Adrenomedullin (ADM) is a 52 amino acid vasodilator peptide isolated, in 1993, from human pheochromocytoma. It has been demonstrated in the adrenal medulla of several mammalian species, including humans and rats. There have been conflicting results of the tissue distribution in the adrenal cortex. Hypertension is a complex trait with multiple genetic and environmental influences. Furthermore, salt-sensitive hypertension is characterized by a cluster of renal, hormonal, and metabolic derangements that might favour the development of cardiovascular and renal complications. Therefore the objective of this study was to investigate the adrenal distribution of ADM as well as to semi-quantitatively assess the adrenomedullin secretory capacity of the adrenal gland in the rat model of salt sensitive hypertension. Fourty-four male weanling rats were divided into 4 experimental groups and placed on a dietary regimen for 6 weeks viz. Dahl salt sensitive (DSS) rats on a high sodium diet (8% NaCl), DSS on a normal sodium diet (1% NaCl) matched with normotensive Dahl salt resistant (DSR) rats on the same dietary treatments. Blood pressure was monitored by tail-cuff readings and by the end of the six weeks, the DSS rats developed hypertension with tachycardia irrespective of the diet they were fed. The normal sodium diet was found to delay the development of hypertension, whilst the high sodium diet exacerbated the development of hypertension. Kidney weights and heart weights were greater in DSS rats than DSR rats probably due to their renal pathology or cardiac hypertrophy. Adrenomedullin immunopositivity was found predominantly in the adrenal medulla, and to varying degrees in the zona glomerulosa and zona reticularis of the adrenal cortex. The semi-quantitative analysis indicate that there was a 6.3 fold increase in ADM content of DSS rats compared to the DSR rats, where both consumed the 1% NaCI supplemented diet (DSR : 5.98 ± 0.3 vs. DSS : 37.85 ± 0.5, P / Thesis (M.Sc.)-University of Durban-Westville, 2003.

