bluuebunny/crossref_metadata_2025 huggingface dataset:
PUBLISHING BIOETHICS AND BIOETHICS – REFLECTIONS ON ACADEMIC PUBLISHING BY A JOURNAL EDITOR
Authors: SCHÜKLENK UDO
Published: December 2010

This article by one of the Editors of Bioethics, published in the 25th anniversary issue of the journal, describes some of the revolutionary changes academic publishing has undergone during the last decades. Many humanities journals went from typically small print‐runs, counting by the hundreds, to on‐line availability in thousands of university libraries worldwide. Article up‐take by our subscribers can be measured efficiently. The implications of this and other changes to academic publishing are discussed. Important ethical challenges need to be addressed in areas such as the enforcement of plagiarism‐related policies, the so‐called ‘impact factor’ and its impact on academic integrity, and the question of whether on‐line only publishing can currently guarantee the integrity of academic publishing histories.
PERSONAL GENOMES: NO BAD NEWS?
Authors: CHADWICK RUTH
Published: December 2010

Issues in genetics and genomics have been centre stage in Bioethics for much of its history, and have given rise to both negative and positive imagined futures. Ten years after the completion of the Human Genome Project, it is a good time to assess developments. The promise of whole genome sequencing of individuals requires reflection on personalization, genetic determinism, and privacy.
A Contradiction in Terms? Making Sense of Emotional Intelligence in a Construction Management Environment
Authors: Lindebaum Dirk , Cassell Catherine
Published: December 2010

Emotional intelligence (EI) has been hailed as being critical to individual performance within organizations. However, recent theoretical debates indicate that scholars need to apply a more differentiated lens when examining the utility of EI in a particular organizational context. In this study, we seek to contribute preliminary empirical evidence to this debate. Drawing upon an interpretivist approach and a narrative analysis, we examine how UK construction project managers make sense of EI, and how this shapes their receptiveness to the construct. Our data analysis suggests that there are enduring, albeit changing, characteristics of the industry and the sensemaking processes of project managers that renders the construct, at least for the time being, of limited utility. Thus, our analysis is a cautionary tale for those management scholars and practitioners who argue for the ‘trainability’ of EI.
A STATE‐LEVEL ANALYSIS OF BUSINESS CYCLE ASYMMETRY
Authors: Ewing Bradley T. , Thompson Mark A.
Published: December 2010

This paper provides a comprehensive examination of asymmetry in US state‐level business cycles. We consider two different types of asymmetry in the adjustment process of a stationary time series: deepness and steepness. The data used in the study are a comparable set of state‐level coincident indexes (SCIs) developed by the Federal Reserve Bank of Philadelphia. Specifically, results from using the momentum‐threshold autoregressive model provide evidence of asymmetry in the growth rate of 23 SCIs as well as the equivalent national coincident index.
Quasi‐Symmetric Graphical Log‐Linear Models
Authors: GOTTARD ANNA , MARCHETTI GIOVANNI MARIA , AGRESTI ALAN
Published: December 2010

Abstract. We propose an extension of graphical log‐linear models to allow for symmetry constraints on some interaction parameters that represent homologous factors. The conditional independence structure of such quasi‐symmetric (QS) graphical models is described by an undirected graph with coloured edges, in which a particular colour corresponds to a set of equality constraints on a set of parameters. Unlike standard QS models, the proposed models apply with contingency tables for which only some variables or sets of the variables have the same categories. We study the graphical properties of such models, including conditions for decomposition of model parameters and of maximum likelihood estimates.
Choosing Priors for Constrained Analysis of Variance: Methods Based on Training Data
Authors: WESEL FLORYT VAN , HOIJTINK HERBERT , KLUGKIST IRENE
Published: December 2010

Abstract. This article combines the best of both objective and subjective Bayesian inference in specifying priors for inequality and equality constrained analysis of variance models. Objectivity can be found in the use of training data to specify a prior distribution, subjectivity can be found in restrictions on the prior to formulate models. The aim of this article is to find the best model in a set of models specified using inequality and equality constraints on the model parameters. For the evaluation of the models an encompassing prior approach is used. The advantage of this approach is that only a prior for the unconstrained encompassing model needs to be specified. The priors for all constrained models can be derived from this encompassing prior. Different choices for this encompassing prior will be considered and evaluated.
Controlled Direct and Mediated Effects: Definition, Identification and Bounds
Authors: VANDERWEELE TYLER J.
Published: December 2010

Abstract. Results are given which provide bounds for controlled direct effects when nounmeasured confounding assumptions required for the identification of these effects do not hold. Previous results concerning bounds for controlled direct effects rely on monotonicity relationships between the treatment, mediator and the outcome themselves; the results presented in this article instead assume that monotonicity relationships hold between the unmeasured confounding variable or variables and the treatment, mediator and outcome. Whereas prior results give bounds that contain the null hypothesis of no direct effect, the results presented here will in many instances yield bounds that do not contain the null hypothesis of no direct effect. For contexts in which a set of variables intercepts all paths between a treatment and an outcome, it is possible to provide a definition for a controlled mediated effect. We discuss the identification of these controlled mediated effects; the bounds for controlled direct effects are applicable also to controlled mediated effects. An example is given to illustrate how the results in the article can be used to draw inferences about direct and mediated effects in the presence of unmeasured confounding variables.
Should Monetary Policy Respond to Money Growth? New Results for the Euro Area
Authors: Scharnagl Michael , Gerberding Christina , Seitz Franz
Published: December 2010

