Introduction: The human menstrual cycle is regulated by sex-steroid hormones, including oestrogen (E), progesterone (P4) and androgens which act by ligand binding to their cognate receptors. Perturbation of the complex series of events governing the menstrual cycle may lead to heavy menstrual bleeding (HMB). This is a common debilitating condition and often associated with uterine fibroids. There remains an unmet need for effective, long-term medical treatment so women avoid surgery and preserve their fertility. Selective progesterone receptor modulators (SPRMs, e.g. ulipristal acetate, UPA) are synthetic ligands that bind the progesterone receptor (PR). Many SPRMs have been developed but only mifepristone (for the management of unwanted pregnancy) and UPA are in current clinical use. UPA is licensed for the intermittent treatment of symptomatic fibroids. SPRMs have potential utility for treatment of HMB as administration rapidly induces amenorrhoea but the mechanisms by which this is achieved are unknown. SPRM administration results in unique endometrial morphological changes (progesterone receptor modulator-associated endometrial changes; PAEC). Despite endometrial unopposed estradiol exposure these morphological changes do not appear to be associated with malignancy or pre-malignancy risk. Indeed endometrial cell proliferation appears reduced despite relative progesterone-antagonism. Based upon findings with other SPRMs it was hypothesised that: (i) administration of UPA would have an endometrial specific effect upon the reproductive tract, with regard to alteration in morphology, localisation of sex steroid receptors (SSR) and cell proliferation.; (ii) administration of UPA would impact upon progesterone-regulated (Pregulated) genes in the endometrium. Methods: The data presented within this thesis are derived from biopsies obtained at hysterectomy from the endometrium, fallopian tubes and cervices of women with symptomatic fibroids administered UPA for 8-15 weeks. Samples were obtained for histological assessment, immunohistochemistry and RNA extraction for subsequent quantitative RT-qPCR of sex-steroid receptors (SSR) and proliferation markers. In addition key P-regulated genes within the endometrium were investigated by RT-qPCR and selected protein expression. To further interrogate the anti-proliferative effect, RNA was extracted from “paired” endometrial biopsies from the same woman in the proliferative phase of the menstrual cycle and following subsequent treatment with UPA for at least eight weeks and microarray gene analyses undertaken. Results: Morphological alteration of the endometrium with UPA administration was consistent with previously published data, but with a higher prevalence than previously described. There was a striking alteration in expression and localization of SSRs, particularly PR and androgen receptor (AR), and alteration of many P-regulated genes, consistent with UPA acting with low progesteroneagonism within the endometrium. There was no alteration of SSR expression within the cervix and proliferation was unchanged. Fallopian tube morphology and SSR expression was consistent with proliferative phase but cell proliferation was reduced following UPA administration, consistent with secretory phase levels. Microarray analyses identified multiple transcripts altered relative to proliferative phase, with GREM2 the most significantly down-regulated gene and MUC1 one of the most significantly upregulated genes. Consistent with low levels of mitotic figures and cell proliferation, the most down regulated KEGG pathway was the cell cycle. Multiple elements within this were subsequently validated (RT-qPCR) and included key regulators of all elements of the mitotic cell cycle, many of which were novel to those previously described following administration of another SPRM, mifepristone. In summary the novel data presented in this thesis considerably extend the data available to date concerning the actions of the SPRM, UPA, on the female reproductive tract, and increases knowledge regarding a compound with promising utility for the management of the debilitating complaint of HMB.

