Orientador: Leonardo Fernandes Fraceto / Resumo: Considerando os danos causados pelas arboviroses disseminadas pelo vetor Aedes aegypti, o Brasil vem sofrendo, porém buscando estratégias de combate a tal realidade, uma vez que teve um custo total de R$ 2,3 bilhões, apenas no ano de 2016, distribuídos no combate ao vetor, em inseticidas e larvicidas e nos custos diretos e indiretos. Valor esse, correspondente a cerca de 2 % do montante investido na Saúde no mesmo ano. Esse quadro ressalta a necessidade de novas ações e táticas na procura de minimizar a situação, como a elaboração de repelentes que possuam um sistema mais efetivo no combate do vetor responsável pela disseminação do vírus Zika, da Dengue, do Chikungunya e da Febre Amarela. Hoje, sabe-se que um dos ativos repelentes mais eficientes é a icaridina, porém, ela pode causar intoxicação nos organismos não alvos. Também, tem-se o geraniol, que é um ativo de origem botânica, bastante eficaz em sua atuação repelente. E, na busca de aprimorar a ação dos ativos, existe a opção da utilização de sistemas de liberação lenta, o que resulta no aumento da faixa de efeito biológico do ativo de interesse, devido ao prolongamento da liberação do mesmo. No entanto, nota-se a existência de intensa preocupação e responsabilidade na elaboração de sistemas que, além de se mostrarem mais eficientes, sejam, também, focados na diminuição de possíveis mecanismos de resistência que o vetor possa desenvolver. Dessa forma, o presente estudo teve por objetivo o desenvolvimento de sistemas de l... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Considering the damage caused by arboviruses disseminated by the vector Aedes aegypti, Brazil has been suffering, but seeking strategies to combat this reality, since it had a total cost of R$ 2.3 billion, only in the year 2016, distributed in combat to the vector, in insecticides and larvicides and in direct and indirect costs. This amount corresponds to approximately 2 % of the amount invested in Health in the same year. This scenario highlights the need for new actions and tactics in order to minimize the situation, such as the elaboration of repellents that have a more effective system in the fight against the vector responsible for the spread of the Zika virus, Dengue, Chikungunya and Yellow Fever. It is now known that one of the most effective repellent actives is icaridin, but it can cause intoxication in non-target organisms. Also, one has the geraniol, that is an active of botanical origin, quite effective in its action repellent. And, in the search to improve the action of the assets, there is the option of using slow release systems, which results in the increase of the biological effect range of the asset of interest, due to the prolongation of the release of the same. However, we note the existence of intense concern and responsibility in the elaboration of systems that, in addition to being more efficient, are also focused on the reduction of possible mechanisms of resistance that the vector can develop. Thus, the present study aimed at the development of sustai... (Complete abstract click electronic access below) / Mestre

Att släppa musik, alltså att offentliggöra musik, är något som är lätt att tänka sig enbart är en rolig angelägenhet för artister och musikproducenter, men hur mår vi som gör det egentligen i processen innan, under och efter att musiken har släppts? Många uttrycker rädslor och prestationsångest som dominerande känslor snarare än glädje och upprymdhet. Jag kände mig intresserad av att undersöka om det fanns flera som kände som jag, att det inte är okomplicerat att släppa musik, och vad folk har för strategier för att hantera det som känns jobbigt. Genom att undersöka min egen process när jag släpper musik samt skicka ut frågor till andra som gör det har jag försökt ta reda på om det finns sätt som får oss att må bättre eller sämre. Syftet har varit att skaffa mig erfarenheter för mina framtida släpp, samt möjligheten att kunna dela med mig av dem till andra. I min undersökning har jag fått mina föraningar att det inte bara är jag som brottas med mitt mående kring att släppa musik bekräftade. Det verkar vara väldigt vanligt. En av de tydligaste känslor som uttryckts är rädslan för vad andra ska tycka om dem som person när de försöker sprida sin musik, snarare än om musiken i sig. En annan är att väldigt många brottas med prestationsångest och känslor av otillräcklighet. Några saker som däremot verkar få folk att må bättre, inklusive mig själv är att inte göra allt arbete kring ett låtsläpp själv, att ge plats i livet för annat än musiken och att ha ett nytt projekt på gång så fort ett släpp är slutfört. / <p>Låten som det konstnärliga arbetet berör:https://www.youtube.com/watch?v=UXoK5FjExBk</p>

