bluuebunny/crossref_metadata_2025 huggingface dataset:
PERSUASIVE REASONING AND DEFECTIVE ACTION1
Authors: MACIEJEWSKI JEFFREY
Published: February 2010

The idea that the operations of the mind are carried out discursively, even linguistically, has won wide acceptance among contemporary Thomists. What has not been explored, however, is the role of persuasion in motivating the actions of the intellect and will. This paper explores the possibility that some form of persuasive discourse is employed by the mind to move the intellect and will to precipitate action. Drawing on essentialism as a foundational ontology, I offer a prefatory theory of persuasive reasoning –‘natural rhetoric’– to explain how it is that we persuade ourselves (and others) to do things, including things that are defective.
Supporting parents: development of a tool to measure self‐efficacy of parents with learning disabilities
Authors: Bloomfield Linda , Kendall Sally , Fortuna Sandra
Published: February 2010

Accessible summary

 Many parents with learning disabilities have their children removed and put into care.

 Parents with learning disabilities often need support to manage their children and to be good parents.

 This article is about how we worked with parents to find a way of seeing whether the support given to them is helpful.

 If parenting support is seen to be helpful, more funding may be available for future support.

There has been a steady increase over the last 20 years in the number of parents with learning disabilities who are referred to social workers and community health practitioners. It is a common experience for parents with learning disabilities to have their child removed from the home and placed permanently in care, and although they are often judged as inadequate parents, it is known that they can be good enough parents when provided with parenting support. This article reports the development of a tool to measure the self‐efficacy of parents with learning disabilities, which will help to evaluate parenting initiatives specifically aimed at this parent group. A tool to measure parenting self‐efficacy (TOPSE) has been adapted to be accessible to parents with learning disabilities. Eighteen parents took part in the study to complete and comment on the tool with the help of a researcher from the community learning disabilities team. This tool, which consists of 45 self‐efficacy statements, now needs to be tested on a larger sample of parents with learning disabilities.
Re‐engineering Legal Opportunity Structures in the European Union? The Starting Line Group and the Politics of the Racial Equality Directive
Authors: EVANS CASE RHONDA , GIVENS TERRI E.
Published: February 2010

Using the Racial Equality Directive to test competing explanations concerning the types of actors who seek to liberalize legal opportunity structures, we find that it was pursued by a coalition of societal interests working through European Union institutions that sought reforms intended to facilitate strategic litigation.
Effect of l‐Dopa on metabotropic glutamate receptor 5 in the brain of parkinsonian monkeys
Authors: Ouattara Bazoumana , Gasparini Fabrizio , Morissette Marc , Grégoire Laurent , Samadi Pershia , Gomez‐Mancilla Baltazar , Di Paolo Thérèse
Published: February 2010

J. Neurochem. (2010) 113, 715–724.

Behavioral investigations of selective and potent metabotropic glutamate receptor type 5 (mGluR5) antagonists in animal models suggest involvement of mGluR5 in compensatory mechanisms of the basal ganglia circuitry in Parkinson’s disease and levodopa (l‐Dopa) induced motor complications. This study investigated mGluR5 changes in MPTP lesioned monkeys. The effect of a chronic 1 month treatment with l‐Dopa on mGluR5‐specific binding and mRNA levels was investigated in MPTP monkeys killed 4 or 24 h after their last l‐Dopa administration. [3H]ABP688 specific binding in the putamen was elevated in l‐Dopa‐treated MPTP monkeys killed 24 h but not 4 h after their last l‐Dopa dose compared with vehicle‐treated MPTP monkeys. Caudate nucleus [3H]ABP688‐specific binding was elevated in both groups of l‐Dopa treated compared with vehicle–treated MPTP monkeys. In contrast, caudate nucleus and putamen mGluR5 mRNA levels were elevated only in l‐Dopa‐treated MPTP monkeys killed 4 h after their last l‐Dopa administration. MPTP monkeys killed 4 h after their last l‐Dopa treatment showed higher caudate nucleus and putamen l‐Dopa concentrations compared with those killed after 24 h. Hence, mGluR5 in the putamen are sensitive to presence of l‐Dopa leading to a rapid decrease of [3H]ABP688‐specific binding possibly involving a direct mGluR5/dopamine receptors interaction.
Longterm quiescent cells in the aged human subventricular neurogenic system specifically express GFAP‐δ
Authors: Van Den Berge Simone A. , Middeldorp Jinte , Zhang C. Eleana , Curtis Maurice A. , Leonard Brian W. , Mastroeni Diego , Voorn Pieter , Van De Berg Wilma D. J. , Huitinga Inge , Hol Elly M.
Published: January 2010

A main neurogenic niche in the adult human brain is the subventricular zone (SVZ). Recent data suggest that the progenitors that are born in the human SVZ migrate via the rostral migratory stream (RMS) towards the olfactory bulb (OB), similar to what has been observed in other mammals. A subpopulation of astrocytes in the SVZ specifically expresses an assembly‐compromised isoform of the intermediate filament protein glial fibrillary acidic protein (GFAP‐δ). To further define the phenotype of these GFAP‐δ expressing cells and to determine whether these cells are present throughout the human subventricular neurogenic system, we analysed SVZ, RMS and OB sections of 14 aged brain donors (ages 74‐93). GFAP‐δ was expressed in the SVZ along the ventricle, in the RMS and in the OB. The GFAP‐δ cells in the SVZ co‐expressed the neural stem cell (NSC) marker nestin and the cell proliferation markers proliferating cell nuclear antigen (PCNA) and Mcm2. Furthermore, BrdU retention was found in GFAP‐δ positive cells in the SVZ. In the RMS, GFAP‐δ was expressed in the glial net surrounding the neuroblasts. In the OB, GFAP‐δ positive cells co‐expressed PCNA. We also showed that GFAP‐δ cells are present in neurosphere cultures that were derived from SVZ precursors, isolated postmortem from four brain donors (ages 63‐91). Taken together, our findings show that GFAP‐δ is expressed in an astrocytic subpopulation in the SVZ, the RMS and the OB. Importantly, we provide the first evidence that GFAP‐δ is specifically expressed in longterm quiescent cells in the human SVZ, which are reminiscent of NSCs.
Short‐term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress
Authors: Rippe Catarina , Lesniewski Lisa , Connell Melanie , LaRocca Thomas , Donato Anthony , Seals Douglas
Published: January 2010

