bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating infectious diseases incidence: validity of capture–recapture analysis and truncated models for incomplete count data
Authors: VAN HEST N. A. H. , GRANT A. D. , SMIT F. , STORY A. , RICHARDUS J. H.
Published: March 2007

Capture–recapture analysis has been used to evaluate infectious disease surveillance. Violation of the underlying assumptions can jeopardize the validity of the capture–recapture estimates and a tool is needed for cross-validation. We re-examined 19 datasets of log-linear model capture–recapture studies on infectious disease incidence using three truncated models for incomplete count data as alternative population estimators. The truncated models yield comparable estimates to independent log-linear capture–recapture models and to parsimonious log-linear models when the number of patients is limited, or the ratio between patients registered once and twice is between 0·5 and 1·5. Compared to saturated log-linear models the truncated models produce considerably lower and often more plausible estimates. We conclude that for estimating infectious disease incidence independent and parsimonious three-source log-linear capture–recapture models are preferable but truncated models can be used as a heuristic tool to identify possible failure in log-linear models, especially when saturated log-linear models are selected.
Ten years of viral and non-bacterial serology in adults with cystic fibrosis
Authors: CLIFTON I. J. , KASTELIK J. A. , PECKHAM D. G. , HALE A. , DENTON M. , ETHERINGTON C. , CONWAY S. P.
Published: March 2007

Viral infections are associated with pulmonary exacerbations in children with cystic fibrosis (CF), but few studies have addressed the frequency in adults. This paper investigates the frequency and impact of viral infections in adults with CF receiving intravenous antibiotics. Pre- and post-treatment spirometry, inflammatory markers and antibody titres against influenza A, influenza B, adenovirus, respiratory syncytial virus, Mycoplasma pneumoniae, Chlamydia psittaci, and Coxiella burnetti were analysed over a 10-year period. Non-bacterial infections were identified in 5·1% of 3156 courses of treatment. The annual incidence of admissions per patient associated with viral infection was 4·9%. The presence of viral infection in association with a pulmonary exacerbation did not adversely affect lung function or inflammatory markers in the short term. Adults with CF have a lower incidence of respiratory viral infections associated with pulmonary exacerbations requiring intravenous antibiotics compared to children and infants with CF.
Evaluating measles surveillance using laboratory-discarded notifications of measles-like illness during elimination
Authors: WANG Y.-H. J. , ANDREWS R. M. , KELLY H. , LAMBERT S. B.
Published: March 2007

For jurisdictions implementing measles elimination strategies, a minimum surveillance benchmark of 1/100 000 population per year measles-like illness (MLI) cases initially notified, but then rejected based on laboratory testing was proposed. We used this standard to assess the quality of the Victorian enhanced measles surveillance between 1998 and 2003. Victorian enhanced measles surveillance includes interviews with notified cases and confirmatory laboratory testing for notifications. We found 72% (918/1281) of measles notifications were discarded after testing. The median annual rate of discard was 2·9/100 000. The annual discard rate was inversely associated with the age of the notifications, and measles negative with no other diagnosis made was the most common laboratory outcome. The annual rates of discarded notifications in Victoria were consistently above the minimum recommended standard. The rate of discarded MLIs as a surveillance threshold should be useful in measles endemic regions, but may require modification where disease elimination has occurred.
Editors' note
Authors: Aarts Bas , Denison David , Hogg Richard
Published: March 2007

In our first editorial note, published in ELL 1.1 in 1997, we said:
There has until now been no one journal which covers the range that ELL is intended to cover, a ‘natural class’ of research interests which deserves to be treated in one place, and at the highest level. English Language and Linguistics exists to promote knowledge and inquiry in the interlocking fields of its title. We hope that ELL will prove so useful that authors will come to regard it as their first choice for submission, while readers turn to it readily because they know it is bound to contain work of value and interest.
A history of English evidential verbs of appearance
Authors: GISBORNE NIKOLAS , HOLMES JASPER
Published: March 2007

In this corpus-based article we explore the development of evidential meanings in English verbs of appearance, together with their acquisition of evaluative meanings. We explore the relationship of these semantic changes to the question of whether there is an increase in subjectivity diachronically, and we show that subjectivity is orthogonal to both develop-ments: an increase in subjectivity appears rather to go with the spread of small clause constructions.
The development of English each other: grammaticalization, lexicalization, or both?
Authors: HAAS FLORIAN
Published: March 2007

The historical development of the English reciprocal expression each other exemplifies different aspects of language change, both morphosyntactic and semantic. This article examines the formation of the reciprocal marker from the perspective of grammaticalization theory, with a special focus on the relationship between grammaticalization and lexicalization. It will be argued that an adequate distinction between lexicalization and grammaticalization can only be achieved if we define the two concepts with reference not to an expression's grammatical status before and after the change, but rather to the diachronic processes involved, namely context expansion in the case of grammaticalization, and univerbation combined with fossilization in the case of lexicalization. The development of each other provides evidence for this view. It has its origin in syntactic structures of the type Each of the kings hates the others and has undergone univerbation and fossilization as well as context expansion. It will also be shown that definitions of lexicalization and grammaticalization that are too closely linked to the opposition between lexicon and grammar are problematic for an analysis of the changes undergone by the reciprocal marker. Furthermore, our analysis regards the development of each other as a case of simultaneous lexicalization and grammaticalization.
Were they ‘dropping their aitches’? A quantitative study of h- loss in Middle English
Authors: CRISMA PAOLA
Published: March 2007