Visando à obtenção de biomateriais que atuem como suporte que direcione e auxilie o processo de regeneração tecidual, materiais poliméricos naturais como a quitosana e o colágeno têm sido estudados. A utilização da quitosana e do colágeno se baseia em propriedades como: biocompatibilidade, ação antimicrobiana, capacidade de ativar macrófagos, estimular a proliferação celular e baixa antigenicidade. Também se tem buscado a utilização de fitoterápicos como, por exemplo, o extrato de semente de uva que no processo de cicatrização tecidual, atua estimulando o fator de crescimento endotelial vascular (angiogênese) e proliferação de fibroblastos. Este trabalho teve como objetivo o preparo e caracterização de esponjas de quitosana/colágeno e quitosana/colágeno/glicerol (1:1) e (1:2) contendo extrato de semente de uva. A caracterização foi feita por calorimetria exploratória diferencial (DSC), espectroscopia de absorção no infravermelho (FTIR), microscopia eletrônica de varredura (MEV), absorção de tampão fosfato salino (PBS) e liberação in vitro do extrato de semente de uva. Estudos de DSC mostraram que ocorre um aumento na temperatura de desnaturação do colágeno com o aumento da concentração do extrato, indicando um efeito de reticulação que é mais pronunciado nas esponjas (1:2) e na presença de glicerol. Os espectros FTIR mostraram que ocorre um deslocamento das bandas de amida I e II devido à interferência do anel aromático presente no extrato. O aumento da proporção de colágeno, de extrato e a adição do glicerol contribuíram para o aumento no número e diâmetro dos poros das esponjas, observados por MEV. A presença do extrato aumenta a capacidade de absorção de PBS das esponjas, o aumento da concentração de extrato aumenta a velocidade de absorção, mas diminui sua capacidade de absorção. Ensaios de liberação in vitro mostraram que as quantidades de extrato liberado em meio PBS aumentaram até as primeiras 24 h. A maior porcentagem de liberação ocorreu para a esponja Q1C2E2 (44%). A presença do glicerol influiu na liberação do extrato, diminuindo-a. Os valores de n mostraram que a liberação do extrato ocorreu por difusão, no qual os valores estão próximos 0,5 caracterizando um mecanismo de transporte Fickiano, exceto para as esponjas Q1C1E05 e Q1C2GE05, sendo por transporte anômalo (0,5<n<0,89). / Aiming to obtain biomaterials that act as a support to direct and assist the process of tissue regeneration, natural polymeric materials such as collagen and chitosan have been used. The use of chitosan and collagen is based on properties such as biocompatibility, antimicrobial activity, low antigenicity, ability to activate macrophages and stimulate cell proliferation. The use of herbal medicines, for example, grape seed extract in the process of tissue healing, acts by stimulating vascular endothelial growth factor (angiogenesis) and fibroblast proliferation. This work aimed to the preparation and characterization of chitosan/collagen and chitosan/collagen/glycerol sponges (1:1) and (1:2) containing grape seed extract. The characterization was made by differential scanning calorimetry (DSC), infrared absorption spectroscopy (FTIR), scanning electron microscopy (SEM), absorption of phosphate buffered saline (PBS) and in vitro release of grape seed extract. DSC studies have shown that there is an increase in denaturation temperature of collagen with increasing extract concentration, indicating a crosslinking effect that is more pronounced in the sponges (1:2) in the presence of glycerol. The FTIR spectra show that there is a displacement of bands I and amide II due to interference of the aromatic ring present in the extract. Increasing the proportion of collagen, extract and addition of glycerol contributed to the increase in the number and diameter of the pores of the sponges, observed by SEM. The presence of the extract increases the absorption capacity of PBS in the sponges, the concentration of the extract increases the absorption rate, but decreases its absorbent capacity. In vitro release tests showed that the released amounts of extract increased up to 24 h. The highest percentage of release was observed for the sponge Q1C2E2 (44%). The presence of glycerol influenced the release of the extract, decreasing it. The values of n showed that the release occurred by diffusion of the extract, in which the values are close to 0.5 featuring a Fickian transport mechanism, except for the sponges Q1C1E05 and Q1C2GE05, that occurred by anomalous transport (0.5 <n<0.89).

