CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors:a comparison of effects of adrenomedullin 22-52, CGRP 8-37 and BIBN4096BS

1. Adrenomedullin (AM) has two known receptors formed by the calcitonin receptor-like receptor (CL) and receptor activity-modifying protein (RAMP) 2 or 3: We report the effects of the antagonist fragments of human AM and CGRP (AM 22-52 and CGRP 8-37) in inhibiting AM at human (h), rat (r) and mixed species CL/RAMP2 and CL/RAMP3 receptors transiently expressed in Cos 7 cells or endogenously expressed as rCL/rRAMP2 complexes by Rat 2 and L6 cells. 2. AM 22-52 (10 μM) antagonised AM at all CL/RAMP2 complexes (apparent pA 2 values: 7.34±0.14 (hCL/hRAMP2), 7.28±0.06 (Rat2), 7.00±0.05 (L6), 6.25±0.17(rCL/hRAMP2)). CGRP 8-37 (10 μM) resembled AM 22-52 except on the rCL/hRAMP2 complex, where it did not antagonise AM (apparent PA 2 values: 7.04±0.13 (hCL/hRAMP2), 6.72±0.06 (Rat2), 7.03±0. 12 (L6)). 3. On CL/RAMP3 receptors, 10 μM CGRP 8-37 was an effective antagonist at all combinations (apparent pA 2 values: 6.96±0.08 (hCL/hRAMP3), 6.18±0.18 (rCL/rRAMP3), 6.48±0.20 (rCL/ hRAMP3)). However, 10 μm AM 22-52 only antagonised AM at the hCL/hRAMP3 receptor (apparent PA 2 6.73±0.14). 4. BIBN4096BS (10 μM) did not antagonise AM at any of the receptors. 5. Where investigated (all-rat and rat/human combinations), the agonist potency order on the CL/ RAMP3 receptor was AM∼βCGRP>αCGRP. 6. rRAMP3 showed three apparent polymorphisms, none of which altered its coding sequence. 7. This study shows that on CL/RAMP complexes, AM 22-52 has significant selectivity for the CL/ RAMP2 combination over the CL/RAMP3 combination. On the mixed species receptor, CGRP 8-37 showed the opposite selectivity. Thus, depending on the species, it is possible to discriminate pharmacologically between CL/RAMP2 and CL/RAMP3 AM receptors.

The impact of the closing call auction:an examination of effects in London

This article examines the impact on market quality that the introduction of a closing call auction had at the London Stock Exchange (LSE). Using the market model approach of Cohen et al. (1983a, b) OpenURL Aston University, b) we show that opening and closing market quality improved for those Financial Times and Stock Exchange 100 (FTSE 100) securities participating in the closing call. A control sample of stocks is not characterized by discernable changes to market quality.

The interaction of sodium chlorite with phospholipids and glutathione:a comparison of effects in vitro, in mammalian and in microbial cells

In this study the interaction of the preservative sodium chlorite with unsaturated lipids and glutathione was investigated, in comparison with peroxides, sodium hypochlorite, and benzalkonium chloride. The aim was to determine whether the action of sodium chlorite could involve membrane lipid damage or antioxidant depletion, and how this related to toxicity in both mammalian and microbial cells. The treatment of phospholipids with chlorite yielded low levels of hydroperoxides, but sodium chlorite oxidized the thiol-containing antioxidant glutathione to its disulfide form very readily in vitro, with a 1:4 oxidant:GSH stoichiometry. In cultured cells, sodium chlorite also caused a substantial depletion of intracellular glutathione, whereas lipid oxidation was not very prominent. Sodium chlorite had a lower toxicity to ocular mammalian cells than benzalkonium chloride, which could be responsible for the different effects of long-term application in the eye. The fungal cells, which were most resistant to sodium chlorite, maintained higher percentage levels of intracellular glutathione during treatment than the mammalian cells. The results show that sodium chlorite can cause oxidative stress in cells, and suggest that cell damage is more likely to be due to interaction with thiol compounds than with cell membrane lipids. The study also provides important information about the differential resistance of ocular cells and microbes to various preservatives and oxidants.

Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development

Mood stabilising drugs such as lithium (LiCl) and valproic acid (VPA) are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neurosphere-based in vitro model to characterise the pharmacological and toxicological effects of LiCl and VPA using gene expression changes linked to phenotypic alterations in cells. Treatment with VPA and LiCl resulted in the differential expression of 331 and 164 genes respectively. In the subset of VPA targeted genes, 114 were downregulated whilst 217 genes were upregulated. In the subset of LiCl targeted genes, 73 were downregulated and 91 were upregulated. Gene ontology (GO) term enrichment analysis was used to highlight the most relevant GO terms associated with a given gene list following toxin exposure. In addition, in order to phenotypically anchor the gene expression data, changes in the heterogeneity of cell subtype populations and cell cycle phase were monitored using flow cytometry. Whilst LiCl exposure did not significantly alter the proportion of cells expressing markers for stem cells/undifferentiated cells (Oct4, SSEA4), neurons (Neurofilament M), astrocytes (GFAP) or cell cycle phase, the drug caused a 1.4-fold increase in total cell number. In contrast, exposure to VPA resulted in significant upregulation of Oct4, SSEA, Neurofilament M and GFAP with significant decreases in both G2/M phase cells and cell number. This neurosphere model might provide the basis of a human-based cellular approach for the regulatory exploration of developmental impact of potential toxic chemicals.

Influence of iron deprivation and sub-inhibitory concentrations of antifungal antibiotics on surface antigens of candida albicans yeast cells

This study examined the effect of iron deprivation and sub-inhibitory concentrations of antifungal agents on yeast cell surface antigen recognition by antibodies from patients with Candida infections. Separation of cell wall surface proteins by sodium dodecyl-polyacrylamide gel electrophoresis (SDS-PAGE) and immunological detection by immunoblotting, revealed that antigenic profiles of yeasts were profoundly influenced by the growth environment. Cells grown under iron-depleted conditions expressed several iron-regulated proteins that were recognized by antibodies from patient sera. An attempt to characterize these proteins by lectin blotting with concanavalin A revealed that some could be glycoprotein in nature. Furthermore, these proteins which were located within cell walls and on yeast surfaces, were barely or not expressed in yeasts cultivated under iron-sufficient conditions. The magnitude and heterogeneity of human antibody responses to these iron-regulated proteins were dependent on the type of Candida infection, serum antibody class and yeast strain. Hydroxamate-type siderophores were also detected in supernatants of iron depleted yeast cultures. This evidence suggests that Candida albicans expresses iron-regulated proteins/glycoproteins in vitro which may play a role in siderophore-mediated iron uptake in Candida albicans. Sequential monitoring of IgG antibodies directed against yeast surface antigens during immunization of rabbits revealed that different antigens were recognized particularly during early and later stages of immunization in iron-depleted cells compared to iron-sufficient cells. In vitro and in vivo adherence studies demonstrated that growth phase, yeast strain and growth conditions affect adhesion mechanisms. In particular, growth under iron-depletion in the presence of sub-inhibitory concentrations of polyene and azole antifungals enhanced the hydrophobicity of C.albicans. Growth conditions also influenced MICs of antifungals, notably that of ketoconazole. Sub-inhibitory concentrations of amphotericin B and fluconazole had little effect on surface antigens, whereas nystatin induced profound changes in surface antigens of yeast cells. The effects of such drug concentrations on yeast cells coupled with host defence mechanisms may have a significant affect on the course of Candida infections.

