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Laisse, Claudio Joao Mourao. "Characterization of tuberculous lesions in naturally infected African buffalo (Syncerus caffer)." Thesis, Stellenbosch : University of Stellenbosch, 2010. http://hdl.handle.net/10019.1/5348.
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Thesis (MScMedSc (Biomedical Sciences. Medical Biochemistry))--University of Stellenbosch, 2010.ENGLISH ABSTRACT: Mycobacterium bovis has a wide host range and infects many wild and domestic animal species as well as humans. African buffalo (Syncerus caffer) is considered to be a wildlife reservoir of M. bovis in certain environments in South Africa, such as in the Kruger National Park (KNP) and Hluhluwe-iMfolozi Park (HiP). A detailed pathological study was conducted on 19 African buffalos (Syncerus caffer) from a herd in the HiP in South Africa. The animals tested positive to the intradermal bovine tuberculin test and were euthanazed during a test-and-cull operation to decrease the prevalence of bovine tuberculosis (bTB) in the park. The superficial, head, thoraxic and abdominal lymph nodes and the lungs were examined grossly for presence of tuberculous lesions and were scored on a 1-5 scale for macroscopic changes. The gross lesions were examined histologically and scored I-IV according to a grading system used for bTB lesions in domestic cattle. Macroscopical lesions were limited to the retropharyngeal, bronchial, and mediastinal lymph nodes and the lungs. The most frequently affected lymph nodes were the bronchial (16/19) and mediastinal (11/19). All four grades of microscopic lesions were observed, although grade II lesions were the most frequent. Acid-fast bacilli were observed only rarely. Bovine tuberculosis was confirmed by PCR analyses. All animals were in good body condition and most of the lesions were in an early stage of development, indicating an early stage of the disease. The absence of lesions in the mesenteric lymph nodes and the high frequency of lesions in respiratory tract associated lymph nodes suggest that the main route of M. bovis infection in African buffalo is inhalatory rather than alimentary. This study presents a systematic evaluation and semiquantification of the severity and stages of development of tuberculous lesions in buffalo. The results may contribute to i) the understanding of the pathogenesis of the disease, ii) the evaluation of experimental models of M. bovis infection in Syncerus caffer, and iii) the interpretation of pathological data from vaccination trials.
AFRIKAANSE OPSOMMING: Mycobacterium bovis het ‘n wye reeks van gashere en dit infekteer verskeie wilde en mak dierespesies, sowel as mense. Die buffel (Syncerus caffer) word beskou as die wild reservoir van M. bovis in sekere dele van Suid Afrika, soos in die Kruger Nasionale Park (KNP) en Hluhluwe-iMfolozi Park (HiP). ‘n Breedvoerige patologiese studie is uitgevoer op 19 buffels afkomstig vanaf ‘n trop in die HiP in Suid Afrika. Die diere het almal positief getoets vir die intradermale beestuberkulin toets en is uitgesit tydens ‘n toets-en-slag operasie met die doel om die voorkoms van beestuberkulose (bTB) in die park te bekamp. Die oppervlakkige, kop, toraks en abdominale limfknope en longe is oorsigtelik ondersoek vir die teenwoordigheid van tuberkulose letsels en was ‘n punt toegeken op ‘n skaal van 1-5 vir die teenwoordigheid van makroskopiese veranderinge. Die opsigtelike letsels is histologies ondersoek en ‘n I-IV punt toegeken volgens die gradering wat gebruik word vir bTB letsels in beeste. Makroskopiese letsels was beperk tot die retrofaringeale, brongiale, en mediastinale limfknope en in die longe. Die brongiale (16/19) en mediastinale (11/19) limfknope was meestal geaffekteerd. Al vier grade van mikroskopiese letsels is gevind, alhoewel graad II letsels die volopste was. Suur-vaste basille is slegs selde waargeneem. Beestuberkulose is bevestig deur PKR analises. Al die diere was in ‘n goeie kondisie en meeste van die letsels was in ‘n vroeë stadium van ontwikkeling, wat aandui op ‘n vroeë fase van die siekte. Die afwesigheid van letsels in die mesenteriese limfknope en die hoë frekwensie van letsels in die lugweg geassosieerde limfkliere dui daarop dat the belangrikste roete van M. bovis infeksie in die buffel deur inaseming geskied eerder as deur opname in die spysverteringskanaal. Hierdie studie bied ‘n stelselmatige evaluering en semi-kwantifisering van die graad van erns en die stadia van ontwikkeling van tuberkulose letsels in buffels. Die resultate kan bydra tot i) die begrip van die patogenese van die siekte, ii) die evaluering van eksperimentele modelle van M. bovis infeksie in Syncerus caffer, en iii) die interpretasie van patologiese data van inentingsproewe.
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Senate, University of Arizona Faculty. "Faculty Senate Minutes March 4, 2013." University of Arizona Faculty Senate (Tucson, AZ), 2013. http://hdl.handle.net/10150/279132.
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Carrivick, Luke Andrew. "Probabilistic models in the biomedical sciences." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425082.
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Luo, Yuan. "Novel Biomedical Imaging Systems." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/193907.
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The overall purpose of the dissertation is to design and develop novel optical imaging systems that require minimal or no mechanical scanning to reduce the acquisition time for extracting image data from biological tissue samples. Two imaging modalities have been focused upon: a parallel optical coherence tomography (POCT) system and a volume holographic imaging system (VHIS). Optical coherence tomography (OCT) is a coherent imaging technique, which shows great promise in biomedical applications. A POCT system is a novel technology that replaces mechanically transverse scanning in the lateral direction with electronic scanning. This will reduce the time required to acquire image data. In this system an array with multiple reduced diameter (15μm) single mode fibers (SMFs) is required to obtain an image in the transverse direction. Each fiber in the array is configured in an interferometer and is used to image one pixel in the transverse direction. A VHIS is based on volume holographic gratings acting as Bragg filters in conjunction with conventional optical imaging components to form a spatial-spectral imaging system. The high angular selectivity of the VHIS can be used to obtain two-dimensional image information from objects without the need for mechanical scanning. In addition, the high wavelength selectivity of the VHIS can provide spectral information of a specific area of the object that is being observed. Multiple sections of the object are projected using multiplexed holographic gratings in the same volume of the Phenanthrenquinone- (PQ-) doped Poly (methyl methacrylate) (PMMA) recording material.
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Zhao, Weiyu. "Development of Functionalized Biomaterials for Biomedical Applications." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1594988786199951.
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Ekblad, Tobias. "Hydrogel coatings for biomedical and biofouling applications." Doctoral thesis, Linköpings universitet, Sensorvetenskap och Molekylfysik, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-54304.
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Many applications share a substantial and yet unmet need for prediction and control of interactions between surfaces and proteins or living cells. Examples are blood-contacting biomaterials, biosensors, and non-toxic anti-biofouling coatings for ship hulls. The main focus of this thesis work has been the synthesis, characterization and properties of a group of coatings, designed for such applications. Many types of substrates, particularly plastics, were coated directly with ultrathin, hydrophilic polymer coatings, using a newly developed polymerization method initiated by short-wavelength ultraviolet light. The thesis contains eight papers and an introduction aimed to provide a context for the research work. The common theme, discussed and analyzed throughout the work, has been the minimization of non-specific binding of proteins to surfaces, thereby limiting the risk of uncontrolled attachment of cells and higher organisms. This has mainly been accomplished through the incorporation of monomer units bearing poly(ethylene glycol) (PEG) side chains in the coatings. Such PEG-containing “protein resistant” coatings have been used in this work as matrices for biosensor applications, as blood-contacting inert surfaces and as antibiofouling coatings for marine applications, with excellent results. The properties of the coatings, and their interactions with proteins and cells, have been thoroughly characterized using an array of techniques such as infrared spectroscopy, ellipsometry, atomic force microscopy, surface plasmon resonance and neutron reflectometry. In addition, other routes to fabricate coatings with high protein resistance have also been utilized. For instance, the versatility of the fabrication method has enabled the design of gradients with varying electrostatic charge, affecting the protein adsorption and leading to protein resistance in areas where the charges are balanced. This thesis also describes a novel application of imaging surface plasmon resonance for the investigation of the surface exploration behavior of marine biofouling organisms, in particular barnacle larvae. This technique allows for real-time assessment of the rate of surface exploration and the deposition of protein-based adhesives onto surfaces, a process which was previously very difficult to investigate experimentally. In this thesis, the method was applied to several model surface chemistries, including the hydrogels described above. The new method promises to provide insights into the interactions between biofouling organisms and a surface during the critical stages prior to permanent settlement, hopefully facilitating the development of antibiofouling coatings for marine applications.
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Abbas, Aiman Omar Mahmoud. "Chitosan for biomedical applications." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/771.
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Chitosan, a copolymer of glucosamine and N-acetyl glucosamine, is a polycationic, biocompatible and biodegradable polymer. In addition, chitosan has different functional groups that can be modified with a wide array of ligands. Because of its unique physicochemical properties, chitosan has great potential in a range of biomedical applications, including tissue engineering, non-viral gene delivery and enzyme immobilization.
In our work, the primary amine groups of chitosan were utilized for chitosan modification through biotinylation using N-hydroxysuccinimide chemistry. This was followed by the addition of avidin which strongly binds to biotin. Biotinylated ligands such as polyethylene glycol (PEG) and RGD peptide sequence, or biotinylated enzymes such as trypsin, were then added to modify the surface properties of the chitosan for a variety of purposes. Modified chitosans were formulated into nano-sized particles or cast into films. Different factors affecting fabrication of chitosan particles, such as the pH of the preparation, the inclusion of polyanions, the charge ratios and the degree of deacetylation and the molecular weight of chitosan were studied. Similarly, parameters affecting the fabrication of chitosan films, such as cross-linking, were investigated for potential applications in tissue engineering and enzyme immobilization.
It was found that the inclusion of dextran sulfate resulted in optimum interaction between chitosan and DNA, as shown by the high stability of these nanoparticles and their high in vitro transfection efficiencies in HEK293 cells. When applying these formulations as DNA vaccines in vivo, chitosan nanoparticles loaded with the ovalbumin antigen and the plasmid DNA encoding the same antigen resulted in the highest antibody response in C57BL/6 mice.
Furthermore, engineering of the surface of chitosan nanoparticles was done by utilizing the avidin-biotin interaction for attaching PEG and RGD. The modified formulations were tested for their in vitro gene delivery properties and it was found that these ligands improved gene transfection efficiencies significantly.
Chitosan nanoparticles were optimized further for enzyme immobilization purposes using sodium sulfate and glutaraldehyde as physical and chemical cross-linking agents, respectively. These particles and chitosan films were used for immobilizing trypsin utilizing several techniques. Enzyme immobilization via avidin-biotin interaction resulted in high immobilization efficiency and high enzymatic activity in different reaction conditions. Additionally, the immobilized trypsin systems were stable and amenable to be regenerated for multiple uses.
Finally, glutaraldehyde cross-linked chitosan films were modified with PEG and RGD for their cell repellant and cell adhesion properties, respectively, using avidin-biotin interaction. This method was again effective in engineering chitosan surfaces for modulating cell adhesion and proliferation.
In conclusion, using avidin-biotin technique to modify biotinylated chitosan surfaces is a facile method to attach a wide variety of ligands in mild reaction conditions, while preserving the functionality of these ligands.
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Bauer, Sebastian [Verfasser]. "Algorithms for knowledge integration in biomedical sciences / Sebastian Bauer." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1029850844/34.
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Grigor, Ian Edward. "The career and course choices of biomedical sciences undergraduates." Thesis, University of Leeds, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496540.
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Al-Showaikh, Faisal Nasser Mohammed. "Numerical modelling of some systems in the biomedical sciences." Thesis, Brunel University, 1998. http://bura.brunel.ac.uk/handle/2438/6628.
