bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of an attachment-based intervention on the cortisol production of infants and toddlers in foster care
Authors: Dozier Mary , Peloso Elizabeth , Lewis Erin , Laurenceau Jean-Philippe , Levine Seymour 
Published: July 2008

AbstractStudies with nonhuman primates and rodents, as well as with human children, have suggested that early separations from caregivers are often associated with changes in the functioning of the hypothalamus–pituitary–adrenal (HPA) axis. On the basis of these findings, we designed a relational intervention that was intended to normalize HPA functioning among children in foster care. This paper presents findings from a randomized clinical trial that assessed the effectiveness of a relational intervention (Attachment and Biobehavioral Catch-up [ABC]) with regard to HPA functioning. The ABC intervention was intended to enhance children's ability to regulate physiology and behavior. The control intervention (Developmental Education for Families) was intended to enhance children's cognitive skills. A comparison group of children who had never been in foster care was also included. Children's cortisol production was assessed upon arrival at the lab, and 15 and 30 min following the Strange Situation. Random effects analyses of variance were performed to assess differences in initial values and change between children in the two intervention groups. Children in the ABC intervention and comparison group children showed lower initial values of cortisol than children in the treatment control group, considering arrival at lab as initial values (p < .05). Groups did not differ significantly in change over time. These results suggest that the ABC intervention is effective in helping children regulate biology in ways more characteristic of children who have not experienced early adversity.
Prevention of bipolar disorder in at-risk children: Theoretical assumptions and empirical foundations
Authors: Miklowitz David J. , Chang Kiki D. 
Published: July 2008

AbstractThis article examines how bipolar symptoms emerge during development, and the potential role of psychosocial and pharmacological interventions in the prevention of the onset of the disorder. Early signs of bipolarity can be observed among children of bipolar parents and often take the form of subsyndromal presentations (e.g., mood lability, episodic elation or irritability, depression, inattention, and psychosocial impairment). However, many of these early presentations are diagnostically nonspecific. The few studies that have followed at-risk youth into adulthood find developmental discontinuities from childhood to adulthood. Biological markers (e.g., amygdalar volume) may ultimately increase our accuracy in identifying children who later develop bipolar I disorder, but few such markers have been identified. Stress, in the form of childhood adversity or highly conflictual families, is not a diagnostically specific causal agent but does place genetically and biologically vulnerable individuals at risk for a more pernicious course of illness. A preventative family-focused treatment for children with (a) at least one first-degree relative with bipolar disorder and (b) subsyndromal signs of bipolar disorder is described. This model attempts to address the multiple interactions of psychosocial and biological risk factors in the onset and course of bipolar disorder.
How can the study of biological processes help design new interventions for children with severe antisocial behavior?
Authors: van Goozen Stephanie H. M. , Fairchild Graeme 
Published: July 2008

AbstractChildren with severe antisocial behavior have an increased risk of showing violently aggressive and other forms of problem behavior in adolescence and adulthood. It is well established that both biological and social factors are involved in the development of antisocial behavior. The primary aim of this paper is to discuss the evidence that specific neurobiological systems are involved in the etiology of childhood-onset antisocial behavior. These factors are responsible for the severity of the behavioral problems observed in antisocial children, but they also play a role in their persistence, because they influence children's interactions with their environment. We will discuss the possible causes of disruptions in neurobiological systems in childhood antisocial behavior and point out the implications of these findings for theory and clinical practice. We will argue that familial factors (e.g., genetic influences, early childhood adversity) are linked to negative behavioral outcomes (e.g., antisocial behavior problems) through the mediating and transactional interplay with neurobiological deficits. An investigation of neurobiological functioning in antisocial children might not only indicate which children are most likely to persist in engaging in severe antisocial behavior, but also guide the development of new interventions.
Interactions of Sox10 and Egr2 in myelin gene regulation
Authors: Jones Erin A. , Jang Sung-Wook , Mager Gennifer M. , Chang Li-Wei , Srinivasan Rajini , Gokey Nolan G. , Ward Rebecca M. , Nagarajan Rakesh , Svaren John 
Published: July 2008