<p>Mild hyperthermia (39°C-43°C) has numerous therapeutic benefits as an adjuvant therapy in the treatment of a variety of tumor types. Hyperthermia increases tumor blood flow and vascular permeability, promoting drug delivery and tumor oxygenation. Hyperthermia enhances the uptake and efficacy of numerous chemotherapeutic agents, including cisplatin, resulting in increased cytotoxicity. In addition to these biological responses, hyperthermia can be used as a drug-release trigger for temperature-sensitive nanoparticles, resulting in an improved and more targeted drug delivery system. Cisplatin was chosen because 1) it shows broad spectrum activity against a wide range of heatable cancers (i.e., those in sites such as the pancreas, colon and rectum, cervix and bladder, and 2) the same hyperthermic temperatures that enable temperature-sensitive lipsome-drug release also enhance cisplatin-induced cytotoxicity.</p><p>The role of hyperthermia in enhancing cisplatin delivery and cytotoxicity was investigated at both the cellular and tissue levels. While hyperthermia treatment is applicable to a variety of tumor types, the focus of this work was on bladder cancer. The synergistic effects of hyperthermia and cisplatin were investigated, along with the role of copper transport protein 1 (Ctr1) in this process. In addition, cisplatin was encapsulated within temperature-sensitive liposomes, which were used in combination with hyperthermia for targeted drug delivery. These studies demonstrated that the combination of cisplatin and hyperthermia improved drug delivery, and potentially anti-tumor efficacy, and that targeted delivery was enhanced through incorporation of temperature-sensitive liposomes. As many current methods for administering bladder hyperthermia have drawbacks, such as invasiveness and regional heating, the final aim of this study was to develop and test a less-invasive and more focused preclinical bladder heating device in a rat model. </p><p>Hyperthermia sensitizes cells to the cytotoxic effects of the commonly used chemotherapeutic agent cisplatin by increasing drug accumulation and subsequent platinum-DNA adduct formation. However, the molecular mechanisms underlying this enhancement remain unclear. Understanding the fundamental mechanisms involved in the synergistic interaction is necessary to increase the therapeutic benefits of this combination in the clinic. The synergism between the anti-cancer benefits of cisplatin and the drug delivery benefits of hyperthermia may offer a novel and more effective treatment for many cancer patients. We hypothesized that hyperthermia increases cisplatin accumulation and efficacy in part by modulating the function of Ctr1, a major regulator of cellular cisplatin uptake. To test this hypothesis, we examined the significance of Ctr1 during combined hyperthermia and cisplatin therapies and assessed the importance of cisplatin- and hyperthermia-induced Ctr1 multimerization in enhancing cisplatin cytotoxicity. We observed increased Ctr1 multimerization following hyperthermia treatment (41°C) in vitro, compared to normothermic controls (37°C), suggesting that this may be a mechanism for increased cisplatin uptake in heat-treated cells. The impact of increased Ctr1 multimerization was evaluated by measuring platinum accumulation in wild-type (WT) and Ctr1-/- cells. WT cells contained greater levels of platinum compared to Ctr1-/- cells. A further increase in platinum was observed following hyperthermia treatment, but only in the WT cells. Hyperthermia enhanced cisplatin-mediated cytotoxicity in WT cells with a dose-modifying factor (DMF) of 1.8 compared to 1.4 in Ctr1-/- cells. Our data suggest that heat increases Ctr1 activity by increasing multimerization, resulting in enhanced drug accumulation. Although we recognize that the effect of heat on cells is multi-factorial, our results support the hypothesis that Ctr1 is, in part, involved in the synergistic interaction observed with cisplatin and hyperthermia treatment. </p><p>In addition to assessing cisplatin delivery at the cellular level, we evaluated cisplatin delivery at the tissue level, using novel cisplatin-loaded temperature-sensitive liposomes. We hypothesized that delivering cisplatin encapsulated in liposomes under hyperthermic conditions would improve the pharmacokinetic profiles of cisplatin, increase drug delivery to the tumor, decrease normal tissue toxicity, and enhance the anti-tumor activity of cisplatin. We successfully prepared temperature-sensitive liposomes loaded with cisplatin and demonstrated that heat (42°C) sensitizes cisplatin-resistant cells to the cytotoxic effects of cisplatin in vitro. </p><p>Decreased toxicity was observed in animals treated with the cisplatin liposome (± heat) compared to the free drug treatments. A pharmacokinetic study of cisplatin-loaded temperature-sensitive liposomes and free drug was performed in tumor-bearing mice under normothermic and hyperthermic conditions. Cisplatin half-life in plasma was increased following liposome treatment compared to free cisplatin, and cisplatin delivery to the tumors was greatest in mice that received liposomal cisplatin under hyperthermia. These initial in vivo data demonstrate the potential effectiveness of this cisplatin-loaded liposome formulation in the treatment of certain types of cancer. To assess the anti-cancer efficacy of the liposome treatment, a tumor growth delay study was conducted and demonstrated equivalent efficacy for the cisplatin-loaded temperature-sensitive liposome compared to free drug. </p><p>In addition to the liposome work, we developed and evaluated a novel heating device for the bladder. Despite the evidence that hyperthermia is an effective adjuvant treatment strategy, current clinical heating devices are inadequate, warranting the development of a new and improved system. We induced hyperthermia using ferromagnetic nanoparticles and an alternating magnetic field device developed by Actium Biosystems. Initial preclinical studies in a rat model demonstrated preferential bladder heating. However, our preliminary studies show severe toxicity with the direct instillation of the nanoparticles in the bladder, and further studies are needed to potentially modify the nanoparticle coating, the catheterization procedure, as well as to develop a different animal model.</p> / Dissertation

F. tularensis is a Gram-negative bacterial pathogen and it is the causative agent of tularemia. It has the ability to replicate to high numbers within a variety of host cells, including macrophages. Little is known of its virulence mechanisms; however, all species of Francisella contain a cluster of virulence genes known as the Francisella Pathogenicity Island (FPI), which is thought to encode a type 6 secretion system. While 14 of the 18 FPI genes encode products required for intracellular growth in macrophages, the functions of most of these proteins remain to be determined. Therefore, further work is required to understand the role played by the FPI in Francisella pathogenesis. In this thesis, the localization of the core FPI proteins IglA, IglB, IglC and IglD, was examined in order to further elucidate of the structure and activities of the FPI-encoded secretion system. Deletion mutagenesis of pdpA was performed to determine how host intracellular signalling might be affected by secretion of the putative FPI effector protein PdpA. In addition, variations in virulence between different biotypes of Francisella were investigated with respect to the role played by the FPI protein PdpD. Considering the highly infectious nature of Francisella and the absence of a quality vaccine, it is clear that this organism represents an excellent model for proof of principle investigations focussing on new vaccine technologies for intracellular pathogens. The second half of this thesis describes the construction and characterization of live attenuated temperature-sensitive vaccines. These vaccines were created in the intracellular pathogen F. novicida through allelic replacement of essential genes with naturally-occurring, cold-adapted, thermolabile homologues isolated from Arctic bacteria. Thus, the objectives of this work were twofold: to provide further characterization of the structural components and effector proteins associated with the FPI-encoded secretion system, and to develop a new and effective vaccine technology for use against intracellular bacteria. / Graduate