The neurotoxic effects of enzyme inhibitors at the neuromuscular junction

Current knowledge of the long-term, low dose effects of carbamate (CB) anti-cholinesterases on skeletal muscle or on the metabolism and regulation of the molecular forms of acetylcholinesterase (AChE) is limited. This is largely due to the reversible nature of these inhibitors and the subtle effects they induce which has generally made their study difficult and preliminary investigations were conducted to determine suitable study methods. A sequential extraction technique was used to rapidly analyse AChE molecular form activity at the mouse neuromuscular junction and also in peripheral parts of muscle fibres. AChE in the synaptic cleft involved in the termination of cholinergic transmission was successfully assessed by the assay method and by an alternative method using a correlation equation which represented the relationship between synaptic AChE and the prolongation of extra-cellular miniature endplate potentials. It was found that inhibition after in vivo Carbamate (CB) dosing could not be maintained during tissue analysis because CB-inhibited enzyme complexes decarbamoylated vary rapidly and could not be prevented even when maintained on ice. The methods employed did not therefore give a measure of inhibition but presented a profile of metabolic responses to continual, low dose CB treatment. Repetitive and continual infusion with low doses of the CBs: pyridostigmine and physostigmine induced a variety of effects on mouse skeletal muscle. Both compounds induced a mild myopathy in the mouse diaphragm during continual infusion which was characterised by endplate deformation without necrosis; such deformation persisted on termination of treatment but had recovered slightly 14 days later. Endplate and non-endplate AChE molecular forms displayed selective responses to CB treatment. During treatment endplate AChE was reduced whereas non-endplate AChE was largely unaffected, and after treatment, endplate AChE recovered, whereas non-endplate AChE was up-regulated. The mechanisms by which these responses become manifest are unclear but may be due to CB-induced effects on nerve-mediated muscle activity, neurotrophic factors or morphological and physiological changes which arise at the neuromuscular junction. It was concluded that, as well as inhibiting AChE, CBs also influence the metabolism and regulation of the enzyme and induce persistent endplate deformation; possible detrimental effects of long-term, low-dose determination requires further investigation.

An investigation into the effects of processing instruction on the acquisition of English relative clauses by Syrian learners

The purpose of this research was to investigate the effects of Processing Instruction (VanPatten, 1996, 2007), as an input-based model for teaching second language grammar, on Syrian learners’ processing abilities. The present research investigated the effects of Processing Instruction on the acquisition of English relative clauses by Syrian learners in the form of a quasi-experimental design. Three separate groups were involved in the research (Processing Instruction, Traditional Instruction and a Control Group). For assessment, a pre-test, a direct post-test and a delayed post-test were used as main tools for eliciting data. A questionnaire was also distributed to participants in the Processing Instruction group to give them the opportunity to give feedback in relation to the treatment they received in comparison with the Traditional Instruction they are used to. Four hypotheses were formulated on the possible effectivity of Processing Instruction on Syrian learners’ linguistic system. It was hypothesised that Processing Instruction would improve learners’ processing abilities leading to an improvement in learners’ linguistic system. This was expected to lead to a better performance when it comes to the comprehension and production of English relative clauses. The main source of data was analysed statistically using the ANOVA test. Cohen’s d calculations were also used to support the ANOVA test. Cohen’s d showed the magnitude of effects of the three treatments. Results of the analysis showed that both Processing Instruction and Traditional Instruction groups had improved after treatment. However, the Processing Instruction Group significantly outperformed the other two groups in the comprehension of relative clauses. The analysis concluded that Processing Instruction is a useful tool for instructing relative clauses to Syrian learners. This was enhanced by participants’ responses to the questionnaire as they were in favour of Processing Instruction, rather than Traditional Instruction. This research has theoretical and pedagogical implications. Theoretically, the study showed support for the Input hypothesis. That is, it was shown that Processing Instruction had a positive effect on input processing as it affected learners’ linguistic system. This was reflected in learners’ performance where learners were able to produce a structure which they had not been asked to produce. Pedagogically, the present research showed that Processing Instruction is a useful tool for teaching English grammar in the context where the experiment was carried out, as it had a large effect on learners’ performance.

Evaluating the capacity of long haul soliton transmission

We review recent developments in the use of optical solitons for communication systems spanning transoceanic distances. The implementation of "soliton control" to alleviate the detrimental impact of effects such as amplifier noise is shown to be critical for obtaining advantages over competing technologies. The potential performance of two control strategies, namely straight line filtering and synchronous phase modulation, is examined in detail. Design diagrams are used to determine the maximum permissible amplifier spacing, which is a key determinant of system economics. To focus the enquiry, two example system spans are taken, representing transatlantic and transpacific distances. It is concluded that straight line filtering provides very little improvement over a basic design without control. However synchronous phase modulation, which may be implemented using a handful of actively driven components, provides very substantial benefits. These may be used either to extend the overall bit-rate-distance product of the system or to increase the amplifier spacing at more moderate capacities.