In recent years, the relevance of money growth indicators for the conduct of monetary policy has been questioned in the mainstream academic literature. It is widely argued that monetary policy should directly relate short‐term interest rates to inflation and the output gap. The present paper investigates whether the performance of this type of interest rate rule can be significantly improved by adding a policy response to money growth. In contrast to most previous studies, our analysis explicitly takes into account the fact that real‐time data on both actual and potential output, and hence the output gap, may be subject to substantial measurement errors. Broadly speaking, we find that the greater the degree of output gap uncertainty, the greater the benefits of incorporating a money growth response are in terms of reducing volatility in output, inflation and interest rates. The main reason is that real‐time data on money growth contain valuable information on the true level of current output growth, which is not otherwise known to policy makers in real time with a sufficient degree of precision. Hence, we conclude that policy makers should explicitly account for money growth in the setting of policy rates.
Some Simple Tests of the Globalization and Inflation Hypothesis*
Authors: Ihrig Jane , Kamin Steven B. , Lindner Deborah , Marquez Jaime
Published: December 2010

This paper evaluates the hypothesis that globalization has increased the role of international factors and decreased the role of domestic factors in the inflation process in industrial economies. Towards that end, we estimate standard Phillips curve inflation equations for 11 industrial countries and use these estimates to test several predictions of the globalization and inflation hypothesis. Our results provide little support for this hypothesis. First, the estimated effect of foreign output gaps on domestic consumer price inflation is generally insignificant and often of the wrong sign. Second, we find no evidence that the trend decline in the sensitivity of inflation to the domestic output gap observed in many countries owes to globalization. Finally, and most surprisingly, our econometric results indicate no increase over time in the responsiveness of inflation to import prices for most countries.
Identifying the Effect of the Bank of Japan's Liquidity Facilities: The Case of Commercial Paper Operations During the Financial Turmoil*
Authors: Hirose Yasuo , Ohyama Shinsuke
Published: December 2010

How do we evaluate the effects of unconventional monetary policy measures? To answer this question, we propose a simple structural model that enables us to identify the effects of liquidity facilities during financial turmoil. Specifically, we develop a model that examines the effects of the Bank of Japan's (BoJ's) commercial paper (CP) operations on the CP primary market. On the basis of the structural model, we measure the effects of CP operations as differences between the actual rates in the primary market and the counterfactual rates without the operations, and decompose the effects into three factors. We apply our model to identifying the effects of CP operations from October 2008 to May 2009, including the period after the BoJ introduced the outright purchase of CP and its special funds‐supplying operation accepting CPs as collateral in addition to the CP repo operation. Our results suggest that the CP repo operation and the outright purchase of CP had marked effects initially; however, these effects were subdued subsequently. Moreover, the effects of the special funds‐supplying operation were substantial and persistent from January to April 2009.
Avène Thermal Spring Water: an active component with specific properties
Authors: Merial‐Kieny C , Castex‐Rizzi N , Selas B , Mery S , Guerrero D
Published: December 2010

Avène Thermal Spring Water (TSW) is a natural active component characterized by a low mineral content. In vitro experiments have demonstrated the effect of Avène TSW on membrane fluidity, its antiradical and anti‐inflammatory properties, its effects on many mediators involved in the immune response and its stimulating effect on keratinocyte differentiation.  The clinical efficacy of the water was demonstrated at the hydrotherapy centre in chronic and disabling diseases such as atopic dermatitis but also in various settings in medical and post dermatology procedure such as photodynamic therapy or photothermolysis.  All these data support the fact that the Avène TSW is an active component.
Inhibition of TNF‐alpha induced‐adhesion molecules by Avène Thermal Spring Water in human endothelial cells
Authors: Castex‐Rizzi N , Charveron M , Merial‐Kieny C
Published: December 2010

Background  Cell adhesion molecules, such as E‐selectin or intercellular adhesion molecule 1 (ICAM‐1), play an important role in mediating leucocyte capture and rolling on the surface of blood vessels in atopic skin. The effectiveness of Avène hydrotherapy in patients suffering from atopic dermatitis has previously been demonstrated. Thus, we examined the effect of Avène Thermal Spring Water (TSW) on adhesion molecules to understand its mechanism of action.

Methods  Human endothelial cells EA.hy926 were treated with tumour necrosis factor‐α (TNFα) in the presence or not of Avène TSW during 4 h. As nuclear factor ‐κB (NF‐κB) is involved in the signalisation of inflammatory mediators such as the adhesion molecules, the translocation of NF‐κB in endothelial cells was assessed by immunohistochemistry with anti‐NF‐κBp65. The protein and mRNA levels of TNFα‐induced ICAM‐1 and E‐selectin were assessed by ELISA assay and RT‐PCR. These adhesion molecules were also detected by immunohistochemistry.