This thesis describes the design and implementation of the IPE, an interactive proof editor for first-order intuitionistic predicate calculus, developed at the University of Edinburgh during 1983-1986, by the author together with John Cartmell and Tatsuya Hagino. The IPE uses an attribute grammar to maintain the state of its proof tree as a context-sensitive structure. The interface allows free movement through the proof structure, and encourages a "proof-byexperimentation" approach, since no proof step is irrevocable. We describe how the IPE's proof rules can be derived from natural deduction rules for first-order intuitionistic logic, how these proof rules are encoded as an attribute grammar, and how the interface is constructed on top of the grammar. Further facilities for the manipulation of the IPE's proof structures are presented, including a notion of IPE-tactic for their automatic construction. We also describe an extension of the IPE to enable the construction and use of simply-structured collections of axioms and results, the main provision here being an interactive "theory browser" which looks for facts which match a selected problem.

No description available.

We present an algorithm for c-approximate nearest neighbor problem in a d-dimensional Euclidean space, achieving query time ofO(dn^{1/c^2+o(1)}) and space O(dn + n^{1+1/c^2+o(1)}).

There are many reactions that are sensitive to the surface structure of a catalyst. In order to obtain a comprehensive understanding of structure sensitive surface chemistry we use Surface Structure Spread Single Crystals (S4Cs) that expose a continuous distribution of crystal planes across their surfaces. Those crystal planes that lack mirror symmetry contain terraces, monatomic steps, and kinks and can be described as chiral with an R or an S orientation. When coupled with spatially resolved surface analysis techniques, S4Cs can be used to study the effects of surface structure and chirality on surface chemistry across a continuous distribution of crystal planes. A set of six Cu S4Cs has been created that spans all possible crystal planes of Cu. The Cu(111) S4C was used to study the structure sensitivity of L- and D-tartaric acid (TA) decomposition and the Cu(100) S4C was used to study the structure sensitivity of L-4-13C and D-aspartic acid (AA) decomposition. Isothermal Temperature Programmed Reaction Spectroscopy (TPRS) was implemented in which the S4Cs with monolayers of TA and AA were held at a temperature below the temperature of peak decomposition observed in a standard TPR experiment (heating at 1 K/s). At various times during isothermal heating, the surface was cooled to quench the reaction. Spatially resolved X-ray Photoelectron Spectroscopy (XPS) was performed to identify those regions on the surface in which the adsorbates had decomposed and those in which they were still intact. On the Cu(111) S4C which exposes both (100) and (110) step edges, TA decomposition is most sensitive to the density of (100) steps. AA decomposition on the Cu(100) S4C was enantioselective: L-AA-4-13C decomposed on S surfaces before R surfaces while D-AA decomposed on R surfaces before S surfaces. The decomposition of CH3CH2OH, CD3CD2OD, and CF3CH2OH on Zn was studied using temperature programmed reaction spectroscopy (TPRS). The decomposition products of each reaction were determined and a reaction mechanism was proposed for CH3CH2OH decomposition based on the product ratios and peak temperature locations. The CH3CH2OH decomposition mechanism includes the formation of two intermediate species on the surface: CH3CH2- to form CH2=CH2 and CH3CH2O- to form CH3CH=O.

This article reviews the academic literature (1996-2016) that emerged under value sensitive design (VSD). It investigates those VSD projects that employed the tripartite methodology, examining the use of VSD methodological elements, and illustrating common practices and identifying shortcomings. The article provides advice for VSD researchers on how to complete and enhance their methodological approach as the research community moves forward.

