investigated in 25 patients by analysis of epitopic and isotypic IgG profile of anti-FVIII Abs using x-MAP technology. Individual biomarkers (anti-FVIII A1 and -A2 Abs), and original combinations were identified (0,841 < AUC < 0,946). Hemorrhagic manifestations can occur in non-hemophiliac patients, due to anti-FVIII autoAbs (acquired HA). In some patients, the autoAbs appear in postpartum period but few data are available on the immune response due to the rarity of the disease. In a second study of 73 cases, we found a different immunological profile between patients with postpartum HA and the other acuired HA patients. IgG profiles of anti-FVIII we have established are promising for predicting the effectiveness of ITI and generate an accurate mapping of autoimmune response in patients with acquired HA.

Les anticorps sont les molécules effectrices de l’immunité adaptatrice humorale. Ils se lient spécifiquement et neutralisent une large panoplie d’antigènes. Au-delà de leurs fonctions classiques, les anticorps possèdent les propriétés moins explorées que sont l’activité catalytique, qui permet aux anticorps de se comporter comme des enzymes, et la polyréactivité, qui représente la capacité d’une molécule d’anticorps à se lier à plusieurs antigènes structurellement différents. Les anticorps catalytiques sont retrouvés dans plusieurs pathologies chez l’homme, telle que l’hémophilie acquise, une maladie caractérisée par la survenue d’autoanticorps anti-facteur VIII. Dans ce travail, nous décrivons des IgG hydrolysant et activant le facteur IX de la coagulation chez les patients avec hémophilie acquise. Par ailleurs, nous avons effectué une étude longitudinale de deux ans des IgG catalytiques chez les patients subissant une transplantation rénale. Les anticorps polyréactifs représentent une proportion importante du répertoire des immunoglobulines circulantes. De plus, les sites inflammatoires sont abondants en molécules, telles que l’hème libre, capables de rendre polyréactives certaines IgG monoréactives. Nous avons étudié l’influence de la nature des régions constantes de la chaîne lourde des anticorps sur leur susceptibilité à devenir polyréactifs. Ce travail apporte un nouvel éclairage sur l’importance physiopathologique des anticorps catalytiques et polyréactifs. / Antibodies are effector molecules of the humoral arm of the adaptive immune system that bind specifically and neutralize diverse array of antigens. Beyond the classical function of antibodies exist the relatively less explored properties, of “catalytic activity” that enable antibodies to act as enzymes and “polyreactivity” that confers the ability to bind to several structurally unrelated antigens. Catalytic antibodies have been associated with several autoimmune, inflammatory and infectious diseases. Acquired hemophilia is an autoimmune disease, reported with the presence of catalytic antibodies against coagulation factor FVIII. In the present work, we have investigated the presence of factor IX (FIX) hydrolyzing IgG in patients with acquired hemophilia. We investigated the molecular mechanism and the physiological relevance of FIX activation upon hydrolysis by patients’ IgG. In addition, a longitudinal follow-up for 2 years was done in patients undergone renal transplant to investigate the evolution of catalytic antibodies in the course of disease. Polyreactive antibodies constitute a major portion of the natural antibody repertoire. Additionally, sites of inflammation are abundant in protein destabilizing agents like free heme that can induce polyreactivity in monoreactive antibodies. We have investigated the effect of the antibody constant domain on heme-induced polyreactivity. The present work has allowed us a better understanding of the physiopathological relevance of catalytic and polyreactive antibodies.

The intention of this thesis is to describe the process of putting together a performance of a lecture recital on the song cycle Try Me, Good King: Last words of the wives of Henry VIII by modern composer Libby Larsen, and to conduct an in depth exploration of the characters of the first five wives of King Henry VIII of England. Each wife’s character will be investigated in relation to their roles in this song cycle which draws its’ text from the final words of these five women. Each wife’s character will be investigated from three perspectives, that of history, that of Libby Larsen, my own perspective (Morgan Tingle). The ultimate result will be a solid developed character for each wife that is the culmination of my studies portrayed by myself, soprano Morgan Tingle, in the final lecture recital.

Thesis (M.Sc. (Nutrition))--North-West University, Potchefstroom Campus, 2007.

