Adventures in the pharmacological analysis of P2 receptors

The pharmacological classification of P2 receptors owes its origin to the pioneering efforts of Geoff Burnstock and those who followed him, research that was conducted primarily in physiological experimental systems. Over recent years, the techniques of molecular biology have been increasingly applied in the study of P2 receptors while, at the same time, advances in their pharmacological analysis have been limited by a lack of potent and selective agonist or antagonist ligands. This has resulted in a classification scheme which is largely structural in nature, with relatively little contribution from pharmacology. Our endeavours in this area have been directed towards the discovery of ligands with which the pharmacological analysis and definition of P2 receptors could be advanced, the ultimate goal being the design of therapeutic agents. This article will describe some of our experiences in this challenging but rewarding Nea. (C) 2000 Elsevier Science B.V. All rights reserved.

How and why do insects migrate?

Countless numbers of insects migrate within and between continents every year, and yet we know very little about the ultimate reasons and proximate mechanisms that would explain these mass movements. Here we suggest that perhaps the most important reason for insects to migrate is to hedge their reproductive bets. By spreading their breeding efforts in space and time, insects distribute their offspring over a range of environmental conditions. We show how the study of individual long-distance movements of insects may contribute to a better understanding of migration. In the future, advances in tracking methods may enable the global surveillance of large insects such as desert locusts.

The Diffusion of Risks in Public Private Partnership Contracts

Purpose The UK government argues that the benefits of public private partnership (PPP) in delivering public infrastructure stem from: transferring risks to the private sector within a structure in which financiers put their own capital at risk; and, the performance based payment mechanism, reinforced by the due diligence requirements imposed by the lenders financing the projects (HM Treasury, 2010). Prior studies of risk in PPPs have investigated ‘what’ risks are allocated and to ‘whom’, that is to the public or the private sector. The purpose of this study is to examine ‘how’ and ‘why’ PPP risks are diffused by their financiers. Design/methodology/approach This study focuses on the financial structure of PPPs and on their financiers. Empirical evidence comes from interviews conducted with equity and debt financiers. Findings The findings show that the financial structure of the deals generates risk aversion in both debt and equity financiers and that the need to attract affordable finance leads to risk diffusion through a network of companies using various means that include contractual mitigation through insurance, performance support guarantees, interest rate swaps and inflation hedges. Because of the complexity this process generates, both procurers and suppliers need expensive expert advice. The risk aversion and diffusion and the consequent need for advice add cost to the projects impacting on the government’s economic argument for risk transfer. Limitations and implications The empirical work covers the private finance initiative (PFI) type of PPP arrangements and therefore the risk diffusion mechanisms may not be generalisable to other forms of PPP, especially those that do not involve the use of high leverage or private finance. Moreover, the scope of this research is limited to exploring the diffusion of risk in the private sector. Further research is needed on how risk is diffused in other settings and on the value for money implication of risk diffusion in PPP contracts. Originality/value The expectation inherent in PPP is that the private sector will better manage those risks allocated to it and because private capital is at risk, financiers will perform due diligence with the ultimate outcome that only viable projects will proceed. This paper presents empirical evidence that raises questions about these expectations. Key words: public private partnership, risk management, diffusion, private finance initiative, financiers

Physicochemical and drug diffusion analysis of rifampicin containing polyethylene glycol-poly(epsilon-caprolactone) networks designed for medical device applications

