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.

Résumé : La maladie osseuse de Paget (MP) est un désordre squelettique caractérisé par une augmentation focale et désorganisée du remodelage osseux. Les ostéoclastes (OCs) de MP sont plus larges, actifs et nombreux, en plus d’être résistants à l’apoptose. Même si la cause précise de la MP demeure inconnue, des mutations du gène SQSTM1, codant pour la protéine p62, ont été décrites dans une proportion importante de patients avec MP. Parmi ces mutations, la substitution P392L est la plus fréquente, et la surexpression de p62P392L dans les OCs génère un phénotype pagétique partiel. La protéine p62 est impliquée dans de multiples processus, allant du contrôle de la signalisation NF-κB à l’autophagie. Dans les OCs humains, un complexe multiprotéique composé de p62 et des kinases PKCζ et PDK1 est formé en réponse à une stimulation par Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL), principale cytokine impliquée dans la formation et l'activation des OCs. Nous avons démontré que PKCζ est impliquée dans l’activation de NF-κB induite par RANKL dans les OCs, et dans son activation constitutive en présence de p62P392L. Nous avons également observé une augmentation de phosphorylation de Ser536 de p65 par PKCζ, qui est indépendante d’IκB et qui pourrait représenter une voie alternative d'activation de NF-κB en présence de la mutation de p62. Nous avons démontré que les niveaux de phosphorylation des régulateurs de survie ERK et Akt sont augmentés dans les OCs MP, et réduits suite à l'inhibition de PDK1. La phosphorylation des substrats de mTOR, 4EBP1 et la protéine régulatrice Raptor, a été évaluée, et une augmentation des deux a été observée dans les OCs pagétiques, et est régulée par l'inhibition de PDK1. Également, l'augmentation des niveaux de base de LC3II (associée aux structures autophagiques) observée dans les OCs pagétiques a été associée à un défaut de dégradation des autophagosomes, indépendante de la mutation p62P392L. Il existe aussi une réduction de sensibilité à l’induction de l'autophagie dépendante de PDK1. De plus, l’inhibition de PDK1 induit l’apoptose autant dans les OCs contrôles que pagétiques, et mène à une réduction significative de la résorption osseuse. La signalisation PDK1/Akt pourrait donc représenter un point de contrôle important dans l’activation des OCs pagétiques. Ces résultats démontrent l’importance de plusieurs kinases associées à p62 dans la sur-activation des OCs pagétiques, dont la signalisation converge vers une augmentation de leur survie et de leur fonction de résorption, et affecte également le processus autophagique. / Abstract : Paget’s disease of bone (PDB) is a skeletal disorder characterized by focal and disorganized increases in bone turnover. In PDB, osteoclasts are larger, more active, more numerous, and resistant to apoptotic stimuli. While no single root cause has been identified, mutations to the gene encoding the p62 protein, SQSTM1, have been described in a significant population of patients with PDB. Among these mutations, the P392L substitution is the most prevalent, and overexpression of p62P392L in osteoclasts generates at least a partial pagetic phenotype in vitro. Normally this protein mediates a number of cell functions, from control of NF-κB signaling to autophagy. In human osteoclasts, a multiprotein complex containing p62 and protein kinases PKCζ and PDK1 (the principal kinase of Akt), form in response to stimulation by receptor activator of nuclear factor kappa-B ligand (RANKL), the principal osteoclastogenic-signaling cytokine. We found that PKCζ is involved in RANKL-induced activation of NF-κB, and that it contributed to a basal activation of NF-κB observed in p62P392L mutants. This may be regulated in part by a PKCζ dependent increase in p65 phosphorylation at Ser536 which we characterized, independent of IκB. This could represent one alternative pathway by which mutant p62 leads to increased NF-κB activation. We observed increased basal phosphorylation of survival regulators ERK and Akt in PDB that was reduced upon PDK1 inhibition. The activity of 4EBP1 and Raptor, associated with mTOR activity, were also altered in pagetic osteoclasts and regulated by PDK1 inhibition. We then identified autophagic defects common to pagetic osteoclasts; with higher basal levels of LC3II (associated with autophagic structures), regardless of p62 mutation, and reduced sensitivity to autophagy induction in PDB. These results suggest an accumulation of non-degradative autophagosomes. Inhibition of PDK1 not only induced apoptosis in PDB and controls, but significantly reduced resorption in PDB, and with regards to autophagy, PDK1 inhibition was more potent in PDB than in controls. Therefore PDK1/Akt signaling represents an important checkpoint to PDB osteoclast activation. In sum, these results demonstrate the importance of several p62-associated kinases in the over-activation of pagetic osteoclasts, through increased survival and altered signaling. As p62 mutations alone do not account for most cases of PDB, the characterization of these pathways may identify a common factor linking pagetic osteoclasts. Therefore these studies represent a novel approach to osteoclast apoptosis, activation, and autophagy associated with PDB.