Non contributory periods is one of the key issues in the public discussion on the planned reform of the pension system in the Czech Republic and is being widely discussed by economists, social scientists and political representatives. The PhD thesis focuses on a detailed analysis of non-contributory periods in the Czech pension system and their impact on pension system balance and micro and macro economic connections. It includes an international comparison of non contributory periods and a minute description of one selected non contributory period -- child care in selected European countries. The extent of non contributory periods considered in the pension system represents one of the theoretical possibilities of parametric changes to the pension insurance system. Non contributory periods are taken into account in pension schemes either because the individual is carrying out a non-wage-earning activity beneficial to society or because the individual through no fault of their own finds themselves in an (adverse) social situation which from a humanitarian perspective justifies their participation in pension insurance without making insurance payments. The institution of non contributory periods helps to secure the universality of the pension system, which enables the participation of economically inactive persons in the pension insurance system. The amount of non contributory periods or the proportion between non contributory periods and years worked, or the proportion between paid insurance and non contributory periods (potential loss of insurance contributions) has, to date, merely been estimated in the Czech Republic. This PhD thesis presents the first accurate figures, based on unique individual data on insured persons; methods of analysis, synthesis, comparison, simulations were used and statistical methods were applied. The analysis reveals that non contributory periods are a significant element of the Czech pension system amounting to 22.4% of the total insurance period which is unacceptable especially as regards the principle of equivalence. The average duration of non-contributory periods for current pensioners is 8.7 years. The proportion of hypothetical insurance calculated from the average wage at potential total income from insurance was in the observed year 30% or 13% (calculation based on the minimum wage). Non contributory periods in the Czech pension system have a significant impact on its balance. Paying premiums for non contributory periods (included in pension law) would cause a decrease in the contribution rate to 18% (calculation based on the average wage). If non contributory periods were not considered, the potential savings on pensions paid out would be almost CZK 35 billion in the observed year. That represents 16.5% of expenditure on pension payments and more than twice the deficit of the pension insurance account for the observed year. Therefore the author recommends in the thesis the restriction of non contributory periods and the introduction of payments for such non-contributory periods from those people who will be entitled to a pension from such non contributory periods in the future.

published_or_final_version / Fine Arts / Master / Master of Philosophy

The third generation of hip resurfacing commenced in the U.K. in the 1990’s with the Birmingham Hip Resurfacing system and is now becoming more commonplace as an attractive alternative for young and active patients due to premature failure in total hip replacement in this patient group. However the Swedish National Hip Arthroplasty Register (2010) suggests that premature failure of resurfacing arthroplasty may be more prevalent than first expected. The aim of this study is to investigate, through Finite Element Analysis, the short, medium and long term performance of Poly Methyl Methacrylate (PMMA) bone cement of the femoral component in hip resurfacing arthroplasty. The study takes a forensic engineering approach, analysing the performance of PMMA bone cement in order to provide understanding, awareness and an insight into lifestyle options. Finite Element Analysis explores and models the effect of resting periods during daily activities, patients’ bone quality and PMMA bone cement Young’s modulus on the PMMA bone cement stresses within the femoral hip resurfacing component. Mechanical tests are used to illustrate the use of the Finite Element Analysis results. Contributing to knowledge, this study verifies the significance of high metal-on-metal friction due to resting periods, developing a dynamic FEA model to quantify the premature fatigue failure of PMMA bone cement, within the femoral component of hip resurfacing arthroplasty. A decrease in bone quality added to the effect of resting periods increase the risk of PMMA fatigue failure and PMMA-metal interface failure due to an increase of PMMA tensile and shear stresses, suggesting that patients with low bone quality should avoid hip resurfacing procedures. The use of low PMMA Young’s modulus could greatly enhance the long term success of hip resurfacing arthroplasty generally and specifically reduce the risk of interface failure and PMMA bone cement failure due to resting periods and patient bone quality. Moreover, this study shows that the consequence of PMMA fatigue failure and PMMA-metal interface failure must be included in the design, patient selection, screening process, post-operative rehabilitation and long term lifestyle attributes. This study suggests that occupational therapists and patients with hip resurfacing arthroplasty should be aware of high metal-on-metal friction situations, which could lead to early failure indicated by this research. The deleterious effect of resting periods indicated by this research could be alleviated by appropriate re-initiation of synovial lubrication by movement prior to full loading. Recommendations for further work include the compilation of a PMMA bone-cement fatigue properties database and further development of the FEA modelling technique for application upon other arthroplasty procedures.