This study reports the physicochemical and drug diffusion properties of rifampicin containing poly(epsilon-caprolactone) (PCL)/polyethylene glycol (PEG) networks, designed as bioactive biomaterials. Uniquely, the effects of the states of both rifampicin and PEG and the interplay between these components on these properties are described. PCL matrices containing rifampicin (1-5%, w/w) and PEG 200 (0-15%, w/w) were prepared by casting from an organic solvent (dichloromethane). The films were subsequently characterized in terms of their thermal/thermorheological, surface and tensile properties, biodegradation and drug diffusion/release properties. Incorporation of PEG and/or rifampicin significantly affected the tensile and surface properties of PCL, lowering the ultimate tensile strength, % elongation at break, Young modulus and storage and loss moduli. Both in the absence and presence of PEG, solubilisation of rifampicin within the crystalline domains of PCL was observed. PEG was present as a dispersed liquid phase. The release of rifampicin (3% loading) was unaffected by the presence of PEG. Similarly the release of rifampicin (5%) was unaffected by low concentrations of PEG (5-10%) however, at higher loadings, the release rate of rifampicin was enhanced by the presence of PEG. Rifampicin release (10% loading) was enhanced by the presence of PEG in a concentration dependent fashion. These observations were accredited to enhanced porosity of the matrix. In all cases, diffusion-controlled release of rifampicin occurred which was unaffected by polymer degradation. This study has uniquely illustrated the effect of hydrophilic pore formers on the physicochemical properties of PCL. Interestingly, enhanced diffusion controlled release was only observed from biomaterials containing high loadings of PEG and rifampicin (5, 10%), concentrations that were shown to affect the mechanical properties of the biomaterials. Care should therefore be shown when adopting this strategy to enhance release of bioactive agents from biomaterials. (C) 2011 Elsevier B.V. All rights reserved.

Non-linear finite-element analysis of punching capacities of steel-concrete bridge deck slabs

Punching failure is the common failure mode in concrete bridge deck slabs when these structural components are subjected to local patch loads, such as tyre loads. Past research has shown that reinforced concrete slabs in girder–slab type bridges have a load-carrying capacity far greater than the ultimate static loads predicted by traditional design methods, because of the presence of compressive membrane action. However, due to the instability problems from punching failure, it is difficult to predict ultimate capacities accurately in numerical analyses. In order to overcome the instability problems, this paper establishes an efficient non-linear finite-element analysis using the commercial finite-element package Abaqus. In the non-linear finite-element analysis, stabilisation methods were adopted and failure criteria were established to predict the ultimate punching behaviour of deck slabs in composite steel–concrete bridges. The proposed non-linear finite-element analysis predictions showed a good correlation on punching capacities with experimental tests.

Towards an understanding of the causes and effects of software requirements change: two case studies

Changes to software requirements not only pose a risk to the successful delivery of software applications but also provide opportunity for improved usability and value. Increased understanding of the causes and consequences of change can support requirements management and also make progress towards the goal of change anticipation. This paper presents the results of two case studies that address objectives arising from that ultimate goal. The first case study evaluated the potential of a change source taxonomy containing the elements ‘market’, ‘organisation’, ‘vision’, ‘specification’, and ‘solution’ to provide a meaningful basis for change classification and measurement. The second case study investigated whether the requirements attributes of novelty, complexity, and dependency correlated with requirements volatility. While insufficiency of data in the first case study precluded an investigation of changes arising due to the change source of ‘market’, for the remainder of the change sources, results indicate a significant difference in cost, value to the customer and management considerations. Findings show that higher cost and value changes arose more often from ‘organisation’ and ‘vision’ sources; these changes also generally involved the co-operation of more stakeholder groups and were considered to be less controllable than changes arising from the ‘specification’ or ‘solution’ sources. Results from the second case study indicate that only ‘requirements dependency’ is consistently correlated with volatility and that changes coming from each change source affect different groups of requirements. We conclude that the taxonomy can provide a meaningful means of change classification, but that a single requirement attribute is insufficient for change prediction. A theoretical causal account of requirements change is drawn from the implications of the combined results of the two case studies.

Fast-track construction with slag cement concrete: Adiabatic strength development and strength prediction

The early-age strength development of concrete containing slag cement has been investigated to give guidance for its use in fast-track construction. Measurements of temperature rise under adiabatic conditions have shown that high levels of slag cement-for example, 70% of the total binder-are required to obtain a significant reduction in the peak temperature rise. Despite these temperature rises being lower than those for portland cement mixtures, however the early-age strength under adiabatic conditions of slag cement concrete can be as high as 250% of the strength of companion cubes cured at 20 degrees C (68 degrees F). The maturity and, hence, strength development were calculated from the adiabatic temperature histories based on several Maturity functions available in the literature. The predicted strength development with age was compared with the experimental results. Maturity functions that take into account the lower ultimate strengths obtained at elevated curing temperatures were found to be better at predicting the strength development.

