bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of plasmodial RESA protein on deformability of human red blood cells harboring
Plasmodium falciparum
Authors: Mills J. P. , Diez-Silva M. , Quinn D. J. , Dao M. , Lang M. J. , Tan K. S. W. , Lim C. T. , Milon G. , David P. H. , Mercereau-Puijalon O. , Bonnefoy S. , Suresh S.
Published: May 2007

During intraerythrocytic development,
Plasmodium falciparum
exports proteins that interact with the host cell plasma membrane and subplasma membrane-associated spectrin network. Parasite-exported proteins modify mechanical properties of host RBCs, resulting in altered cell circulation. In this work, optical tweezers experiments of cell mechanical properties at normal physiological and febrile temperatures are coupled, for the first time, with targeted gene disruption techniques to measure the effect of a single parasite-exported protein on host RBC deformability. We investigate
Pf
155/Ring-infected erythrocyte surface antigen (RESA), a parasite protein transported to the host spectrin network, on deformability of ring-stage parasite-harboring human RBCs. Using a set of parental, gene-disrupted, and revertant isogenic clones, we found that RESA plays a major role in reducing deformability of host cells at the early ring stage of parasite development, but not at more advanced stage. We also show that the effect of RESA on deformability is more pronounced at febrile temperature, which ring-stage parasite-harboring RBCs can be exposed to during a malaria attack, than at normal body temperature.
Combination brain and systemic injections of AAV provide maximal functional and survival benefits in the Niemann-Pick mouse
Authors: Passini Marco A. , Bu Jie , Fidler Jonathan A. , Ziegler Robin J. , Foley Joseph W. , Dodge James C. , Yang Wendy W. , Clarke Jennifer , Taksir Tatyana V. , Griffiths Denise A. , Zhao Michael A. , O'Riordan Catherine R. , Schuchman Edward H. , Shihabuddin Lamya S. , Cheng Seng H.
Published: May 2007

Niemann-Pick disease (NPD) is caused by the loss of acid sphingomyelinase (ASM) activity, which results in widespread accumulation of undegraded lipids in cells of the viscera and CNS. In this study, we tested the effect of combination brain and systemic injections of recombinant adeno-associated viral vectors encoding human ASM (hASM) in a mouse model of NPD. Animals treated by combination therapy exhibited high levels of hASM in the viscera and brain, which resulted in near-complete correction of storage throughout the body. This global reversal of pathology translated to normal weight gain and superior recovery of motor and cognitive functions compared to animals treated by either brain or systemic injection alone. Furthermore, animals in the combination group did not generate antibodies to hASM, demonstrating the first application of systemic-mediated tolerization to improve the efficacy of brain injections. All of the animals treated by combination therapy survived in good health to an investigator-selected 54 weeks, whereas the median lifespans of the systemic-alone, brain-alone, or untreated ASM knockout groups were 47, 48, and 34 weeks, respectively. These data demonstrate that combination therapy is a promising therapeutic modality for treating NPD and suggest a potential strategy for treating disease indications that cause both visceral and CNS pathologies.
Evolutionary and geographical history of the
Leishmania donovani
complex with a revision of current taxonomy
Authors: Lukeš Julius , Mauricio Isabel L. , Schönian Gabriele , Dujardin Jean-Claude , Soteriadou Ketty , Dedet Jean-Pierre , Kuhls Katrin , Tintaya K. Wilber Quispe , Jirků Milan , Chocholová Eva , Haralambous Christos , Pratlong Francine , Oborník Miroslav , Horák Aleš , Ayala Francisco J. , Miles Michael A.
Published: May 2007

Leishmaniasis is a geographically widespread severe disease, with an increasing incidence of two million cases per year and 350 million people from 88 countries at risk. The causative agents are species of
Leishmania
, a protozoan flagellate. Visceral leishmaniasis, the most severe form of the disease, lethal if untreated, is caused by species of the
Leishmania donovani
complex. These species are morphologically indistinguishable but have been identified by molecular methods, predominantly multilocus enzyme electrophoresis. We have conducted a multifactorial genetic analysis that includes DNA sequences of protein-coding genes as well as noncoding segments, microsatellites, restriction-fragment length polymorphisms, and randomly amplified polymorphic DNAs, for a total of ≈18,000 characters for each of 25 geographically representative strains. Genotype is strongly correlated with geographical (continental) origin, but not with current taxonomy or clinical outcome. We propose a new taxonomy, in which
Leishmania infantum
and
L. donovani
are the only recognized species of the
L. donovani
complex, and we present an evolutionary hypothesis for the origin and dispersal of the species. The genus
Leishmania
may have originated in South America, but diversified after migration into Asia.
L. donovani
and
L. infantum
diverged ≈1 Mya, with further divergence of infraspecific genetic groups between 0.4 and 0.8 Mya. The prevailing mode of reproduction is clonal, but there is evidence of genetic exchange between strains, particularly in Africa.
Mice lacking NKCC1 are protected from development of bacteremia and hypothermic sepsis secondary to bacterial pneumonia
Authors: Nguyen MyTrang , Pace Amy J. , Koller Beverly H.
Published: May 2007