AbstractMyelination in the PNS is accompanied by a large induction of the myelin protein zero (Mpz) gene to produce the most abundant component in peripheral myelin. Analyses of knockout mice have shown that the EGR2/Krox20 and SOX10 transcription factors are required for Mpz expression. Our recent work has shown that the dominant EGR2 mutations associated with human peripheral neuropathies cause disruption of EGR2/SOX10 synergy at specific sites, including a conserved enhancer element in the first intron of the Mpz gene. Further investigation of Egr2/Sox10 interactions reveals that activation of the Mpz intron element by Egr2 requires both Sox10-binding sites. In addition, both Egr1 and Egr3 cooperate with Sox10 to activate this element, which indicates that this capacity is conserved among Egr family members. Finally, a conserved composite structure of Egr2/Sox10-binding sites in the genes encoding Mpz, myelin-associated glycoprotein and myelin basic protein genes was used to screen for similar modules in other myelin genes, revealing a potential regulatory element in the periaxin gene. Overall, these results elucidate a working model for developmental regulation of Mpz expression, several facets of which extend to regulation of other peripheral myelin genes.
Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model
Authors: Giovannoni Roberto , Maggio Nicola , Rosaria Bianco Maria , Cavaliere Carlo , Cirillo Giovanni , Lavitrano Marialuisa , Papa Michele 
Published: July 2008

AbstractSpinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeats within the coding sequence of the ataxin-1 protein. In the present study, we used a conditional transgenic mouse model of SCA1 to investigate very early molecular and morphological changes related to the behavioral phenotype. In mice with neural deficits detected by rotarod performance, and simultaneous spatial impairments in exploratory activity and uncoordinated gait, we observed both significant altered expression and patchy distribution of excitatory amino acids transporter 1. The molecular changes observed in astroglial compartments correlate with changes in synapse morphology; synapses have a dramatic reduction of the synaptic area external to the postsynaptic density. By contrast, Purkinje cells demonstrate preserved structure. In addition, severe reactive astrocytosis matches changes in the glial glutamate transporter and synapse morphology. We propose these morpho-molecular changes are the cause of altered synaptic transmission, which, in turn, determines the onset of the neurological symptoms by altering the synaptic transmission in the cerebellar cortex of transgenic animals. This model might be suitable for testing drugs that target activated glial cells in order to reduce CNS inflammation.
The cardiovascular and pharmacokinetic profile of dofetilide in conscious telemetered beagle dogs and cynomolgus monkeys
Authors: Haushalter T M , Friedrichs G S , Reynolds D L , Barecki‐Roach M , Pastino G , Hayes R , Bass A S 
Published: July 2008

Background and purpose:The effects of dofetilide were studied in monkeys and dogs. Pharmacokinetic data were generated together with the monitoring of cardiovascular changes in order to compare effects relative to human exposure.Experimental approach:Beagle dogs and cynomolgus monkeys were telemetered to collect arterial blood pressure, heart rate and ECG for 6 h after selected oral doses of dofetilide. Pharmacokinetic parameters were determined for each dose.Key results:Dogs: increases in the QTcinterval reached 56 ms in dogs dosed with 0.3 mg kg−1of dofetilide. Premature ventricular contractions and right bundle branch block were evident at this dose, without changes in cardiovascular parameters. The meanCmaxvalues were 3.35 and 60.15 ng mL−1at doses of 0.03 and 0.3 mg kg−1, respectively.Monkeys: increases in QTcintervals reached 40–50 ms after 0.03 mg kg−1. T‐wave changes were observed after 0.03 mg kg−1without changes in cardiovascular parameters. The meanCmaxvalues following oral doses of 0.01 and 0.03 mg kg−1were 0.919 ng mL−1and 1.85 ng mL−1, respectively.Conclusions and implications:Despite dofetilide exposure comparable to that in humans, QTcresponses in dogs were greater than those reported in humans. A comparable human dose used in the monkey achieved only half of the exposure but was associated with twofold greater increases in QTc. Our data support the view that safety risk assessments of new drugs in animal models should ensure that the clinical therapeutic range of exposure is achieved and any untoward effects interpreted accordingly.British Journal of Pharmacology(2008)154, 1457–1464; doi:10.1038/bjp.2008.275; published online 7 July 2008
Principles of Safety Pharmacology
Authors: Pugsley M K , Authier S , Curtis M J 
Published: July 2008