O uso de materiais de revestimento na agricultura se constitui em uma das mais importantes aplicações de polímeros, principalmente, no encapsulamento da ureia. Devido a seu elevado conteúdo de nitrogênio entre 44 a 46 % em massa, a ureia leva muita vantagem na adubação nitrogenada. A escolha recaiu sobre um sistema polimérico acrilato incorporando vinhaça, melaço e carbonato de cálcio (aditivo inorgânico), sendo o foco deste sistema reter e liberar, controladamente, os nutrientes. Foram feitos bio-ensaios usando três tipos de fertilizantes ureia, material comercial e ureia revestida, sendo possível avaliar o filme como um sistema de revestimento bastante eficaz. Para determinar a quantidade de íon amônio (NH4+), empregaram-se técnicas de análise simples como a micro-destilação e micro-volumetria. Além disso, foi aplicado métodos instrumentais FTIR, TG, DTG, DSC, MEV e EDX para caracterizar a estrutura e morfologia do material polimérico. Os resultados mostraram que a presença do composto inorgânico (CaCO3) no compósito, tem um papel relevante na estrutura aniônica do polímero-base, este atua na retenção de cargas opostas por interações eletrostáticas, controlando a taxa de liberação de nitrogênio como íon amônio, mostrando que o polímero revestido presenta melhor eficiência e desempenho na liberação em quanto ao polímero comercial e a ureia. A opção pela investigação de fertilizantes revestidos foi devido à relevância do tema e do impacto na sustentabilidade ambiental e econômica. / The use of coating materials in agriculture constitutes one of the most important applications of polymers, mainly in the encapsulation of urea. Due to its high nitrogen content between 44-46% by weight, urea takes much advantage in nitrogen fertilization. The choice fell on a polymeric acrylate system incorporating vine, molasses and calcium carbonate (inorganic additive), the center of this system hold and release controlled nutrients. Bioassays were performed using three types of fertilizer urea, commercial material and coated urea being possible to evaluate the film as a very effective coating system. To determine the amount of ammonium ion (NH4+) simple analysis techniques, such as micro-distillation and micro-volumetric were employed. In addition, instrumental methods, including FTIR, TG, DTG, DSC, MEV and EDX were applied to characterize the structure and morphology of the polymeric material. The results showed that the presence of the inorganic compound (CaCO3) in the composite plays an important role in the structure of anionic polymer base, it acts on the retention of opposite charge by electrostatic interaction by controlling the release rate of nitrogen as ammonium ion, showing the improved efficiency and performance of coated polymer in the release compared to the commercial polymer and the urea. The option for the investigation of coated fertilizers was due to the relevance of the issue and the impact on economic and environmental sustainability.

