Dissertations / Theses on the topic 'RD'
To see the other types of publications on this topic, follow the link: RD.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'RD.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Blabla, Ondřej. "Akumulace elektrické energie pro RD." Master's thesis, Vysoké učení technické v Brně. Fakulta strojního inženýrství, 2016. http://www.nusl.cz/ntk/nusl-254351.
Full textAbstract:
This diploma thesis deals with the accumulation of electrical energy in the scale of small house. The theoretical part describes the various ways of storing power. The practical part is devoted to the design and comparison of electrical energy accumulation for a particular house.
2
Buchta, Jan. "Optimalizace chlazení RD využívajícího zemní vrty." Master's thesis, Vysoké učení technické v Brně. Fakulta stavební, 2015. http://www.nusl.cz/ntk/nusl-227800.
Full textAbstract:
The master’s thesis deals with optimization of cooling system of family house using borehole heat exchanger as a single cooling source. In the experimental part of the thesis was carried out long-term mearurements. The main part of the master’s thesis is the development and verification mathematical and physical model of thermal behavior chilled room. The result are computer simulations and evaluation of individual scenarios and design requirements for a potential optimization of measurement and control system. The theoretical part generally deals with radiant cooling systems.
3
Valkó, Attila. "Zajištění stavební jámy na stavbě RD." Master's thesis, Vysoké učení technické v Brně. Fakulta stavební, 2019. http://www.nusl.cz/ntk/nusl-402982.
Full textAbstract:
Diploma thesis deals with securing of foundation pit of family house in given geological conditions situated in Brno-Kohoutovice. The aim of the thesis is to list possible solutions of securing foundation pits in general and solve this geotechnical problem with an appropriate solution. Static calculations were performed by geotechnical software GEO5.
4
Martin, Charles 1966. "Hausdorff dimension of harmonic measures in Rd." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=69764.
Full textAbstract:
In 1986, J. Bourgain showed that, for a given dimension d $ ge$ 2, there exists $ rho sb{d}$ $<$ d such that any harmonic measure in $ Re sp{d}$ is supported by a set of Hausdorff dimension at most $ rho sb{d}$.This thesis presents a detailed and comprehensive exposition of Bourgain's theorem. Formal definitions of harmonic measures and Hausdorff dimensions are provided and all the required preliminary results about these concepts are rigorously proved. Generally speaking, the proof of the theorem itself is similar to the one originally presented by Bourgain. However, a more structured approach and an increased level of details make the argument easier to follow and understand.
5
Martynek, Václav. "Kogenerační jednotky pro RD – hodnocení a simulace." Master's thesis, Vysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií, 2013. http://www.nusl.cz/ntk/nusl-220173.
Full textAbstract:
Master’s thesis deals with cogeneration units of low power that are used for heating of buildings and to cover the heat demand of small industrial enterprises. The introductory chapters are focusing on clarifying the principles of combined heat and power (CHP) as well as on the basic advantages and important indicators of CHP. The thesis presents a brief overview of cogeneration devices by type of primary units and also provides an overview of cogeneration units suitable for family houses that are currently available on the market. The text describes how to install and connect the cogeneration unit. The fourth chapter includes description of elemental thermal processes and possibility of heat transfer. The fifth chapter describes the thermal circuit model and calculation efficiency of a cogeneration unit. Thermal circuit consists of a cogeneration unit and a multivalent tank for hot water heating system and potable hot water system. The object of master’s thesis is to create a model of thermal circuit cogeneration units in a simulation program and a graphical user interface, that will allow a simple way to evaluate the operation of the cogeneration unit when changing the input parameters.
6
König, Michal. "Ekonomická analýza cash flow nízkoenergetických staveb RD." Master's thesis, Vysoké učení technické v Brně. Fakulta stavební, 2014. http://www.nusl.cz/ntk/nusl-227043.
Full textAbstract:
The subject of my master´s thesis is analysis of the operating costs in households in various energy categories of houses. The theoretical part is focused on passive homes issue where I explained principles and differences of standard constructions. The practical part is based on a concrete example of the differences and the structure of costs. The aim is to confirm or refute the hypothesis, which say that higher investment costs for the construction of low energy buildings could reduce costs and family budgets in the future. They also lead to higher liquidity.
7
Palkovič, Peter. "Možnosti snížení nákladů za energie pro RD." Master's thesis, Vysoké učení technické v Brně. Fakulta strojního inženýrství, 2015. http://www.nusl.cz/ntk/nusl-231826.
Full textAbstract:
Thesis deals with the possibility of reducing the energy costs of a typical family house located in Brno. In the first part is a detailed calculation of heat loss of the building, considering heat gain and subsequent quantification of costs for heating, hot water and total annual costs. In other sections provide specific calculation of the economics for the partial implementations of planned procedures leading to a reduction in heating costs (replacing windows, doors, facades and floor ceiling). A calculation for changing the heating method and compared to the existing boiler. A possible reduction in the energy required when using energy from the Sun. In the penultimate section briefly review the options for what you get a subsidy from the grant program "New Green Savings Programme" and reduce the initial investment. Finally the comprehensive proposals of different options exchanges boiler insulation, replacing windows and doors, and the subsequent evaluation of the best solution when investing 350 000 CZK.
8
Okrouhlý, Petr. "Stanovení rozdílu cen garáží u RD v Havířově." Master's thesis, Vysoké učení technické v Brně. Ústav soudního inženýrství, 2013. http://www.nusl.cz/ntk/nusl-232811.
Full textAbstract:
This thesis focuses on the comparison of selected methods for the valuation of property type garage in Havirov, namely the garage of brick blocks. In this work will be the comparison of prices according to the current administrative price regulation and market prices according to the comparative method and itemized budget. In addition to administrative price comparison market price, I will further explore the resulting price difference between the cost valuation method and comparison method of valuation real problem situation.
9
Páleník, Petr. "Stanovení rozdílu cen garáží u RD v Olomouci." Master's thesis, Vysoké učení technické v Brně. Ústav soudního inženýrství, 2014. http://www.nusl.cz/ntk/nusl-232917.
Full textAbstract:
Master thesis is focused on determination of differences in ways of valuation in city Olomouc. Fifteen garages were used to price estimate in this city. The first part of work deals with basic terms and theoretical definition of methods of valuation. Due to instructions of the work, the methods of valuation were chosen: cost method, comparison according to law and comparison based on databases. In the following parts are described chosen garages and there is undertaken evaluation. Differences of ways of valuation and their causes, which are based on obtained data, are discussed at the end of work.
10
Crowley, Jacqueline H. "The Marinhieros Project: Roseneath Rd & Patterson Ave." VCU Scholars Compass, 2005. http://scholarscompass.vcu.edu/etd/692.
Full textAbstract:
In questioning the very nature of a thing, at its most basic level, a new assessment can be made of what the thing in question truly is. When we ask ourselves, what is a weed, we begin to pull the word apart - to decrypt the word from the cultural baggage that has collected around it over the course of the history of language.The cultural connotations of 'weed' cling to it like barnacles, removing the word from its true value. We reevaluate meaning, chronicling all the possible constructions of a word, all the possible varieties, where it came from, what its uses are, etc. We can then begin to develop an aggregate meaning based on an inherently more textured meaning, nuanced and built to sustain an elaboration of new information within the word itself. Weeds may serve as a successful metaphor for humanities quest for value, but it should not be assumed - we must first plot a course before we set sail.
11
Köhnlein, Dieter. "Asymptotisches Verhalten von Lösungen stochastischer linearer Differenzengleichungen im Rd." Bonn : [s.n.], 1988. http://catalog.hathitrust.org/api/volumes/oclc/20267120.html.
Full text
12
Bárta, Martin. "Renovace RD na budovu s téměř nulovou spotřebou energie." Master's thesis, Vysoké učení technické v Brně. Fakulta stavební, 2016. http://www.nusl.cz/ntk/nusl-240192.
Full text
13
Suchomel, Jan. "Zjištění vlivu krnovského obchvatu na ceny RD nacházejících se v jeho bezprostřední blízkosti a dopad odklonu dopravy na cenu RD v centru města." Master's thesis, Vysoké učení technické v Brně. Ústav soudního inženýrství, 2012. http://www.nusl.cz/ntk/nusl-232655.
Full textAbstract:
The Master’s thesis „Determination of the Impact of Krnov Bypass on Prices of Detached Houses in its Close Proximity and the Effect of Traffic Diversion on Detached House Prices“ has as one’s task a determination of the influences of a by-pass road on the prices of family houses. In pursuance of this task it has been used several kinds of the valuation methods, as for example the cost approach according to the price order, the comparative method according to the price order and the comparative method Standard unit market price (non-promulgation). In the conclusion of the Master’s thesis there is a separate determination of the influence of the by-pass road on the prices of the family houses, which are located in its neighbourhood and the impact of a deflection on the prices of the family houses in Krnov city centre.
14
Arnoldsson, Joel. "Adsorption Chillers : uptake of Ethanol on Type RD Silica gel." Thesis, Linköpings universitet, Energisystem, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-80930.
Full textAbstract:
The adsorption cooling technology has the potential to replace all vapor compression based chillers in the future. So, in all over the world immense researches are going on in this field. The purpose of this report is to experimentally investigate whether ethanol could serve as a refrigerant in the technology. Compared to water it has freezing point below 0 °C (-114.1 °C) and can therefore in theory be used in refrigeration applications. The report begins with the theory regarding the adsorption cooling process, describing the cycle and parameters that affect the Coefficient of Performance (COP).In the actual experiment, adsorption between the silica gel and the ethanol vapor is studied at various pressures by maintaining isothermal conditions. An experimental apparatus (Constant Volume Variable Pressure apparatus - CVVP) was fabricated, assembled and tested for this project. After the assembly and testing, volume calibration for the apparatus was carried out as it is essential to know in further experimental calculation. All the data related with the fabrication, assembly and testing of the apparatus and the volume calibrations are presented later in this report in detail.Adsorption experiments are conducted at 301.15K, 311.15K, 321.15K and 331.15K with varying inlet pressure condition to the system and then the uptake data is calculated for each and every experiments using ideal gas equation. Subsequently, the validations of the experimental data with the standard adsorption isotherms are done. Dubinin-Astakhov is found to be the most ideal isotherm to simulate the theoretical data. Its RMSE (Root Mean Square Error) value is found to be 0.506%. It is concluded that ethanol valid option for refrigeration, but further research is needed and recommended.
15
Kakule, Matumo Jean Bosco. "Tiers secteur et développement participatif à Beni Lubero, RD Congo." Thesis, Lyon 2, 2015. http://www.theses.fr/2015LYO22021/document.