Safety Pharmacology is a rapidly developing discipline that uses the basic principles of pharmacology in a regulatory‐driven process to generate data to inform risk/benefit assessment. The aim of Safety Pharmacology is to characterize the pharmacodynamic/pharmacokinetic (PK/PD) relationship of a drug's adverse effects using continuously evolving methodology. Unlike toxicology, Safety Pharmacology includes within its remit a regulatory requirement to predict the risk of rare lethal events. This gives Safety Pharmacology its unique character. The key issues for Safety Pharmacology are detection of an adverse effect liability, projection of the data into safety margin calculation and finally clinical safety monitoring. This article sets out to explain the drivers for Safety Pharmacology so that the wider pharmacology community is better placed to understand the discipline. It concludes with a summary of principles that may help inform future resolution of unmet needs (especially establishing model validation for accurate risk assessment). Subsequent articles in this issue of the journal address specific aspects of Safety Pharmacology to explore the issues of model choice, the burden of proof and to highlight areas of intensive activity (such as testing for drug‐induced rare event liability, and the challenge of testing the safety of so‐called biologics (antibodies, gene therapy and so on.). British Journal of Pharmacology (2008) 154, 1382–1399; doi:10.1038/bjp.2008.280; published online 7 July 2008
Production of a specific extracellular inhibitor of TRPM3 channels
Authors: Naylor J , Milligan C J , Zeng F , Jones C , Beech D J 
Published: July 2008

Background and purpose:Isoform‐specific ion channel blockers are useful for target validation in drug discovery and can provide the basis for new therapeutic agents and aid in determination of physiological functions of ion channels. The aim of this study was to generate a specific blocker of human TRPM3 channels as a tool to help investigations of this member of the TRP cationic channel family.Experimental approach:A polyclonal antibody (TM3E3) was made to a conserved peptide of the third extracellular (E3) loop of TRPM3 and tested for binding and functional effect. Studies of channel activity were made by whole‐cell planar patch‐clamp and fura‐2 intracellular Ca2+ measurement.Key results:Ionic current mediated by TRPM3 was inhibited partially by TM3E3 over a period of 5–10 min. Ca2+ entry in TRPM3‐expressing cells was also partially inhibited by TM3E3 in a peptide‐specific manner and independently of the type of agonist used to activate TRPM3. TM3E3 had no effect on TRPC5, TRPV4, TRPM2 or an endogenous ATP response.Conclusions and implications:The data show the successful development of a specific TRPM3 inhibitor and give further confidence in E3 targeting as an approach to producing isoform‐specific ion channel blockers.British Journal of Pharmacology (2008) 155, 567–573; doi:10.1038/bjp.2008.283; published online 7 July 2008
Interaction with the hERG channel and cytotoxicity of amiodarone and amiodarone analogues
Authors: Waldhauser K M , Brecht K , Hebeisen S , Ha H R , Konrad D , Bur D , Krähenbühl S 
Published: July 2008