É analisado o desempenho de um motor de ignição por compressão turboalimentado por uma mistura temária de combustíveis (diesel, biodiesel e etanol) através do comportamento do motor operando com um combustível principal, o qual poderá ser o diesel ou biodiesel ou misturas destes dois, com e sem sua substituição parcial por etanol no coletor de admissão. A análise do desempenho é feita através das curvas de torque, potência, rendimento térmico e consumo específico de combustível. A combustão do motor é estudada através de um programa simulador que utiliza um modelo zero-dimensional, que avalia a taxa de liberação de calor durante a combustão e tem como dado de entrada a curva de evolução da pressão dentro do cilindro. Faz-se a identificação e quantificação do fenômeno da detonação utilizando análise espectral, através do sinal de pressão da câmara de combustão, para o motor operando com diversas misturas combustíveis. São analisadas também as emissões gasosas do motor com as misturas, e a viabilidade técnica do uso de biodiesel em motores de ignição por compressão, além de um estudo geral sobre o uso do éster de óleo vegetal. / The performance of a three-fuel system (diesel, biodiesel and ethanol) turbocharged compression-ignition engine is analyzed, through the engine behavior supplied by mixtures of diesel or biodiesel or mixtures of these fuels with ethanol in the intake manifold. The performance analysis is made by torque, power, specific fuel consumption and thermal efficiency curves. The engine combustion is studied by a simulator program that uses a zero-dimensional model, that evaluate the heat release rate during the combustion and it has as input data the pressure evolution curves inside the cylinder. The knocking phenomenon is studied by spectral analysis. The pollutant gases emissions and the technical viability of the utilization of biodiesel also are analyzed, beyond a general study about of vegetal oil ester.

A lagoa do Taquaral localiza-se no interior do Parque Portugal, no bairro do Taquaral-Campinas (SP). Foi construída em 1968, por meio do represamento do Córrego Guanabara, principalmente para fins recreativos. Apesar de ter recebido a influência direta de descargas de esgotos durante muitos anos e ainda hoje existirem despejos clandestinos, tem sido pouco estudada. Com a finalidade de conhecer a limnologia e o processo de eutrofização desenvolvido na mesma, foi realizado um estudo incluindo: morfometria da lagoa, determinação da taxa de sedimentação com o uso de armadilhas de sedimentação, determinação da taxa de liberação de fósforo do sedimento, caracterização física, química e biológica da coluna da água e caracterização do sedimento. As amostragens foram realizadas em 2000, considerando, (1) o final do período chuvoso (março), (2) o início do período de estiagem (maio) e (3) o final do período de estiagem (agosto). Com base na morfometria da lagoa, foram escolhidos dois pontos de coleta, sendo um localizado na saída da água, (próximo ao vertedouro, com uma profundidade de 5,70 metros) e outro na região central da lagoa (com uma profundidade de 3,50 metros). Experimentos \"in situ\" com armadilhas foram realizados para: 1) determinar as taxas de sedimentação de sólidos totais, matéria orgânica, inorgânica, clorofila a e fósforo, 2) determinar a liberação de fósforo do sedimento para a coluna da água. As armadilhas que mediram a liberação de fósforo e a sedimentação,permaneceram por um período de incubação de 48 horas. Paralelamente à incubação das armadilhas, foram efetuadas as medidas de temperatura, pH, condutividade, oxigênio dissolvido, penetração de luz, material em suspensão, clorofila \'a\' e feofitina, nutrientes totais e dissolvidos bem como análises das comunidades zooplanctônica e fitoplanctônica. Os resultados obtidos demonstraram valores mais elevados de deposição de material em suspensão no ) período chuvoso (taxa de sedimentação de 24.400 mg/m2.dia e 22.575 mg/m2.dia, nas estações 1 e 2, respectivamente). A maior contribuição do material em suspensão correspondeu à fração orgânica (entre 50 e 60%). A deposição de fósforo total e clorofila apresentaram um comportamento semelhante ao do material em suspensão, com valores máximos no período chuvoso. Para as outras variáveis consideradas, também verificaram-se diferenças temporais. Os dados obtidos para as taxas de sedimentação de material em suspensão e nutrientes, em comparação a outros sistemas, são considerados elevados, demonstrando o acelerado processo de eutrofização. Os resultados do ensaio de liberação de fósforo do sedimento para a coluna da água demonstraram uma liberação de 5 mg P/m2.dia. Entre a comunidade zooplanctônica, os rotíferos e os copépodos foram mais abundantes que os cladóceros. No fitoplâncton, o grupo mais abundante foi o das cianofíceas, seguido pelas clorofíceas. Os fatores