Results  Tumour necrosis factor‐α induced the activation of p65 NF‐κB nuclear translocation. TNFα also induced E‐selectin and ICAM‐1 in a dose‐dependant manner in EA.hy926 endothelial cells. In the presence of Avène TSW, a significant inhibition of the TNFα‐induced E‐selectin and ICAM‐1 expression (−22% and −7%, respectively, P < 0.05) was observed.

Conclusion  These data suggest that Avène TSW mediated inhibition of TNFα‐induced E‐selectin and ICAM‐1 expression. The inhibition of such adhesion molecules is attributable to the suppression of NF‐κB transcription factor pathway activation.
Impact of Avène hydrotherapy on the quality of life of atopic and psoriatic patients
Authors: Taieb C , Sibaud V , Merial‐Kieny C
Published: December 2010

Background  Atopic dermatitis and psoriasis engender a significant deterioration in patients’ quality of life. Although the efficacy of patient management at the Avène hydrotherapy centre has been demonstrated by clinical studies, few data relating to changes in the quality of life following therapeutic management are available. The objective of this study was to evaluate the short‐ and medium‐term effects of hydrotherapy not only on the patients’ quality of life, but also on the quality of life of the parents of the treated children.

Methods  In this 6‐month longitudinal observational study, adult (n = 174) and paediatric (n = 212) atopic patients and psoriatic patients (n = 262) had to complete questionnaires relating to the quality of life at the beginning (D0) and after 3 weeks hydrotherapy (W3), and then, 3 (M3) and 6 months (M6) later. The dermatology life quality index (DLQI) and the Short‐Form‐12 Health Survey (SF‐12) generic questionnaire were given to adult patients. The children’s dermatological life quality index (CDLQI) was given to paediatric patients, and the SF‐12 to their parents.

Results  At D0, the DLQI score was 29.7 ± 20.1 and 26.9 ± 18.9 for atopic and psoriatic patients, respectively. At W3, this score had decreased significantly to reach 16.8 ± 14.9 (P < 0.01) and 10.0 ± 10.5 (P < 0.001) for atopic and psoriatic patients, respectively. The DLQI scores at M3 and M6 were 20.7 ± 16.4 and 23.1 ± 18.8 for atopic patients and 18.8 ± 16.7 and 21.9 ± 19.6 for psoriatic patients and remained significantly lower in comparison with D0 values (P < 0.05).

Conclusion  A 3‐week course of treatment at the Avène hydrotherapy centre significantly improved the quality of life of patients suffering from skin diseases. This improvement persisted 3 and 6 months after management by hydrotherapy.
Usefulness of TrichoScan professional in the evaluation of hair loss in females. Report of 180 cases
Authors: López V. , Martín J.M. , Sánchez R. , Ortega C. , Ricart J.M.
Published: December 2010

Background  TrichoScan Professional is a computerized program used for digital measurement of hair growth and hair loss. The aim of our study was to undertake an evaluation with TrichoScan Professional of female patients consulting at our hospitals for hair loss. The purpose of our study was to determine whether TrichoScan was able to identify differences in hair parameters that would correlate with the pattern of alopecia or according to the age of the patients evaluated.

Material and methods  One hundred‐eighty women that consulted consecutively for loss of hair were included. Patients were aged between 8 and 85 years (mean age 36 years). Data including age, the number of hairs, hair density per square centimetre, anagen and telogen percentage and percentage of terminal and miniaturized hair were analysed.

Results  Results observed with TrichoScan were as below: number of hairs (mean 154.9; range 34–316). Hair density per square centimetre (mean 239; range 52–486). Hair in anagen phase (mean 62.4%; range 9–93%). Hair in telogen phase (mean 37.4%; range 7–91%). Terminal hair (mean 95.2%; range 82–100%). Vellus hair (mean 4.7%; range 0–17%). Pearson′s correlation test was used to measure the strength of the association of age with the rest of parameters. The statistical analysis showed a significant correlation between age and both the number of hairs and the hair density per square centimetre. However, no significant correlation between age and rest of the parameters was observed.

Conclusions  TrichoScan Professional may help to quantify hair density and in our sample, this was the only parameter showing a significant decrease according to age in various types of alopecia affecting the females.
Physiological and cellular aspects of phytotoxicity tolerance in plants: the role of membrane transporters and implications for crop breeding for waterlogging tolerance
Authors: Shabala Sergey
Published: December 2010

Waterlogging affects large areas of agricultural land, resulting in severe economic penalties because of massive losses in crop production. Traditionally, plant breeding for waterlogging tolerance has been based on the field assessment of a range of agronomic and morphological characteristics. This review argues for a need to move towards more physiologically based approaches by targeting specific cellular mechanisms underling key components of waterlogging tolerance in plants. Also, while the main focus of researchers was predominantly on plant anoxia tolerance, less attention was given to plant tolerance to phytotoxins under waterlogged conditions. This paper reviews the production of major elemental and organic phytotoxins in waterlogged soils and describes their adverse effects on plant performance. The critical role of plasma membrane transporters in plant tolerance to secondary metabolite toxicity is highlighted, and ionic mechanisms mediating the this tolerance are discussed. A causal link between the secondary metabolite‐induced disturbances to cell ionic homeostasis and programmed cell death is discussed, and a new ethylene‐independent pathway for aerenchyma formation is put forward. It is concluded that plant breeding for waterlogging tolerance may significantly benefit from targeting mechanisms of tolerance to phytotoxins.
An elaborate heterotrimeric G‐protein family from soybean expands the diversity of plant G‐protein networks
Authors: Bisht Naveen C. , Jez Joseph M. , Pandey Sona
Published: December 2010