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La maladie de Paget est une ostéopathie caractérisée par une augmentation multifocale du remodelage osseux, qui débute par un front de résorption osseuse, suivi d'une formation osseuse excessive, avec un remodelage anarchique et intense. Les ostéoclastes "OCs" impliqués dans la phase initiale sont les cellules responsables dans l'initiation du processus pagétique. Les OCs pagétiques sont caractérisés par une résistance à l'apoptose, et des anomalies du processus de l'autophagie "en particulier défaut d'induction"; afin de voir si ces deux caractéristiques étaient liées, nous avons émis l'hypothèse d’un rôle des complexes Bcl2-Beclin1. Beclin-1 est une protéine inductrice de l'autophagie qui peut lier les protéines anti-apoptotiques de la famille Bcl-2; Bcl-2 inhibe alors Beclin-1 "et donc l'induction de l'autophagie" en conservant ses fonctions anti-apoptotiques. Dans le but d'étudier l'impact de l'expression de Bcl2 sur l’autophagie dans les OCs humains, nous avons utilisé un modèle de différenciation in vitro à partir de monocytes dérivés de sang de cordon ombilical, cultivés en présence de RANKL et MCSF pendant 21 jours. Ces conditions permettent d'obtenir des cellules multinucléées au phénotype ostéoclastique. Pour augmenter l’expression de Bcl-2 dans les OCs et analyser son impact sur l’autophagie par interaction avec Beclin-1, les cultures ont été stimulées par TNFα ou RANKL dans le but d'induire une activation de NF-κB. L'expression de Beclin1 et Bcl2 a été confirmée par immunobuvardage dans les OCs. L’autophagie était induite dans les cultures réalisées en conditions stringentes "milieu pauvre en nutriments", sans variation de l'expression de Bcl2 ou Beclin 1 selon les conditions, et sans impact de TNFa ou RANKL. TNFa stimulait de manière significative l'activation de NF-kB dans les cellules HEK mais pas dans les OCs. Toutefois, et quelque soit les conditions, les immunoprécipitations ne permettaient pas de retrouver d'association entre Beclin1 et Bcl2. En revanche, le partenaire d'interaction classique de Beclin1, PI3K type III, était associé à Beclin1. En conclusion, notre travail n'a pas permis d'étudier la formation des complexes Beclin1/Bcl2 et les relations entre apoptose et autophagie, en partie du fait de la complexité du modèle "effets multiples de NF-kB et TNFa" ce qui n'exclut pas l'hypothèse initiale "à ré-évaluer par une méthodologie plus appropriée". En revanche les différentes techniques d'analyse sont maintenant au point pour la poursuite de l'étude. / Abstract : Paget's disease is an osteopathy characterized by a multifocal increase in bone remodeling, which begins with excessive bone resorption followed by increased bone formation. Osteoclasts "OCs" were incriminated in the initiation of the pagetic process. Pagetic OCs are characterized by a resistance to apoptosis, and abnormalities in the process of autophagy “in particular induction defect”. In order to define whether these two characteristics were linked, we hypothesized the role of Bcl2-Beclin1 complexes. Beclin-1 is an autophagy-inducing protein that can bind anti-apoptotic proteins of the Bcl-2 family; Bcl-2 then inhibits Beclin-1 "and thus the induction of autophagy" while retaining its anti-apoptotic functions. To study the impact of Bcl2 expression on autophagy in human OCs, we used an in vitro differentiation model that uses monocytes, which are derived from umbilical cord blood and grown in the presence of RANKL and MCSF for 21 days. These conditions make it possible to obtain multinucleated cells with an osteoclastic phenotype. To increase the expression of Bcl-2 in OCs and analyze its impact on autophagy due to its interaction with Beclin-1, cultures were stimulated with TNFα or RANKL in order to induce NF-κB activation. The expression of Beclin1 and Bcl2 was confirmed by immunoblotting of Ocs cell lysates. Autophagy was induced in cultures carried out under stringent conditions "nutriment-deprived mediun", but we did not observe any variation in the expression of Bcl2 or Beclin 1 according to the culture conditions or TNFα or RANKL stimulation. TNFα significantly stimulated the activation of NF-κB in HEK cells but not in OCs. However, whatever the conditions, results from immunoprecipitaion experiments did not reveal any association between Beclin1 and Bcl2. On the other hand, the classic interaction partner of Beclin1, PI3K type III, was associated with Beclin1. In conclusion, our work did not allow us to demonstrate the formation of Beclin1 / Bcl2 complexes and the relationship between apoptosis and autophagy, partly because of the complexity of the model "multiple effects of NF-κB and TNFα". Our initial hypothesis should thereby be re-evaluated using a more appropriate methodology. On the other hand, the different techniques are now ready for further study.

A 53 year-old male presented with a one-day history of a swollen arm and dull, aching pain in the right upper extremity. The patient reported commencing exercising daily over the prior week with a modified, oscillating dumbbell; commonly referred to as a Shake Weight. Imaging revealed an occlusive thrombus in the right axillary, proximal brachial and basilic veins. The patient was treated with a 24-hour tPA infusion followed by mechanical thrombectomy, balloon angioplasty, and stent placement for a residual thrombus and stenosis. The patient was discharged the following day on warfarin and aspirin. This is the first report of effort-induced thrombosis of the upper extremity following the use of a modified, oscillating dumbbell. Due to the growing popularity of modified dumbbells and the possible risk for axillary vein thrombosis, consideration should be made to caution consumers of this potential complication.