In this article I present extensive quantitative evidence showing that it is possible to distinguish different Middle English varieties on the basis of the treatment of word-initial h-, and that it is necessary to postulate that, in some varieties, word-initial h- fails to surface in given contexts, though being present as a consonantal phoneme in the underlying representation. This casts a new light on the old problem of whether word-initial h- was lost in Middle English and restored at a later stage: the data presented here suggest that h- loss was never generalized, though h-less forms did surface as contextual variants of h-ful forms.
Parameters of variation between verb–subject and subject–verb order in late Middle English
Authors: WARNER ANTHONY
Published: March 2007

This article sets out to clarify the contribution of syntactic properties and subject weight for variation between verb–subject and subject–verb order in a database of fourteenth- and fifteenth-century prose. It sets out the syntactic structures which are assumed, and investigates the impact on ordering of a set of factors, using established quantitative methodologies. A series of conclusions includes the continuing distinct status of initial then, the systematic importance of clause-final position, the different impacts of subject length in different contexts, and the presence of a definiteness effect for the late placement of a subject after a nonfinite unaccusative.
The sound patterns of Englishes: representing phonetic similarity
Authors: MCMAHON APRIL , HEGGARTY PAUL , MCMAHON ROBERT , MAGUIRE WARREN
Published: March 2007

Linguists are able to describe, transcribe, and classify the differences and similarities between accents formally and precisely, but there has until very recently been no reliable and objective way of measuring degrees of difference. It is one thing to say how varieties are similar, but quite another to assess how similar they are. On the other hand, there has recently been a strong focus in historical linguistics on the development of quantitative methods for comparing and classifying languages; but these have tended to be applied to problems of language family membership, at rather high levels in the family tree, not down at the level of individual accents. In this article, we outline our attempts to address the question of relative similarity of accents using quantitative methods. We illustrate our method for measuring phonetic similarity in a sample of cognate words for a number of (mainly British) varieties of English, and show how these results can be displayed using newer and more innovative network diagrams, rather than trees. We consider some applications of these methods in tracking ongoing changes in English and beyond, and discuss future prospects.
Emerging variation: determiner genitives and noun modifiers in English
Authors: ROSENBACH ANETTE
Published: March 2007

This article discusses the emerging variation between determiner genitives and noun modifiers in Present-day English. Based on the results of corpus analyses and previous studies I show that this variation (1) was not present in earlier English, and (2) results from the fact that determiner genitives have come to be used with nouns low in animacy while noun modifiers have come to be used with nouns high in animacy (mainly) in the course of Modern English. This semantic shift (or rather ‘convergence’) of genitives and noun modifiers has helped to create contexts which are compatible with both determiner and classifier function, i.e. the functions typically expressed by determiner genitives and noun modifiers, respectively. The article complements earlier work on the gradience between s-genitive constructions and noun+noun constructions (Rosenbach, 2006a), providing fur-ther evidence for the claim that semantic overlap may give rise to constructional gradience.
The spread of the progressive and its ‘future’ use
Authors: NESSELHAUF NADJA
Published: March 2007

Numerous factors have been identified as being relevant to the spread of the progressive in Late Modern English. The potential role of the ‘future’ use of the construction (as in I'm flying home next week) has, however, been neglected so far. The present study aims to fill this gap by providing a comprehensive analysis of the development of the progressive with future time reference since 1750 in British English. The investigation focuses on the question of whether and to what degree the factors at work in the development of the construction coincide with factors relevant to the development of other types of progressives.

The analysis demonstrates that the ‘future’ use of the progressive does indeed play a part in the spread of the progressive. Several hitherto unknown factors special to the development of the ‘future’ use of the progressive are also uncovered, among them an increased (and possibly) new use of the construction to express spontaneous decisions.
A pair of Partridges
Authors: GREEN JONATHON
Published: March 2007

Tom Dalzell, with Terry Victor, The new Partridge dictionary of slang. London: Routledge, 2005. 2 volumes. Pp. xvii + 2189. ISBN 9780415212588/0415212588.

