bluuebunny/crossref_metadata_2025 huggingface dataset:
Managing Ambiguity in New Product Development Projects
Authors: Brun Eric , Sætre Alf Steinar
Published: February 2009

Ambiguity, defined in this study as the existence of two or more interpretations of the same cue, is an essential component of ‘fuzziness’ in new product development (NPD) projects. In this paper, we present a model by which ambiguity in NPD projects can be classified and managed. The model has been developed grounded in case data from four NPD projects in companies making medical devices. Ambiguity is classified according to two axes: subjects of ambiguity and sources of ambiguity. Subjects of ambiguity include product, market, process and organizational resources. Sources of ambiguity include multiplicity, novelty, validity and reliability. Ambiguity can be managed by two means: reducing or sustaining it. If clarity is a main priority in the NPD project, reducing ambiguity is necessary and can be effectively achieved by applying the hypothetical‐deductive method. If novelty and flexibility are high project priorities, sustaining certain ambiguities can be useful. Managing ambiguity requires a constant harmonizing of the need for clarity and the need for novelty and flexibility.
Low‐Cost versus Innovation: Contrasting Outsourcing and Integration Strategies in Manufacturing
Authors: Bengtsson Lars , Von Haartman Robin , Dabhilkar Mandar
Published: February 2009

This paper analyses how two different outsourcing manufacturing strategies relate to plant performance and innovation capability when taking into account the organizational integration of design and manufacturing as well as product complexity. The study discriminates between low‐cost‐oriented outsourcing and innovation‐oriented outsourcing. The empirical data used is based on a survey of 267 engineering firms, of which half have outsourced manufacturing. We found that the two outsourcing strategies do have different effects, which illustrates that outsourcing represents a trade‐off between improving innovation capability and lowering costs. The study furthermore shows that manufacturing and supplier integration in product design processes is mainly beneficial when applying innovation‐oriented outsourcing, and in particular when products and manufacturing processes are complex.
How to Use an Innovation Audit as a Learning Tool: A Case Study of Enhancing High‐Involvement Innovation
Authors: Hallgren Erik W.
Published: February 2009

Many types of innovation auditing exist, though there are few descriptions of them being tested. Little effort has been made to examine their effect on companies, and even less to considering whether these audits could be used more efficiently. First, this article discusses some of the reasons for doing an innovation audit; then, it examines a new, facilitated, interactive way of using an innovation audit to achieve/improve high‐involvement innovation in small‐ and medium‐sized enterprises through a learning process.
‘New Governance’ in European Corporate Law Regulation as Transnational Legal Pluralism
Authors: Zumbansen Peer
Published: February 2009

The present transformation of European corporate governance regulation mirrors the challenges that have been facing the EU's continuously evolving polity, marked by tensions between centralised integration programmes, on the one hand, and Member State's embedded capitalisms, path‐dependencies and rent‐seeking, on the other. As longstanding concerns with remaining obstacles to more mobility for workers, services, business entities and capital in recent years are aligned with post‐Lisbon commitments to creating the world's leading competitive market, European corporate governance regulation (ECGR) has become exposed to and implicated in a set of highly dynamic regulatory experiments. In this context, ‘New Governance’ offers itself as both a tentative label and immodest proposal for a more responsive and innovative approach to European law making. The following article assesses the recently emerging regulatory forms in ECGR as illustrations of far‐reaching transformations in market governance. The arguable parallels between the EU's regulatory transformation in response to growing legitimacy concerns and the recurring question about whose interests a business corporation is intended to serve, provide the framework for an exploration of current regulatory trajectories in European corporate law that can most adequately be understood as a telling example of transnational legal pluralism.
Nation‐building and informal politics
Authors: Vine Victor T. Le
Published: February 2009

Among the problems that confront nation‐builders in new states is dealing with their country's informal sector and its politics, manifest not only in the informal economy of markets and hidden transactions, but also its traditional authority systems, networks of patronage, bonds of ethnic and other parochial identities, and illicit activities, including corruption and criminal organisations. Some of these aspects of the informal sector have survived from pre‐independence or colonial periods. Others, like kleptocracy and the criminalisation of the state, are outgrowths of the new state and its leadership cadre. These problems largely arise in the so‐called juridical state, the legal‐rational construct of new statehood, and reflect the failure, or unwillingness of the managers of the new state to move beyond the juridical state to the empirical state, that is, to nationhood and a generalised national identity and citizenship.
Social cohesion in a post‐conflict context: case study of South Africa 12 years on
Authors: Bradshaw Gavin
Published: February 2009

The article focuses on South Africa as an example of a post‐conflict society. It reflects on the levels of social cohesion that might be expected, after a period of deep‐rooted social conflict. Reviewing material from a number of recent surveys carried out in the country from the theoretical perspective of the analytical conflict resolution school, and taking cognisance of a number of recent political events that reveal that real fault‐lines still persist, it leads us to question whether the democratic political settlement achieved in 1994 will prove durable as levels of social tension continue to rise.
Democracy and the political culture orientations of ordinary citizens: a typology for the Arab world and beyond
Authors: Tessler Mark , Gao Eleanor
Published: February 2009

