The percutaneous absorption of ionisable compounds

The effects of ionisation on transdermal drug delivery using excised human epidermis (HS) and silastic rubber (SR) as model permeation barriers were investigated in vitro using Franz-type absorption cells. Suspensions and solutions of salicylic acid (SA), the model ionogenic permeant, were used as donors and the variables studied were vehicle pH and trans-membrane pH-gradients. For solutions, the pH effect was related to the level of ionisation of the drug and the degree of saturation of the solution. With suspensions, the observed permeation rate was unaffected by pH. The penetration profiles through HS and SR were similar, although the overall flux through HS was about 70% of that observed through SR. Pretreatment of the membranes with various enhancer regimens, including oleic acid, Azone and N, N-dimethylamides in propylene glycol (PG) and isopropyl myristate (IPM) promoted the penetration of SA. SR was not a suitable model for enhancer pretreatment using IPM as a vehicle as the membrane was significantly disrupted by this vehicle. The results from comparable experiments with and without a trans-membrane pH-gradient did not have a significant effect upon flux or flux enhancement after pretreatment with the above enhancers. A theoretical model for the extraction coefficients of weak acids was derived using the partition coefficients of the ionised and unionised species, pH and pKa. This model was shown to account for the variation in overall partition of salicylic acid dependent upon pH and pKa. This model was shown to account for the variation in overall partition of salicylic acid dependent upon pH and pKa. The distribution of this solute between aqueous and oily phases, with and without added enhancer, was measured as a function of pH. The extraction coefficients determined were consistent with the model and showed that the behaviour of the system can be explained without referral to ion-pair mechanisms. Phosphonoacetate is an effective antiviral agent. However, as it is charged at physiological pH, its permeation across cell membranes is limited. To assess the improvement of the transport properties of this molecule, mono-, di- and tri-ester prodrugs were examined. These were assessed for stability and subsequent breakdown with respect to pH by HPLC. In vitro percutaneous absorption was observed using the triester, but not the ionic mono- or di-esters. The triester absorption could be potentiated using a range of enhancers with oleic acid being the most effective. Cyclodextrins (CD) have a role as absorption enhancers for peptide compounds across nasal epithelium. One potential mode of action is that CDs include these compounds, protect them from enzymic attack and thereby increase their residence time in the nasal epithelium. This study investigated the potential of CDs to protect ester prodrugs from enzymatic breakdown and prevent production of poorly transportable ionic species. Using a range of CD to ester molar ratios (10:1 to 2500:1) a small, but measurable, protection for the model esters (parabens) against esterase attack was observed. Possible mechanisms for this phenomenon are that CDs include the ester, making it unavailable for hydrolysis, the CDs may also affect the esterase in some way preventing access for the ester into the active site.

A study in radiopaque polymeric materials

The problems associated with x-ray-transparent denture base are defined and conventional approaches to their solution are assessed. Consideration of elemental absorption parameters leads to the postulation that atoms such as zinc, and bromine, may be effective radiopacifiers over at least part of the clinical x-ray spectrum. These elements had hitherto been considered too light to be effective. Investigation of copolymers of methylmethacrylate and p-bromostyrene revealed no deleterious effects arising from the aromatically brominated monomer (aliphatic bromination caused UV destabilisation). For effective x-ray absorption a higher level of bromination would be necessary, but the expense of suitable compounds made further study unjustifiable. Incorporation of zinc atoms into the polymer was accomplished by copolymerisation of zinc acrylate with methylmethacrylate in solution. At high zinc levels this produced a powder copolymer convenient for addition to dental polymers in the dough moulding process. The resulting mouldings showed increasing brittleness at high loadings of copolymer. Fracture was shown to be through the powder particles rather than around them, indicating the source of weakness to be in the internal structure of the copolymer. The copolymer was expected to be cross-linked through divalent zinc ions and its insolubility and infusibility supported this. Cleavage of the ionic cross links with formic acid produced a zinc-free linear copolymer of high molecular weight. Addition of low concentrations of acrylic acid to the dough moulding monomer appeared to 'labilise' the cross links producing a more homogeneous moulding with adequate wet strength. Toxicologically the zinc-containing materials are satisfactory and though zinc is extracted at a measurable rate in an aqueous system, this is very small and should be acceptable over the life of a denture. In other respects the composite is quite satisfactory and though a marketable product is not claimed the system is considered worthy of further study.