The contribution of the Na+-K+-Cl− transporter (NKCC1) to fluid in ion transport and fluid secretion in the lung and in other secretory epithelia has been well established. Far less is known concerning the role of this cotransporter in the physiological response of the pulmonary system during acute inflammation. Here we show that mice lacking this transporter are protected against hypothermic sepsis and bacteremia developing as a result of Klebsiella pneumoniae infection in the lung. In contrast, this protection was not observed in NKCC1−/− mice with K. pneumoniae—induced peritonitis. Although overall recruitment of cells to the lungs was not altered, the number of cells present in the airways was increased in the NKCC1−/− animals. Despite this robust inflammatory response, the increase in vascular permeability observed in this acute inflammatory model was attenuated in the NKCC1−/− animals. Our studies suggest that NKCC1 plays a unique and untoward unrecognized role in acute inflammatory responses in the lung and that specific inhibition of this NKCC isoform could be beneficial in treatment of sepsis.
Th2-driven, allergen-induced airway inflammation is reduced after treatment with anti–Tim-3 antibody in vivo
Authors: Kearley Jennifer , McMillan Sarah J. , Lloyd Clare M.
Published: May 2007

T cell immunoglobulin and mucin domain–containing molecule-3 (Tim-3) is a surface molecule that is preferentially expressed on activated Th1 cells in comparison to Th2 cells. Blockade of Tim-3 has been shown to enhance Th1-driven pathology in vivo, suggesting that blockade of Tim-3 may improve the development of Th2-associated responses such as allergy. To examine the effects of Tim-3 blockade on the Th2 response in vivo, we administered anti–Tim-3 antibody during pulmonary inflammation induced by transfer of ovalbumin (OVA)-reactive Th2 cells, and subsequent aerosol challenge with OVA. In this model, anti–Tim-3 antibody treatment before each airway challenge significantly reduced airway hyperreactivity, with a concomitant decrease in eosinophils and Th2 cells in the lung. We examined Th1 and Th2 cytokine levels in the lung after allergen challenge and found that pulmonary expression of the Th2 cytokine IL-5 was significantly reduced, whereas IFN-γ levels were significantly increased by anti–Tim-3 antibody treatment. Thus, blocking Tim-3 function has a beneficial effect during pulmonary inflammation by skewing the Th2 response toward that of a Th1 type, suggesting an important role for Tim-3 in the regulation of allergic disease.
G-CSF rescues the memory impairment of animal models of Alzheimer's disease
Authors: Tsai Kuen-Jer , Tsai Yueh-Chiao , Shen Che-Kun James
Published: May 2007

Most of the current clinical treatments for Alzheimer's disease (AD) are largely symptomatic and can have serious side effects. We have tested the feasibility of using the granulocyte colony-stimulating factor (G-CSF), which is known to mobilize hematopoietic stem cells (HSCs) from the bone marrow into the peripheral blood, as a therapeutic agent for AD. Subcutaneous administration of G-CSF into two different β-amyloid (Aβ)–induced AD mouse models substantially rescued their cognitive/memory functions. The rescue was accompanied by the accumulation of 5-bromo-2′deoxyuridine–positive HSCs, as well as local neurogenesis surrounding the Aβ aggregates. Furthermore, the level of acetylcholine in the brains of Tg2576 mice was considerably enhanced upon G-CSF treatment. We suggest that G-CSF, a drug already extensively used for treating chemotherapy-induced neutropenia, should be pursued as a novel, noninvasive therapeutic agent for the treatment of AD.
Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone
Authors: Coutanceau Emmanuelle , Decalf Jeremie , Martino Angelo , Babon Aurélie , Winter Nathalie , Cole Stewart T. , Albert Matthew L. , Demangel Caroline
Published: May 2007

Mycolactone is a polyketide toxin produced by Mycobacterium ulcerans (Mu), the causative agent of the skin disease Buruli ulcer (BU). Surprisingly, infected tissues lack inflammatory infiltrates. Structural similarities between mycolactone and immunosuppressive agents led us to investigate the immunomodulatory properties of mycolactone on dendritic cells (DCs), the key initiators and regulators of immune responses. At noncytotoxic concentrations, phenotypic and functional maturation of both mouse and human DCs was inhibited by mycolactone. Notably, mycolactone blocked the emigration of mouse-skin DCs to draining lymph nodes, as well as their maturation in vivo. In human peripheral blood–derived DCs, mycolactone inhibited the ability to activate allogeneic T cell priming and to produce inflammatory molecules. Interestingly, production of the cytokines interleukin (IL) 12, tumor necrosis factor α, and IL-6 was only marginally affected, whereas production of the chemokines macrophage inflammatory protein (MIP) 1α, MIP-1β, regulated on activation, normal T cell expressed and secreted, interferon γ–inducible protein 10, and monocyte chemoattractant protein 1 was abolished at nanomolar concentrations. Importantly, mycolactone endogenously expressed by Mu mediated similar inhibitory effects on β-chemokine production by DCs. In accordance with the histopathological features of BUs, our results suggest that bacterial production of mycolactone may limit both the initiation of primary immune responses and the recruitment of inflammatory cells to the infection site. Moreover, they highlight a potential interest in mycolactone as a novel immunosuppressive agent.
Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains
Authors: Pickering Matthew C. , de Jorge Elena Goicoechea , Martinez-Barricarte Rubén , Recalde Sergio , Garcia-Layana Alfredo , Rose Kirsten L. , Moss Jill , Walport Mark J. , Cook H. Terence , de Córdoba Santiago Rodriguez , Botto Marina
Published: May 2007

Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype–phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS.
Regulation of glutamate receptor B pre-mRNA splicing by RNA editing
Authors: Schoft Vera K. , Schopoff Sandy , Jantsch Michael F.
Published: May 2007

RNA-editing enzymes of the ADAR family convert adenosines to inosines in double-stranded RNA substrates. Frequently, editing sites are defined by base-pairing of the editing site with a complementary intronic region. The glutamate receptor subunit B (GluR-B) pre-mRNA harbors two such exonic editing sites termed Q/R and R/G. Data from ADAR knockout mice and in vitro editing assays suggest an intimate connection between editing and splicing of GluR-B pre-mRNA.

By comparing the events at the Q/R and R/G sites, we can show that editing can both stimulate and repress splicing efficiency. The edited nucleotide, but not ADAR binding itself, is sufficient to exert this effect. The presence of an edited nucleotide at the R/G site reduces splicing efficiency of the adjacent intron facilitating alternative splicing events occurring downstream of the R/G site.

Lack of editing inhibits splicing at the Q/R site. Editing of both the Q/R nucleotide and an intronic editing hotspot are required to allow efficient splicing. Inefficient intron removal may ensure that only properly edited mRNAs become spliced and exported to the cytoplasm.
FISH mapping of 57 BAC clones reveals strong conservation of synteny between Galliformes and Anseriformes
Authors: Fillon V. , Vignoles M. , Crooijmans R. P. M. A. , Groenen M. A. M. , Zoorob R. , Vignal A.
Published: May 2007

Karyotypes of chicken (Gallus gallus domesticus; 2n = 78) and mallard duck (Anas platyrhynchos; 2n = 80) share the typical organization of avian karyotypes including a few macrochromosome pairs, numerous indistinguishable microchromosomes, and Z and W sex chromosomes. Previous banding studies revealed great similarities between chickens and ducks, but it was not possible to use comparative banding for the microchromosomes. In order to establish precise chromosome correspondences between these two species, particularly for microchromosomes, we hybridized 57 BAC clones previously assigned to the chicken genome to duck metaphase spreads. Although most of the clones showed similar localizations, we found a few intrachromosomal rearrangements of the macrochromosomes and an additional microchromosome pair in ducks. BAC clones specific for chicken microchromosomes were localized to separate duck microchromosomes and clones mapping to the same chicken microchromosome hybridized to the same duck microchromosome, demonstrating a high conservation of synteny. These results demonstrate that the evolution of karyotypes in avian species is the result of fusion and/or fission processes and not translocations.
Effects of NMDA receptor antagonists on visceromotor reflexes and on intestinal motility, in vivo
Authors: Shafton A. D. , Bogeski G. , Kitchener P. D. , Sanger G. J. , Furness J. B. , Shimizu Y.
Published: May 2007

Abstract  Antagonists of NMDA receptors can inhibit both the transmission of pain signals from the intestine and enteric reflexes. However, it is unknown whether doses of the NMDA antagonist, ketamine, that are used in anaesthetic mixtures suppress motility reflexes and visceromotor responses (VMRs). In fact, whether intestinal motility is affected by NMDA receptor blockers in vivo has been little investigated. We studied the effects of ketamine and memantine, administered intravenously or intrathecally. Rats were maintained under α‐chloralose plus xylazine or pentobarbitone anaesthesia; VMR and jejunal motility were measured. Under α‐chloralose/xylazine anaesthesia, i.v. ketamine inhibited VMRs at 6 mg kg h−1, but not at 3 mg kg h−1. It did not inhibit propulsive reflexes in the jejunum at 10 mg kg h−1, but reduced them by 30% at 20 mg kg h−1. Under α‐chloralose/pentobarbitone anaesthesia, i.v. ketamine reduced propulsive reflexes at 40 mg kg h−1 and VMR at 10 mg kg h−1. Memantine inhibited VMRs at 20 mg kg h−1 and propulsion at 2 mg kg h−1. Ketamine and memantine, intrathecally, prevented VMRs, but not jejunal propulsion. We conclude that peripherally administered ketamine reduces both VMR and motility reflexes, but not at doses used in anaesthetic mixes (1.8–2.4 mg kg h−1). Effects on motility reflexes are likely to be due to non‐NMDA receptor actions, possibly on nicotinic receptors.
Sigmoid‐colonic motility in health and irritable bowel syndrome: a role for 5‐hydroxytryptamine
Authors: Houghton L. A. , Atkinson W. , Lockhart S. , Fell C. , Whorwell P. J. , Keevil B.
Published: May 2007

Abstract  Evidence suggests that sigmoid‐colonic motility is increased in patients with irritable bowel syndrome (IBS). 5‐Hydroxytryptamine (5‐HT) plays a role in the control of motility, but its involvement in the dysmotility seen in IBS remains unclear. To investigate the relationship between platelet depleted plasma 5‐HT (PDP 5‐HT) concentration and sigmoid‐colonic motility in patients with IBS and healthy volunteers. Pre‐ and postprandial PDP 5‐HT concentrations were assessed while recording sigmoid‐colonic motility in 35 IBS patients (aged 19–53 years, eight male) and 16 healthy volunteers (aged 18–39 years, six male). Motility was recorded using a five‐channel solid‐state catheter introduced to a depth of 35 cm into an unprepared bowel. 5‐Hydroxytryptamine concentration was measured by reverse‐phase HPLC with fluorimetric detection. Irritable bowel syndrome patients had elevated concentrations of PDP 5‐HT under fasting (P < 0.004) and fed (P = 0.079) conditions compared with controls. Likewise, they exhibited increased sigmoid‐colonic motility under fasting (activity index: P < 0.02) and fed (P < 0.05) conditions compared with controls. Platelet depleted plasma 5‐HT concentration positively correlated with colonic activity index under both fasting (r = 0.402; P = 0.003) and fed (r = 0.439; P = 0.001) conditions. These data show a possible relationship between endogenous concentrations of 5‐HT and sigmoid‐colonic motility recorded in both IBS and healthy subjects.
Does co‐administration of a non‐selective opiate antagonist enhance acceleration of transit by a 5‐HT4 agonist in constipation‐predominant irritable bowel syndrome? A randomized controlled trial
Authors: Foxx‐orenstein A. E. , Camilleri M. , Szarka L. A. , Mckinzie S. , Burton D. , Thomforde G. , Baxter K. , Zinsmeister A. R.
Published: May 2007

Abstract  Opioid neurons exhibit tonic restraint on intestinal motility; opioid antagonists stimulate peristalsis and increase transit. In vitro, 5‐hydroxytryptamine (5‐HT4) agonists combined with selective opioid antagonists significantly increased colonic propulsion relative to a 5‐HT4 agonist alone. We hypothesized that the combination of 5‐HT4 agonist and non‐selective opioid antagonist enhances intestinal transit more than either treatment alone in female constipation‐predominant irritable bowel syndrome (C‐IBS) patients. Our aim was to examine the effect of tegaserod 6 mg b.i.d. alone and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with C‐IBS. Forty‐eight patients were randomized to tegaserod alone, naltrexone alone or in combination with tegaserod or placebo for 6 days. Small bowel, ascending colon half‐life (in pharmacokinetics) (t1/2), and colonic geometric centre (8, 24, 48 h) were assessed by scintigraphy. Tegaserod increased small bowel (P < 0.01) and colon transit (P < 0.01). Naltrexone did not accelerate colonic transit relative to placebo. Combination treatment did not significantly accelerate transit relative to tegaserod alone. Tegaserod and tegaserod with naltrexone resulted in looser stool form (P < 0.01). In female C‐IBS patients, tegaserod accelerates small bowel and colon transit and contributed to looser stool consistency. Use of naltrexone, 50 mg, does not support the hypothesis that combination of 5‐HT4 agonist and non‐selective opioid antagonist enhances intestinal transit.
Activation of the cannabinoid 2 (CB2) receptor inhibits murine mesenteric afferent nerve activity
Authors: Hillsley K. , Mccaul C. , Aerssens J. , Peeters P. J. , Gijsen H. , Moechars D. , Coulie B. , Grundy D. , Stead R. H.
Published: May 2007

Abstract  Cannabinoid 2 (CB2) receptors have both antinociceptive and antihypersensitivity effects, although the precise mechanisms of action are still unclear. In this study, the modulatory role of CB2 receptors on the mesenteric afferent response to the endogenous immunogenic agent bradykinin (BK) was investigated. Mesenteric afferent recordings were obtained from anaesthetized wild‐type and CB2−/− mice using conventional extracellular recording techniques. Control responses to BK were obtained in all experiments prior to administration of either CB2 receptor agonist AM1241, or AM1241 plus the CB2 receptor antagonist AM630. Bradykinin consistently evoked activation of mesenteric afferents (n = 32). AM1241 inhibited the BK response in a dose dependent manner. In the presence of AM630 (10 mg kg−1), however, AM1241 (10 mg kg−1) had no significant effect on the BK response. Moreover, AM1241 had also no significant effect on the BK response in CB2−/− mice. Activation of the CB2 receptor inhibits the BK response in mesenteric afferents, demonstrating that the CB2 receptor is an important regulator of neuroimmune function. This may be a mechanism of action for the antinociceptive and antihypersensitive effects of CB2 receptor agonists.
Corticotropin‐releasing factor receptor 1‐deficient mice show decreased anxiety and colonic sensitivity
Authors: Trimble N. , Johnson A. C. , Foster A. , Greenwood‐van Meerveld B.
Published: May 2007

Abstract  Corticotropin releasing factor (CRF) is an important mediator in the stress response. Previous studies in rodent models demonstrated that stress‐induced colonic hypersensitivity was inhibited by CRF1 receptor antagonism. As CRF1R‐deficient mice have an impaired stress response our goal was to further explore the importance of CRF1R in the development of colonic hypersensitivity. Using conscious CRF1R (+/+), CRF1R (+/−) and CRF1R (−/−) mice colonic sensitivity was assessed via a visceromotor behavioural response (VMR) induced by colorectal distension (CRD, 0–60 mmHg). In the CRF1R (+/+) mice there was a pressure‐dependent increase in the VMR to CRD that was moderately attenuated in the CRF1R (+/−) mice. However in the CRF1R (−/−) mice a VMR to CRD was only observed at the highest distension pressure (60 mmHg). A CRF1R antagonist, NBI 30775 (30 mg kg−1 i.p.) significantly decreased the VMR to CRD in CRF1R +/+ mice. An identical inhibitory effect of NBI 30775 was observed in 43% of the CRF1R +/− mice. This study provides pharmacological and genetic evidence for the importance of CRF1R in colonic sensitivity and suggests a link between stress and visceral perception.
Leadership and Effectiveness in the Context of Gender: The Role of Leaders' Verbal Behaviour*
Authors: Mohr Gisela , Wolfram Hans‐Joachim
Published: May 2007

This field study focuses on verbal consideration, which is a leadership behaviour that expresses esteem for the follower and her or his work, knowledge and opinion. It was assumed that the relationship between verbal consideration and various outcomes is moderated by the leader's gender. One‐hundred‐and‐forty leaders and 455 of their direct followers were surveyed in a one‐wave questionnaire study in Germany. Male and female leaders showed the same degree of verbal consideration as rated by their followers. Verbal consideration is related to three out of four outcome variables for both sexes. One unexpected moderating effect of leaders' gender was found: followers of male leaders displaying verbal consideration report less ‘irritation’ (a state of exhaustion considered a threat to good task fulfilment). One explanation may be that male leaders get ‘extra credit’ for showing verbal consideration as it may be thought to entail special effort, whereas for female leaders it may be seen as normal and routine. This assumption should be examined in further studies in order to get more information about the different mechanisms by which female and male leaders reach the same quality of outcomes.
Behavioural Outcomes of Psychological Contract Breach in a Non‐Western Culture: The Moderating Role of Equity Sensitivity*
Authors: Restubog Simon Lloyd D. , Bordia Prashant , Tang Robert L.
Published: May 2007

This study tests the effects of psychological contract breach on several employee outcomes: workplace deviant behaviours directed at the organization (WD‐O) and its organizational members (WD‐I), in‐role performance, and organizational citizenship behaviours directed at the organization (OCB‐O) and its co‐workers (OCB‐I). It also examines the moderating effects of equity sensitivity in the relationship between breach and these outcomes. Data were collected from 162 sales executives and their direct supervisors. We found that breach was related to all behavioural outcomes. Equity sensitivity and breach also interacted in predicting OCB‐I, OCB‐O and WD‐I. The negative relationships between breach and OCB‐O and OCB‐I were stronger for employees with an outcome‐focused approach to organizational relationships than for those with an input‐focused approach. In addition, breach had stronger positive effects on WD‐I especially for those individuals who are output‐oriented compared to those who are input‐focused.
Corporate Strategy Formulation and Taxation: Evidence from UK Firms*
Authors: Glaister Keith W. , Hughes Jane Frecknall
Published: May 2007

This paper considers the relationship between corporate strategy formulation and taxation. Drawing on prior literature we briefly review the important influence that international taxation has on an array of corporate strategy decisions. We then consider issues in strategy formulation and taxation planning in order to develop an understanding of when and how taxation factors impinge on strategic decision‐making. We draw out the apparent paradox between the nature of strategic decision‐making and financial decision‐making and look for areas of reconciliation. In order to shed light on some of these issues we present findings from the qualitative analysis of a set of personal interviews undertaken with senior tax practitioners in seven UK‐based multinational enterprises and then consider quantitative responses from the tax practitioners working in 145 UK firms.
‘I felt like I did something good’— the impact on mainstream pupils of a peer tutoring programme for children with autism
Authors: Jones Val
Published: May 2007

