bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repetitive and stereotyped behaviours in pervasive developmental disorders
Authors: Carcani‐Rathwell Iris , Rabe‐Hasketh Sophia , Santosh Paramala J. 
Published: November 2005

Background: Repetitive and stereotyped behaviours are a heterogeneous group of behaviours present in many neuropsychiatric disorders. Despite their core significance in PDD, it is not clear whether there are distinct groups of these behaviours with different specificity to autism.Methods: A two‐factor model of the repetitive behaviours, namely sensory/motor (lower‐order) and cognitive rigidity (higher‐order), was conceptualised. The model's goodness of fit to the data was examined in a clinic population of children with PDD, with and without mental retardation, and of those with only mental retardation (MR).Results: Subjects with PDD had higher rates of all repetitive behaviours compared to those with MR only. The existence of two independent ‘lower‐order’ and ‘higher‐order’ sub‐groups of the repetitive behaviours was confirmed only in the MR group. The lower‐order behaviours appear to be associated more with global developmental problems, whereas the higher‐order behaviours were significantly associated with ruminations in the PDD group.Conclusions: This study suggests that there may be two distinct sub‐groups of repetitive behaviours whereby the sensory and motor repetitive behaviours are generally associated with lower developmental age and less specific to the autistic syndrome whereas the ‘higher‐order’ behaviours may be a more ‘autism specific’ feature. The co‐occurrence of the lower‐ and higher‐order behaviours in PDD might reflect the end result of diffuse altered neural networks in these disorders thus being a specific feature of PDD. There is a need for more systematic studies of these behaviours not only in autistic disorders but also in other neuropsychiatric disorders.
Maternal smoking during pregnancy and offspring overt and covert conduct problems: a longitudinal study
Authors: Monuteaux Michael C. , Blacker Deborah , Biederman Joseph , Fitzmaurice Garrett , Buka Stephen L. 
Published: November 2005

Background: Empirical evidence demonstrates that conduct disorder (CD) symptoms tend to cluster into covert and overt domains. We hypothesized that overt and covert CD symptoms may be distinct constructs with distinct risk factors. An important risk factor for CD is maternal smoking during pregnancy. We further investigated this association, attending to overt and covert CD symptom subtypes. Also, we tested whether gender and socioeconomic status (SES) modified this association.Method: Participants were male and female adult offspring (n = 682) of a community sample of pregnant women followed longitudinally from prenatal life to age 22. Prospective assessments of maternal smoking during pregnancy were used to predict self‐reported DSM‐III CD symptoms.Results: Prenatal exposure to smoking was significantly associated with increased overt CD symptoms for participants of low SES, but not for participants of high SES, whereas covert CD symptoms were not associated with prenatal exposure. Gender did not significantly modify the relationship between maternal smoking and CD symptom subtypes.Conclusions: These results suggest that the previously documented association between maternal smoking and CD may be specific to overt CD symptoms, providing support for the heuristic value of differentiating overt and covert CD symptoms as distinct syndromes. These findings further support smoking prevention programs for pregnant women.
Joint attention and symbolic play in young children with autism: a randomized controlled intervention study
Authors: Kasari Connie , Freeman Stephanny , Paparella Tanya 
Published: November 2005

Background:  Delays and deficits in joint attention and symbolic play constitute two important developmental problems in young children with autism. These areas of deficit have been well studied in autism but have rarely been the focus of treatment efforts (see Kasari, Freeman, & Paparella, 2001). In this study, we examine the efficacy of targeted interventions of joint attention and symbolic play.Methods:  Participants were 58 children with autism aged 3 and 4 years (46 boys). Children were randomized to a joint attention intervention, a symbolic play intervention, or control group. Interventions were conducted 30 minutes daily for 5–6 weeks. Both structured assessments of joint attention and play skills and mother–child interactions were collected pre and post intervention by independent assessors.Results:  Results indicate that both intervention groups improved significantly over the control group on certain behaviors. Children in the joint attention intervention initiated significantly more showing and responsiveness to joint attention on the structured joint attention assessment and more child‐initiated joint attention in the mother–child interaction. The children in the play group showed more diverse types of symbolic play in interaction with their mothers and higher play levels on both the play assessment and in interaction with their mothers.Conclusions:  This randomized controlled trial provides promising data on the specificity and generalizability of joint attention and play interventions for young children with autism. Future studies need to examine the long‐term effects of these early interventions on children's development.
Genetic and environmental influences on extreme personality dispositions in adolescent female twins
Authors: Pergadia Michele L. , Madden Pamela A.F. , Lessov Christina N. , Todorov Alexandre A. , Bucholz Kathleen K. , Martin Nicholas G. , Heath Andrew C. 
Published: November 2005