externos (precipitação e vento) foram determinantes dos processos físicos, químicos e biológicos na lagoa. / Taquaral lagoon is situated in Portugal Park in Taquaral district in the Campinas city (SP). It was made on 1968 by damming the Guanabara Brook, for entertaining purposes. In spite of the results due to the sewer discharge during many years, which still exist nowadays (illegal discharges), that lagoon has been few studied. In order to know better the limnology and the eutrophication process in development in the lagoon an study was done including: morphology of the lagoon, determination of the sedimentation rates by using sedimentation traps, determination of phosphorus liberation rates from the sediment, physical, chemical and biological characterization of water column and the sediment characterization too. The samples were colleted during three period of the 2000: 1) at the end of rainy weather (March); 2) at the begin of the dry weather (may); 3) at the end of the dry weather (August). Based on the lagoon morphology, two places of collection were selected: one at the near center of the lagoon 3,50 meter deep and the other near the outlet of the water 5,70 meter deep. Experiments in situ, with traps were done in order to: 1) measure sedimentation rates of total solids, organic and inorganic material, chlorophyll a and phosphorous; 2) measure the phosphorus release from the sediment for the water column. The traps used for measuring the phosphorus release and the sedimentation remained for a long time in incubation (48 hours). At the same time of traps incubationthey were done the measurements of temperature, pH, conductivity, dissolved oxygen, light penetration, suspended material, chlorophyll a and feopigments, total and dissolved nutrients as well as analysisof zooplanktonic and phytoplanktonic communities. The resulting data showed higher values of suspended material deposition during the rainy weather (sedimentation rate about 24.400 mg/m2.d and 22.575 mg/m2.d, in the places 1 and 2, respectively). The higher contribution of suspended material is corresponding to the organic fraction (between 50 and 60%). The total phosphorus deposition and the chlorophyll, presented a conduct like the suspended material, with maximum values in the rainy weather. In respect to the other analyzed parameters, it was found a temporal difference. The resulting data for sedimentation rate of suspended material and nutrients, in comparison with other systems are considered high, which shows the high eutrophycation process. The results of the test of phosphorus release from the sediment to the water column demonstrated a release about 5 mg P/m2.d. In the zooplanktonic community, the rotifers and copepods were more abundant than the cladocerans. In the phytoplankton the group more abundant was that of cianoficeas, followed by cloroficeas. Outside influences, like wind and rain were determinatives for the physical, chemical and biological processes in the lagoon.

No description available.

As key components of flexible organic electronics, the synthesis of polythiophenes via less toxic and more cost-effective routes is demanded. An efficient synthetic route for the production of thienyl-containing homopolymers and copolymers has been developed. The synthetic approach consists of: i) the synthesis in high yield and high purity of thienyl borane monomers protected with N-methyliminodiacetic acid (MIDA) via C-H electrophilic borylation. This reaction uses a combination of inexpensive reagents BCl3, AlCl3, and 2,6-dichloropyridine (Cl2Py) for the regioselective electrophilic aromatic substitution of thiophenes, followed by addition of a second aprotic amine pre-esterification to reduce the Brønsted acidity of the reaction mixture. In situ esterification provided the desired thienyl MIDA boronateester monomers in one-pot at room temperature. ii) Subsequent Suzuki-Miyaura polymerisation of the synthesised monomers to produce well defined thienyl containing pie-conjugated polymers in high molecular weight and high yields. Key reaction parameters for successful Suzuki-Miyaura polymerisation of thienyl-derived MIDA boronate esters under mild temperatures (i.e., 55 °C in THF) were found: a) an optimal monomer:H2O:base ratio, which enables controlled hydrolysis of the BMIDA moiety into its corresponding boronic acid at appropriate rates for high fidelity polymerisation. b) Nature of the base, where K3PO4 provided the best results for production of homopolymers (e.g., rr-P3HT), or KOH which gave excellent results for the formation of copolymers across a range of electronically different comonomers (e.g., pCPDT-BT). Thus, it is demonstrated that the approach is a general strategy for the highly efficient production of thienyl containing pie-conjugated regioregular, regiosymmetric and Donor-Acceptor polymers.

