Chan, Po Tai. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 128-150). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese; some appendixes in Chinese.

Introdução: Os mecanismos envolvidos na patogênese molecular dos tumores hipofisários corticotróficos são complexos, heterogêneos e permanecem na maioria dos casos desconhecidos. Alterações da expressão de componentes da via Ikaros (Ik), tais como do receptor 4 dos fatores de crescimento de fibroblastos (FGFR4) têm sido detectadas em tumores hipofisários, inclusive nos corticotropinomas. O desbalanço entre as isoformas longas e curtas do Ikaros resulta em um início de transcrição alternativa do FGFR4, codificando uma isoforma truncada do gene (pdt- FGFR4) que foi associada a tumores hipofisários maiores e mais invasivos. A isoforma curta Ik6 promove a expressão do fator anti-apoptótico Bcl-XL in vitro, um efeito independente da interação com as isoformas longas. Além disso, um polimorfismo do FGFR4, com substituição da glicina por arginina no códon 388 (G388R), tem sido associado à evolução desfavorável em vários tipos tumorais humanos. Objetivos: Analisar a expressão do Bcl-XL, das isoformas do Ikaros (Ik1+Ik2/Ik total) e do FGFR4 em corticotropinomas humanos. Avaliar a freqüência dos genótipos do códon 388 do FGFR4 nos pacientes com doença de Cushing e sua associação com a evolução pósoperatória após a primeira cirurgia transesfenoidal. Métodos: Noventa e sete pacientes com diagnóstico de doença de Cushing foram estudados. Os dados clínicos, hormonais e histopatológicos foram avaliados retrospectivamente. O estudo da expressão do Bcl-XL, do Ikaros, e do FGFR4 foi realizado por PCR em tempo real em 20 amostras de corticotropinomas, sendo dois tumores correspondentes à síndrome de Nelson. A determinação dos genótipos no códon 388 do FGFR4 foi realizada nos 97 pacientes e em 103 indivíduos controles, por PCR de fragmento do exon 9 do gene FGFR4 seguida de digestão com a enzima de restrição BstNI. A evolução pós-operatória (remissão/recidiva) da doença de Cushing foi avaliada em 76 pacientes. Foram considerados em remissão aqueles pacientes com níveis normais de cortisol urinário durante todo o primeiro ano após a cirurgia, na ausência de reposição hormonal, bem como os que necessitaram de reposição com glicocorticóide no mesmo período. Resultados: Dos 76 pacientes submetidos à primeira cirurgia transesfenoidal, a remissão pós-operatória ocorreu em 68,4% dos pacientes. Treze pacientes (25%) evoluíram com recidiva da doença de Cushing após remissão inicial. A expressão do Bcl-XL foi semelhante à hipófise normal na maioria das amostras tumorais [mediana (mín-máx): 1,36 (0,6 - 2,70)]. Aumento da expressão das isoformas longas do Ikaros foi detectado em 40% dos tumores, enquanto as isoformas curtas corresponderam a mais de 50% da expressão do Ikaros em apenas 3 casos, não havendo associação da expressão do Ikaros com qualquer das variáveis analisadas. O aumento da expressão do FGFR4 foi detectado em 8/18 (44,4%) dos corticotropinomas com doença de Cushing, havendo associação entre a hiperexpressão do FGFR4 e a menor freqüência de remissão pós-operatória da doença de Cushing (p = 0,009). A distribuição genotípica do polimorfismo G388R foi semelhante entre pacientes e controles. O genótipo glicina em homozigose (Gly/Gly) não foi associado à menor frequência de remissão pós-operatória da doença, no entanto, uma freqüência maior de recidiva pós-operatória foi encontrada no grupo de pacientes Gly/Gly (p = 0,019). O genótipo Gly/Gly foi ainda associado à redução da sobrevida livre de doença (hazard ratio [HR], 6,91; Intervalo de Confiança (IC) de 95%, 1,14 a 11,26; p = 0,028). Outras variáveis que se associaram significativamente com maior freqüência de recidiva foram: tamanho e grau de invasão tumoral de acordo com a classificação de Hardy modificada (p = 0,017), o sexo masculino (p = 0,033), a não confirmação Imuno-histológica do tumor produtor de ACTH (p = 0,026) e os valores de cortisol > 2 ?g/dL no pós-operatório precoce (p = 0,01). Conclusões: A expressão normal detectada do Bcl-XL e das isoformas curtas do Ikaros, na maioria das amostras tumorais, sugere a não participação destes fatores na patogênese dos tumores corticotróficos. O aumento da expressão do FGFR4 e o genótipo glicina em homozigose foram associados, respectivamente, à