See also the Commentary by Roux
Differential age effects on lexical ambiguity resolution mechanisms
Authors: Lee Chia‐Lin , Federmeier Kara D.
Published: December 2010

Multiple neurocognitive subsystems are involved in resolving lexical ambiguity under different circumstances. We examined how processing in these subsystems changes with normal aging by comparing ERP responses to homographs and unambiguous words completing congruent sentences (with both semantic and syntactic contextual information) or syntactic prose (syntactic information only). Like young adults in prior work, older adults elicited more negative N400s to homographs in congruent sentences, suggesting mismatch between the context and residual activation of the contextually irrelevant sense. However, the frontal negativity seen in young adults to homographs in syntactically well‐defined but semantically neutral contexts was absent in older adults as a group, suggesting a decline in recruiting additional neural resources to aid difficult semantic selection. A subset of older adults with high verbal fluency maintained a young‐like effect pattern.
Paranoid induction reduces N400s of healthy subjects with delusional‐like ideation
Authors: Prévost Marie , Rodier Mitchell , Lionnet Claire , Brodeur Mathieu , King Suzanne , Debruille J. Bruno
Published: December 2010

A previous study suggests that the amplitude of the N400 event‐related potentials (ERPs) of healthy subjects does not vary with their delusional‐like ideations. This contrasts with the smaller N400 amplitudes observed in more‐ than in less‐deluded schizophrenia patients. Here, we hypothesize that these smaller N400 amplitudes were related to the paranoid feelings patients had during the ERP recording. We thus induced this type of feelings in healthy subjects. Delusional‐like ideation was assessed with the schizotypal personality questionnaire. Thirty‐four healthy subjects completed a semantic categorization task. Paranoid feelings were significantly enhanced by the induction. In these conditions, greater delusional‐like ideation scores were associated with smaller N400 amplitudes and larger late positive components. Controlling for the two other schizotypal factors strengthened these results. These findings may help us understand why delusions persist.
Kindling alters neurosteroid‐induced modulation of phasic and tonic GABAAreceptor‐mediated currents: role of phosphorylation
Authors: Kia Arash , Ribeiro Fabiola , Nelson Renee , Gavrilovici Cezar , Ferguson Stephen S. G. , Poulter Michael O.
Published: December 2010

J. Neurochem. (2011)116, 1043–1056.

We have previously shown that after kindling (a model of temporal lobe epilepsy), the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) was unable to augment GABA type A receptor (GABAA)‐mediated synaptic currents occurring on pyramidal cells of the piriform cortex. Phosphorylation of GABAAreceptors has been shown previously to alter the activity of THDOC, so we tested the hypothesis that kindling induces changes in the phosphorylation of GABAAreceptors and this accounts for the loss in efficacy. To assay whether GABAAreceptors are more phosphorylated after kindling, we examined the phosphorylation state of the β3 subunit and found that it was increased. Incubation of brain slices with the protein kinase C activator phorbol 12‐myristate 13‐acetate (PMA) (100 nM) also increased phosphorylation in the same assay. In patch clamp, recordings from non‐kindled rat brain slices PMA also reduced the activity of THDOC in a manner that was identical to what is observed after kindling. We also found that the tonic current was no longer augmented by THODC after kindling and PMA treatment. The protein kinase C (PKC) antagonist bisindolylmaleimide I blocked the effects PMA on the synaptic but not the tonic currents. However, the broad spectrum PKC antagonist staurosporine blocked the effects of PMA on the tonic currents, implying that different PKC isoforms phosphorylate GABAAreceptors responsible for phasic and tonic currents. The phosphatase activator Li+palmitate restored the ‘normal’ activity of THDOC on synaptic currents in kindled brain slices but not the tonic currents. These data demonstrate that kindling enhances the phosphorylation state of GABAAreceptors expressed in pyramidal neurons reducing THDOC efficacy.
Understanding the pathogenesis of Alzheimer’s disease: will RNA‐Seq realize the promise of transcriptomics?
Authors: Sutherland Greg T. , Janitz Michal , Kril Jillian J.
Published: December 2010