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Finite-difference numerical methods are developed for the solution of some systems in the biomedical sciences; namely, a predator-prey model and the SEIR (Susceptible/Exposed/ Infectious/Recovered) measles model. First-order methods are developed to solve the predator-prey model and one second-order method is developed to solve the SEIR measles model. The predator-prey model is extended to one-space dimension to incorporate diffusion. The SEIR measles model is extended to one-space dimension to incorporate (i) diffusion, (ii) convection and (iii) diffusion-convection. The SEIR measles model is extended further to model diffusion in two-space dimensions. The reaction terms in these systems of partial differntial equations contain nonlinear expressions. Nevetheless, it is seen that the numerical solutions are obtained by solving a linear algebraic system at each time step, as opposed to solving a nonlinear algebraic systems, which is often required when integrating non-linear partial differential equations. The development of each numerical method is made in the light of experience gained in solving the system of ordinary differential equations for each system. The numerical methods proposed for the solution of the initial-value problem for the predator-prey and measles models are characterized to be implicit. However, in each case it is seen that the numerical solutions are obtained explicitly. In a series of numerical experiments, in which the ordinary differential equations are solved first of all, it is seen that the proposed methods have superior stability properties to those of the well-known, first-order, Euler method to which they are compared. Incorporating the proposed methods into the numerical solution of partial differential equations is seen to lead to economical and reliable methods for solving the systems.
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Kennedy, David Glenn. "Analytical research & investigations in biomedical and veterinary sciences." Thesis, Queen's University Belfast, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.679235.
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The thesis contains a collection of 195 refereed publications, dating from 1980 to 2013. The work has been classified into 3 broad themes. The first theme, biomedical research (undertaken between 1980 and 1987) concentrated mainly on the pharmacokinetics of anticancer drugs in vivo and their metabolism in vitro. and resulted in 13 refereed publications. The second theme, animal nutritional disorders (undertaken between 1987 and 2002) resulted in 58 refereed publications. Most of the work concentrated on the affects of vitamin/trace element deficiency (mainly on either cobalt/vitamin B12 or vitamin E/selenium deficiency) on animal producti0f.l (iisEJases and the metabolic perturbations accompanying those diseases. Some of the work focussed on title benefits of increased supplementation of animal diets with vitamin E.
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Malviya, Ajay. "The role of hip arthroscopic intervention for femoroacetabular impingement on the quality of life and deferring the need for hip replacement." Thesis, University of Sunderland, 2016. http://sure.sunderland.ac.uk/6586/.
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Background: The role of hip arthroscopic intervention for Femoroacetabular impingement (FAI) is evolving with increasing ability to deal with impingement lesions and repair the chondrolabral tears. Initially, the procedure was thought to be most appropriate for treatment of athletes but the objective benefits in terms of return to sport at the same level were not considered. Moreover, any benefit in terms of overall quality of life, and potential efficacy of arthroscopic treatment in non-athletes has not been clarified. Currently, this procedure is still very new, and most published studies involve retrospective analysis of small numbers of patients and do not give an accurate picture of the frequency and severity of complications, in particular the potential to delay the need the have hip replacement. Aim: The aim of this thesis is to establish the benefit of hip arthroscopic intervention for FAI by answering pertinent questions about the procedure: • Is it effective in terms of improvement in quality of life? • Is it beneficial for non-athletes? • Is it possible for athletes to return to sport at the same level? • What is the short-term complication rate? • Does it defer the need to have hip replacement in the future? Methods: This thesis is based on four original published papers in various peer-reviewed journals that address the above questions. Results: Does hip arthroscopic intervention improve quality of life (QoL) of patients with FAI? This publication reported the largest single-surgeon series, at the time of publication, and was the first to consider QoL outcomes. In a series of 612 patients at a mean follow-up of 3.2 years, we found that the QoL improved significantly after surgical intervention in 77%, remained unchanged in 14% and deteriorated in 9% of patients. The significant predictors of change in QoL were preoperative QoL scores and female gender. Is hip arthroscopic intervention for FAI only for athletes? In this prospective comparative study the trend for improvement in hip scores after surgery was compared between athletes and non-athletes and we found that, while the athletes had a significantly better score at six weeks, there were no significant differences between the two groups after one year. This study was the first prospective comparative study to look at these two groups of patients and demonstrated that arthroscopic surgery may be an appropriate treatment for FAI in both athletes and non-athletes. Does hip arthroscopic intervention for FAI improve the outcome in athletes? In this prospective comparative study we noted that both the training and time in competition improved approximately three-fold after surgery, with a mean time to return to sport at the same level of 5.4 months. Professional athletes (4.2 months) recovered more quickly than recreational athletes (6.8 months). A greater proportion of the professional athletes (88%) returned to their pre-injury level of sport than the recreational athletes (73%). Prior to this study, objective measures of return to sport were lacking, and there had been no prospective comparative studies of recovery time in professional and recreational athletes. What is the short-term complication rate? The national hospital episode statistics data on short-term complications after hip arthroscopy showed that, in 6395 hip arthroscopies performed in England between April 2005 and Jan 2013, the 30-day readmission rate was 0.5%; the 90-day incidence of deep vein thrombosis (DVT) was 0.08% and of pulmonary embolus (PE) 0.08%; and the 90-day mortality rate was 0.02%. Does it defer the need to have hip replacement in the future? In this series of 6395 hip arthroscopies, 680 patients (10.6%) underwent total hip replacement (THR), at a mean of 1.4 years after the index operation. Female patients had a 1.68 times (95% CI, 1.41 to 2.01) higher risk of conversion to THR than male patients, and patients aged 50 years or older had a 4.65 (95% CI, 3.93 to 5.49) times higher risk of requiring hip replacement than patients younger than 50 years. Kaplan-Meier survival analysis revealed an eight-year survival of 82%; while Cox proportional hazard analysis, adjusting for age, gender and Charlson comorbidity score, revealed an eight-year survival of 86%. Conclusion: Arthroscopic surgery for FAI improves QoL, is beneficial for non athletes as well as athletes, enables athletes to return to their professional level of function and may delay the need for total hip replacement. These papers have helped, not only in establishing the outcome of surgery but also in identifying the patients who would benefit from intervention. This information is critical to the clinicians’ understanding of both the success of the intervention and limitations of the technique. Important information has been generated from this work that will be helpful during preoperative counselling, when it is imperative to obtain properly informed consent.
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Ibasco, Suzette. "Magnesium phosphate precipitates and coatings for biomedical applications." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40691.
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Metals are extensively used materials in orthopaedics and oral implants and several research studies have reported that coating the surface improves the osteoconduction and bone bonding ability of the metal. Low temperature aqueous precipitation techniques are advantageous over other coating processes as they allow the incorporation of thermally unstable compounds. Although some magnesium phosphates have been shown to be well tolerated in bone tissue [Zimmermann 2006], they are relatively unstudied as bioceramics. The first part of this research project was to determine the precipitation conditions at which different magnesium phosphate phases form. Ultimately, the primarily goal of this study was to investigate a new low temperature route to produce magnesium phosphate coatings by reacting substrates sputter coated with magnesium metal in an aqueous phosphate solution. X-ray diffraction (XRD) and scanning electron microscopy (SEM) coupled with energy dispersion spectroscopy (EDS) were used to characterize and identify the magnesium phosphate precipitates. SEM revealed that coatings formed by the reaction of magnesium metal with ammonium dihydrogen phosphate formed a continuous coating of struvite crystals. Importantly, this coating was durable enough to withstand the peel test (ASTM D 3359). Furthermore, this coating was also useful as a reactive surface to form hydroxyapatite coating. Biocompatibility assays, showed that magnesium phosphates precipitates and coatings were non-toxic and sustained cell viability. This study shows the possibility of forming a number of potentially biocompatible surface coatings on a metal model through a low temperature in situ process. This process shows good promise in producing enhanced coatings with many advantages over currently used techniques.Les métaux sont largement utilisés comme matériaux dans la conception d’implants orthopédiques et dentaires et plusieurs études ont montré qu’un revêtement de leurs surfaces améliore leur propriété d’ostéoconduction et leur capacité de liaison au tissu osseux. Les techniques de précipitation aqueuse à basse température sont plus élaborées comparées aux autres techniques de revêtement car elles permettent l’incorporation de composés thermiquement instables. Bien que certains phosphates de magnésium soient bien tolérés au sein du tissu osseux [Zimmermann 2006], ils sont relativement peu étudiés comme biocéramiques. La première partie de ce projet de recherche était de déterminer les conditions de précipitations auxquelles les différentes phases des phosphates de magnésium se forment. L’objectif majeur de cette étude était d’explorer une nouvelle méthode, à basse température, pour produire des revêtements de phosphate de magnésium par la réaction de substrats revêtus par pulvérisation avec des métaux magnésiens, dans une solution aqueuse de phosphate.La diffraction des rayons X et la microscopie électronique à balayage, couplée à la spectrométrie par dispersion d’énergie, furent utilisées pour caractériser et identifier les précipités de phosphates de magnésium. La microscopie électronique à balayage a révélé que les revêtements produits par la réaction d’un métal magnésiun avec un phosphate diacide d’ammonium forment un revêtement continu de cristaux de struvite. Ce revêtement présentait également la caractéristique majeure de résister au test d’arrachage. Les tests de biocompatibilité ont montré que les précipités de phosphates de magnésium ainsi que les revêtements de surface étaient non toxiques et amélioraient la viabilité cellulaire. Cette étude démontre la possibilité de former un éventail de revêtements potentiellement biocompatibles à la surface d’un$
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Wijesinghe, Nishadh P. "Regulation of hypoxia responsive gene expression by specificity protein family transcription factors in breast cancer." Thesis, University of Hull, 2017. http://hydra.hull.ac.uk/resources/hull:16874.
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Cancer accounts for the highest amounts of disease related premature deaths worldwide with 8.1 million of deaths being associated with malignancy. In the cancer microenvironment, particularly in solid tumours, hypoxia plays a significant role in progression and metastasis by altering signal transduction and gene regulation which leads to aggressive phenotypes, poor prognosis and lower survival rates. Hypoxia-Inducible Factor (HIF) driven gene regulation is well established and believed to promote survival of tumour cells under the hypoxic microenvironment. Accumulating evidence also suggests that Specificity protein (Sp) family transcription factors might also play a role in the hypoxic microenvironment by regulating transcription of key hypoxia responsive genes such as VEGFA in either a HIF dependent or independent manner. In normal cells, Sp transcription factors are ubiquitously expressed and known to regulate numerous genes involved in vital cellular pathways such as cell cycle, apoptosis and angiogenesis. In tumour environments, deregulated Sp protein levels have been demonstrated and shown to correlate with poor prognosis and treatment response. However, the exact role of Sp transcription factors in hypoxic microenvironment is not fully understood. This study aimed to identify the effect of severe (chronic) hypoxia on Sp transcription factors and hypoxia-responsive gene regulation using breast cancer as a cell model. Initial studies measured the expression levels and binding activity of Sp transcription factors. Subsequently, an integrative genomic analysis was performed to identify Sp driven hypoxia-responsive genes in breast cancer cells. The study was further extended to analyse the binding kinetics of Sp protein inhibitors using surface plasmon resonance spectroscopy. Finally, transcriptional changes of hypoxia responsive genes were examined after addition of Sp inhibitors or knockdown of Sp1 level under the hypoxic environment. Expression analysis of Sp family members (Sp1-4) showed that the transcript levels of Sp genes were unaffected due to chronic hypoxic exposure whilst Sp protein levels were induced in all three cell lines. However, expression patterns were dependent on tissue type and severity of hypoxia. Twenty genes were identified as potential Sp driven hypoxia responsive genes which are consist of GC-rich putative Sp binding sites in their promoters. Gene expression analysis validated the hypoxic induction of these genes and their dependency on Sp protein-mediated transcription. Affinity studies of Sp protein inhibitors prove binding of antibiotic derivatives, Mithramycin A and Chromomycin A to GC-rich regions with different binding affinities and kinetics. Different Equilibrium constants (Kd) of Mithramycin A and Chromomycin A were identified which varied according to the promoter sites (10−3 to 10−6 M range). Furthermore, novel data also confirm the Mithramycin-DNA interaction is independent of cation Mg2+ which has been considered obligatory for DNA interaction. Interestingly, nordihydroguaiaretic acid (NDGA) derivative, Terameprocol exhibits no detectable interaction with linear DNA consisting of Sp binding sites. These results emphasise the importance of Sp proteins as regulators of hypoxia-mediated gene transcription. Sp-regulated transcription is vital in altering hypoxia-related cellular pathways and has a potential as biomarkers for solid tumours. Moreover, these results suggest the potential use of Sp antagonists to inhibit expression of key hypoxic genes in the cancer microenvironment. Results also provide solid background knowledge on pharmacokinetics of Sp inhibitors which will be useful in synthesis of new derivatives which can be used in novel therapeutic strategies for cancer and perhaps other diseases. Understanding the molecular mechanisms of Sp mediated hypoxic gene regulation can be further extended to elucidate other cellular stress and cellular adaptive mechanism.