The renegade subset of the English language that is defined as ‘slang’ is, to pun quite unashamedly on both slang and its standard cousin, a ‘bastard’, a term that here stretches its usual definition as ‘illegitimate’ to mean, as the OED has it, ‘having the appearance of, somewhat resembling; an inferior or less proper kind of; … things resembling, but not identical with, the species which legitimately bear the name’. Like standard English it is a language, variously, if inaccurately, synonymized as an argot, a cant, and a jargon, but it is undeniably a rougher-edged variety of that language. A bastard in both registers. It deals, unsurprisingly, with the rougher edges of life. As the essayist J. Y. P. Greig put it in 1938, the content of slang concentrates on ‘sex, money and intoxicating liquor’, and if one adds the vocabulary of ‘recreational’ drugs (which after all are no more than an alternative form of intoxication, albeit one that has drawn the short straw of illegality) there is no reason to feel that anything has changed. Nor had it done in the five centuries of slang-gathering that preceded Greig's analysis. A broad-brush taxonomy of the slang lexis covers crime (notably murder, nonterminal violence, robbery, confidence trickery, and prostitution, as well as the whole world of punishment, especially as regards police and prisons, wherein a whole new subset of language has been coined); intoxication (especially the state of drunkenness); insults whether personal, national, religious or racial; sexuality (including parts of the body and the uses to which they are put, plus of course defecation and allied bodily functions). It is unreservedly sexist: there are few positive words for women, and those only in terms of their sexuality. The word ‘mother’ is most commonly found combined with ‘fucker’, the oedipal polysyllable. There are few abstracts, no philosophizing other than the occasional cynical aphorism. Of caring, sharing, and compassion, as slang itself might have it: ‘sweet fuck all’. It is a rude, brutal vocabulary which revels in its lack of correctness, political or otherwise (it is as orthographically unruly as it is socially: the most ‘spoken’ of all vocabularies, its spelling defies regulation, and who is to say how centuries-old terms were in fact pronounced?); it is, to its credit, honest in its declarations: the word's most likely etymology lies in various Scandinavian terms meaning ‘throw’; to extend the image, it is a language that is wholly ‘in your face’. Yet it is not without wit, nor is the prevalent coarseness there merely for its own sake. It has a purpose. Of humanity most human it reflects our innate tendency to say ‘no’, to run counter to what has been established. If there is a standard, then we evolve an opposition, a contrary, counter-form; if the standard is linguistic, then slang is a counter-language.
Epigenetic control of cellular senescence in disease: opportunities for therapeutic intervention
Authors: Atkinson Stuart P. , Keith W. Nicol
Published: March 2007

Understanding how senescence is established and maintained is an important area of study both for normal cell physiology and in tumourigenesis. Modifications to N-terminal tails of histone proteins, which can lead to chromatin remodelling, appear to be key to the regulation of the senescence phenotype. Epigenetic mechanisms such as modification of histone proteins have been shown to be sufficient to regulate gene expression levels and specific gene promoters can become epigenetically altered at senescence. This suggests that epigenetic mechanisms are important in senescence and further suggests epigenetic deregulation could play an important role in the bypass of senescence and the acquisition of a tumourigenic phenotype. Tumour suppressor proteins and cellular senescence are intimately linked and such proteins are now known to regulate gene expression through chromatin remodelling, again suggesting a link between chromatin modification and cellular senescence. Telomere dynamics and the expression of the telomerase genes are also both implicitly linked to senescence and tumourigenesis, and epigenetic deregulation of the telomerase gene promoters has been identified as a possible mechanism for the activation of telomere maintenance mechanisms in cancer. Recent studies have also suggested that epigenetic deregulation in stem cells could play an important role in carcinogenesis, and new models have been suggested for the attainment of tumourigenesis and bypass of senescence. Overall, proper regulation of the chromatin environment is suggested to have an important role in the senescence pathway, such that its deregulation could lead to tumourigenesis.
A Constructive semantic characterization of aggregates in answer set programming
Authors: SON TRAN CAO , PONTELLI ENRICO
Published: March 2007

This technical note describes a monotone and continuous fixpoint operator to compute the answer sets of programs with aggregates. The fixpoint operator relies on the notion ofaggregate solution. Under certain conditions, this operator behaves identically to the three-valued immediate consequence operator ΦaggrPfor aggregate programs, independently proposed in Pelov (2004) and Pelovet al.(2004). This operator allows us to closely tie the computational complexity of the answer set checking and answer sets existence problems to the cost of checking a solution of the aggregates in the program. Finally, we relate the semantics described by the operator to other proposals for logic programming with aggregates.
Social Assistance Dynamics in the Netherlands: Exploring the Sustainability of Independence from Social Assistance via Labour Market Inclusion
Authors: van Berkel Rik
Published: March 2007

The current emphasis in European welfare states on ‘activation’ increases the relevance of insight into social assistance dynamics and work–welfare/welfare–work transitions. This article reports on a study that explored the employment, unemployment and social assistance careers of a large group of people who managed to become independent from social assistance by finding a job. Using the databases of social security agencies in the Dutch city of Rotterdam, it investigates the sustainability of social assistance independence and labour market inclusion, and identifies groups that are more or less likely to be confronted with spells of renewed social assistance dependency or unemployment.
Who Receives Targeted Benefits in Transition? The Effect of Household Characteristics on Take-Up Rates in Russia's Child Allowance Programme
Authors: Alexandrova Anastasia , Grishina Elena
Published: March 2007

This article addresses the issue of low targeting efficiency of the Russian child allowance programme. We look at non-take-up of eligible households and inclusion of the non-eligible, and show that household characteristics are significant determinants of the programme take-up, as they affect households' earning potential and expected level of benefit. We believe that the results of the research give useful suggestions on how targeting of child allowances can be improved in Russia.
The Cultural Context of Youth Suicide in Australia: Unemployment, Identity and Gender
Authors: Gilchrist Heidi , Howarth Glennys , Sullivan Gerard
Published: March 2007

