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Die anspruchsvolle Behandlung von Knorpelschäden sowie die weite Verbreitung dieser Krankheitsbilder rücken die bestehenden Therapien sowie die Entwicklung alternativer Therapieansätze in den Mittelpunkt der heutigen Forschung. Der Ansatz eines unterstützenden Knorpeladhäsivums ist vielversprechend. Ziel dieser Dissertation war es im Rahmen eines Push-out-Modells einen standardisierten Versuchsaufbau zur Analyse der Knorpelintegration in vitro sowie einen reproduzierbaren Versuchsablauf zu erarbeiten und somit eine Untersuchung und einen Vergleich von Bioadhäsiva in Bezug auf ihre Bindungskraft zu gewährleisten. Nur eine fehlerfreie und reproduzierbare Messung ermöglicht dezidierte Aussagen über eine direkte Adhäsionsstärke. Wie in dieser Arbeit dargelegt, gibt es eine Vielzahl von Störungsquellen, welche eine solche Messung beeinträchtigen können und so einen Vergleich bzw. eine Aussage über die Bindungsstärke erschweren. Über die verschiedenen Entwicklungsstufen hinweg konnten alle Fehlerquellen identifiziert und beseitigt werden, sodass zum Ende der Etablierung ein Versuchsaufbau sowie ein Versuchsablauf zur Verfügung stand, der eine fehlerfreie Messung, einen Vergleich sowie eine Wertung der Bindungsstärke von Bioadhäsiva ermöglichte. Es konnte gezeigt werden, dass besonders die Probengeometrie einen entscheidenden Einfluss auf die Messergebnisse hat. So wurden im Rahmen der verschiedenen Entwicklungsstufen diverse Vorrichtungen entwickelt, die die Probenherstellung optimierten und vereinfachten. Hier hatten die Schneidevorrichtungen eine besondere Bedeutung, da bei einem optimalen und genauen Schneidevorgang die Fehleranfälligkeit der darauffolgenden Arbeitsschritte deutlich reduziert werden konnte. Somit erbringt diese Arbeit einen wichtigen Anteil im Bereich der Grundlagenforschung und kann zukünftigen Forschungsgruppen bei der Untersuchung von Bioadhäsiva von Nutzen sein. Im zweiten Teil dieser Dissertation wurden verschiedene Adhäsiva, bestehend aus BSA und Glutaraldehyd, auf ihre Adhäsionsstärke sowie auf die praktische Anwendbarkeit und Zytokompatibilität hin untersucht. Neben dem kommerziell erwerbbaren BioGlue®, wurden dessen Bestandteile (BSA sowie Glutaraldehyd) in verschiedenen Verhältnissen sowie unterschiedlichen Konzentrationen des Glutaraldehyds analysiert. Es konnten für die verschiedenen Verhältnisse sowie für die unterschiedlichen Glutaraldehydkonzentrationen beachtliche direkte Adhäsionskräfte nachgewiesen werden. Außerdem ließ sich eine Abhängigkeit der Bindungsstärke von der Glutaraldehydkonzentration als auch von dem Verhältnis der zwei Komponenten verdeutlichen. Zuletzt wurde das Adhäsivum auf seine Zytokompatibilität geprüft. Hier zeigte sich eine deutliche Zytotoxizität, was einen Einsatz als Knorpelkleber stark limitiert. Da sich die Glutaraldehydkonzentration von 10 % auf fast alle Knorpelzellen letal auswirkt, ist ein langfristiges Zusammenwachsen der Knorpelgrenzen nach der initialen Versorgung mit dem Klebergemisch aus aktueller Sicht nicht zu erreichen. Ob eine Reduktion der Glutaraldehydkonzentration bei noch erhaltener Bindungskraft die zytotoxische Wirkung soweit herabsetzen kann, dass eine langfristige Integration stattfindet, scheint ebenfalls eher unwahrscheinlich. Mit diesen Ergebnissen gilt es den Einsatz von BioGlue® in der praktischen Medizin neu zu hinterfragen. / Establishment of a biomechanical push out test to evaluate the adhesive strength of bioadhesives in general. Biomechanical testing of BSA/Glutaraldehyde in different Glutaraldehyde-concentrations and proportions with the established push out test. Histological presentation and in vitro cytocompatibility testing of BSA/Glutaraldehyde

Las hemianopsias homónimas se pueden definir como la pérdida absoluta o parcial de la visión en las mitades derechas o izquierdas de los campos visuales de ambos ojos. Los pacientes que sufren un defecto hemianópsico homónimo completo, evidencian una gran dificultad en la orientación espacial. Así, aunque la mayoría de las veces presentan una buena agudeza visual tanto en visión lejana como cercana, tienen grandes dificultades en su vida cotidiana. Considerando la problemática actual de estos pacientes que cada vez en mayor número y a causa de un proceso neurológico, sufren una secuela de campo que les impide desarrollar su vida con normalidad, hemos investigado la efectividad de algunas técnicas de rehabilitación existentes