The intra-firm diffusion of complementary innovations: Evidence from the adoption of management practices by British establishments

This paper presents a simple profitability-based decision model to show how synergistic gains generated by the joint adoption of complementary innovations may influence the firm's adoption decision. For this purpose a weighted index of intra-firm diffusion is built to investigate empirically the drivers of the intensity of joint use of a set of complementary innovations. The findings indicate that establishment size, ownership structure and product market concentration are important determinants of the intensity of use. Interestingly, the factors that affect the extent of use of technological innovations do also affect that of clusters of management practices. However, they can explain only part of the heterogeneity of the benefits from joint use.

Aspects of health among an employed population

This survey collected information on aspects of health amongst an employed population, employees in 14 different organisations in the West Midlands Regional Health Authority; and was a stratified sample of senior managers, middle managers and operatives. Nine hundred and sixty questionnaires were distributed asking for both quantitative and qualitative information on 58 questions covering health, work, family, leisure activities and life-style. A response rate of 48% (459 returned questionnaires) came from 290 men (63%), 165 women (36%) and four people (1%) who did not answer the gender question. The initial findings from this study are unique in that there has not been a specific review of the health of people at work. In answer to the main research questions, 92% felt they were healthy. Compared to others of a similar age, 34% felt their health was `above average', 58% `average', and 7&37 `below average'. Thirty two percent of respondents had visited their GP in the past 1-2 months; the highest reason given was disorders of the respiratory system, 20%. People's perceptions on the effects of work on their health were: good effect, 13% fair effect, 20% no effect, 27% poor effect, 27% and bad effect, 7%. The effects of leisure activities on health were thought to be more positive: good effect, 46% fair effect, 20% no effect, 21% poor effect, 3% and bad effect, 2%. The perceptions of effects of life-style on health were considered to be: good effect, 32% fair effect, 32% no effect, 20% poor effect, 9% and bad effect, 1%.  In this survey, leisure and life-style were seen by employees to have more beneficial effects on health than work. Future implications include a review of occupational health as a major policy development area within primary care. There is a need to influence the education and training of health care practitioners in order to affect their ability to practise effectively in this new and challenging area of work.

The prevention and diagnosis of central venous catheter-related infection

The potential source of CVC colonisation was assessed. Isolates of coagulase-negative staphylococci (CoNS) recovered from the skin and CVC components of 3 cardiothoracic surgery patients were characterised by pulsed-field gel electrophoresis (PFGE). The genetic heterogeneity of CoNS isolated from the skin was demonstrated and specific genotypes implicated in catheter colonisation. In addition, phenotypic and genotypic typing techniques were assessed for their ability to characterise strains of CoNS recovered from 33 patients who developed catheter-related bloodstream infection (CR-BSI) on a bone marrow transplant (BMT) unit and Siaphylococcus aureus recovered from 6 cardiothoracic surgery patients with surgical site infection (SSI) following median sternotomy. This epidemiological investigation revealed that common strains of CoNS and 51 aureus where not associated with infection in patients with CR-BSI or sternal SSI during the study period. Furthermore, there was no correlation between phenotypic and genotypic characterisation results. The variable expression of phenotypic traits within strains of staphylococci was evident whilst PFGE and randomly amplified polymorphic DNA (RAPD) were highly discriminatory for the molecular characterisation of S. aureus and CoNS. This was highlighted in 8 stem cell transplant (SCT) patients whereby it was demonstrated that routine identification and characterisation of CoNS by phenotypic techniques may not be adequate for the diagnosis of CR-BSI by current guidelines. The potential of the lipid S ELISA to facilitate the diagnosis of CR-BSI in 38 haematology/SCT patients and sternal SSI in 57 cardiothoracic surgery patients was also assessed. The ELISA proved to be a sensitive test for the rapid serodiagnosis of infection due to staphylococci in immunocompetent patients. The acridine orange leucocyte cytospin test (AOLC) was also evaluated for the rapid diagnosis of CR-BSI in 16 haematology/SCT patients with Hickman CVC in situ. Although the sensitivity of the test was low, it may provide a useful adjunct to conventional methods for the in situ sampling of catheters to predict and diagnose CR-BSI, preventing the unnecessary removal of CVC.