menor freqüência de remissão e maior recidiva pós-operatória da doença de Cushing. Estes resultados sugerem que o FGFR4 pode ter um papel na progressão dos tumores corticotróficos favorecendo a persistência e/ou recidiva da doença de Cushing. / Introduction: The mechanisms involved in the molecular pathogenesis of corticotroph pituitary tumors are complex, heterogeneous and in most cases remain unknown. Changes in the expression of components of Ikaros (Ik) pathway, such as receptor 4 of fibroblast growth factor (FGFR4), have been detected in pituitary tumors including corticotropinomas. Imbalance between long and short Ik isoforms results in alternative transcription initiation of FGFR4 and encodes a truncated isoform of the gene (pdt-FGFR4) which was associated with larger and more invasive pituitary tumors. The Ik6 short isoform promotes Bcl-XL expression in vitro, an effect independent of the interaction with the long isoforms. In addition, a polymorphism of FGFR4 gene, the substitution of glycine by arginine at codon 388 (G388R), has been associated with adverse outcome in several human tumor types. Objectives: To analyze the expression of Bcl-XL, Ikaros isoforms (Ik1 + Ik2/Ikaros total), and FGFR4 in human corticotropinomas. To determine the frequency of each genotype at codon 388 of FGFR4 in patients with Cushing\'s disease and its association with the postoperative outcome after the first transsphenoidal surgery. Methods: Ninety-seven patients with Cushing\'s disease were evaluated. Clinical, hormonal and histopathological findings were assessed retrospectively. The expression of Bcl-XL, Ikaros and FGFR4 were evaluated by real-time PCR in 20 samples of corticotropinomas, including two samples of Nelson\'s syndrome. The FGFR4 genotype was determined in the 97 patients and 103 control subjects by PCR fragment of exon 9 of the FGFR4 gene, followed by digestion with the BstNI restriction enzyme. The postoperative outcome (remission/relapse) of Cushing\'s disease was assessed in 76 patients. The patients with normal urinary cortisol levels during the first year after surgery, in the absence of hormone replacement therapy, and those who required glucocorticoid replacement within the same period were considered in remission. Results: Of the 76 patients who underwent the first transsphenoidal surgery, remission was achieved in 68.4% of patients. Thirteen patients (25%) developed recurrence of Cushing\'s disease after initial remission. The expression of Bcl-XL in the majority of tumor samples was similar to normal pituitary [median (min-max): 1.36 (0.6 - 2.70)]. Overexpression of long isoforms of Ik was detected in 40% of tumors, while the short isoforms represented more than 50% of the expression in only 3 samples. Ik expression was not associated with any of the variables analysed. FGFR4 transcripts were overexpressed in 8/18 (44.4%) of corticotropinomas with Cushing\'s disease. There was an association between the overexpression of FGFR4 and lower postoperative remission rate (p = 0.009). The FGFR4 genotype distribution at codon 388 was similar between control individuals and patients. The glycine homozygous genotype (Gly/Gly) was not associated with lower remission rate. However, a higher frequency of postoperative recurrence was found in the Gly/Gly group (p = 0.019). The Gly/Gly genotype was also associated with reduced disease-free survival (hazard ratio [HR] 6.91, confidence interval (CI) 95%, 1.14 to 11.26; p = 0.028). Other variables that were significantly associated with higher frequency of recurrence were: size and tumor invasion according to modified Hardy classification (p = 0.017), male gender (p = 0.033), non-immuno-histological confirmation of ACTH secreting tumor (p = 0.026) and cortisol levels > 2 ?g/dL in the early postoperative period (p = 0.01). Conclusions: The normal expression of Bcl-XL and short isoforms of Ik in most samples suggest that these factors are not involved in the pathogenesis of corticotroph tumors. Overexpression of FGFR4 and the glycine homozygous genotype were associated with lower frequency of remission and higher postoperative recurrence of Cushing\'s disease, respectively. These results suggest that FGFR4 may play a role in progression of corticotroph tumors favoring the persistence and/or recurrence of Cushing\'s disease.