en esta área, como los prismas Fresnel, los prismas adosados y el espejo nasolaterovisor de Palomar. Para ello diseñamos un estudio longitudinal con noventa y tres pacientes con hemianopsia homónima. Hemos analizado los resultados obtenidos con las tres técnicas de rehabilitación visual empleadas, así como el tiempo de adaptación. Mediante un cuestionario de calidad de vida específicamente diseñado para este fin, y realizado antes, al mes y a los tres meses de la adaptación de las diferentes ayudas visuales, se ha cuantificado la respuesta subjetiva del paciente respecto al grado de mejoría obtenida (deambulación, orientación espacial, capacidad de lectura, etc). Los resultados evidencian que las tres técnicas son efectivas aunque la adaptación de prismas adosados ofrece unas mejoras significativamente superiores en la calidad de vida del paciente. Complementariamente, hemos llevado a cabo un estudio con pacientes sanos, a los cuales se ha simulado un defecto hemianópsico, mediante gafas o lentes de contacto hemianópsicas, con el objetivo de evidenciar la gravedad del problema y el impacto negativo en las actividades más comunes de la vida cotidiana que padecen las personas que presentan una hemianopsia homónima completa. Para ello hemos analizado las dificultades de estos pacientes simulados para realizar tareas sencillas como subir escaleras, deambular por un pasillo, mirar la hora en un reloj de pulsera o utilizar un servicio de mesa. En los casos en los que se pudo falsear correctamente la hemianopsia, se evidenciaron los grabes problemas que conlleva este cuadro neurológico, de forma aislada del impacto emocional del paciente real. Para determinar si las perdidas hemianopsicas, respetaban o no la línea media (aspecto relevante en la adaptación de las ayudas visuales), hemos desarrollado el programa informático “Prueba de Fenómeno de Extinción Visual (FEV-PAL)”, con el cual es posible realizar una exploración rápida, válida y fiable de los veinte grados centrales, dado que se ha constatado una coincidencia del diagnóstico clínico del 100%, comparándolo con la campimetría computadorizada y Goldmann. En definitiva, en función de los resultados obtenidos en este estudio, puede afirmarse que los pacientes que sufren una pérdida de campo de tipo hemianopsia homónima, tienen la posibilidad de mejorar su calidad de vida, mediante procedimientos de rehabilitación y ayudas visuales. Por ello la difusión de estas técnicas es de gran importancia y resulta crucial para animar a otros profesionales a trabajar en este interesante campo, con el objeto de prestar ayuda a pacientes, a los que, en demasiadas ocasiones se deja sin tratamiento / Les hemianòpsies homònimes es poden definir com la pèrdua absoluta o parcial de la visió en les meitats dretes o esquerres dels camps visuals d’ambdós ulls. Els pacients que pateixen un defecte hemianòpsic homònim complet, evidencien una gran dificultat en la orientació espacial. Així, encara que la majoria de vegades presenten una bona agudesa visual tant en visió llunyana com d’aprop, experimenten grans dificultats en la seva vida quotidiana. Atesa la problemàtica actual d'aquests pacients que cada vegada en major nombre i a causa d'un procés neurològic, pateixen una seqüela de camp que els impedeix desenvolupar la seva vida amb normalitat, hem investigat l'efectivitat d'algunes tècniques de rehabilitació existents en aquesta àrea, com són els prismes Fresnel, els prismes adossats i el mirall nasolaterovisor de Palomar. Per a això vam dissenyar un estudi longitudinal amb noranta-tres pacients amb hemianòpsia homònima. Hem analitzat els resultats obtinguts amb les tres tècniques de rehabilitació visual emprades, així com el temps d'adaptació. Mitjançant un qüestionari de qualitat de vida específicament dissenyat per a aquest fi i realitzat abans, al mes i als tres mesos de l'adaptació dels diferents ajuts visuals, s'ha quantificat la resposta subjectiva del pacient respecte al grau de millora obtinguda (deambulació, orientació espacial, capacitat de lectura, etc). Els resultats evidencien que les tres tècniques són efectives encara que l'adaptació de prismes adossats ofereix unes millores significativament superiors en la qualitat de vida del pacient. Complementàriament, hem dut a terme un estudi amb pacients sans, als quals s'ha simulat un defecte hemianòpsic, mitjançant ulleres o lents de contacte hemianòpsiques, amb l'objectiu d'evidenciar la gravetat del problema i l'impacte