To determine if short‐term calorie restriction reverses vascular endothelial dysfunction in old mice, old (O, n = 30) and young (Y, n = 10) male B6D2F1 mice were fed ad libitum (AL) or calorie restricted (CR, approximately 30%) for 8 weeks. Ex vivo carotid artery endothelium‐dependent dilation (EDD) was impaired in old ad libitum (OAL) vs. young ad libitum (YAL) (74 ± 5 vs. 95 ± 2% of maximum dilation, P < 0.05), whereas old calorie‐restricted (OCR) and YCR did not differ (96 ± 1 vs. 94 ± 3%). Impaired EDD in OAL was mediated by reduced nitric oxide (NO) bioavailability associated with decreased endothelial NO synthase expression (aorta) (P < 0.05), both of which were restored in OCR. Nitrotyrosine, a cellular marker of oxidant modification, was markedly elevated in OAL (P < 0.05), whereas OCR was similar to Y. Aortic superoxide production was 150% greater in OAL vs. YAL (P < 0.05), but normalized in OCR, and TEMPOL, a superoxide dismutase (SOD) mimetic that restored EDD in OAL (to 97 ± 2%), had no effect in Y or OCR. OAL had increased expression and activity of the oxidant enzyme, NADPH oxidase, and its inhibition (apocynin) improved EDD, whereas NADPH oxidase in OCR was similar to Y. Manganese SOD activity and sirtuin1 expression were reduced in OAL (P < 0.05), but restored to Y in OCR. Inflammatory cytokines were greater in OAL vs. YAL (P < 0.05), but unaffected by CR. Carotid artery endothelium‐independent dilation did not differ among groups. Short‐term CR initiated in old age reverses age‐associated vascular endothelial dysfunction by restoring NO bioavailability, reducing oxidative stress (via reduced NADPH oxidase–mediated superoxide production and stimulation of anti‐oxidant enzyme activity), and upregulation of sirtuin‐1.
Long‐Term Outcome Following Successful Catheter Ablation of Atrial Tachycardia Originating From the Pulmonary Veins: Absence of Late Atrial Fibrillation
Authors: TEH ANDREW W. , KALMAN JONATHAN M. , MEDI CAROLINE , ROSSO RAPHAEL , BALASUBRAMANIAM RICHARD , LEE GEOFFREY , HALLORAN KAREN , SPARKS PAUL B. , MORTON JOSEPH B. , VOHRA JITENDRA K. , KISTLER PETER M.
Published: February 2010

Atrial Fibrillation and Pulmonary Vein Tachycardia. Objectives: This study aimed to characterize the long‐term outcome and incidence of atrial fibrillation (AF) in patients following catheter ablation of focal atrial tachycardia (AT) from the pulmonary veins (PV).

Background:
Although both AT and AF may originate from ectopic foci within PVs, it is unknown whether PV AT patients subsequently develop AF.

Methods:
Twenty‐eight patients with 29 PV ATs (14%) from a consecutive series of 194 patients who underwent RFA for focal AT were included. Patients with concomitant AF prior to the index procedure were excluded.

Results:
The minimum follow‐up duration was 4 years; mean age 38 ± 18 years with symptoms for 6.5 ± 10 years, having tried 1.5 ± 0.9 antiarrhythmic drugs. The distribution of foci was: left superior 12 (41%), right superior 10 (34%), left inferior 5 (17%), and right inferior 2 (7%). The focus was ostial in 93% and 2–4 cm distally within the vein in 7%. Mean tachycardia cycle length was 364 ± 90 ms. Focal ablation was performed in 25 of 28 patients. There were 6 recurrences with 5 from the original site. Twenty‐six patients were available for long‐term clinical follow‐up. At a mean of 7.2 ± 2.1 years, 25 of 26 (96%) were free from recurrence off antiarrhythmic drugs. No patients developed AF.

Conclusions:
Focal ablation for tachycardia originating from the PVs is associated with long‐term freedom from both AT and AF. Therefore, although PV AT and PV AF share a common anatomic distribution, PV AT is a distinct clinical entity successfully treated with focal RFA and not associated with AF in the long term. (J Cardiovasc Electrophysiol, Vol. pp. 747‐750, July 2010)
Epigenetics in atherosclerosis and inflammation
Authors: Wierda Rutger J. , Geutskens Sacha B. , Jukema J. Wouter , Quax Paul H.A. , van den Elsen Peter J.
Published: January 2010