Using recent survey data from Jordan, the Palestinian Territories and Algeria, the authors examine the interrelationship among six normative and behavioural orientations emphasised in the literature on democratic transitions: support for gender equality, tolerance, interpersonal trust, civic participation, political interest and political knowledge. Factor analysis indicates that these orientations form two distinct and independent conceptual clusters, one involving gender equality and tolerance, described as a pluralism dimension; and the other involving interpersonal trust, civic participation, political interest and political knowledge, described as an involvement dimension. The dichotomisation and juxtaposition of these two independent dimensions creates a four‐category typology of the political culture orientations of ordinary citizens: democratic – high on both dimensions; indifferent – high on the pluralism dimension and low on the involvement dimensions; activist – low on the pluralism dimension and high on the involvement dimensions; and parochial – low on both dimensions. In addition to offering this typology as a way to map norms and behaviour patterns that are important for democracy, the study compares the distribution of Jordanian, Palestinian and Algerian citizens across the four categories of political orientation and offers insights about the reasons for differences among the three countries.
Character, civil society and prospects for democracy
Authors: Braun Jerome
Published: February 2009

In this article a framework is developed for comparing a number of present‐day societies in terms of their ability to produce social order and moral character. America is compared with Europe, and then, in less detail, to Latin America and the Islamic world. Reference is also made to Alain Touraine's What is democracy? to show a present‐day French perspective on democracy. The place of the middle class in America and in Europe in providing compromise solutions for their societies is noted, together with the possible relationship between social and political democracy, and how they may converge and diverge. Cultural elements involved in the production of social order are taken into account. Reference is made to the different checks and balances in different societies between the central and local government and local communities, as well as between elites and the masses. This reflects the cultural factors as well as the degree of bureaucratisation of these societies. Finally, there is a summary of various principles of honour governing differing structures of political power derived from the Baron de Montesquieu's The spirit of the laws.
Support for multiculturalism in The Netherlands
Authors: Schalk‐Soekar Saskia R. G. , Breugelmans Seger M. , Van De Vijver Fons J. R.
Published: February 2009

A study on the support for multiculturalism was carried out among 250 members of the majority group in a Dutch city. The concept of multiculturalism was found to be one‐dimensional. The e2nd2orsement of multiculturalism was moderate and varied across domains; the respondents were neutral towards the (dis)approval of cultural diversity and the acculturation strategies of majority group members, positive towards equal societal participation and interaction between majority group members and immigrants, and negative about the acculturation strategies of immigrants. Further, gender, age and income showed no influence on multiculturalism, while education had a positive effect. The present study replicated an earlier study (in 1999) carried out before the murder on Fortuyn (a Dutch politician). The previous and current studies found identical scores on multiculturalism.
Gender‐based violence: a study of Iraqi women
Authors: Lafta Riyadh K. , Al‐Saffar Atheer J. , Eissa Sahar A. , Al‐Nuaimi Maha A.
Published: February 2009

The purpose of this article is to examine and analyse the incidence of violence against women in Iraq. Until recently, gender‐based violence has been viewed in this country as a private or family matter. Nevertheless, there gradually has been a shift in thinking in the past few years on this phenomenon, and it is now viewed as both a public health problem and a violation of human rights. As a first step toward understanding this problem, the authors conducted an experimental analysis of women in Iraq, focusing on gender‐based violence. The results show that violence against women is principally carried out by their husbands and by brothers. The article explains the reasons behind this violent behaviour by analysing a sample survey of 1,000 women and 100 men. The findings show that gender‐based violence is a prevalent medical and social problem in Iraq that requires prompt and in‐depth intervention so as to prevent or at least control it. This study was undertaken in order to understand the possible solutions to prevent gender‐based violence and to change the accepted norms of gender‐based social roles and social tolerance.
Genetic influences on heart rate variability at rest and during stress
Authors: Wang Xiaoling , Ding Xiuhua , Su Shaoyong , Li Zhibin , Riese Harriette , Thayer Julian F. , Treiber Frank , Snieder Harold
Published: February 2009

We tested whether the heritability of heart rate variability (HRV) under stress is different from rest and its dependency on ethnicity or gender. HRV indexed by root mean square of successive differences (RMSSD) and high‐frequency (HF) power was measured at rest and during 3 stressors in 427 European and 308 African American twins. No ethnic or gender differences were found for any measures. There was a nonsignificant increase in heritability of RMSSD (from 0.48 to 0.58) and HF (from 0.50 to 0.58) under stress. Up to 81% and 60% of the heritabilities of RMSSD and HF under stress could be attributed to genes influencing rest levels. The heritabilities due to genes expressed under stress were 0.11 for RMSSD and 0.23 for HF. The findings suggest that, independent of ethnicity and gender, HRV regulation at rest and under stress is largely influenced by the same genes with a small but significant contribution of stress‐specific genetic effects.
Postauricular reflex responses to pictures varying in valence and arousal
Authors: Gable Philip A. , Harmon‐Jones Eddie
Published: February 2009

Reflexes are modulated by emotions. Much research has revealed that the startle reflexive eyeblink response is modulated by emotion, particularly in response to pictures of emotional scenes. Investigations of other reflexes are limited. Recently, research suggested that the postauricular reflex in response to a startling noise was modulated by emotion. In particular, pleasant stimuli enhanced the postauricular reflex. However, these first investigations were limited: One experiment demonstrated only a marginal difference between the pleasant stimuli and neutral stimuli and the other lacked the typical neutral scene comparison. The present experiment was designed to assess whether significant emotion versus neutral differences would occur. Results demonstrated that pleasant stimuli, regardless of arousal level, evoked larger postauricular reflex activation than neutral and unpleasant emotional stimuli.
Concordant up‐regulation of cytochrome P450 Cyp3a11, testosterone oxidation and androgen receptor expression in mouse brain after xenobiotic treatment
Authors: Meyer Ralf Peter , Gehlhaus Marcel , Schwab Ricarda , Bürck Carolin , Knoth Rolf , Hagemeyer Christoph Eugen
Published: February 2009