Title Coordination abilities in long-term concept sports training of children Objective The point of the thesis is handle the issue of coordination ability. In the first part of the thesis I will talk about general issues of children's sports training, developmental patterns and the characteristic of sensitive periods. The fundamental basis of my research part is find out how the coordination skills involved in long-term sports training, what is their role in motor development of children and what their biological basis. Methods The thesis has a theoretical character and it uses qualitative methods: compares, analyses and interprets texts and data acquired through background research. Results Coordination skills have proven essential element of successful mastery of motor skills in the concept of long-term sports training more or less dependent on coordination. If there are individual skills developed in the sensitive periods is very difficult to catch up with missed this and achieve the same level of skills acquired. Important role in the development of coordination skills and heredity plays a connection with the state and function of the central nervous system. Key words sports training of children, coordination, development, sensitive periods

In Islamic Sharia law, prescription has been more commonly referred to as murūr al-zamān [the lapse of time]. It has been claimed that the abstract principle of the lapse of time only has the effect of barring a claim and that is not capable of creating and extinguishing the right itself. In the context of Islamic law, this concept of prescription is often ascribed only to the Hanafi and Maliki schools of Sharia law, and it has been claimed that such principle has not been recognized by the Hanbali School. Based on that, my reading shows that, under Saudi jurisdiction (which is principally based on uncodified Hanbali Sharia law), this hypothesis is a key problem as in practice there are many secondary Saudi laws in place applying prescription rules to bar civil actions. Thus, by arguing that such principle has not been recognized by Sharia law as applied in Saudi Arabia, the legality of such provisions would be in question, given the fact that all Saudi enacted laws must conform with Islamic law. Moreover, my analysis argues that in studies of Saudi Hanbali law, prescription has neither been discussed widely nor given serious independent consideration. In the context of Saudi and Hanbali law, issues of prescription have not only been marginalized and minimized, but also inaccuracies and mis-readings are often found in related academic literature. Drawing on findings across various disciplines, including studies of classical and modern Islamic law, as well as legal studies on Saudi and Arab laws, this study presents new readings of the issues of the existence and origins of the legal concept of civil prescription from the perspectives of the Saudi-Hanbali School of law. Moreover, it presents the first comprehensive survey of the extent of implementation of the rules of prescription in the Saudi civil regulations over the last eight decades. Finally, from both theory and practice aspects, the thesis attempts to conclude with a critical analysis of the single ‘negative’ perspective of prescription in both Islamic and Saudi law.

Made available in DSpace on 2017-07-25T19:29:52Z (GMT). No. of bitstreams: 1 Kleber Martin Andrade.pdf: 456779 bytes, checksum: 84d9448f5d5728eab48fc6d5281e85c7 (MD5) Previous issue date: 2011-11-24 / For the wheat crop is proven the importance of the use of growth regulators by reducing the lodging, mainly caused by high doses of nitrogen and the high susceptibility of some cultivars. As a result there is a need to use new technologies that will help to avoid productivity losses caused by lodging. In this sense, there were three experiments (E1, E2 and E3) to evaluate the effects of growth regulators applied at different doses and times in agronomic traits, yield components and yield of wheat cultivars. The experiments were performed at the Farm School, State University of Ponta Grossa (UEPG), Ponta Grossa, PR, in 2009. In E1 we used two regulators (trinexapac-ethyl and prohexadioncalcium) at doses of 0.0, 37.5, 75.0, 112.5 and 150.0 g ha-1 and 0.0, 41, 2, 82.5, 123.7 and 165.0 g ha-1 respectively,in the cultivar BRS-249. We used the experimental design of randomized blocks with ten treatments in a factorial 2 x 5 (x regulators doses) with four replications. In E2 we used two