Background and purpose:Amiodarone (2‐n‐butyl‐3‐[3,5 diiodo‐4‐diethylaminoethoxybenzoyl]‐benzofuran, B2‐O‐CH2CH2‐N‐diethyl) is an effective class III antiarrhythmic drug demonstrating potentially life‐threatening organ toxicity. The principal aim of the study was to find amiodarone analogues that retained human ether‐a‐go‐go‐related protein (hERG) channel inhibition but with reduced cytotoxicity.Experimental approach:We synthesized amiodarone analogues with or without a positively ionizable nitrogen in the phenolic side chain. The cytotoxic properties of the compounds were evaluated using HepG2 (a hepatocyte cell line) and A549 cells (a pneumocyte line). Interactions of all compounds with the hERG channel were measured using pharmacological andin silicomethods.Key results:Compared with amiodarone, which displayed only a weak cytotoxicity, the mono‐ and bis‐desethylated metabolites, the further degraded alcohol (B2‐O‐CH2‐CH2‐OH), the corresponding acid (B2‐O‐CH2‐COOH) and, finally, the newly synthesized B2‐O‐CH2‐CH2‐N‐pyrrolidine were equally or more toxic. Conversely, structural analogues such as the B2‐O‐CH2‐CH2‐N‐diisopropyl and the B2‐O‐CH2‐CH2‐N‐piperidine were significantly less toxic than amiodarone. Cytotoxicity was associated with a drop in the mitochondrial membrane potential, suggesting mitochondrial involvement. Pharmacological andin silicoinvestigations concerning the interactions of these compounds with the hERG channel revealed that compounds carrying a basic nitrogen in the side chain display a much higher affinity than those lacking such a group. Specifically, B2‐O‐CH2‐CH2‐N‐piperidine and B2‐O‐CH2‐CH2‐N‐pyrrolidine revealed a higher affinity towards hERG channels than amiodarone.Conclusions and implications:Amiodarone analogues with better hERG channel inhibition and cytotoxicity profiles than the parent compound have been identified, demonstrating that cytotoxicity and hERG channel interaction are mechanistically distinct and separable properties of the compounds.British Journal of Pharmacology(2008)155, 585–595; doi:10.1038/bjp.2008.287; published online 7 July 2008
Dopamine‐induced programmed cell death is associated with cytochrome c release and caspase‐3 activation in snail salivary gland cells
Authors: Pirger Zsolt , Rácz Boglárka , Kiss Tibor 
Published: July 2008

Background information. PCD (programmed cell death) is a common mechanism to remove unwanted and excessive cells from organisms. In several exocrine cell types, PCD mode of release of secretory products has been reported. The molecular mechanism of the release, however, is largely unknown. Our aim was to study the molecular mechanism of saliva release from cystic cells, the specific cell type of snail SGs (salivary glands).Results. SG cells in active feeding animals revealed multiple morphological changes characteristic of PCD. Nerve stimulation and DA (dopamine) increased the number of TUNEL (terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling)‐positive cells both in inactive and feeding animals. The DA‐induced PCD was prevented by TEA (tetraethylammonium chloride) and eticlopride, emphasizing the role of K channels and D2 receptors in the PCD of cystic cells. DA enhanced cyto‐c (cytochrome c) translocation into the cytosol and methyl‐β‐cyclodextrin prevented it, suggesting apoptosome formation and ceramide involvement in the PCD linking of the surface DA receptor to mitochondria. Western blot analysis revealed that the release of cyto‐c was under the control of Bcl‐2 and Bad. DA also increased the active caspase‐3 in gland cells while D2 receptor antagonists and TEA attenuated it.Conclusion. Our results provide evidence for a type of transmitter‐mediated pathway that regulates the PCD of secretory cells in a mitochondrial‐caspase‐dependent manner. The activation of specific molecules, such as K channels, DA receptors, cyto‐c, ceramide, Bcl‐2 proteins and caspase‐3, but not caspase‐8, was demonstrated in cells involved in the DA‐induced PCD, suggesting that PCD is a physiological method for the release of saliva from SG cells.
Asp218 participates with Asp213 to bind a Ca2+ atom into the S1 subsite of aminopeptidase A: a key element for substrate specificity
Authors: Claperon Cédric , Rozenfeld Raphael , Iturrioz Xavier , Inguimbert Nicolas , Okada Mayumi , Roques Bernard , Maigret Bernard , Llorens-Cortes Catherine 
Published: July 2008