Background:  The objective was to determine whether the pattern of environmental and genetic influences on deviant personality scores differs from that observed for the normative range of personality, comparing results in adolescent and adult female twins.Methods:  A sample of 2,796 female adolescent twins ascertained from birth records provided Junior Eysenck Personality Questionnaire data. The average age of the sample was 17.0 years (S.D. 2.3). Genetic analyses of continuous and extreme personality scores were conducted. Results were compared for 3,178 adult female twins.Results:  Genetic analysis of continuous traits in adolescent female twins were similar to findings in adult female twins, with genetic influences accounting for between 37% and 44% of the variance in Extraversion (Ex), Neuroticism (N), and Social Non‐Conformity (SNC), with significant evidence of shared environmental influences (19%) found only for SNC in the adult female twins. Analyses of extreme personality characteristics, defined categorically, in the adolescent data and replicated in the adult female data, yielded estimates for high N and high SNC that deviated substantially (p < .05) from those obtained in the continuous trait analyses, and provided suggestive evidence that shared family environment may play a more important role in determining personality deviance than has been previously found when personality is viewed continuously. However, multiple‐threshold models that assumed the same genetic and environmental determinants of both normative range variation and extreme scores gave acceptable fits for each personality dimension.Conclusions:  The hypothesis of differences in genetic or environmental factors responsible for N and SNC among female twins with scores in the extreme versus normative ranges was partially supported, but not for Ex.
Regulation of spinophilin Ser94 phosphorylation in neostriatal neurons involves both DARPP‐32‐dependent and independent pathways
Authors: Uematsu Ken , Futter Marie , Hsieh‐Wilson Linda C. , Higashi Hideho , Maeda Hisao , Nairn Angus C. , Greengard Paul , Nishi Akinori 
Published: November 2005

AbstractSpinophilin is a protein phosphatase‐1 (PP‐1)‐ and actin‐binding protein that is enriched in dendritic spines. Phosphorylation of the actin‐binding domain of rat spinophilin at one or more sites by protein kinase A (PKA) inhibits actin binding. Here, we investigated the regulation of mouse spinophilin that contains only a single PKA‐site (Ser94) within its actin‐binding domain. In vitro phosphorylation of Ser94 resulted in the dissociation of spinophilin from actin filaments. In mouse neostriatal slices, phospho‐Ser94 (p‐Ser94) was dephosphorylated mainly by PP‐1 and also by PP‐2A. Activation of dopamine D1 receptors in striatonigral medium spiny neurons, and of adenosine A2A receptors in striatopallidal medium spiny neurons increased, whereas activation of dopamine D2 receptors in striatopallidal neurons decreased, spinophilin Ser94 phosphorylation. In neostriatal slices from DARPP‐32 (dopamine‐ and cAMP‐regulated phosphoprotein of 32 kDa) knockout mice, the effects of D1, D2 and A2A receptors were largely attenuated. Activation of NMDA receptors decreased Ser94 phosphorylation in a PP‐2A‐dependent, but DARPP‐32‐independent, manner. These results suggest that PKA‐dependent phosphorylation of spinophilin at Ser94 in both striatonigral and striatopallidal neurons requires synergistic contributions from the PKA and DARPP‐32/PP‐1 pathways. In addition, PP‐2A plays a role in Ser94 dephosphorylation in response to activation of both D2 and NMDA receptors.
Consequence of the presence of two different β subunit isoforms in a GABAAreceptor
Authors: Boulineau Nathalie , Baur Roland , Minier Frédéric , Sigel Erwin 
Published: November 2005