This article considers the impact, in terms of life and death choices, of the economic exclusion of young people in Australia, where suicide is the leading cause of death by injury. In the two decades from 1980 there was a dramatic increase in suicide rates for young males. Research demonstrates a correlation between youth suicide and unemployment but the complex relationship between the two has not been fully investigated. This article explores the perceptions of young people, parents and service providers of the cultural context of suicide and how it comes to be constructed as an option for young people experiencing economic marginalisation.
Social Policy, Professional Regulation and Health Support Work in the United Kingdom
Authors: Saks Mike , Allsop Judith
Published: March 2007

This paper examines the neglected area of health support work in the United Kingdom in the context of recent social policy and studies of professionalisation. A variety of socio-economic trends have led policy makers to give greater consideration to this section of the healthcare workforce. Professional regulatory issues and recent reviews in the health field have provided the leverage to alter existing healthcare boundaries, as well as to enhance public protection. Drawing on commissioned research, it is argued that health support workers are not only an important area of study in their own right, but also raise interesting questions about the broader process of health policy making and professionalisation.
Developing a Guideline of Good Practice in a North–South Health Research Collaboration: A Participatory Approach
Authors: Jentsch Birgit , Hussein Julia
Published: March 2007

North–South health research collaborations have a colonial history, and a contested presence in which organisations from resource-poor countries depend on collaborations with grant-holding institutions from affluent countries. Despite this sensitive context, there is a remarkable lack of guidance to support North–South health research collaborations in a comprehensive manner. A reference document of practical advice can establish standards from the beginning, thereby promoting equitable and open relationships. This article explains the process and some results of the development of such a document – a Guideline of Good Practice (GGP)– for the international health research collaboration Initiative for Maternal Mortality Programme Assessment (IMMPACT).
Networks, Connectedness and Resilience: Learning From the Children's Fund in Context
Authors: Barnes Marian , Morris Kate
Published: March 2007

During the past decade, expectations placed on child welfare services in the UK have moved away from individualised provision geared to meeting the needs of specific children at risk, to consideration of the broader context for children. The introduction of a series of national programmes aimed at addressing social exclusion and tasked with stimulating new approaches to enabling better outcomes for children formed the background for the recent legislation and guidance for local children's services. The Children's Fund was one of a raft of New Labour social policies promoting partnerships between statutory and voluntary organisations in order to address the cross-cutting issue of social exclusion. It was announced following the UK 2000 Spending Review and drew from the Policy Action Team12 (PAT12) Report, ‘Young People at Risk’ (SEU, 2000). Funding started in January 2001 and continues until 2008 with a total allocation during this period of £960 million. Like most special policy initiatives instigated following 1997, the establishment of the Children's Fund was accompanied by both national and local evaluation requirements. The National Evaluation of the Children's Fund (NECF) was undertaken by a team from the Universities of Birmingham and London and this themed section draws on selected findings from that evaluation. Overall results are reported in Edwards et al., (2006).
Conceptualising Connectedness: Implications for Policy and Practice
Authors: Barnes Marian , Prior David
Published: March 2007

This paper reviews four texts that address connectedness in social relationships. It considers concepts of care and social capital and how these are applied in policy and practice. It argues the importance of understandings deriving from these concepts in developing policies that support well-being, reflect the significance of moral decision making and enable the development of supportive networks.
Working with Children's Existing Networks – Building Better Opportunities?
Authors: Morris Kate , Burford Gale
Published: March 2007

There is a considerable body of research that demonstrates the positive impact of involving children's families and networks in designing and developing the services children need. This paper – using empirical evidence from evaluations conducted in the UK, USA and New Zealand – suggests professionals are struggling to promote participative practice. The paper explores this apparent resistance and raises some questions about the understandings held by professionals about children and families who take up child welfare services that enable traditional exclusive forms of practice to be sustained.
Preventing Social Exclusion of Refugee and Asylum Seeking Children: Building New Networks
Authors: Beirens Hanne , Hughes Nathan , Hek Rachel , Spicer Neil
Published: March 2007

Research demonstrates the important role of refugees and asylum seekers' social networks in providing both the practical and emotional support necessary to mitigate social exclusion and promote integration within receiving societies. Based on research conducted by the National Evaluation of the Children's Fund, we highlight the barriers to network building for refugee and asylum seeking children and families, and the ways in which Children's Fund strategies and practices are tackling these. Using the ‘Indicators of Integration Framework’ developed by Ager and Strang (2004), we describe the activity of Children's Fund services in relation to the concepts social bonds, social links and social bridges. Such attempts to reduce social exclusion are seen to have limited effectiveness when framed by a government policy context favouring the development of social bridges at the expense of social links and bonds.
Inclusion, Social Networks and Resilience: Strategies, Practices and Outcomes for Disabled Children and their Families
Authors: Evans Ruth , Plumridge Gill
Published: March 2007