By using adaptation theory and Linda Hutcheon’s depiction of adapters in the process of adaptation as “first interpreters and then creators” (18), this article argues how the original Sherlock Holmes illustrations, penciled most notably by Sidney Paget, are both a canonical element of the Holmes legacy and themselves an adaptation. This creates a means of exploring why and how the television show Sherlock Holmes (1984-1994), developed by Granada Television, uses the original Holmes illustrations as a source of adaptation to create the appearance of fidelity to Arthur Conan Doyle’s Sherlock Holmes stories. Being faithful to the Holmes stories is not a common adaptation practice. Granada’s Holmes chooses to be faithful to the original illustrations and to the Victorian era, not so much to be unique among Holmes adaptations but to be similar to the 1980s heritage cinema trend of faithfully adapting English literature. Heritage cinema, as Andrew Higson states, is a “potent marketing of the past” (1), and through its propensity to adapt literature faithfully to a past time period, heritage cinema reflects a cultural desire for national nostalgia in 1980s Britain. In the case of Granada’s Holmes, this tactic turns Sherlock Holmes into both financial and cultural capital. By being seemingly faithful to the original illustrations, Granada’s Holmes is left vulnerable to the kinds of fidelity or comparative criticisms that adaptation scholars often denounce. Adaptation studies criticizes efforts to compare the source text to the adaptation, saying it will inevitably lead to privileging the source text. Through my investigation, however, I argue that there is a need to use forms of fidelity criticism in order to more fully explore the reasons why Granada’s Holmes hinges its success around fidelity to the original Holmes illustrations.

Le terme « cément » est utilisé pour désigner l’ensemble des tissus conjonctifs minéralisés retrouvés sur la surface externe de la racine d’une dent ainsi que sur certaines zones de l’émail ou au niveau du foramen apical. Il appartient à deux unités fonctionnelles : la dent et le parodonte et constitue avec l’os alvéolaire un point d’attache essentiel du ligament alvéolo-dentaire. Dans certaines conditions non encore élucidées la synthèse de l’une de ses variétés, le cément cellulaire mixte stratifié, est excessive, elle dépasse la « normalité » : il s’agit d’une hypercémentose. Une revue critique de la littérature nous a permis de mettre en évidence un certain nombre de problématiques concernant sa définition, sa classification, sa fréquence, ses étiologies et certaines de ses caractéristiques anatomiques. Afin d’y répondre nous avons élaboré un protocole d’étude dont le matériel comprenait trois séries d’Hommes sub-actuels (675 individus ; 8861 dents dont 419 hypercémentosées) et dont les méthodes ont fait appel à la photographie, la radiographie, la stéréomicroscopie, la microscopie électronique à balayage et l’histologie. Au terme de notre étude nous avons mis au point une définition et une classification de l’hypercémentose reposant sur des critères reproductibles, nous avons évalué sa fréquence au sein de grands échantillons et déterminé ses principales étiologies (éruption continue liée à la perte des dents antagonistes, parodontite apicale, atteintes parodontales, inclusion dentaire, pathologies générales, syndromes génétiques, hérédité, idiopathie). Nous avons également fourni certaines données inédites concernant les épaisseurs du cément hyperplasique et l’anatomie des foramens apicaux. Nos résultats ont enfin été appliqué à un certain nombre de dents néandertaliennes ce qui nous a permis de reconsidérer l’hypothèse selon laquelle l’importance des contraintes occlusales au sein de ce taxon est la cause principale des hypercémentoses. / The term "cement" is used to refer to all mineralised connective tissue found on the external surface of the root of a tooth and also on certain areas of the enamel or around the apical foramen. It pertains to two functional units, the tooth and the periodontium, and together with the alveolar bone forms an essential point of attachment for the periodontal ligament. In certain conditions that have still to be clarified, synthesis of one variety of cement, cellular mixed stratified cementum, is excessive, going beyond "normal" levels: this is hypercementosis. From a review of the literature, we identified a certain number of questions relating to the definition, classification, frequency, and etiologies of this term, and also to some of its anatomical characteristics. To find answers to these questions, we set up a study protocol on material consisting of three series of modern Humans (675 individuals; 8,861 teeth, 419 with hypercementosis), using photography, radiography, stereomicroscopy, scanning electron microscopy and histology techniques. From this we were able to produce a definition and a classification of hypercementosis based on reproducible criteria, we assessed frequency using a large set of samples and determined the main etiologies (continuous eruption associated with the loss of opposing teeth, apical periodontitis, periodontal injuries, dental inclusion, general pathologies, genetic syndromes, heredity, idiopathy). We were also able to provide new data on hyperplastic cement thicknesses and the anatomy of apical foramens. Finally, our results were applied to a number of Neanderthal teeth, which led us to reconsider the hypothesis according to which the importance of occlusal stress in this taxon is the main cause of hypercementosis.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19174号 / 医博第4016号 / 新制||医||1010(附属図書館) / 32166 / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 淳, 教授 村井 俊哉, 教授 渡邉 大 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM