bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing a Public Interest School of Management
Authors: Ferlie Ewan , McGivern Gerry , De Moraes Ailson
Published: February 2010

This ‘think piece’ paper contributes to the recent ‘business school business’ debate by examining whether an alternative form of the business school – specifically, the public interest model – can be created. Current criticisms of conventional business schools are reviewed and alternative models explored. We take some examples from our own field of health management research. We define the public interest school model in more detail than in previous accounts and compare and contrast it with other models of the reformed business school. We identify certain conditions in which this form is more likely to succeed and suggest a future empirical research agenda.
Fetal Genotype for the Xenobiotic Metabolizing Enzyme NQO1 Influences Intrauterine Growth Among Infants Whose Mothers Smoked During Pregnancy
Authors: Price Thomas S. , Grosser Tilo , Plomin Robert , Jaffee Sara R.
Published: February 2010

Maternal smoking during pregnancy retards fetal growth and depresses infant birth weight. The magnitude of these effects may be moderated by fetal genotype. The current study investigated maternal smoking, fetal genotype, and fetal growth in a large population sample of dizygotic twins. Maternal smoking retarded fetal growth in a dose‐dependent fashion. In a subsample of 497 twin pairs whose mothers smoked during pregnancy, a functional polymorphism in the NAD(P)H:quinone oxidoreductase gene (NQO1 Pro187Ser; rs1800566) was significantly associated with fetal growth within families. The effect was strongest among moderate smokers. This is the first demonstration that fetal genotype for an enzyme involved in tobacco smoke metabolism influences intrauterine growth independent of maternal genotype. Future studies should conduct formal tests of Fetal Genotype × Maternal Smoking interactions.
Frontal Electroencephalogram Asymmetry, Salivary Cortisol, and Internalizing Behavior Problems in Young Adults Who Were Born at Extremely Low Birth Weight
Authors: Schmidt Louis A. , Miskovic Vladimir , Boyle Michael , Saigal Saroj
Published: February 2010

The authors examined internalizing behavior problems at middle childhood, adolescence, and young adulthood and brain‐based measures of stress vulnerability in 154 right‐handed, nonimpaired young adults (M age = 23 years): 71 (30 males, 41 females) born at extremely low birth weight (ELBW; < 1,000 g) and 83 (35 males, 48 females) controls born at normal birth weight (NBW). Internalizing behavior problems increased from adolescence to young adulthood among ELBW individuals. ELBW adults exhibited greater relative right frontal electroencephalogram activity at rest and more concurrent internalizing behavior problems than NBW controls. Being born at ELBW may have subtle influences on brain–behavior relations even in survivors without major impairments and evidence of these influences may not emerge until young adulthood.
The Differential Impacts of Early Physical and Sexual Abuse and Internalizing Problems on Daytime Cortisol Rhythm in School‐Aged Children
Authors: Cicchetti Dante , Rogosch Fred A. , Gunnar Megan R. , Toth Sheree L.
Published: February 2010

The impact of early physical and sexual abuse (EPA/SA) occurring in the first 5 years of life was investigated in relation to depressive and internalizing symptomatology and diurnal cortisol regulation. In a summer camp context, school‐aged maltreated (n = 265) and nonmaltreated (n = 288) children provided morning and late afternoon saliva samples on 5 consecutive days. Child self‐report and adult observer reports of child internalizing and depressive symptoms were obtained. Children experiencing EPA/SA and high depressive or internalizing symptoms uniquely exhibited an attenuated diurnal decrease in cortisol, indicative of neuroendocrine dysregulation. These results were specific to EPA/SA rather than later onset physical or sexual abuse or early occurring neglect or emotional maltreatment.
Biological Sensitivity to Context: The Interactive Effects of Stress Reactivity and Family Adversity on Socioemotional Behavior and School Readiness
Authors: Obradović Jelena , Bush Nicole R. , Stamperdahl Juliet , Adler Nancy E. , Boyce W. Thomas
Published: February 2010

This study examined the direct and interactive effects of stress reactivity and family adversity on socioemotional and cognitive development in three hundred and thirty‐eight 5‐ to 6‐year‐old children. Neurobiological stress reactivity was measured as respiratory sinus arrhythmia and salivary cortisol responses to social, cognitive, sensory, and emotional challenges. Adaptation was assessed using child, parent, and teacher reports of externalizing symptoms, prosocial behaviors, school engagement, and academic competence. Results revealed significant interactions between reactivity and adversity. High stress reactivity was associated with more maladaptive outcomes in the context of high adversity but with better adaption in the context of low adversity. The findings corroborate a reconceptualization of stress reactivity as biological sensitivity to context by showing that high reactivity can both hinder and promote adaptive functioning.
Written narrations by 8‐ to 10‐year‐old Turkish pupils in Flemish primary education: A follow‐up of seven text features
Authors: Verheyden Lieve , Van den Branden Kris , Rijlaarsdam Gert , Van den Bergh Huub , De Maeyer Sven
Published: February 2010