O objetivo deste trabalho foi avaliar in vitro e in situ o potencial erosivo do suco de laranja modificado por cálcio e alguns polímeros alimentares. Este estudo foi dividido em quatro fases. Na primeira, as seguintes substâncias: lactato de cálcio (Ca), goma xantana (XG), hexametafosfato de sódio (HMP), tripolifosfato de sódio (STP), pirofosfato de sódio (PP) e suas combinações, foram adicionadas a um suco de laranja, disponível comercialmente, criando 15 sucos modificados. O suco sem aditivos foi utilizado como controle negativo (C-), e um suco de laranja modificado com cálcio (disponível comercialmente), como controle positivo (C+). Os sucos tiveram o seu potencial erosivo avaliado com o método do pH-stat. A variável resposta foi o volume de titulador necessário para manter o pH dos sucos nos valores iniciais. Após, seis sucos foram selecionados e testados na segunda fase, com um modelo de ciclagem de erosão-remineralização. Na terceira fase, os episódios de erosão e de remineralização foram estudados independentemente. A variável resposta para essas duas fases foi a microdureza de superfície (MDS) para esmalte, e a perfilometria ótica, para esmalte e dentina. Na quarta fase, os sucos Ca, Ca+HMP e HMP, mais os controles, foram testados com um modelo de erosão in situ, crossover, cego, de 5 fases, envolvendo 10 voluntários. Em cada fase, os voluntários inseriam aparelhos palatinos contendo espécimes de esmalte na boca e, após 5min, realizavam os desafios erosivos nos tempos experimentais de 0 (controle), 10, 20 e 30min. Dois espécimes eram aleatoriamente removidos dos aparelhos, após cada tempo. A variável resposta foi a alteração da microdureza de superfície (em %). Antes dos procedimentos clínicos, em cada fase, os voluntários realizaram um teste cego de sabor, onde o suco modificado designado a aquela fase foi comparado cegamente com C-. Na primeira fase, todos os aditivos foram capazes de reduzir o potencial erosivo do suco, com exceção da adição de XG isoladamente. Na segunda fase, não houve perda de estrutura de esmalte detectável quando Ca, HMP e Ca+HMP foram adicionados ao suco; XG, STP e PP apresentaram uma perda de esmalte similar ao grupo C-. Ca+HMP apresentaram a menor redução da MDS, seguido por Ca; todos os outros grupos apresentaram uma redução da MDS similar ao grupo C-. Para dentina, somente Ca+HMP apresentou uma redução na perda de estrutura. Na terceira fase, Ca, HMP e Ca+HMP protegeram contra erosão e nenhum dos compostos interferiu com o processo de remineralização. Na quarta fase, Ca e Ca+HMP reduziram a erosão, sem diferenças significantes entre esses grupos; o HMP não apresentou efeito protetor. 5/10 voluntários notaram uma diferença no sabor de C+, 4/10 para Ca e 2/10 para C-. Conclui-se que, in vitro, tanto o HMP, quanto o Ca, nas concentrações testadas, reduziram a erosão causada pelo suco em esmalte e a combinação desses aditivos aumentou seus efeitos protetores. Para dentina, apenas a combinação Ca+HMP reduziu a erosão. In situ, Ca reduziu a erosão provocada pelo suco, porém, alterações no sabor foram notadas por alguns voluntários. HMP não apresentou efeito protetor. / The aim of this study was to evaluate in vitro and in situ the erosive potential of the orange juice modified with calcium and some food-approved polymers. This study was divided into four fases. In the first, the following substances: calcium lactate (Ca), xanthan gum (XG), sodium hexametaphosphate (HMP), sodium trypoliphosphate (STP), sodium pyrophosphate (PP) and some of their combinations were added to a commercially available orange juice, creating 15 modified juices. The juice without additives was used as a negative control (C-) and a commercially available calcium-modified juice as positive control (C+). These juices were tested for erosive potential using pH-stat. The response variable was the volume of titrant needed to maintain the pH of the juices in their baseline values. After, six selected juices were tested in the second phase with an erosion-remineralization cycling model. In the third phase, the erosion and remineralization episodes were tested independently. The reponse variable for these phases was surface microhardness for enamel and optical perfilometry for enamel and dentin. In the fourth phase, the juices