Con l’edizione commentata di un’opera giovanile di Sforza Pallavicino, il poema inedito e incompleto 'I fasti sacri', si cerca di fornire una ulteriore tessera utile a comprendere e definire le caratteristiche della poetica del circolo barberiniano nella Roma di inizio Seicento. In apertura dell’opera il 'Discorso intorno al seguente poema' raccoglie le dichiarazioni esplicite della poetica del Pallavicino, a partire dalla riflessione di Tasso sul poema; seguono poi sette canti, ognuno dei quali è anticipato e riassunto da un 'Soggetto' in prosa. In essi l’autore, sul modello dei 'Fasti' di Ovidio, rilegge il calendario in chiave cristiana, raccontando le vicende dei principali santi e martiri di ogni mese. La stesura del testo, sotto la supervisione di Papa Urbano VIII, sembra avvicinarsi alle operazioni di revisione del 'Martyrologium Romanum', in particolare all’edizione voluta dallo stesso Urbano nel 1630. L’opera, in stretta sintonia con la 'Poetica sacra' di Giovanni Ciampoli ma che dialoga anche con altri testi del classicismo barberiniano, si propone come alternativa alla poesia avvertita come lasciva e mendace della scuola marinista, in un’opposizione spesso polemica, ma che mostra a volte alcune interessanti consonanze con le opere di Marino stesso e di alcuni esponenti del marinismo moderato. / The commented edition of the unpublished and unfinished poem ‘I fasti sacri’, written by Sforza Pallavicino in the first years of his poetic activity, proposes new interesting information about Barberini’s circle in Rome, at the beginning of XVII century. Explicit definitions on poetic matter are in the ‘Discorso intorno al seguente poema’, with argumentations taken from the theoretical consideration on the epic poem by Tasso. On the model of Ovid’s ‘Fasti’, throughout seven cantos, each one anticipated by a subject in prose, the author covers the Christian calendar narrating the stories of some important saints and martyrs, in the same years of the revision of ‘Martyrologium Romanum’ promoted by the Pope Urban VIII. The poem, extremely close to ‘Poetica sacra’ by Giovanni Ciampoli but also in dialogue with other works of the classicism of Barberini’s circle, proposes itself as an alternative to Marino’s poetry, perceived like lascivious and mendacious. Notwithstanding an often polemic opposition to Secentismo, the text reveals some interesting consonances with Marino’s works, as well as with other authors of the moderate Marinism.

Die empirische Untersuchung setzt sich mit der aktuellen Beratungstätigkeit der "insoweit erfahrenen Fachkraft" und deren Rahmenbedigungen gemäß § 8a Abs. 4 SGB VIII im Freistaat Sachsen auseinander.

Cardiovascular disease (CVD) is a major cause of adult morbidity and mortality in developed as well as in developing countries. In black population groups, stroke is more prominent than ischaemic heart disease. This may be attributed to a combination of risk factors seen in this population group inter alia raised haemostatic markers, which favour the development of stroke since it is well known that a disturbance in the haemostatic balance (a hypercoagulable and a hypofibrinolytic state) predisposes to CVD. It is generally accepted that childhood genetic, environmental and behavioural factors lay the groundwork for the manifestation of adult CVD. Therefore, one of the studies that form part of this dissertation was a cross-sectional study to determine whether haemostatic abnormalities are already present in black African adolescents and to determine whether high risk groups exist [in relation to the following haemostatic markers: fibrinogen, factor VIII (FVIII), plasminogen activator inhibitor type 1 activity (PAI-Iact), and thrombin anti-thrombin complex (TAT)] for the development of CVD later in life. The population subdivisions were made according to gender, body fat %, maturity status, height for age Z-score, and habitual PA levels. Since behavioural factors [diet, physical activity (PA), smoking and drinking habits] are controllable determinants, it could be possible to improve CVD risk to a certain degree. Therefore, the second study that forms part of this dissertation attempted to establish whether a PA programme will successfully reduce haemostatic variables in a subset of the study population used in the first study. The reader is referred to the abstracts at the beginning of each separate study manuscript (Chapters 3 and 4), for a description of the subjects, study design and methods used in each study. The results of the cross-sectional study showed that in African adolescents (a) gender independently contributed to the variability in PAI-Iact, but that the gender difference in fibrinogen and TAT could be explained by the significant differences in fat mass and PA levels observed between the genders; (b) fibrinogen was significantly higher in the stunted compared to the non-stunted children indicating that childhood chronic malnutrition may possibly predispose independently to CVD; (c) fitness influences TAT concentrations positively and that (d) no significant differences in FVIII could be found between any of the subdivisions. As these determinants seem to be modifiable through behavioural changes and optimal nutrition status through early life, it raises a sense of urgency to develop strategies for the prevention and treatment of these risk factors. The results of the intervention study showed that an 11-week outdoor PA intervention programme had no significant effect on the haemostatic markers of African adolescents, but the results of this study should be interpreted with caution since (a) seasonal variations could have clouded the effect of the PA intervention as baseline measurements were taken in the summer and end measurements in the winter; (b) attendance of the PA sessions does not necessarily implicate compliance to the exercises given; (c) baseline values seem to play a prominent role in the changes that could be expected during an intervention and, therefore, improvements in the haemostatic profile would most likely be more significant in individuals with raised baseline levels. Similar research on African children is warranted since studies investigating PA's effect on haemostatic variables remain a topic of debate and speculation and data on African population groups are scanty. / Thesis (M.Sc. (Nutrition))--North-West University, Potchefstroom Campus, 2007