Full textAbstract:
Les recherches récentes sur le pluralisme socioéconomique et développemental dans le monde réhabilitent les intuitions de Polanyi : la révision fondamentale du sophisme économiste et l’encastrement de l’économique. Dans cette optique, la présente thèse a pour objet de penser l’articulation de trois phénomènes : le tiers secteur, le développement et la participation, à partir de l’observation des pratiques des acteurs du mouvement de solidarité associative à Beni Lubero, en RD Congo. Son approche pluridisciplinaire effectue, par une analyse beaucoup plus qualitative que quantitative, des allers et retours entre théories et faits empiriques in situ. Les deux premières parties tentent d’y identifier l’existence d’une gamme d’institutions susceptibles de compter parmi le tiers secteur compris, à l’interstice des secteurs public et privé et au creux d’autres concepts de l’économie plurielle, comme la stratégie d’auto-organisation collective, pour entreprendre ensemble et autrement ; en fonction d’un centre d’intérêts commun. La troisième partie, repensant le changement du paradigme du développement, assume celui-ci comme participatif par essence et, partant, stigmatise la pesanteur des interférences sur la conquête du concept ; et surtout en RD Congo. Elle vérifie combien, au sein de la société civile locale, le tiers-secteur de Beni Lubero est l'un des véritables leviers du processus d’auto-développement, grâce à sa multi-combativité participative. La dernière partie précise le contenu de la participation : son caractère trifacial (réfléchir, décider et agir), la nature triadique de son acte (s’associer, contribuer et bénéficier), les modes, techniques et méthodes de sa promotion ; ainsi que la transversalité de sa notion en sciences sociales et humaines. Puis, au filtre du design participatif d’Archon Fung, elle corrobore l’effectivité de la participation au sein du tiers secteur étudié. A moins de décrocher sa vigilance sur le balancier entre excellence et obstacle, la participation y paraît un tremplin à la plus-value incontestable ; notamment, en termes de membership, de leadership, d’entrepreneurship, de relationship et partnership, d’empowerment, d’ownershipThe recent research on the socioeconomic and developmental pluralism worldwide rehabilitate the insights of Polany i: fundamental review of sophistry economist (economist fallacy) and promoting the embedding of the economy. This thesis is in their view. Its purpose is to consider the linkages between three phenomena: the third sector, development and participation. To assess their articulation, it’s based on the observation of practices of the actors of various associations and solidarity movement in Beni Lubero, DR Congo. Its approach is multidisciplinary and its analysis is more qualitative than quantitative. It makes back and forth between theories and empirical facts in situ. The first two parts attempt to verify the existence of a range of institutions likely to be among third sector. The latter is then designed to the interstices of private and public socio- economic sectors; and in the hollow of the other concepts of the plural economy, such as collective self-organization strategy to undertake all together and otherwise; according to common interests. The third part rethinks the change in the development paradigm. It assumes that it’s essentially participatory. Therefore, it stigmatizes gravity of interference against the conquest of this concept, especially in DR Congo. Then, it checks how the Beni Lubero third sector, as part of the local civil society, is emerging as one of the real levers of self-development process, through its participatory multi-fighting. The final part specifies the content of participation: its triple facet (think, decide and act) and the triadic nature of its act (associate or join, contribute and benefit); methods, techniques and methods for its promotion; and the transversality of its concept through social sciences. Then, checking its practices through the participatory design of Archon Fung confirms the effectiveness of the participation in the Beni Lubero third sector. Unless failing in vigilance on the balance between excellence and obstacle, participation there seems a springboard whit a gain undeniable ; in particular, in development of membership, leadership, entrepreneurship, relationship, partnership, empowerment, ownership
16
Hořínková, Dita. "Stavebně technologický projekt výstavby komplexu RD SLAVKOV - Pod Zlatou horou." Master's thesis, Vysoké učení technické v Brně. Fakulta stavební, 2020. http://www.nusl.cz/ntk/nusl-409928.
Full textAbstract:
The subject of the diploma thesis is the solution of chosen parts of the construction technology project of the 1st phase of the construction „Komplex RD Slavkov, Pod Zlatou horou“. These are 4 semi-detached houses, overall 8 family houses. The work deals with technological regulations for the superstructure including roof, study of the realization of the construction technology project, design of the main construction machines and mechanisms and control and test plan. For the whole construction is elaborated time and financial plan in two variants, namely the gradual and current method of construction, and a detailed schedule for one semi-detached house. The technical report of the building site equipment is completed with the drawings, itemized budget of the building part of the house, noise study and specialization focused on the photovoltaic system, with an alternative solution to use solar collectors. The thesis also includes a case study of construction methods focused on the gradual and current method of construction.
17
Hájek, Jan. "Oceňování nemovitostí pro potřeby pojišťovnictví - RD v Brně poškozený sněhem." Master's thesis, Vysoké učení technické v Brně. Ústav soudního inženýrství, 2014. http://www.nusl.cz/ntk/nusl-232906.
Full textAbstract:
The aim of the thesis is to determine the amount of indemnity for damage to the family house caused by excessive snow loads, calculation of material value (time value) immovable assets immediately before the insured event cost method using analytical methods wear, determining the cost of putting immovable in working condition, the calculation of substantive value of intangible assets for the repairs. In this thesis, the emphasis on the clarification process when the risk to the family house and a practical example of an insured event the immovable. At the same time the analysis of the results, which display graphs show how the event affected the development of insurance rates immovable.
18
Kolmačková, Lucie. "Oceňování nemovitostí pro potřeby pojišťovnictví - RD v Lipovci poškozený vichřicí." Master's thesis, Vysoké učení technické v Brně. Ústav soudního inženýrství, 2014. http://www.nusl.cz/ntk/nusl-232907.
Full textAbstract:
The aim of my diploma thesis is to establish the expenditure on house insurance in a particular case, namely on a detached house in a village called Lipovec. The fundamental terms, which one has to be familiar with to understand the issues of the thesis, are illuminated in the introduction. The theoretical part is dedicated to the methods of evaluation and procedures focused on insurance business and evaluation. The particular area and the detached house are described in the practical part. Procedures stated in the theoretical part are used for conducting a survey of the particular case. Firstly, the value of the object before an insurance event (a hurricane, for instance) will be calculated. Secondly, the expenditure on refurbishment of the damaged features of the house will be calculated. Finally, considering the cost of refurbishment, the value of the object will be evaluated again. The diploma thesis might be used as an exemplary piece of work. Furthermore, it provides a reader with a deep insight into its issues.
19
Tázlerová, Radka. "Porovnání ceny rozestavěné stavby RD s cenou provedených stavebních prací." Master's thesis, Vysoké učení technické v Brně. Ústav soudního inženýrství, 2015. http://www.nusl.cz/ntk/nusl-234446.
Full textAbstract:
The thesis " Comparison of an unfinished house price with the price of the construction work finished" aims to determine the cost of a building under construction house at the stage of rough construction cost method and compare it with the cost of construction works, which will be determined itemized budget. Their mutual prices compare, evaluate differences and to determine whether and at what price you can sell the unfinished building on the real estate market in Brno-venkov.
20
Čížek, Roman. "Energetická a finanční analýza jednotlivých zdrojů energie pro provoz RD." Master's thesis, Vysoká škola ekonomická v Praze, 2008. http://www.nusl.cz/ntk/nusl-81531.
Full textAbstract:
The aim of the diplom thesis is to evaluate systems of different heat sources from economical, environmental and user aspect for modern low-energy construction and classic house from 80 of the 20century.
21
Dutta, Sumanta. "An investigation of the relationship between patient physiology, inflammatory response and outcome in patients with oesophageal and gastric cancer." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4648/.
Full textAbstract:
Upper gastrointestinal tract cancers originating from oesophagus, oesophago-gastric junction or stomach constitute a major health problem around the world as well as in UK. Chapter 1 of the thesis describes the incidence, mortality, aetiology, staging, treatment and outcome of patients with oesophageal and gastric cancer. Each year approximately 8,000 people are diagnosed with oesophageal cancer and a similar number of people diagnosed with gastric cancer in UK. Early detection and surgery confers the greatest chance of long-term cure in oesophageal and gastric cancer. However, upper GI cancer surgery is associated with considerable morbidity and mortality. Postoperative mortality following gastro-oesophageal cancer resection is significant and has been reported as varying from 1%–23%. Therefore, preoperative surgical risk assessment is a vital part of modern surgical practice. Pathological TNM staging by American Joint Committee on Cancer (AJCC) is an established factor in predicting long term survival following resection of oesophageal and gastric cancer. However, it is increasingly recognised that, not only the intrinsic properties of tumour cells determine tumour spread but also the host inflammatory response has a vital role. Indeed, the systemic inflammatory response, as evidenced by elevated circulating concentrations of C-reactive protein, prior to surgery, has previously been shown to have independent prognostic value in patients with resectable gastro-oesophageal cancer. The overall aim of the thesis was to examine the inter-relationships between patient physiology, local and systemic inflammatory response and outcome (both short and long term), in patients undergoing resection for oesophageal and gastric cancer. Chapter 2 compared the POSSUM (Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity) and mGPS (modified Glasgow prognostic score) models in prediction of post-operative outcome, both short and long term, in 121 patients undergoing resection of oesophago-gastric cancer. The results in this chapter demonstrated that, the POSSUM physiological score was an independent predictor of post-operative complications. On the other hand, elevated systemic inflammatory response as evidenced by the mGPS and not, patient physiology or post-operative complications, was independently associated with poor cancer specific survival. Therefore, results of the present study suggested that, pre-operative host related factors were important in determining both short and long term outcome following potentially curative resection of oesophago-gastric cancer. Chapter 3 examined the value of serial daily post-operative markers of systemic inflammatory response such as white cell count, albumin and C-reactive protein concentrations in the prediction of post-operative infectious complications in 136 patients following resection of oesophago-gastric cancer. The results showed that the magnitude of the systemic inflammatory response, in particular C reactive protein, following resection of oesophago-gastric cancer was associated with the development of post operative complications, in particular surgical site infections and anastomotic leak. Furthermore, C reactive protein threshold of 180mg/l on post operative days 3 and 4 was shown to predict surgical site infection and anastomotic leak with good and very good diagnostic accuracy respectively. Chapter 4 compared the prognostic value of selected markers of systemic inflammatory response such as white cell count, neutrophil count, lymphocyte count, neutrophil-lymphocyte ratio (NLR), platelet- lymphocyte ratio (PLR) and mGPS in 112 patients undergoing potentially curative resection of oesophageal cancer. The result demonstrated that, only mGPS was significantly associated with cancer specific survival and had prognostic value independent of pathological TNM stage. Therefore, an acute-phase protein-based prognostic score, the mGPS, was established to have the superior predictive value, compared to cellular components of the systemic inflammatory response in predicting survival in oesophageal cancer. Chapter 5 compared the prognostic value of selected markers of systemic inflammatory response such as white cell count, neutrophil count, lymphocyte count, neutrophil-lymphocyte ratio (NLR), platelet- lymphocyte ratio (PLR) and mGPS in 120 patients undergoing potentially curative resection of gastric cancer. The result showed that, only mGPS was significantly associated with cancer specific survival and had prognostic value independent of pathological TNM stage. Therefore, an acute-phase protein-based prognostic score, the mGPS, was established to have the superior predictive value, compared to cellular components of the systemic inflammatory response in predicting survival in gastric cancer. Chapter 6 examined the relationship between tumour necrosis, tumour proliferation, local and systemic inflammatory response, microvessel density and survival in 98 patients undergoing potentially curative resection of oesophageal adenocarcinoma. The results suggested that, among the tissue based factors, tumour macrophage infiltration appeared to play a central role in the proliferative activity and coordination of the inflammatory cell infiltrate and was also independently associated with poor outcome in patients with oesophageal adenocarcinoma. There was no direct relationship between local and systemic inflammatory response, tumour necrosis and angiogenesis; suggesting that the mechanisms underlying the relationship between local and systemic inflammatory responses and cancer-specific survival are likely to be complex. Chapter 7 examined the relationship between tumour necrosis, tumour proliferation, local and systemic inflammation, microvessel density and survival in 104 patients undergoing potentially curative resection of gastric cancer. The results suggested that, local peritumoural inflammatory infiltrate and intra tumoural necrosis appeared to play a role in tumour proliferation and poor outcome in patients with gastric cancer. There was no direct relationship between local and systemic inflammatory responses, tumour necrosis and angiogenesis; suggesting that the mechanisms underlying the relationship between local and systemic inflammatory responses and cancer-specific survival are likely to be complex. In summary, preoperative patient’s physiological status (as measured by POSSUM model) has been shown to be a good predictor of short term outcome i.e. postoperative morbidity and mortality following resection of oesophago-gastric cancer. Moreover postoperative serial measurements of C-reactive protein have been shown to be a useful tool to predict infectious complications. An elevated systemic inflammatory response (as evidenced by the mGPS) preoperatively has been established to be a predictor of poor survival, independent of tumour stage in both oesophageal and gastric cancer. Therefore, these results suggest that measurement of the mGPS should be performed routinely as part of preoperative clinical staging, to improve stratification of patients and therefore enable clinicians to optimise the treatment of patients with oesophageal and gastric cancer.