This semi‐longitudinal study examined the development of narrative writing quality of young Turkish second language learners in mainstream Dutch‐only education, and the impact of student‐level and classroom‐level predictors of narrative writing quality, using hierarchical linear modelling. Writing samples of 106 third graders and 111 fourth graders of seven Flemish primary schools were collected at the beginning and at the end of the school year. Measures included one holistic primary trait judgement, and six objective indices of text quality. Student‐level predictors included age, SES and home language, while the classroom‐level predictor focused on the home language pattern of the classroom. There was a significant mean growth for each index in each grade, but effect sizes differed from quite large for content and word level indices over moderate for sentence level indices to small for the text level index. Home language (Turkish) had a significant negative effect on all but one variables, particularly in Grade 4, while the negative effect of low SES was much more limited. A supplementary negative effect was found for homogeneity of classroom population. Implications of the study highlight the importance of student and classroom characteristics in writing achievement as well as the need to consider the poor performance of Turkish children.
Second and fourth graders' copying ability: from graphical to linguistic processing
Authors: Grabowski Joachim , Weinzierl Christian , Schmitt Markus
Published: February 2010

Particularly in primary school, good performance on copy tasks is an important working technique. With respect to writing skills, copying is a very basic process on which more complex writing abilities are based. We studied the copying ability of second and fourth graders across four types of symbols which vary with respect to their semantic and phonological characteristics: arbitrary graphical objects, unpronounceable consonant strings, numerals and meaningful text. Results show, in terms of average copying speed, significant effects of both factors: fourth graders performed generally faster than second graders, and for both class levels, the number of copied characters per time decreased from meaningful text to graphical objects, all pair‐wise contrasts between symbol types being statistically significant. Moreover, a significant interaction shows that fourth graders improved more when copying symbols that form pronounceable chunks, namely meaningful text and numerical strings. This indicates an increasing role of phonological (and probably also semantic) processes involved in copying across primary school.
Undergraduate students' ability to revise text effectively: relationships with topic knowledge and working memory
Authors: Adams Anne‐Marie , Simmons Fiona , Willis Catherine , Pawling Ralph
Published: February 2010

In order to communicate understanding, students are often required to produce texts which present an explicit, coherent argument. This study examined the extent to which individual differences in undergraduates' topic knowledge and working memory skills were related to their ability to revise texts to better fulfil these goals. Forty‐seven students revised texts containing three types of error: language, structure and argument. Topic knowledge was indexed by multiple choice test performance. Verbal short‐term and working memory were measured using forward and backward digit recall and reading span. Rates of identification, diagnosis and correction of errors were generally poor. Contrary to expectations neither topic knowledge nor verbal working memory was associated with text revision although significant associations were identified with verbal short‐term memory. When revising texts students may focus on the surface features of the text rather than addressing issues of structure and argument. Possible accounts of this tendency are considered.
Combining knowledge from different sources
Authors: Straszecka Ewa
Published: February 2010

Abstract:The present paper deals with the problem of an assessment of symptoms in medical diagnosis. A unified interpretation of symptoms is necessary to estimate their significance in a diagnosis. Yet, even if they are properly defined, different evaluations of them based on experts' knowledge or statistical estimation are possible. The present study aims at combining evaluations that may originate from an expert or can be found from statistical features of the data, as well as those determined for ‘easy’ and ‘difficult’ diagnostic cases. A model of diagnostic inference is proposed in the framework of the Dempster–Shafer theory extended for fuzzy focal elements. The basic probability assignment defined in this theory estimates weights of symptoms. Two basic probability assignments can be created and then combined. In this way weights of symptoms represent knowledge common for two kinds of data or obtained from an expert and from data. Thus, a combination of heuristics and data mining results becomes possible. An algorithm of the basic probability assignment calculation is suggested and tested for medical data: a database from the internet and individually gathered data.
Open architecture computer‐aided diagnosis system
Authors: Pietka Ewa , Kawa Jacek , Badura Pawel , Spinczyk Dominik
Published: February 2010

Abstract: In this study an approach to open architecture computer‐aided diagnosis (CAD) is presented. The traditional goal of a CAD system, to assist the physicians in performing the diagnosis and treatment, has been extended. The platform also supports the system designer in developing a new CAD workflow by implementing general‐purpose modules as well as problem‐dependent procedures. A new CAD may require new procedures to be added, yet some of the already implemented functions can be employed. The CAD environment is subjected to the developmental process of three systems: the multiple sclerosis CAD, the lung nodule CAD and the pneumothorax CAD. Modules and procedures are briefly described and the CAD systems are evaluated. Results obtained during the CAD evaluation show prospective flexibility of the infrastructure. The trade‐offs, well known to CAD designers, can easily be handled by the operators in a user‐friendly manner by choosing various workflow paths.
Human–machine interface in bioprosthesis control using EMG signal classification
Authors: Wołczowski Andrzej , Kurzyński Marek
Published: February 2010

Abstract:We present a concept of human–machine interface intended for the task of bioprosthesis decision control by means of sequential recognition of the patient's intent based on the electromyography (EMG) signal acquired from his/her body. The EMG signal characteristics, the problem of processing the signals including acquisition and feature extraction and their classification are discussed. The contextual (sequential) recognition via fuzzy relations for the classification of the patient's intent is considered and the implied decision algorithms are presented. In the proposed method, the fuzzy relation is determined on the basis of the learning set as a solution of an appropriate optimization problem and then this relation is used in the form of a matrix of membership degrees at successive instants of the sequential decision process. Three algorithms of sequential classification which differ from one another in the sets of input data and procedure are described. The proposed algorithms were experimentally tested in the recognition of phases of the grasping process of the hand on the basis of the EMG signal, where the real‐coded genetic algorithm was used as an optimization procedure. The concept of the measurement stand which was the source of information exploited in the experimental investigations of the algorithms is also described.
An iris recognition approach through structural pattern analysis methods
Authors: Proença Hugo
Published: February 2010

Abstract: Continuous efforts have been made to improve the robustness of iris coding methods since Daugman's pioneering work on iris recognition was published. Iris recognition is at present used in several scenarios (airport check‐in, refugee control etc.) with very satisfactory results. However, in order to achieve acceptable error rates several imaging constraints are enforced, which reduce the fluidity of the iris recognition systems. The majority of the published iris recognition methods follow a statistical pattern recognition paradigm and encode the iris texture information through phase, zero‐crossing or texture‐analysis based methods. In this paper we propose a method that follows the structural (syntactic) pattern recognition paradigm. In addition to the intrinsic advantages of this type of approach (intuitive description and human perception of the system functioning), our experiments show that the proposed method behaves comparably to the statistical approach that constitutes the basis of nearly all deployed systems.
Functional and physical interactions between formyl‐peptide‐receptors and scavenger receptor MARCO and their involvement in amyloid beta 1–42‐induced signal transduction in glial cells
Authors: Brandenburg Lars‐Ove , Konrad Maximilian , Wruck Christoph J. , Koch Thomas , Lucius Ralph , Pufe Thomas
Published: February 2010

J. Neurochem. (2010) 113, 749–760.

Recent studies suggest that the chemotactic G protein‐coupled receptor formyl‐peptide‐receptor‐like‐1 (FPRL1) or the scavenger receptor MARCO (macrophage receptor with collagenous structure) plays an essential role in the inflammatory response of host defense mechanisms and neurodegenerative disorders such as Alzheimer’s disease. We therefore analyzed the involvement of FPRL1 and MARCO in amyloid β1–42 (Aβ1–42)‐induced signalling by extracellular‐signal regulated kinases 1/2 (ERK1/2) phosphorylation and cAMP level measurement in glial cells (astrocytes and microglia) and in transfected HEK293 cells. Receptors were inhibited by small interference RNA and the consequences in Aβ1–42‐ and MARCO agonist fucoidan‐induced signal transduction were determined. Receptor deactivation by antagonists or small interference RNA verified the importance of FPRL1 for Aβ1–42‐mediated signal transduction by ERK1/2 phosphorylation and cAMP level measurement in glial cells. Furthermore, for the first time, we have demonstrated a functional interaction between FPRL1 and scavenger receptors in fucoidan‐mediated signalling by ERK1/2 phosphorylation and cAMP level measurement. In addition, co‐immunoprecipitation data and fluorescence microscopy measurements revealed a physical interaction between FPR, FPRL1 and MARCO. These results suggest that FPRL1 plays a pivotal role for Aβ1–42‐induced signal transduction in glial cells and the interaction with MARCO could explain the broad ligand spectrum of formyl peptide receptors.
Dynamic monitoring of NET activity in mature murine sympathetic terminals using a fluorescent substrate
Authors: Parker Lauren K , Shanks Julia A , Kennard James AG , Brain Keith L
Published: February 2010

Background and purpose: To validate a fluorescence approach for monitoring norepinephrine transporter (NET) transport rate in mature sympathetic terminals, and to determine how prejunctional muscarinic receptors affect NET rate.

Experimental approach: Confocal imaging of a fluorescent NET substrate [neurotransmitter transporter uptake assay (NTUA)] as it accumulates in the mature sympathetic nerve terminals of the mouse isolated vas deferens. Fluorescence recovery after photobleaching (FRAP), enhanced green fluorescence protein (EGFP)‐transgenic mice and contraction studies were also used.

Key results: NTUA fluorescence accumulated linearly in nerve terminals, an effect that was prevented with NET inhibition with desipramine (1 µM). Such accumulation was reversed by amphetamine (10 µM), which is known to reverse the direction of transport of NET substrates. NTUA labelling was not present in cholinergic terminals (identified using EGFP fluorescence expressed in transgenic mice under a choline acetyltransferase promoter). FRAP experiments, altered nerve terminal distribution with reserpine pretreatment and co‐imaging in terminals filled with a cytoplasmic marker (Alexa 594 dextran) indicated that the NTUA labelling was largely confined to vesicles within varicosities; vesicular exchange between varicosities was rare. The rate of NTUA accumulation was slower in the presence of the muscarinic agonist carbachol (10 µM) demonstrating muscarinic inhibition of NET rate.

Conclusions and implications: A straightforward protocol now exists to monitor NET transport rate at the level of the single nerve terminal varicosity, providing a useful tool to understand the physiology of NET regulation, the action of NET inhibitors on mature sympathetic terminals, dynamic vesicular tracking and to identify sympathetic terminals from mixed terminal populations in living organs.

This article is part of a themed section on Imaging in Pharmacology. To view the editorial for this themed section visithttp://dx.doi.org/10.1111/j.1476‐5381.2010.00685.x
A role for transient receptor potential vanilloid 4 in tonicity‐induced neurogenic inflammation
Authors: Vergnolle N , Cenac N , Altier C , Cellars L , Chapman K , Zamponi GW , Materazzi S , Nassini R , Liedtke W , Cattaruzza F , Grady EF , Geppetti P , Bunnett NW
Published: February 2010

Background and purpose:  Changes in extracellular fluid osmolarity, which occur after tissue damage and disease, cause inflammation and maintain chronic inflammatory states by unknown mechanisms. Here, we investigated whether the osmosensitive channel, transient receptor potential vanilloid 4 (TRPV4), mediates inflammation to hypotonic stimuli by a neurogenic mechanism.

Experimental approach:  TRPV4 was localized in dorsal root ganglia (DRG) by immunofluorescence. The effects of TRPV4 agonists on release of pro‐inflammatory neuropeptides from peripheral tissues and on inflammation were examined.

Key results:  Immunoreactive TRPV4 was detected in DRG neurones innervating the mouse hindpaw, where it was co‐expressed in some neurones with CGRP and substance P, mediators of neurogenic inflammation. Hypotonic solutions and 4α‐phorbol 12,13‐didecanoate, which activate TRPV4, stimulated neuropeptide release in urinary bladder and airways, sites of neurogenic inflammation. Intraplantar injection of hypotonic solutions and 4α‐phorbol 12,13‐didecanoate caused oedema and granulocyte recruitment. These effects were inhibited by a desensitizing dose of the neurotoxin capsaicin, antagonists of CGRP and substance P receptors, and TRPV4 gene knockdown or deletion. In contrast, antagonism of neuropeptide receptors and disruption of TRPV4 did not prevent this oedema. TRPV4 gene knockdown or deletion also markedly reduced oedema and granulocyte infiltration induced by intraplantar injection of formalin.

Conclusions and implications:  Activation of TRPV4 stimulates neuropeptide release from afferent nerves and induces neurogenic inflammation. This mechanism may mediate the generation and maintenance of inflammation after injury and during diseases, in which there are changes in extracellular osmolarity. Antagonism of TRPV4 may offer a therapeutic approach for inflammatory hyperalgesia and chronic inflammation.
A comparative analysis of the activity of ligands acting at P2X and P2Y receptor subtypes in models of neuropathic, acute and inflammatory pain
Authors: Andó RD , Méhész B , Gyires K , Illes P , Sperlágh B
Published: February 2010

Background and purpose: This study was undertaken to compare the analgesic activity of antagonists acting at P2X1, P2X7, and P2Y12 receptors and agonists acting at P2Y1, P2Y2, P2Y4, and P2Y6 receptors in neuropathic, acute, and inflammatory pain.

Experimental approach: The effect of the wide spectrum P2 receptor antagonist PPADS, the selective P2X7 receptor antagonist Brilliant Blue G (BBG), the P2X1 receptor antagonist (4,4′,4″,4‐[carbonylbis(imino‐5,1,3‐benzenetriyl‐bis(carbonylimino))]tetrakis‐1,3‐benzenedisulfonic acid, octasodium salt (NF449) and (8,8′‐[carbonylbis(imino‐3,1‐phenylenecarbonylimino)]bis‐1,3,5‐naphthalene‐trisulphonic acid, hexasodium salt (NF023), the P2Y12 receptor antagonist (2,2‐dimethyl‐propionic acid 3‐(2‐chloro‐6‐methylaminopurin‐9‐yl)‐2‐(2,2‐dimethyl‐propionyloxymethyl)‐propylester (MRS2395), the selective P2Y1 receptor agonist ([[(1R,2R,3S,4R,5S)‐4‐[6‐amino‐2‐(methylthio)‐9H‐purin‐9‐yl]‐2,3‐dihydroxybicyclo[3.1.0]hex‐1‐yl]methyl] diphosphoric acid mono ester trisodium salt (MRS2365), the P2Y2/P2Y4 agonist uridine‐5′‐triphosphate (UTP), and the P2Y4/P2Y6 agonist uridine‐5′‐diphosphate (UDP) were examined on mechanical allodynia in the Seltzer model of neuropathic pain, on acute thermal nociception, and on the inflammatory pain and oedema induced by complete Freund's adjuvant (CFA).

Key results: MRS2365, MRS2395 and UTP, but not the other compounds, significantly alleviated mechanical allodynia in the neuropathic pain model, with the following rank order of minimal effective dose (mED) values: MRS2365 > MRS2395 > UTP. All compounds had a dose‐dependent analgesic action in acute pain except BBG, which elicited hyperalgesia at a single dose. The rank order of mED values in acute pain was the following: MRS2365 > MRS2395 > NF449 > NF023 > UDP = UTP > PPADS. MRS2365 and MRS2395 had a profound, while BBG had a mild effect on inflammatory pain, with a following rank order of mED values: MRS2395 > MRS2365 > BBG. None of the tested compounds had significant action on oedema evoked by intraplantar injection of CFA.

Conclusions and implications: Our results show that antagonism at P2X1, P2Y12, and P2X7 receptors and agonism at P2Y1 receptors define promising therapeutic strategies in acute, neuropathic, and inflammatory pain respectively.
Fluorescent ligand binding reveals heterogeneous distribution of adrenoceptors and ‘cannabinoid‐like’ receptors in small arteries
Authors: Daly CJ , Ross RA , Whyte J , Henstridge CM , Irving AJ , McGrath JC
Published: February 2010

Background and purpose: Pharmacological analysis of synergism or functional antagonism between different receptors commonly assumes that interacting receptors are located in the same cells. We have now investigated the distribution of α‐adrenoceptors, β‐adrenoceptors and cannabinoid‐like (GPR55) receptors in the mouse arteries.

Experimental approach: Fluorescence intensity from vascular tissue incubated with fluorescent ligands (α1‐adrenoceptor ligand, BODIPY‐FL‐prazosin, QAPB; β‐adrenoceptor ligand, TMR‐CGP12177; fluorescent angiotensin II; a novel diarylpyrazole cannabinoid ligand (Tocrifluor 1117, T1117) was measured with confocal microscopy. Small mesenteric and tail arteries of wild‐type and α1B/D‐adrenoceptor‐KO mice were used.

Key results: T1117, a fluorescent form of the cannabinoid CB1receptor antagonist AM251, was a ligand for GPR55, with low affinity for CB1receptors. In mesenteric arterial smooth muscle cells, α1A‐adrenoceptors were predominantly located in different cells from those with β‐adrenoceptors, angiotensin receptors or cannabinoid‐like (GPR55) receptors. Cells with β‐adrenoceptors predominated at arterial branches. Endothelial cells expressed β‐adrenoceptors, α‐adrenoceptors and cannabinoid‐like receptors. Only endothelial α‐adrenoceptors appeared in clusters. Adventitia was a rich source of G protein‐coupled receptors (GPCRs), particularly fibroblasts and nerve tracts, where Schwann cells bound α‐adrenoceptor, β‐adrenoceptor and CB‐receptor ligands, with a mix of separate receptor locations and co‐localization.

Conclusions and implications: Within each cell type, each GPCR had a distinctive heterogeneous distribution with limited co‐localization, providing a guide to the possibilities for functional synergism, and suggesting a new paradigm for synergism in which interactions may be either between cells or involve converging intracellular signalling processes.

This article is part of a themed section on Imaging in Pharmacology. To view the editorial for this themed section visithttp://dx.doi.org/10.1111/j.1476‐5381.2010.00685.x
16α‐Hydroxycleroda‐3,13 (14)Z‐dien‐15,16‐olide from Polyalthia longifolia: a safe and orally active antileishmanial agent
Authors: Misra Pragya , Sashidhara Koneni V , Singh Suriya Pratap , Kumar Awanish , Gupta Reema , Chaudhaery Shailendra S , Gupta Souvik Sen , Majumder HK , Saxena Anil K , Dube Anuradha
Published: February 2010

Background and purpose:  New antileishmanials from natural products are urgently needed due to the emergence of drug resistance complicated by severe cytotoxic effects. 16α‐Hydroxycleroda‐3,13 (14)Z‐dien‐15,16‐olide (Compound 1) from Polyalthia longifolia was found to be a potential antileishmanial and non‐cytotoxic, as evidenced by long‐term survival (>6 months) of treated animals. This prompted us to determine its target and, using molecular modelling, identify the interactions responsible for its specific antileishmanial activity.

Experimental approach:  In vitro activity of compound was assessed using intracellular transgenic green fluorescent protein‐stably expressed Leishmania donovani parasites. In vivo activity and survival of animals post‐treatment were evaluated in L. donovani‐infected hamsters. Known property of clerodane diterpenes as potent human DNA topoisomerase inhibitors led us to evaluate the inhibition of recombinant L. donovani topoisomerase I using relaxation assay. Mode of cell death induced by Compound 1 was assessed by phosphotidylserine exposure post‐treatment. Molecular modelling studies were conducted with DNA topoisomerase I to identify the binding interactions responsible for its activity.

Key results:  Bioassay‐guided fractionation led to isolation of Compound 1 as a non‐cytotoxic, orally active antileishmanial. Compound 1 inhibited recombinant DNA topoisomerase I which, ultimately, induced apoptosis. Molecular docking studies indicated that five strong hydrogen‐bonding interactions and hydrophobic interactions of Compound 1 with L. donovani DNA‐topoisomerase are responsible for its antileishmanial activity.

Conclusions and implications:  The data reveal Compound 1 is a potent and safe antileishmanial. The study further exploited the structural determinants responsible for its non‐cytotoxic and potent activity, to raise the feasibility of specifically targeting the target enzyme responsible for its activity through rational drug design.
Statins suppress interleukin‐6‐induced monocyte chemo‐attractant protein‐1 by inhibiting Janus kinase/signal transducers and activators of transcription pathways in human vascular endothelial cells
Authors: Jougasaki Michihisa , Ichiki Tomoko , Takenoshita Yoko , Setoguchi Manabu
Published: February 2010

Background and purpose:  The mechanisms of anti‐inflammatory actions of statins, 3‐hydroxy‐3‐methylglutaryl CoA (HMG‐CoA) reductase inhibitors, remain unclear. We investigated the effects of statins on interleukin (IL)‐6‐induced monocyte chemo‐attractant protein (MCP)‐1 expression and monocyte chemotaxis.

Experimental approach:  Cultures of human aortic endothelial cells (HAECs) were stimulated with IL‐6 in the absence and presence of statins. Gene expression and protein secretion of MCP‐1, phosphorylation of Janus kinase (JAK) and the signal transducers and activators of transcription (STAT) pathway, and human monocyte migration were examined.

Key results:  IL‐6 plus its soluble receptor sIL‐6R (IL‐6/sIL‐6R) promoted THP‐1 monocyte migration, and increased gene expression and protein secretion of MCP‐1, more than IL‐6 alone or sIL‐6R alone. Various statins inhibited IL‐6/sIL‐6R‐promoted monocyte migration and MCP‐1 expression in HAECs. Co‐incubation of mevalonate and geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, reversed the inhibitory effects of statins on MCP‐1 expression. Geranylgeranyl transferase inhibitor, but not farnesyl transferase inhibitor, suppressed IL‐6/sIL‐6R‐stimulated MCP‐1 expression. IL‐6/sIL‐6R rapidly phosphorylated JAK1, JAK2, TYK2, STAT1 and STAT3, which were inhibited by statins. Transfection of STAT3 small interfering RNA (siRNA), but not STAT1 siRNA, attenuated the ability of IL‐6/sIL‐6R to enhance THP‐1 monocyte migration. In addition, statins blocked IL‐6/sIL‐6R‐induced translocation of STAT3 to the nucleus.

Conclusions and implications:  Statins suppressed IL‐6/sIL‐6R‐induced monocyte chemotaxis and MCP‐1 expression in HAECs by inhibiting JAK/STAT signalling cascades, explaining why statins have anti‐inflammatory properties beyond cholesterol reduction.
Nicotinic acetylcholine receptors expressed in the ventralposterolateral thalamic nucleus play an important role in anti‐allodynic effects
Authors: Ueda M , Iida Y , Tominaga A , Yoneyama T , Ogawa M , Magata Y , Nishimura H , Kuge Y , Saji H
Published: February 2010

Background and purpose: Much interest is currently being focused on the anti‐nociceptive effects mediated by nicotinic acetylcholine (nACh) receptors, including their location and mechanism of action. The purpose of this study was to elucidate these issues using 5‐iodo‐3‐(2(S)‐azetidinylmethoxy)pyridine (5IA), a nACh receptor agonist, and [125I]5IA.

Experimental approach: We partially ligated the sciatic nerve of Sprague‐Dawley rat to induce neuropathic pain [Seltzer's partial sciatic nerve ligation (PSL) model]. We then examined the changes in nACh receptor density in the CNS using [125I]5IA autoradiography and the involvement of nACh receptors in anti‐nociceptive effects in the region where changes occurred.

Key results: Autoradiographic studies showed that the accumulation of [125I]5IA and the number of nACh receptors in the thalamus of PSL rats were increased about twofold compared with those in the sham‐operated rats. No change was observed in other brain regions. Rats injected in the ventral posterolateral thalamic nucleus (VPL) with 5IA demonstrated a significant and dose‐dependent anti‐allodynic effect and this effect was completely antagonized by mecamylamine, injected with 5IA, into the VPL. The blockade of nACh receptors in the VPL by mecamylamine decreased by 70% the anti‐allodynic effect of 5IA, given i.c.v. Moreover, mecamylamine given intra‐VPL by itself, induced significant hyperalgesia.

Conclusions and implications: Our findings suggest that the nACh receptors expressed in the VPL play an important role in the anti‐allodynic effects produced by exogenous and endogenous agonists.
Poly(lactic acid‐glycolic acid) nanoparticles markedly improve immunological protection provided by peptide P10 against murine paracoccidioidomycosis
Authors: Amaral André C , Marques Alexandre F , Muñoz Julián E , Bocca Anamélia L , Simioni Andreza R , Tedesco Antonio C , Morais Paulo C , Travassos Luiz R , Taborda Carlos P , Felipe Maria Sueli S
Published: February 2010

Background and purpose:  The present study reports on the preparation and testing of a sustained delivery system for the immunomodulatory peptide P10 aimed at reducing the in vivo degradation of the peptide and the amount required to elicit a protective immune response against paracoccidioidomycosis.

Experimental approach:  BALB/c mice were infected with the yeast Paracoccidioides brasiliensis to mimic the chronic form of paracoccidioidomycosis. The animals were treated daily with sulfamethoxazole/trimethoprim alone or combined with peptide P10, either emulsified in Freund's adjuvant or entrapped in poly(lactic acid‐glycolic acid) (PLGA) nanoparticles at different concentrations (1 µg, 5 µg, 10 µg, 20 µg or 40 µg·50 µL−1). Therapeutic efficacy was assessed as fungal burden in tissues and the immune response by quantitative determination of cytokines.

Key results:  Animals given combined chemotherapy and P10 nanotherapy presented a marked reduction of fungal load in the lungs, compared with the non‐treated animals. After 30 days of treatment, P10 entrapped within PLGA (1 µg·50 µL−1) was more effective than ‘free’ P10 emulsified in Freund's adjuvant (20 µg·50 µL−1), as an adjuvant to chemotherapy. After treatment for 90 days, the higher doses of P10 entrapped within PLGA (5 or 10 µg·50 µL−1) were most effective. Treatment with P10 emulsified in Freund's adjuvant (20 µg·50 µL−1) or P10 entrapped within PLGA (1 µg·50 µL−1) were accompanied by high levels of interferon‐gamma in lung.

Conclusions and implications:  Combination of sulfamethoxazole/trimethoprim with the P10 peptide entrapped within PLGA demonstrated increased therapeutic efficacy against paracoccidioidomycosis. P10 incorporation into PLGA nanoparticles dramatically reduced the peptide amount necessary to elicit a protective effect.
Non‐synaptic receptors and transporters involved in brain functions and targets of drug treatment
Authors: Vizi ES , Fekete A , Karoly R , Mike A
Published: February 2010

Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high‐affinity receptors. While synaptic transmission is responsible for the ‘what’ of brain function, the ‘how’ of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non‐synaptically using the extracellular space as communication channel. It is principally the ‘how’ that can be modulated by medicine. In this paper, we discuss different forms of non‐synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non‐synaptic transmission, such as synaptic–extrasynaptic receptor trafficking, neuron–glia communication and retrograde signalling. We review structural and functional aspects of non‐synaptic transmission, including (i) anatomical arrangement of non‐synaptic release sites, receptors and transporters, (ii) intravesicular, intra‐ and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non‐synaptic targets and the subsequent development of selective pharmacological tools to influence them.
Differing effects of exogenous and endogenous hydrogen sulphide in carrageenan‐induced knee joint synovitis in the rat
Authors: Ekundi‐Valentim E , Santos KT , Camargo EA , Denadai‐Souza A , Teixeira SA , Zanoni CI , Grant AD , Wallace JL , Muscará MN , Costa SK
Published: February 2010

Background and purpose:  Recent findings suggest that the noxious gas H2S is produced endogenously, and that physiological concentrations of H2S are able to modulate pain and inflammation in rodents. This study was undertaken to evaluate the ability of endogenous and exogenous H2S to modulate carrageenan‐induced synovitis in the rat knee.