J. Neurochem. (2011) 116, 937–946.

The prevalence of Alzheimer’s disease (AD) is increasing rapidly in the western world and is poised to have a significant economic and societal impact. Current treatments do not alter the underlying disease processes meaning new treatments are required if this imminent epidemic is to be averted. The clinical manifestations of AD are secondary to a substantial loss of cortical neurons. To be effective, neuroprotective strategies will need to be implemented prior to this cell loss. However, this requires the discovery of both pre‐clinical markers to identify susceptible patients and the early pathogenic mechanisms to serve as therapeutic targets. Although the biomarkers and pathogenic mechanisms may overlap, it is likely that new approaches are required to identify novel elements of the disease. Transcriptomic analyses, that assume no a priori etiological hypotheses, promise much in elucidating the pathogenesis of complex diseases like AD. Microarrays are the most popular platform for transcriptomic analysis and have been applied across AD models, patient samples and postmortem brain tissue. The results of these studies have been largely discordant which could, to some extent, reflect the limitations of this probe‐hybridization‐based methodology. In comparison, whole transcriptome sequencing (RNA‐Seq) utilizes a highly efficient, next‐generation DNA sequencing method with improved dynamic range and scope of transcript detection. RNA‐Seq is not only highly suited to investigations of the genomically complex human brain tissue but it can potentially overcome technical issues inherent to case–control comparisons of postmortem brain tissue in neurodegenerative diseases. The volume of data generated by this platform looms as the major logistical hurdle and a systematic experimental approach will be required to maximise the detection of pathogenically relevant signals. Nevertheless, RNA‐Seq looks set to deliver a quantum leap forward in our understanding of AD pathogenesis.
Learning to live with irritabel bowel syndrome. The influence of a group‐based patient education programme on peoples’ ability to manage illness in everyday life
Authors: Håkanson Cecilia , Sahlberg‐Blom Eva , Ternestedt Britt‐Marie , Nyhlin Henry
Published: December 2010

Scand J Caring Sci; 2011; 25; 491–498
 
Learning to live with irritabel bowel syndrome. The influence of a group‐based patient education programme on peoples’ ability to manage illness in everyday life

Background:  Living with chronic irritable bowel syndrome sets limitations in peoples’ everyday lives. This is due to bad health and the difficulty to find strategies that will manage their problem. In encounters with health care providers, these people feel that they are not getting the appropriate support to manage their illness‐related troubles, and they perceive themselves to be insufficiently informed about the disease.

Aim:  To evaluate the influence of a group‐based patient education programme about irritable bowel syndrome, on people’s ability to manage their illness in everyday life.

Methods:  The study used an evaluative research design. Fifty‐one individuals with irritable bowel syndrome completed the ways of coping questionnaire, and the irritable bowel syndrome severity scoring system, before and after participating in a multidisciplinary group‐based patient education programme.

Results:  In the participants’ self assessments, statistical significances (p > 0.05) were found for the mean frequency of efforts used on the coping strategies distancing and escape‐avoidance. Distancing was used more often after the education programme, while escape‐avoidance, was used more seldom. The proportional use of the strategy self‐controlling (relative score) was enhanced after the education programme. The participants’ overall severity of symptoms was significantly reduced after the education programme. The individuals with a clinically noteworthy improvement in symptom severity (decrease ≤ 50) had greater changes in relative score values than those that showed a lesser improvement in symptom severity.

Conclusion:  Coping patterns were changed and symptoms were scored significantly less severe among the participants who participated in the education programme. Controlled studies following individuals over a longer period are suggested to establish the validity and sustainability of these changes, and qualitative interview studies would provide additional understanding about the significance of the separate parts of the education programme, and about the meaning of the programme to peoples’ everyday lives as a whole.
Predicting impacts of climate change on biodiversity: a role for semi‐mechanistic community‐level modelling
Authors: Mokany Karel , Ferrier Simon
Published: December 2010

Aim  Robust and reliable predictions of the effects of climate change on biodiversity are required in formulating conservation and management strategies that best retain biodiversity into the future. Significant challenges in modelling climate change impacts arise from limitations in our current knowledge of biodiversity. Community‐level modelling can complement species‐level approaches in overcoming these limitations and predicting climate change impacts on biodiversity as a whole. However, the community‐level approaches applied to date have been largely correlative, ignoring the key processes that influence change in biodiversity over space and time. Here, we suggest that the development of new ‘semi‐mechanistic’ community‐level models would substantially increase our capacity to predict climate change impacts on biodiversity.

Location  Global.

Methods  Drawing on an expansive review of biodiversity modelling approaches and recent advances in semi‐mechanistic modelling at the species level, we outline the main elements of a new semi‐mechanistic community‐level modelling approach.

Results  Our quantitative review revealed a sharp divide between mechanistic and non‐mechanistic biodiversity modelling approaches, with very few semi‐mechanistic models developed to date.

Main conclusions  We suggest that the conceptual framework presented here for combining mechanistic and non‐mechanistic community‐level approaches offers a promising means of incorporating key processes into predictions of climate change impacts on biodiversity whilst working within the limits of our current knowledge.
Age‐associated increase in heterochromatic marks in murine and primate tissues
Authors: Kreiling Jill A. , Tamamori‐Adachi Mimi , Sexton Alec N. , Jeyapalan Jessie C. , Munoz‐Najar Ursula , Peterson Abigail L. , Manivannan Jayameenakshi , Rogers Elizabeth S. , Pchelintsev Nikolay A. , Adams Peter D. , Sedivy John M.
Published: December 2010

Chromatin is highly dynamic and subject to extensive remodeling under many physiologic conditions. Changes in chromatin that occur during the aging process are poorly documented and understood in higher organisms, such as mammals. We developed an immunofluorescence assay to quantitatively detect, at the single cell level, changes in the nuclear content of chromatin‐associated proteins. We found increased levels of the heterochromatin‐associated proteins histone macro H2A (mH2A) and heterochromatin protein 1 beta (HP1β) in human fibroblasts during replicative senescence in culture, and for the first time, an age‐associated increase in these heterochromatin marks in several tissues of mice and primates. Mouse lung was characterized by monophasic mH2A expression histograms at both ages, and an increase in mean staining intensity at old age. In the mouse liver, we observed increased age‐associated localization of mH2A to regions of pericentromeric heterochromatin. In the skeletal muscle, we found two populations of cells with either low or high mH2A levels. This pattern of expression was similar in mouse and baboon, and showed a clear increase in the proportion of nuclei with high mH2A levels in older animals. The frequencies of cells displaying evidence of increased heterochromatinization are too high to be readily accounted for by replicative or oncogene‐induced cellular senescence, and are prominently found in terminally differentiated, postmitotic tissues that are not conventionally thought to be susceptible to senescence. Our findings distinguish specific chromatin states in individual cells of mammalian tissues, and provide a foundation to investigate further the progressive epigenetic changes that occur during aging.
Corporate Tax Consolidation and Enhanced Cooperation in the European Union*
Authors: Bettendorf Leon , Van Der Horst Albert , De Mooij Ruud A. , Vrijburg Hendrik
Published: December 2010

We assess the economic impact of introducing consolidation with formula apportionment in the European Union and consider alternative enhanced cooperation agreements. We find that the consolidation is likely to yield a small aggregate welfare gain in Europe. However, not all countries benefit. A coalition of winning countries reduces the welfare gain and may induce a process of adverse selection which destroys the possibility of cooperation. We find that a coalition of similar countries (in terms of the size of their multinational sector) is more feasible in achieving agreement and is actually preferred by those countries over a Europe‐wide reform.
Revenue Elasticities in Complex Income Tax Structures: An Application to Spain*
Authors: Creedy John , Sanz‐Sanz José Félix
Published: December 2010

This paper derives analytical expressions for the revenue elasticity of complex income tax systems, as applied to tax units and in aggregate. Among the complexities considered are the schedular nature of income tax systems and the role of central and regional governments, along with the existence of a range of intricate tax credits and eligible expenditures and deductions. Empirical estimates are obtained for the case of Spain using a cross‐sectional data set, which enables a number of important ancillary elasticities (relating to allowances and tax credits, and different income sources) to be estimated. It is found that there is considerable variation among tax units in the revenue elasticity, with highly positively skewed distributions. The nature of the distributions varies among regions of Spain, and the aggregate elasticities for each region were found to display some variation associated with income distribution differences. The national aggregate is found to be around 1.3.
Anti‐angiogenic effects of two cystine‐knot miniproteins from tomato fruit
Authors: Cavallini C , Trettene M , Degan M , Delva P , Molesini B , Minuz P , Pandolfini T
Published: December 2010

BACKGROUND AND PURPOSE Cystine‐knot miniproteins are characterized by a similar molecular structure. Some cystine‐knot miniproteins display therapeutically useful biological activities, as antithrombotic agents or tumour growth inhibitors. A critical event in the progression of tumours is the formation of new blood vessels. The aim of this work was to test two tomato cystine‐knot miniproteins for their effects on endothelial cell proliferation and angiogenesis in vitro.

EXPERIMENTAL APPROACH Two tomato cystine‐knot miniproteins (TCMPs) were expressed and purified either as recombinant or as native proteins from tomato fruits. The Matrigel assay was used to investigate the effects of TCMPs on in vitro angiogenesis. Viability and proliferation of endothelial cells were tested. Extracellular signal‐regulated kinase (ERK)1/2 phosphorylation was assayed in either HUVEC or A431 epidermal growth factor receptor (EGFR)‐overexpressing cells treated with TCMPs. EGFR phosphorylation was tested in A431 cells.

KEY RESULTS Both recombinant and native TCMPs inhibited in vitro angiogenesis of HUVEC cells at concentrations of 15–100 nM. The anti‐angiogenic effect of TCMPs was associated with the inhibition of ERK phosphorylation. The two miniproteins did not alter the viability and proliferation of the endothelial cells.

CONCLUSIONS AND IMPLICATIONS The anti‐angiogenetic properties of TCMPs are of potential pharmacological interest because they are common and natural components of the human diet, they possess low toxicity, they are active at submicromolar concentrations, they share a common molecular structure that can be used as a molecular platform for the design of molecules with enhanced biological activity.
Inhibition of fatty acid amide hydrolase unmasks CB1receptor and TRPV1 channel‐mediated modulation of glutamatergic synaptic transmission in midbrain periaqueductal grey
Authors: Kawahara H , Drew GM , Christie MJ , Vaughan CW
Published: December 2010

BACKGROUND AND PURPOSEWhile arachidonyl ethanolamine (anandamide) produces pharmacological effects mediated by cannabinoid CB1 receptors, it is also an agonist at the transient receptor potential vanilloid type 1 (TRPV1) ion channel. This study examined the cellular actions of anandamide in the midbrain periaqueductal grey (PAG), a region implicated in the analgesic actions of cannabinoids, and which expresses both CB1 receptors and TRPV1.

EXPERIMENTAL APPROACHIn vitrowhole cell patch clamp recordings of glutamatergic excitatory postsynaptic currents (EPSCs) were made from rat and mouse PAG slices.