22
Wearn, Christopher Michael Francis. "The metabolomic response to severe thermal injury and the impact of age." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7751/.
Full textAbstract:
Severe thermal injury results in a profound hypermetabolic response and is associated with increased morbidity, mortality and delayed rehabilitation of burn survivors. Serum 1H-NMR metabolomics was used to examine early global metabolic changes in the response to severe thermal injury (>15% TBSA) in young adults (16-64 years) and older adults (< 15% TBSA). Early changes in the metabolome reflected hypoxic metabolism, hyperglycaemia, increased ketogenesis, peripheral lipolysis and increased energy production in both cohorts. Early metabolic profiles from the young adult group were used to construct OPLSDA models that could discriminate with high accuracy between outcome groups. Models from 0-24hrs serum samples predicted survival (AUC 0.92), whilst models from 24-96hrs samples predicted Multiple organ failure (MOF) (AUC 0.92) and sepsis (AUC 0.89). Untargeted LC-MS metabolomics was applied to study the longitudinal changes in the serum metabolome after severe thermal injury in 13 young adults, from admission until 6-months post-injury. Univariate ANOVA analysis revealed significant changes in 432 metabolite features, affecting 35 distinct classes, representing global metabolic disturbance. Changes in 300 lipid metabolite features may represent a ‘lipid storm’ in serum after severe thermal injury. Novel areas of metabolism and metabolites were identified as putative biomarkers warranting further targeted study.
23
Owen, Andrew Philip. "Cellular interactions underpinning the immunomodulatory action of mesenchymal stromal cells in models of liver transplant injury." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8570/.
Full textAbstract:
End stage liver disease represents a common end point for a number of disease processes, the only current treatment for which is liver transplantation, but the demand for donor organs exceeds the supply. This has led to the use of more marginal donors with an increase in the rates of complications. Mesenchymal stem/stromal cells (MSC) are a multipotent cell capable of modulating the immune system through a number of different processes and represent a potential therapy in post transplantation liver injury. In this study I describe the prospective isolation and culture expansion of murine MSC. In in vitro assays MSC suppressed T lymphocytes and following stimulus with inflammatory cytokines MSC secreted a number of cytokines including Il-10. In the MDR2-/- model intravenous MSC therapy led to a reduction in liver injury with an increase in restorative macrophages. Subcutaneous administration of MSC showed no beneficial effect. MSC were also tested in a hepatic ischaemia reperfusion injury model where no effect was seen. In summary MSC were able to suppress lymphocyte proliferation and secrete anti-inflammatory cytokines in vitro, and in vivo they were able to reduce liver injury in the MDR2-/- model but not the hepatic ischaemia reperfusion injury mode.
24
Hussey, Keith Kelso. "Connexin 43 as a biological marker of ischaemia in occlusive arterial disease of the lower limb." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/30744/.
Full textAbstract:
Diabetes mellitus is a worldwide health issue. It is a major and growing cause of morbidity and mortality. Rates of end-organ damage are increasing proportionately, as are the associated personal, societal and economic costs. Diabetic foot ulceration is responsible for a significant proportion of this. The development of diabetic foot ulceration is complex with multiple injurious processes potentially affecting a foot at any time. Defining the significance of ischaemia as a consequence of peripheral arterial occlusive disease can be difficult and identifying which patients may benefit from revascularisation in terms of reversing of the natural history of the disease process remains poorly understood. The utility of the University of Texas classification to identify patients at highest risk of major adverse clinical events has been explored from 971 ulcer episodes affecting 515 limbs (388 patients). Peripheral arterial occlusive disease was identified in 44.6%. These patients had a significantly higher risk of major amputation than patients without peripheral arterial occlusive disease (13.5 versus 4%). University of Texas scoring would appear to robustly identify patients at highest risk of major adverse clinical events. The potential usefulness of Connexin 43 and its phosphorylated isoform Connexin 43(Serine368) as biological markers of ischaemia in skin have been explored. Immunohistochemistry provided qualitative data demonstrating up regulation of Connexin 43(Serine368) in skin biopsies from ischaemic feet – this is a novel finding. Connexin 43 (Serine368) was not identified in any of the controls nor in proximal skin biopsies of patients with peripheral arterial occlusive disease. Connexin 43 expression did not appear to be modified. When human fibroblasts and keratinocytes were subjected to hypoxic conditions (1% oxygen/4% carbon dioxide/nitrogen) in vitro, both Connexin 43 and Connexin 43(Serine368) were up regulated with protein expression peaking between 12 to 24 and 6 to 12 hours respectively. Peptidoglycan challenge appeared to up-regulate the expression of Connexin 43 protein, but did not influence the expression of Connexin 43(Serine368). These data suggest that Connexin 43(Serine 368) may have potential utility as a biological marker of ischaemia in human skin.
25
Khan, Muhammad Farhan. "Design optimisation for stent manufacture." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/52353/.
Full textAbstract:
Intravascular stents of various designs are currently used to prop open diseased arteries and there is evidence that different stent geometries have different in-stent restenosis rates. The majority of commercially available stents are designed generically to fit all individuals. Recent advances in imaging and catheter technologies, however, allow measurement of lesion shape and stiffness. Incorporating patient specific data into the stent design process could enable the development of customised stents. Considering the variety of lesion types, it is envisaged that better outcomes will be achieved if a stent is custom designed in such a way that it has variable radial stiffness longitudinally to hold the varying pressure of plaque and healthy artery at the same time while maintaining an acceptable lumen diameter. This type of operation is suitable for topology optimisation potentially allowing for optimal material distribution of a stent. The primary aim of this research is to develop new stent designs for a set of plaque types and investigate the final radius of the lumen after stent implantation. Stent geometries were obtained by topology optimisation for minimised compliance under different stenosis levels and plaque materials. Three types of stenosis levels by area, i.e. 30%, 40% and 50% with each type having three different plaque material properties i.e. calcified, cellular and hypocellular were studied. The optimisation results were transformed to clear design concepts and their performance was evaluated by implanting them in their respective stenosed artery types using finite element analysis. The results were compared with a generic stent in similar arteries, which showed that the new designs showed less recoil. In the hardest (calcified) of plaques studied, topology optimised designs overall resulted in 2%, 2% and 6% residual area stenosis compared to 10%, 29% and 35% from the generic design in arteries with 30%, 40% and 50% stenosis respectively. It was shown that higher material distribution resulted in the central region of the stent in order to resist implantation recoil due to higher plaque compressive loads. Additive manufacturing (AM) was utilised to validate the computational approach used in this thesis. This work provides a proof of concept for stents tailored to specific lesions in order to minimise recoil and maintain a patent lumen in stenotic arteries.
26
MacKenzie, Douglas James. "A functional dissection of the relationships between BRAF, DNMT3B and the CpG island methylator phenotype in colorectal cancer." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8867/.
Full textAbstract:
Approximately 10-20% of human colorectal cancers harbour an activating BRAFV600E mutation, which acts as a founder mutation for an alternative, serrated pathway of colorectal carcinogenesis. Conversely, BRAFV600E mutations are detectable in hyperplastic colonic polyps: lesions traditionally considered not to harbour malignant potential. Furthermore, both in vitro and in vivo, activated oncogenic BRAFV600E induces a stable proliferation arrest: oncogene induced senescence, which is a fundamental intrinsic tumour-suppressor mechanism. Thus, for neoplastic transformation to occur, it is clear that additional genetic and epigenetic events are required. BRAFV600E-mutant colorectal cancers are frequently associated with a CpG island methylator phenotype (CIMP), which is proposed to promote neoplastic transformation by bypass of intrinsic tumour-suppressor mechanisms, such as silencing of CDKN2A/INK4A. Consistent with this, neoplastic transformation in the serrated pathway is characterised by the progressive development of a CIMP phenotype. An emerging body of evidence supports a model in which the BRAFV600E mutation directly induces CIMP through the de novo methyltransferase, DNMT3B. Separately, elevated DNMT3B expression has previously been linked to the development of CIMP in both murine and human colorectal cancer. The published data however do not universally support this model, and significant questions over its validity remain. In the present work, the relationships between BRAFV600E mutation, DNMT3B expression and the CpG island methylator phenotype were examined by multiple approaches. A panel of DNMT3B antibodies were first characterised and validated. Significantly, the antibody previously used to link DNMT3B and CIMP in human colon cancer was demonstrated not to react with human DNMT3B. The ability of BRAFV600E to induce CIMP was next tested by whole genome bisulfite sequencing in a primary cell culture model. Surprisingly, activated BRAFV600E repressed expression of DNMT3B and failed to induce a CIMP phenotype. Consistent with this, human colorectal cancer cell lines expressing activated BRAFV600E typically expressed a low level of DNMT3B, and inactivation of DNMT3B in a BRAFV600E-mutant, CIMP-positive cell line did not reverse gene silencing characteristic of CIMP. An in vitro model system was next designed to test functional interactions between BRAFV600E and DNMT3B. Ectopic expression of DNMT3B antagonised BRAFV600E-induced proliferation arrest: a hallmark of senescence. Moreover, ectopic DNMT3B expression was demonstrated to accelerate BrafV600E-induced intestinal carcinogenesis in a mouse model, and conversely, Dnmt3b knockout impaired BrafV600E-induced murine intestinal carcinogenesis. Analysis of human colorectal cancer TCGA data was next undertaken, and confirmed that expression of DNMT3B is frequently elevated in human colorectal cancer and that this is often linked to amplification of the DNMT3B gene. However, more detailed analysis of human TCGA data revealed that BRAFV600E mutation is neither necessary nor sufficient to induce CIMP, and that both BRAFV600E mutations and CIMP are both linked to low expression of DNMT3B. Thus, while both BRAFV600E and DNMT3B both harbour oncogenic potential, they do not appear to cooperate to induce CIMP, and do not appear to cooperate frequently in human colorectal cancer by any mechanism.
27
McCarthy, Benjamin P. "Synthesis and characterisation of multi-substituted hydroxyapatites." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/47482/.
Full textAbstract:
This thesis presents a range of novel mono and di-substituted hydroxyapatite powders, characterised by a range of techniques to ascertain their chemical composition, crystallographic composition, physical properties, and in vitro bioactivity. The novel compositions consist of substituting a range of Borate, Sulphate, Silicate, and Strontium in levels ranging from 1.5 mol.%, up to 5 mol.%. It was found that a 4 mol.% inclusion of 2 mol.% Sr2+ and 2 mol.% SO42- gave a significant increase in the amount of osteocalcin produced and may represent an improved biomaterial warranting further study.
28
Al-Fadhli, Mohammed. "Design and evaluation of a novel soft active-vest for human back assistance." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/52213/.