Experimental approach:  Synovitis was induced in Wistar rats by intra‐articular injection of carrageenan into the knee joint. Sixty minutes prior to carrageenan injection, the rats were pretreated with indomethacin, an inhibitor of H2S formation (dl‐propargylglycine) or an H2S donor [Lawesson's reagent (LR)].

Key results:  Injection of carrageenan evoked knee inflammation, pain as characterized by impaired gait, secondary tactile allodynia of the ipsilateral hindpaw, joint swelling, histological changes, inflammatory cell infiltration, increased synovial myeloperoxidase, protein nitrotyrosine residues, inducible NOS (iNOS) activity and NO production. Pretreatment with LR or indomethacin significantly attenuated the pain responses, and all the inflammatory and biochemical changes, except for the increased iNOS activity, NO production and 3‐NT. Propargylglycine pretreatment potentiated synovial iNOS activity (and NO production), and enhanced macrophage infiltration, but had no effect on other inflammatory parameters.

Conclusions and implications:  Whereas exogenous H2S delivered to the knee joint can produce a significant anti‐inflammatory and anti‐nociceptive effect, locally produced H2S exerts little immunomodulatory effect. These data further support the development and use of H2S donors as potential alternatives (or complementary therapies) to the available anti‐inflammatory compounds used for treatment of joint inflammation or relief of its symptoms.
Inhalational anaesthetics andn‐alcohols share a site of action in the neuronal Shaw2 Kvchannel
Authors: Bhattacharji Aditya , Klett Nathan , Go Ramon Christopher V , Covarrubias Manuel
Published: February 2010

Background and purpose: Neuronal ion channels are key targets of general anaesthetics and alcohol, and binding of these drugs to pre‐existing and relatively specific sites is thought to alter channel gating. However, the underlying molecular mechanisms of this action are still poorly understood. Here, we investigated the neuronal Shaw2 voltage‐gated K+(Kv) channel to ask whether the inhalational anaesthetic halothane andn‐alcohols share a binding site near the activation gate of the channel.

Experimental approach: Focusing on activation gate mutations that affect channel modulation byn‐alcohols, we investigatedn‐alcohol‐sensitive andn‐alcohol‐resistant Kvchannels heterologously expressed inXenopusoocytes to probe the functional modulation by externally applied halothane using two‐electrode voltage clamping and a gas‐tight perfusion system.

Key results: Shaw2 Kvchannels are reversibly inhibited by halothane in a dose‐dependent and saturable manner (K0.5= 400 µM;nH= 1.2). Also, discrete mutations in the channel's S4S5 linker are sufficient to reduce or confer inhibition by halothane (Shaw2‐T330L and Kv3.4‐G371I/T378A respectively). Furthermore, a point mutation in the S6 segment of Shaw2 (P410A) converted the halothane‐induced inhibition into halothane‐induced potentiation. Lastly, the inhibition resulting from the co‐application ofn‐butanol and halothane is consistent with the presence of overlapping binding sites for these drugs and weak binding cooperativity.

Conclusions and implications: These observations strongly support a molecular model of a general anaesthetic binding site in the Shaw2 Kvchannel. This site may involve the amphiphilic interface between the S4S5 linker and the S6 segment, which plays a pivotal role in Kvchannel activation.
Critical Study of Observation of the Sternal End of the Right 4th Rib
Authors: Fanton Laurent , Gustin Marie‐Paule , Paultre Ulysse , Schrag Bettina , Malicier Daniel
Published: February 2010

Abstract: Studies of the method of estimating age at death by the 4th rib exclusively concerned the phase method without fundamentally challenging the method as such. The present study analyzed observation of the variables on which the İşcan method is based. Ten observers made two assessments of the stage of pit depth, pit shape, rim and wall configurations of 59 right 4th ribs harvested from males (mean age: 49 years; range: 47–94 years). Observation showed poor reproducibility and repeatability for all three variables (Wilcoxon test, κ‐coefficient). Analysis of problem ribs revealed difficulty in measuring and imprecision in describing pit depth and failure to take account of continual aging for the other two variables. Despite these results, İşcan’s variables provide objective information on age at death. It is recommended that the method be improved by better description of the variables and use of multivariate statistical analysis.
Quantitative Analysis of Gamma‐Hydroxybutyrate at Endogenous Concentrations in Hair using Liquid Chromatography Tandem Mass Spectrometry
Authors: Stout Phillip A. , Simons Kelsie D. , Kerrigan Sarah
Published: February 2010

Abstract:  A method capable of quantifying endogenous concentrations of gamma‐hydroxybutyrate (GHB) in human head hair was developed and validated using liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS). Hair was digested under alkaline conditions, and GHB was isolated using liquid–liquid extraction. LC/MS/MS was performed using atmospheric pressure chemical ionization in the negative mode, multiple reaction monitoring, and deuterated internal standard (GHB‐D6). Linearity was observed between 0.1 and 100 ng/mg GHB (R2 = 1.000). The limits of detection and quantitation in human hair were 0.2 and 0.4 ng/mg, respectively. Accuracy at 2 ng/mg and 10 ng/mg was determined to be 97% and 94%, and intra‐assay CVs at these concentrations were 5.2% and 7.4% (n = 4). Beta‐hydroxybutyrate (BHB), alpha‐hydroxybutyrate, gamma‐butyrolactone, and 1,4‐butanediol did not produce an interference, and there was negligible ion suppression or enhancement from the matrix.
Bleedings into the Anterior Aspect of the Intervertebral Disks in the Lumbar Region of the Spine as a Diagnostic Sign of Hanging
Authors: Hejna Petr , Rejtarová Olga
Published: February 2010