There have been many research projects studying the use of peer intervention strategies to develop the social, communication and interaction skills of children with autism, yet few of these studies focus in detail on the impact of such strategies on the mainstream peers. In this article, Val Jones, an advisory teacher for autism spectrum conditions, explores the impact of peer tutoring children with autism on the peer tutors themselves. This enquiry focuses on ten to eleven‐year‐old mainstream pupils who were paired with twelve children with autism and associated learning difficulties for weekly peer tutoring sessions at a primary school with a specialist autism unit. At the end of a series of tutoring sessions, the perspectives of the peer tutors were gathered through questionnaires. All of the peer tutors reported that they had enjoyed the experience and most felt that the peer tutoring had brought them direct benefits by building confidence, teaching responsibility, encouraging caring attitudes and helping them to acknowledge diversity. Val Jones also gathered the views of parents and school staff who again reported largely positive outcomes from the peer tutoring process. While this small‐scale study focuses on findings from one school, there are wider implications here for the development of inclusive policies and practices and this article will be of interest to professionals working across the range of specialist and mainstream settings.
Behaviour and skills in six‐year‐old children in a ‘high risk’ programme
Authors: Knivsberg Ann‐Mari , Iversen Synnøve , Nødland Magne , Reichelt Karl‐L
Published: May 2007

Problem behaviour hampers learning and the normal development of skills and competencies. The children in focus in this article from Norway are six‐year‐olds with persistent problem behaviour. Early identification of these children is imperative for the implementation of structured educational interventions. Knowledge about their behaviour and skills is therefore important. The aim of the study reported here by Ann‐Mari Knivsberg, professor of special education at the National Centre for Reading Education and Research at the University of Stavanger, Synnøve Iversen, physiotherapist and research fellow at the University of Bergen, Magne Nødland, speech therapist and special educator, and Karl‐L Reichelt, senior consultant and researcher at the Paediatric Research Institute at the National Hospital in Oslo, was to assess the participants' behaviour and their cognitive, linguistic and motor skills and to correlate behaviour and skills. The participants were 31 children enrolled in a ‘high‐risk’ programme for children with problem behaviour. Standardised test materials were used to obtain information on their behaviours and skills. Social problems, attention problems, anxiety and depressive traits were the most frequently reported behavioural problems. Linguistic delay, lower than normal cognitive scores and severe motor co‐ordination difficulties were also detected. Correlations were found between various behavioural traits and between the behaviour and the skills. Attention problems were most frequently correlated to cognitive, linguistic and motor functioning. At the end of their article, the authors call for multi‐disciplinary approaches to the design of future assessment and intervention strategies and to further research into the effectiveness of available screening instruments and intervention programmes.
The role of special schools for children with profound and multiple learning difficulties: is segregation always best?
Authors: Simmons Ben , Bayliss Phil
Published: May 2007

The education of young people with profound and multiple learning difficulties continues to raise challenges and controversies. In this article, Ben Simmons, an ESRC funded PhD student and research assistant, and Phil Bayliss, programme director for the masters degree in special education and disability, both based in the School of Education and Lifelong Learning at the University of Exeter, describe their research into provision for pupils with profound and multiple learning difficulties in a special school in the south west of England. Their work, based in an interpretivist, qualitative approach, set out to illuminate issues relating to the inclusion of pupils with profound and multiple learning difficulties. The findings presented here suggest that the school, in spite of its strong reputation, struggled significantly to provide appropriate learning experiences for pupils with profound and multiple learning difficulties. Ben Simmons and Phil Bayliss discuss the need for improved staff development opportunities focused on enhancing current levels of knowledge and skills. They conclude by calling for a reappraisal of the established view that special schools necessarily provide the best learning environment for pupils with profound and multiple learning difficulties.
Even while they teach, newly‐qualified teachers learn
Authors: Barber Nicola , Turner Mark
Published: May 2007

The Training and Development Agency sets national standards in the UK for qualified teacher status. These standards set out the areas of knowledge and skills that aspiring teachers should acquire during their training. One of these areas of knowledge and skills concerns the identification and teaching of pupils with special educational needs yet the effectiveness of current training routes for teachers in this area remains a matter of ongoing debate. In this article, Nicola Barber, a senior educational psychologist working in Medway, and Mark Turner, who runs an online training company and is a part‐time tutor at the University of East London and senior educational psychologist in Medway, focus on the experiences of newly‐qualified teachers during their induction and first year of teaching. These authors sent out questionnaires to newly‐qualified teachers working in primary schools in two local authorities and received 60 responses. Their results suggest that these teachers, during this opening phase of their careers, experienced an increase in confidence in relation to special educational needs and report that they feel more skilled in this area at the end of their first year of teaching. Nicola Barber and Mark Turner analyse the factors that contribute to this scenario and begin to draw out implications for future approaches to the training and induction of teachers with regard to special educational needs and inclusion.
Consulting with children and young people who have disabilities: views of accessibility to education
Authors: Woolfson Richard C. , Harker Michael , Lowe Dorothy , Sheilds Mary , Mackintosh Hilary
Published: May 2007