Full textAbstract:
Back muscle weakness and lower back pain affect the quality of life and productivity at work, and such age-related problems are prevalent among middle-aged and elderly people. Wearable exoskeletons/soft suits offer substantial promise as a means to augment strength, assist movement and improve stability of the human body. This thesis presents the design, modelling and evaluation of a novel soft suit (“Active-Vest”) for human back support. Active-Vest is human-friendly, flexible, lightweight and able to reduce the efforts of back muscles and reaction forces at the lumbar spine joints during flexion-flexion motions of the back in the sagittal plane. The design of the Active-Vest allows the support of the back without involving the lower limbs, meaning it may provide a better walking experience. The assistance capabilities and safe application of the vest design were assessed in OpenSim software employing a series of biomechanical models of the proposed vest united with an enhanced human musculoskeletal model assembly. The simulation revealed that the soft actuator system reduced the erector spinae muscle force required to articulate the back during flexion-extension motions in the sagittal plane by 60%. Simultaneously, the maximum compression and shearing forces acting on the lumbosacral and L1-L2 joints were reduced by 39% and 32% respectively, as the vest actuators act on a larger lever arm than the corresponding muscles. The Active-Vest prototype has been fabricated and laboratory evaluations on a healthy subject have been performed to quantify human-vest interaction. Evaluations confirmed that wearing the vest reduced the magnitude of the surface Electromyography signal (EMG) of erector spinae muscles by 61% during said flexion-extension motions in the sagittal plane, supporting the prediction of the computer simulations of reduced erector spinae muscle activity and reduced reaction force at lumbar joints. Further, the prototype reduced the EMG signal by 43% to maintain the trunk status in the transverse plane against gravity. These results demonstrate the practicability and promise of Active-Vest to aid people with reduced back strength and to decrease lower back pain and risk of back injury. Considering these promising results, the methods proposed in this work contribute towards a more human-back assistance/lower back pain/injury risk reduction. In future, the vest will be able to involve the aid of all spinal range of motions and present the feasibility of wide-community utilization. Future work will increase the number of actuators of the Active-Vest and the vest could be expanded to a full body suit.
29
Barrera, Betanzos Fernando. "Development of innovative techniques for the manufacture of bioresorbable composites intended as fracture fixation devices." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/49087/.
Full textAbstract:
In this project innovative manufacturing processes have been developed and characterised for the efficient and effective fabrication of PGF-PLA composites which have adequate properties for the fixation of fractured bones in flat and curved geometries. Fully bioresorbable composite plates where produced by compression moulding of unidirectional phosphate glass fibre mats and PLA films alternatively stacked inside the mould cavity. The implementation of cyclic pressure during the compression moulding consolidation stage resulted in the production the strongest PGF-PLA composites hitherto reported. The strength of the composites consolidated via cyclic pressure was at least 30% higher with respect to the control samples fabricated using the conventional static pressure profile, reaching values of 480 MPa for plates reinforced with 0.45 fibre volume fraction. The increases in composite strength were attributed to the influence of pressure cycling on the fibre network permeability, melt viscosity and capillary pressure, leading to improved fibre impregnation with respect to statically applied pressure, obviating the need for elevated processing temperatures to reduce the melt viscosity. Pressure cycling seemed to promote the formation of transcrystalline layer around the fibres which could have also contributed to the superior properties of composites consolidated under cyclic pressure. PGF-PLA composite rods with cylindrical cross sections were manufactured via uniaxial compression and plane strain forging of preconsolidated composite blanks obtained from compression moulded composite plates. Forging under uniaxial conditions reduced both the flexural strength and the elastic modulus of all the composite rods in comparison to the compression moulded composite plates by as much as 85% and 47%, respectively, for the 0.35vf samples consolidated under cyclic pressure, as a result of the fracture of the fibres consequent to the extensional flow. Fibre fracture was prevented through confinement of the deformation to the x-y plane during plane strain forging. The mechanical properties of the compression moulded composite plates were preserved in the forged composite rods with 0.15 and 0.25 fibre volume fractions, but the high segregation of fibres in the 0.35vf and 0.45vf compression moulded composite plates fabricated with thick glass fibre mats led to the reduction of both the flexural strength and modulus of the forged composite rods with respect to the compression moulded composite plates by as much as 74% and 29%, respectively, for the 0.45vf consolidated under cyclic pressure, as a result of the nucleation of intra-ply cracks during plane strain forging. The deleterious effect of intra-ply cracks in the plane strain forged composite rods was significantly reduced by stacking a larger number of thinner phosphate glass fibre mats prior to compression moulding of the 0.35vf and 0.45vf composite plates. The properties of the forged composite rods decreased in aqueous media. The initial loss of strength and modulus was attributed to the water-mediated lubrication of the fibre-matrix interface. Further decreases in mechanical properties were related to the fibre diameter reduction as a result of quick glass dissolution, which impaired the frictional stress transfer. Complete loss of the reinforcing effect of glass fibres was observed after 15 days of immersion in aqueous media. Cylindrical PGF-PLA composite rods were also produced via a new and leaner manufacturing method consisting in compression moulding of thermoplastic hybrid preforms. Hybrid preforms were produced by depositing a sheath of PLA on phosphate glass fibre bundles continuously fed into a cross head extrusion die. Due to the characteristics of the technique, composites could be reinforced with both as-drawn and annealed phosphate glass fibres which were embrittled as a result of anisotropy relaxation and the formation of a surface tensile layer following heat treatment. On account of the effect of annealing on the phosphate glass fibres mechanical properties, the flexural strength of as-drawn fibre reinforced compression moulded composite rods was higher with respect to annealed fibre reinforced ones, the former reaching maximum strength values of 371 MPa for the 0.45vf samples in comparison to 278 MPa for the latter. The flexural moduli of the composites rods manufactured through consolidation of PLA-sheathed fibre bundles were the highest hitherto reported for bioresorbable composites reaching values in excess of 30 GPa for the samples with 0.45vf. The higher modulus values of this type of rods with respect to conventional laminated composites were associated with their unique reinforcement distribution achievable by compression moulding of PLA-sheathed fibre bundles. Annealed fibre reinforced composites showed a better retention of mechanical properties in wet conditions with respect to as-drawn fibre reinforced ones, as a result of the slow degradation of annealed fibres, managing to present values even exceeding the human cortical bone range during the 30 day in vitro degradation study.
30
Beard, Maria. "An exploration of the factors associated with paediatric burn injuries in rural and peri-urban Malawi." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/49174/.
Full textAbstract:
Background: Burn injuries disproportionally affect the world’s poorest regions. However, there is a lack of data from these areas to determine the true extent of this public health problem. Children in Malawi are at high risk of burn injuries and poor health because of the nature of their environment, and the paucity of burn prevention programmes. At present, the research that reflects the factors associated with these injuries has been limited to the interpretation of quantitative, hospital based data, which may provide patterns of burns risks, but does not reflect the context or perception of burn injuries necessary to create culturally appropriate and targeted prevention initiatives. Moreover, while it has been suggested that the use of improved cookstoves (ICS) in these areas might mitigate children’s exposure to burn injuries more research is needed. Aim: To explore the factors associated with paediatric burn injuries in rural and peri-urban Malawi. Methods: This study employed a qualitative approach to explore the contextual factors, associated with paediatric burn injuries, across four villages in Malawi. Three of these villages had been previously exposed to an ICS intervention. In addition to conducting observations of household environments, multiple perspectives of burn injuries were sought from 32 parents, 12 health professionals and 6 key stakeholders using semi-structured interviews. Focus groups were conducted with household participants to gain a better understanding of safety in relation to their cooking methods. The data obtained were analysed using thematic analysis. Results: The study revealed a number of environmental and social factors which put children at risk of burn injuries across rural and peri-urban Malawi. Parents are often limited in their ability to provide adequate protection against such injuries because of: a lack of knowledge about injury prevention, a lack of safety equipment, a lack of control to make alterations to their housing and an inability to adequately supervise children. Additionally, health professionals reported that, due to a lack of time and resources, they were unable to consistently provide information to parents and caregivers about preventing burn injuries in the home. Those working with existing ICS initiatives in Malawi revealed that, although kitchen safety is currently discussed as part of organisations’ promotional activities, there is a lack of data measuring the effectiveness of this teaching. Conclusion: The factors associated with paediatric burn injuries and prevention, both actual and perceptual, are multifaceted and intertwined with the complex nature of the household environment and those who live within it. This study has provided a starting point from which to understand these factors and gives a voice to those affected. Overall the results demonstrate that there is an urgent need to raise an awareness of the burns problem to policy makers, key stakeholders, health professionals and parents, to initiate the development of comprehensive prevention initiatives. Future strategies need to consider the integration of multilevel support to address the challenges faced by families living in rural and peri-urban Malawi.
31
Atikovic, Emina. "Anaerobic treatment of army ammunition production wastewater containing perchlorate and Rd." Cincinnati, Ohio : University of Cincinnati, 2006. http://www.ohiolink.edu/etd/view.cgi?acc%5Fnum=ucin1163767781.
Full textAbstract:
Thesis (M.S.)--University of Cincinnati, 2006.Title from electronic thesis title page (viewed Jan. 29, 2007). Includes abstract. Keywords: Perchlorate, RDX, fluidized bed reactors. Includes bibliographical references.
32
Koch, Karsten. "Interpolating scaling vectors and multiwavelets in Rd : a multiwavelet cookery book /." Berlin : Logos-Verl, 2007. http://deposit.d-nb.de/cgi-bin/dokserv?id=2917176&prov=M&dok_var=1&dok_ext=htm.
Full text
33
Koch, Karsten. "Interpolating scaling vectors and multiwavelets in Rd a multiwavelet cookery book." Berlin Logos-Verl, 2006. http://deposit.d-nb.de/cgi-bin/dokserv?id=2917176&prov=M&dok_var=1&dok_ext=htm.
Full text
34
Zeman, Radek. "Spojení kondenzačního kotle se solárními kolektory pro zásobování RD tepelnou energií." Master's thesis, Vysoké učení technické v Brně. Fakulta strojního inženýrství, 2016. http://www.nusl.cz/ntk/nusl-254319.
Full textAbstract:
This diploma thesis deals with practical design of heat supply of real house in Libhošť, Nový Jičín. Main strategy of heat supply is gas condensation boiler, that replaces current gas boiler, with solar collector. From known house heat loss we determine temperatures of heating water and power of boiler, that heats the house and hot water. System with solar collector is designed to heat hot water in the house. All necessary equations are calculated both for long term measured meteorological data and for data in year 2015. Heat gains and payback periods of investment in solar system are determined from them. Payback periods are calculated given to price of heat that gas boiler produces. Equations and payback period evaluation are made for systems with one to four solar collectors. There is recommendation at the end of thesis, whether the solar system is advantageous, or not.
35
Coe, Samuel C. "The deposition, characterisation and biocompatibility of hydroxyapatite and silicon doped hydroxyapatite thin film coatings for orthopaedic applications." Thesis, University of Nottingham, 2008. http://eprints.nottingham.ac.uk/10984/.