negatiu en les activitats més comunes de la vida quotidiana que pateixen les persones que presenten una hemianòpsia homònima completa. Per a això hem analitzat les dificultats d'aquests pacients simulats per realitzar tasques senzilles com pujar escales, recórrer un passadís, mirar l'hora en un rellotge de polsera o utilitzar un servei de taula. En els casos en què es va poder falsejar correctament la hemianòpsia, es van evidenciar els greus problemes que comporta aquest quadre neurològic, sense la influència de l’impacte emocional dels pacients reals. Per determinar si les perdudes hemianòpsiques, respectaven o no la línia mitjana (aspecte rellevant a l’hora d’adaptar les ajudes visuals), hem desenvolupat el programa informàtic "Prova del Fenomen d'Extinció Visual (FEV-PAL)", amb el qual es pot fer una exploració ràpida, vàlida i fiable dels vint graus centrals, atès que s'ha constatat una coincidència del diagnòstic clínic del 100%, comparant-lo amb la campimetria computada y Goldmann. En funció dels resultats obtinguts en aquest estudi es pot afirmar que els pacients que pateixen una pèrdua de camp de tipus hemianòpsia homònima, tenen la possibilitat de millorar la seva qualitat de vida, mitjançant procediments de rehabilitació i ajudes visuals. Per això, la difusió d'aquestes tècniques és de gran importància i resulta crucial per animar d’altres professionals a treballar en aquest interessant camp, amb l'objectiu de prestar ajuda a pacients, als quals, en massa ocasions es deixa sense tractament. / Patients diagnosed with a complete hemianopsic defect, even with far distance and near visual acuity, complaint of significant difficulties in their daily activities, including inadequate mobility and frequent collision with unseen objects among others. Considering the current problem of these patients, who, in a growing number and as a consequence of this neurological process, suffer from limiting field sequels, we have investigated the effectiveness of some existing rehabilitation techniques in this area, such as Fresnel prisms, ground-in sectorial prisms and the nasolateral attached mirror of Palomar. We designed a longitudinal, partly retrospective and partly prospective study of ninety-three patients with homonymous hemianopia. We have analyzed the results obtained with the three employed visual rehabilitation techniques, as well as the time of adaptation. A specifically designed questionnaire for homonymous hemianopia visual impairment assessment was employed to investigate the difficulties in visually dependent daily activities (walking, spatial orientation, reading ability, etc.) encountered by the patients before and at one and three months after the adaptation of the different visual aids. The results show that, although the three techniques were effective, the ground-in sectorial prisms provided significantly greater improvements in the quality of life of the patients. Additionally, we conducted a study with healthy subjects, to which, as a kind of control group, we have simulated a hemianopic defect by means of hemianopic glasses or contact lenses, with the goal of highlighting the severity of the problem and the negative implications on the most common activities of everyday life experienced by the hemianopic patient, independently of the emocional impact. Thus, we have discussed the difficulties of these simulated patients to perform simple tasks like climbing stairs, walking along a corridor, checking the time on a wristwatch, or using a table service. In these cases in which the hemianopia could be successfully simulated, the great problems caused by this neurological condition became apparent. To determine whether the hemianopic field defect respected or not the midline (a very relevant aspect in the adaptation of visual aids), we have developed the software "Test of Visual Extinction Phenomenon (FEV-PAL)", by which a quick, valid and reliable scan of the central twenty degrees is performed. This instrument presents a 100% clinical diagnosis coincidence when compared with Goldmann or computerized perimetry. According to the results gathered in the present study, it can be asserted that hemianopic patients have the potential to improve their quality of life through rehabilitation procedures and visual aids. Thus, the diffusion of these techniques is of great importance to encourage other professionals to work in this exciting field, in order to assist patients, who, are too often left untreated.