Introduction

Epigenetics explained

Atherosclerosis

Epigenetics and association with atherosclerosis

Epigenetic regulation of cell activity

Chemokines, their receptors and other genes involved in inflammation

Epigenetics in (vascular) inflammation

MicroRNAs

Conclusions

Atherosclerosis is a multifactorial disease with a severe burden on western society. Recent insights into the pathogenesis of atherosclerosis underscore the importance of chronic inflammation in both the initiation and progression of vascular remodelling. Expression of immunoregulatory molecules by vascular wall components within the atherosclerotic lesions is accordingly thought to contribute to the ongoing inflammatory process. Besides gene regulatory proteins (transcription factors), epigenetic mechanisms also play an essential and fundamental role in the transcriptional control of gene expression. These epigenetic mechanisms change the accessibility of chromatin by DNA methylation and histone modifications. Epigenetic modulators are thus critically involved in the regulation of vascular, immune and tissue‐specific gene expression within the atherosclerotic lesion. Importantly, epigenetic processes are reversible and may provide an excellent therapeutic target. The concept of epigenetic regulation is gradually being recognized as an important factor in the pathogenesis of atherosclerosis. Recent research provides an essential link between inflammation and reprogramming of the epigenome. In this review we therefore discuss the basis of epigenetic regulation – and the contribution thereof in the regulation of inflammatory processes in general and during atherosclerosis in particular. Moreover we highlight potential therapeutic interventions based on epigenetic mechanisms.
Interstitial cells of Cajal, macrophages and mast cells in the gut musculature: morphology, distribution, spatial and possible functional interactions
Authors: Mikkelsen Hanne B.
Published: January 2010

Introduction

Identification of the cells

Cell distribution

Inflammation

Diabetes mellitus

Conclusions

Interstitial cells of Cajal (ICC) are recognized as pacemaker cells for gastrointestinal movement and are suggested to be mediators of neuromuscular transmission. Intestinal motility disturbances are often associated with a reduced number of ICC and/or ultrastructural damage, sometimes associated with immune cells. Macrophages and mast cells in the intestinal muscularis externa of rodents can be found in close spatial contact with ICC. Macrophages are a constant and regularly distributed cell population in the serosa and at the level of Auerbach’s plexus (AP). In human colon, ICC are in close contact with macrophages at the level of AP, suggesting functional interaction. It has therefore been proposed that ICC and macrophages interact. Macrophages and mast cells are considered to play important roles in the innate immune defence by producing pro‐inflammatory mediators during classical activation, which may in itself result in damage to the tissue. They also take part in alternative activation which is associated with anti‐inflammatory mediators, tissue remodelling and homeostasis, cancer, helminth infections and immunophenotype switch. ICC become damaged under various circumstances – surgical resection, possibly post‐operative ileus in rodents – where innate activation takes place, and in helminth infections – where alternative activation takes place. During alternative activation the muscularis macrophage can switch phenotype resulting in up‐regulation of F4/80 and the mannose receptor. In more chronic conditions such as Crohn’s disease and achalasia, ICC and mast cells develop close spatial contacts and piecemeal degranulation is possibly triggered.
Mechanisms in the loss of capillaries in systemic sclerosis: angiogenesis versus vasculogenesis
Authors: Manetti Mirko , Guiducci Serena , Ibba‐Manneschi Lidia , Matucci‐Cerinic Marco
Published: January 2010

Introduction

Mechanisms and biomarkers of endothelial damage in SSc

Mechanisms of defective angiogenesis in SSc

Mechanisms of defective vasculogenesis in SSc

Conclusions and perspectives on vascular treatment strategies

Systemic sclerosis (SSc, scleroderma) is a chronic, multisystem connective tissue disorder affecting the skin and various internal organs. Although the disease is characterized by a triad of widespread microangiopathy, fibrosis and autoimmunity, increasing evidence indicates that vascular damage is a primary event in the pathogenesis of SSc. The progressive vascular injury includes persistent endothelial cell activation/damage and apoptosis, intimal thickening, delamination, vessel narrowing and obliteration. These profound vascular changes lead to vascular tone dysfunction and reduced capillary blood flow, with consequent tissue ischemia and severe clinical manifestations, such as digital ulceration or amputation, pulmonary arterial hypertension and scleroderma renal crisis. The resulting tissue hypoxia induces complex cellular and molecular mechanisms in the attempt to recover endothelial cell function and tissue perfusion. Nevertheless, in SSc patients there is no evidence of significant angiogenesis and the disease evolves towards chronic tissue ischemia, with progressive and irreversible structural changes in multiple vascular beds culminating in the loss of capillaries. A severe imbalance between pro‐angiogenic and angiostatic factors may also lead to impaired angiogenic response during SSc. Besides insufficient angiogenesis, defective vasculogenesis with altered numbers and functional defects of bone marrow‐derived endothelial progenitor cells may contribute to the vascular pathogenesis of SSc. The purpose of this article is to review the contribution of recent studies to the understanding of the complex mechanisms of impaired vascular repair in SSc. Indeed, understanding the pathophysiology of SSc‐associated vascular disease may be the key in dissecting the disease pathogenesis and developing novel therapies. Either angiogenic or vasculogenic mechanisms may potentially become in the future the target of therapeutic strategies to promote capillary regeneration in SSc.
Sub‐lethal heat shock induces plasma membrane translocation of 70‐kDa heat shock protein in viable, but not in apoptotic, U‐937 leukaemia cells
Authors: LASUNSKAIA ELENA B. , FRIDLIANSKAIA IRINA , ARNHOLDT ANDREA V. , KANASHIRO MILTON , GUZHOVA IRINA , MARGULIS BORIS
Published: February 2010

Lasunskaia EB, Fridlianskaia I, Arnholdt AV, Kanashiro M, Guzhova I, Margulis B. Sub‐lethal heat shock induces plasma membrane translocation of 70‐kDa heat shock protein in viable, but not in apoptotic, U‐937 leukaemia cells. APMIS 2010; 118: 179–87.