Full textAbstract:
Silicon doped hydroxyapatite (SiHA) could be used as a thin film coating on load bearing bone implants to provide a bioactive layer enabling bone to form a direct bond with the implant/bone interface thus increasing implant lifetime by lowering the chances of aseptic loosening. This study has been undertaken to investigate silicon additions to RF magnetron sputtered hydroxyapatite (HA) thin films. Detailed characterisation was carried out on SiHA thin films to establish the structural, chemical, mechanical and compositional properties. Silicon content was altered by adjusting the power density applied to silicon targets in a co-deposition process resulting in SiHA films containing 0.0, 1.8, 4.2 and 13.4 wt.% silicon. All as-deposited thin films were found to be amorphous. After annealing at 600˚C in flowing argon for 2 h, it was found that films exhibited a single phase HA structure. The addition of silicon inhibited HA crystallite growth and acted to lower the stability of HA films in aqueous solutions. The 13.4 wt.% SiHA thin film did not recrystallise until a heat treatment at 800˚C. From the work presented here, it is proposed that, in post-plasma-deposited heat treated films, silicon substitutes as silicate species into the HA lattice. Asdeposited silicon containing thin films were found to be amorphous and have a polymeric silicate configuration, suggesting that, silicate groups may be randomly distributed throughout the amorphous film. After post-deposition annealing silicon containing films were in a monomeric state suggesting silicate groups had substituted for phosphate tetrahedra in the HA lattice. Furthermore, an HA-like phase was found to be present. Contrary to these findings, FTIR analysis did not manifest any silicate-based bands. This may, however, be due to the fact that technique used only samples a very small amount of material and, due to the low doping quantities of silicon in the HA films. Furthermore, Ca/P ratios consistently differed from the stoichiometric value of HA (1.67). This combined evidence raises the question of whether the post-deposition heat-treated films have a true HA-like structure. More work is required in order to truly understand the structures present in heat-treated SiHA thin films. HA thin film composition is commonly measured in terms of the Ca/P ratio. Energy dispersive X-ray analysis (EDX) and XPS were evaluated in terms of accuracy in conjunction with Rutherford backscattering spectroscopy (RBS) to measure the Ca/P ratio of HA thin films to establish the most appropriate technique for accurate compositional analysis. This was was found to the RBS, achieving an accuracy of within 2 %, with EDX averaging 8 % and XPS ranging from 25 - 42%. It was concluded that XPS gave such large differences in values because the top few atomic layers of thin films was of a different composition than the bulk of the coating. A Human osteoblast cell (HOB) model was used to establish the in vitro cellular response of SiHA thin films. Initially, HA and SiHA thin films annealed at 600˚C were compared. Cells attached and proliferated well on HA surfaces compared to SiHA surfaces, however, improved cell growth was seen with increasing silicon content. Dissolution studies showed that SiHA thin films were highly unstable in cell culture media and it is thought that the films dissolved, and where cell adhesion and growth did occur it was because cells adhered to the titanium substrates beneath the films. This was then compared with HA and SiHA thin films annealed at 700˚C. No significant difference was found between the two surfaces in terms of cell growth or protein expression indicating that silicon content and crystallinity play an important role in the cellular response of SiHA thin film.
36
Will, Malcolm B. "Gene expression profiling of mesenchymal stem cells aged in vitro." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/1964/.
Full textAbstract:
Mesenchymal Stem Cells (MSC’s) have shown promise as a cell-based therapy for myocardial repair. However, MSC’s have a finite replicative lifespan and lose proliferative and differentiation capacity during expansion in vitro. Therefore, understanding the molecular mechanisms that regulate ageing and senescence of MSC’s should enhance our ability to use these cells in cell-based approaches and give insight into mechanisms of tissue ageing. We established MSC cultures from the sternal bone marrow of eight donors undergoing coronary artery bypass surgery. After thirty population doublings (nine passages) MSC’s displayed morphological abnormalities, expression of senescence associated β-galactosidase, telomere erosion and decreased adipogenic and osteogenic differentiation capacity. Using serial analysis of gene expression (SAGE) we identified 243 known genes differentially expressed between MSC’s at passages two and nine. Analysis of known direct interactions between genes revealed a regulatory signaling network centered on down-regulation of the transcription factor, activator protein 1 (AP-1). Transcriptional changes in MSC’s at passage nine included genes associated with inflammation, regulation of cell cycle, metabolism and extracellular matrix re-modelling. The validation studies corroborated the SAGE results and eighteen genes were identified as differentially expressed in late passage MSC’s from multiple donors. Furthermore, caveolin 1, cyclin D1, tissue plasminogen activator and olfactomedin-like 3 were able to discriminate MSC’s of different culture age. In addition, we show evidence that the p38 MAPK signalling pathway contributes to the decline in proliferation and differentiation of MSC’s during expansion and is critical for the maintenance of genomic stability. The results provide further evidence that MSC’s senesce prematurely in response to undefined culture stresses. Our studies have provided novel markers that identify MSC ageing in vitro and suggest that identifying factors that activate p38 MAPK signalling should enhance our ability to use MSC’s in cell-based therapies.
37
Denley, Simon M. "The role of the systemic inflammatory response, the JAK STAT pathway and the MAPK pathway in the prognosis of resectable pancreatic cancer." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/523/.
Full textAbstract:
Pancreatic cancer is a devastating disease with a five year survival of only 2-3%. Only 10-15% of patients have resectable disease at presentation and the only potential cure is major surgery with adjuvant chemotherapy. The outcomes of surgery are disappointing with a median survival of only15-17 months and operative mortality and morbidity figures of 5-10% and 40% respectively. This abysmal prognosis is likely due to the highly aggressive nature of the tumour, its resistance to adjuvant therapy, its late presentation and the likely presence of micro-metastases not detectable at staging or surgery. A pre-operative systemic inflammatory response (as measured by CRP) is known to be associated with a poor prognosis in a number of cancers including pancreatic cancer. The reasons behind this poor prognosis are not yet known. The main driver of plasma CRP levels is the cytokine IL-6, known to be elevated in the plasma of patients with pancreatic cancer. This thesis hypothesises that upregulation of two IL-6-dependent pathways, the JAK STAT and MAPK pathways is responsible for the poor prognosis associated with an inflammatory response in pancreatic cancer. Both of these pathways are known to be involved in cellular growth, differentiation and apoptosis and when activated they may confer a growth or survival advantage to tumour cells. The aims of this thesis were to establish the prognostic role of a systemic inflammatory response in resectable pancreatic cancer in both a retrospective and prospective cohort and establish whether increased protein expression in either the JAK STAT or MAPK pathways is associated with a poor prognosis in the same retrospective cohort. A retrospective database of 148 patients who had undergone Whipple resection for either pancreatic cancer (PC) or non-pancreatic peri-ampullary cancer (NPPC) was created with pre-operative CRP values and survival data. The author then created tissue micro-arrays (TMA’s) with both tumour and normal pancreatic duct tissue from each of the 148 patients in the retrospective cohort and carried out immunohistochemistry on 12 antibodies known to be crucial in IL-6 signalling (6 in the JAK STAT and 6 in the MAPK pathways). Following staining the author scored each of the antibodies using the weighted histoscore to allow analysis of antigen expression. During the period of research the author also created a prospective database of 36 patients who underwent surgery for either PC or NPPC. Plasma was stored pre-operatively from each of the patients and this was later thawed and using an ELISA kit another research fellow (JL) was able to establish plasma levels of IL-6 in the prospective cohort. On univariate analysis a raised pre-operative CRP was associated with poorer survival, 374 days versus 618 days (p=0.0001) in the retrospective PC group only. On multivariate analysis, only pre-operative CRP retained statistical significance amongst those factors shown to be significant on univariate analysis (P=0.009). In the prospective group, patients with low levels of IL-6 had a median survival of 799 days, against a median survival of 537 days in those with high plasma IL-6 levels (P=0.002) when all 36 patients were analysed together. On analysis of protein expression, no significant relationship between increased expression and poor survival was seen for any of the 12 proteins analysed. The results from this thesis confirm that a pre-operative inflammatory response is associated with poor survival in patients with resectable pancreatic cancer. Raised plasma levels of IL-6 are also associated with poorer survival in similar patients. However, the poor prognosis appears to be via a JAK STAT/ MAPK independent mechanism. Other possible explanations for this poor prognosis including the connection between inflammation and cachexia and other important inflammatory proteins such as NF-κB and SOCS are explored in the discussion of this thesis.
38
MacKay, Graham J. "The effect of intravenous fluids and other factors on patient recovery following elective abdominal surgery." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/438/.
Full textAbstract:
The subject matter for this research work is the area of perioperative recovery for patients undergoing major abdominal surgery. During clinical studies we have investigated some of the factors influencing postoperative recovery as well as suggesting strategies to improve patient care. The main focus of the scientific work of this thesis is the role of intravenous fluids in the perioperative management of patients undergoing abdominal surgery. We found that restriction of intravenous fluid in the postoperative period does not significantly improve recovery in terms of gastrointestinal function (4.2 (3.2-6.9) versus 4.7 (3.7-6.1) days; p=0.80) or hospital stay (5.9 (4.0-7.9) versus 5.8 (4.1-7.3) days; p=0.90). Analysing our findings in the context of what is already known suggests that the immediate perioperative period when the effect of the metabolic-endocrine response is at its greatest is the most important period for fluid management. During this period fluid optimisation has an important role in patient recovery but following this period the body’s own homeostatic mechanisms are more able to cope with any fluid excess. We also found that using a ‘fast-track’ regime we could reduce hospital stay to levels comparable with other studies in the published literature. Our work using a multi-modal rehabilitation regime in association with both laparoscopic and open surgery suggests that it is the postoperative care package which has the more major influence on recovery. Our findings are in agreement with other small sized studies beginning to appear in the literature and indicate that further large scale studies are required to determine the role of laparoscopic surgery and any potential benefits. One of the most significant causes of morbidity for patients undergoing abdominal surgery is postoperative ileus. During the course of our studies we found that the extent of surgery and particularly handling and exposure of the intestines seems to have little effect on the duration of postoperative ileus. These findings add to the previously contradictory findings of other groups. Our experience with ‘fast-track’ postoperative programmes was also applied to liver surgery, an area where it has not previously been reported, to show that a variety of abdominal procedures may benefit from this approach. By comparing our results with series published in the medical literature we found that hospital stay can be significantly reduced (4 versus 5-8 days).
39
Tatarov, Oleg. "The role of SRC family kinases in the development and progression of prostate cancer." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/1608/.
Full textAbstract:
Prostate cancer is the most common cancer in men and the second leading cause of cancer-related death in western world. Typically, the treatment of advanced and metastatic prostate cancer consists of castration therapy, which suppresses the development of the disease for 2 years in average. Virtually all patients, undergoing androgen deprivation therapy eventually develop castration-resistant prostate cancer. Currently, only taxane class of drugs has been proven to provide short survival advantage in patients with castration-resistant prostate cancer. This form of the disease is the cause of significant morbidity, resulting in long periods of gradual deterioration of patients’ condition, pain related to local extension of the tumour and distant metastases, renal failure due to the invasion into the ureters etc. Castration resistance allows prostate tumours to progress despite androgen deprivation. Several mechanisms have been described, outlining the nature of molecular pathways, employed by prostate cancer cells in order to proliferate and migrate in low androgen environment. Hormone-sensitive prostate cancer cells rely on androgens for their growth needs with androgens acting through the androgen receptor (AR). In castration-resistant prostate cancer AR can be activated by reduced concentrations of androgens, AR antagonists, protein kinases or bypassed altogether. Detailed knowledge of these processes should allow better understanding of molecular patterns, driving the progression of prostate cancer and, ultimately, could lead to the development of novel molecular targeted therapies. Molecular pathways, implicated in the development of castration-resistant prostate cancer frequently show cross-talk, resulting in the ability of cancer cells to adapt to changing microenvironment. Inhibiting the proteins, facilitating these cross-talks provides an attractive targeting mechanism. Src family of non-receptor tyrosine kinases (SFK) represent proteins involved in the development of various solid malignancies, including prostate cancer. These proteins are often found on the cross-roads of intracellular pathways, integrating molecular systems into complex signalling networks. SFK interact with receptor tyrosine kinases, G-protein coupled receptors, motility and adhesion factors and, thus, influence multiple cell functions. In prostate cancer, SFK have been demonstrated to form complexes with AR, activating AR by means of tyrosine phosphorylation. SFK inhibitory compounds have been developed and are now in Phase II clinical trial in patients with castration-resistant prostate cancer. However, there is considerable lack of data regarding the role of SFK expression and activation in prostate cancer in clinical settings. In this thesis, we studied the role of SFK in prostate cancer using matched paired prostate cancer samples, taken from patients prior to castration therapy being administered and following the development of castration resistance. Using paired tissue specimens allows following molecular changes through the natural history of the disease and correlating these changes with various clinical parameters. We also conducted in vitro experiments, employing hormone-sensitive LNCaP cell line and its counterpart, castration-resistant LNCaP-SDM cell line, developed by gradual withdrawal of androgens from the culture medium. Our main finding is that in a subgroup of prostate cancer patients, the increase in SFK activity in the transition of prostate cancer from hormone-sensitive to castration-resistant state is associated with significant decrease in survival (p<0.0001). Furthermore, the presence of bone metastases in patients with castration-resistant prostate cancer was associated with higher SFK activity in prostate tissue specimens. Our in vitro experiments have demonstrated that in prostate cancer the relationship between SFK and AR are important as androgen deprivation resulted in significant reduction in SFK activity. Using SFK inhibitor dasatinib, we have shown that in prostate cancer cell lines, SFK activity was inhibited at low nanomolar concentrations. Inhibition of SFK activity was accompanied by the inhibition of downstream protein FAK at Src-specific phsophorylation site. Although the treatment with SFK inhibitor suppressed migration of both LNCaP and LNCaP-SDM cell lines, only proliferation of LNCaP-SDM cell was affected by dasatinib. Taken together, our date suggests that SFK inhibitors may have a role in the treatment of castration-resistant prostate cancer. However, important considerations should be given to the molecular heterogeneity of prostate cancer in order to improve the outcomes of clinical trials and the response to treatment. There is considerable evidence that SFK inhibitors suppress prostate cancer cells migration and future studies will hopefully further clarify their role in cancer cells proliferation.