Abstract:  Simon’s hemorrhages are ventral intervertebral hemorrhages located beneath the anterior longitudinal ligament that have been described in cases of hanging and tend to appear in the lumbar region of the spine. There are also reports of Simon’s hemorrhages in cases of blunt trauma, asphyxia, drowning, and putrefaction. In a prospective analysis of 2226 autopsies, we found Simon’s hemorrhages in 65 out of 178 cases of hanging and also in 17 cases in a group of 350 controls with various causes of death. The relative frequency of occurrence of Simon’s bleedings in cases of hanging was 37%. Simon’s hemorrhages can be considered an objective vital finding, which is not absolutely specific for hanging. The absence of hemorrhages in intervertebral disks does not exclude death by hanging. This study suggests that Simon’s bleedings in cases of hanging are more frequent in rather young individuals, in cases with free body suspension, and in individuals with minimal degenerative changes in the lumbosacral part of the spinal column.
Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine
Authors: Van Der Loos M. L. M. , Mulder P. , Hartong E. G. Th. M. , Blom M. B. J. , Vergouwen A. C. , Van Noorden M. S. , Timmermans M. A. , Vieta E. , Nolen W. A. ,   for the LamLit Study Group
Published: February 2010

van der Loos MLM, Mulder P, Hartong EGThM, Blom MBJ, Vergouwen AC, van Noorden MS, Timmermans MA, Vieta E, Nolen WA, for the LamLit Study Group. Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.

Objective:  In a previous paper, we reported about the efficacy of the addition of lamotrigine to lithium in patients with bipolar depression. In the second phase of this study paroxetine was added to ongoing treatment in non‐responders.

Method:  Bipolar depressed patients (n = 124) treated with lithium were randomized to addition of lamotrigine or placebo. In non‐responders after 8 weeks, paroxetine 20 mg was added for another 8 weeks to ongoing treatment.

Results:  After 8 weeks the improvement in patients treated with lamotrigine vs. patients treated with placebo was significant. After addition of paroxetine this difference disappeared as a result of greater further improvement in the non‐responders to placebo.

Conclusion:  Addition of lamotrigine to lithium was found effective in bipolar depressed patients. Further addition of paroxetine in non‐responders to lithium plus lamotrigine did not appear to provide additional benefit, while it appeared to do so in non‐responders to lithium plus placebo.
Cancer risk from diagnostic radiology in a deliberate self‐harm patient
Authors: Norelli L. J. , Coates A. D. , Kovasznay B. M.
Published: February 2010

Norelli LJ, Coates AD, Kovasznay BM. Cancer risk from diagnostic radiology in a deliberate self‐harm patient.

Objective:  Patients who engage in recurrent deliberate self‐harm (DSH) behaviours have increased morbidity and mortality and use emergency services more than others. Unrecognized iatrogenic injury may play a role. Specifically, we call attention to the potential danger of cumulative radiation exposure.

Method:  Case presentation and discussion.

Results:  A 29‐year‐old woman with multiple episodes of deliberate foreign body ingestion received over 400 diagnostic radiology examinations during a 12 year period. The patient’s calculated total radiation dose reached an average of 20.5 mSv per year, a dose comparable to atomic bomb survivors and nuclear industry workers, populations in which there is a significant excess cancer risk.

Conclusion:  Patients with recurrent self‐injurious behaviours, frequent users of healthcare services who often undergo repeated medical assessment and treatment, are likely at higher risk for iatrogenic adverse events. Multiple diagnostic radiology examinations have recently come under scrutiny for causing increased lifetime risk of cancer. Healthcare providers, in particular psychiatrists and emergency department physicians, should consider the cumulative risks of radiological procedures when assessing and treating patients with DSH.
Microsatellites and single nucleotide polymorphisms in avian hybrid identification: a comparative case study
Authors: Väli Ülo , Saag Pauli , Dombrovski Valery , Meyburg Bernd‐Ulrich , Maciorowski Grzegorz , Mizera Tadeusz , Treinys Rimgaudas , Fagerberg Sofie
Published: February 2010

The correct identification of hybrids is essential in avian hybridisation studies, but selection of the appropriate set of genetic markers for this purpose is at times complicated. Microsatellites and single nucleotide polymorphisms (SNPs) are currently the most commonly used markers in this field. We compare the efficiency of these two marker types, and their combination, in the identification of the threatened avian species, the greater spotted eagle and the lesser spotted eagle, as well as hybrids between the two species. We developed novel SNP markers from genome‐wide distributed 122 candidate introns using only sympatric samples, and tested these markers successfully in 60 sympatric and allopatric spotted eagles using Bayesian model‐based approaches. Comparatively, only one out of twelve previously described avian nuclear intron markers showed significant species‐specific allele frequency difference, thus stressing the importance of selecting the proper markers. Twenty microsatellites outperformed selected nine SNPs in species identification, but were poorer in hybrid detection, whereas the resolution power of ten microsatellites remained too low for correct assignment. A combination of SNPs and microsatellites resulted in the most efficient and accurate identification of all individuals. Our study shows that the use of various sets of markers could lead to strikingly different assignment results, hybridisation studies may have been affected by too low a resolution power of used markers, and that an appropriate set of markers is essential for successful hybrid identification.