This paper explores the strategies of service providers and the benefits reported by disabled children and their parents/carers in three Children's Fund programmes in England. Based on National Evaluation of the Children's Fund research, we discuss how different understandings of ‘inclusion’ informed the diverse strategies and approaches service providers adopted. While disabled children and families perceived the benefits of services predominantly in terms of building individual children's resilience and social networks, the paper highlights the need for holistic approaches which have a broad view of inclusion, support children's networks and tackle disabling barriers within all the spheres of children's lives.
Gypsy/Traveller Children and Families: The Potential of Working with Networks
Authors: Mason Paul , Broughton Kevin
Published: March 2007

This article describes a service that aimed to support the development of play and leisure opportunities for Gypsy/Traveller children. It uncovered a high demand for direct service provision, and there was limited capacity for action to make existing provision more inclusive. The article suggests how a focus upon networks, between Gypsy/Traveller communities, between service providers, and upon bridges between the two, could reduce the exclusion experienced by Gypsy/Traveller children and families.
Working Collaboratively to Build Resilience: A CHAT Approach
Authors: Edwards Anne
Published: March 2007

Evidence from two studies of social exclusion based in England are drawn on to suggest that responsible agency can be seen as a feature of resilience. I argue that this agency, or capacity to act effectively in the world, is developed relationally and is evident in people's thoughtful actions in their worlds, but is also contingent on the affordances for such action in any environment. That is, resilience can be seen as responsible engagement with one's world as well as a capacity to withstand difficulties. The theoretical basis of this argument is Cultural Historical Activity Theory (CHAT) which proposes that we are shaped by but also shape our worlds. The implications for professional practices are discussed.
Relational Social Work: Principles and Practices
Authors: Folgheraiter Fabio
Published: March 2007

Relational social work engages with existing networks to enhance their resilience and capacity to resolve difficulties. It does this by addressing the identified problem, and by engaging, mobilising and developing both supportive and problem-solving networks. These networks can include family members, friends, teachers and any other significant actors who have a contribution to make. The participative approach offers a way of translating policies that aspire to social inclusion into practice.
Networks, Connectedness and Resilience
Authors: Hughes Nathan , Evans Ruth
Published: March 2007

In addition to the references listed at the end of each article, there are a range of further sources that may be of relevance to those interested in social capital, social networks, and resilience, and their relation to child and family policy. Whilst the articles in this journal relate to a number of empirical issues, the references given here are intentionally broad in focus. These sources are in addition to those discussed in detail by Barnes and Prior in this edition.
Marital Aggression and Children's Responses to Everyday Interparental Conflict
Authors: Cummings E. Mark , Kouros Chrystyna D. , Papp Lauren M.
Published: March 2007

This study examined parents' past marital aggression as a (1) predictor of everyday marital conflict expressions, and (2) moderator of children's responses to marital conflict. In a laboratory setting, children watched their parents discuss an everyday topic of disagreement and then reported their own emotional and behavioral reactions, and rated their parents' conflict resolution. Controlling for current marital aggression, couples with higher levels of past marital aggression used less constructive and more destructive conflict tactics, and displayed less positive and more negative emotions. Children's responses to marital conflict were moderated by parents' past marital aggression: Children whose parents had been more maritally aggressive in the past were more sensitive to parents' use of constructive conflict tactics and positive emotions. Thus, controlling for current marital aggression, past interparental aggression had implications for both parents' everyday interparental conflict and children's responding to everyday marital conflict.
Relationship between helium isotopes and heat flux from hot springs in a non‐volcanic region, Kii Peninsula, southwest Japan
Authors: Umeda Koji , Sakagawa Yukihiro , Ninomiya Atusi , Asamori Koichi
Published: March 2007

In order to examine the potential correlation between heat and helium isotope signatures in a non‐volcanic region, we estimated the local heat flux using Peclet number analysis of the thermal profiles from of deep, vertical boreholes in the Kii Peninsula, Southwest Japan. There is a distinct correlation between the common logarithms of the 3He/4He ratios and heat flux. Hot springs with 3He/4He ratios higher than the expected value of 3.4 RA, which is attributed to mantle helium trapped in igneous intrusions of Middle Miocene age, have heat flux values higher than 90 mW/m2. Upward flow of deep fluids predominates over the groundwater recharge of the local hydrology there. These results support the hypothesis that the hot springs with significantly higher 3He/4He ratios in the Kii Peninsula originate due to the effective transfer of mantle helium through the crust, dominantly by advection associated with ascending high temperature, deep fluids along mantle‐derived volatiles.
Nitropravastatin stimulates reparative neovascularisation and improves recovery from limb Ischaemia in type‐1 diabetic mice
Authors: Emanueli C , Monopoli A , Kraenkel N , Meloni M , Gadau S , Campesi I , Ongini E , Madeddu P
Published: March 2007

Background and purpose:

Mature endothelial cells and their progenitors are dysfunctional in diabetes, resulting in deficient neovascularisation following arterial occlusion. This study aimed to evaluate the therapeutic activity of a nitric oxide (NO) releasing statin in the setting of experimental diabetes and peripheral ischaemia.

Experimental approach:

The effects of NCX 6550, an NO‐releasing pravastatin derivative, on angiogenesis in ischaemic limbs was studied in normoglycaemic mice or mice made diabetic by treatment with streptozotocin (STZ). Control mice received an equimolar dosage of the parent statin compound, pravastatin. The therapeutic action of NCX 6550 was also tested in mice lacking the gene for endothelial nitric oxide synthase (eNOS).

Key Results:

In normoglycaemic or STZ‐diabetic CD1 mice, only NCX 6550 stimulated skeletal muscle revascularisation. In addition, NCX 6550 induced greater improvement in limb reperfusion and salvage, than pravastatin. The number of circulating endothelial progenitor cells was decreased in STZ‐diabetic mice, this defect being prevented by NCX 6550 and, to a lesser extent by pravastatin. In vitro, high glucose concentrations reduced the migratory capacity of endothelial progenitor EPCs, which was partly reversed by preincubation with pravastatin and completely reversed by NCX 6550. The postischaemic recovery of eNOS knockout mice was severely impaired as a consequence of depressed angiogenesis and this recovery was improved by treatment with NCX 6550, but not with pravastatin.

Conclusions and implications:

These findings indicate that incorporation of a bioactive NO moiety improves the therapeutic profile of statins for the treatment of peripheral vascular disease.

British Journal of Pharmacology (2007) 150, 873–882. doi:10.1038/sj.bjp.0707142
EPO tecting the Endothelium
Authors: Peterson T E , Katusic Z S
Published: March 2007

Erythropoietin is a 30.4 kDa protein that is produced and secreted from the kidney in response to anemia and hypobaric hypoxia. Binding of EPO to its receptor (EPO‐R) on bone marrow‐derived erythroid progenitor cells results in the stimulation of red blood cell production. Evidence is accumulating however, that the biological effects of recombinant EPO therapy extend beyond the stimulation of erythropoiesis. The discovery that the EPO‐R is expressed on vascular endothelial cells suggests that the vasculature may be a biological target of EPO. Indeed, several studies have now demonstrated that the protective effect of EPO administration involves the activation of the protein kinase B/Akt pathway which can protect cells from apoptosis. Future work is likely to provide further insight into the mechanisms by which EPO protects vascular endothelial cells from injury and give us a better understanding of the pharmacological doses that are required to achieve this protection.

British Journal of Pharmacology (2007) 150, 823–825. doi:10.1038/sj.bjp.0707162
Capsaicin‐induced mucus secretion in rat airways assessedin vivoand non‐invasively by magnetic resonance imaging
Authors: Karmouty‐Quintana H , Cannet C , Sugar R , Fozard J R , Page C P , Beckmann N
Published: March 2007

Background and purpose:

An up‐regulation of the sensory neural pathways in the lung has been implicated in asthma and chronic obstructive pulmonary disease (COPD) and is thought to contribute to mucus hypersecretion, an essential feature of both diseases. The aim of this study was to assess non‐invasively the acute effects (up to 60 min) of sensory nerve stimulation by capsaicin in the lung, using magnetic resonance imaging (MRI).

Experimental approach:

Male Brown Norway rats were imaged prior to and 10, 30 and 60 min after intra‐tracheal challenge with capsaicin (30μgkg−1) or vehicle (0.5% ethanol solution). In subsequent studies, pre‐treatment with the transient receptor potential vanilloid (TRPV)‐1 antagonist, capsazepine; the dual neurokinin (NK) 1 and NK2 receptor antagonist, DNK333 and the mast cell stabilizer, di‐sodium cromoglycate (DSCG) was used to modulate the effects of capsaicin.

Key results:

Diffuse fluid signals were detected by MRI in the lung as early as 10 min after capsaicin, remaining constant 30 and 60 min after treatment. Broncho‐alveolar lavage (BAL) fluid analysis performed 60 min after capsaicin revealed increased mucin concentration. Capsazepine (3.5 mgkg−1), DNK333 (10 mgkg−1) but not DSCG (10 mgkg−1) administered prophylactically were able to block the effect of capsaicin in the airways.

Conclusions and implications:

These observations suggest that the fluid signals detected by MRI after capsaicin administration reflected predominantly the release of mucus following activation of sensory nerves. They point to the opportunity of non‐invasively assessing with MRI the influence of neuronal mechanisms in animal models of asthma and COPD.

British Journal of Pharmacology(2007)150, 1022–1030. doi:10.1038/sj.bjp.0707168
Correlation of apparent affinity values from H3‐receptor binding assays with apparent affinity (pKapp) and intrinsic activity (α) from functional bioassays
Authors: Harper E A , Shankley N P , Black J W
Published: March 2007

Background and purpose:

Agonist apparent affinities (pKI′) in histamine H3‐receptor binding assays were higher than expected from apparent affinity values (pKapp) estimated in bioassay. Here, we investigate whether the degree of pKI′ overestimation is related to agonist intrinsic efficacy, by studying the effect of buffer composition on the pKI′ of ligands with varying intrinsic activity.