40
Jackson, Andrew John. "Cellular aspects of intimal hyperplasia formation." Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2417/.
Full textAbstract:
Introduction: 12,000 infrainguinal bypass grafts are performed annually in the UK. Despite improvements in surgical technique, outcomes remain suboptimal: 20% of above knee grafts require intervention to maintain patency by 3 years. Only antiplatelet agents have been demonstrated thus far to improve graft survival. 80% of graft failure is as a result of intimal hyperplasia, an inflammatory process characterised by the proliferation and migration of vascular smooth muscle cells. Toll Like Receptors (TLR), part of the innate immune system, have been implicated in atherosclerosis formation but not investigated in a model of infrainguinal graft failure. When a vein is used as a conduit for infrainguinal bypass graft it has been exposed to ischaemic and hypoxic conditions: preliminary data has demonstrated that ischaemic vascular smooth muscle cell explants are hyperproliferative. Phospholipase C γ (PLC γ) is a signalling pathway with potential links to innate immune pathways and pathways induced by hypoxia and ischaemia. Methods: Human vein tissue was obtained from patients undergoing amputation and coronary artery bypass surgery and used for immunohistochemistry and to obtain vascular smooth muscle cells by explant method. Immunohistochemistry was used to determine the presence of TLR4 and PLC γ in human vein tissue. Specific TLR Ligands were used to determine the functional response of TLR’s in vascular smooth muscle cells as measured by Interleukin 8 ELISA. Radiolabelled Thymidine incorporation was used to measure proliferation of vascular smooth muscle cells in response to TLR4 activation, hypoxia and PLC γ inhibition. Results: TLR4 was demonstrated to be present in human vein tissue, and functionally active in human vascular smooth muscle cells. Furthermore stimulation with the specific ligand of TLR4 caused enhanced proliferation of vascular smooth muscle cells. Hypoxia (5% and 10% Oxygen) significantly enhanced proliferative responses of vascular smooth muscle cells. PLC γ was demonstrated to be present in human vein tissue, and inhibition, using U73122 in vascular smooth muscle cells reduced proliferation. Conclusion: TLR activation and hypoxia appear to enhance the proliferative responses of human vascular smooth muscle cells, a key cellular pathway of intimal hyperplasia formation and infrainguinal graft failure. Inhibition of PLC γ reduces proliferative responses. Further research is required to confirm that PLC γ is a key common pathway mediating enhances of proliferation caused by TLR activation and hypoxia.
41
Glen, Paul. "An investigation of liver blood flow in systemic inflammation." Thesis, University of Glasgow, 2009. http://theses.gla.ac.uk/1190/.
Full textAbstract:
If the intrinsic control of the liver is responsible for these changes it would be important to show that the liver is more metabolic as the changes occur. An intervention to lower the metabolic demand on the liver is difficult and may not be ethical given that the normal response to injury or infection is an acute phase response. One area where this could be said to have been performed is the tight control of blood glucose in intensive care medicine which reduces the demand on the liver to perform gluconeogenesis. While there are other benefits of lower serum glucose levels this may contribute to the reported improved outcome in such patients. Clinically, measurement of hepatic arterial and portal venous blood flow has been shown to be feasible in the critically ill patient and may be used as a non-invasive measurement of the liver response to a drug or therapy.
42
Alani, Ahmed M. "Management of asymptomatic inguinal hernias." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/453/.
Full textAbstract:
Hernia surgery remains one of the most common operations carried out by general surgeons worldwide with more than 800,000 repairs performed in the USA alone in 2003. Advancement in surgical technique has meant fewer recurrences are now encountered with figures dropping to less than 2% using the laparoscopic approach. Yet despite the progress achieved in securing the repair, post operative pain remains an issue with many authors reporting figures of 30% in patients following groin hernia repair 1,2, 3% of patients report sever pain that limits their daily activities and renders them off work. Many patients with inguinal hernia have very little in the way of symptoms and even some of them are asymptomatic, having noticed their hernia by accident or by their general practitioner. In order to clarify two issues (the first being the incidence of acute hernia presentation, its management and subsequent outcome, while the second was the management of patients with an asymptomatic inguinal hernia) 4 studies were carried out: The first study was a prospective observational study looking at all patients presenting to our unit with an acute hernia, the aim of the study was to prospectively assess the presentation and management of acute hernias in light of recent changes in hernia management. Data on all patients admitted with an acute hernia between 2001 and 2004 was collected prospectively. During the 3 year study period 91 patients were admitted with an acute hernia. 46 had a previous medical assessment either as an acute admission (12) at a surgical clinic (22) or by a General Practitioner (12). Eighteen had been declared unfit for operation at that assessment, 10 were ASA4, 5 ASA3 and 3 ASA2. Eleven patients were on the waiting list for operation 3 of whom had a previous acute hospital admission. For 30 patients this hospital admission was the first indication that they had a hernia while the remainder refused operation or did not seek medical advice. Five patients died, 2 while being assessed for operation and 3 postoperatively, 3 were ASA4 while 2 were ASA3. The number of patients undergoing operation for an acute hernia amounted to 8.4% (80 of 952) of all hernia operations carried-out during the study period. This study concluded that despite advances in hernia surgery there was still room for improvement, to ensure that all suitable patients presenting with an acute hernia receive an operation during their acute hospital admission. The second study was a prospective study of all patients presenting with subacute bowel obstruction in one teaching hospital between 2003 and 2004. The aim of the study was to identify the most frequent causes of strangulation in patients presenting with small bowel obstruction. During the study one hundred and sixty-one patients with symptoms and signs of small bowel obstruction were admitted. Eighty-nine were confirmed with contrast studies. The male: female ratio was 1:1.6. The aetiology of obstruction was hernia in 29 (18%), adhesions in 97 patients (60.2%), and miscellaneous in 35 (21.8%) Operative procedures were performed on 74 patients (46%), 31 of them (42%) with adhesions, 25 (34%) with hernias and 18 (24%) due to other causes. Strangulated bowel occurred in 15 patients (9.3%); 12 had hernias whilst three had adhesions (P < 0.0001). Of the strangulated hernias, ten were femoral, one was inguinal and one was paraumbilical. Our conclusion was that whilst adhesions are the most common cause of small bowel obstruction, femoral and not inguinal hernias remain the most frequent cause of strangulation. The third and main study was a prospective randomized trial comparing surgery and no intervention for asymptomatic inguinal hernias. The aim of the study was to compare operation with a wait and see policy in patients with an asymptomatic hernia. 160 male patients 55 years or older were randomly assigned to observation or operation. Patients were assessed clinically and sent questionnaires at 6 months and 1 year. The primary endpoint was pain and general health status at 12 months; other outcome measures included costs to the health service and the rate of operation for a new symptom or complication. At 12 months there were no significant differences between the randomised groups of observation or operation, in visual analogue pain scores at rest, 3.7mm versus 5.2mm (P=0.34), or on moving, 7.6mm versus 5.7mm (P=0.39). Also the number of patients who recorded pain on moving 29 versus 24 (P=0.31), and the number taking regular analgesia, 9 versus 17, (P=0.14) was similar. At 6 months there were significant improvements in most of the dimensions of the SF-36 for the operation group, while at 12 months although the trend remained the same the differences were only significant for change in health (P=0.039). The rate of crossover from observation to operation was 23 patients at a median follow-up of 574 days, this was higher than predicted. The observation group also suffered 3 serious hernia related adverse events compared to none in the operation group. Finally a sub study was generated from the non randomised patients within the asymptomatic trial. The aim here was to assess the outcome of patients opting for no surgery in terms of need for surgery and outcome. There were 72 patients (58 opting for observation and 14 wanting an operation), 13 patients (22.4%) in the observation group became symptomatic and required an operation, 9 patients had died at the time of data analysis, all of which were due to co morbid illnesses. The final 2 studies concluded that repair of an asymptomatic inguinal hernia did not affect the rate of long-term chronic pain and might be beneficial to patients in improving overall health and reducing potentially serious morbidity.
43
Gibson, Simon C. "Peri-operative cardiac morbidity : prediction, prevention and the novel role of B-type natriuretic peptide." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/446/.