Ca, Ca+HMP and HMP, plus the controls were tested with an erosion in situ model, consisting of a 5-phase, single blind crossover clinical trial involving 10 subjects. In each phase, subjects inserted custom-made palatal appliances containing enamel specimens in the mouth and, after 5 min equilibration period, performed erosive challenges for total of 0 (control), 10, 20, and 30 min. Two specimens were randomly removed from the appliances, after each challenge period. The reponse variable was the percentage of surface microhardness change. Before the procedures, in each phase, the subjects performed a taste test, where the modified juice assigned to that phase was blindly compared to C-. In first phase, all the additives were able to reduce the erosive potential of the juice, except the addition of XG alone. In the second phase, no detectable enamel loss was observed when Ca, HMP and Ca+HMP were added to the juice; XG, STP and PP had enamel loss similar to C-. Ca+HMP showed the lowest reduction in the surface microhardness, followed by Ca;all the other groups presented a reduction in the surface microhardness similar to C-. For dentin, only Ca+HMP reduced surface loss. In the third phase, Ca, HMP and Ca+HMP protected against erosion; and none of the tested compounds seemed to interfere with the remineralization process. In the fourth phase, Ca and Ca+HMP reduced erosion, with no difference between them. HMP did not show any protective effect. 5/10 subjects noticed a difference in the taste of C+; 4/10 for Ca; and 2 /10 for C-. In conclusion, in vitro, HMP and Ca, in the concentrations tested, reduced erosion on enamel and this effect was enhanced by their combination. For dentin, only the combination Ca+HMP caused a significant reduction. In situ, Ca reduced the erosion caused by the juice; however, taste changes were noticed by some volunteers. HMP did not show any protective effect.

Climate exerts considerable control on wildfire regimes, and climate and wildfire are both major drivers of forest growth and succession in interior Northwest forests. Estimating potential response of these landscapes to anticipated changes in climate helps researchers and land managers understand and mitigate impacts of climate change on important ecological and economic resources. Spatially explicit, mechanistic computer simulation models are powerful tools that permit researchers to incorporate climate and disturbance events along with vegetation physiology and phenology to explore complex potential effects of climate change over wide spatial and temporal scales. In this thesis, I used the simulation model FireBGCv2 to characterize potential response of fire, vegetation, and landscape dynamics to a range of possible future climate and fire management scenarios. The simulation landscape (~43,000 hectares) is part of Deschutes National Forest, which is located at the interface of maritime and continental climates and is known for its beauty and ecological diversity. Simulation scenarios included all combinations of +0��C, +3��C, and +6��C of warming; +10%, ��0%, and -10% historical precipitation; and 10% and 90% fire suppression, and were run for 500 years. To characterize fire dynamics, I investigated how mean fire frequency, intensity, and fuel loadings changed over time in all scenarios, and how fire and tree mortality interacted over time. To explore vegetation and landscape dynamics, I described the distribution and spatial arrangement of vegetation types and forest successional stages on the landscape, and used a nonmetric multidimensional scaling (NMS) ordination to holistically evaluate overall similarity of composition, structure, and landscape pattern among all simulation scenarios over time. Changes in precipitation had little effect on fire characteristics or vegetation and landscape characteristics, indicating that simulated precipitation changes were not sufficient to significantly affect vegetation moisture stress or fire behavior on this landscape. Current heavy fuel loads controlled early fire dynamics, with high mean fire intensities occurring early in all simulations. Increases in fire frequency accompanied all temperature increases, leading to decreasing fuel loads and fire intensities over time in warming scenarios. With no increase in