Wong Lai Lok. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 162-173). / Abstracts in English and Chinese. / Abstract --- p.ii / Acknowledgements --- p.vi / Publications --- p.vii / Abbreviations --- p.viii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1. --- Historical Background --- p.2 / Chapter 1.2. --- Heterogeneity of mast cells --- p.3 / Chapter 1.3. --- Mast cell mediators --- p.5 / Chapter 1.3.1. --- Performed and granule associated mediators --- p.5 / Chapter 1.3.2. --- Newly synthesized mediators --- p.8 / Chapter 1.3.3. --- Cytokines --- p.10 / Chapter 1.4. --- Mast cell activation --- p.10 / Chapter 1.4.1. --- Aggregation of IgE Receptors (FcεRI) --- p.10 / Chapter 1.4.2. --- Activation of Phospholipase C --- p.11 / Chapter 1.4.3. --- Activation of Adenylate cyclase --- p.13 / Chapter 1.5. --- Adenosine --- p.14 / Chapter 1.5.1. --- Adenosine receptors --- p.14 / Chapter 1.5.2. --- Selective agonists and antagonists --- p.17 / Chapter 1.5.3. --- Physiological and pathological roles of adenosine --- p.20 / Chapter 1.6. --- Role of adenosine receptors in mast cell activation --- p.21 / Chapter 1.7. --- Aims of the study --- p.23 / Chapter Chapter 2 --- Materials and Methods --- p.30 / Chapter 2.1. --- Materials --- p.31 / Chapter 2.1.1. --- Mast cells secretagogues --- p.31 / Chapter 2.1.2. --- Anti-allergic compounds --- p.31 / Chapter 2.1.3. --- Adenosine receptor agonists and antagonists --- p.31 / Chapter 2.1.4. --- Materials for buffers --- p.32 / Chapter 2.1.5. --- Materials for rat sensitization --- p.32 / Chapter 2.1.6. --- Materials for histamine assay --- p.33 / Chapter 2.1.7. --- Miscellaneous --- p.33 / Chapter 2.2. --- Buffers and stock solutions --- p.34 / Chapter 2.2.1 --- Buffer ingredients --- p.34 / Chapter 2.2.2 --- Stock solutions --- p.34 / Chapter 2.3. --- Source of mast cells --- p.35 / Chapter 2.3.1. --- Animals --- p.35 / Chapter 2.3.2. --- Sensitization of animals --- p.35 / Chapter 2.3.3. --- Isolation of rat peritoneal mast cells --- p.35 / Chapter 2.3.4. --- Mast cells purification --- p.36 / Chapter 2.3.5. --- Cell counting --- p.36 / Chapter 2.4. --- General protocol for histamine release --- p.37 / Chapter 2.4.1. --- Histamine assay --- p.37 / Chapter 2.4.2. --- Antagonist studies --- p.38 / Chapter 2.4.3. --- Determination of histamine contents --- p.38 / Chapter 2.4.4. --- Calculation of histamine levels --- p.39 / Chapter 2.5. --- Statistical analysis --- p.40 / Chapter Chapter 3 --- "Effects of adenosine, adenosine deaminase and adenosine receptor agonists on mast cell activation" --- p.42 / Chapter 3.1. --- Introduction --- p.43 / Chapter 3.2. --- Materials and methods --- p.44 / Chapter 3.3. --- Results --- p.45 / Chapter 3.3.1. --- Effects of adenosine on anti-IgE induced histamine release in HEPES buffer --- p.45 / Chapter 3.3.2. --- Effects of NECA on anti-IgE induced histamine release in HEPES buffer --- p.46 / Chapter 3.3.3. --- Effects of CCPA on anti-IgE induced histamine release in HEPES buffer --- p.47 / Chapter 3.3.4. --- Effects of CPA on anti-IgE induced histamine release in HEPES buffer --- p.47 / Chapter 3.3.5. --- Effects of CGS21680 on anti-IgE induced histamine release in HEPES buffer --- p.48 / Chapter 3.3.6. --- Effects of Cl-MECA on anti-IgE induced histamine release in HEPES buffer --- p.49 / Chapter 3.3.7. --- Effects of adenosine deaminase on anti-IgE induced histamine release from rat peritoneal mast cells --- p.50 / Chapter 3.3.8. --- Effects of