Vasoactive hormone studies in man using urotensin II and vasopressin

BACKGROUND Within this thesis we have examined the effects on vascular tone of two peptide hormones, urotensin II and vasopressin. Human urotensin II is a novel vasoactive peptide hormone with receptors located on human arterial tissue and ventricular myocytes. It is the most potent arterial vasoconstrictor yet discovered and has a sustained effect on blood vessels from a variety of species with potency 28 to 50 fold greater than endothelin-1. Vasopressin has however, been known to have arterial vasoconstrictor properties in man in vivo for many years. However, peptide antagonists for the VI receptor, mediating vasoconstriction, and the V2 receptor, mediating vasodilatation, have often been of poor selectivity and subject to inter-species variation, thus clouding the true arterial pharmacodynamic effects of vasopressin. Two novel peptidic arginine vasopressin antagonists have recently been produced and offer potentially more receptor selectivityOBJECTIVES The aims of this thesis were: first to assess the effects of urotensin II on human resistance vessels and venous tone in vivo; second, to study the effects of systemic intravenous urotensin II on human haemodynamics such as blood pressure, pulse, vascular resistance and arterial stiffness; third, to explore the human in vivo pharmacodynamics of vasopressin in human resistance vessels in the skin microcirculation and forearm as preparation for VI and V2 receptor antagonist studies; forth, to demonstrate that vasopressin induced vasodilatation is mediated by nitric oxide; and finally, fifth, to combine novel VI and V2 receptor antagonists with vasopressin in the human skin and forearm to assess the efficacy of novel vasopressin peptide antagonistsMETHODS Using the established method ofbilateral venous occlusion plethysmography to measure forearm blood flow, combined with intra-arterial infusion of drugs into the brachial artery, we sought to determine the effects of urotensin II on human forearm blood flow. Other methods such as the Aellig venous displacement technique, to assess venous tone, and pulse wave analysis, to quantify arterial stiffness were also used during local and systemic urotensin II intravenous infusions respectively. Doppler flowmetry was used to assess skin microcirculation combined with intra-dermal peptide injection we assessed skin blood flow in response to vasopressin alone and in combination with a novel selective VI antagonist. Venous occlusion plethysmography was again used to determine forearm blood flow responses to vasopressin alone and in combination with VI and V2 antagonists.RESULTS During intra-arterial infusion ofurotensin II we did not observe any significant changes in forearm blood flow, even in the presence of endothelial inhibitors such as aspirin and a 'nitric oxide clamp' nor was change observed in venous tone. Moreover, no alteration in systemic haemodynamics or arterial stiffness was seen during systemic intravenous infusion. We observed a significant fall in skin blood flow with intra¬ dermal injection of vasopressin, however, the VI receptor antagonist did not alter skin vasoconstriction. Intra-arterial infusion of vasopressin caused a reproducible biphasic change in forearm blood flow, low doses causing vasoconstriction and high doses, nitric x oxide mediated vasodilatation. Vasodilatation was subject to tachyphylaxis during prolonged infusion ofhigh dose vasopressin. Neither intra-arterial VI or V2 antagonist, when co-infused with vasopressin, altered this biphasic vasoconstriction and vasodilatationCONCLUSION The majority of our findings for urotensin II were in contrast to our hypothesis. Until a selective urotensin II antagonist is developed the physiological role of urotensin II in human cardiovascular physiology will remain difficult to ascertain. Its role may alternatively lie in longer term regulation of vascular tone or in sodium and metabolic homeostasis. We defined the pharmacodynamics of vasopressin in humans in vivo to a greater depth than previous studies and confirmed, using a 'nitric oxide clamp', the dependence of vasopressin induced vasodilatation on locally derived nitric oxide. Both vasopressin antagonists have yet again been subject to considerable inter-species variation, as demonstrated by the efficacy of the VI receptor antagonist in our rat biopressor assay. To date there are no truly selective peptidic vasopressin receptor antagonists available for human in vivo studies

Virtual assembly rapid prototyping of near net shapes

Virtual reality (VR) provides another dimension to many engineering applications. Its immersive and interactive nature allows an intuitive approach to study both cognitive activities and performance evaluation. Market competitiveness means having products meet form, fit and function quickly. Rapid Prototyping and Manufacturing (RP&M) technologies are increasingly being applied to produce functional prototypes and the direct manufacturing of small components. Despite its flexibility, these systems have common drawbacks such as slow build rates, a limited number of build axes (typically one) and the need for post processing. This paper presents a Virtual Assembly Rapid Prototyping (VARP) project which involves evaluating cognitive activities in assembly tasks based on the adoption of immersive virtual reality along with a novel non-layered rapid prototyping for near net shape (NNS) manufacturing of components. It is envisaged that this integrated project will facilitate a better understanding of design for manufacture and assembly by utilising equivalent scale digital and physical prototyping in one rapid prototyping system. The state of the art of the VARP project is also presented in this paper