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Javaheri, Hoda. "Wet granulated liquisolid drug delivery systems with hydrophobic and hydrophilic drugs." Thesis, University of Sunderland, 2017. http://sure.sunderland.ac.uk/8549/.
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The formulation of hydrophobic drugs into appropriate dosage forms is challenging due to the problems associated with those drugs such as low solubility and poor dissolution. Using a liquisolid system is a promising method to improve the dissolution of hydrophobic drugs and in sustaining the release of hydrophilic drugs, in which solid drugs are dispersed in non-volatile liquid vehicles. The aim of this research was to use the liquisolid technique to enhance the dissolution rate of glibenclamide, a model hydrophobic drug, and to sustain the release of metformin-HCl, as a model hydrophilic drug. The wet granulation process was applied to liquisolid powders with the aim of overcoming issues of poor powder flowability and compressibility, especially using high viscosity liquid vehicles. This process was performed with liquisolid powders prior to compaction into tablets. Different liquisolid formulations were prepared using three liquid vehicles (polyethylene glycol400 (PEG® 400), Synperonic® PE/L44 and Cremophor® ELP), at 10 and 30 % w/w drug concentrations for glibenclamide; and 30% and 60% w/w drug concentrations for metformin-HCl. Avicel®PH102 was used as a carrier, whilst colloidal silicon dioxide was employed as a coating material to convert the wet mixtures into dry powders. Potato starch, 5% w/w, as a disintegrant was blended with the mixtures manually for 10 minutes and then 0.75% of magnesium stearate as a lubricant was added and mixed for 5 minutes. The final powder (depending on its flowability and compactability) was then compacted automatically using a single-punch tableting machine to give tablets with 4 mg for glibenclamide and 40 mg for metformin-HCl. Prepared liquisolid compacts were characterized by using British Pharmacopeia quality control tests: uniformity of weight, friability, disintegration, hardness and drug dissolution. iii It was found, for both drugs, that by application of wet granulation to liquisolid powder admixtures, the large-scale production of liquisolid compacts is feasible, which can be easily adapted to the pharmaceutical industry. In addition to enhancing the flowability and compressibility of the powders, the glibenclamide dissolution was also improved due to the enhanced binding of particles and because of the wetting effect of liquid vehicles on the hydrophobic drug, which make the drug more available for dissolution. For the sustained release preparations of liquisolid metformin-HCl, hydroxyl propyl cellulose (HPC) was used as a novel carrier in liquisolid compacts. The results showed 92% drug release after 12 hours using Cremophor®ELP (with 30% w/w drug concentration) which was the best sustained drug release formulation. Additionally, Eudragit® RL30D and Eudragit® RLPO have been used to study their effects on drug release from liquisolid formulations, examining if they can sustain or give more rapid drug release. Both types of Eudragit revealed immediate release with metformin-HCl rather than sustained drug release, with the tablets disintegrating within seconds. This suggests formulating orodispersible metformin-HCl tablets using Eudragit® RL30D as a liquid vehicle. In summary, liquisolid technology has led to promising results, not only in enhancing the drug dissolution of hydrophobic drugs, but also in sustaining and promoting the release of hydrophilic drugs.
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Alam, Muhammad Irfan. "Formulation and advantages of furazolidone in spray dried and liposomal drug delivery systems." Thesis, University of Sunderland, 2017. http://sure.sunderland.ac.uk/8552/.
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The current study has focused on the local delivery of furazolidone to the gut with the aim of generating alternative approaches for the treatment of Helicobacter pylori (H. pylori). Furazolidone has proven antibacterial activity against H. pylori, which has a unique niche in the stomach mucus. This drug was chosen as it is not currently used for the treatment of H. pylori and thus resistance is not expected to be a problem. Chitosan micro-particles were formulated by the spray drying technique, followed by optimization of mucoadhesion and drug release profiles using glutaraldehyde crosslinking agent at two pH values (1.3 and 4.5). Results revealed that increasing glutaraldehyde decreased the mucin adsorption and at low pH drug release was increased. For liposomal formulations, the effects of furazolidone concentration, chitosan and cholesterol on encapsulation efficacy and in vitro drug release were evaluated. It was found that increasing the pH from 1.3 to 4.5 increased the mucoadhesive behaviour of chitosan coated liposomes from 42% to 60%. Also, increasing the furazolidone amount from 4mg to 5mg increased encapsulation efficiency. A combination of two antibiotics (including furazolidone) was prepared in muco-penetrative liposomal formulations; N-acetylcysteine was used for the muco- penetration effect with Pluronic F-127. These formulations were investigated for their charge effect on muco-penetration and drug encapsulation. The data showed that neutral liposomes easily diffuse through the mucus layer. Escherichia coli was selected to establish the assay protocol for Helicobacter pylori. The microdilution approach was used for assaying the furazolidone minimum inhibitory concentration (MIC), which was found to be 16 μg/ml for E. coli and 4 μg/ml for H. pylori. In time-dependent killing studies, it was possible to observe iii complete killing of the bacteria. Increasing furazolidone concentration by two fold of its MIC, reduced the time required to kill bacteria. The mucoadhesive drug formulations also increased the residence time of furazolidone in the stomach mucus from 2- 3 hours to 4-6 hours; this time period would then be appropriate for killing the bacteria in the stomach. For mucopenetration study complete killing was achieved in 2.5 hours when furazolidone with 1 % minimum inhibitory concentration of NAC which was used. Which was otherwise six hours when NAC was not added for augmentation. To conclude, delivery of furazolidone was via application of novel liposomal and spray dried formulations to either increase movement across gastric mucosa (via a muco-penetration effect) or to increase binding to the mucus (via mucoadhesive action). Hence, the various approaches used in this research have showed success (to deliver effective amounts of furazolidone locally into the stomach mucus) and the co-encapsulation of furazolidone and N-acetylcysteine is a novel approach for the delivery of antimicrobial agents to the stomach.
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Alshegifi, Mohammed. "Identification and functional characterisation of putative mitochondrial nucleotide transporters from the human pathogen Trypanosome brucei." Thesis, University of Hull, 2018. http://hydra.hull.ac.uk/resources/hull:16890.
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Trypanosoma brucei is a medically important protozoan parasite that causes African sleeping sickness in humans. Although disease treatment is possible, it is hindered by the limited availability of effective drugs and the rapid emergence of drug resistance. It is, therefore, important to identify novel drug targets for the development of new, more effective drugs. Mitochondrial carrier family (MCF) proteins transport a wide range of key metabolites across the mitochondrial inner membrane. They are important for the maintenance of key metabolic pathways in all eukaryotic cells. In particular, the MCF proteins that have been implicated in mitochondrial adenosine triphosphate (ATP) import appear to be essential for cell function and survival due to their roles in defence against oxidative stress and in the provision of the ATP required for mitochondrial electron transport and associated ATP production. Based on their important physiological roles, mitochondrial nucleotide transporters are potential novel drug targets. The main aim of this thesis was to identify and functionally characterise the putative mitochondrial nucleotide transporters in T. brucei. Sequence analysis revealed that the T. brucei genome contains 5 MCF proteins: TbMCP1, TbMCP15, TbMCP16, TbMCP20 and TbMCP23. The proteins were predicted to have roles in mitochondrial nucleotide transport based on their homology to functionally characterised MCF proteins that transport nucleotides. Of these TbMCPs, TbMCP1 has the highest sequence similarity to functionally characterised mitochondrial flavin carriers and peroxisomal ATP/adenosine monophosphate carriers in other eukaryotes, such as Flx1 in Saccharomyces cerevisiae. Sequence analysis further predicted that TbMCP15 and TbMCP16 were closely related to mitochondrial adenosine diphosphate (ADP/ATP) transporters, such as AAC2 in S. cerevisiae, whereas TbMCP20 appeared to be closely related to mitochondrial S-adenosylmethionine transporters, such as SAM5 in S. cerevisiae, and TbMCP23 appeared to be closely related to mitochondrial pyrimidine transporters, such as S. cerevisiae RIM2.
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Bibby, Becky Ann Selina. "Investigating the role of microRNAs as modulators of sensitivity to neoadjuvant chemoradiation therapy in oesophageal adenocarcinoma patients." Thesis, University of Hull, 2015. http://hydra.hull.ac.uk/resources/hull:17129.
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Oesophageal cancer is the eight most common cancer and the sixth leading cause of deaths worldwide. There are two major histological subtypes of oesophageal cancer, with the most predominant subtype in Europe and the USA being oesophageal adenocarcinoma (OAC). The standard of care for OAC patients with locally advanced disease is neoadjuvant therapy and surgical resection. Unfortunately, ~70% of patients do not respond to neoadjuvant therapy and non-responders gain no benefit from the aggressive treatment regimen whilst compromising their quality of life. There is an unmet clinical need for biomarkers predicative of patient's response to neoadjuvant chemoradiation therapy (neo-CRT). In a pre-treatment setting, predictive biomarkers indicative of patient response could enable the stratification of patients and would ensure individual patients receive the most effective treatment. However, the greater clinical benefit for patients may come from the development of new or combination therapeutics for OAC. Novel chemosensitising and radiosensitising therapeutics could be administered with neo-CRT to enhance tumour sensitivity, improve CRT efficacy and increase survival rates for OAC patients. MicroRNAs (miRNA/miRs) are short non-coding RNA that function to regulate gene expression at the post-transcriptional level. A single miRNA can potentially target hundreds or thousands of mRNA and subsequently alter the expression of multiple genes and proteins. As essential regulators of gene expression, miRNA are involved in all cellular processes and are dysregulated in cancer and other diseases. Furthermore, miRNA have been identified as predictors and modifiers of tumour sensitivity to chemotherapy and radiotherapy in numerous cancer types. Playing a causal role in disease development and progression, miRNA are promising biomarkers and therapeutic targets. In this study miRNA were investigated as biomarkers of OAC patient response to neo-CRT and as potential therapeutic targets through which to enhance tumour sensitivity to neo-CRT. In pre-treatment OAC biopsies, 67 miRNA that were differentially expressed between responders and non-responders to neo-CRT were identified. MiR-330-5p and miR-187 were downregulated in the pre-treatment biopsy samples of the neo-CRT non-responders. The functional roles of miR-330-5p and miR-187 were investigated as modulators of tumour sensitivity to CRT. In vitro the silencing of miR-330-5p enhanced, albeit subtly, cellular resistance to radiation. Furthermore, silencing miR-330-5p altered the expression of extracellular proteases and protease inhibitors, including MMP1. In vivo a pilot study indicated miR-330-5p silencing enhanced tumour growth and may alter tumour sensitivity to cisplatin. In vitro miR-187 overexpression enhanced cellular sensitivity to radiotherapy and cisplatin, implying that the downregulated miR-187 expression in the non-responders may confer resistance to CRT. Furthermore, miR-187 induced apoptosis in vitro and induction of apoptosis is a potential mechanism by which miR-187 enhances radiosensitivity. MiR-187 altered the expression of genes encoding extracellular proteins, including C3 and other immune related genes. Both miR-330-5p and miR-187 are potential regulators of the secretome, thus emphasising the role of miRNA as modulators of the tumour microenvironment. This study has identified miR-330-5p and miR-187 as potential therapeutic targets that could augment OAC tumour sensitivity to neo-CRT.
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Dunn, Cherise. "Investigating the role of the Renin Angiotensin System in cancer." Doctoral thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/26862.