Experimental approach:

In the guinea‐pig ileum bioassay, intrinsic activity (α) was determined from the maximal inhibition of the contraction produced by increasing agonist concentration. pKapp values were estimated using the method of Furchgott. The pKL of [3H]clobenpropit in guinea‐pig cerebral cortex was estimated by saturation analysis in 20 mM HEPES‐NaOH buffer (buffer B(0,0,0)), or buffer B(0,0,0) containing 70 mM CaCl2, 100 mM NaCl and 100 mM KCl (buffer B(0.07,0.1,0.1)). PKI values were determined in competition studies in both buffers.

Key results:

[3H]clobenpropit saturation isotherms had nH values of unity in both buffers. In buffer B(0.07,0.1,0.1), agonist pKI′ values were closer to pKapp values than in buffer B(0,0,0) but were associated with nH values <1. A two‐site analysis of agonist data in buffer B(0.07, 0.1, 0.1) provided a better fit than a one‐site fit and low affinity values (pKIL) were comparable to pKapp. Differences between the pKI′ in buffer B(0,0,0) and pKIL values in buffer B(0.07,0.1,0.1) (ΔpK) were correlated with α.

Conclusions and implications:

H3‐receptor binding assays conducted in buffer B(0,0,0) and buffer B(0.07,0.1,0.1) can provide a measure of ligand affinity (pKapp) and intrinsic efficacy. The assay predicts that some ligands previously classified as H3‐receptor antagonists may possess residual intrinsic efficacy.

British Journal of Pharmacology (2007) 151, 109–124. doi:10.1038/sj.bjp.0707174
Evidence that ATP or a related purine is an excitatory neurotransmitter in the longitudinal muscle of mouse distal colon
Authors: Zizzo M G , Mulè F , Serio R
Published: March 2007

Background and purpose:

This study analysed the contribution of the purinergic system to enteric neurotransmission in the longitudinal muscle of mouse distal colon.

Experimental approach:

Motor responses to exogenous ATP and to nerve stimulationin vitrowere assessed as changes in isometric tension.

Key results:

ATP induced a concentration‐dependent contraction, reduced by 4‐[[4‐formyl‐5‐hydroxy‐6‐methyl‐3‐[(phosphonooxy)methyl]‐2‐pyridinyl]azo]‐1,3‐benzene disulphonic acid (PPADS), suramin, P2Y purinoreceptor desensitisation with adenosine 5’‐O‐2‐thiodiphosphate (ADPβS), and atropine, but unaffected by P2X purinoceptor desensitisation with α,β‐methylene ATP (α,β‐meATP) and by 2,2‐dimethyl‐propionic acid 3‐(2‐chloro‐6‐methylaminopurin‐9‐yl)‐2‐(2,2‐dimethyl‐propionyloxymethyl)‐propyl ester (MRS 2395), a P2Y12selective antagonist. The response to ATP was increased by 2′‐deoxy‐N6‐methyl adenosine 3′,5′‐diphosphate (MRS 2179), a P2Y1selective antagonist, tetrodotoxin (TTX) or Nω‐nitro‐L‐arginine methyl ester (L‐NAME). ADPβS, a P2Y‐purinergic agonist, induced muscular contraction, with the same pharmacological profile as the ATP‐induced contraction. ADP, a natural ligand for P2Y1receptors, induced muscular relaxation, antagonized by MRS 2179 and by TTX or L‐NAME. Nerve stimulation elicited a transient nitrergic relaxation, followed by contraction. Contractile responses was reduced by atropine, PPADS, suramin, P2Y purinoceptor desensitisation, but not by P2X purinoceptor desensitisation, MRS 2179 or MRS 2395. None of the purinergic antagonists modified the nerve‐evoked relaxation.

Conclusions and implications:

In the longitudinal muscle of mouse distal colon, ATP, through ADPβS‐sensitive P2Y purinoceptors, contributed to the excitatory neurotransmission acting directly on smooth muscle and indirectly via activation of cholinergic neurons. Moreover, P2Y1 purinoceptors appear to be located on nitrergic inhibitory neurons. This study provides new insights into the role of purines in the mechanism inducing intestinal transit in mouse colon.

British Journal of Pharmacology(2007)151, 152–160. doi:10.1038/sj.bjp.0707188
Calcium and reactive oxygen species increase in endothelial cells in response to releasers of endothelium‐derived contracting factor
Authors: Tang E H C , Leung F P , Huang Y , Feletou M , So K‐F , Man R Y K , Vanhoutte P M
Published: March 2007

Background and Purpose:

Experiments were designed to assess whether or not the intracellular concentration of calcium and reactive oxygen species (ROS) increase in endothelial cells of the rat thoracic aorta in response to releasers of endothelium‐derived contracting factor (EDCF) and if so, whether or not a difference exists between spontaneously hypertensive (SHR) and normotensive (WKY) rats.

Experimental approach:

Calcium and ROS were measured by confocal microscopy, using Fura‐red in combination with Fluo‐4 and dichlorodihydrofluorescein diacetate, respectively.