APA (aminopeptidase A; EC 3.4.11.7) is a membrane-bound zinc metallopeptidase, also activated by Ca2+, involved in the formation of brain angiotensin III, which exerts a tonic stimulatory action on the central control of blood pressure in hypertensive animals. In the present study, in the three-dimensional model of the ectodomain of mouse APA, we docked the specific APA inhibitor glutamate phosphonate, in the presence of Ca2+. The model showed the presence of one Ca2+ atom in an hydrophilic pocket corresponding to the S1 subsite in which the lateral chain of the inhibitor is pointing. In this pocket, the Ca2+ atom was hexaco-ordinated with the acidic side chains of Asp213 and Asp218, the carbonyl group of Glu215 and three water molecules, one of them being engaged in a hydrogen bond with the negatively charged carboxylate side chain of the inhibitor. Mutagenic replacement of Asp213 and Asp218 with a conservative residue maintained the ability of mutated APAs to be activated by Ca2+. However, the replacement by a non-conservative residue abolished this property, demonstrating the crucial role of these residues in Ca2+ binding. We also showed the involvement of these residues in the strict specificity of APA in the presence of Ca2+ for N-terminal acidic residues from substrates or inhibitors, since mutagenic replacement of Asp213 and Asp218 induced a decrease of the inhibitory potencies of inhibitors homologous with acidic residues. Finally, this led to the rational design of a new potent APA inhibitor, NI926 (Ki=70 nM), which allowed us to precisely localize Asp213 at the entrance and Asp218 at the bottom of the S1 subsite. Taken together, these data provide new insight into the organization and functional role of the APA S1 subsite and will allow the design of pharmacophore of the inhibitor, helpful for the development of a new generation of APA inhibitors as central-acting antihypertensive agents.
A heterogeneity test for fine‐scale genetic structure
Authors: SMOUSE PETER E. , PEAKALL ROD , GONZALES EVA 
Published: July 2008

AbstractFor organisms with limited vagility and/or occupying patchy habitats, we often encounter nonrandom patterns of genetic affinity over relatively small spatial scales, labelled fine‐scale genetic structure. Both the extent and decay rate of that pattern can be expected to depend on numerous interesting demographic, ecological, historical, and mating system factors, and it would be useful to be able to compare different situations. There is, however, no heterogeneity test currently available for fine‐scale genetic structure that would provide us with any guidance on whether the differences we encounter are statistically credible. Here, we develop a general nonparametric heterogeneity test, elaborating on standard autocorrelation methods for pairs of individuals. We first develop a ‘pooled within‐population’ correlogram, where the distance classes (lags) can be defined as functions of distance. Using that pooled correlogram as our null‐hypothesis reference frame, we then develop a heterogeneity test of the autocorrelations among different populations, lag‐by‐lag. From these single‐lag tests, we construct an analogous test of heterogeneity for multilag correlograms. We illustrate with a pair of biological examples, one involving the Australian bush rat, the other involving toadshade trillium. The Australian bush rat has limited vagility, and sometimes occupies patchy habitat. We show that the autocorrelation pattern diverges somewhat between continuous and patchy habitat types. For toadshade trillium, clonal replication in Piedmont populations substantially increases autocorrelation for short lags, but clonal replication is less pronounced in mountain populations. Removal of clonal replicates reduces the autocorrelation for short lags and reverses the sign of the difference between mountain and Piedmont correlograms.
Interannual Variations in Mixed Rossby–Gravity Waves and Their Impacts on Tropical Cyclogenesis over the Western North Pacific
Authors: Chen Guanghua , Huang Ronghui 
Published: July 2008

Abstract
The present study investigates the transition from mixed Rossby–gravity (MRG) waves to tropical depression (TD)-type disturbances and its interannual variations over the western North Pacific (WNP), using ECMWF high-resolution data for the years of 1980–2001. As the equatorially trapped MRG waves propagate westward into the WNP, the MRG waves transit to TD-type disturbances because of background flow change. Interannual variations in the transition of MRG waves are related to monsoon circulation change in response to tropical convective heating over the warm pool (WP) region. When the WP is in a warm state, convective heating is enhanced in the western part of the WNP and the monsoon trough retreats westward, which induces a westward shift of the wave transition zone. In contrast, when the WP is in a relatively cold state, the eastward penetration of convection and monsoon trough shifts the wave transition to the eastern part of the WNP.
The zonal wind convergence and shear in the monsoon trough region provide a favorable condition for MRG waves to asymptote to Rossby waves. The asymmetric basic flow contributes to MRG waves moving off the equator toward the northwest. The northeast–southwest-oriented axis of TD-type disturbances in collaboration with the monsoonal environment is favorable for the conversion of eddy kinetic energy from the mean flow. The intensification of the amplitude and shortening of the wavelength during wave transition, to a certain extent, is associated with tropical cyclogenesis over the WNP. Therefore, interannual variations in the longitudinal location of tropical cyclone formation may be interpreted partly by displacement of the wave transition zone. Moreover, this phenomenon of cyclogenesis induced by the wave transition is more common during the cold years in which the monsoon trough penetrates eastward and equatorward.