Heat shock protein 70 kDa, Hsp70, is an important intracellular factor that protects cells from stress. Unusual plasma membrane expression of Hsp70, observed in some cancer cells, contributes to the cell’s recognition and elimination by the immune system. Induction of apoptosis in cancer cells was demonstrated to increase Hsp70 translocation to the surface membrane, enhancing immunogenic effects through the stimulation of dendritic cells. As hyperthermia is proposed as a method of choice for anti‐cancer therapy, we examined whether apoptosis induction by heat shock enhances Hsp70 membrane translocation in U‐937 leukaemia cells. Cells were exposed to sub‐lethal heat shock, and intracellular and membrane‐bound Hsp70 expression was evaluated in apoptotic and viable cell sub‐populations, employing flow cytometry and immunofluorescence. Heat shock induced Hsp70 membrane translocation in the viable cells that were able to enhance Hsp70 production upon heating, but not in the cells undergoing apoptosis that continued to express low basal levels of the intracellular protein. Data suggest that the protein translocation was associated with the increasing Hsp70 content rather than the apoptotic process. Apoptosis does not contribute to externalization of Hsp70, at least in the cells with low levels of this protein.
Assessment of RNA amplification by multiplex RT‐PCR and IgM detection by indirect and capture ELISAs for the diagnosis of measles and rubella
Authors: SANZ JUAN CARLOS , MOSQUERA MAR , RAMOS BELÉN , RAMÍREZ ROSA , DE ORY FERNANDO , ECHEVARRIA JUAN EMILIO
Published: February 2010

Sanz JC, Mosquera M, Ramos B, Ramírez R, de Ory F, Echevarria JE. Assessment of RNA amplification by multiplex RT‐PCR and IgM detection by indirect and capture ELISAs for the diagnosis of measles and rubella. APMIS 2010; 118: 203–9.

The aim of the study was to compare RNA amplification using multiplex RT‐PCR and IgM detection by means of indirect and capture ELISAs for the diagnosis of measles and rubella. A total of 229 cases of maculopapular rash with serum and throat swab samples were included. Specific serological IgM to measles and rubella was determined by Enzygnost® (Siemens) and PlateliaTM (Bio‐Rad). Both viruses were researched using multiplex RT‐PCR performed on throat samples. Criteria for inclusion of measles or rubella cases were a positive RT‐PCR result for one virus and negative for the other; and/or a positive IgM result for one virus by both ELISAs and negative RT‐PCR for the other virus. A total of 74 cases were classified as measles and 54 as rubella. In measles, sensitivity and specificity were 93.2% and 100% for RT‐PCR, 97.3% and 98.1% for Enzygnost®, and 90.5% and 95.5% for PlateliaTM. For rubella, these values were 42.6% and 100% for RT‐PCR, 100% and 97.1% for Enzygnost®, and 94.4% and 98.3% for PlateliaTM. Enzygnost® and PlateliaTM are useful techniques for detecting IgM against measles and rubella. RNA amplification by RT‐PCR was both sensitive and specific for the diagnosis of measles; however, for rubella, the sensitivity of this technique must be improved.
Evaluation of coxsackievirus and adenovirus receptor expression in human benign and malignant thyroid lesions
Authors: GIAGINIS CONSTANTINOS , ZARROS APOSTOLOS , ALEXANDROU PARASKEVI , KLIJANIENKO JERZY , DELLADETSIMA IOANNA , THEOCHARIS STAMATIOS
Published: February 2010

Giaginis C, Zarros A, Alexandrou P, Klijanienko J, Delladetsima I, Theocharis S. Evaluation of coxsackievirus and adenovirus receptor expression in human benign and malignant thyroid lesions. APMIS 2010; 118: 210–21.

Coxsackievirus and adenovirus receptor (CAR) expression on tumor cells is associated with sensitivity to adenoviral infection, being considered as a surrogate marker for monitoring and/or predicting adenovirus‐mediated gene therapy. The aim of this study was to evaluate the clinical significance of CAR expression in human benign and malignant thyroid lesions. CAR protein expression was assessed immunohistochemically on paraffin‐embedded thyroid tissues from 107 patients with benign and malignant lesions and was statistically analyzed in relation to histopathologic type; tumor size; lymph node metastasis; capsular, lymphatic and vessel invasion; as well as follicular cells’ proliferative capacity. CAR immunoreactivity was characterized as negative/weak in 53 (49.53%), moderate in 31 (28.97%) and strong in 23 (21.50%) of 107 thyroid cases. CAR immunoreactivity was significantly increased in malignant compared with that in benign thyroid lesions (p = 0.00002). Both malignant and benign thyroid lesions with enhanced follicular cells’ proliferative capacity showed significantly increased CAR immunoreactivity (p = 0.00027). In malignant thyroid lesions, enhanced CAR immunoreactivity was significantly associated with larger tumor size (p = 0.0067). The current data revealed that CAR immunoreactivity could be considered of diagnostic utility in thyroid neoplasia. Further research effort is warranted to delineate whether CAR could be considered clinically important for both diagnosis and future (gene) therapeutic applications in thyroid neoplasia.
Psychological predictors of sport injuries among junior soccer players
Authors: Johnson U. , Ivarsson A.
Published: February 2010