KEY RESULTSCapsaicin (1 µM) increased the rate, but not the amplitude of miniature EPSCs in subpopulations of neurons throughout the rat and mouse PAG. Capsaicin had no effect on miniature EPSCs in PAG neurons from TRPV1 knock‐out mice. In mouse PAG neurons, anandamide (30 µM) had no effect on the rate of miniature EPSCs alone, or in the presence of either the CB1 antagonist AM251 (3 µM) or the TRPV1 antagonist iodoresiniferatoxin (300 nM). Anandamide produced a decrease in miniature EPSC rate in the presence of the fatty acid amide hydrolase (FAAH) inhibitor URB597 (1 µM). By contrast, anandamide produced an increase in miniature EPSC rate in the presence of both URB597 and AM251, which was absent in TRPV1 knock‐out mice.

CONCLUSIONS AND IMPLICATIONSThese results suggest that the actions of anandamide within PAG are limited by enzymatic degradation by FAAH. FAAH blockade unmasks both presynaptic inhibition and excitation of glutamatergic synaptic transmission which are mediated via CB1 receptors and TRPV1 respectively.
Development of radiotracers for oncology – the interface with pharmacology
Authors: Sharma Rohini , Aboagye Eric
Published: December 2010

There is an increasing role for positron emission tomography (PET) in oncology, particularly as a component of early phase clinical trials. As a non‐invasive functional imaging modality, PET can be used to assess both pharmacokinetics and pharmacodynamics of novel therapeutics by utilizing radiolabelled compounds. These studies can provide crucial information early in the drug development process that may influence the further development of novel therapeutics. PET imaging probes can also be used as early biomarkers of clinical response and to predict clinical outcome prior to the administration of therapeutic agents. We discuss the role of PET imaging particularly as applied to phase 0 studies and discuss the regulations involved in the development and synthesis of novel radioligands. The review also discusses currently available tracers and their role in the assessment of pharmacokinetics and pharmacodynamics as applied to oncology.

LINKED ARTICLES This article is part of a themed section on Imaging. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2011.163.issue‐8BJP has previously published an Imaging in Pharmacology themed section, edited by A Davenport and C Daly. To view this section visit http://dx.doi.org/10.1111/bph.2010.159.issue‐4
Effects on resting cerebral blood flow and functional connectivity induced by metoclopramide: a perfusion MRI study in healthy volunteers
Authors: Fernández‐Seara María A , Aznárez‐Sanado Maite , Mengual Elisa , Irigoyen Jaione , Heukamp Franz , Pastor María A
Published: December 2010

BACKGROUND AND PURPOSE The substituted benzamide, metoclopramide, is a dopamine receptor antagonist and is widely prescribed in the symptomatic treatment of nausea and vomiting, although it can cause adverse motor and non‐motor side effects. The effects of metoclopramide on brain metabolism have not been investigated to date.

EXPERIMENTAL APPROACH To determine the effects of metoclopramide on brain function, cerebral perfusion changes after a single oral dose were assessed in healthy volunteers using magnetic resonance imaging (MRI) techniques. Arterial spin labelling (ASL) perfusion MRI was used to measure cerebral blood flow before and after metoclopramide. Blood haemodynamics in the vertebral and internal carotid arteries were evaluated using phase‐contrast MRI.

KEY RESULTS Metoclopramide altered haemodynamics in the carotid arteries and the cerebral perfusion. Perfusion increased bilaterally in the putamen, consistent with antagonism of dopamine D2 receptors by metoclopramide and possibly related to its motor side effects. In contrast, reduced perfusion was observed in the insular cortices and anterior temporal lobes. In addition, functional connectivity between the insular cortex and the dorsolateral prefrontal cortex was decreased. These cortical changes affecting neural circuits between high‐order association areas may underlie certain neuropsychiatric conditions occasionally reported after metoclopramide administration.

CONCLUSIONS AND IMPLICATIONS The present results show the sensitivity of ASL to detect small changes in regional blood flow, closely related to brain function, after a single pharmacological challenge, highlighting the potential of this technique for human pharmacological studies.

LINKED ARTICLES This article is part of a themed section on Imaging. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2011.163.issue‐8BJP has previously published an Imaging in Pharmacology themed section, edited by A Davenport and C Daly. To view this section visit http://dx.doi.org/10.1111/bph.2010.159.issue‐4
Does airway smooth muscle express an inflammatory phenotype in asthma?
Authors: Damera Gautam , Panettieri, Jr Reynold A
Published: December 2010

In addition to hyperresponsiveness in asthma, airway smooth muscle (ASM) also manifests an inflammatory phenotype characterized by augmented expression of mediators that enhance inflammation, contribute to tissue remodelling and augment leucocyte trafficking and activity. Our present review summarizes contemporary understanding of ASM‐derived mediators and their paracrine and autocrine actions in airway diseases.

LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue‐1
Effects of cannabinoids and cannabinoid‐enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes
Authors: De Petrocellis Luciano , Ligresti Alessia , Moriello Aniello Schiano , Allarà Marco , Bisogno Tiziana , Petrosino Stefania , Stott Colin G , Di Marzo Vincenzo
Published: December 2010

BACKGROUND AND PURPOSE Cannabidiol (CBD) and Δ9‐tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system.