Inactivation of testosterone by specific hydroxylations is a main function of cytochrome P450 (P450, CYP) in the brain. Recent data imply that induction of brain P450s by neuroactive drugs alters steroid hormone levels and endocrine signalling, giving rise to endocrine disorders. In this study, we investigated this drug–hormone crosstalk in mouse brain. Phenytoin led to a significant increase of 2α‐, 2β‐, 6β‐, 16α‐ and 16β‐hydroxytestosterones, while 6α‐ and 15α‐hydroxytestosterones showed no significant alteration of their metabolism compared with untreated controls. Inhibition of testosterone hydroxylation using the chemical inhibitors orphenadrine, chloramphenicol, ketoconazole and nifedipine as well as antibodies against CYP3A‐ and 2B‐isoforms pointed to major role of Cyp3a11 and an only minor function of Cyp2b9/10 in mouse brain. Cyp3a11 revealed to be the major isoform affected by phenytoin. There was considerable overlap of Cyp3a11 and AR expression in neuronal structures of the limbic system, namely the hippocampus, amygdala, hypothalamus and thalamus. Phenytoin treatment led to an increase of both, Cyp3a11 and AR expression in the limbic system. Additionally, the coherence between CYP3A and AR expression was analysed in PC‐12 cells. Inhibition of phenytoin‐induced endogenous CYP3A2 and AR by ketoconazole led a reduction of their expression to basal levels. We conclude that Cyp3a11 plays a crucial role in directing drug action to hormonal response within the limbic system of mouse brain in a so‐called drug–hormone crosstalk.
Simultaneous single neuron recording of O2 consumption, [Ca2+]i and mitochondrial membrane potential in glutamate toxicity
Authors: Gleichmann Marc , Collis Leon P. , Smith Peter J. S. , Mattson Mark P.
Published: February 2009

In order to determine the sequence of cellular processes in glutamate toxicity, we simultaneously recorded O2 consumption, cytosolic Ca2+ concentration ([Ca2+]i), and mitochondrial membrane potential (mΔψ) in single cortical neurons. Oxygen consumption was measured using an amperometric self‐referencing platinum electrode adjacent to neurons in which [Ca2+]i and mΔψ were monitored with Fluo‐4 and TMRE+, respectively, using a spinning disk laser confocal microscope. Excitotoxic doses of glutamate caused an elevation of [Ca2+]i followed seconds afterwards by an increase in O2 consumption which reached a maximum level within 1–5 min. A modest increase in mΔψ occurred during this time period, and then, shortly before maximal O2 consumption was reached, the mΔψ, as indicated by TMRE+ fluorescence, dissipated. Maximal O2 consumption lasted up to 5 min and then declined together with mΔψ and ATP levels, while [Ca2+]i further increased. mΔψ and [Ca2+]i returned to baseline levels when neurons were treated with an NMDA receptor antagonist shortly after the [Ca2+]i increased. Our unprecedented spatial and time resolution revealed that this sequence of events is identical in all neurons, albeit with considerable variability in magnitude and kinetics of changes in O2 consumption, [Ca2+]i, and mΔψ. The data obtained using this new method are consistent with a model where Ca2+ influx causes ATP depletion, despite maximal mitochondrial respiration, minutes after glutamate receptor activation.
Glutamate‐induced post‐activation inhibition of locus coeruleus neurons is mediated by AMPA/kainate receptors and sodium‐dependent potassium currents
Authors: Zamalloa Teresa , Bailey Christopher P. , Pineda Joseba
Published: February 2009

Background and purpose:  Locus coeruleus (LC) neurons respond to sensory stimuli with a glutamate‐triggered burst of spikes followed by an inhibition. The aim of our work was to characterize the inhibitory effect of glutamate in the LC.

Experimental approach:  Single‐unit extracellular and patch‐clamp recordings were performed to examine glutamate responses in rat brain slices containing the LC.

Key results:  Glutamate caused an initial activation followed by a late post‐activation inhibition (PAI). Both effects were blocked by an AMPA/kainate receptor antagonist but not by NMDA or metabotropic glutamate receptor antagonists. All glutamate receptor agonists were able to activate neurons, but only AMPA and quisqualate caused inhibition. In neurons clamped at −60 mV, glutamate and AMPA induced inward, followed by outward, currents, with the latter reversing polarity at −110 mV. Glutamate‐induced PAI was not modified by α2‐adrenoceptor, µ opioid, A1 adenosine and GABAA/B receptor antagonists or Ca2+‐dependent release blockade, but it was reduced by raising the extracellular K+ concentration. Glutamate‐induced PAI was not affected by several potassium channel, Na+/K+ pump, PKC and neuronal NO synthase inhibitors or lowering the extracellular Ca2+ concentration. The Na+‐activated K channel opener bithionol concentration‐dependently potentiated glutamate‐induced PAI, whereas partial (80%) Na+ replacement reduced glutamate‐ and AMPA‐induced PAI. Finally, reverse transcription polymerase chain reaction assays showed the presence of mRNA for the Ca2+‐impermeable GluR2 subunit in the LC.

Conclusions and implications:  Glutamate induces a late PAI in the LC, which may be mediated by a novel postsynaptic Na+‐dependent K+ current triggered by AMPA/kainate receptors.

Mandarin translation of abstract
Post‐conditioning restores pre‐ischaemic receptor coupling in rat isolated hearts
Authors: Schreckenberg Rolf , Maier Thorsten , Schlüter Klaus‐Dieter
Published: February 2009

Background and purpose:  Ischaemic preconditioning (IPC) and ischaemic post‐conditioning (IPoC) activate signal transduction pathways that are also involved in receptor de‐ and re‐sensitization such as phosphatidylinositol (PI) 3‐kinase. Therefore, IPC and IPoC may affect post‐infarct receptor coupling.

Experimental approach:  Rat isolated hearts (Langendorff mode, constant flow) were exposed to 45 min flow arrest followed by 120 min reperfusion, including IPC or IPoC. Control hearts were perfused without a 45 min flow arrest. Left ventricular developed pressure (LVdevP) was determined. Thirty min after reperfusion, hearts were exposed to parathyroid hormone‐related peptide (PTHrP) or isoprenaline for 10 min to monitor receptor responsiveness. Reperfusion injury was quantified by enzyme release.

Key results:  IPC and IPoC significantly reduced enzyme release compared with ischaemia and reperfusion alone by 75% and 62% respectively. Wortmannin or chelerythrine inhibiting either PI 3‐kinase or protein kinase C, respectively, attenuated protection. Application of PTHrP 30 min after reperfusion did not change LVdevP in hearts exposed to ischaemia (+1 ± 11%), but IPoC restored the normal and non‐ischaemic response to PTHrP characterized by a negative inotropism (−8.3 ± 3.9% and −12.9 ± 6.1%). IPC restored a small negative inotropic effect (−4.4 ± 4.7%). Application of a PTHrP receptor antagonist during the 45 min flow arrest attenuated receptor desensitization (ΔLVdevP: −6.1 ± 1.7%). Wortmannin but not chelerythrine attenuated the re‐sensitizing effect of IPoC on post‐ischaemic receptor coupling (ΔLVdevP: +6.2 ± 10.5 and −15.0 ± 7.7%). As observed with PTHrP receptors, IPoC restored β‐adrenoceptors (ΔLVdevP: +9.3 ± 11.8% vs. 62.3 ± 15.8%).

Conclusions and implications:  IPoC restores PTHrP receptor coupling in a PI 3‐kinase‐dependent way. A similar mechanism may allow β‐adrenoceptor re‐sensitization.
Protopanaxadiol and protopanaxatriol bind to glucocorticoid and oestrogen receptors in endothelial cells
Authors: Leung Kar Wah , Leung Fung Ping , Mak Nai Ki , Tombran‐Tink Joyce , Huang Yu , Wong Ricky NS
Published: February 2009

Background and purpose: Ginsenosides are used widely for medicinal purposes, but the mechanisms of their action are still unclear, although there is some evidence that these effects are mediated by nuclear receptors. Here we examined whether two metabolites of ginsenoside, protopanaxadiol (g‐PPD) and protopanaxatriol (g‐PPT), could modulate endothelial cell functions through the glucocorticoid receptor (GR) and oestrogen receptor (ER).

Experiment approaches: The effects of g‐PPD and g‐PPT on intracellular calcium ion concentration ([Ca2+]i) and nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) were measured using Fura‐2‐acetoxymethyl ester, 4‐amino‐5‐methylamino‐2′,7′‐difluorofluorescein and Griess reagent. Effects on expression of GR and ER isoforms in HUVECs were determined using reverse transcriptase‐/real‐time PCR and immunocytochemistry. Phosphorylation of endothelial NO synthase (eNOS) was assessed by Western blotting.

Results: Ginsenoside protopanaxadiol and g‐PPT increased [Ca2+]i, eNOS phosphorylation and NO production in HUVECs, which were inhibited by the GR antagonist, RU486, the ER antagonist, ICI 182,780 and siRNA targeting GR or ERβ. The NO production was Ca2+‐dependent and the [Ca2+]ielevation in HUVECs resulted from both intracellular Ca2+release and extracellular Ca2+influx.

Conclusions and implications: Ginsenoside protopanaxadiol and g‐PPT were functional ligands for both GR and ERβ, through which these ginsenoside metabolites exerted rapid, non‐genomic effects on endothelial cells.

Mandarin translation of abstract
Pharmacology of α7 nicotinic acetylcholine receptor mediated extracellular signal‐regulated kinase signalling in PC12 cells
Authors: Kouhen R El , Hu M , Anderson DJ , Li J , Gopalakrishnan M
Published: February 2009

Background and purpose: Neuronal nicotinic acetylcholine receptors (nAChR) can modulate cell survival and memory processing. The involvement of specific nAChR subtypes in downstream signalling events has been ill defined thus far, because of a lack of subtype‐selective ligands. In this study, we investigated activation and modulation of α7 nAChR‐mediated phosphorylation of extracellular signal‐regulated kinases (ERK1/2) in PC12 cells, using selective agonists and positive allosteric modulators.

Experimental approach: We used undifferentiated PC12 cells endogenously expressing α7 nAChR for both biochemical and functional studies. ERK phosphorylation changes were measured by using a novel In‐Cell Western procedure. α7 nAChR‐mediated Ca2+signalling was determined by using the fluorometric imaging plate reader assay.

Key results: Robust induction of ERK phosphorylation followed exposure of PC12 cells to the selective agonist PNU‐282987 in the presence of the α7 nAChR modulator PNU‐120596. ERK phosphorylation was transient and was attenuated by the selective antagonist methyllycaconitine. Consistent with allosteric modulation of α7 nAChRs, PNU‐120596 enhanced both the agonist potency and efficacy in activating ERK. Moreover, α7 nAChR agonists could be quantitatively differentiated based on their potency in activating ERK signalling. The rank order of potencies correlated fairly well with the corresponding bindingKivalues of these α7 nAChR agonists.

Conclusions and implications: The present work extends previous observations demonstrating the involvement of α7 nAChRs in ERK1/2 phosphorylation in PC12 cells. The In‐Cell Western procedure allowed a detailed investigation of α7 nAChR function and downstream ERK signalling in response to agonist and allosteric modulators.

Mandarin translation of abstract
Pentameric concatenated (α4)2(β2)3 and (α4)3(β2)2 nicotinic acetylcholine receptors: subunit arrangement determines functional expression
Authors: Carbone A‐L , Moroni M , Groot‐Kormelink P‐J , Bermudez I
Published: February 2009

Background and purpose:  α4 and β2 nicotinic acetylcholine (ACh) receptor subunits expressed heterologously in Xenopus oocytes assemble into a mixed population of (α4)2(β2)3 and (α4)3(β2)2 receptors. In order to express these receptors separately in heterologous systems, we have engineered pentameric concatenated (α4)2(β2)3 and (α4)3(β2)2 receptors.

Experimental approach:  α4 and β2 subunits were concatenated by synthetic linkers into pentameric constructs to produce either (α4)2(β2)3 or (α4)3(β2)2 receptors. Using two‐electrode voltage‐clamp techniques, we examined the ability of the concatenated constructs to produce functional expression in Xenopus oocytes. Functional constructs were further characterized in respect to agonists, competitive antagonists, Ca2+ permeability, sensitivity to modulation by Zn2+ and sensitivity to up‐regulation by chaperone protein 14‐3‐3.

Key results:  We found that pentameric concatamers with a subunit arrangement of β2_α4_β2_α4_β2 or β2_α4_β2_α4_α4 were stable and functional in Xenopus oocytes. By comparison, when α4 and β2 were concatenated with a subunit order of β2_β2_α4_β2_α4 or β2_α4_α4_β2_α4, functional expression in Xenopus oocytes was very low, even though the proteins were synthesized and stable. Both β2_α4_β2_α4_β2 and β2_α4_β2_α4_α4 concatamers recapitulated the ACh concentration response curve, the sensitivity to Zn2+ modulation, Ca2+ permeability and the sensitivity to up‐regulation by chaperone protein 14‐3‐3 of the corresponding non‐linked (α4)2(β2)3 and (α4)3(β2)2 receptors respectively. Using these concatamers, we found that most α4β2‐preferring compounds studied, including A85380, 5I‐A85380, cytisine, epibatidine, TC2559 and dihydro‐β‐erythroidine, demonstrate stoichiometry‐specific potencies and efficacies.

Conclusions and implications:  We concluded that the α4β2 nicotinic ACh receptors produced with β2_α4_β2_α4_β2 or β2_α4_β2_α4_α4 pentameric constructs are valid models of non‐linked (α4)2(β2)3 and (α4)3(β2)2 receptors respectively.
Synthetic and plant‐derived cannabinoid receptor antagonists show hypophagic properties in fasted and non‐fasted mice
Authors: Riedel Gernot , Fadda Paola , McKillop‐Smith Susan , Pertwee Roger G , Platt Bettina , Robinson Lianne
Published: February 2009

Background and purpose:  Obesity is a severe health problem in the modernized world and understanding the central nervous mechanisms underlying food‐seeking behaviour and reward are at the forefront of medical research. Cannabinoid receptors have proven an efficient target to suppress hunger and weight gain by their pharmacological inactivation.

Experimental approach:  A standard fasted protocol and a novel long‐term home‐cage observation system with free‐feeding animals were used to assess the feeding behaviour of mice treated with the CB1 antagonist AM251. Similarly, the effects of the phytocannabinoid Δ9‐tetrahydrocannabivarin (Δ9‐THCV), which behaves like a CB1 antagonist, were also determined in free‐feeding animals.

Key results:  AM251 suppressed food intake and weight gain in fasted and non‐fasted animals. The suppression of food intake by AM251 (10 mg·kg−1) endured for a period of 6–8 h when administered acutely, and was continuous when injected for four consecutive days. Pure Δ9‐THCV also induced hypophagia and weight reduction at doses as low as 3 mg·kg−1. No rebound was observed on the following day with all drug groups returning to normal activity and feeding regimes. However, a Δ9‐THCV‐rich cannabis‐extract failed to suppress food intake and weight gain, possibly due to residual Δ9‐tetrahydrocannabinol (Δ9‐THC) in the extract. This Δ9‐THC effect was overcome by the co‐administration of cannabidiol.

Conclusions and implications:  The data strongly suggest (i) the long‐term home‐cage observation system is a sensitive and obesity‐relevant tool, and (ii) the phytocannabinoid Δ9‐THCV is a novel compound with hypophagic properties and a potential treatment for obesity.
Quantitative analysis of the loss of muscarinic receptors in various peripheral tissues in M1–M5receptor single knockout mice
Authors: Ito Yoshihiko , Oyunzul Luvsandorj , Seki Masanao , Fujino (Oki) Tomomi , Matsui Minoru , Yamada Shizuo
Published: February 2009

Background and purpose: To compare loss in binding to muscarinic receptor (mAChR) subtypes with their known functions, the total density of muscarinic receptors was measured in peripheral tissues from wild type (WT) and mAChR knockout (KO) mice.