temperature or in fire frequency, high fire intensities and heavier fuel loads were sustained. Over time, more fire associated with warming or less fire suppression increased the percentage of the landscape occupied by non-forest and fire-sensitive early seral forest successional stages, which tended to increase the percentage of fire area burning at high severity (in terms of tree mortality). This fire-vegetation relationship may reflect a return to a more historical range of conditions on this landscape. Higher temperatures and fire frequency led to significant spatial migration of forest types across the landscape, with communities at the highest and lowest elevations particularly affected. Warming led to an upslope shift of warm mixed conifer and ponderosa pine (Pinus ponderosa) forests, severely contracting (under 3�� of warming) or eliminating (under 6�� of warming) area dominated by mountain hemlock (Tsuga mertensiana) and cool, wet conifer forest in the high western portion of the landscape. In lower elevations, warming and fire together contributed to significant expansion of open (<10% tree canopy cover) forest and grass- and shrubland. The compositional changes and spatial shifts simulated in the warming scenarios suggest that climate change is likely to significantly affect forests on this landscape. Warming and associated fire also tended to increase heterogeneity of forest structural stages and landscape pattern, resulting in a more diverse distribution of structural stages, especially in lower elevations, and a more divided landscape of smaller forest stands. The NMS ordination emphasized the dissimilarity between the severe +6�� scenarios and the other two temperature scenarios. The +0�� and +3�� scenarios differed from each other in composition (mainly because cool forest was lost in the +3�� scenarios), but within a given level of fire suppression they remained remarkably similar in terms of overall composition, structure, and landscape pattern, while the +6�� scenarios separated noticeably from them. Such decisive differences suggest that under the simulated ranges of precipitation and fire suppression, the interval between 3 and 6 degrees of warming on this landscape may capture an ecological threshold, or tipping point. Additional simulation research that incorporates (for example) management actions, insects and pathogens, and a wider array of precipitation scenarios could help illuminate more clearly the possible range of future landscape conditions. Still, these results provide a glimpse of potential divergent outcomes on this important landscape under possible future climates, and suggest that these forests will undergo considerable changes from both historical and current conditions in response to higher temperatures expected in this area. Some changes may be inevitable with warming, such as the upslope shift of warm forest types, but careful planning for fire and fuels management might allow land managers to modulate fire behavior and steer vegetation dynamics toward the most desirable outcome possible. / Graduation date: 2013

Dissertation (Ph.D.)--University of South Florida, 2009. / Title from PDF of title page. Document formatted into pages; contains 164 pages. Includes vita. Includes bibliographical references.

In eastern Kentucky, as in much of central Appalachia, current local storylines narrate the frictions and contradictions involved in the structural transition from a post-WWII Fordist industrial economy and a Keynesian welfare state to a Post-Fordist service economy and Neoliberal hollow state, starving for energy to sustain consumer indulgence (Jessop, 1993; Harvey, 2003; 2005). Neoliberalism is the ideological force redefining the “societal infrastructure of language” that legitimates this transition, in part by redefining the key terms of democracy and citizenship, as well as valorizing the market, the individual, and technocratic innovation (Chouliaraki & Fairclough, 1999; Harvey, 2005). This project develops a perspective that understands cancer prevention and control in Appalachiaas part of the structural transition that is realigning community social ties in relation to ideological forces deployed as “commonsense” storylines that “lubricate” frictions that complicates the transition.