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It has recently been discovered that cancer shares a link with metabolic diseases, including that of cardiovascular disease, diabetes, amongst others, where common sets of genes show similar gene expression. There is thus interest to investigate current therapies for metabolic diseases as possible anti-cancer agents. The renin-angiotensin system (RAS) regulates blood pressure and cardiovascular homeostasis through Angiotensin Converting Enzyme-1 (ACE-1) and its homolog ACE-2. RAS has also been implicated in the progression of various cancers due to the increased action of the vasoconstrictor, angiotensin II, which requires ACE-1 and specifically the Angiotensin Type 1 Receptor (AT1R) for its function. In this study, we investigated the potential association of the endogenous ACE-1 and ACE-2 enzymes in cervical cancer. Our results showed that ACE-1 and AT1R protein expression was elevated in cervical cancer cell lines compared to normal cells and that this correlated with elevated ACE-1 enzyme activity in cancer cells. Treatment with the ACE-1 inhibitors, Captopril and Lisinopril, reduced this activity. We showed that ACE-1 axis stimulation in cancer cells results in increased calcium signaling preferentially via the AT1R and this associates with cancer cell proliferation. Candesartan, an AT1R blocker significantly reduced these effects. ACE-2 expression and activity were decreased in cancer compared to normal cells. Our data shows that ACE2 activators, the natural peptide angiotensin 1-7 and small molecule Diminazene aceturate (DIZE) have anticancer effects with DIZE inducing a G2/M arrest in cancer cells. We also investigated associations between drugs targeting RAS and current chemotherapeutic agents, Cisplatin (CDDP) and Doxorubicin (DOX). Our data shows that ACE-1 axis inhibitors have an antagonistic effect on CDDP, while the ACE-2 activator DIZE associates synergistically with DOX. Taken together, these results suggest that elevated ACE- 1 expression associates with cervical cancer and that the inhibitors of ACE-1 function or activators of ACE-2 function have potential as anticancer therapies as single agents or in combination treatments with current chemotherapeutics.
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Senate, University of Arizona Faculty. "Faculty Senate Minutes February 6, 2017." University of Arizona Faculty Senate (Tucson, AZ), 2017. http://hdl.handle.net/10150/622775.
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Small, Evan. "A study of redox enzymes in Sulfolobus solfataricus and their potential use in bio-sensors." Honors in the Major Thesis, University of Central Florida, 2005. http://digital.library.ucf.edu/cdm/ref/collection/ETH/id/807.
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This item is only available in print in the UCF Libraries. If this is your Honors Thesis, you can help us make it available online for use by researchers around the world by following the instructions on the distribution consent form at http://library.ucfBachelors
Burnett School of Biomedical Sciences
Molecular Biology and Microbiology
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Goldenberg, Maya. "The theory and practice of biomedical ethics : a troubled divide." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=30792.
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Biomedical ethics does not lend itself to easy categorisation as either a 'theoretical' or a 'practical' enterprise because inquiry into the quandaries of morality requires both situational and 'translocal' perspectives. These types of investigation bring into question the legitimacy of the theory/practice divide that has dominated intellectual thought since antiquity. This division hinders the development of bioethics by fostering internal dispute within the discipline regarding appropriate methodology and the practice of clinical ethics. In this thesis, I argue that much of these disciplinary disjunctions are due to an undue labeling of bioethics as either 'applied ethics' or 'practical ethics', and a failure to recognise the intricate way in which theory and practice inform each other and are integral and interrelated parts of moral deliberation. I argue for an integration of the theory and practice of bioethics.
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Efstathiou, Sophia. "The use of 'race' as a variable in biomedical research." Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p3352326.
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Thesis (Ph. D.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed May 8, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 240-245).
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Najjar, Deborah Anne. "Towards a more ethical animal model in biomedical research." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/120675.
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Thesis: S.M., Massachusetts Institute of Technology, School of Architecture and Planning, Program in Media Arts and Sciences, 2018.Cataloged from PDF version of thesis.
Includes bibliographical references (pages [69]-[75]).
Since the early twentieth century, mice have emerged as the standard mammalian model organism for biomedical research. When pain relief is provided during experimentation, it typically comes in the form of transient and sometimes ineffective analgesics or anesthesia. This thesis proposes an alternative to the current method of research in the form of an engineered mouse model in which pain sensing can be ablated before an experiment. An ERT2-inducible Cre recombinase under the Wntl promoter was designed to be combined with a floxed Nav1.7 ion channel mouse model. When a 4- hydrotamoxifan class small molecule is fed to the mouse, Cre recombinase expression in the peripheral nervous system will disrupt function of the ion channel involved in inflammatory and mechanosensory pain. Additional designs for floxed Nav1.6 ion channel and Nax ion-like channel were made to explore disruption of peripheral cancer-induced neuropathic pain. In parallel with mouse model development, a survey was conducted to understand the potential for adoption of this new animal model by researchers. The survey was sent to IACUC members questioning if this model was needed, as well as how it may be regulated under the existing protocol approval framework. Results indicated that there is a both a need and desire for further refinement strategies within animal research, and that this inducible painfree mouse model could be categorized as alternative analgesic upon sufficient characterization and peer-reviewed publications. Additional input was provided that will shape testing done on the generated animals to assure that this model can mitigate animal suffering while still recapitulating important biological processes investigated in biomedical research.
by Deborah Anne Najjar.
S.M.
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Tew, Sarada. "Methacrylate esters of cyclic alcohols of potential biomedical utility." Thesis, London Metropolitan University, 1988. http://repository.londonmet.ac.uk/2967/.
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3-Hydroxytetrahydrofuran, 3,4-epoxybutan-1-o1 and 3,4-epoxy-3- methylbutan-1-o1 were synthesized. The corresponding methacrylate esters were also prepared and their spectroscopic data are presented. The commercially available 3-methyloxetan-3- ylmethanol was converted to its methacryloyl ester and the analytical data was presented.
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Gustafson, Laura L. "Nonlethal health assessment of the freshwater mussel Elliptio complanata." NCSU, 2003. http://www.lib.ncsu.edu/theses/available/etd-01032003-130125/.
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Freshwater mussels are in decline, with over 70% of North American species categorized as endangered, threatened or of special concern. In an effort to create a nonlethal protocol for health evaluation of freshwater mussels we conducted a series of investigations on wild and captive populations of Elliptio complanata. We tested a method for nonlethal hemolymph collection and found no growth or survival effects in 30 sampled animals relative to 30 controls. We surveyed unionid populations from 19 different stream reaches from a rural region of North Carolina to provide a set of baseline ranges for hemolymph composition in healthy populations. These parameters included hemolymph calcium, magnesium, phosphorus, cell count, glucose, aspartate aminotransferase (AST), ammonia and protein. We tested these parameters in a captive population held under relatively uniform conditions and found most stable over time. Delta 15N declined substantially over time in captivity, likely in response to a large change in environmental _15N signatures. We tested health parameters in three groups of Elliptio complanata after three months under low, moderate or high feed conditions. The treatment groups varied in hemolymph glycogen, magnesium, calcium and phosphorus concentrations and in foot tissue _15N and _13C, providing possible indicators of subtle change in nutritional condition. We also transplanted Elliptio complanata from a stream enriched in _15N-N03 to a relatively depleted stream and evaluated the lag time required for mussel nitrogen isotope signatures to reflect new environmental signatures. We found a slow turnover time but relatively little variability compared to water signatures, suggesting that bivalves may be useful indicators of chronic nutrient loading in rivers and streams. We conclude that, with further research, hemolymph can be a valuable and safe tool for assessment of freshwater mussel population and habitat health.
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Nutter, Felicia Beth. "Evaluation of a Trap-Neuter-Return Management Program for Feral Cat Colonies: Population Dynamics, Home Ranges, and Potentially Zoonotic Diseases." NCSU, 2005. http://www.lib.ncsu.edu/theses/available/etd-11302005-195423/.
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Management of feral cats is controversial, and alternatives to lethal control methods are gaining popularity. To evaluate the effectiveness of sterilization programs, nine feral cat colonies were divided into groups of three, managed either by spaying females and castrating males, spaying females and vasectomizing males, or leaving all cats intact. Colonies were followed intensively for four years, and intermittently for three additional years. Most cats were trapped in fewer than ten trap nights each. Breeding females produced a mean of 1.4 litters/year and 3 kittens/litter. Kitten mortality was 75% by 6 months of age. Feral and pet domestic cats had similar baseline health status and prevalences of FIV, FeLV, Cryptosporidium, Giardia, and Toxocara cati, but feral cats had higher prevalences of Bartonalla henselae and Toxoplasma gondii. Castrated male and spayed female cats survived longer than intact male and female cats. Survival times of vasectomized males were equivalent to those of intact males. Control colonies decreased in size and remained stable in composition, while intact colonies increased in size and had high turnover. One neutered colony went extinct and several others had fewer than five cats at the end of the project. Home ranges of both intact and neutered cats were small, usually less than 1 ha. Vasectomized males had larger home ranges than either intact or castrated males, probably because they were searching for intact females. Community-level stakeholder meetings were successful in building consensus among groups, and a basic decision tree for feral cat management was developed. Computer simulation modeling using VORTEX software suggested that harvesting breeding colonies every one or two years at 50% to 100% can keep colonies small, but will not lead to long-term reductions in cat numbers. Models of neutered colonies suggested that 75% to 80% sterilization is necessary to cause population decrease and eventual extinction. The mean estimated time to extinction of 12.8 years fits well with ongoing observations of steady decline in sterilized colonies.
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Healy, Laura N. "Effect of background strain on the hematologic toxicity ofinhaled benzene in FVB/N-Tg.AC and C57BL/6- Trp 53 +/- knockout mice." NCSU, 2000. http://www.lib.ncsu.edu/theses/available/etd-20000110-094819.
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Benzene is an industrial solvent and a ubiquitous environmental pollutant that induces hematopoietic damage; although, the mechanism by which this damage occurs is uncertain. The hematologic effects of benzene vary widely among different mouse strains, and intermittent exposure of mice to benzene is more highly toxic and carcinogenic than low, constant exposure. The goal of the research described in this dissertation was to investigate the sensitivity of two genetically engineered mouse models of carcinogenesis, Tg.AC and p53 +/- mice, and parental strains FVB/N and C57BL/6 respectively, to hematologic toxicicity resulting from inhaled benzene. Tg.AC mice contain an activated v-Ha-ras oncogene, and the p53 +/- mouse is haplosufficient for the p53 gene. Hypotheses of this work included that benzene ishematotoxic, and that greater genotoxic damage caused by benzene would be evident in the p53 +/- mouse. Another hypothesis was that benzene would induce Tg.AC transgene expression in the spleen. The research was divided into three specific aims. First, genotoxicity resulting from exposure to benzene was determined by micronucleus formation in blood. These studies showed a time-dependent, but not a concentration-dependent increase in micronuclei following benzene exposure. The p53 +/- mice were not more sensitive to benzene-induced micronuclei than the parental strain (p53 +/+). For the second specific aim, benzene hematotoxicity was assessed and spleen analyses were conducted. Benzene induced a significant cytopenia and reduced spleen weight in all of the strains examined. The C57BL/6 mice were less sensitive to benzene hematotoxicity than the FVB/N strain for all of the hematologic parameters examined. For the third specific aim, expression of theTg.AC transgene mRNA was assessed by reverse transcriptase-polymerase chain reaction of splenic tissue. Evidence of the Tg.AC transgene expression was absent in these tissues. Overall, the findings showed a marked strain-related difference between FVB/N and C57BL/6 mice in the hematotoxicity of benzene. In most parameters investigated, the Tg.AC or p53+/- genetic alterations were not useful adjuncts for investigating the hematotoxic mechanisms of benzene. Investigation of the genetic differences between these two mouse strains may lead to further understanding of the biological determinants of benzene hematotoxicity.
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Anderson, Steven P. "Gene modulation during peroxisome proliferator-induced hepatocarcinogenesis." NCSU, 2001. http://www.lib.ncsu.edu/theses/available/etd-20011101-131940.
