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Cell-cycle progression in mammalian cells is coordinated by a series of control points. The D-type cyclins are a family of key cell cycle regulators that are controlled largely by mitogens and their association with and activation of cdk 4 and 6 at the G1 phase of the cell cycle. This study seeks to first analyze cyclins D1, D2, and D3 expression patterns in preimplantation mouse embryos using in vivo studies and then analyze the effects of Dilantin on the cyclin D1 expression pattern in cultured embryos. Antibody staining against cyclin D1, D2, and D3 via indirect immunofluorescence using a Zeiss Confocal Microscope and analysis of individual embryo staining intensities using Zeiss computer software were employed to evaluate expression patterns throughout the first three cell cycles. The data showed that all three D cyclins were present throughout the first three cell cycles. Cyclin D1 had peak average fluorescence intensity at the G2 phase of the second cell cycle with a decrease at the G1 in the third cell cycle. Cyclin D2 had a consistent increase of fluorescence intensity throughout all three cell cycles. Cyclin D3 had peak average fluorescence intensity at the G2 phase of the second cell cycle with an immediate decrease at the Gl phase in the third cell cycle. Cyclin D1 was localized to the nucleus in G1 phases of the cell cycle. In contrast, cyclin D2 was found in the nucleus during G2 phases of the cell cycle rather than in G1. Cyclin D3 was not localized to the nucleus in either cell cycle phase throughout the first three cell cycles. These unique nuclear staining patterns seen by D1, D2, and D3 may reflect a function in the cell cycle. Embryos cultured in the presence of l0gg/ml of Dilantin were found to be slowed in development indicated by the absence of transition from the one-cell to the two-cell stage when compared to the controls. Since the Dilantin cultured embryos never reached G1 of the second cell cycle the increase in fluorescence intensity seen was still considered to be a representation of the G2 phase of the first cell cycle. Cyclin Dl's fluorescence intensity was affected by Dilantin and accompanied with unstained nuclei during the G2 phase of the first cell cycle. The peak average fluorescence intensity occurred during the G1 phase of the second cell cycle for cyclin D1 stained CZB control, while the vehicle control, 0.001N NaOH, remained constant. Both CZB and 0.001N NaOH had similar expression patterns seen previously in the cyclin D1 in vivo data. The information gained from the in vivo and in vitro experiments will help to better understand what causes the problems associated with exposure to Dilantin, and also the effects Dilantin has on the cell cycle. / Department of Biology

This thesis investigates the modelling of drying processes for the promotion of market-led Demand Side Management (DSM) as applied to the UK Public Electricity Suppliers. A review of DSM in the electricity supply industry is provided, together with a discussion of the relevant drivers supporting market-led DSM and energy services (ES). The potential opportunities for ES in a fully deregulated energy market are outlined. It is suggested that targeted industrial sector energy efficiency schemes offer significant opportunity for long term customer and supplier benefit. On a process level, industrial drying is highlighted as offering significant scope for the application of energy services. Drying is an energy-intensive process used widely throughout industry. The results of an energy survey suggest that 17.7 per cent of total UK industrial energy use derives from drying processes. Comparison with published work indicates that energy use for drying shows an increasing trend against a background of reducing overall industrial energy use. Airless drying is highlighted as offering potential energy saving and production benefits to industry. To this end, a comprehensive review of the novel airless drying technology and its background theory is made. Advantages and disadvantages of airless operation are defined and the limited market penetration of airless drying is identified, as are the key opportunities for energy saving. Limited literature has been found which details the modelling of energy use for airless drying. A review of drying theory and previous modelling work is made in an attempt to model energy consumption for drying processes. The history of drying models is presented as well as a discussion of the different approaches taken and their relative merits. The viability of deriving energy use from empirical drying data is examined. Adaptive neuro fuzzy inference systems (ANFIS) are successfully applied to the modelling of drying rates for 3 drying technologies, namely convective air, heat pump and airless drying. The ANFIS systems are then integrated into a novel energy services model for the prediction of relative drying times, energy cost and atmospheric carbon dioxide emission levels. The author believes that this work constitutes the first to use fuzzy systems for the modelling of drying performance as an energy services approach to DSM. To gain an insight into the 'real world' use of energy for drying, this thesis presents a unique first-order energy audit of every ceramic sanitaryware manufacturing site in the UK. Previously unknown patterns of energy use are highlighted. Supplementary comments on the timing and use of drying systems are also made. The limitations of such large scope energy surveys are discussed.