Strength development of mortars containing ground granulated blast-furnace slag: Effect of curing temperature and determination of apparent activation energies

The strength development of mortars containing ground granulated blast-furnace slag (ggbs) and portland cement was investigated. Variables were the level of ggbs in the binder, water-binder ratio and curing temperature. All mortars gain strength more rapidly at higher temperatures and have a lower calculated ultimate strength. The early age strength is much more sensitive to temperature for higher levels of ground granulated blast-furnace slag. The calculated ultimate strength is affected to a similar degree for all ggbs levels and water-binder ratios, with only the curing temperature having a significant effect. Apparent activation energies were determined according to ASTM C1074 and were found to vary approximately linearly with ggbs level from 34 kJ/mol for portland cement mortars to around 60 kJ/mol for mortars containing 70% ggbs. The water-binder ratio appears to have little or no effect oil the apparent activation energy. (c) 2005 Elsevier Ltd. All rights reserved.

Recycled carbon fiber filled polyethylene composites

Composites of recycled carbon fiber (CF) with up to 30 wt % loading with polyethylene (PE) were prepared via melt compounding. The morphology of the composites and the degree of dispersion of the CF in the PE matrix was examined using scanning electron microscopy, and revealed the CF to be highly dispersed at all loadings and strong interfacial adhesion to exist between the CF and PE. Raman and FTIR spectroscopy were used to characterize the surface chemistry and potential bonding sites of recycled CF. Both the Young's modulus and ultimate tensile stress increased with increasing CF loading, but the percentage stress at break was unchanged up to 5 wt % loading, then decreased with further successive addition of CF. The effect of CF on the elastic modulus of PE was examined using the Halpin-Tsai and modified Cox models, the former giving a better fit with the values determined experimentally. The electrical conductivity of the PE matrix was enhanced by about 11 orders of magnitude on addition of recycled CF with a percolation threshold of 7 and 15 wt % for 500-mu m and 3-mm thick samples. (c) 2007 Wiley Periodicals, Inc.

Cystic fibrosis research in allied health and nursing professions

This report is the result of the "Allied Health and Nursing Professions Working Group" meeting which took place in Verona, Italy, November 2009, which was organised by the European Cystic Fibrosis Society, and involved 32 experts. The meeting was designed to provide a "roadmap" of high priority research questions that can be addressed by Allied Health Professionals (AHP) and nursing. The other goal was to identify research skills that would be beneficial to AHP and nursing researchers and would ultimately improve the research capacity and capability of these professions. The following tasks were accomplished: 1) a Delphi survey was used to identify high priority research areas and themes, 2) common research designs used in AHP and nursing research were evaluated in terms of their strengths and weaknesses, 3) methods for assessing the clinimetric and psychometric properties, as well as feasibility, of relevant outcome measures were reviewed, and 4) a common skill set for AHPs and nurses undertaking clinical research was agreed on and will guide the planning of future research opportunities. This report has identified important areas and themes for future research which include: adherence; physical activity/exercise; nutritional interventions; interventions for the newborn with CF and evaluation of outcome measures for use in AHP and nursing research. It has highlighted the significant challenges AHPs and nurses experience in conducting clinical research, and proposes strategies to overcome these challenges. It is hoped that this report will encourage research initiatives that assess the efficacy/effectiveness of AHP and nursing interventions in order to improve the evidence base. This should increase the quality of research conducted by these professions, justify services they currently provide, and expand their skills in new areas, with the ultimate goal of improving care for patients with CF.