Investigation of the metabolism of N, N-Dimethylformamide and its metabolites

The industrial solvent N, N-dimethylformamide (DMF) causes liver damage in humans. The hepatotoxicity of N-alkylformamides seems to be linked to their metabolism to N-alkylcarbamic acid thioesters. To clarify the role of metabolism in DMF hepatotoxicity, the metabolic fate of DMF was investigated in rodents. DMF was rapidly metabolised and excreted in the urine as N-hydroxymethyl-N-methyl-formamide (HMMF), N-acetyl-S-(N-methylcarbamoyl) cysteine (AMCC) and a metabolite measured as formamide by GLC. At high doses (0.7 and 7.0mmo1/kg) a small proportion of the dose was excreted unchanged. AMCC, measured by GLC after derivatisation to ethyl N-methylcarbamate, was a minor metabolite. Only 5.2% of the dose (0.1mmo1/kg) in rats or 1.2% in mice was excreted as AMCC. The minor extent of this metabolic pathway in rodents might account for the marginal liver damage induced by DMF in these species. In a collaborative study, volunteers were shown to metabolise DMF to AMCC to a greater extent than rodents. Nearly 15% of the inhaled dose (0.049mmo1/kg) was excreted as AMCC. This result suggests that the metabolic pathway leading to AMCC is more important in humans than in rodents. Consequently the risk associated with exposure to DMF might be higher in humans than in rodents. The metabolism of formamides to S-(N-alkylcarbamoyl) glutathione, the metabolic precursor of the thioester mercapturates, was studied using mouse, rat and human hepatic microsomes. The metabolism of NMF (10mM) to S-(N-methylcarbanoyl)glutathione (SMG) required the presence of GSH, NADPH and air. Generation of S-(N-methyl-carbamoyl)glutathione (SMG) was inhibited when incubations were conducted in an atmosphere of CO:air (1:1) or when SKF 525-A (3.0mM) was included in the incubations. Pre-treatment of mice with phenobarbitone (PB, 80mg/kg for 4 days) or beta-naphthoflavone (BNF, 50mg/kg for 4 days) failed to increase the microsomal formation of SMG from NMF. This result suggests that the oxidation of NMF is catalysed by a cytochrome P-450 isozyme which is unaffected by PB or BNF. Microsomal incubations with DMF (5 or 10mM) failed to generate measurable amounts of SMG although DMF was metabolised to HMMF. Incubations of microsomes with HMMF resulted in the generation of a small amount of SMG which was affected by inhibitors of microsomal enzymes in the same way as in the case of NMF. HMMF was metabolised to AMCC by rodents in vivo. This result suggests that HMMF is a major intermediate in the metabolic activation of DMF.

The cutting performance of sialon ceramic tools

The thesis deals with a research programme in which the cutting performance of a new generation of ceramic cutting tool material is evaluated using the turning process. In part one, the performance of commercial Kyon 2000 sialon ceramic inserts is studied when machining a hardened alloy steel under a wide range of cutting conditions. The aim is to formulate a pattern of machining behaviour in which tool wear is related to a theoretical interpretation of the temperatures and stresses generated by the chip-tool interaction. The work involves a correlation of wear measurement and metallographic examination of the wear area with the measurable cutting data. Four main tool failure modes are recognised: (a) flank and crater wear (b) grooving wear (c) deformation wear and (d) brittle failure Results indicate catastrophic edge breakdown under certain conditions. Accordingly in part two, the edge geometry is modified to give a double rake tool; a negative/positive combination. The results are reported for a range of workpiece materials under orthogonal cutting conditions. Significant improvements in the cutting performance are achieved. The improvements are explained by a study of process parameters; cutting forces, chip thickness ratio, chip contact length, temperature distribution, stress distribution and chip formation. In part three, improvements in tool performance are shown to arise when the edge chamfer on a single rake tool is modified. Under optimum edge chamfer conditions a substantial increase in tool life is obtained compared with the commercial cutting geometry.

Assessment of the impact of discharges from surface water sewers on receiving water quality

A broad based approach has been used to assess the impact of discharges to rivers from surface water sewers, with the primary objective of determining whether such discharges have a measurable impact on water quality. Three parameters, each reflecting the effects of intermittent pollution, were included in a field work programme of biological and chemical sampling and analysis which covered 47 sewer outfall sites. These parameters were the numbers and types of benthic macroinvertebrates upstream and downstream of the outfalls, the concentrations of metals in sediments, and the concentrations of metals in algae upstream and downstream of the outfalls. Information on the sewered catchments was collected from Local Authorities and by observation of the time of sampling, and includes catchment areas, land uses, evidence of connection to the foul system, and receiving water quality classification. The methods used for site selection, sampling, laboratory analysis and data analysis are fully described, and the survey results presented. Statistical and graphical analysis of the biological data, with the aid of BMWP scores, showed that there was a small but persistent fall in water quality downstream of the studied outfalls. Further analysis including the catchment information indicated that initial water quality, sewered catchment size, receiving stream size, and catchment land use were important factors in determining the impact. Finally, the survey results were used to produce guidelines for the estimation of surface water sewer discharge impacts from knowledge of the catchment characteristics, so that planning authorities can consider water quality when new drainage systems are designed.