in English This thesis is a review of substances contained in medicinal plants, the side effects and complications that they provoke. The adverse drug reactions are directly related to the constituents contained in each plant. Information for this work was taken from sources published from 1965 until 2013, especially from The Essential Guide To Herbal Safety and from the databases webmd.com and ncbi.nlm.nih.gov. It is discussed how the use of natural medicinal drugs affect vital organs in the human organism and in which cases their consumption is contraindicated. Central nervous, cardiovascular, urinary, gastrointestinal, endocrine, haemopoietic, respiratory, urinary systems are affected and allergic reactions are possible to occur as complications. Hypericum perforatum is typical for causing gastrointestinal irritations and Chamaemelum nobile and Achillea millefolium are found to cause dermatic complications. Finally, Piper methysticum may induce extreme sedation, since it has anxiolytic and antiepileptic properties. Keywords: side effects, contraindications, medicinal plants, uses, constituents.

M.Tech. / In spite of the improvement in the delivery of anti-cancer treatments over the past decade, side effects from these treatments remain inevitable. A common, distressing side effect that all cancer patients experience is fatigue. However, cancer related fatigue (CRF) remains one that is under-reported and under-treated. CRF is a topic that has received very limited attention in the South African context. Regardless of the amount of literature available on CRF, many questions continue to go unanswered. CRF has been identified as a side effect that is associated with physical, mental and psychological elements. Consequently, it has the ability to cause a delay in treatment schedules, impinge on daily functioning and impact negatively on the quality of life (QoL) in the cancer patient. Effective management strategies for patients during and after radiation treatment are thus essential to improve QoL. The aim of the study was to investigate the general pattern of fatigue experienced by patients diagnosed with various types of cancers during a radical course of radiotherapy. For the purpose of this study fatigue was defined according to the National Comprehensive Cancer Network (NCCN) Practice Guidelines in Oncology (www.nccn.org): “a distressing persistent subjective sense of tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” A cross-sectional, theory-generating study was conducted to explore and describe the prevalence of fatigue, factors that could influence fatigue scores, strategies being used to alleviate this side effect and the impact of fatigue on QoL. One hundred and eighty patients were asked to complete a self-developed questionnaire in three oncology centres in Gauteng, South Africa. The NCCN Clinical Practice Guidelines in Oncology were used as a framework to direct the study. The results of the study illustrate that fatigue scores increased as radiotherapy progressed. However, not all the variables explored in the study significantly impacted on fatigue scores. The study revealed, though, that all cancer patients do experience CRF irrespective of the diagnosis. Management of the causes of CRF is thus essential to improve QoL for cancer patients.