Experimental approach: Binding parameters of [N‐methyl‐3H]scopolamine methyl chloride ([3H]NMS) were determined in 10 peripheral tissues of WT and M1–M5receptor KO mice. Competition between [3H]NMS and darifenacin (selective M3receptor antagonist) was also measured

Key results: There was an extensive loss of [3H]NMS‐binding sites (maximal number of binding sites,Bmax) in heart and smooth muscle from M2KO mice, compared with WT mice. Smooth muscle from M3KO mice also showed a moderate loss ofBmax.Bmaxfell in pancreas and bladder of M4KO mice and in prostate in M1KO and M3KO mice. There was a large loss ofBmaxin exocrine and endocrine glands of M3KO mice with a moderate decrease in M2KO mice. Darifenacin inhibited specific [3H]NMS binding in submandibular gland and bladder of WT, M2KO and M3KO mice.Ki(inhibition constant) values for darifenacin in the submandibular gland were the same in WT and M2KO mice but increased in M3KO mice. However,Kivalues in bladder were decreased in M2KO mice and increased in M3KO mice.

Conclusions and implications: Single mAChR KO mice exhibit a loss of mAChR in peripheral tissues that generally paralleled the reported loss of function. Quantitative analysis of data, however, also suggested that, in some instances, normal expression of a receptor subtype depended on expression of other subtypes.
Roles of purines in synaptic modulation evoked by hypercapnia in isolated spinal cord of neonatal ratin vitro
Authors: Otsuguro K , Ban M , Ohta T , Ito S
Published: February 2009

Background and purpose: The purine compounds, adenosine 5′‐triphosphate (ATP) and adenosine, are known to accumulate in the extracellular space and to elicit various cellular responses during hypoxia/ischemia, whereas the roles of purines during hypercapnia are poorly understood. In this study, we examined the effects of various drugs affecting purine turnover on the responses to hypercapnia in the spinal cord.

Experimental approach: Electrically evoked reflex potentials were measured in anin vitropreparation of the isolated spinal cord of the neonatal rat by extracellular recording. Extracellular adenosine concentrations were assayed by high performance liquid chromatography (HPLC) methods.

Key results: Hypercapnia (20% CO2) depressed the reflex potentials, which were partially reversed by an adenosine A1receptor antagonist, 8‐cyclopentyl theophylline, but not by a P2 receptor antagonist, pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid. Exogenous adenosine and ATP also depressed the reflex potentials via adenosine A1receptors. The hypercapnia‐evoked depression was not reversed by inhibitors of gap junction hemichannels, anion channels, P2X7receptors or equilibrative nucleoside transporters, all of which might be involved in purine efflux pathways. The adenosine accumulation evoked by hypercapnia was not inhibited by tetrodotoxin, ethylene glycol‐bis(β‐amino ethyl ether) tetraacetic acid (EGTA) or an ecto‐ATPase inhibitor, ARL 67156. Homocysteine thiolactone, used to trap intracellular adenosine, significantly reduced extracellular adenosine accumulation during hypercapnia.

Conclusions and implications: These results suggest that hypercapnia released adenosine itself from intracellular sources, using pathways different from the conventional exocytotic mechanism, and that this adenosine depressed spinal synaptic transmission via adenosine A1receptors.
Effect of tumour necrosis factor‐α and irradiation alone or in combination on the viability of hepatocellular and biliary adenocarcinoma cell lines in vitro
Authors: Qesaraku Blendi , Dudas Joszef , Rave‐Fränk Margret , Hess Clemens Friedrich , Ramadori Giuliano , Saile Bernhard , Christiansen Hans
Published: February 2009

Background: Tumour necrosis factor α (TNF‐α) may exhibit antitumoral activity and can influence the reaction of both tumour and normal tissue to radiation.

Aims: To test the effect of TNF‐α and/or irradiation on hepatocellular (HepG2, Hep3B, Sk‐Hep1, HuH7) and cholangiocellular (Sk‐chA1, Mz‐chA1) tumour cell lines.

Methods: Colony formation, apoptosis analysis and trypan blue exclusion were used to assess cell viability. Doses of radiation (2–25 Gy) and TNF‐α (100–50 000 U) as well as their respective sequencing were varied (24 and 12 h before and 6 h after). The expression of TNF‐α and TNF receptors 1/2 was determined using real‐time polymerase chain reaction and IκBα protein expression was detected by Western blot.

Results: Sole irradiation induced a reduction in colony formation in all cell lines and sole TNF‐α in HepG2 and Sk‐chA1 cells only. No difference in apoptosis induction after TNF‐α or irradiation was observed. Cellular death induced by the combination of TNF‐α and radiation was not superior to the use of any of the two agents alone. All cell lines revealed that radiation induced upregulation of TNF‐α whereas the extent of TNF receptor‐specific transcription did not change. Furthermore, radiation‐induced changes in IκBα expression were not detectable.

Conclusions: Our data suggest that both TNF‐α and radiation may be treatment options for hepatocellular and cholangiocellular carcinomas. Because TNF‐α and radiation do not interact in terms of radiosensitization, anti‐TNF‐α treatment may have the potential to protect against hepatocellular injury after abdominal irradiation. However, further in vivo studies are needed to confirm that anti‐TNF‐α treatment does not compromise tumour control and actually attenuates radiation‐induced liver injury.
Genotoxic Hazard and Cellular Stress in Pediatric Patients Treated for Psoriasis with the Goeckerman Regimen
Authors: Borska Lenka , Andrys Ctirad , Krejsek Jan , Hamakova Kvetoslava , Kremlacek Jan , Ettler Karel , Vellappally Sajith , Vimal Jacob , Fiala Zdenek
Published: February 2009