Previous researches have established models that specify psychological factors that could predict sport injuries. One example is Williams and Andersen's stress–injury model stressing factors such as anxiety, negative life stress and few coping resources. The purpose of the current study was to find psychological factors that could lead to an increased injury risk among junior soccer players, in addition to construct an empirical model of injury risk factors for soccer players. The participants were 108 male and female soccer players (m=17, 6) studying at soccer high schools in southwest Sweden. Five questionnaires were used, State Trait Anxiety Inventory, Sport Anxiety Scale, Life Events Survey for Collegiate Athletes, Athletic Coping Skills Inventory‐28 and Swedish universities Scales of Personality. Injury record was collected by athletic trainers at the schools during a period of 8 months. The result suggested four significant predictors that together could explain 23% of injury occurrence. The main factors are life event stress, somatic trait anxiety, mistrust and ineffective coping. These findings partly support Williams and Andersen's stress–injury model and are organized into an empirical model. Recommendations are given to sport medicine teams and coaches concerning issues in sport injury prevention.
Exploring exercise behavior, intention and habit strength relationships
Authors: de Bruijn G. J. , Rhodes R. E.
Published: February 2010

The purpose of this study was to explore the relevance of integrating exercise habit strength within the framework of the theory of planned behavior. Data were obtained from 538 undergraduate students [mean age=21.19 (SD=2.57); 28.4% males] using validated questionnaires and analyzed using regression analysis and discriminant function analysis. Findings indicated that exercise has both a cognitive and an automatic component and that stronger exercise habits make exercise less intentional, with the intention–exercise relationship nearly three times stronger at lower levels of exercise habit strength than at higher levels. Further, outcome expectancies regarding health and weight management resulting from sufficient exercise did not significantly differ between most profiles that were created from exercise behavior, motivation and habit strength. The results from this study demonstrate the usefulness of incorporating measures of exercise habit strength in order to further our understanding of relevant determinants of exercise behavior. Results also indicate that health outcomes of sufficient exercise are generally well known, implying that persuasive strategies should rather shift in emphasis toward instilling a sense of exercise confidence in various situations. This potentially valuable information may allow for a more thorough understanding of exercise determinants and the development of more effective interventions that target increased exercise levels.
Association of dopamine‐ and serotonin‐related genes with canine aggression
Authors: Våge J. , Wade C. , Biagi T. , Fatjó J. , Amat M. , Lindblad‐Toh K. , Lingaas F.
Published: January 2010

Human‐directed canine aggression was studied using 50 aggressive and 81 non‐aggressive dogs. We examined 62 single nucleotide polymorphisms (SNPs) occurring in or in the close vicinity of 16 neurotransmitter‐related genes. Allelic associations with aggression were identified for DRD1, HTR1D, HTR2C and SLC6A1. Risk or protective haplotypes for aggressive behaviour based on 2–5 SNPs were identified. The frequency of aggressive dogs varied significantly between the haplotypes within loci and the odds ratios of aggression in dogs with risk haplotypes compared with protective haplotypes varied from 4.4 (HTR2C) to 9.0 (SLC6A1). A risk haplotype across the neurotransmitter receptor gene HTR1D harboured a non‐synonymous SNP with a potential effect on protein function. We identified no haplotypes in complete association with the recorded phenotypes, supporting a complex inheritance of aggression.
α8‐Integrins are required for hippocampal long‐term potentiation but not for hippocampal‐dependent learning
Authors: Chan C.‐S. , Chen H. , Bradley A. , Dragatsis I. , Rosenmund C. , Davis R. L.
Published: January 2010

Integrins are heterodimeric transmembrane cell adhesion receptors that are essential for a wide range of biological functions via cell–matrix and cell–cell interactions. Recent studies have provided evidence that some of the subunits in the integrin family are involved in synaptic and behavioral plasticity. To further understand the role of integrins in the mammalian central nervous system, we generated a postnatal forebrain and excitatory neuron‐specific knockout of α8‐integrin in the mouse. Behavioral studies showed that the mutant mice are normal in multiple hippocampal‐dependent learning tasks, including a T‐maze, non‐match‐to‐place working memory task for which other integrin subunits like α3‐ and β1‐integrin are required. In contrast, mice mutant for α8‐integrin exhibited a specific impairment of long‐term potentiation (LTP) at Schaffer collateral–CA1 synapses, whereas basal synaptic transmission, paired‐pulse facilitation and long‐term depression (LTD) remained unaffected. Because LTP is also impaired in the absence of α3‐integrin, our results indicate that multiple integrin molecules are required for the normal expression of LTP, and different integrins display distinct roles in behavioral and neurophysiological processes like synaptic plasticity.
The structure of innate vocalizations in Foxp2‐deficient mouse pups
Authors: Gaub S. , Groszer M. , Fisher S. E. , Ehret G.
Published: January 2010

Heterozygous mutations of the human FOXP2 gene are implicated in a severe speech and language disorder. Aetiological mutations of murine Foxp2 yield abnormal synaptic plasticity and impaired motor‐skill learning in mutant mice, while knockdown of the avian orthologue in songbirds interferes with auditory‐guided vocal learning. Here, we investigate influences of two distinct Foxp2 point mutations on vocalizations of 4‐day‐old mouse pups (Mus musculus). The R552H missense mutation is identical to that causing speech and language deficits in a large well‐studied human family, while the S321X nonsense mutation represents a null allele that does not produce Foxp2 protein. We ask whether vocalizations, based solely on innate mechanisms of production, are affected by these alternative Foxp2 mutations. Sound recordings were taken in two different situations: isolation and distress, eliciting a range of call types, including broadband vocalizations of varying noise content, ultrasonic whistles and clicks. Sound production rates and several acoustic parameters showed that, despite absence of functional Foxp2, homozygous mutants could vocalize all types of sounds in a normal temporal pattern, but only at comparably low intensities. We suggest that altered vocal output of these homozygotes may be secondary to developmental delays and somatic weakness. Heterozygous mutants did not differ from wild‐types in any of the measures that we studied (R552H ) or in only a few (S321X ), which were in the range of differences routinely observed for different mouse strains. Thus, Foxp2 is not essential for the innate production of emotional vocalizations with largely normal acoustic properties by mouse pups.
Association between AKT1 but not AKTIP genetic variants and increased risk for suicidal behavior in bipolar patients
Authors: Magno L. A. V. , Miranda D. M. , Neves F. S. , Pimenta G. J. , Mello M. P. , De Marco L. A. , Correa H. , Romano‐Silva M. A.
Published: January 2010