regulators (trinexapac-ethyl and prohexadion-calcium) at doses of 0.0, 37.5, 75.0, 112.5 and 150.0 g ha-1 and 0.0, 41, 2, 82.5, 123.7 and 165.0 g ha-1 respectively, in the cultivar Marfim. Experimental design used was randomized blocks with ten treatments in a factorial 2 x 5 (x regulators doses) with four replications. At E3 we used three growth regulators (trinexapac-ethyl, prohexadion-calcium and chloride 1,1 - dimethyl piperidine) at doses of 125.0 g ha-1, 137.5 and 125.0 g ha-1 g ha-1 respectively applied in two seasons (between the 1st and 2nd node and between 2 ° and 3 ° we have seen), the cultivar Marfim. Experimental design used was randomized blocks in 4 x 2 factorial arrangement and four replications. In the E1 prohexadion trinexapac-ethyl and calcium-promoted reduction of internode length and plant height, stem diameter increased, the number of leaves per plant, flag leaf width and productivity. In the E2 prohexadion-calcium and trinexapac-ethyl were effective in reducing internode length, plant height and mass of thousand grains, and prohexadion-calcium that showed potential for use in wheat crop. At the E3 prohexadion-calcium and trinexapac-ethyl promoted decrease in plant height without affecting the diameter of the stem and productivity. The 1,1- chloride dimethyl piperidine did not affect plant height, and promoted an increase in the number of leaves per plant, but without effect on components of production and productivity. The application period did not promote changes in most variables indicating a greater range of use of regulators in the cultivar Marfim. / Para a cultura do trigo está provada a importância da utilização de reguladores de crescimento, pela redução do acamamento, causado principalmente pelo uso de altas doses de nitrogênio e pela alta suscetibilidade de algumas cultivares. Em decorrência disso verifica-se a necessidade de utilização de novas tecnologias que venham a contribuir para evitar as perdas de produtividade causadas pelo acamamento. Nesse sentido, realizaram-se três experimentos (E1, E2 e E3) para avaliar os efeitos de reguladores de crescimento aplicados em diferentes doses e épocas em características agronômicas, componentes da produção e produtividade de cultivares de trigo. Os experimentos foram realizados na Fazenda Escola da Universidade Estadual de Ponta Grossa (UEPG), município de Ponta Grossa, PR, no ano de 2009. No E1 utilizaram-se dois reguladores (trinexapac-ethyl e prohexadionecálcio) nas doses de 0,0; 37,5; 75,0; 112,5 e 150,0 g.ha-1 e 0,0; 41,2; 82,5;123,7 e 165,0 g.ha-1 de ingrediente ativo respectivamente, na cultivar BRS-249. Foi utilizado o delineamento experimental de blocos ao acaso com dez tratamentos dispostos em esquema fatorial de 2 x 5 (reguladores x doses) com quatro repetições. No E2 utilizaram-se dois reguladores (trinexapac-ethyl e prohexadione-cálcio) nas doses de 0,0; 37,5; 75,0; 112,5 e 150,0 g.ha-1 e 0,0;41,2; 82,5; 123,7 e 165,0 g.ha-1 de ingrediente ativo respectivamente, na cultivar Marfim. Foi utilizado delineamento experimental de blocos ao acaso com dez tratamentos dispostos em esquema fatorial 2 x 5 (reguladores x doses) com quatro repetições. No E3 utilizaram-se três reguladores de crescimento (trinexapac-ethyl, prohexadione-cálcio e cloreto 1,1- dimetil piperidíneo) nas doses de 125,0 g.ha-1; 137,5 g.ha-1 e 125,0 g.ha-1 de ingrediente ativo respectivamente aplicados em duas épocas(entre o 1º e o 2° nó e entre o 2° e o 3° nó perceptível), na cultivar Marfim. Foi utilizado delineamento experimental de blocos ao acaso, no esquema fatorial 4 x 2 e quatro repetições. No E1 o trinexapac-ethyl e o prohexadione-cálcio promoveram redução do comprimento dos entrenós e da altura de plantas,aumento do diâmetro do colmo, do número de folhas por planta, da largura da folha bandeira e da produtividade. No E2 o trinexapac-ethyl e o prohexadionecálcio foram eficientes na redução do comprimento dos entrenós, da altura de plantas e da massa de mil grãos; sendo que o prohexadione-cálcio mostrou potencial de uso na cultura do trigo. No E3 o trinexapac-ethyl e prohexadionecálcio promoveram diminuição da altura das plantas sem afetar o diâmetro do colmo e a produtividade. O cloreto 1,1-dimetil piperidíneo não afetou a altura de plantas, e promoveu aumento do número de folhas por planta, mas sem efeitos sobre componentes de produção e produtividade. A época de aplicação não promoveu alterações na maioria das variáveis indicando uma maior amplitude de uso dos reguladores na cultivar Marfim.