Abstract:  The Goeckerman regimen (GR) represents a local treatment of psoriasis and includes topical dermal application of crude coal tar (containing polycyclic aromatic hydrocarbons) and exposure to UV‐irradiation. The aim of the study was to evaluate contribution of GR to genotoxic risk and cellular stress in pediatric patients who represent a sensitive population subgroup. Genotoxic risk (42 patients) was evaluated by using chromosomal aberrations (CA) in peripheral lymphocytes. Cellular stress (26 patients) was assessed by using heat shock proteins (Hsp70). All indicators were determined in blood samples collected before GR and immediately after GR. Decreasing of psoriasis area and severity index (PASI) score indicated higher likelihood of GR (p < 0.001). Significantly increased CA (p < 0.001) and Hsp70 (p < 0.05) indicated higher genotoxic risk and cellular stress in sensitive pediatric patients, immediately after GR.
The Spectrum of Skin Disease Among Indian Children
Authors: Sardana Kabir , Mahajan Supriya , Sarkar Rashmi , Mendiratta Vibhu , Bhushan Premanshu , Koranne R. V. , Garg Vijay K.
Published: February 2009

Abstract:  Skin diseases in children are encountered frequently and their characterization is essential for the preparation of academic, research and health plans. A retrospective study was designed to evaluate the epidemiologic features of pediatric dermatoses in India. The setting was a tertiary care referral center in India (Kalawati Saran Children’s Hospital, New Delhi) during January 1997 to December 2003. A total of 30,078 children less than 12 years of age with 32,341 new dermatoses were recorded, with a male to female ratio of 1.07:1. Most of the disease was seen in the 1‐ to 5‐year age group (44.94%). The most common skin diseases were infections and infestations (47.15%) consisting of bacterial infections (58.09%) and scabies (21.54%), followed by eczemas (26.95%), infantile seborrheic dermatitis, scabies, and pityriasis alba. Other unique dermatoses in our settings were papular uticaria (3.59%), miliaria (5.46%), postinflammatory pigmentary abnormalities (1.68%), and nutritional deficiency dermatoses (0.45%). A majority of patients were diagnosed clinically and special diagnostic tests were conducted in 2.6% of patients. The most common diagnostic test used was KOH mount (59.2%), followed by skin biopsy (39%). Nearly 90% of patients were seen without any referral and in the remaining, a majority were referred by pediatricians (75%). A majority of patients were diagnosed to have infection followed by dermatitis in our setting.
Childhood Linear IgA Bullous Dermatosis in Tunisia
Authors: Kenani Nesrine , Mebazaa Amel , Denguezli Mohamed , Ghariani Najet , Sriha Badreddine , Belajouza Colandane , Nouira Rafia
Published: February 2009

Abstract:  The objective was to determine the demographic characteristics, the clinical features, the immuno‐histological findings and response to treatment of childhood linear IgA bullous dermatosis (LABD) in Tunisia. We collected all the cases of auto‐immune bullous diseases of childhood, diagnosed from January 1987 to December 2006. Based on clinical, histological, and immunofluorescent features, we identified 25 cases of LABD. Sixteen male and nine female children with a mean age of 7.5 years were identified. Clinical manifestations were characterized by a vesiculo‐bullous eruption in all cases associated with mucous membrane involvement in two cases. Dapsone was the main therapy in 19 cases, associated with systemic corticosteroids in eight cases. Exclusive antibiotic therapy was successful in five cases. Sixteen of those patients had resolution of disease after a mean period of 15 months and eight patients had severe clinical presentation and required a prolonged follow‐up. Childhood LABD is the most frequent bullous dermatosis in Tunisia. The majority of our patients responded rapidly to dapsone treatment and were stabilized for long time. Our cases were characterized by a minimal mucosal involvement and favorable outcome. Treatment with antibiotherapy was interesting. Erythromycin and oxacillin may be considered as an alternative therapy.
A Case of Juvenile Bullous Pemphigoid— Successful Treatment with Diaminodiphenylsulfone and Prednisone
Authors: Marcus Karen A. , Halbertsma Feico J. J. , Van Steensel Maurice A. M.
Published: February 2009

Abstract:  Blistering skin diseases can be difficult to diagnose, particularly in children. Because of the wide variety of bullous disorders and the considerable clinical overlap between them, it is difficult to differentiate one from the other on clinical features alone. Appropriate additional investigations are required to confirm the diagnosis. These include routine histologic examination of the skin, in addition to immunohistochemical staining and immune serology. Here, we present a rare case of juvenile bullous pemphigoid, which we will use to illustrate the difficulties encountered in the diagnostic process and to show how acquired blistering disorders of childhood should be approached.
Profuse Congenital Milia in a Family
Authors: Rutter Kirsty J. , Judge Mary R.
Published: February 2009

Abstract:  Milia are keratin containing dermal cysts and are seen very frequently in neonates. They generally resolve spontaneously within the first few months of life. However, the presence of congenital milia may also be associated with a number of inherited disorders. We present a family with congenital milia and no other associated abnormalities in whom the milia were profuse and more persistent than usual. A number of inherited disorders which may be associated with the presence of milia are also discussed.
Idiopathic Infantile Pyoderma Gangrenosum with Stridor Responsive to Infliximab
Authors: Rajan Neil , Das Sharmila , Taylor Aileen , Abinun Mario , Spencer David , Carmichael Andrew
Published: February 2009

Abstract:  A 4‐month‐old female infant presented with widespread pyoderma gangrenosum associated with stridor, presumed secondary to tracheal involvement. No underlying cause was revealed despite extensive investigation. Treatment with immunosuppressive agents only partially suppressed disease activity. Complete resolution followed treatment with infliximab. We review this rare condition in infants and discuss treatment with infliximab not previously described in this age group.
Incontinentia Pigmenti with a Foreshortened Hand: Evidence for the Significance of NFκB in Human Morphogenesis
Authors: Kmetz Emily C. , Shashidhar Pai Gurpur , Burges Gene E.
Published: February 2009