Novel semi-interpenetrating hydrogel networks with enhanced mechanical properties and thermoresponsive engineered drug delivery, designed as bioactive endotracheal tube biomaterials

Thermoresponsive polymeric platforms are used to optimise drug delivery in pharmaceutical systems and bioactive medical devices. However, the practical application of these systems is compromised by their poor mechanical properties. This study describes the design of thermoresponsive semi-interpenetrating polymer networks (s-IPNs) based on cross-linked p(NIPAA) or p(NIPAA-co-HEMA) hydrogels containing poly(e-caprolactone) designed to address this issue. Using DSC, the lower critical solution temperature of the co-polymer and p(NIPAA) matrices were circa 34 °C and 32 °C, respectively. PCL was physically dispersed within the hydrogel matrices as confirmed using confocal scanning laser microscopy and DSC and resulted in marked changes in the mechanical properties (ultimate tensile strength, Young's modulus) without adversely compromising the elongation properties. P(NIPAA) networks containing dispersed PCL exhibited thermoresponsive swelling properties following immersion in buffer (pH 7), with the equilibrium-swelling ratio being greater at 20 °C than 37 °C and greatest for p(NIPAA)/PCL systems at 20 °C. The incorporation of PCL significantly lowered the equilibrium swelling ratio of the various networks but this was not deemed practically significant for s-IPNs based on p(NIPAA). Thermoresponsive release of metronidazole was observed from s-IPN composed of p(NIPAA)/PCL at 37 °C but not from p(NIPAA-co-HEMA)/PCL at this temperature. In all other platforms, drug release at 20 °C was significantly similar to that at 37 °C and was diffusion controlled. This study has uniquely described a strategy by which thermoresponsive drug release may be performed from polymeric platforms with highly elastic properties. It is proposed that these materials may be used clinically as bioactive endotracheal tubes, designed to offer enhanced resistance to ventilator associated pneumonia, a clinical condition associated with the use of endotracheal tubes where stimulus responsive drug release from biomaterials of significant mechanical properties would be advantageous. © 2012 Elsevier B.V. All rights reserved.

Predictive markers for colorectal cancer:current status and future prospects

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Although there is clear evidence of the benefit of chemotherapy in adjuvant and metastatic settings, its use continues to be suboptimal because of intrinsic or acquired drug resistance. 5-Fluorouracil continues to be the mainstay of CRC therapy, and combinations with newer chemotherapeutic agents such as irinotecan and oxaliplatin have resulted in improved response rates and survival. The role of other agents including cyclooxygenase-2 inhibitors, epidermal growth factor receptor, and farnsyl transferase inhibitors remains to be elucidated. Despite these improvements, many patients undergo chemotherapy without benefit. Increased understanding of the biology of CRC has led to the identification of prognostic markers that may help identify patients who will benefit from chemotherapy. Furthermore, studies have also begun to identify markers that predict whether a tumor will respond to a particular chemotherapy. The ultimate goal of this research is to prospectively identify patients who should receive chemotherapy and, thus, to tailor treatment to the molecular profile of the tumor and patient. Such an approach has the potential to dramatically improve response rates. This review highlights potentially important prognostic and predictive factors in CRC and discusses the potential for their use in the treatment of this disease.

Granular anchors under vertical loading - axial pull

Granular anchors are a relatively new concept in ground engineering with relatively little known regarding their load–displacement behaviour, failure modes, ultimate pullout capacity and also potential applications. A granular anchor consists of three main components: a base plate; tendon and compacted granular backfill. The tendon is used to transmit the applied load to the base plate which compresses the granular material to form the anchor. A study of the load–displacement response and ultimate pullout capacity of granular anchors constructed in intact lodgement till and made ground deposits is reported in this paper. Parallel tests were also performed on cast insitu concrete anchors which are traditionally used for anchoring purposes. A new method of analysis for the determination of the ultimate pullout capacity of granular anchors is presented and verified experimentally, with the dominant mode of failure controlled by the column length to diameter ratio. Granular anchors with L/D > 7 principally failed on bulging whereas short granular anchors failed on shaft resistance, with the latter mobilising similar pullout capacities as conventional concrete anchors.