NECA on anti-IgE induced histamine release with and without adenosine deaminase --- p.50 / Chapter 3.3.9. --- Effects of Cl-MECA on anti-IgE induced histamine release with and without adenosine deaminase --- p.53 / Chapter 3.3.10. --- Effects of CV1808 on anti-IgE induced histamine release in HEPES buffer --- p.55 / Chapter 3.4. --- Discussion --- p.76 / Chapter 3.5. --- Conclusion --- p.83 / Chapter Chapter 4 --- Effects of adenosine receptor antagonists on mast cell activation --- p.88 / Chapter 4.1. --- Introduction --- p.89 / Chapter 4.2. --- Materials and methods --- p.90 / Chapter 4.3. --- Results --- p.91 / Chapter 4.3.1. --- Effects of A1 receptor antagonist DPCPX on modulations of anti-IgE induced histamine release by adenosine receptor agonists --- p.91 / Chapter 4.3.2. --- Effects of A2A receptor antagonist ZM241385 on modulations of anti-IgE induced histamine release by adenosine receptor agonists --- p.91 / Chapter 4.3.3. --- Effects of A2B receptor antagonist MRS 1706 on modulations of anti-IgE induced histamine release by adenosine receptor agonists --- p.92 / Chapter 4.3.4. --- Effects of A3 receptor antagonist VUF5574 on modulations of anti-IgE induced histamine release by adenosine receptor agonists --- p.93 / Chapter 4.3.5. --- Further characterization of adenosine mediated potentiation of anti-IgE histamine release using VUF5574 and ZM241385 --- p.93 / Chapter 4.3.6. --- Effects of theophylline on anti-IgE induced percentage potentiation in HEPES buffer --- p.95 / Chapter 4.4. --- Discussion --- p.130 / Chapter 4.5. --- Conclusion --- p.135 / Chapter Chapter 5 --- Further characterization of the effects of adenosine on mast cells --- p.138 / Chapter 5.1. --- Introduction --- p.139 / Chapter 5.2. --- Materials and methods --- p.141 / Chapter 5.3. --- Results --- p.142 / Chapter 5.3.1. --- Effects of anti-IgE induced histamine release in calcium free and HEPES buffers --- p.142 / Chapter 5.3.2. --- Effects of adenosine on anti-IgE induced histamine release in calcium free buffer --- p.143 / Chapter 5.3.3. --- Effects of adenosine deaminase on compound48/80 induced histamine release from rat peritoneal mast cells --- p.143 / Chapter 5.3.4. --- Effects of adenosine on compound 48/80 induced histamine release in HEPES buffer --- p.144 / Chapter 5.3.5. --- Effects of adenosine deaminase on A23187 induced histamine release from rat peritoneal mast cells --- p.144 / Chapter 5.3.6. --- Effects of adenosine on calcium ionophore A23187 induced histamine release in HEPES buffer --- p.145 / Chapter 5.3.7. --- Effects of adenosine receptor antagonists on inosine mediated enhancement of anti-IgE induced histamine release --- p.145 / Chapter 5.4. --- Discussion --- p.157 / Chapter 5.5. --- Conclusion --- p.160 / References --- p.162

Background: Abdominal solid organ transplantation has evolved from an experimental procedure to a well-established therapy within a few decades. This success is largely due to the introduction of calcineurin inhibitor immunosuppression. Tacrolimus is the most widely used calcineurin inhibitor but has a narrow therapeutic range which requires close drug monitoring to prevent both toxicity and inadequate immunosuppression. Previous studies in renal transplantation have shown that genetic polymorphisms, CYP3A5, CYP3A4*22 and ABCB1 can influence the bioavailability and pharmacokinetics of tacrolimus. These polymorphisms are closely linked to ethnicity and have never been studied in a Scottish population