No regrets? Measuring the career benefits of a psychology placement year

We report an analysis of whether a psychology placement year provides a significant benefit to graduates’ careers. Destination of Leavers from Higher Education (DLHE) survey data six months post-graduation suggested that placement programme graduates across the university are more likely to be (i) in work and (ii) in graduate level jobs. For psychology, the association between graduates’ placement status and employment status at six months post graduation was not significant overall. However, when analyses were split by degree classification obtained, it was shown that amongst those graduates with 2.1 classification degrees reporting themselves as working, more placement programme vs. non-placement programme graduates had obtained graduate level jobs (63% vs. 33%). In 2.2 graduates there was no significant association. This pattern persisted in the data from a survey of psychology alumni (from 18 months to six and a half years post graduation). Psychology placement programme alumni were more satisfied with their careers even when ethnicity, gender, degree classification and entry year were taken into account. They also earn more, although not when background factors are taken into account. This study was therefore able to show some measurable and persistent effects of a psychology placement year, although whether the benefits can be claimed to outweigh the costs is inconclusive. Limitations and implications are discussed.

Achieving continuous improvement through self-assessment

In 2007 the UK Office of Government Commerce was mandated to carry out Procurement Capability Reviews (PCR) across the 16 top spending UK Government Departments. Since then, this programme has evolved into a self assessment based approach which is markedly different from the original approach. Will the move from a centre-led strategic review of procurement capability to a department-led model based on self assessment continue to strengthen and improve procurement capability across Central Civil Government? OGC is currently working with UK Government Departments to carry out their PCRs using a self-assessment tool which incorporates qualitative and quantitative measures. Results are generated based on a capability maturity model. The results are assured independently. OGC expectations are that tangible and measurable capability improvements will be realised when departments embed the self-assessment model and implement the findings as part of a continuous improvement regime. This paper is a case study, using some relevant literature to reflect on past and possible future development of the PCR self assessment scheme.

State-of-the-art of ‘Lean’ in the aviation maintenance, repair, and overhaul industry

The increasing need for maintenance, repair, and overhaul (MRO) organizations to meet customers' demands in quality and reduced lead times is key to its survival within the aviation industry. Furthermore, with the unpredictability in the global market and difficulties with forecasting characteristic of the MRO industry there is an increased need for the reevaluation of the operation models of organizations within this sector. However, severe economic turmoil and ever-increasing global competition introduce the opportunity for the adoption of a resilient, tried, and tested business operation model such as 'Lean'. In order to understand this concept, its long-term viability, and its application within the aerospace MRO sector fully, this paper presents the state-of-the-art in terms of the adoption of Lean within the MRO industry by carrying out a systematic review of the literature. This paper establishes the common perception of Lean by the MRO industry and the measurable progress that has been made on the subject. Some issues and challenges are also highlighted including the misconceptions that arise from the direct transference of the perception of Lean from other industrial sectors into the aerospace MRO industry. The 'enablers and inhibitors' of Lean within the aviation industry are also discussed. This paper exposes the scarcity of the literature and the general lagging behind of the industry to the adoption of the Lean paradigm and thus highlights areas where further research is required. © 2011 Authors.

Drawing association rules between purchases and in-store behavior:an extension of the market basket analysis

Shopping behavior is often exclusively studied through consumer purchases, since they are an easily measurable ouput. Still, the observation of in-store physical behavior (paths, moves and actions) is crucial, as is the quantification of its impact on purchases. Using an innovative PDA tool to precisely record and time stamp consumer’s moves and gestures, we extend the classical Market Basket Analysis (MBA) by integrating this new kind of information. We draw associations not only from purchases but also from in-store consumer moves and actions. We compare results of our new method with classical MBA results and show a significant improvement.

Drawing association rules between purchases and in-store behaviour:an extension of the market basket analysis

Shopping behavior is often exclusively studied through consumer purchases, since they are an easily measurable ouput. Still, the observation of in-store physical behavior (path, moves and actions) is crucial, as is the quantification of its impact on purchases. Using an innovative PDA tool to precisely record and time stamp consumers' moves and actions, we extend the classical Market Basket Analysis (MBA) by integrating this new information: associations between product categories are measured not only from purchases but also from consumer physical behavior. We compare results of our new method with classical MBA results and show a significant improvement.