AbstractThe major isoforms of GABAAreceptors are thought to be composed of two α, two β and one γ subunit(s). GABAAreceptors containing two β1subunits respond differently to the anticonvulsive compound loreclezole and the general anaesthetic etomidate than receptors containing two β2subunits. Receptors containing β2subunits show a much larger allosteric stimulation by these agents than those containing β1subunits. We were interested to know how receptors containing both β1and β2subunits, in different positions respond to loreclezole and etomidate. To answer this question, subunits were fused at the DNA level to form dimeric and trimeric subunits. Concatenated receptors (α1‐β1‐α1/γ2‐β1, α1‐β2‐α1/γ2‐β1, α1‐β1‐α1/γ2‐β2and α1‐β2‐α1/γ2‐β2) were expressed in Xenopus ooctyes and functionally compared in their response to the agonist GABA and to the positive allosteric modulators, loreclezole and etomidate. We have shown that (I) in the presence of both β1and β2subunits in the same pentamer (mixed receptors) direct gating by etomidate is similar to exclusively β1containing receptors; (II) In mixed receptors, stimulation by etomidate assumed characteristics intermediate to exclusively β1or β2containing receptors, but the values for the concentrations < 10 µmwere always much closer to those observed in α1‐β1‐α1/γ2‐β1receptors; and (III) mixed receptors show no positional effects.
Biophysical characterization of longer forms of amyloid beta peptides: possible contribution to flocculent plaque formation
Authors: Lambermon Mark H. L. , Rappaport Rebecca V. , McLaurin JoAnne 
Published: November 2005

AbstractAlzheimer's disease is characterized by amyloid deposits in the parenchyma and vasculature of the brain. The plaques are mainly composed of amyloid beta (Aβ) peptides ending in residues 40 and 42. Novel longer Aβ peptides were found in brain homogenates of mouse models of Alzheimer's disease and human brain tissue of patients carrying the familial amyloid precursor protein V717F mutation. The biophysical characteristics of these longer Aβ peptides and their role in plaque formation are not understood. We chose to focus our studies on Aβ peptides ending in residues Ile45, Val46 and Ile47 as these peptides were identified in human brain tissue. A combination of circular dichroism and electron microscopy was used to characterize the secondary and tertiary structures of these peptides. All three longer Aβ peptides consisted mainly of a β‐sheet secondary structure. Electron microscopy demonstrated that these β‐structured peptides formed predominantly amorphous aggregates, which convert to amyloid fibres over extended time periods. As these longer peptides may act as seeds for the nucleation of fibrils composed predominantly of shorter amyloid peptides, these interactions were studied. All peptides accelerated the random to β‐structural transitions and fibril formation of Aβ40 and 42.
Comprehensive regional and temporal gene expression profiling of the rat brain during the first 24 h after experimental stroke identifies dynamic ischemia‐induced gene expression patterns, and reveals a biphasic activation of genes in surviving tissue
Authors: Rickhag Mattias , Wieloch Tadeusz , Gidö Gunilla , Elmér Eskil , Krogh Morten , Murray Joseph , Lohr Scott , Bitter Hans , Chin Daniel J. , Von Schack David , Shamloo Mehrdad , Nikolich Karoly 
Published: November 2005

AbstractIn order to identify biological processes relevant for cell death and survival in the brain following stroke, the postischemic brain transcriptome was studied by a large‐scale cDNA array analysis of three peri‐infarct brain regions at eight time points during the first 24 h of reperfusion following middle cerebral artery occlusion in the rat. K‐means cluster analysis revealed two distinct biphasic gene expression patterns that contained 44 genes (including 18 immediate early genes), involved in cell signaling and plasticity (i.e. MAP2K7, Sprouty2, Irs‐2, Homer1, GPRC5B, Grasp). The first gene induction phase occurred at 0–3 h of reperfusion, and the second at 9–15 h, and was validated by in situ hybridization. Four gene clusters displayed a progressive increase in expression over time and included 50 genes linked to cell motility, lipid synthesis and trafficking (i.e. ApoD, NPC1, G3P‐dehydrogenase1, and Choline kinase) or cell death‐regulating genes such as mitochondrial CLIC. We conclude that a biphasic transcriptional up‐regulation of the brain‐derived neurotrophic factor (BDNF)–G‐protein coupled receptor (GPCR)–mitogen‐activated protein (MAP) kinase signaling pathways occurs in surviving tissue, concomitant with a progressive and persistent activation of cell proliferation signifying tissue regeneration, which provide the means for cell survival and postischemic brain plasticity.
3‐Nitropropionic acid: a mitochondrial toxin to uncover physiopathological mechanisms underlying striatal degeneration in Huntington's disease
Authors: Brouillet Emmanuel , Jacquard Carine , Bizat Nicolas , Blum David 
Published: November 2005

AbstractHuntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the gene encoding Huntingtin. The mechanisms underlying the preferential degeneration of the striatum, the most striking neuropathological change in HD, are unknown. Of those probably involved, mitochondrial defects might play an important role. The behavioural and anatomical similarities found between HD and models using the mitochondrial toxin 3‐nitropropionic acid (3NP) in rats and primates support this hypothesis. Here, we discuss the recently identified mechanisms of 3NP‐induced striatal degeneration. Two types of important factor have been identified. The first are the ‘executioner’ components that have direct roles in cell death, such as c‐Jun N‐terminal kinase and Ca2+‐activated protease calpains. The second are ‘environmental’ factors, such as glutamate, dopamine and adenosine, which modulate the striatal degeneration induced by 3NP. Interestingly, these recent studies support the hypothesis that 3NP and mutated Huntingtin have certain mechanisms of toxicity in common, suggesting that the use of 3NP might give new insights into the pathogenesis of HD. Research on 3NP provides additional proof that the neurochemical environment of a given neurone can determine its preferential vulnerability in neurodegenerative diseases.
In vitro characterization of a γ‐secretase radiotracer in mammalian brain
Authors: Patel Shil , O'Malley Stacey , Connolly Brett , Liu Wensheng , Hargreaves Richard , Sur Cyrille , Gibson Raymond E. 
Published: November 2005

AbstractInhibition of γ‐secretase is a potential therapeutic target for Alzheimer's disease (AD). The present studies have characterized the in vitro properties of a radiolabeled small molecule γ‐secretase inhibitor, [3H]compound D (Yan et al., 2004, J. Neurosci.24, 2942–2952) in mammalian brain. [3H]Compound D was shown to bind with nanomolar affinity (Kd = 0.32–1.5 nM) to a single population of saturable sites in rat, rhesus and human brain cortex homogenates, the density of binding sites ranging from 4 to 7 nM across the species. Competition studies with a structurally diverse group of γ‐secretase inhibitors with a wide range of binding affinities showed that the binding affinities of these compounds correlated well with their ability to inhibit γ‐secretase in vitro. Autoradiographic studies showed that the specific binding of [3H]compound D was widely distributed throughout adult rat, rhesus and normal human brain. There did not appear to be any difference in distribution of [3H]compound D specific binding sites in AD cortex compared with control human cortex as measured using tissue section autoradiography, nor any correlation between γ‐secretase binding and plaque burden as measured immunohistochemically. [3H]compound D is a useful tool to probe the expression and pharmacology of γ‐secretase in mammalian brain.
A presenilin‐independent aspartyl protease prefers the γ‐42 site cleavage
Authors: Lai Ming‐Tain , Crouthamel Ming‐Chih , DiMuzio Jillian , Pietrak Beth Lynn , Donoviel Dorit B. , Bernstein Alan , Gardell Stephen J. , Li Yue‐Ming , Hazuda Daria 
Published: November 2005

Abstractβ‐Amyloid peptides (Aβ40 and Aβ42) are the major constituents of amyloid plaques, which are one of the hallmarks of Alzheimer's disease (AD). The Aβ is derived from sequential cleavages of amyloid precursor protein (APP) by β‐ and γ‐secretases. γ‐Secretase consists of at least four proteins where presenilins (PS1 and PS2 or PS) are the catalytic subunit involved in the γ‐site cleavage of APP. Secretion of both Aβ40 and Aβ42 is significantly reduced in PS1 knock‐out cells and completely abolished in cells deficient for both PS1 and PS2. Consequently, both the PS proteins play essential roles in the production of the secretory of Aβ from cells. Recent studies in primary neurons, however, suggest that PSs are not required for intracellular Aβ42 accumulation; thus the intracellular Aβ42 appears to be generated in a PS‐independent manner. Here we present the first biochemical evidence indicating that Aβ, especially Aβ42, can be generated in the absence of PS based on an in vitroγ‐secretase assay employing membranes prepared from PS‐deficient Blastocyst‐derived (BD) cells. This PS‐independent γ‐secretase (PSIG) activity is sensitive to the changes in pH and displays an optimal activity at pH 6.0. Pepstatin A is a potent inhibitor for this proteolytic activity with IC50 of 1.2 nm and 0.4 nm for Aβ40 and Aβ42 generation, respectively. These results indicate that these PS‐independent γ‐site cleavages are mediated by an aspartyl protease. More importantly, the PSIG activity displays a distinct preference in mediating the 42‐site cleavage over the 40‐site cleavage, thereby generating Aβ42 as the predominant product.
Melatonin and 6‐hydroxymelatonin protect against iron‐induced neurotoxicity
Authors: Maharaj Deepa S. , Maharaj Himant , Daya Santy , Glass Beverley D. 
Published: November 2005