Full textAbstract:
Cardiovascular disease is the leading cause of death in surgical patients and because of this a number of strategies have been utilised to attempt to predict the cardiac risk of surgery. Theoretically, accurate pre-operative risk stratification would allow patients at low risk to have their surgery expedited efficiently, whilst those at higher risk could have a change made to their treatment plan such as peri-operative cardiac optimisation or in some cases, modification of the operative procedure. Despite this rationale, no guidelines currently exist in the United Kingdom for the management of the surgical patient at high cardiac risk. This may partly reflect the limited methods of risk stratification currently available. Clinical scoring systems are simple and inexpensive but limited by their predictive value. Trans-thoracic echocardiography provides prognostic information but is inconsistent, adding little to clinical information alone. The most accurate methods of pre-operative cardiac risk prediction at the present time are dobutamine stress echocardiography and dipyridamole thallium scanning. However they are expensive, time consuming and have shown poor positive predictive ability, even in high risk cohorts. Few studies have studied the usefulness of biochemical markers in the prediction of post-operative cardiac events. In particular, no information was available in the literature regarding the role of B-type natriuretic peptide (BNP) in the prediction of cardiac events in non-cardiac surgical patients; despite the fact that its measurement has been shown to be an important prognostic tool in both non-surgical and cardiac surgical cohorts. In this thesis the aim was to determine whether pre-operative BNP concentration related to cardiac outcome following non-cardiac surgery; and also to determine whether measurement of other markers such as C- reactive protein (CRP) and cardiac troponin I (CTnI) would be of benefit in pre-operative cardiac risk stratification. To assess the effectiveness of plasma BNP measurement in the prediction of peri-operative cardiac morbidity a pilot study of 41 patients undergoing vascular surgery was conducted. To ensure that any post-operative rise in CTnI was due to operative stress, this was measured pre-operatively along with CRP. Median pre-operative BNP concentration was significantly higher in patients who suffered a post-operative cardiac event (cardiac death, non-fatal myocardial infarction (MI)) than in those who did not (210 (165-380) pg/ml vs. 34.5 (14-70) pg/ml, p<0.001). On the basis of these results a single-centre, prospective, observational cohort study was performed of all patients undergoing non-cardiac surgery. Of the 149 patients recruited to this study, 15 had a cardiac event. The median BNP in those patients having a cardiac event was more than ten-times higher than in those who did not (351 (127-1034) vs. 30.5 pg/ml (11-79.5), p<0.001). A BNP concentration of 108.5pg/ml was the best performing cut-off value having a sensitivity and a specificity of 87%. Although CTnI had originally been measured to ensure that any post-operative rise was due to operative stress, 3 patients had a pre-operative elevation all of whom underwent lower extremity amputation. The amputation group, and in particular those patients who had a raised pre-operative cTnI were therefore analysed further. Amputation patients in general had a high cardiac event rate (23%); however the outcome in those patients who had a raised pre-operative cTnI was particularly poor with 2 suffering a cardiac death post-operatively and one suffering a non-fatal MI. A pre-operative rise in CTnI was the only significant single predictor of peri-operative cardiac events in patients undergoing amputation (p= 0.009). Pre-operative CRP concentration was measured routinely in vascular patients. The concentration in those who had a cardiac event was significantly higher than those who did not (69 (0-260) vs. 12 (0-285), (p=0.003). The cardiac event rate rose with each logarithmic increment in CRP concentration (0-10mg/l (5.7%); 11-100mg/l (22.4%), >100mg/l (55.6%) (p=0.002). Measurement of CRP was of most potential benefit in patients undergoing aortic aneurysm surgery. In conclusion, this thesis has shown that pre-operative measurement of biochemical markers (BNP, CTnI, and CRP) can allow accurate peri-operative risk stratification. BNP concentration in particular was a sensitive and specific predictor of cardiac outcome. Careful case selection using a combination of clinical assessment and the results of these markers may lead to a reduction in the cardiac event rate.
44
Zino, Samer M. Walid. "Investigations into the expression of sirtuins in breast cancer : in vivo and in vitro studies." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/2189/.
Full textAbstract:
Breast cancer remains the most common malignancy in women and a major cause of morbidity and mortality in the western World, despite the advances in diagnosis and treatment. The main challenge remains to identify new, and improve existing treatment modalities. Understanding the mechanism by which tumours grow and metastasise is key to developing new therapeutic targets Similar to most cancers, the incidence of breast cancer increases with age. Therefore, genes involved in biological ageing and factors affecting genomic integrity, considered critical to cellular senescence and organismal life span, are also relevant to neoplastic transformation and tumour growth. Thus exploring factors associated with biological ageing in cancer may improve our understanding of the disease as an aberration of normal biological ageing and result in new prognostic markers or therapeutic targets. There is increasing evidence for the involvement of sirtuins in biological ageing, along with other essential cellular processes including cell cycle control, DNA damage repair and differentiation. This is suggestive of a possible role for sirtuins in cancer. Therefore, this study was conducted to investigate a potential role for sirtuins in breast cancer disease (including anti-tumour treatment). Firstly, Real time PCR was used to compare the transcriptional expression level of individual sirtuin genes in vivo. The experimental result showed that only SIRT1 and SIRT4 showed an association with age in “normal patients” (normal and non malignant patient grouped together), with decreasing levels of SIRT1 and increasing levels of SIRT4 being associated with increasing chronological age. All sirtuin levels were significantly decreased in malignant tumours, when compared to either normal and/ or non-malignant biopsies. Decreased relative transcriptional expression of SIRT1, SIRT2, SIRT3, SIRT6 and SIRT7 showed significant association with higher tumour grade, when breast cancer patients were divided according to the known histopathological markers. The Kaplan-Meier analysis for cancer specific survival and tumour recurrence was preformed on entire patient cohorts and in patient subgroups selected to have moderate prognosis (ER+ve and NPI between 3.4 and 5.4). The Kaplan-Meier survival analysis showed that higher levels of SIRT6 and SRT7 were associated with a longer survival period in all patient cohorts. Furthermore, higher levels of SIRT6 remained significantly associated with better survival, when breast cancer patients were selected to have intermediate prognosis (ER+ve and NPI between 3.4 and 5.4). Whereas, higher levels of SIRT7 remained significantly associated with longer survival period only in patients with ER+ve tumours. The Kaplan-Meier analysis showed that lower levels of SIRT1 gene expression were associated with longer patient survival and lower tumour recurrence in a patient group, selected by NPI, to have an intermediate clinical prognosis. Multivariate Cox-regression analysis demonstrated that the relative transcriptional level of the SIRT6 gene was independent of tumour size, grade, nodal status, oestrogen receptor status, lymphovascular invasion status, and the NPI in influencing survival. The decreased sirtuin gene expression observed in this study is consistent with an anti-cancer effect and suggests that sirtuins might be implicated in breast cancer pathogenesis. For example, decreased levels of SIRT2 might assist DNA-damaged tumour cells, as indicated by the decreased expression of another sirtuin involved in DNA damage responses, SIRT6, in escaping cell cycle arrest during tumour initiation and progression. Furthermore, The associations between sirtuins and survival period suggest that these sirtuins (especially SIRT6) might be used as an additional prognostic marker in breast cancer patients, especially in those individuals who have equivocal prognostic pathological markers. Therefore, the level of expression of sirtuin genes (SIRT6) might help explaining those breast cancer cases, which behave unexpectedly, according to the known pathological prognostic markers. Secondly, The changes in the relative transcriptional expression levels of the sirtuin genes were investigated in response to adjuvant chemotherapy therapies, commonly used in breast cancer (Tamoxifen and Docetaxel), in breast caner cell lines. The first experiment determining sirtuins changes in response to Docetaxel treatment for 72 hours in ER-ve breast cancer cell line (MDA-MB-231) showed significant increase in the relative transcriptional expression levels of all sirtuins after Docetaxel treatment. These data were consistent with the pro-apoptotic role for SIRT1, SIRT3 and SIRT7, and suggestive of DNA damage involvement at higher doses of Docetaxel, as indicated by increased SIRT6 and XRCC5. Finally, increased SIRT2 levels are suggestive of SIRT2 involvement in the mitotic arrest caused by Docetaxel, through its contribution to microtubule dysfunction. The second experiment, determining sirtuin changes in response to Tamoxifen treatment in ER+ve (MCF-7) and ER-ve (MDA-MB-453) breast cancer cell lines, showed significant increase in the relative transcriptional expression levels of all sirtuins after Tamoxifen treatment. These data were consistent with the pro-apoptotic role for sirtuins. Furthermore, the observed increased levels of SIRT6 are suggestive of DNA damage involvement at higher doses of Tamoxifen. Another noteworthy result of this experiment is the increased levels of SIRT2 in response to Tamoxifen treatment. This might explain the failure of a TAM-treated cell to proceed through the cell cycle, in spite of the increases in transcription factors that promote cell cycle after Tamoxifen treatment. There was no significant difference in sirtuin changes after Tamoxifen treatment between these two cell lines to indicate that sirtuin changes were ER-dependent. In total, the data accumulated from this study demonstrated the involvement of sirtuins in breast cancer disease (pathogenesis and anti-tumour treatment) and suggest the possible use of SIRT6 as a novel, additional and biological prognostic marker. Finally, this study suggests that sirtuins activators, rather than inhibitors, might be beneficial in breast cancer disease and enhance the response to adjuvant chemotherapy.
45
Crumley, Andrew B. C. "An investigation of the relationship between the inflammatory response and outcome in patients with gastro-oesophageal cancer." Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2584/.
Full textAbstract:
The thesis reviews the literature regarding the relationship between the local and systemic inflammatory responses and outcome in patients with gastro-oesophageal cancer. The study chapters then examine the relationship between the systemic inflammatory response and survival, in operable and inoperable disease and within, a cohort treated with palliative chemotherapy. The local inflammatory response and its relationship with tumour related factors, the systemic inflammatory response and survival, was examined in patients who underwent potentially curative surgery Also, the clinical utility of a systemic inflammation based score (Glasgow Prognostic Score) as a part of clinical staging, was then examined. The importance of these studies in a scientific and clinical context are discussed. Future work is also discussed.
46
Page, Blaithin. "Chronic pain following inguinal hernia repair." Thesis, University of Glasgow, 2009. http://theses.gla.ac.uk/2579/.
Full textAbstract:
Introduction: In the past five years chronic post herniorrhaphy pain has become the predominant post operative complication following the common procedure of inguinal hernia repair. However information regarding the precise aetiological factors of this chronic post surgical pain is lacking. To date no previous studies have assessed the long term outcome of patients who report chronic severe pain following inguinal hernia surgery. There are no studies assessing the presence of preoperative pain and the effect of surgical intervention on these pain scores. One factor thought to contribute to post herniorrhaphy chronic pain is the mesh type used by the surgeon. The characteristics of two different mesh types are evaluated with respect to postoperative chronic pain. Aims: The aim of the first study was to assess the outcome of patients who report severe or very severe pain three months after groin hernia repair. The aim of the second study was to quantify patients’ pain from their inguinal hernia prior to surgery and to examine the effect of surgery on this pain. The aim of the third study was to compare the composite partially absorbable and ultimately lighter weight (Vypro 11) mesh with an example of a conventional polyprolene mesh (Atrium) in a tension free repair of an inguinal hernia. Methods: One hundred and twenty five patients were identified as experiencing severe chronic pain at 3 months post herniorrhaphy, from the prospective National Hernia database1 of 5506 patients (97% of total) between 1 April 1998 and 31 march 1999. These 125 patients were assessed at 30 months post-surgery, with the use of the modified SF36 quality of life questionnaire. For the second study, consecutive patients referred for elective inguinal hernia repair between January 1998 and October 2000 completed visual analogue pain scores (VAS) pre- and 1 year post-repair. These patients were Western Infirmary patients who were part of a larger multicentre clinical trial comparing local versus general anaesthesia 2 for inguinal hernia repair. The third study examined patients who were involved in a multicentre trial comparing the incidence and severity of chronic pain following elective inguinal hernia repair, comparing the light weight or partially absorbable (PA) to the standard heavy weight or non-absorbable (NA) mesh. Results: In the first study, of the 125 patients who experienced severe chronic pain at three months post repair, at 30 months post-surgery 25% had persistent, unchanged chronic pain 45% had a reduction in pain to mild or very mild, and 29% were pain-free. In the 25% of patients that had persistence of severe chronic pain, the symptoms had a significant effect on all daily activities and quality of life, for example in measurement of general enjoyment of life, those with mild pain scored 2.32 (1.5-3.13) compared to 7.14 (5.97 - 8.30) in those with persistent severe pain (P<0.05) . In the second study 63% of patients completed VAS scores at follow-up. Prior to surgery the majority of patients had no pain or only mild pain at rest (80.5%) or on movement (58.8%). At 1 year follow-up the mean (SD) VAS score reduced by 2.9 (1.2) at rest, and reduced by 9.2 (1.8) on movement. However the majority of the beneficial effect was seen in those with moderate to high pre=operative pain scores. Those with preoperatively VAS score >10 had a reduction of 22.8 (3.7) at rest, compared to a slight increase in pain (+1.8) in those with no pain pre-operatively (P<0.05). Similar effects were seen on movement (improvement of 32.2 (4.8) in those with preoperative pain score >10, and little change in pain, -0.3 (1.6), in those with no, or only mild, preoperative pain (P<0.05). In the third study 162 patients received the PA mesh and 159 received the NA mesh. The PA mesh was not associated with less pain at 1 year postoperatively, compared to the NA mesh, with the proportion experiencing any pain being 39.5% in the PA group compared to 51.6% in the NA group (P=0.033). The proportion experiencing severe pain was similar, being 3% for the PA group and 4% for the NA group, and the recurrence rate was greater with the PA mesh compared to the NA mesh (4.9% versus 0.6%, P=0.037). Conclusion: Of those with chronic severe pain at 3 months post inguinal hernia repair, the majority will have still have some pain at 30 months post operatively. The greatest benefit in terms of pain reduction in patients undergoing inguinal hernia repair is experienced by those with the more severe preoperative pain. From our data there is no clear overall benefit in using the PA mesh over the standard mesh, as whilst pain scores were slightly lower in the PA group, this was countered by a higher recurrence rate. Further attention to the multiple factors that contribute to pain post-inguinal hernia repair is required, including the development of superior mesh technology.