Technology flows, outsourcing and productivity:an analysis of UK trade and FDI

The literature on technology spillovers from trade and FDI is ambiguous in its findings. This may in part be because of the assumption in much of the work that trade and FDI flows are homogeneous in their determinants and thus in their effects. We develop a taxonomy of trade and FDI determinants based on R&D intensity and unit labour cost differentials, and test for the presence of spillovers from inward investment and imports on an extensive sample of UK manufacturing plants. We find that both trade and FDI have measurable spillover effects, but the sign and extent of these effects varies depending on the technological and factor cost differentials between the recipient and host economies. There is therefore an identifiable link between the determinants and effects of trade and FDI which the previous literature has not explored.

Implementing collaborative practices in the healthcare supply chain:insights into hospital-vendor operations

The paper discusses the characteristics of healthcare supply chains, and puts particular emphasis on the implementation of VMI/CMI in this sector specific context. By the means of case study research the paper provides empirical data on the benefits of the above collaborative practices for both the hospital and vendors. The paper contributes to the stream of research on VMI/CMI in the healthcare sector, where limited research attempts have been conducted so far. In contrast to other surveys this case study shows that specific and measurable cost reductions exist, in addition to other improvements such as better control over the inventories, and also in reduction of administrative work. Results obtained may be also relevant to other hospitals and vendors and as they can form a basis for comparisons. Copyright © 2013 Inderscience Enterprises Ltd.

Technology flows, outsourcing and productivity:an analysis of UK trade and FDI

The literature on technology spillovers from trade and FDI is ambiguous in its findings. This may in part be because of the assumption in much of the work that trade and FDI flows are homogeneous in their determinants and thus in their effects. We develop a taxonomy of trade and FDI determinants based on R&D intensity and unit labour cost differentials, and test for the presence of spillovers from inward investment and imports on an extensive sample of UK manufacturing plants. We find that both trade and FDI have measurable spillover effects, but the sign and extent of these effects varies depending on the technological and factor cost differentials between the recipient and host economies. There is therefore an identifiable link between the determinants and effects of trade and FDI which the previous literature has not explored.

Structure-activity relationships of the N-terminus of calcitonin gene-related peptide:key roles of alanine-5 and threonine-6 in receptor activation

Background and purpose - The N-terminus of calcitonin gene-related peptide (CGRP) is important for receptor activation, especially the disulphide-bonded ring (residues 1-7). However, the roles of individual amino acids within this region have not been examined and so the molecular determinants of agonism are unknown. This study has examined the role of residues 1, 3-6 and 8-9, excluding Cys-2 and Cys-7. Experimental approach - CGRP derivatives were substituted with either cysteine or alanine; further residues were introduced at position 6. Their affinity was measured by radioligand binding and their efficacy by measuring cAMP production in SK-N-MC cells and ß-arrestin 2 translocation in CHO-K1 cells at the CGRP receptor. Key results - Substitution of Ala-5 by cysteine reduced affinity 270-fold and reduced efficacy for production of cAMP in SK-N-MCs. Potency at ß-arrestin translocation was reduced by 9-fold. Substitution of Thr-6 by cysteine destroyed all measurable efficacy of both cAMP and ß-arrestin responses; substitution with either alanine or serine impaired potency. Substitutions at positions 1, 4, 8 and 9 resulted in approximately 10-fold reductions in potency at both responses. Similar observations were made at a second CGRP-activated receptor, the AMY1(a) receptor. Conclusions and implications - Ala-5 and Thr-6 are key determinants of agonist activity for CGRP. Ala-5 is also very important for receptor binding. Residues outside of the 1-7 ring also contribute to agonist activity.

Living with uncertainty in the age of runtime models

Uncertainty can be defined as the difference between information that is represented in an executing system and the information that is both measurable and available about the system at a certain point in its life-time. A software system can be exposed to multiple sources of uncertainty produced by, for example, ambiguous requirements and unpredictable execution environments. A runtime model is a dynamic knowledge base that abstracts useful information about the system, its operational context and the extent to which the system meets its stakeholders' needs. A software system can successfully operate in multiple dynamic contexts by using runtime models that augment information available at design-time with information monitored at runtime. This chapter explores the role of runtime models as a means to cope with uncertainty. To this end, we introduce a well-suited terminology about models, runtime models and uncertainty and present a state-of-the-art summary on model-based techniques for addressing uncertainty both at development- and runtime. Using a case study about robot systems we discuss how current techniques and the MAPE-K loop can be used together to tackle uncertainty. Furthermore, we propose possible extensions of the MAPE-K loop architecture with runtime models to further handle uncertainty at runtime. The chapter concludes by identifying key challenges, and enabling technologies for using runtime models to address uncertainty, and also identifies closely related research communities that can foster ideas for resolving the challenges raised. © 2014 Springer International Publishing.