The South African coastal and marine environment is an essential ecologic and economic asset. Its associated services and products are substantially contributing to economic growth and sustainable development of the country. However, it is internationally and nationally recognised that land-based marine pollution (LBMP) is the most important single risk to the health and sustainability of coastal and marine waters and the associated ecosystems. The regulation of LBMP at the national level is still difficult and challenging. The issue of LBMP management has only recently been introduced in South Africa with the development of the National Programme of Action to Protect Marine Environment from Land-based Activities, 2008. South Africa is only starting to consider the question of LBMP regulation. This thesis aims to conduct a critical analysis of the South African regulatory framework pertaining to LBMP in comparison to international best practice and the French regulatory framework, in order to identify the key South African challenges in this regard and to make recommendations to address them. In order to do so, this research commences by providing an analysis of LBMP and the theoretical foundations associated with LBMP regulation, as promoted by international best practice. The study identifies and assesses the main regulatory features to be considered in the development, implementation and/or assessment of a regulatory framework pertaining to LBMP. These features will form the methodological framework to conduct the comparative legal assessment between the French and South African regulatory frameworks pertaining to LBMP. This thesis then provides a detailed and thorough legal analysis of the French and South African regulatory frameworks pertaining to LBMP using the methodological framework developed using guidance from international best practice. Finally, based on lessons learnt from the comparative legal study, this study concludes with a set of recommendations for the South African context. / Thesis (LL.D.)--North-West University, Potchefstroom Campus, 2011.

The South African coastal and marine environment is an essential ecologic and economic asset. Its associated services and products are substantially contributing to economic growth and sustainable development of the country. However, it is internationally and nationally recognised that land-based marine pollution (LBMP) is the most important single risk to the health and sustainability of coastal and marine waters and the associated ecosystems. The regulation of LBMP at the national level is still difficult and challenging. The issue of LBMP management has only recently been introduced in South Africa with the development of the National Programme of Action to Protect Marine Environment from Land-based Activities, 2008. South Africa is only starting to consider the question of LBMP regulation. This thesis aims to conduct a critical analysis of the South African regulatory framework pertaining to LBMP in comparison to international best practice and the French regulatory framework, in order to identify the key South African challenges in this regard and to make recommendations to address them. In order to do so, this research commences by providing an analysis of LBMP and the theoretical foundations associated with LBMP regulation, as promoted by international best practice. The study identifies and assesses the main regulatory features to be considered in the development, implementation and/or assessment of a regulatory framework pertaining to LBMP. These features will form the methodological framework to conduct the comparative legal assessment between the French and South African regulatory frameworks pertaining to LBMP. This thesis then provides a detailed and thorough legal analysis of the French and South African regulatory frameworks pertaining to LBMP using the methodological framework developed using guidance from international best practice. Finally, based on lessons learnt from the comparative legal study, this study concludes with a set of recommendations for the South African context. / Thesis (LL.D.)--North-West University, Potchefstroom Campus, 2011.

Along with industrial and economic growth there is a persistent risk of permanently increasing air pollution. Air pollution has especially grown in the second half of the 20th century due to intense development of energy, industry and transport sectors. These pollution sources still remain the largest air polluters. Solvents, paints, glues, ink and other substances, emitting volatile organic compounds to air are used in such industries like reel, metal and wood coating, covering with glue sticks, footwear production, production of pharmaceutical products, printing, dry (chemical) surface cleaning etc. Emissions of volatile organic compounds make harm both to people and environment as well as damage the ozone layer. Volatile organic compounds also affect smog formation and green house effect. In the paper it is hypothesised that after implementation of EU legislation, observing the given emission limit values, improving technologies and implementing new treatment technologies, applying the measures to reduce pollution with volatile organic compounds and replacing the materials, emitting volatile organic compounds, with less polluting ones or those without pollution, air emission of volatile organic compounds will reduce dramatically. This master’s paper reviews the measures and ways to manage pollution with volatile organic compounds (VOC): directives and their requirements, transferred to the national laws of the member states, addressed to solve the VOC pollution problem... [to full text]

Dissertation (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 187 pages. Includes vita. Includes bibliographical references.