47
Dunbar, Mark Robert. "Patient factors associated with outcome after total knee replacement : research towards the design of a multicenter prospective cohort study." Thesis, University of Warwick, 2008. http://wrap.warwick.ac.uk/2269/.
Full textAbstract:
This thesis set out to explore the influence of patient factors that may be associated with outcome after total knee replacement for osteoarthritis. It starts with an introduction to the general subject, looking in detail at the methods for measuring the outcome of total knee replacement and also methods of measuring the status of various possible patient factors. This is followed by a systematic review of the evidence currently available on the influence of patient factors on the outcome of total knee replacement. This systematic review highlights a number of deficiencies in the available evidence. The next logical step was to perform an appropriate study to provide better quality evidence. However, there were six areas of uncertainty that presented significant difficulty when designing such a study. These areas of uncertainty became the focus of this thesis and were explored in detail. Through a process of experimentation and careful evaluation of the results these uncertainties were resolved. This thesis has provided the critical information required to design and conduct a multicentre study that would define which patient factors are important in determining outcome for total knee replacement for osteoarthritis.
48
Fox, Nicholas J. "Surgical healing, power and social structure : an ethnographic and historical study." Thesis, University of Warwick, 1989. http://wrap.warwick.ac.uk/34815/.
Full textAbstract:
How the everyday activities of surgery mediate and reproduce surgical authority and privilege is studied by ethnographic study and interview material in and around the operating theatres of a large district general hospital, on surgical wards, and in a day surgery unit, using a case study approach. Routinised movements of staff, patients and instruments within the operating theatre suite (0T) order the activities by which patients pass through surgery. These movements are structured, and culturally designated, to ensure the safety of the patient during the dangerous transgression of boundaries in surgery. The history of surgical sterility indicates the symbolic significance of sterile garb, to mask the polluting bodies of the surgical staff and designate them purifiers of corrupting nature. Sterile techniques signify the superiority of cultural definitions over those based in 'nature'. While the surgeon is concerned with a patient's Illness, the anaesthetist is concerned with her/his Fitness. This interaction enables all operations other than those where both Fitness is reduced and Illness is not reduced, to be proclaimed 'successful'. Consequently, patients may be allocated a socially defined status of 'healed', despite no improvement in physiological status. Cross-cultural comparison suggests that surgical healing involves a social status passage from a negative status of victim to a positive one of survivor. Healing is socially reintegrative: it re-creates apparent congruence between the life-scales of the sick person and social structure, which is destroyed by illness. Case studies refine the hypothesis that this social recategorisation legitimates surgical authority and privilege. Both the operation's 'success' and patient discharge are found to be necessary for a full claim to have healed. The potential to generalise the model to all medical intervention, and the implications for surgery and the sociology of health and healing are discussed.
49
Cahoon, Neil John. "Efficacy and mechanism of nicorandil in perioperative protection of skeletal muscle from ischaemia and reperfusion injury in a porcine model." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/4127/.
Full textAbstract:
Background: Prolonged ischaemia time during autogenous free muscle transfer, can lead to ischaemia reperfusion (I/R) injury and local necrosis of the muscle. It has been demonstrated that the phenomenon of ischaemic preconditioning (IPC) confers biphasic infarct protection in a porcine skeletal muscle flap model. Further to this, the hybrid nitrovasodilator and KATP channel opener Nicorandil, is known to induce 24h uninterrupted infarct protection in myocardial models. We therefore hypothesised that Nicorandil could pharmacologically confer late-phase infarct protection of skeletal muscle from I/R injury. Methods: Yorkshire pigs (mean 17.9kg) with bilateral 8x13cm Latissimus Dorsi (LD) muscle flaps, received i.v. Nicorandil (3mg/kg) before being subjected to 4h ischaemia followed by 48h reperfusion. Results: Nicorandil induced late-phase preconditioning appeared at 24h after Nicorandil injection and lasted for 72h before waning. LD infarction rates were reduced to 22+/-2, 25+/-2 and 28+/-2% at 24h, 48h and 72h respectively, compared to the ischaemic control of 40+/-2%. Further to this, Nicorandil preconditioning was associated with a reduction in mitochondrial free calcium content, preservation of muscle ATP content and attenuation of neutrophilic myeloperoxidase activity during the first hour of reperfusion. Injection with the specific sarcolemmal KATP (sKATP) inhibitor HMR-1098 or non-specific KATP inhibitor Glibenclamide before Nicorandil injection completely blocked the infarct-protective effects. Injection of the specific mitochondrial KATP (mKATP) inhibitor 5-HD or Glibenclamide before the onset of reperfusion also abolished Nicorandil preconditioning. Conclusion: These findings support the hypothesis that a single dose of Nicorandil induces 48h of uninterrupted late-phase infarct protection in skeletal muscle. Further to this, sKATP and mKATP channels play a central role in the trigger and mediator mechanisms, respectively. Nicorandil is a potential new therapy to augment the ischaemic tolerance of skeletal muscle for patients undergoing autogenous free muscle transfer or composite tissue allotransplantation.
50
Maxwell, Fraser. "The influence of biological ageing in the pathogenesis of colorectal cancer." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4264/.
Full textAbstract:
Despite improvements in risk factor awareness, diagnosis and enhanced management strategies, the incidence and five year survival of colorectal cancer, has remained largely unchanged over the last twenty years. As with many epithelial cancers, a preponderance of new colorectal cancer diagnoses occur in the over sixty five age group, making chronological age a strong risk factor. Given this indelible link between ageing and cancer in general, genetic pathways which are implicated in one process could influence the other. Thus, an understanding of the biology of ageing and factors which regulate it may provide insight into cancer pathogenesis. Telomeres are nucleo-protein complexes sited at the ends of all chromosomes and have a critical function in the protection of the genome. Telomeres are implicated in the ageing process as a result of the inadequacies of the DNA replication machinery in somatic cells meaning that a section of telomeric DNA sequence is lost during each round of cell division, thus telomere length reduces with age and is a putative marker of biological ageing. Control of telomere length is complex and involves interplay between a number of genetic and environmental factors, of which oxidative stress is particularly important. However, critically short and hence dysfunctional telomeres have been implicated in cancer development through an inability to maintain genomic intergrity and an effect on senescence. Telomeres play an integral role in the sensing and repair of DNA damage, however, cells must possess a finely tuned mechanism through which they can sense DNA damage and initiate a response. This usually involves the activation of cell cycle checkpoints, either temporarily to allow repair, or on an irreversible basis to prevent the clonal expansion of cells with deleterious mutations. If the damage is deemed irrepairable apoptotic pathways are initiated. The sirtuins are a group of genes first discovered and shown to control longevity in saccharomyces cerevisiae. Intense work has defined seven mammalian homologs termed SIRT1-7 which vary in their sub-cellular localisation, and have critical cellular functions ranging from the control of apoptosis, mitochondrial biogenesis, glucose and lipid metabolism, maintenance of genomic integrity and cell cycle control. Given these functions it is therefore no surprise that aberrancy of sirtuin expression is implicated in ageing and its commonly related diseases, particularly cancer. The aim of this study was therefore, to determine if patients with colorectal cancer display aberrancy of ageing related factors, namely telomere biology and sirtuin expression. This study was undertaken using two sources of material for investigation. Quantitative-PCR was utilised to measure telomere length in the peripheral blood leucocytes of 64 colorectal cancer patients and 1348 controls. In addition, telomere length was similarly measured in colorectal cancer tumour and normal adjacent tissue. Telomere length was then correlated with a number of clinical and pathological parameters to determine diagnostic or prognostic utility. Furthermore, an attempt was made to establish whether telomere lengths were reflected in circulating mediators of inflammation and redox control factors, including fetuin-A a circulating modulator of calcium homeostasis. Sirtuin relative transcriptional expression (SIRT1-7) was then measured in the tumour and normal tissue samples. Clinically relevant information was derived by analysing the SIRT1-7 transcriptional data in terms of clinico-pathological, inflammatory and outcome variables. Finally, sirtuin expression was correlated with other factors known to be involved with biological ageing to determine any potential association. Colorectal cancer patients had significantly shorter telomeres in their peripheral blood leucocytes (adjusted mean RelT/S=0.61) compared with chronologically older controls (mean age 75, adjusted mean RelT/S=0.70) (ANCOVA, p=0.004), indicating colorectal cancer patients were biologically older than their control counterparts. In addition, telomere length in tumour tissue (median=0.43, IQR=0.40) was significantly shorter than adjacent normal tissue (median=0.65, IQR=0.28) (p=0.004). Patients with low plasma fetuin-A levels were shown to have significantly shorter telomeres (p=0.041) and patients with rectal tumours had significantly higher levels of fetuin-A than those with colonic tumours (p=0.045). There was no correlation between telomere length and other redox factors, namely anti-oxidant vitamins, micronutrients and divalent cations. There was, however, a significant association between telomere length and systemic inflammation as determined by the neutrophil to lymphocyte ratio. SIRT 1-7 were differentially expressed between tumour and normal tissue, with significant attenuation evident in tumour samples when compared with normal tissue (p<0.0001 except SIRT2 p=0.003). SIRT2 (p=0.021) and SIRT4 (p=0.027) expression in tumour samples, was significantly associated with anatomical tumour site and pathologically determined nodal status respectively. Whilst, SIRT3 expression in normal tissue correlated with pro-inflammatory status, indicated by higher serum CRP levels. Finally, there was a significant inverse relationship with colorectal cancer tissue telomere length and SIRT3. When overall survival was considered, Kaplan-Maier analysis revealed a significant difference in survival in relation to SIRT4 expression levels. We have observed that patients with colorectal cancer display clear evidence of telomere attrition compared with controls. This is congruent with accelerated biological ageing in the pathogenesis of colorectal cancer and indicates cancer patients have ‘more miles on the clock’. An imbalance in redox control mechanisms and calcium homeostasis may be a contributing factor to telomere dynamics in these patients. The demonstration of attenuated sirtuin expression in colorectal cancer suggests a role as potential tumour suppressors and provides further evidence implicating biological ageing in the oncogenic process. Furthermore, plasma fetuin-A and tissue SIRT2 expression levels can be used to distinguish between colon and rectal cancers, providing further information regarding the molecular characteristics of these tumours. Telomere biology and the sirtuins could both play a pivotal role in the MTR (Mitochondria Telomere Ribosome biogenesis) paradigm, aberrancy of which could explain the apparent link between biological ageing and cancer. Enhancement of the understanding of the determinants of telomere length could mean that manipulation could lead to reduced colorectal cancer risk at the population level. In addition, the data provided in this thesis strengthens the evidence base which suggests that targeting individual sirtuins could be a future chemotherapeutic strategy, or indeed prove useful as markers of prognosis.