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ANDERSON, STEVEN PAUL. Gene modulation in peroxisome proliferator-induced hepatocarcinogenesis. (Under the direction of Russell C. Cattley and John M. Cullen). Recognition that peroxisome proliferator chemicals are potent hepatic mitogens and carcinogens in rats and mice has generated concern about possible human health risks associated with exposure to several of these chemicals, many of which have medical or commercial utility. Our broad objective was to improve the estimation of human health risk following peroxisome proliferator exposure by defining a subset of the molecular events associated with the rodent tumors. Our working hypothesis was that peroxisome proliferator-induced tumors in rodents result from specific, peroxisome proliferator-activated receptor-a(Ppara)-modulated changes in gene expression. The research was directed toward three specific aims. First, we sought to identify genes associated with hepatocarcinogenesis induced by the peroxisome proliferator, Wy-14, 643, in the rat. The principle conclusion of these studies - that peroxisome proliferators dysregulate expression of hepatic acute-phase protein genes - suggested possible perturbations in cytokine signaling networks that also regulate cell growth. Second, although Ppara is necessary for the rodent hepatocarcinogenesis induced by peroxisome proliferators, we were interested in identifying more proximate mediators of the increased cell proliferation. Thus, we examined cytokine signaling in mice treated with peroxisome proliferators. We found that peroxisome proliferator-induced increases in cell proliferation is not mediated via Tnfasignaling, but instead may be mediated through interleukin-1b or interleukin-6. Third, because Ppara is necessary for the cell proliferation that follows peroxisome proliferator exposure, we hypothesized that the receptor may play a role in hepatocellular proliferation induced by other stimuli. Following partial hepatectomy, liver regeneration in Ppara-null mice is transiently impaired, and may result from altered expression of genes regulating the G1/S cell cycle checkpoint in hepatocytes from these mice. Overall, our studies suggest that hepatic Ppara activation (1) alters inflammatory mediators, (2) modulates several potentially mitogenic cytokines, and (3) is necessary for normal liver regeneration after partial hepatectomy. Our data, compared with data from similar experiments on human hepatocytes, may provide further clues about the differences and similarities between peroxisome proliferator exposure in humans and laboratory animals.
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Langdale, Christopher Lawrence. "Lactational Exposure of Atrazine and the role of Prolactin in the Development of the Adult Male TIDA Neuronal System." NCSU, 2004. http://www.lib.ncsu.edu/theses/available/etd-01222004-143940/.
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Previous studies by Stoker et al., (1999b) and Shyr et al., (1986) examined the role of the rat dam's prolactin (Prl) during lactation on subsequent development on the offspring. Shyr identified a critical role for milk-derived Prl in postnatal development of tuberoinfundibular dopamanergic neurons (TIDA) by dosing lactating dams with bromocriptine, a dopamine (DA) agonist, on postnatal day (PND) 2-5, and PND 9-12 to block the release of maternal Prl in the milk. Offspring deprived of milk Prl from PND 2-5 showed a decrease in DA concentration and turnover rate in the median eminence on PND 33-35, demonstrating the importance of Prl to normal TIDA development. Furthermore, this decrease in DA was associated with hyperprolactinemia in male offspring when serum concentrations were measured on PND 30-32. However, no disruption of the TIDA development was observed in dams dosed from PND 9-12, suggesting that PND 2-5 was a sensitive time point for normal development of TIDA neurons. Stoker et al., (1999b) found that exposure of the dam to atrazine during the first 4 days of lactation suppressed maternal suckling-induced prolactin release. Interestingly, this treatment also led to an increased incidence of lateral prostate inflammation in adult offspring. However, prostate inflammation was absent in the male offspring when the atrazine-treated dam was co-treated with ovine prolactin. These observations have led to the hypothesis that decreased maternal prolactin (following atrazine or bromocriptine exposure) will lead to impaired TIDA development and elevated levels of prolactin in the juvenile male offspring (as shown by Shyr et al., 1986 and Stoker et al., 1999b). The two basic assumptions of this hypothesis have yet to be examined and are the focus of this study. First, can an increase in the concentration of serum Prl be determined in male offspring of dams treated with atrazine during early lactation; and second, is there evidence of a decrease in TIDA neuronal activity (DA concentration and turnover) following atrazine exposure? The potential of this herbicide to affect hormones normally present in milk and transiently alter development of the human offspring may be of concern to human health. Lactating females were dosed from PND 1-9, twice a day with 12.5, 25, or 50 mg/kg atrazine or 0.209 mg/kg bromocritine (PND 1-5). Male pups were selected and killed two hours before lights were turned off (14:10 light cycle). Serum Prl and TIDA neuronal development results supported both basic assumptions. An increase in serum Prl in male offspring of both atrazine 12.5 mg/kg and bromocriptine-treated dams were identified on PND 12 and 35, which was also consistent with prior reports by Shyr et al. (1986). The increase in serum Prl also coincided with decreased TIDA neuronal activity on PND 35. However, a non-linear dose response was observed following atrazine exposure to the dam in both brain aminergic and serum Prl concentrations in the offspring. Also, both compounds caused significant changes in the developmental profiles of dopamine and dopaminergic activity in all three brain areas tested. Although the atrazine data revealed a non-linear dose response in the offspring, the fact that the lowest dose of this herbicide produced changes that were similar to the positive control suggests that indeed this complex mode of action is affected by atrazine-treatment. Due to the complexity of the maternal-neonatal unit, subsequent studies examining the offspring at a later age will be required.
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Barlow, Norman James. "Antiandrogens and Development of the Male Rat Reproductive Tract." NCSU, 2003. http://www.lib.ncsu.edu/theses/available/etd-02102003-053205/.
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Di(n-butyl) phthalate (DBP) is an antiandrogen with known human exposure. The objectives of this thesis were to investigate the development of male reproductive tract malformations secondary to in utero DBP exposure from the fetus to the adult, to characterize the effects of DBP on fetal testicular gene expression for the steroidogenic enzymes, and to further explore DBP?s potential for inducing Leydig cell adenomas following gestational exposure. In utero DBP exposure led to a characteristic set of fetal testicular lesions including large aggregates of fetal Leydig cells, multinucleated gonocytes, and increased numbers of gonocytes. In addition to the testicular effects, DBP also caused maldevelopment of the epididymides. During the early postnatal period the fetal testicular lesions became less apparent while decreased numbers of spermatocytes were observed. Underdeveloped epididymides noted in fetuses remained small or failed to fully develop resulting in epididymides with missing components. Malformed epididymides were fully manifest in the adult with absent portions observed both unilaterally and bilaterally. Testicular atrophy with loss of spermatocytes became more severe as gestationally exposed animals matured. Gene expression for the steroidogenic enzymes was examined in testes exposed to DBP in utero. Gene expression was decreased for P450 side-chain cleavage enzyme, 3beta-hydroxysteroid dehydrogenase, and P450c17; while mRNA expression for 17beta-hydroxysteroid dehydrogenase, which catalyzes the final step in testosterone biosynthesis, was not altered. In utero exposure to DBP failed to induce an increased incidence of classical Leydig cell adenomas. However, a dysgenetic lesion composed of numerous poorly differentiated Leydig cells surrounding immature seminiferous tubules was identified. Testicular dysgenesis was observed with a similar incidence between age groups in mature rats, which supports in utero induction by DBP rather than development over time. Together these data provide insight into the molecular mechanisms underlying the induction of DBP-initiated male reproductive tract malformations.
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Beck, Karen. "Epidemiology of coyote introgression into the red wolf genome." NCSU, 2006. http://www.lib.ncsu.edu/theses/available/etd-03252005-042952/.
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Extensive predator control programs and habitat alterations reduced red wolves, once native to the southeastern United States, to a remnant population found in only a small portion of their historic range by the late 1960?s. Coyotes expanded their range into territories previously occupied by red wolves. As wolves became scarce, they began to breed with the more prevalent coyote. Introgression threatened the continued existence of the genetic integrity of the red wolf. The U.S. Fish and Wildlife Service, following a planned extirpation and institution of a captive breeding program, reintroduced red wolves to northeastern North Carolina in 1987. Though surveys had shown no evidence of coyotes in the reintroduction area, coyotes expanded their range eastward and a small red wolf population again interfaced with an increasing coyote population. The movement of introgression within the red wolf population is akin to the movement of an infectious disease. Identification of ?infected? and ?non-infected? individuals is accomplished at an early age in this population through pup assessments in the den. Intervention is accomplished through the use of sterilized coyotes and coyote-wolf hybrids to prevent the spread of the ?disease? to ?susceptible? individuals. Understanding how the ?disease? moves through the population by describing movement rates and the potential for contact between ?infected? and ?susceptible? individuals is accomplished through the analysis of telemetry locations of radiocollared individuals. The model for this ?disease? is also presented and evaluated to determine the effectiveness of intervention strategies in controlling the spread of this ?disease?.
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Booth, Brian William. "Mechanisms of interleukin-13 induced proliferation of normal human bronchial epithelial cells in vitro." NCSU, 2004. http://www.lib.ncsu.edu/theses/available/etd-04132004-101835/.
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Airway remodeling observed in chronic inflammatory diseases of the respiratory system is characterized by mucous cell hyperplasia, smooth muscle cell proliferation and subepithelial fibrosis. Interleukin (IL)-13 is a central mediator in the pathogenesis of inflammatory airway diseases playing a significant role in epithelial remodeling. In this study, we examined mechanisms through which IL-13 induces proliferation of normal human bronchial epithelial (NHBE) cells maintained in air/liquid interface culture in vitro, a model that allows for the maintenance of differentiated structure and function. It was found that IL-13-induced proliferation of NHBE cells is mediated by the autocrine/paracrine action of transforming growth factor-a (TGFa) that is produced by the epithelial cells and subsequently binds to the epidermal growth factor receptor (EGFR) on these cells. IL-13-induced release of TGFa involves the rapid mobilization of intracellular stores of TGFa to the apical cell surface, where membrane bound TGFa is cleaved by tumor necrosis factor-a converting enzyme (TACE), resulting in released growth factor. Both neutralizing anti-TGFa antibodies and the EGFR tyrosine kinase inhibitor AG1478 block IL-13-induced proliferation in concentration-dependent manners. Additionally, IL-13 induces the activation of the mitogen activated (MAP) kinase pathway and the phosphatidylinositol 3-kinase (PI3K) pathway, both of which are required for IL-13-induced proliferation. However, activation of the MAP kinase pathway by IL-13 does not appear to be TGFa mediated, as neutralizing anti-TGFa antibodies and EGFR tyrosine kinase inhibitors have little effect on IL-13-induced MAP kinase. PI3K was found to be involved in IL-13-induced release of TGFa as the specific inhibitor of PI3K, LY294002, blocks release of the growth factor. In summary, IL-13-induced proliferation of NHBE cells involves the intracellular redistribution and subsequent TACE-mediated release of TGFa, an event mediated by PI3K. This proliferation then involves the interaction of TGFa with the EGFR and requires activation of both the MAP kinase and the PI3K signaling cascades. These data establish a mechanistic framework for further study into the effects of IL-13 on bronchial epithelial cells as well as additional cell types that may interact with IL-13, or growth factors induced by this cytokine, in an in vivo setting.
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Humphries, LeRoy F. "EFFECTS OF POLYCYCLIC AROMATIC HYDROCARBON EXPOSURE ON THREE LIFE STAGES OF FRESHWATER MUSSELS (BIVALVIA: UNIONIDAE)." NCSU, 2006. http://www.lib.ncsu.edu/theses/available/etd-04212006-181938/.