Key results:

Acetylcholine caused a rapid increase in cytosolic calcium concentration in endothelial cells of both SHR and WKY, which was significantly more pronounced in aortae of the former strain. This rise of calcium was not affected by indomethacin (an inhibitor of cyclooxygenase) or Tiron plus diethyldithiocarbamate acid (DETCA) (membrane permeable antioxidants). In the presence of a nitric oxide synthase blocker, acetylcholine also caused a rapid increase in ROS in endothelial cells of SHR but not in those of WKY. The burst of ROS was prevented by indomethacin or Tiron plus DETCA.

Conclusions and implications:

These experiments show that endothelial cells of SHR are more prone to calcium and ROS overload upon stimulation with acetylcholine. The abnormal accumulation of calcium is a prerequisite to initiate the release of EDCF and can be mimicked using the calcium ionophore A23187. The sequence of events occurring during endothelium‐dependent contractions firstly requires the accumulation of calcium, which then activates cyclooxygenase and produces ROS along with EDCF that in turn stimulates TP‐receptors, resulting in EDCF‐mediated contractions.

British Journal of Pharmacology (2007) 151, 15–23. doi:10.1038/sj.bjp.0707190
Pharmacokinetic and pharmacodynamic consequences of inhibition of terazosin metabolism via CYP3A1 and/or 3A2 by DA‐8159, an erectogenic, in rats
Authors: Oh E Y , Bae S K , Kwon J W , You M , Lee D C , Lee M G
Published: March 2007

Background and purpose:

Recently, orthostatic hypotension was observed in patients with benign prostatic hyperplasia who are taking vardenafil (a PDE 5 inhibitor) and terazosin (a long acting alpha blocker). Therefore, this study was performed with DA‐8159 (a long acting PDE 5 inhibitor) and terazosin in rats to find whether or not pharmacokinetic and pharmacodynamic interactions between the two drugs were observed.

Experimental approach:

Pharmacokinetic and pharmacodynamic (changes in blood pressure) interactions between DA‐8159 and terazosin were evaluated after simultaneous i.v. and p.o. administration of DA‐8159 (30 mg kg−1) and terazosin (5 mg kg−1) to male Sprague–Dawley rats.

Key results:

After simultaneous i.v. and p.o. administration of terazosin and DA‐8159, the total area under the plasma concentration–time curve from time zero to time infinity (AUC) of terazosin became significantly greater (57.4 and 75.4% increase for i.v. and p.o. administration, respectively) than those of without DA‐8159. The blood pressure dropping effect was considerable after simultaneous p.o. administration of DA‐8159 and terazosin compared with each drug alone.

Conclusions and implications:

The significantly greater AUC of terazosin after both simultaneous i.v. and p.o. administration of both drugs could be due to the hepatic (both i.v. and p.o.) and intestinal (p.o.) inhibition of the metabolism of terazosin via CYP3A1 and/or 3A2 by DA‐8159, since both DA‐8159 and terazosin are metabolized via CYP3A1 and/or 3A2 in rats. The blood pressure lowering effect after simultaneous p.o. administration of both drugs could be due to significant increase in plasma concentrations of terazosin.

British Journal of Pharmacology (2007) 151, 24–34. doi:10.1038/sj.bjp.0707192
NA+‐ and K+‐channels as molecular targets of the alkaloid ajmaline in skeletal muscle fibres
Authors: Friedrich O , V Wegner F , Wink M , Fink R H A
Published: March 2007

Background and purpose:

Ajmaline is a widely used antiarrhythmic drug. Its action on voltage‐gated ion channels in skeletal muscle is not well documented and we have here elucidated its effects on Na+ and K+ channels.

Experimental approach:

Sodium (INa) and potassium (IK) currents in amphibian skeletal muscle fibres were recorded using ‘loose‐patch’ and two‐microelectrode voltage clamp techniques (2‐MVC). Action potentials were generated using current clamp.

Key results:

Under ‘loose patch’ clamp conditions, the IC50 for INa was 23.2 μM with Hill‐coefficient h=1.21. For IK, IC50 was 9.2 μM, h=0.87. Clinically relevant ajmaline concentrations (1‐3 μM) reduced peak INa by ∼5% but outward IK values were reduced by ∼20%. Na+ channel steady‐state activation and fast inactivation were concentration‐dependently shifted towards hyperpolarized potentials (∼10 mV at 25 μM). Inactivation curves were markedly flattened by ajmaline. Peak‐IK under maintained depolarisation was reduced to ∼30% of control values by 100 μM ajmaline. IK activation time constants were increased at least two‐fold. Lower concentrations (10 or 25 μM) reduced steady‐state‐IK slightly but peak‐IK significantly. Action potential generation threshold was increased by 10 μM ajmaline and repolarisation prolonged.

Conclusions and implications:

Ajmaline acts differentially on Na+ and K+ channels in skeletal muscle. This suggests at least multiple sites of action including the S4 subunit. Our data may provide a first insight into specific mechanisms of ajmaline‐ion channel interaction in tissues other than cardiac muscle and could suggest possible side‐effects that need to be further evaluated.

British Journal of Pharmacology (2007) 151, 63–74. doi:10.1038/sj.bjp.0707194