before. Additionally, increasing evidence suggests that high variability of tacrolimus is linked to increased graft loss in kidney transplant patients. Methods: 5889 subjects were genotyped for the genetic polymorphisms CYP3A5 A > G allele transition, CYP3A4*22 C > T and ABCB1 C > T transition. This included 4899 healthy individuals from Generation Scotland bio-resource and 990 patients who underwent renal, liver, or simultaneous pancreas kidney transplants or were organ donors. Tacrolimus dose, trough level and renal function were measured at 11 time points from date of transplant up to and including 12 months post-transplant. Clinical data including episodes of acute rejection, graft and patient survival were compared between the different genotypes. Separate analyses were undertaken for kidney, SPK transplants, as well as liver transplants, the latter looking at recipient and liver donor genotype. A separate cohort of 103 renal transplant patients converted from twice-daily to once-daily tacrolimus had their tacrolimus variability calculated and compared with graft survival. Results: The distribution of the 3 different genotypes of CYP3A5, CYP3A4*22 and ABCB1 were comparable with other Caucasian populations studied previously. In renal transplant recipient expression of the A allele (GA/AA) led to significantly increased dose requirements of tacrolimus and initially lower tacrolimus trough levels. The different genotypes of ABCB1 had no effect. Expression of a CYP3A4*22 T allele trended towards a lower tacrolimus dose requirement but this was not significant. There was no difference in renal function, graft survival or patient survival with any of the polymorphisms. SPK patients had comparable results. In the liver transplant patients, the donor genotype had a greater influence than the recipient one. The donors with CYP3A5 A allele expression had significantly higher tacrolimus dose requirements and lower initial tacrolimus levels. This was apparent to a lesser extent with the recipient expression of CYP3A5 and did not reach statistical significance at all time points. There was no significant difference in tacrolimus dose requirements or level with either donor or recipient expression of ABCB1 or CYP3A4*22. There was a significantly higher incidence of acute rejection in donor CYP3A5 A allele expressers of liver transplant patients in univariate and multivariate analysis. There was no significant different in acute rejection with ABCB1 or CYP3A4*22 genotype. No differences in graft or patient survival with either donor or recipient genotype of any of the 3 polymorphisms were noted. Conversion from twice-daily to once-daily tacrolimus in the first 12 months post-transplant reduced tacrolimus variability. Patients with high tacrolimus variability pre and post conversion had significantly greater graft loss than patients with low tacrolimus variability. Conclusion: CYP3A5 expression results in increased tacrolimus requirements to achieve adequate immunosuppression in renal transplant and SPK patients. Donor rather than recipient CYP3A5 expression is relevant for liver transplantation and dose requirements. There may be an association with donor CYP3A5 expression in liver transplant patients and acute rejection which needs further evaluation. ABCB1 and CYP3A4*22 do not appear to have a significant impact in any of the organ transplants. High tacrolimus variability is associated increased graft loss in renal transplant patients.