In the last decade, multi-threaded systems and resource sharing have brought a number of technologies that facilitate our daily tasks in a way we never imagined. Among others, cloud computing has emerged to offer us powerful computational resources without having to physically acquire and install them, while smartphones have almost acquired the same importance desktop computers had a decade ago. This has only been possible thanks to the ever evolving performance optimization improvements made to modern microarchitectures that efficiently manage concurrent usage of hardware resources. One of the aforementioned optimizations is the usage of shared Last Level Caches (LLCs) to balance different CPU core loads and to maintain coherency between shared memory blocks utilized by different cores. The latter for instance has enabled concurrent execution of several processes in low RAM devices such as smartphones. Although efficient hardware resource sharing has become the de-facto model for several modern technologies, it also poses a major concern with respect to security. Some of the concurrently executed co-resident processes might in fact be malicious and try to take advantage of hardware proximity. New technologies usually claim to be secure by implementing sandboxing techniques and executing processes in isolated software environments, called Virtual Machines (VMs). However, the design of these isolated environments aims at preventing pure software- based attacks and usually does not consider hardware leakages. In fact, the malicious utilization of hardware resources as covert channels might have severe consequences to the privacy of the customers. Our work demonstrates that malicious customers of such technologies can utilize the LLC as the covert channel to obtain sensitive information from a co-resident victim. We show that the LLC is an attractive resource to be targeted by attackers, as it offers high resolution and, unlike previous microarchitectural attacks, does not require core-colocation. Particularly concerning are the cases in which cryptography is compromised, as it is the main component of every security solution. In this sense, the presented work does not only introduce three attack variants that can be applicable in different scenarios, but also demonstrates the ability to recover cryptographic keys (e.g. AES and RSA) and TLS session messages across VMs, bypassing sandboxing techniques. Finally, two countermeasures to prevent microarchitectural attacks in general and LLC attacks in particular from retrieving fine- grain information are presented. Unlike previously proposed countermeasures, ours do not add permanent overheads in the system but can be utilized as preemptive defenses. The first identifies leakages in cryptographic software that can potentially lead to key extraction, and thus, can be utilized by cryptographic code designers to ensure the sanity of their libraries before deployment. The second detects microarchitectural attacks embedded into innocent-looking binaries, preventing them from being posted in official application repositories that usually have the full trust of the customer.

Typescript, etc. / Digitized by Kansas Correctional Industries

Despite significant regulatory and academic interest in sell-side analyst forecasts and an extensive literature demonstrating the impact of teamwork in general, we lack evidence of the effect of teamwork on analyst forecasts. In 2005 analyst teams issued nearly three-fourths of analyst reports for a sample of 89 large, heavily followed companies. Over a twelve-year period 86 of those companies had more reports issued by analyst teams than by individual analysts. Using a hand-collected sample of more than 17,000 analyst reports, I document that forecasts issued by analyst teams systematically differ from the forecasts of individual analysts in ways predicted by team literature. I find that prior to the year 2000 analyst teams issue forecasts that are less accurate and more biased than forecasts issued by individual analysts. Beginning in 2000, the relative benefit of analyst teamwork strengthens, consistent with changes due to Regulation Fair Disclosure, brokerage closures, and other regulatory interventions. In addition I find that, within company-year, team-issued forecasts are less pessimistically biased but not less optimistically biased than the forecasts issued by individual analysts. Lastly, the benefits of teamwork vary with the size of the team and over the life of the team, following an inverted u-shaped pattern. My results inform regulators as they consider factors that impact analyst forecast accuracy and bias.