The Education (Disability Strategies and Pupils' Educational Records) (Scotland) Act 2002 requires local authorities to prepare and implement an accessibility strategy to improve access to education for young people with disabilities. In this article, Dr Richard Woolfson, Principal Psychologist, Michael Harker, Depute Principal Psychologist, Dorothy Lowe, Senior Psychologist, Mary Shields, Senior Psychologist, and Hilary Mackintosh, Research Assistant, all from Renfrewshire Educational Psychology Service, report the response of one local authority. Staff from the psychological service carried out a two‐stage research study with children and young people. Stage One involved a postal questionnaire for 290 pupils with a range of disabilities; parents and carers were asked to assist their children with the questionnaire. Stage Two involved young people with disabilities in a number of focus groups. The results recorded here confirm that the area of greatest pupil satisfaction is physical access to the school environment. Few problems are identified regarding access to information from school and most pupils with disability consider that their opinions are listened to and respected. Other findings suggest that pupils with disability generally view their teachers as supportive, while pupils often struggle to complete homework. Further, the pupils indicated that they would like to be more closely consulted about access to the curriculum, working independently and the provision of support. Older students suggested that preparation for post‐school options should start much earlier. In the light of these findings, the authors discuss recommendations for future practice and for further research.
The work of classroom assistants in special and mainstream education in Finland
Authors: Takala Marjatta
Published: May 2007

The contribution of teaching assistants, learning support assistants or classroom assistants is becoming increasingly important in inclusive and specialist classrooms. In this article, Marjatta Takala, professor in special education at the University of Helsinki, describes her research into the work of 14 classroom assistants working in a mix of mainstream and special schools in Helsinki, Finland. The results reveal that the tasks undertaken by assistants are different in mainstream and specialist settings and vary also according to the ages of the children involved. The assistants spent more of their time, for example, working directly with children if they worked in mainstream schools. Assistants in special schools, by comparison, spent more time assisting the teacher. Further, assistants working among older children spent more time waiting or simply listening to the lesson than those working with younger children, who seemed to be more actively involved with supporting learning. Marjatta Takala analyses her results by the full range of tasks encountered; according to three broad types of work; and in terms of the planning and co‐operation undertaken by assistants and teachers at the class level. Her discussion will be of interest to anyone concerned with the development of support in the classroom and the education of both teachers and teaching assistants.
Characterization of the human basilar artery contractile response to 5‐HT and triptans
Authors: Silva Sónia A. , Marques Francisco B. , Fontes Ribeiro Carlos A.
Published: May 2007

To study the contractile responses of the human basilar artery to 5‐hydroxytryptamine (5‐HT), sumatriptan, zolmitriptan and naratriptan, and to characterize the 5‐HT receptor subtypes involved on those responses, human basilar artery rings were prepared for isometric contraction, protein isolation and Western blotting analysis. Concentration–response (CR) curves were made for all agonists in the absence or in the presence of selective antagonists at 5‐HT1B (cyanopindolol), 5‐HT1D (BRL 15,572) and 5‐HT2 (ketanserin) receptors. We also used anti‐5‐HT1B and 5‐HT1D receptor antibodies to search for the expression of protein of these receptor subtypes.

From the CR curves, the relative intrinsic activity and potency of these agonists were determined. The ranking order for the intrinsic activity was 5‐HT ≥ sumatriptan > zolmitriptan ≥ naratriptan, whereas that for the potency was zolmitriptan ≥ 5‐HT ≥ sumatriptan > naratriptan.

Our results also show that the human basilar artery seems to have a mixed population of 5‐HT1B/1D receptors mediating the contractile response to triptans, which is also suggested by the expression of both receptor subtypes. There is also a population of 5‐HT2 receptors for which the antimigraine drugs used have no apparent affinity. From this study, one can conclude that the second generation triptans have lower contractile capacity than sumatriptan, suggesting that they have a better cerebrovascular safety profile.
Effects of KR‐33028, a novel Na+/H+ exchanger‐1 inhibitor, on ischemia and reperfusion‐induced myocardial infarction in rats and dogs
Authors: Oh Kwang‐Seok , Seo Ho Won , Yi Kyu Yang , Lee Sunkyung , Yoo Sung‐eun , Lee Byung Ho
Published: May 2007