O saco vitelino é o único anexo embrionário presente em todas as espécies animais cuja função é manter o desenvolvimento primário do feto até que a placenta assuma esta função. Além disso, ele desempenha funções importantes como: nutrição do embrião, síntese proteica, atividade fagocitária, transferência de materiais e hematopoiese. A utilização de células-tronco embrionárias gera muitas discussões devido às questões éticas associadas à obtenção destas células, além de questões religiosas e também as relações de baixa plasticidade das células-tronco adultas motivam os pesquisadores ao crescente interesse em outras fontes de célulastronco. Com isso, células provenientes de tecidos como as dos anexos embrionários chamam cada vez mais atenção devido à sua facilidade de acesso, crescimento rápido e boa plasticidade. Nosso grupo tem demonstrado que as células do saco vitelino têm boa capacidade de proliferação e são multipotentes. Vários pesquisadores vêm demonstrando que o período no qual as células são obtidas pode ser de fundamental importância para a diferenciação. Sendo assim, neste projeto tivemos como objetivo estabelecer e caracterizar células-tronco de saco vitelino de cães em dois estágios gestacionais, visando analisar de forma comparativa o perfil de expressão de marcadores mesenquimais, hematopoiéticos e pluripotência de forma a entender o comportamento das mesmas. Neste trabalho observamos que as células de saco vitelino obtidas de gestações com 40 e 50 dias aderiram ao plástico, tiveram morfologia fibroblastóide, boa proliferação celular, se diferenciaram em adipócitos, condrócitos e ostéocitos e expressaram alguns marcadores mesenquimais, sugerindo assim ser uma célula-tronco mesenquimal. Além disso, não levaram à formação tumoral quando injetadas em camundongos imunossuprimidos, nudes. / The yolk sac is an embryonic attachment present in all animal species, which function is to keep the primary development of the fetus until the placenta assumes this function. Moreover, it plays important roles as: nutrition of the embryo, protein synthesis, phagocytic activity, transfer of materials and hematopoiesis. The use of embryonic stem cells generates many discussions because of the ethical and religious issues associated with the obtaintion of these cells. Also the relationship of low plasticity of adult stem cells motivates researchers to explore other sources of stem cells. Thus, cells from tissues such as the embryonic anexes call more attention, due to its ease of access, rapid growth and good plasticity. Our group has shown that cells of the yolk sac has good ability to proliferate and are multipotent. Several researchers have shown that the period in which the cells are obtained can be critical for differentiation. Therefore, in this project we aimed to establish and characterize stem cells from dog yolk sac in two stages of pregnancy, in order to analyze comparatively the expression profile of mesenchymal, hematopoietic and plurypotency markers, and study their behavior and plasticity potencial in vitro. In this study we observed that yolk sac cells obtained from pregnancies at 40 and 50 days adhered to plastic, had fibroblast like-morphology, good cell proliferation and differentiated into adipocytes and osteocytes and expressed some mesenchymal markers, therefore suggesting to be a mesenchymal stem cell. Also, they did not lead to tumor formation when injected into immunosuppressed mice, nude.