Abstract not available

Purpose: The aim of this study was to investigate the usefulness of formulation approaches to minimise injection site reactions for poorly soluble drugs. The specific objectives were to modify the injection site reactions by identification of irritant components in the formulation and control of their release kinetics; and to gain understanding of formulation approaches to create a favourable microenvironment in the tissues allowing better tissue tolerance and drug absorption. Methods: Physicochemical properties of the model drug, ricobendazole (RBZ) were characterised using conventional methods. Three formulation approaches to minimise irritancy of the low pH RBZ solution were assessed. An in vitro method using 96-well microplates and a microtiter plate reader was used for detection of drug precipitation on dilution for formulation characterisation. Cellular damage by the formulations was investigated in L929 fibroblasts using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and lactate dehydrogenase (LDH) assays. Tissue tolerance and pharmacokinetics were simultaneously investigated after subcutaneous injection in sheep. A low pH RBZ solution was used as a reference formulation. Results: Preformulation studies showed that RBZ was practically insoluble in water and oils, and was slightly soluble in commonly used co-solvents. Solubility was slightly improved by complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD, K₁:₁ = 311 M⁻�) or a combination of low pH (> 2) with surfactants or co-solvents. A U-shaped pH-solubility profile in aqueous solutions indicated that RBZ is an ampholyte. pKa values measured by absorbance spectroscopy and pH solubility methods were 3.45 and 3.76 (basic) and 9.82 and 9.53 (acidic) respectively. The partition coefficient was 14.3 - 15.2 at pH 6 - 9 and less at higher or lower pH. In aqueous solutions, RBZ showed a V-shaped pH-degradation rate profile and was most stable at pH 4.8. Degradation pathways were identified as hydrolysis and oxidation. Three RBZ injectables (5%) were obtained by modification of the low pH RBZ solution; addition of 20% HP-β-CD, incorporation into a w/o emulsion, and a microemulsion (ME). On dilution with SPB, the onset time of drug precipitation was prolonged and the rate was reduced in the presence of HP-β-CD. The w/o emulsion had a low viscosity (< 60 mPa.s) and exhibited Newtonian flow. Drug release versus the square root of time was linear and the release rate could be adjusted by phase ratio and droplet size. Drug release was found to be by diffusion. A coarse emulsion layer appeared at the interface between the ME and buffer. Drug release from the ME was faster than from the emulsion and was linear with the square root of time. On titration into SPB, the three formulations showed controlling effects on the release of H₃O⁺ compared to the reference formulation. RBZ (0.1 mg/ml) was more toxic to L929 cells than the co-solvent propylene glycol (50 mg/ml). The formulations showed greater cytotoxicity than their vehicles in the order: ME > RBZ solution = emulsion > HP-β-CD. HP-β-CD and emulsion excipients showed little or no cytotoxicity. The MEs exhibited more toxicity in the LDH assay than in the MTS assay. A reversed phase HPLC assay for simultaneous determination of RBZ and its metabolite in sheep plasma using an isocratic system with UV detection was developed and used in the pharmacokinetic studies. Plasma samples were prepared by solid phase extraction. A suitable internal standard was selected by quantitative structure-retention relationships analysis. The composition of a ternary mobile phase was optimised with the assistance of multiple linear regression. The assays were linear over the concentration range 10 - 1000 ng/ml for both analytes (r > 0.999) with satisfactory inter-day and intra-day precision and accuracy (CV < 10%). The recoveries for all analytes were > 96%. A pilot study in sheep suggests that injection of the vehicles (the CD, emulsion and ME) caused virtually no pain on injection or site reactions. Both the reference formulation and its vehicle induced pain on injection and resulted in swollen tissues. Histology after two weeks showed granulation for the formulation, but not the vehicle. In contrast, animals showed virtually no injection site reactions with the ME and emulsion. The HP-β-CD formulation gave transient pain on injection but a two-fold increase in bioavailability compared with the reference. The emulsion produced sustained drug release and increased drug absorption. In the main study, the HP-β-CD vehicle showed good tissue compatibility. Irritation by the HP-β-CD formulation was attributed to the low pH. Cmax, tmax and AUC0-[infinity] for the reference formulation were 1.3 � 0.3 [mu]g/ml, 9.6 � 2.9 h and 36.7 � 9.2 [mu]g�h/ml respectively, while the corresponding data for the HP-β-CD formulation were 2.9 � 0.8 [mu]g/ml, 5.0 � 0.6 h and 54.5 � 15.3 [mu]g�h/ml respectively. The half-life following the injection of the HP-β-CD formulation (5.5 � 2.8 h) was shorter than that of the reference formulation (8.5 � 3.4 h). Conclusions: Injection site reactions may be minimised by identification of irritant components in a formulation and by controlling their release. Controlling the burst release of the poorly water soluble drug RBZ in a low pH solution could improve tissue tolerance and minimise post-injection precipitation, and hence increase drug bioavailability. In addition, HP-β-CD was a useful local injectable carrier which significantly enhanced the absorption of RBZ after subcutaneous injection in sheep.