The following study investigates the British government�s response to maritime predation in the period 1810-1830 and evaluates the effectiveness of the measures implemented to protect British trade and shipping. A necessary prerequisite for this task is to establish the impact of commerce raiding activity on the British mercantile marine, which has thus far eluded historians. Chapters one and two of the following study are dedicated to this purpose. In chapter one, the key findings of previous works with regard to the organizational and operational features of commerce-raiding activity are synthesised and the extent and nature of the threat posed to British trade and shipping is established. The ways in which this threat became a reality for British merchants is the subject of chapter two. The impact of predation on the British mercantile marine is identified through the use of quantitative and qualitative data. A database of prize actions, which can be defined as encounters between British merchant vessels and maritime predators, has been constructed for this study from the intelligence contained in contemporary newspapers and government correspondence. The database provides statistics on the number of British vessels affected by maritime predators, the annual frequency of prize actions, and the perpetrators responsible for their initiation. Adding depth to these statistics are the letters, petitions, memorials and claims certificates received by the British government, which give detailed breakdowns of the losses incurred by merchants in individual prize cases. In chapter three the wider political context within which the British government received merchant appeals for assistance is established, providing a framework with which to identify and explain the measures implemented to tackle the problems being experienced at sea and to evaluate their effectiveness. Chapters four through to seven thematically analyse the British government�s response to maritime predation. British countermeasures against the depredations of independent Spanish American commerce-raiders are addressed in chapter four. The British government�s response to Spanish predation is the subject of chapters five and six, while chapter seven provides an analysis of British policy towards Cuban-based piracy. These four chapters draw heavily upon government correspondence when identifying the measures implemented by British statesmen to counter the threat of maritime predation, while the public debates and the proceedings of the Anglo-Spanish claims commission underpin appraisals of the effectiveness of these measures. Given that commerce-raiding activity during the Spanish American Wars of Independence has never been examined from a British perspective, this study will add a new dimension to the existing literature. In doing so, this study will provide a platform from which to reassess the arguments of previous works with regard to the character of predation in the early nineteenth century, the motivation of those individuals who participated in the activity, and the contribution of commerce-raiding to the outcome of the independence conflict. However, the following study also has the potential to raise points of wider significance and make contributions to knowledge and understanding of other aspects of history. The focus of the current study on the effectiveness of British policy in protecting the interests of British merchants from the threat of predation therefore to shed light on wider social, political and economic changes occurring within Britain during the early nineteenth century The upsurge in commerce-raiding activity during the Spanish American Wars of Independence occurred at a time of profound change in the direction of British economic policy. Cain and Hopkins have outlined the nature of this change and explained the rationale with which it was underpinned. They argue that between 1688 and 1850 Britain was ruled by a gentlemanly elite made up of an alliance between the landed aristocracy and financiers in the City of London. This alliance sought to service the national debt, fund patronage and manage the political system in ways that preserved privilege, civil peace and the constitution. In the period prior to 1815 the pursuit of these objectives saw the British government play a protectionist role in the economy. However, following the Napoleonic Wars it became clear that fundamental changes were needed to restore the health of the economy, maintain civil order and deflect growing criticism of the patronage system that had begun to circulate in the late eighteenth century. Consequently, the ruling class embarked on a process of redefining its role and purpose and gradually began to introduce reforms of the constitution, of the patronage system, of social legislation, and of economic policy. In the economic realm following the Napoleonic Wars, forward-looking members of the Tory government, who were inspired by Adam Smith�s attack on mercantilism in the Wealth of Nations, adopted a laissez-faire outlook and began to progressively withdraw the government from direct participation in the economic process.57 By 1850 the transition was effectively complete and mercantilism had given way to an era of free trade. As D.C.M. Platt has demonstrated, for the remainder of the nineteenth century the British government maintained an urgent official interest in the general welfare of British commerce overseas but exhibited a distinct prejudice against promoting individual financial and trading interests. This study promises to shed further light on early nineteenth-century British economic policy by providing a case-study with which to view this transition in action and with which to assess its significance to the lives of British subjects.