AbstractOxidative damage of biological macromolecules is a hallmark of most neurodegenerative disorders such as Alzheimer, Parkinson and diffuse Lewy body diseases. Another important phenomenon involved in these disorders is the alteration of iron homeostasis, with an increase in iron levels. The present study investigated whether 6‐hydroxymelatonin (6‐OHM) can reduce Fe2+‐induced lipid peroxidation and necrotic cell damage in the rat hippocampus in vivo. It was found that 6‐OHM administration proved successful in reducing Fe2+‐induced neurotoxicity in rat hippocampus. This study provides some evidence of the neuroprotective effects of 6‐OHM.
Down‐regulation of drebrin A expression suppresses synaptic targeting of NMDA receptors in developing hippocampal neurones
Authors: Takahashi Hideto , Mizui Toshiyuki , Shirao Tomoaki 
Published: November 2005

AbstractDrebrin is a major F‐actin‐binding protein in the brain. We have recently demonstrated that drebrin A (neurone‐specific isoform) clusters at synapses and governs targeting of the post‐synaptic density 95 protein to synapses during development. To determine the role of drebrin A on excitatory synapse formation, we analysed whether the suppression of drebrin A expression affects filopodia‐spine morphology and synaptic targeting of NMDA receptors in cultured hippocampal neurones. Suppression of developmentally programmed up‐regulation of drebrin A by antisense treatment significantly decreased the density and width of filopodia‐spines. Immunocytochemistry showed that the antisense treatment did not attenuate synaptic clustering of NMDA receptors under conditions that permitted spontaneous activities but inhibited the accelerated targeting of NMDA receptors into synapses by its antagonist d‐(–)‐2‐amino‐5‐phosphonopentanoic acid. These results indicate that drebrin A up‐regulation plays a pivotal role in spine morphogenesis and activity‐dependent synaptic targeting of NMDA receptors.
Enhanced episodic‐like memory and kindling epilepsy in a rat model of tuberous sclerosis
Authors: Waltereit Robert , Welzl Hans , Dichgans Johannes , Lipp Hans‐Peter , Schmidt Werner J. , Weller Michael 
Published: November 2005

AbstractTuberous sclerosis complex (TSC) is a common neurological autosomal‐dominant syndrome caused by mutations in the TSC1 or TSC2 genes. TSC starts in early childhood and is characterized by cerebral hamartomas (benign tumours), severe epilepsy and cognitive deficits such as mental retardation and autism. The hamartomas are characterized by loss of the remaining wild‐type TSC allele, and clinical data implicate cerebral hamartomas in the generation of epileptic seizures, which may play a significant role in the development of mental retardation. The TSC2 mutation predicts alterations in mitogen‐associated protein kinase (MAPK) and, together with the TSC1 mutation, in mammalian target of rapamycin (mTOR) signalling pathways. Both pathways are involved in neuronal plasticity. We therefore hypothesized that the heterozygous mutation itself, besides cerebral hamartomas, contributes to the pathogenesis of cognitive deficits and possibly also epilepsy. Here, we show that young adult TSC2+/– rats, which are virtually free of cerebral hamartomas, exhibit enhanced episodic‐like memory and enhanced responses to chemically‐induced kindling. The activation of cyclic adenosine monophosphate (cAMP) in the hippocampus results in stronger induction of phospho‐p42‐MAPK in TSC2+/– rats than in wild‐type animals. Thus, the cognitive phenotype and, possibly, epilepsy in TSC patients may result not only from the focal hamartomatous lesions but also, from altered neuronal plasticity in the heterozygous tissue.