The west coast of Vancouver Island is located at the northern end of the California Current System, one of the world’s Eastern Boundary Current Systems. The region is characterized by wind driven coastal upwelling and high productivity, which supports fisheries and related industries. Climate change poses a challenge to these industries by increasing seawater acidity and decreasing dissolved oxygen levels, which are two of the multi-stressors of marine organisms. This thesis explores the relative importance of different physical and biological mechanisms that affect oxygen and carbon extremes in the region. The relatively weak local wind in the region is not well-correlated with local currents and temperature. Results of coherence analyses between multi-depth current and temperature measured at a single mooring site (48.5 ◦ N, 126 ◦ W) in the west coast of southern Vancouver Island and coincident time series of North America Regional Reanalysis (NARR) 10 m wind stress in the geographic domain 36 – 54 ◦ N, 120 – 132 ◦ W are presented. The two-decade long (1989 – 2008) current records from the three shallowest depths (35, 100 and 175 m) show a remote response to winds from as far south as 36 ◦ N. In contrast, temperature only at the deepest depth (400 m) show strong coherences with remote winds. The frequency window of maximum coherence and the estimated average time-lags are consistent with the frequencies and pole-ward propagating phase speeds of coastal trapped waves. Lack of coherence between remote winds and the 400 m currents suggests that the temperature variations at that depth are driven by vertical motion resulting from poleward travelling coastal trapped waves (CTWs). In order to study the relative roles of physical and biological processes on controlling oxygen and carbon tendencies, oxygen cycle has been successfully added to an existing biogeochemical model of the west coast of Vancouver Island. This idealized model then was forced with a long synthetic record of present-day conditions, specifically 1017 years of stochastically generated daily resolved forcing including local and remote winds. The seasonal cycles of the modelled DIC and O2 compare well with depth averaged observational data. They are also found to be strongly coupled in the lower layers, where biological processes are more important. In the upper layer, physical processes such as the differing gas exchange rates partially decouple DIC and O2 . Robust statistics on DIC and oxygen extreme events were calculated by using the long realizations of the model baseline experiment. In the upper mixed layer, O2 extreme events occur 2–3 times more frequently than DIC extreme events. Both extreme events show a much larger interannual variability in the lower layer. In this layer, oxygen extreme events events occur late in the summer, following intense upwelling events early in the upwelling season. Counter-intuitively, within the summer upwelling season, when sporadic upwelling events are expected to cause extreme conditions, the fraction of days with joint DIC–O2 extreme events is negligible. Sensitivity analysis shows that increased primary production, via increased phytoplankton growth rate, decreases the small fraction of days with joint DIC-O2 extreme events in the upper layers during the summer upwelling season but increases it in the winter downwelling season. Lowering upwelling intensities lowers the fraction of days with joint DIC–O2 extreme events. Increasing the upwelling intensities had the opposite effect on this fraction. Changes in up/downwelling intensity did not change this fraction within the summer upwelling season. A non-monotonic response by oxygen extreme events in the lower layer is observed when phytoplankton growth rate was increased. Generally, a moderate decrease in growth rate increases the chances of model lower layer O2 extreme events, while near-zero growth rate does not. In some cases, the same parameter perturbation results in different responses by the mean and the extreme events of DIC and O2 , suggesting that results of studies focusing on physical and biological forcing of the mean state may not directly translate result to extremes. This thesis has identified relative locations within the study domain of priority for effective monitoring of dissolved oxygen and carbon extremes in the study region. Finally, joint DIC- O2 extreme events are found to be common at the end of the summer. This information can be used to inform adaptation and mitigation plans aimed at protecting the economic and bequest value of the coast from potential hazards associated with oxygen and carbon extremes. / Graduate

Aggregating performance measures considerably reduces the complexity of a performance evaluation system. This dissertation analyzes the nature and characteristics of the aggregation of performance measures in institutional settings of multiple tasks and multiple periods. In multi-task settings, the number of tasks restricts the feasibility of a statistically sufficient aggregation and the nature of an economically sufficient aggregation. Statistical sufficiency of aggregation can be achieved only by multi-dimensional aggregate measures, whose minimum dimensionality is given by the number of tasks. If the number of aggregate measures is less than the number of tasks, an economically sufficient aggregation incurs loss of information even if there is no loss of information through the likelihood ratio. The results support the use of multi-dimensional aggregate measures to preserve the information content of performance measures in multi-task agencies. In a multi-period setting, the inter-temporal correlations among performance measures restrict the feasibility of a statistically sufficient aggregation and the nature of an economically sufficient aggregation. When performance measures are inter-temporally correlated, there is no statistically sufficient aggregation and an economically sufficient aggregation of the basic measures depends on the effort level to induce. The optimal aggregation is characterized by the agent's characteristics and the economic situation of the agency as well as the statistical properties of performance measures. In a long-term contract with multiple tasks, the inter-temporal covariance risk has a monotonic impact on the endogenous allocation of effort through the optimal relative incentive rate. The inter-temporal covariance risk, as well as the within-period risk premium, prevents the first best allocation of effort from being endogenously achieved even if the first best allocation is feasible. / Accounting