We tested the hypothesis that the presence of AKT1 and AKTIP polymorphisms, target genes that encode key proteins in the signaling of dopaminergic and serotonergic systems, is associated with suicidal behavior in bipolar patients. The subjects were 273 patients diagnosed with bipolar disorder I or II (age = 41.4 ± 12.9). TaqMan single‐nucleotide polymorphism genotyping assays (AKT1: rs2494731, rs3803304, rs3730358, rs10149779, rs2494746, rs1130214 and rs249878; AKTIP: rs9302648 and rs7189819) were used. We found that the AKT1 marker showed an association with suicide attempts (rs1130214, P < 0.05) and attempted violent attacks (rs2494746, P < 0.05). One out of the seven tested markers of AKT1 attained significant genotype association with violent attempt (rs2494731; P < 0.05). A significant association was detected in the AKT1 haplotype test. We did not observe an association between suicidal behavior and AKTIP variants and also did not find an interaction between AKTIP and AKT1 polymorphisms. In addition, we found that demographic and clinical data are associated with lifetime history of suicide attempts. Our data suggest that demographic and clinical characteristics and AKT1 single markers and haplotypes, but not AKTIP polymorphisms or interactions between AKT1 and AKTIP, are associated with increased risk for suicidal behavior in bipolar patients.
BDNF moderates early environmental risk factors for anxiety in mouse
Authors: Carola Valeria , Gross Cornelius
Published: January 2010

Anxiety is known to be influenced by both adverse childhood experiences and genetic susceptibility factors. A polymorphism in the brain‐derived neurotrophic factor (BDNF) gene modulates the association between adverse early experiences and risk for anxiety and depression in adulthood. An animal model of this gene‐by‐environment risk factor is lacking. Using two different early environmental manipulations, we found that a heterozygous null mutation in the mouse BDNF gene moderated the long‐term effect of maternal care on innate anxiety behavior. Although changes in maternal care were associated with mild changes in anxiety in wild‐type mice, this effect was magnified in heterozygous null BDNF mice with high‐ and low‐maternal care associated with low and high levels, respectively, of avoidance behavior as measured in the open field and elevated plus maze tests. These data argue for an increased sensitivity to early environmental influences of mice with reduced BDNF function and support the important role of this neurotrophic factor in the developmental plasticity of brain circuits controlling anxiety.
Association between genetic variants of the metabotropic glutamate receptor 3 (GRM3) and cognitive set shifting in healthy individuals
Authors: Baune B. T. , Suslow T. , Beśte C. , Birosova E. , Domschke K. , Sehlmeyer C. , Konrad C.
Published: January 2010

Set‐shifting and maintenance are complex cognitive processes, which are often impaired in schizophrenia. The genetic basis of these processes is poorly understood. We aimed to investigate the association between genetic variants of the metabotropic glutamate receptor 3 (GRM3) and cognitive set‐shifting in healthy individuals. The relationship between 14 selected single nucleotide polymorphisms (SNPs) of the GRM3 gene and cognitive set‐shifting as measured by perseverative errors using the modified card sorting test (MCST) was analysed in a sample of N = 98 young healthy individuals (mean age in years: 22.7 ± 0.19). Results show that SNP rs17676277 is related to the performance on the MCST. Subjects with the TT genotype showed significantly less perseverative errors as compared with the AA (P = 0.025) and AT (P = 0.0005) and combined AA/AT genotypes (P = 0.0005). Haplotype analyses suggest the involvement of various SNPs of the GRM3 gene in perseverative error processing in a dominant model of inheritance. The findings strongly suggest that the genetic variation (rs17676277 and three haplotypes) in the metabotropic GRM3 is related to cognitive set‐shifting in healthy individuals independent of working memory. However, because of a relatively small sample size for a genetic association study, the present results are tentative and require replication.
Health‐related quality of life and its determinants in children and adolescents born with oesophageal atresia
Authors: Peetsold MG , Heij HA , Deurloo JA , Gemke RJBJ
Published: February 2010

Aim:  Following surgical correction in the neonatal period, patients born with oesophageal atresia have significant co‐morbidity, particularly in childhood. This study evaluates health‐related quality of life and its determinants such as concomitant anomalies and the presence of respiratory and/or gastro‐intestinal symptoms 6–18 years after repair of oesophageal atresia.

Methods:  Parents of 24 patients with oesophageal atresia completed the child health questionnaire for parents and 37 patients completed the child form. Gastro‐intestinal symptoms were assessed by a validated standardized reflux questionnaire. Results were compared with a healthy reference population.

Results:  Parents as well as patients themselves scored significantly lower on the domain general health perception. According to parents, general health perception was negatively affected by age at follow‐up and concomitant anomalies. Patients reported that reflux symptoms reduced general health perception.

Conclusion:  In this first study describing health‐related quality of life in children and adolescents born with oesophageal atresia, we demonstrated that general health remains impaired because of a high incidence of concomitant anomalies and gastrointestinal symptoms in patients with oesophageal atresia when compared with the healthy reference population.
Pain in children with cerebral palsy: a cross‐sectional multicentre European study
Authors: Parkinson KN , Gibson L , Dickinson HO , Colver AF
Published: February 2010

Aim: To determine the prevalence and associations of self‐reported and parent‐reported pain in children with cerebral palsy (CP) of all severities.