The present study was performed to evaluate the cardioprotective effects of KR‐33028, a novel Na+/H+ exchanger subtype 1 (NHE‐1) inhibitor, in rat and dog models of coronary artery occlusion and reperfusion. In anesthetized rats subjected to a 45‐min coronary occlusion and a 90‐min reperfusion, KR‐33028 at 5 min before occlusion (i.v. bolus) dose‐dependently reduced myocardial infarct size from 58.0% to 46.6%, 40.3%, 39.7%, 33.1%, and 27.8% for 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg respectively (P < 0.05). In anesthetized beagle dogs that underwent a 1.0‐h occlusion followed by a 3.0‐h reperfusion, KR‐33028 (3 mg/kg, i.v. bolus) markedly decreased infarct size from 45.6% in vehicle‐treated group to 16.4% (P < 0.05), and reduced the reperfusion‐induced release in creatine kinase myocardial band isoenzyme (MB), lactate dehydrogenase, troponin‐I, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. In separate experiments to assess the effects of timing of treatment, KR‐33028 (1 mg/kg, i.v. bolus) given 10 min before or at reperfusion in rat models also significantly reduced the myocardial infarct size (46.3% and 44.1% respectively) compared with vehicle‐treated group. In all studies, KR‐33028 caused no significant changes in any hemodynamic profiles. In an isolated rat heart model of hypothermic cardioplegia, KR‐33028 (30 μm), which was added to the heart preservation solution (histidin–tryptophan–ketoglutarate) during hypothermic cardioplegic arrest, significantly improved the recovery of left ventricular developed pressure, heart rate and dP/dtmax after reperfusion. Taken together, these results indicate that KR‐33028 significantly reduced the myocardial infarction induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles.
Genetic polymorphism of cytochrome P450s and P‐glycoprotein in the Finnish population
Authors: Hilli Johanna , Rane Anders , Lundgren Stefan , Bertilsson Leif , Laine Kari
Published: May 2007

The objective of this study was to investigate the genetic polymorphism of selected cytochrome P450 (CYP) enzymes and ABCB1 (encoding P‐glycoprotein) of central importance with regard to the disposition of clinically used drugs in the Finnish population and to compare the results to pre‐existing data from Caucasian populations. A random sample of 449 Finns was studied. Single nucleotide polymorphisms (SNPs) were genotyped using blood‐derived genomic DNA and 5′‐nuclease assays. We found that the allele frequencies of CYP1A2 SNP g.‐163C>A, CYP2C8*3, CYP2C9*2, CYP2C9*3 and CYP2C19*2 were similar to those seen in other Caucasian populations. However, the allelic frequency of the variant ABCB1 SNP c.3435C>T allele was lower than previously reported. The frequency of the homozygous CYP3A5*1 expression was significantly higher than expected based on Hardy–Weinberg calculations (observed n = 8 vs. expected n = 3, P = 0.01). Other genotype frequencies corresponded to the expected values. The strong linkage between the CYP2C8*3 and the CYP2C9*2 alleles was confirmed in this study and the number of individuals with the rare haplotype CYP2C8*3*3/CYP2C9*2*2 was higher than expected. We conclude that the frequency of mutated CYP alleles in Finns were in agreement with earlier findings in Caucasian populations, but a lower frequency of the ABCB1 variant allele 3435T corresponding to that reported in Asian populations was found. The higher than expected frequency of the CYP3A5*1*1 genotype and the CYP2C8*3*3/CYP2C9*2*2 haplotype may influence the response to treatment with drugs metabolized by these enzymes.
Effect of chronic chromium picolinate in animal models of anxiety and memory
Authors: Khanam Razia , Pillai K.K.
Published: May 2007

Diabetes mellitus is associated with certain neurological problems such as depression, anxiety, memory impairment, etc. As chromium picolinate (CrP), a widely used trace element is shown to have beneficial effects in diabetes and depression, we investigated its effects on elevated plus maze and spontaneous alternation behavior paradigm as a measure of anxiety and memory, respectively. CrP (8 μg/mL in drinking water) significantly increased percentage preference to open arm in elevated plus maze in diabetic and normal rats. However, no significant changes were observed in percentage alternation after CrP chronic treatment. The possible anxiolytic effect of CrP might be related to its effect on serotonergic transmission.
Childhood Nail Psoriasis: A Useful Treatment with Tazarotene 0.05%
Authors: DILUVIO LAURA , CAMPIONE ELENA , PATERNÒ EVELIN J. , MORDENTI CRISTINA , HACHEM MAYA EL , CHIMENTI SERGIO
Published: May 2007

Abstract:  Nail psoriasis occurs in 7% to 40% of children, with a similar pattern of clinical presentation to that of adults. In 0.6% to 2.3% of the patients nail changes appear as the only sign of the disease, preceding other skin and articular involvement. No pediatric clinical trials are available yet, but considering the successful use of tazarotene for nail dystrophy therapy in adults, we chose this drug to treat a child.
Reduction of Dispersion of Repolarization and Prolongation of Postrepolarization Refractoriness Explain the Antiarrhythmic Effects of Quinidine in a Model of Short QT Syndrome
Authors: MILBERG PETER , TEGELKAMP REGINA , OSADA NANI , SCHIMPF RAINER , WOLPERT CHRISTIAN , BREITHARDT GÜNTER , BORGGREFE MARTIN , ECKARDT LARS
Published: May 2007

Background: Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS.

Methods and Results:
Pinacidil, an IK‐ATP channel opener, was administered in increasing concentrations (50–100 μM) in 48 Langendorff‐perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the IKr blocker sotalol (100 μM) and the class I antiarrhythmic drugs flecainide (2 μM) and quinidine (0.5 μM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with sotalol and flecainide. Moreover, quinidine, in contrast to sotalol and flecainide, reduced dispersion of repolarization.

Conclusion: Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.