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Freshwater mussels (Bivalvia: Unionidae) are among the most threatened aquatic species in the world. One of the major issues implicated in this decline is water pollution. Polycyclic aromatic hydrocarbons (PAHs) are a suite of hydrophobic environmental pollutants common in terrestrial and aquatic ecosystems. These compounds are largely derived from petroleum related sources (e.g., gasoline, oil) and are of major concern from transportation-related runoff to aquatic systems due to the acute and chronic (e.g., mutagenic and carcinogenic) toxic properties of many members of this class. The effects of exposure to PAHs have been investigated in many species of bivalves; however, to date no comprehensive study of the effects of exposure to these compounds on all life stages of native freshwater mussels have been completed. The goals of this study therefore were to investigate the effects of exposure to PAHs on all life stages of freshwater mussels and to develop diagnostic tests that are rapid, accurate, inexpensive, and of minimal impact to the mussels. This study examined the acute (48 h) toxicity of PAHs to the glochidial (larval) and juvenile stages of mussels and the sub-acute (7 d) toxic effects on adult mussels. Additionally, the study examined the use of genetic damage as a biomarker of exposure of mussels to PAHs by utilizing the Comet assay to determine levels of DNA strand breakage following aqueous exposure. Finally, mussels were collected from areas of high and low environmental levels of PAHs and were analyzed to validate laboratory findings and to examine relations to previously obtained field PAH mussel, water and sediment measurements. We found that there were no acute toxic effects of PAHs on glochidia or juveniles of the two species of freshwater mussels examined, up to concentrations approaching water solubility, and well exceeding those commonly measured in the streams of North Carolina. Experiments with adult Elliptio complanata, both in the laboratory and from the field, indicated that genetic damage due to PAH exposure was likely present, however the results were highly variable and the potential for biological, ecological, and toxicological consequences were uncertain. Further development and improvement of assay methods may reduce this variation. Generally, mussels from streams with higher average daily traffic counts (ADTC) exhibited greater levels of genetic damage compared to mussels from streams with lower ADTC values. Data obtained from the laboratory study generally showed increasing DNA damage relative to increasing PAH concentration. Based on the data generated, however, PAHs are not likely contributing to acute toxicity of mussels in North Carolina streams, but the chronic, long-term pervasive effect of PAHs on native freshwater mussels remains uncertain.
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Corrales, Jone. "Antimicrobial Polypeptides, Piscidins and Histone-Like Proteins, in Important Aquacultured Fish and the Effect of Nutrition on their Expression and Susceptibility to Infection in Hybrid Striped (Sunshine) Bass (Morone saxatilis â x M. chrysops â)." NCSU, 2008. http://www.lib.ncsu.edu/theses/available/etd-05052008-171103/.
Full textAbstract:
Innate immunity is the initial response of a host in defending against pathogen invasion (Beutler 2004, Janeway and Medzhitov 2002). The key features of an innate immune response are that it is: non-specific (broad-spectrum), rapid (often within minutes to hours) and conserved in its pattern of recognition. Antimicrobial polypeptides (AMPP) are a key component of the innate system and present in virtually all life forms (Zasloff 2002). One of the most widespread AMPP in fish are the piscidins. Piscidins have potent, broad-spectrum activity against viruses (Chinchar et al 2004), bacteria (Silphaduang and Noga 2001), fungi (Lauth et al 2002) and parasites (Colorni et al, Accepted). Another family of AMPP are histone-like proteins (HLPs), which are highly homologous to core nuclear histones (Robinette et al 1998, Noga et al 2002). Because disease is often the major cause of economic losses in fish farming, understanding how stress affects innate immunity (e.g., expression of AMPP) and thus disease susceptibility could be highly beneficial to the industry. One very important factor that can contribute to stress in aquaculture is inadequate nutrition. Feed is the single largest expenditure in semi-intensive and intensive farms (Lunger et al 2007, Twibell et al 2003, Mbahinzireki et al 2001). Thus, reducing feed costs while still maintaining optimal health is critical for successful production. As nutrient intake decreases, metabolic processes are impaired and susceptibility to disease increases. I anticipated that this would be reflected in the levels of piscidins and HLPs. The overall goal was to investigate the levels of these antibiotics that indicate fish are stressed prior to any pathological signs. For this first, an ELISA for piscidin 4 was developed and validated and its application to asses stress was confirmed. Using this ELISA and various other independent assays the presence of piscidin 4 related AMPP were detected in important aquacultured fish. Next, I found that nutritional deprivation has a deleterious effect on piscidin 4 expression and that susceptibility to an ich increases in hybrid striped bass (Morone saxatilis âx M. chrysops â). The nutritional deprivation also lead to dermatological condition in channel catfish.
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Molina, Reverie Alvarez. "Morphological and Genetic Description of the Freshwater Mussel, Elliptio complanata (Lightfoot, 1786) in the Cape Fear River System, N.C." NCSU, 2004. http://www.lib.ncsu.edu/theses/available/etd-05202004-184213/.
Full textAbstract:
The purpose of this research is to provide a preliminary description of the morphological and genetic variation of a cosmopolitan freshwater mussel E. complanata from one North Carolina river system, Cape Fear River (CFR). Individuals from CFR were collected and compared with known specimens of E. complanata (topotype). Multivariate analyses, such as factor and discriminant analyses were utilized to differentiate the individuals based on thirty morphological shell landmarks. Genetic analyses involved the use of diversity estimates and cluster analyses based on cytochrome oxidase I (COI) sequence and Amplified Fragment Length Polymorphism (AFLP) fingerprint data. Factor analysis suggest that E. complanata from CFR maybe differentiated based on the thickness of posterior and anterior shell angles, and obesity of the shells. Significant differences between the CFR samples and topotypes were demonstrated by discriminant analysis of morphological data and by COI gene diversity estimates. This difference corroborated earlier work suggesting geographic delineation of E. complanata shell form. Genomic fingerprinting suggests further variation even within the topotypes. Phenotype of the topotypic materials seems to support this genomic variability. Heirarchical cluster analyses of morphometry and genetic data further showed different groups supporting earlier research suggesting high form variation within the E. complanata species.
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knuckles, Travis. "In Vitro Cardiotoxicity of Residual Oil Fly Ash." NCSU, 2005. http://www.lib.ncsu.edu/theses/available/etd-06122005-112617/.
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Knuckles, Travis Lee. In Vitro Cardiotoxicity of Residual Oil Fly Ash. (Under the direction of Kenneth B. Adler and Kevin L. Dreher). Epidemiological studies have shown an association between air pollution particulate matter (PM) and adverse cardiovascular effects. Although numerous mechanisms have been proposed, the actual mechanism(s) as well as emission sources and associated causal properties by which PM affects the cardiovascular system remain elusive. At least some adverse PM health effects can be attributed to bioavailable constituents, most notably, the transition metal content of the particles. Toxicological studies in rats using residual oil fly ash (ROFA) combustion source particles show extrapulmonary effects ranging from thermo-regulatory alterations, myocardial necrotic lesions, to fatal cardiac arrhythmias. Exposure of rats to ROFA via intratracheal instillation shows a rapid and transient increase in plasma metal content as early as 15mins post-exposure, suggesting that PM constituents are bioavailable to both the systemic circulation and perfused organs. However, the impact of this systemic exposure on extrapulmonary organs at the cellular and molecular levels is unknown. In this study, cardiomyocytes derived from 1-day-old rat pups were exposed to determine the direct effects of a particle free residual oil fly ash leachate (ROFA-L). Using concentration of leachate relevant to amount that were found in the plasma of rats following pulmonary deposition, I have shown that ROFA bioavailable constituents cytotoxicity in cardiomyocyte cultures and alter cardiomyocyte gene expression and transcription factor activation profiles consistent with alteration in cardiomyocyte growth and function.
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Thibodeaux, Julie Rene. "Perfluorooctane Sulfonate-Induced Thyroid Hormone Disruption in the Rat." NCSU, 2005. http://www.lib.ncsu.edu/theses/available/etd-06242005-103138/.
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Perfluorooctane sulfonate (PFOS) is a perfluoroalkyl acid that has unique surfactant properties and is used widely in industrial and household products. Furthermore, PFOS is an environmentally persistent compound, and its presence has been detected in both humans and wildlife. The maternal and developmental toxicities of PFOS were evaluated in Sprague-Dawley rats given 1, 2, 3, 5, or 10 mg/kg PFOS daily from gestational day (GD) 2 to GD 20. Controls received 0.5% Tween 20 vehicle (1 ml/kg). Serum thyroxine (T4) and triiodothyronine (T3) in the PFOS-treated dams were significantly reduced as early as one week after chemical exposure, although no feedback response of thyroid stimulating hormone (TSH) was observed. The effects of sub-chronic exposure to PFOS (3 mg/kg/day for eight days) on thyroid hormone economy are further characterized in adult male rats, and the thyrotoxic effects of PFOS are compared to propylthiouracil (PTU), a classic goitrogen. This work substantiates the endocrine disrupting effects of PFOS, but fails to provide evidence for its physiological consequences in comparison to PTU based on two biomarkers of hypothyroidism: myocardial beta-adrenergic receptor density and hepatic malic enzyme activity. Furthermore, in vitro static incubation of the pituitary is used to investigate the observed lack of response of the hypothalamic-pituitary-thyroid axis. PFOS does not significantly alter thyrotropin releasing hormone (TRH) induced secretion of TSH from the pituitary. Therefore, it is not likely that PFOS-induced changes in circulating thyroid hormones are due to a disruption at the level of the pituitary.
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Vijay, Vikrant. "Assessment of Cutaneous Permeability of Biocides in Mixtures using QSPR Approach." NCSU, 2009. http://www.lib.ncsu.edu/theses/available/etd-06292009-233331/.
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The purpose of this research work was to assess the dermal permeation of biocides in metalworking fluids (MWFs) to develop predictive QSAR models and to develop an appropriate training set of chemicals to enhance the predictive ability of QSAR models for dermal permeation. Estimation of the amount of chemicals absorbed through skin plays a vital role in dermal risk assessment. Approximately 1.2 million US workers are occupationally exposed to MWFs annually. Different components of MWFs especially biocides, contribute to adverse health effects including irritant and allergic contact dermatitis as well as carcinogenesis. These adverse effects may be positively correlated to their dermal absorption and may cause systemic toxicity if absorbed in significant amount in workers involved in metalworking operations. A lack of scientific data exists regarding the dermal permeation of MWF components, particularly biocides. Therefore, the first two studies were conducted to (1) determine the dermal permeation of biocides and other chemicals (used as training set to develop Linear Solvation Energy Relationship (LSER) models) in commercial and generic MWFs; and (2) develop a LSER model for predicting dermal permeation of other biocides, not used in these studies. Dermal permeation was evaluated in dermatomed porcine skin by utilizing a flow through diffusion cell system. Chemical analysis was performed by employing gas chromatography with a solid phase micro-extraction technique and ultra performance liquid chromatography with a solid phase extraction technique. LSER models, which are a subset of quantitative structure activity relationship models, were constructed by multiple linear regression analysis with permeability coefficient as the response variable and solvatochromic descriptors as the predictor variables. The LSER model is useful to quantitatively measure the difference in interaction between the two phases (skin and vehicle) as well as a predictive tool. Since the training set used to develop a LSER model was not optimally diverse in terms of structure and chemical space, the third study focused on developing a training set of chemicals representing a wider chemical space (in terms of descriptor values) using a best possible chemical selection method. The results from the first two studies demonstrated that (1) the dermal permeation of biocides as well as other chemicals was highest in aqueous solution followed by synthetic, semi-synthetic and soluble oil type of MWFs; (2) addition of water to MWFs for dilution increased dermal permeation; (3) the LSER model adequately predicted the dermal permeability of biocides in MWFs and also shed light on the chemical interactions resulting in reduced permeability. An optimal and less subjective method (uniform coverage design) to select chemicals representing a wider chemical space was identified in the third study. The LSER model based on the new selected training set of chemicals performed statistically better over the LSER model based on the training set used in the previous study. In summary, the aforementioned results demonstrated that there is a difference in the absorption profile of chemicals among the type of MWFs and dilution of MWFs with water increases the dermal permeation of chemicals; the LSER model can be useful to explain the change in vehicle solvatochromic properties upon addition of water as well as can be an effective prediction model for dermal permeation of chemicals in mixtures; finally, a structurally diverse training set of chemicals representing a wider chemical space is required to improve the predictive capability of a model. All of these results will augment the dermal risk assessment of the chemicals in mixtures and contribute to the improvement of computational predictive models.
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Ullal, Anirudh Jaiwant Mr. "DRAFT - Extra-erythrocytic expression of antimicrobial peptides derived from the β-subunit of hemoglobin is associated with a potent anti-parasitic defense in fish." NCSU, 2006. http://www.lib.ncsu.edu/theses/available/etd-11062006-173910/.