Method: Cross‐sectional design using a questionnaire; analysis using ordinal regression. Children aged 8–12 years were randomly selected from population‐based registers of children with CP in eight European regions; a further region recruited 75 children from multiple sources. Outcome measures were pain in the previous week among children who could self‐report and parents’ perception of their child’s pain in the previous 4 weeks.

Results: Data on pain were available from 490 children who could self‐report and parents of 806 children (those who could and could not self‐report). The estimated population prevalence of self‐reported pain in the previous week was 60% (95% CI: 54–65%) and that of parent‐reported pain in the previous 4 weeks was 73% (95% CI: 69–76%). In self‐reporting children, older children reported more pain but pain was not significantly associated with severity of impairment. In parent reports, severity of child impairment, seizures and parental unemployment were associated with more frequent and severe pain.

Conclusion: Pain in children with CP is common. Clinicians should enquire about pain and consider appropriate physical, therapeutic or psychological management.
Respiratory viral infection in lower airways of asymptomatic children
Authors: Thavagnanam S , Christie SN , Doherty GM , Coyle PV , Shields MD , Heaney LG
Published: February 2010

Aim:  The aim of this study was to determine if asthmatic children have viruses more commonly detected in lower airways during asymptomatic periods than normal children.

Methods:  Fifty‐five asymptomatic children attending elective surgical procedures (14 with stable asthma, 41 normal controls) underwent non‐bronchoscopic bronchoalveolar lavage. Differential cell count and PCR for 13 common viruses were performed.

Results:  Nineteen (35%) children were positive for at least one virus, with adenovirus being most common. No differences in the proportion of viruses detected were seen between asthmatic and normal ‘control’ children. Viruses other than adenovirus were associated with higher neutrophil counts, suggesting that they caused an inflammatory response in both asthmatics and controls (median BAL neutrophil count, 6.9% for virus detected vs. 1.5% for virus not detected, p = 0.03).

Conclusions:  Over one‐third of asymptomatic children have a detectable virus (most commonly adenovirus) in the lower airway; however, this was not more common in asthmatics. Viruses other than adenovirus were associated with elevated neutrophils suggesting that viral infection can be present during relatively asymptomatic periods in asthmatic children.
A search for galaxies in and around an HI overdense region at z = 5
Authors: Matsuda Y. , Richard J. , Smail Ian , Kashikawa N. , Shimasaku K. , Frye B. L. , Yamada T. , Nakamura Y. , Hayashino T. , Fujii T.
Published: February 2010

We present the discovery of a large-scale structure of emission-line galaxies at redshift z= 4.86 behind a massive cluster of galaxies, A1689. Previous spectroscopic observations of a galaxy, A1689−7.1 at z= 4.87, near this structure, revealed a possible overdense region of intergalactic medium (IGM) around the galaxy, which extends at least ∼80 comoving Mpc along the line of sight. In order to investigate whether this z∼ 5 IGM overdense region contains a galaxy overdensity, we undertook narrow- and broad-band imaging observations around A1689−7.1 with Subaru/Suprime-Cam. We detected 51 candidates as Lyα emitters at redshift z= 4.86 ± 0.03 in the 32 × 24 arcmin2 field of view. After correction for lensing by the foreground cluster, we found a large-scale (∼20 × 60 comoving Mpc) overdense region of galaxies around A1689−7.1 in the source plane at z= 4.86. The densest peak in this region has an overdensity of δ∼ 4, suggesting that this structure is probably a good candidate for a protocluster which may evolve into a massive cluster of galaxies in the present-day Universe. A1689−7.1 is located at the edge of this region, where the local galaxy density is ∼1.6 times the mean density and is close to the density contrast in the IGM along the line of sight to A1689−7.1 estimated from the optical depth. The overdensities of galaxies we have found may suggest that at least some parts of the IGM overdense region have already started to form galaxies and moreover they relate to the formation of a protocluster. Although we lack information on the three-dimensional distributions of both IGM and galaxy overdense regions, the similarity of the scales of both regions may suggest that the two are parts of a single large-scale structure, which would be an large edge-on sheet along the line of sight with a size of ∼20 × 60 × 80 comoving Mpc.
Induction of apoptosis by A3 adenosine receptor agonist N6‐(3‐iodobenzyl)‐adenosine‐5′‐N‐methylcarboxamide in human leukaemia cells: a possible involvement of intracellular mechanism
Authors: Mlejnek P. , Dolezel P.
Published: January 2010

Aim:  The sensitivity of cancer cells which exhibit multi‐drug resistance phenotype to A3 adenosine receptor (A3AR) agonist N6‐(3‐iodobenzyl)‐adenosine‐5′‐N‐methylcarboxamide (IB‐MECA) was studied.

Methods:  To establish direct relationship between P‐glycoprotein (P‐gp, ABCB1 and MDR1) expression and IB‐MECA induced cell death, a straightforward method for precise estimation of intracellular level of this A3AR agonist was developed.

Results:  We subjected three human leukaemia cell lines HL‐60, K562 and K562/HHT to treatment with micromolar concentrations of IB‐MECA. Although all cell lines used expressed A3AR, there was a large difference in their sensitivity to IB‐MECA. While HL‐60 and K562 cells were almost equally sensitive, the K562/HHT cells, which exhibit a multi‐drug resistance phenotype because of overexpression of P‐gp, were significantly more resistant. We found that the intracellular level of IB‐MECA in K562/HHT cells was approx. 10 times lower than those in HL‐60 or K562 cells. Inhibitors of P‐gp, including cyclosporine A (CsA) and verapamil (Vpa), increased the intracellular level of IB‐MECA and reversed the resistance of K562/HHT cells to this drug. Accordingly, shRNA‐mediated down‐regulation of P‐gp significantly increased the intracellular level of IB‐MECA in K562/HHT cells which simultaneously exhibited reduced resistance to this A3AR agonist. In addition, an in vitro enzyme‐based assay provided evidence that IB‐MECA might serve as a substrate for P‐gp.