Virtual bloXing - assembly rapid prototyping for near net shapes

Virtual reality (VR) provides another dimension to many engineering applications. Its immersive and interactive nature allows an intuitive approach to study both cognitive activities and performance evaluation. Market competitiveness means having products meet form, fit and function quickly. Rapid Prototyping and Manufacturing (RP&M) technologies are increasingly being applied to produce functional prototypes and the direct manufacturing of small components. Despite its flexibility, these systems have common drawbacks such as slow build rates, a limited number of build axes (typically one) and the need for post processing. This paper presents a Virtual Assembly Rapid Prototyping (VARP) project which involves evaluating cognitive activities in assembly tasks based on the adoption of immersive virtual reality along with a novel nonlayered rapid prototyping for near net shape (NNS) manufacturing of components. It is envisaged that this integrated project will facilitate a better understanding of design for manufacture and assembly by utilising equivalent scale digital and physical prototyping in one rapid prototyping system. The state of the art of the VARP project is also presented in this paper

Data Structure for Supporting In-Memory Storage with Multiple Keys

The Object data structure in JavaScript is simply a set of key-value pairs in which the values for each key must be one of the primitive data types. Developers can add multiple value fields for a given key within a JavaScript Object by using an array as the value. Developers can also use an array as a key and retrieve any value via the array. However, developers must query Objects with whole matching key values which prevents execution of queries with partial or multi-key matching. Overcoming these limitations by storing data in a client-side database on the local disk of a user device is an asynchronous, high latency, and potentially risky operation. This disclosure describes a higher-level data structure called InMemoryStorage that can be used to store data with multiple keys in memory. The values for the keys within the InMemoryStorage data structure can be JavaScript objects, each of which can store its own key-value pairs as usual. Developers can retrieve data from the InMemoryStorage data structure by formulating queries based on keys within the objects stored within it. The techniques can be used for any application that requires synchronous, in-memory, client-side storage and access of data with more than one key, such as batching logs in memory prior to transmitting them to remote persistent storage. The techniques extend JavaScript by adding support for partial and multi-key matching

Was Arthur Andersen Different?: An Empirical Examination of Major Accounting Firm Audits of Large Clients

Enron and other corporate financial scandals focused attention on the accounting industry in general and on Arthur Andersen in particular. Part of the policy response to Enron, the criminal prosecution of Andersen eliminated one of the few major audit firms capable of auditing many large public corporations. This article explores whether Andersen\u27s performance, as measured by frequency of financial restatements, measurably differed from that of other large auditors. Financial restatements trigger significant negative market reactions and their frequency can be viewed as a measure of accounting performance. We analyze the financial restatement activity of approximately 1,000 large public firms from 1997 through 2001. After controlling for client size, region, time, and industry, we find no evidence that Andersen\u27s performance significantly differed from that of other large accounting firms

Was Arthur Andersen Different?: An Empirical Examination of Major Accounting Firms\u27 Audits of Large Clients

Enron and other corporate financial scandals focused attention on the accounting industry in general and on Arthur Andersen in particular. Part of the policy response to Enron, the criminal prosecution of Andersen, eliminated one of the few major audit firms capable of auditing many large, public corporations. This article explores whether Andersen’s performance, as measured by frequency of financial restatements, measurably differed from that of other large auditors. Financial restatements trigger significant negative market reactions and their frequency can be viewed as a measure of accounting performance. We analyze the financial restatement activity of approximately 1,000 large, public firms from 1997 through 2001. After controlling for client size, region, time, and industry, we find no evidence that Andersen\u27s performance significantly differed from that of other large accounting firms

Recent Developments Regarding Voltage-Gated Sodium Channel Blockers for the Treatment of Inherited and Acquired Neuropathic Pain Syndromes

Chronic and neuropathic pain constitute significant health problems affecting millions of individuals each year. Pain sensations typically originate in sensory neurons of the peripheral nervous system which relay information to the central nervous system (CNS). Pathological pain sensations can arise as result of changes in excitability of these peripheral sensory neurons. Voltage-gated sodium channels are key determinants regulating action potential generation and propagation; thus, changes in sodium channel function can have profound effects on neuronal excitability and pain signaling. At present, most of the clinically available sodium channel blockers used to treat pain are non-selective across sodium channel isoforms and can contribute to cardio-toxicity, motor impairments, and CNS side effects. Numerous strides have been made over the last decade in an effort to develop more selective and efficacious sodium channel blockers to treat pain. The purpose of this review is to highlight some of the more recent developments put forth by research universities and pharmaceutical companies alike in the pursuit of developing more targeted sodium channel therapies for the treatment of a variety of neuropathic pain conditions

The use of non-intrusive user logging to capture engineering rationale, knowledge and intent during the product life cycle

Within the context of Life Cycle Engineering it is important that structured engineering information and knowledge are captured at all phases of the product life cycle for future reference. This is especially the case for long life cycle projects which see a large number of engineering decisions made at the early to mid-stages of a product's life cycle that are needed to inform engineering decisions later on in the process. A key aspect of technology management will be the capturing of knowledge through out the product life cycle. Numerous attempts have been made to apply knowledge capture techniques to formalise engineering decision rationale and processes; however, these tend to be associated with substantial overheads on the engineer and the company through cognitive process interruptions and additional costs/time. Indeed, when life cycle deadlines come closer these capturing techniques are abandoned due the need to produce a final solution. This paper describes work carried out for non-intrusively capturing and formalising product life cycle knowledge by demonstrating the automated capture of engineering processes/rationale using user logging via an immersive virtual reality system for cable harness design and assembly planning. Associated post-experimental analyses are described which demonstrate the formalisation of structured design processes and decision representations in the form of IDEF diagrams and structured engineering change information. Potential future research directions involving more thorough logging of users are also outlined