Doctor of Philosophy / Department of Curriculum and Instruction / F. Todd Goodson / American education is increasingly driven by standards and high-stakes tests. This creates a dynamic in which curricular content addressed in the standards will be subjected to high-stakes tests while that not addressed in the standards risks being ignored. Such a dynamic threatens poetry—a subject whose strength resides in its ambiguity instead of one correct answer. The literature review establishes poetry as an important area of study for K-12 students and explores how the Standards Movement has affected poetry instruction in other English-speaking countries. This research used context-sensitive textual analysis to examine the treatment of poetry in American English language arts standards from 1971 to 2010 as demonstrated in the following three documents: (1) Representative Performance Objectives for High School English written by the Tri-University Project in 1971, (2) Standards for the English Language Arts written by the National Council of Teachers of English and the International Reading Association in 1996, and (3) the Common Core State Standards for English Language Arts written in 2010. Context-sensitive textual analysis (Huckin, 1992) presumes that the contexts in which texts are written and read impact their meanings. The study describes those impacts, their implications, and suggestions for continued study.

Made available in DSpace on 2014-06-12T15:50:47Z (GMT). No. of bitstreams: 2 arquivo1988_1.pdf: 1433897 bytes, checksum: 2bd67eddaeadba13aa380ec5c913b7e0 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2008 / Uma das propostas da Web Semântica é fornecer uma grande diversidade de serviços de diferentes domínios na Web. Estes serviços são, em sua maioria, colaborativos, cujas tarefas se baseiam em processos de tomada de decisão. Estas decisões, por sua vez, serão mais bem embasadas se considerarem a maior quantidade possível de informação relacionada às tarefas em execução. Neste sentido, este cenário encoraja o desenvolvimento de técnicas e ferramentas orientadas para a integração de informação, procurando soluções para a heterogeneidade das fontes de dados. A arquitetura baseada em mediação, utilizada no desenvolvimento de sistemas de integração de informações tem como objetivo isolar o usuário das fontes de dados distribuídas utilizando uma camada intermediária de software chamada de mediador. O mediador, em um sistema de integração de informações, utiliza um esquema global para a execução das consultas do usuário que são reformuladas em sub-consultas de acordo com os esquemas locais das fontes de dados. Neste caso, um processo de integração de esquemas gera o esquema global (esquema de mediação) como resultado da integração dos esquemas individuais das fontes de dados. O problema maior em integração de esquemas é a heterogeneidade das fontes de dados locais. Neste sentido, a resolução semântica é primordial. A utilização de métodos puramente estruturais e sintáticos na integração de esquemas é pouco eficaz se antes não houver a identificação do real significado dos elementos dos esquemas. Um processo de integração de esquemas tem como resultado um esquema global integrado e um conjunto de mapeamentos inter-esquema e usualmente, compreende algumas etapas básicas como: pré-integração, comparação, mapeamento e unificação de esquemas e geração do esquema de mediação. Em integração de esquemas, resolução de nomes é o processo que determina a qual entidade do mundo real um dado elemento de esquema se refere, levando em consideração um conjunto de informações semânticas disponíveis. A informação semântica necessária para resolução de nomes, em geral, é obtida de vocabulários genéricos e/ou específicos de um determinado domínio de conhecimento. Nomes de elementos podem apresentar significados diferentes dependendo do contexto semântico ao qual eles estão relacionados. Assim, o uso de informação contextual, além da de domínio, pode trazer uma maior precisão na interpretação dos elementos permitindo modificar o seu significado de acordo com um dado contexto. Este trabalho propõe uma abordagem de resolução de nomes baseada em contexto para integração de esquemas. Um de seus pontos fortes é a utilização e modelagem da informação contextual necessária à resolução de nomes em diferentes etapas do processo de integração de esquemas. A informação contextual está modelada utilizando uma ontologia, o que favorece a utilização de mecanismos de inferência, compartilhamento e reuso da informação. Além disto, este trabalho propõe um processo de integração de esquemas simples e extensível de forma que seu desenvolvimento se concentrasse principalmente nos requisitos relacionados à resolução de nomes. Este processo foi desenvolvido para um sistema de integração de informações baseado em mediação, que adota a abordagem GAV e XML como modelo comum para intercâmbio de dados e integração de fontes de dados na Web