Background: Differentiated thyroid cancer (DTC), although rare, is the commonest endocrine malignancy, with a significant recent increase in incidence. Natural history is well understood: the majority of patients have an extremely good prognosis, but with a tendency for late recurrences, up to twenty years post diagnosis. These features have combined to effect a lack of evidence underlying current practice, the majority of guidelines based around retrospective series and opinion. A number of validated risk stratification systems exist, unique to DTC, some applicable at the point of intervention. Although these systems reliably predict outcome, they are inconsistently used to guide the extent of intervention. As such, the three main facets of treatment, surgery to the thyroid, surgery to the lymph nodes, and radioiodine (RAI), are variably applied to the same extent of disease. This may depend at least partly upon the clinician‟s preference towards use of risk stratification systems. Consequently, low risk patients may be at risk of morbidities, both short and long term from unnecessarily aggressive interventions, despite consistently good prognosis. Rationalisation of the approach is attractive from a patient, provider, and health service perspectives; without controlled or long term data, such change in practice requires justification. Aim The overall aim of this thesis is to describe and compare the clinical effectiveness of risk stratified (RS) management of DTC, compared to non risk stratified (NRS) management, in an adult population. UK context is provided by description of current practice and long term disease specific outcomes. Three strands of work are combined to address this aim. Part One: Systematic Review A comparison of RS/NRS approaches necessitated objective and reproducible definition of practice overall, encompassing the three facets of intervention. Thereafter, rigorous methodology was applied to examine the clinical effectiveness of the two approaches, based on review of 76 datasets identified from the literature, with RS/NRS approach assigned; there were no relevant randomised trials nor prospective comparative series. Patients, disease and practice were described and compared, with outcome data grouped by safety, disease control, and survival. Sensitivity analysis was planned around population and practice items. Study quality vi was objectively assessed. Weighted mean effect sizes were calculated for RS/NRS cohorts and compared across the two intervention groups for each outcome, with findings further tested on sensitivity analysis. Broadly, equivalence was shown across the two treatment groups by outcome, with small differences consistent with disease biology/magnitude of intervention. Risk stratification appeared to be applicable not only to primary intervention, but also follow-up strategies. Variations in outcome definitions were highlighted, and a pragmatic, patient-centred definition favoured as an approach for future work. Lack of time-specific data was a significant limiting factor. Part Two: Description and Analysis of UK Practice With no UK dataset within the systematic review, validity for the findings was required, as well as the need to describe and compare practice and outcomes in a contemporary local context. The ideal dataset was defined and participants for a UK collaborative sought. Five centres contributed datasets of adequate quality, at least in part prospective, with time-specific outcome measures. Overall, UK practice was by definition risk stratified – and appeared increasingly so over time. There was considerable variation in practice across the five centres (2 NRS, 3RS), but all with consistent, equivalent outcomes compared with the review, despite patients of somewhat higher risk. Utilising methodologies from the systematic review, the analysis was repeated and augmented, confirming consistency in effect directions. Time-specific, adjusted outcome measures demonstrated a possible lack of effectiveness of RAI in high risk disease – a new finding worthy of further exploration. The comprehensive datasets further reinforced the need to work towards prospective, long term, time specific data with common agreed definitions, and suggestions are made how this can be achieved. Part Three: National Survey of Practice Preference The current UK preference for RS management, notwithstanding current service provision around thyroid cancer, is little known. Through cross-specialty survey, utilising a number of case scenarios validated by external experts, and gathering data on clinician demographics, this information was sought, in order to give further context to the above findings. A high degree of variation was identified within, and across scenarios; the least RS preference for intervention applied to the lowest risk scenarios, implying risk of over-treatment. RS preference was associated independently with fewer years in practice and high volume practice. Conclusion Based on the best available data, and supplemented by congruent, contemporary UK data and perspectives, this thesis confirms safety and equivalence of effectiveness of a risk stratified approach to the management of differentiated thyroid cancer, demonstrates considerable variations in practice and suggests possible tools towards building a better evidence base for the future.

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