Strategies for agricultural change and the UK balance of payments

The world food crisis, Britain's reliance on imported food and feedstuffs and balance of payments difficulties were some of the factors which lent weight to the call for increased self-sufficiency in Britain's agriculture in the 1970s. This project considers two main areas: an investigation of the impact of radical agricultural change, designed to increase self-sufficiency, on the balance of payments; and, an appraisal of the potential role of the food industry within a radically different food system. The study proceeded by: an examination of the principles of agricultural policy and its development in Britain; an overview of the mechanism and meaning of the balance of payments; a consideration of the debate on agricultural import saving; the construction of radical agricultural strategies; the estimation of effects of the strategies, particularly to the balance of. payments; the role of the food industry and possible innovations within the strategies; a case study of textured vegetable proteins; and, the wider implications of implementation of radical agricultural alternatives. Two strategies were considered: a vegan system, involving no livestock; and, an intermediate system, including some livestock and dairy cattle. The study concludes that although agricultural change could in principle make a contribution to the balance of payments, implementation of agricultural change cannot be justified for this purpose alone. First, balance of payments problems can be solved by more appropriate methods. Second, the UK' s balance of payments problem has disappeared for the time being owing to North Sea oil and economic recession. Third, the political and social consequences of the changes investigated would be unacceptable. Progress in UK food policy is likely to be in the form of an integrated food and health policy.

Influence of personal mobile phone ringing and usual intention to answer on driver error

Given evidence of effects of mobile phone use on driving, and also legislation, many careful drivers refrain from answering their phones when driving. However, the distracting influence of a call on driving, even in the context of not answering, has not been examined. Furthermore, given that not answering may be contrary to an individual’s normal habits, this study examined whether distraction caused by the ignored call varies according to normal intention to answer whilst driving. That is, determining whether the effect is more than a simple matter of noise distraction. Participants were 27 young drivers (18-29 years), all regular mobile users. A Theory of Planned Behaviour questionnaire examined predictors of intention to refrain from answering calls whilst driving. Participants provided their mobile phone number and were instructed not to answer their phone if it were to ring during a driving simulation. The simulation scenario had seven hazards (e.g. car pulling out, pedestrian crossing) with three being immediately preceded by a call. Infractions (e.g. pedestrian collisions, vehicle collisions, speed exceedances) were significantly greater when distracted by call tones than with no distraction. Lower intention to ignore calls whilst driving correlated with a larger effect of distraction, as was feeling unable to control whether one answered whilst driving (Perceived Behavioural Control). The study suggests that even an ignored call can cause significantly increased infractions in simulator driving, with pedestrian collisions and speed exceedances being striking examples. Results are discussed in relation to cognitive demands of inhibiting normal behaviour and to drivers being advised to switch phones off whilst driving.

Industrial districts, inward foreign investment and regional development

This article compares the importance of agglomerations of local firms, and inward FDI as drivers of regional development. The empirical analysis exploits a unique panel dataset of the Italian manufacturing sector at the regional and industry levels. We explore whether FDI and firm agglomeration can be drivers of total factor productivity (separately and jointly), with this effect being robust to different estimators, and different assumptions about inter-regional effects. In particular, we isolate one form of firm agglomeration that is especially relevant in the Italian context, industrial districts, in order to ascertain their impact on productivity. In so doing, we distinguish standard agglomeration and localization economies from industrial districts to understand what additional impact the latter has on standard agglomeration effects. Interaction effects between FDI spillovers and different types of agglomeration economies shed some light on the heterogeneity of regional development patterns as well as on the opportunity to fine tune policy measures to specific regional contexts.

Evaluating the Capacity of Phase Modulator-Controlled Long-Haul Soliton Transmission

We review recent developments in the use of optical solitons for communication systems spanning transoceanic distances. The implementation of "soliton control" to alleviate the detrimental impact of effects such as amplifier noise is shown to be critical for obtaining advantages over competing technologies. The potential performance of two control strategies, namely straight line filtering and synchronous phase modulation, is examined in detail. Design diagrams are used to determine the maximum permissible amplifier spacing, which is a key determinant of system economics. To focus the enquiry, two example system spans are taken, representing transatlantic and transpacific distances. It is concluded that straight line filtering provides very little improvement over a basic design without control. However synchronous phase modulation, which may be implemented using a handful of actively driven components, provides very substantial benefits. These may be used either to extend the overall bit-rate-distance product of the system or to increase the amplifier spacing at more moderate capacities. © 1995 Academic Press. All rights reserved.