Full textAbstract:
Innate immunity plays a crucial role in the defense against prokaryotic and eukaryotic pathogens. Major components of this defense are antimicrobial peptides (AMPs). Some AMPs are derived from larger proteins with other recognized functions (e.g., lactoferrin, histones). In this study, we demonstrate the expression of peptides homologous to the β-chain of hemoglobin (Hb-β), one of the two major subunits of this respiratory protein. These Hb-β peptides (HbβP-1, -2 and -3), isolated from gill of the economically important channel catfish (Ictalurus punctatus), had antibacterial activity and were upregulated in gill and skin epithelium in response to parasitic (Ichthyophthirius multifiliis, ich) infection. One peptide (HbβP-1), while having relatively weak antibacterial activity, had antiparasitic activity comparable to that of other potently antiparasitic AMPs. Also, this cidal activity was specifically directed against the trophozoite (trophont) stage of ich at a low concentration (6.2 ug/ml, 1.7 mM) but had no apparent effect on the disseminative (theront) stage or the reproductive (tomont) stage at the highest concentration tested (400 mg/ml, 108 mM). In addition, HbβP-1 was not lytic to channel catfish erythrocytes at the highest concentration tested (400 mg/ml, 108 mM). Immunohistochemistry and in situ hybridization of skin and gill from fish experimentally challenged with ich indicated that the HbβP-1 sequence was both synthesized and expressed in epithelial tissues of skin and gill, which are the target tissues for ich. ?Bug blots? of gill extracts from fish recovering from a bacterial infection suggested that upregulation of these Hb-β related peptides might also occur with other infections. These findings, along with the recent discovery by others that Hb-β is expressed in mammalian macrophages and alveolar epithelium, suggest that hemoglobin-derived AMPs might play a significant role in the non-specific immune response of vertebrates.
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Gebreyes, Wondwossen Abebe. "Molecular Epidemiology of Multi-drug resistant Salmonella in swine production systems." NCSU, 2001. http://www.lib.ncsu.edu/theses/available/etd-20010928-104421.
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The swine industry is often implicated as one of the most significant contributors to foodborne Salmonella infections in humans. As the trend in swine production in the United States is toward larger and more intensive farms, but fewer farm units, it is likely that antimicrobial usage is also increasing. The purpose of this research was to study antimicrobial resistance and determine phenotypic and genotypic diversity of multi-drug resistant Salmonella in swine production systems. We found resistance to specific classes of antimicrobials including tetracycline, b-lactams and chloramphenicol to be common and stable over the study period. Over the time period of the study, we also noticed a significant shift in the patterns of multi-drug resistance, despite the fact that no change in antimicrobial usage had taken place, suggesting that other, currently unidentified selective pressures could be of significance. Bacteriophage typing also revealed that two phage types of importance to public health, DT104 and DT193, often had two predominant pentaresistance patterns. Susceptibility testing on a number of human S. Typhimurium isolates, however, revealed that multi-drug resistance was infrequent among isolates originating from humans. The findings in studying the genetic diversity of these Multi-drug resistant strains imply that vertical transmission, most likely originating from the sow farm, is an important source at the nursery stage, but that horizontal transmission of clonal groups is significant at the finishing phase. Resistance genes detected on multi-drug resistant Salmonella Typhimurium DT193 revealed that the resistance genes and locations are specifically different from that of DT104.Overall, the study findings show that antimicrobial resistance in the swine production environment is common and may be linked to the level of antimicrobial usage. Despite the common occurrence of public health important strains among isolates from swine, strains from humans were distinct and were less likely to be resistant to multiple antimicrobials. This area needs to be of high priority for further research to assess the risk of human Salmonella infection from swine or pork products. Further research on the genetic diversity of Salmonella also must be considered in order to identify significant factors contributing to the dissemination of multi-drug resistant Salmonella in modern swine production systems.
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Odumosu, Patricia. "Evaluation of the plant extracts of an anti-tubercular herbal remedy." Thesis, University of Sunderland, 2012. http://sure.sunderland.ac.uk/3330/.
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Ximenia americana root bark (Olacaceae) and Pavetta crassipes (Rubiaceae) leaf used in Nigerian traditional medicine were tested individually against clinical isolate of Mycobacterium tuberculosis by Lowenstein - Jensen method. Crude aqueous extracts of X. americana and P. crassipes exhibited minimum inhibitory activity (MIC) of 100 μg/mL and 200 μg/mL respectively. Sequential screening with solvents of different polarities was used in evaluation tests to readily locate the source of the activity against tuberculosis and for conditions related to skin diseases since it was readily available. In general, antimicrobial screening of crude extracts gave MICs ranging from 31.25 μg/mL to > 5 mg/mL, with X. americana methanol extract being most active at 31.25 μg/mL against Staphylococcus aureus. In an effort to determine possible mechanisms of action, synergistic interaction studies between standard antibiotics and plant extracts were carried out with some synergy being observed between X. americana extract and streptomycin. Hexane (MIC 60.6 μg/mL) and dichloromethane (MIC 30.5 μg/mL) fractions of X. americana exhibited 94.3 % and 96.4 % inhibition against M. tuberculosis H37HRv (virulent strain) while P. crassipes hexane fraction had 86.7% inhibition at > 64 μg/mL. Using HPLC, TLC, GC, 1D and 2D-NMR as well as mass spectral analyses it was possible to identify rutin and 5-O- caffeoyl quinic acid methyl ester from P. crassipes. It proved extremely difficult to identify compounds from LC and TLC fractions from the non-polar extracts of X. americana responsible for anti-TB activity. There was some spectroscopic evidence from these fractions for closely related phytosterol esters and individual compounds such as stigmast- 3, 5 - diene, stigmastane oleate and β-sitosterol. Subsequent LC work with refractive index detection and SFC with evaporative light scattering data confirmed that the difficulties in assignment arose from the presence of non-UV absorbing non-volatile co-eluting compounds. Preparative xviii SFC or SFC-MS with the aid of the NIST database would have been needed for identification. Overall, these results lend some credence to the claims of the Nigerian remedy and potentially could be a source of assay biomarkers for monitoring its safety, efficacy and quality as required by IRCH (International Regulatory Co-operation for Herbal Medicines).
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McDonald, Carl Peter. "The significance of bacterial contamination in transfusion medicine and strategy to reduce patient morbidity and mortality." Thesis, University of Sunderland, 2008. http://sure.sunderland.ac.uk/3758/.
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Bacterial transmission is the major cause of microbe associated morbidity and mortality in transfusion recipients. In these studies initially the actual clinical impact was assessed and bacterial contamination rate determined in blood components. Until the late 1990 s, no effective intervention had been introduced in the UK to reduce the transmission of bacteria by transfusion. Three strategies were developed: improved donor arm disinfection, diversion of the first 20ml of donated blood and bacterial screen testing of platelet concentrates. These interventions have now been implemented by the National Blood Service (NBS) and other blood services worldwide. Improved donor arm disinfection was shown to be 10 times more efficient than existing practice and reduced bacterial contamination in whole blood by 57% and reduced clinically apparent transmissions by 65% (from 17 to 6 cases per million). Diversion reduced contamination in whole blood by 47% and clinically apparent transmissions from platelet concentrates by 76% (from 21 to 5 cases per million) and 100% in red cell units (previously 0.3 cases per million). BacT/ALERT was adapted for screen testing platelet concentrates and is now used routinely for shelf life extension. Pall eBDS was developed and enhanced by the National Bacteriology Laboratory of the NBS on a collaborative basis for the same purposes. These studies provided data which facilitated Certificate European marking and Food and Drug Administration approval for both systems. Both systems have now been implemented throughout the world and are market leaders. Scansystem (a rapid assay) was investigated, but was not considered suitable for routine use. Screen testing of all NBS platelet concentrates is now under consideration by the service. The studies undertaken have made a significant contribution to knowledge and have helped improve blood transfusion practice worldwide. Practicable and cost effective interventions supported by scientifically robust data have resulted in a marked reduction in transfusion-transmitted bacterial reactions, thereby improving the safety of the blood supply.
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Ansari, Khalid. "A critical evaluation of prognostic indicators of the natural history of chronic obstructive pulmonary disease (COPD)." Thesis, University of Sunderland, 2012. http://sure.sunderland.ac.uk/3790/.
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In order to monitor progression of COPD there is a need to develop indicators that accurately reflect observed symptoms. This information can then be used to inform treatment and also advice patients as to lifestyle changes that should be made to improve the outcome of the disease. Assessment of the natural history of COPD has, since the classic studies of Fletcher and Peto, historically used FEV1 decline as a marker of severity (GOLD Guidelines). However, the more recent introduction of the multidimensional index BODE, derived from Body Mass Index, the degree of airflow obstruction, Medical Research Council Dyspnoea score and Exercise capacity has brought further refinement into the assessment process. This study has investigated BOD, a model whereby the exercise test is omitted. BOD was evaluated using Body Mass Index, the degree of airflow obstruction, the Medical Research Council Dyspnoea score using a cohort of 458 patients. The results show that BOD is an effective index for the measurement COPD progression. The results also suggest that the BOD model may predicts COPD outcomes more accurately than the BODE and GOLD models. Each quartile increase of the BOD score was associated with a lower survival. The quartile with the worst BOD scores had a 10 year mortality rate of about 42% in contrast to the GOLD classification of severity where the worst stage (Grade 4) was associated with a mortality of 58%. The Cox model was utilized to determine if the BOD model could be improved upon by the inclusion of the other factors investigated. It is also observed that addition of pack years smoking history scores (S) in BOD scores improves its accuracy by 3%. Other factors that influence the progression of COPD have also been investigated as potential measures of disease outcome. These include: historical height, lean body mass, hand grip strength, symptoms duration, C reactive protein (CRP), assessments of health related quality of life and wellness. IV Studies into the concept of wellness suggest that assessment of the inner state of mind, as a means of determining wellness status, could be used to improve disease outcomes. The results suggest various stress factors, anger management and spirituality appear to play a vital role as the disease progresses and help to modify patient’s attitude, thinking and coping behaviour during illness. This study has shown that overall there is a need to develop an indicator that measures both physical factors together with a patients’ “wellness”. BOD together with the Sunderland Respiratory Wellness Questionnaire are the first novel steps in this process. ______________________________
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Patel, Sharvil Pankaj. "Development of immobilised biopolymer stationary phases based on the efflux transporters." Thesis, University of Sunderland, 2007. http://sure.sunderland.ac.uk/3756/.
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The body is continuously exposed to a variety of toxins and metabolic waste products but is able to rid itself of these by using various detoxification mechanisms such as enzymes and transmembrane transporters. A large number of the transporters which play an essential role in the detoxification mechanisms are found in the liver, kidney and intestines. The largest family of transporters is the Solute Carrier (SLC) Superfamily with 255 members in humans. While most SLC transporters are highly specialized, a number of these transporters are polyspecific, generalized transporters that play a major role in the elimination process. Accordingly, the aim of this research programme was to develop novel methodology to enable the study of the interaction of drugs and related compounds with these transporters, in a rapid and facile manner. In the initial studies the application of affinity chromatography was carried out with the use of α1-acid glycoprotein (AGP) column to achieve enantioselective separation of the drug ketamine and its metabolites. The enantioselective separation of ketamine and norketamine from plasma samples was achieved and the assay conducted was sensitive and reproducible. Building upon the experience gained in this work on affinity chromatography and LC-MS, these useful tools for the determination of chiral drugs in biological fluids were also used in the study of drug-protein interactions. With the nicotinic acetylcholine receptors it was possible to explore the use of immobilized liquid chromatographic stationary phases containing drug transporters in on-line high throughput screening (HTS). I Thus having demonstrated that a stationary phase containing immobilized membranes can be used to identify substrate/inhibitors of an expressed receptor/transporter the next and principal phase of the programme was to adapt the methodology to other target biopolymers such as P-glycoprotein which over the last decade has been focused upon for its role in drug resistance in cancer treatments. In particular liquid chromatographic columns containing the drug transporters, P-glycoprotein (Pgp) and human organic cation transporter 1 (hOCT1) were prepared, evaluated and exploited. Initial studies were conducted to confirm the functionality of a stably transfected cell line expressing Pgp (Pgp-(+), LCC6/MDR1 cell line) through a comparison with the non-transfected cell line (Pgp-(-), LCC6 cell line). Initially membranes from the Pgp(+) and Pgp(-) cell lines were then immobilized on immobilized artificial membranes. However, although the resulting column could actively bind the Pgp substrates, strong non-specific interactions with the IAM backbone led to large retention times and peak tailing. A more successful approach was to immobilize on the surface of open tubular capillaries. Such columns were used to sort compounds with or without affinity for Pgp, by comparing the differential retention time on the Pgp (+) and Pgp (-) columns. In this way the non-specific interactions with the constituents of the cellular membrane were compensated for. The results from the sorting by differential chromatography were compared with the behavior of the same compounds in Caco-2 monolayers cultured in 96-well transwell plates, the standard method for the determination of substrates for Pgp. A group of 14 compounds II previously characterized as substrates or non-substrates of Pgp were studied using the chromatographic and Caco-2 methods. In the parallel chromatographic screen, the value of
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Roberts, Elizabeth Rose. "The generation of an immunosuppressive microenvironment by soluble factors in head and neck squamous cell carcinoma." Thesis, University of Hull, 2018. http://hydra.hull.ac.uk/resources/hull:16559.