Conclusion:  Our results suggest that P‐gp overexpression prevents cells from IB‐MECA induced apoptosis despite the A3AR expression. Pro‐apoptotic effect of IB‐MECA seemed to strongly depend on its intracellular accumulation rather than on its interaction with A3AR.
Extracellular cAMP inhibits P2X3 receptors in rat sensory neurones through G protein‐mediated mechanism
Authors: Mamenko M. V. , Chizhmakov I. V. , Volkova T. M. , Verkhratsky A. , Krishtal O. A.
Published: January 2010

Aim:  To identify the mechanisms of P2X3 receptor inhibition by extracellular cyclic adenosine monophosphate (cAMP) in rat dorsal root ganglion (DRG) neurones.

Methods:  Whole‐cell currents were measured in cultured DRG neurones using the combination of voltage and concentration clamp.

Results:  We have found that extracellular cAMP inhibits P2X3‐mediated currents in a concentration‐ and use‐dependent manner. The P2X3 currents, activated by ATP applied every 4 min, were inhibited by 55% in the presence of 10 μm cAMP and by 81% in the presence of 30 μm cAMP. At 8 min interval between ATP applications the same concentration of cAMP did not alter the currents. Addition of 0.5 mm of guanosine 5′‐O‐(2‐thiodiphosphate) to intracellular solution blocked the inhibitory action of cAMP. The inhibitory effects of cAMP were not mimicked by extracellular application of 30 μm adenosine.

Conclusions:  In this paper, we demonstrate, for the first time, that extracellular application of cAMP to rat sensory neurones inhibits P2X3 receptors via a G protein‐coupled mechanism in a use‐dependent manner, thus indicating the neuronal expression of specific plasmalemmal cAMP receptor.
Diadenosine tetraphosphate protects sympathetic terminals from 6‐hydroxydopamine‐induced degeneration in the eye
Authors: Hoyle C. H. V. , Pintor J. J.
Published: January 2010

Aims:  To examine diadenosine tetraphosphate (Ap4A) for its ability to protect the eye from neurodegeneration induced by subconjunctival application of 6‐hydroxydopamine (6‐OHDA).

Methods:  Intraocular neurodegeneration of anterior structures was induced by subconjunctival injections of 6‐OHDA. Animals were pre‐treated with topical corneal applications of Ap4A or saline.

Results:  6‐OHDA caused miosis, abnormal pupillary light reflexes, a precipitous drop in intraocular pressure and loss of VMAT2‐labelled (vesicle monoamine transporter‐2, a marker for sympathetic neurones) intraocular neurones. Pre‐treatment with Ap4A prevented all of these changes from being induced by 6‐OHDA, demonstrably preserving the sympathetic innervation of the ciliary processes. This neuroprotective action of Ap4A was not shared with the related compounds adenosine, ATP or diadenosine pentaphosphate. P2‐receptor antagonists showed that the effects of Ap4A were mediated via a P2‐receptor.

Conclusion:  Ap4A is a natural component of tears and aqueous humour, and its neuroprotective effect indicates that one of its physiological roles is to maintain neurones within the eye. Ap4A can prevent the degeneration of intraocular nerves, and it is suggested that this compound may provide the basis for a therapeutic intervention aimed at preventing or ameliorating the development of glaucoma associated with neurodegenerative diseases. Furthermore, subconjunctival application of 6‐OHDA provides a useful model for studying diseases that cause ocular sympathetic dysautonomia.
Estimation of endogenous adenosine activity at adenosine receptors in guinea‐pig ileum using a new pharmacological method
Authors: Nilsson K. F. , Grishina V. A. , Glaumann C. , Gustafsson L. E.
Published: January 2010

Aim: Adenosine modulates neurotransmission and in the intestine adenosine is continuously released both from nerves and from smooth muscle. The main effect is modulation of contractile activity by inhibition of neurotransmitter release and by direct smooth muscle relaxation. Estimation of adenosine concentration at the receptors is difficult due to metabolic inactivation. We hypothesized that endogenous adenosine concentrations can be calculated by using adenosine receptor antagonist and agonist and dose ratio (DR) equations.

Methods: Plexus‐containing guinea‐pig ileum longitudinal smooth muscle preparations were made to contract intermittently by electrical field stimulation in organ baths. Schild plot regressions were constructed with 2‐chloroadenosine (agonist) and 8‐(p‐sulfophenyl)theophylline (8‐PST; antagonist). In separate experiments the reversing or enhancing effect of 8‐PST and the inhibiting effect of 2‐chloroadenosine (CADO) were analysed in the absence or presence of an adenosine uptake inhibitor (dilazep), and nucleoside overflow was measured by HPLC.

Results: Using the obtained DR, baseline adenosine concentration was calculated to 28 nmexpressed as CADO activity, which increased dose dependently after addition of 10−6 mdilazep to 150 nm(P < 0.05). HPLC measurements yielded a lower fractional increment (80%) in adenosine during dilazep, than found in the pharmacological determination (440%).

Conclusion: Endogenous adenosine is an important modulator of intestinal neuro‐effector activity, operating in the linear part of the dose–response curve. Other adenosine‐like agonists might contribute to neuromodulation and the derived formulas can be used to calculate endogenous agonist activity, which is markedly affected by nucleoside uptake inhibition. The method described should be suitable for other endogenous signalling molecules in many biological systems.