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The subject matter of this thesis is the definition, measurement and use of marginal cost as a tool of analysis to assist the process of decision-making in the water supply industry. Demand management is viewed in broad terms to include the establishment of an optimal structure and level of prices and investment in optimal capacity as well as investment in demand-restraining measures such as leakage detection and control. The study examines the definition of marginal cost as a benchmark for price setting. It provides empirical estimates of the various components of marginal cost of water supply in the Hampshire area, part of the Southern Water Authority. These estimates assume an exogenously determined level of demand and therefore exclude any possible direct interaction between the pricing and investment decisions. Departing from this tradition the study also examines a number of models where, under specific assumptions, optimal prices, output and capacity levels over a chosen planning horizon are simultaneously determined. This allows for direct interaction between the pricing and investment decisions. The study simulates optimal paths of prices, output and capacity expansion in the Hampshire area. This is carried out under various assumptions, one of which admits the potential of staging capacity expansion in order to take advantage of economies of scale in the capital cost function. An analysis of leakage detection and control as a demand management tool is presented in the final part of the study. The purpose of this analysis is to investigate how leakage detection and control may be conducted using either cost-benefit analysis or an appropriately defined tool of marginal cost.

There is considerable recent experimental evidence that suggests that stress plays a major role in the development of dependence on drugs of abuse, but the potential mechanisms involved are not yet fully understood. The aims of this thesis were (I) to examine the effect of stress, and of drugs that act on the hypothalamic-pituitary-adrenal axis, on alcohol consumption in the C57 strain of mice. (II) to investigate whether corticosterone levels or spontaneous locomotor activity could be used to predict subsequent alcohol consumption in mice. (Ill) to investigate long-term neurochemical changes during abstinence following chronic alcohol administration. (IV) to develop a method for measuring brain corticosterone levels. Neither total corticosterone levels nor spontaneous locomotor activity could predict alcohol preference. Saline vehicle injections increased alcohol preference in low alcohol preferring, and raised both circulating corticosterone levels and brain corticosterone. The brain concentrations of corticosterone were measured by a novel procedure developed during the thesis. A CRF antagonist (a-helical CRF) increased alcohol preference in low preferring mice, as did the ACTH fragment 4-10. In high preferring mice, ACTH 4-10 reduced alcohol preference, whereas a-helical CRF did not alter preference in these mice. Inhibition of corticosterone synthesis reduced alcohol preference in high alcohol preferring mice but, blockade of corticosterone receptors with specific antagonists did not alter alcohol preference. Chronic alcohol treatment followed by six days abstinence increased free circulating corticosterone levels and this treatment also increased hippocampal corticosterone levels. Dopamine Dl-like receptor affinity was increased following the same chronic treatment schedule. These results demonstrate an important link between the activation of the hypothalamic-pituitary-adrenal axis and alcohol consumption. The results of the chronic treatment experiments provide useful information that may aid the understanding of the phenomenon of relapse to drinking common in abstaining alcoholics.

Introduction – Severe pulmonary bacterial infections are frequently complicated by systemic hypoxaemia and, in the context of acute respiratory distress syndrome (ARDS), inappropriately prolonged neutrophilic inflammation. This combination of acute hypoxaemia and persistent inflammatory response carries significant morbidity and mortality. However, patients with chronic lung disease function in the community with chronic systemic hypoxaemia and bacterial colonisation with much lower acute mortality. The HIF/PHD pathway tightly regulates neutrophilic responses to hypoxia and bacteria. Here, using acute bacterial pneumonia models, I have dissected the differences in innate immune responses to infection in acute hypoxia and following exposure to hypoxia prior to infection (‘preconditioning’). Methods – C57BL/6 mice were housed in room air or ‘preconditioned’ by exposure to 10% ambient hypoxia for seven days. They were then instilled with intratracheal Streptococcus pneumoniae (1x104 or 1x107 cfu to assess macrophage and neutrophil function respectively) under recovery anaesthesia and housed in normoxia (21% O2) or hypoxia (10% O2). At pre-determined time-points, the animals were assessed clinically for sickness and rectal temperature. Blood, bronchoalveolar lavage and tissues were taken for analysis. Transcriptome analysis by RNA-sequencing and functional glycolysis by Seahorse was performed on blood leucocytes. Results – Concurrent exposure to hypoxia and infection resulted in neutrophil-mediated morbidity and mortality. Acute hypoxia caused rapid utilisation of glucose, glycogen and fat stores resulting in systemic hypoglycaemia and death. Preconditioning with exposure to hypoxia prior to infection completely protected the host against hypoxia-induced morbidity and mortality by suppressing leucocyte glycolysis, through suppression of HIF1α, and resultant rescue from the negative energy state and cardiovascular compromise. Conclusion – Hypoxia preconditions the innate immune response by suppression of HIF1α and glycolysis in leucocytes, thereby protecting against acute hypoxia-induced mortality outcomes in acute bacterial pulmonary infection.

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 162-170). Available also in a digital version from Dissertation Abstracts.

The study has intended to analyze the Europeanization of the institutional structure for regional policy in Bulgaria after the first programming period of the country as a full-fledged member state of the EU. Bulgaria joined the EU in 2007 as part of the so called ‘Eastern Enlargement’ that was characterized by power asymmetry and strong conditionality. The study employs two research methods – document analysis of key policy documents and legislation, as well as qualitative interviews with key respondents with involvement or experience in the field of regional policy and development in Bulgaria. The analysis is underpinned by the concept of Europeanization and historical institutionalism which complement each other in order to explain the changes and the reasons for them. The main findings show that the EU requirements are only ‘accommodated’ in the already existing institutional structure of Bulgaria and real transformation has not occurred. The established regional level still does not have a significant role in the regional policy of the country because it represents neither self-government, nor administrative unit. The research suggests directions for future reform and refinement of the current institutional system with regard to the better formulation and implementation of regional policy in the country.