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Tumour infiltrating lymphocytes (TIL) in head neck squamous cell carcinoma (HNSCC) are enriched in Treg, a finding confirmed in the current study, which is thought to be a contributing factor to immunosuppression and tumour evasion. Soluble factors released by malignant HNSCC cells may contribute to the enrichment of Treg by inducing differentiation from naïve T cells and their migration to the tumour. Using multi-colour flow cytometry, increases in CD4+CD25hi, CD4+CD25+CD39+, CD4+CD25+CD26− and CD4+CD25+FoxP3+ Treg phenotypes were observed in TIL from HNSCC compared to PBMC. Following culture of CD4+CD25− T cells with conditioned medium (CM) collected from dispersed tumour samples, there was an increase in CD39 expression but not FoxP3 compared to control cultures that were cultured in complete growth medium. Furthermore these cells were unable to suppress the proliferation of CD4+CD25− T cells in CFSE assays. Soluble factors in CM from UMSCC cell lines and tumour-derived fibroblasts were unable to induce the expression of any Treg markers following culture with CD4+CD25− T cells. Culture with CM also had no effect on T cell apoptosis, with no significant increase in PI-AnexinV+ of CaspACE-binding in T cells cultured with CM compared to controls. The expression of the chemokine receptors, CXCR3, CCR4, CCR5 and CCR6 was analysed on T cell populations from HNSCC PBMC and TIL and healthy control PBMC using five-colour flow cytometry. Increased proportions of CXCR3+ and CCR5+ T cells were observed in HNSCC TIL compared to HNSCC PBMC but were no different between the patient and healthy control PBMC. CCR4 and CCR6 were expressed on a higher proportion of Treg from HNSCC PBMC compared to healthy controls but no difference was observed on CTL. In TIL the percentage expression of CCR4 and CCR6 were no different in that of HNSCC patient PBMC. Despite these observed differences in receptor expression, soluble factors in tumour dispersed CM was unable to induce T cell chemotaxis. Overall, although limited effects were observed from soluble factors in tumour CM, the different expression of chemokine receptors suggests there may be a role for soluble factors in Treg recruitment. However whether this is responsible for Treg accumulation or general to all T cells is unclear.
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Cesta, Mark Francis. "Contribution of Bacterial Lipopolysaccharide to Carbon Nanotube- and Vanadium Pentoxide-Induced Pulmonary Fibrosis in Rats." NCSU, 2010. http://www.lib.ncsu.edu/theses/available/etd-03172010-173120/unrestricted/etd.pdf.
Full text
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Issarow, Chacha M. "Modelling the transmission of tuberculosis." Doctoral thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/23721.
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Airborne infectious diseases, such as tuberculosis (TB), are spread by airborne infectious particles (viable particles with potential for TB infection) in exhaled air from infectious individuals in enclosed spaces. Exhaled air is the carrier of airborne infectious particles and carbon dioxide is used as a surrogate of this exhaled air. Using carbon dioxide as a surrogate for exhaled air, we modified the Wells-Riley model and the prior modified versions of the model, and obtained a exible but sensitive mathematical model that predicts the risks of airborne infectious diseases, such as TB under steady- state and non-steady-state conditions, without assumptions of well mixed airspace and equilibrium conditions. Applying experimental data from in vivo studies to the mathematical model developed in this study, we explored the probability of exposed guinea pigs acquiring infection in these in vivo stud- ies and quantified the number of surviving airborne infectious particles (infective organisms) required to reach the alveolar to establish infection. Our study shows that the number of infective organisms reported in the in vivo studies might have been markedly underestimated. In this study, we investi- gated TB transmission in congregate settings, such as schools, households, public transport, prisons and health care settings and suggested preventive measures. TB transmission in these locations is attributable to numerous factors, including overpopulation and air pollution, which acts as a carrier of airborne infectious particles. We explored the impact of effective contact rate on TB epidemiology using a mathematical model we developed that consists of five states of susceptible, primary infection, reinfected, active TB and treated individuals. An infectious individual with varying effective contact rate (ranging from 5 to 30 per year) was introduced among 100; 000 fully susceptible individuals and we observed the number of primary infection and reinfected individuals at stability points of a TB epidemic. We found that the number of primary infection individuals decreases at the stability point, while that of reinfected individuals increases with increasing effective contact rate. This implies that a large number of active TB cases might be reinfected individuals. Using an age-structured mathemat- ical model developed in this study that incorporates vaccination, we explored TB disease progression in different age groups (from 0 to ≥ 75 years). We found that TB disease progression is age dependent. High TB notification rate was detected for the age groups [0 - 5); [15 - 25); [45 - 55) and [55 - 65) years, and the lowest TB notification rate was detected in the age group [5 - 15) years. Furthermore, we noted that vaccination decreases active disease progression for the age groups [0 - 5) to [15 - 25) years, while TB notification remains high for the age groups [25-35) to ≥ 75) years. The findings in this study suggest that active disease progression depends on age and average duration of the waning of the vaccine effect.
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Ganief, Tariq Ahmad. "A network analysis based proteomic and transcriptomic investigation into HIV-Tat induced neuronal dysfunction and the neuroprotective effect of lithium." Doctoral thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/22759.
Full textAbstract:
HIV-associated neurocognitive disorders (HAND) affect up to 70% of HIV positive individuals and are the leading cause of dementia in patients under 40 years. Despite this, the molecular mechanisms involved in the onset of HAND are not well understood. Among a number of plausible etiological agents of HAND, HIV-Tat has been shown to be neurotoxic in vitro and in vivo, but the basis of its induced neuronal dysregulation remains relatively poorly characterised, giving rise to various competing theories. This thesis describes differential, quantitative proteomic analyses of HIV-Tat-treated neuronal cells in vitro, the goal being to gain deeper insight into the underlying molecular basis of this HIV-Tat-mediated dysregulation, as well as to potentially inform better patient treatments in the future. To achieve this goal, deep, quantitative proteomic analysis of HIV-Tat treated SILAC-labelled SH-SY5Y neuroblastoma cells was carried out, alongside transcriptomic analysis of the same system in which 3077 proteins were identified and quantified with 407 proteins and 1074 genes being differentially expressed. Subsequently, label-free proteomics analysis was used to study the ability of lithium - a proposed new treatment for HAND - to suppress the HIV-Tat induced dysregulated molecular phenotype in SH-SY5Y cells in which 3757 were identified and quantified with 360 and 531 being significantly differentially expressed in HIV-Tat and HIV-Tat + lithium treated cells, respectively.
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Omar, Shatha Sultan Ahmed. "Characterisation of HIV-1 subtype C envelope functional determinants of dual infected individuals." Doctoral thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/29417.
Full textAbstract:
Identification of HIV-1 Envelope (Env) fitness determinants could provide functionally constrained, accessible regions that could be included in subunit vaccines to induce broadly neutralising antibodies (bnAb). We hypothesised that Env fitness determinants are common to circulating variants but that the plasticity of Env structure limits identification. Rapid evolution; however, could select for sequence changes within the determinants coincident with alterations in function, making identification easier. Dual infection with two phylogenetically distinct HIV-1 variants under the same selective pressures might result in rapid functional evolution, facilitating identification of Env fitness determinants. It has been shown that the Env plays a significant role in viral adaptation to the host environment, which then increases disease progression. Therefore, this study used dual infections as a model system to characterise Env function, its role in in vivo viral outgrowth of variants and disease progression and to identify fitness determinants for future vaccine design. Single-genome amplification (SGA)-derived env sequences of four dual infected individuals sampled at enrolment (0 months), 3, 6, and 12 months post infection (mpi) were analysed using Highlighter plots, RIP, DNA pairwise distance and Neighbourjoining trees to determine the in vivo evolution of infecting viral populations and their relative frequency over time within each participant. Representative amplicons were cloned at each time point and compared using a pseudovirus (PSV) entry efficiency assay. 2 characterised by Affinofile system, T-20 IC50 and Western blotting to identify whether tropism, Env expression/cleavage, incorporation into viral particles and fusogenicity were most likely responsible for the variation in Env entry efficiency. All variants were R5- and T-tropic and only Env fusion capacity correlated significantly with Env entry efficiency data (p = 0.02, r = 0.59), suggesting that variants infecting dual infected participants evolved towards higher fusion capacity. Changes in Env fusogenicity indicated that gp41 might be a fitness determinant of PSV entry efficiency and analysis of SGA sequences indicated that recombination within gp41 was common to 3/4 participants. Env chimeras were generated where gp41 was swapped between clones that either had the same (CAP84) or different (CAP267) PSV entry efficiency. For both participants, and (CAP137) gp41 was identified as a potential determinant of Env fitness. Moreover, two potential N-glycan sites (PNG) at position N332 and N339, previously reported to be involved in neutralising antibody escape, were also identified. While N332 enhanced Env entry efficiency in one participant, N339 attenuated Env entry efficiency in another, potentially due to the escape mutation carrying a fitness cost. However, neither PNG seemed to affect Env expression/cleavage, incorporation into viral particles and fusogenicity. As Env phenotypic characterisation focussed on PSV assays, we wanted to determine whether viral replication was also similarly affected. Infectious molecular clones (IMCs) were generated from two participants using a recombination yeast assay and replication capacity (RC) in peripheral blood mononuclear cells (PBMCs) was assessed using parallel replication. A significant correlation between RC of viruses in PBMCs and Env entry efficiency in TZM-bl and fusion capacity (p = 0.03, r = 0.7; p = 0.04, r = 0.7, respectively) was determined. IMC RC was also associated with in vivo outgrowth of viral populations at 12 mpi although this relationship did not always coincide with the frequency of individual variants. Changes in the RC of the Env chimeras and mutants was not associated with phenotypic changes, suggesting that Env entry efficiency determinants did not play the same role in IMC RC as it did in PSV entry. Lastly, there was a significant negative association (p = 0.046, r = -0.59) between Env entry efficiency and CD4+ T decline, a marker of disease progression, supporting the previous finding that Env entry efficiency could be the driving agent of disease progression. This was also corroborated by the trend in association between RC of IMCs and faster CD4+ T decline. 3 Our findings suggest that despite different host pressures, viral competition in most dual infected individuals selected for rapid recombination within gp41 that enhanced fusion capacity. Enhanced gp41 fusogenicity of the dominant viral population at 12 mpi increased PSV entry efficiency and replicative fitness enabling viral outgrowth. Therefore, vaccines that target gp41 might prevent HIV infection or at least attenuate viral fitness and slow disease progression. On the other hand, we showed that targeting the PNG at position N339 of gp120 might influence viral fitness and increase viral load and/or decrease CD4 T cell count. This is in keeping with the association between CD4 T cell decline and PSV entry efficiency and IMC RC, suggesting that Env fitness plays a role in HIV pathogenicity.