Abstract:  The X‐linked disorder incontinentia pigmenti (IP) with its well‐defined underlying defect in the NFκB essential modulator (NEMO) gene and its variability in patients' phenotypes offers an excellent opportunity for expanding knowledge of the function of the NFκB pathway. We report a patient with the classic clinical and histologic characteristics of incontinentia pigmenti in the skin accompanied by foreshortening of the left hand. The occurrence of this limb deformity associated with a reduced expression of NFκB confirms the importance of this transcription factor in normal limb morphogenesis and may support its involvement in sonic hedgehog signaling. Further studies in established animal models may help to further define these roles.
A Population‐based Study of Toenail Onychomycosis in Israeli Children
Authors: LEIBOVICI VERA , EVRON RUTH , DUNCHIN MILKA , WESTERMAN MARIA , INGBER ARIEH
Published: February 2009

Abstract:  Onychomycosis is widespread in the adult population, but considered to be rare in children. A number of studies in recent years show a rise in the prevalence of toenail onychomycosis in children. Of these, only a few were population‐based. Here, we present a comprehensive cross‐sectional population‐based survey of toenail onychomycosis in primary school children in Israel. The survey included 1148 children, 598 boys, and 550 girls aged 5 to 14 from primary schools in the Jerusalem vicinity. Each child underwent a physical examination and completed a personal questionnaire, which provided background information of predisposing factors. The survey shows a prevalence of 0.87% of toenail onychomycosis. Although this figure is too small for statistical analysis, some important conclusions could be drawn: prevalence increased with age: boy/girl ratio was 2.2; the dominant etiologic agent was Trichophyton rubrum followed by Trichophyton mentagrophytes and Candida albicans. Infections were probably transferred from adults via the environment to children. Infected children came from different socio‐economic backgrounds. This condition should be considered in the differential diagnosis of nail diseases in children.
Generalized Lichen Nitidus, with Perioral and Perinasal Accentuation, in Association with Down Syndrome
Authors: HENRY MICHELLE , METRY DENISE W.
Published: February 2009

Abstract:  Generalized cases of lichen nitidus are rare, but have been infrequently reported in association with Down syndrome. We report the third such case, with unusual perioral and perinasal accentuation.
Two Pediatric Cases of Primary Cutaneous B‐cell Lymphoma and Review of the Literature
Authors: Sharon Victoria , Mecca Patricia S. , Steinherz Peter G. , Trippett Tanya M. , Myskowski Patricia L.
Published: February 2009

Abstract:  Primary cutaneous lymphomas are rare in the pediatric population and most often represent mycosis fungoides or CD30+ lymphoproliferative disorders. Primary cutaneous B‐cell lymphoma has rarely been reported in children, and in the past may have been mistaken for disseminated nodal disease or benign cutaneous lymphoid hyperplasias. We describe two cases of marginal zone primary cutaneous B‐cell lymphoma in young males. Thus far both have been managed with local therapy. We review the literature of this rare malignancy.
A Distinct Type of Palmoplantar Keratoderma
Authors: MOHAMMAD ALI MAPAR , AZARBAIK M.
Published: February 2009

Abstract:  Palmoplantar keratodermas (PPK) are a diverse group of disorders. We report a boy with PPK, grayish‐blue hyperkeratotic lesions on the lips and peri‐oral area, opacities on the lower portions of the corneas, mutilation of his right auricle and many other skin lesions.
Systemic therapy as a first choice treatment for idiopathic granulomatous mastitis
Authors: Maffini Fausto , Baldini Federica , Bassi Fabio , Luini Alberto , Viale Giuseppe
Published: February 2009

Idiopathic granulomatous mastitis clinically and histologically mimics an inflammatory carcinoma. A correct approach including ultrasound, clinical and histological analysis can safely identify a patient with this pathology, orienting to adequate therapy with anti‐inflammatory and antibiotic drugs and leaving the surgical approach only for case unresponsive to medical therapy.
Primary giant cell tumor of soft tissue of the groin – a case of 46 years duration
Authors: Boneschi Vinicio , Parafioriti Antonina , Armiraglio Elisabetta , Gaiani Francesca , Brambilla Lucia
Published: February 2009

Background: Soft tissue giant cell tumor (GCT‐ST) of low malignant potential is an uncommon neoplasm, considered the soft tissue counterpart of giant cell tumor of bone. GCT‐ST mainly affects young to middle‐age adults and presents as a painless growing mass mainly located in the lower extremities and trunk. Histologically, this tumor is characterized by a mixture of uniformly scattered osteoclast‐like multinucleated giant cells intimately admixed with short fascicles of spindled cells. Complete excision with negative surgical margins is associated with a benign clinical course in most cases.

Methods: The authors report the clinicopathological and immunohistochemical features of an unusual GCT‐ST of 46 years duration previously histologically misdiagnosed as Kaposi's sarcoma.

Results: Histologically, the tumor was characterized by a multinodular growth pattern with osteoclast‐like multinucleated giant cells admixed with spindle cells partially arranged in a storiform pattern, fibrosis and foci of haemorrhage and mature bone. Immunohistochemistry revealed CD68 reactivity of the multinucleated giant cells.

Conclusion: GCT‐ST is a rare neoplasm characterized by benign clinical course if excised adequately, as shown by our case of exceptionally long duration. Emphasis is placed on the importance of differential diagnosis with other giant cell‐rich soft tissue neoplasms because clinical behaviour, prognosis and treatment significantly differ.