EXPERIMENTAL APPROACH The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N‐acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL‐2H3 cells, were studied using fluorescence‐based calcium assays in transfected cells and radiolabelled substrate‐based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested.

KEY RESULTS CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV‐BDS was the most potent compound at this target. CBG‐BDS and THCV‐BDS were the most potent rat TRPM8 antagonists. All non‐acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors.

CONCLUSIONS AND IMPLICATIONS These results are relevant to the analgesic, anti‐inflammatory and anti‐cancer effects of cannabinoids and Cannabis extracts.

LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7
Low dose of the liver X receptor agonist, AZ876, reduces atherosclerosis in APOE*3Leiden mice without affecting liver or plasma triglyceride levels
Authors: van der Hoorn JWA , Lindén D , Lindahl U , Bekkers MEA , Voskuilen M , Nilsson R , Oscarsson J , Lindstedt EL , Princen HMG
Published: December 2010

BACKGROUND AND PURPOSE Liver X receptor (LXR) agonists are atheroprotective but often induce hypertriglyceridaemia and liver steatosis. We investigated the effect of a novel high‐affinity LXR activator, AZ876, on plasma lipids, inflammation and atherosclerosis, and compared the effects with another LXR agonist, GW3965.

EXPERIMENTAL APPROACH APOE*3Leiden mice were fed an atherogenic diet alone or supplemented with either AZ876 (5 or 20 µmol·kg−1·day−1) or GW3965 (17 µmol·kg−1·day−1) for 20 weeks. Total cholesterol and triglyceride levels were measured using commercial kits. Plasma cytokines were determined by using bead‐based multiplex suspension array kits with the Luminex technology. Atherosclerosis was assessed histochemically and lesion composition was assessed by immunohistochemical methods.

KEY RESULTS Low‐dose AZ876 had no effect on plasma or liver lipids, whereas high‐dose AZ876 increased plasma triglycerides (+110%) and reduced cholesterol (−16%) compared with controls. GW3965 increased plasma triglycerides (+70%). Low‐dose AZ876 reduced lesion area (−47%); and high‐dose AZ876 strongly decreased lesion area (−91%), lesion number (−59%) and severity. In either dose, AZ876 did not affect lesion composition. GW3965 reduced atherosclerosis and collagen content of lesions (−23%; P < 0.01). High‐dose AZ876 and GW3965, but not low‐dose AZ876, reduced inflammation as reflected by lower cytokine levels and vessel wall activation.

CONCLUSIONS AND IMPLICATIONS We have identified a novel LXR agonist that when given in a low dose inhibits the progression of atherosclerosis without inducing anti‐inflammatory effects, liver steatosis or hypertriglyceridaemia. Therefore, the primary protective action of a low‐dose AZ876 is likely to be an increased reverse cholesterol transport.
Arrestins differentially regulate histamine‐ and oxytocin‐evoked phospholipase C and mitogen‐activated protein kinase signalling in myometrial cells
Authors: Brighton Paul J , Rana Shashi , Challiss RA John , Konje Justin C , Willets Jonathon M
Published: December 2010

BACKGROUND AND PURPOSE

The uterotonins oxytocin and histamine, mediate contractile signals through specific G protein‐coupled receptors, a process which is tightly controlled during gestation to prevent preterm labour. We previously identified G protein‐coupled receptor kinase (GRK)2 and GRK6 as respective cardinal negative regulators of histamine H1 and oxytocin receptor signalling. GRK‐mediated phosphorylation promotes arrestin recruitment, not only desensitizing receptors but activating an increasing number of diverse signalling pathways. Here we investigate potential roles that arrestins play in the regulation of myometrial oxytocin/histamine H1 receptor signalling.

EXPERIMENTAL APPROACH

Endogenous arrestins2 and 3 were specifically depleted using RNA‐interference in a human myometrial cell line and the consequences of this for G protein‐coupled receptor‐mediated signalling were assessed using Ca2+/inositol 1,4,5‐trisphophate imaging and standard mitogen‐activated protein kinase (MAPK) assays.

KEY RESULTS

Depletion of arrestin3, but not arrestin2 enhanced and prolonged H1 receptor‐stimulated Ca2+ responses, whilst depletion of either arrestin increased oxytocin receptor responses. Arrestin3 depletion decreased H1 receptor desensitization, whilst removal of either arrestin isoform was equally effective in preventing oxytocin receptor desensitization. Following arrestin3 depletion oxytocin‐induced phospho‐extracellular signal‐regulated kinase1/2 signals were diminished and histamine‐stimulated signals virtually absent, whereas depletion of arrestin2 augmented extracellular signal‐regulated kinase1/2 responses to each agonist. Conversely, depletion of arrestin3 enhanced p38 signals to each agonist, whilst arrestin2 suppression increased oxytocin‐, but not histamine‐induced p38 MAPK responses.

CONCLUSIONS AND IMPLICATIONS

Arrestin proteins are key regulators of H1 and oxytocin receptor desensitization, and play integral roles mediating uterotonin‐stimulated MAPK‐signalling. These data provide insights into the in situ regulation of these receptor subtypes and may inform pathophysiological functioning in preterm labour.