bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Spinophilin 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

The 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

Alzheimer'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

In 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

Huntington'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

Inhibition 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

β‐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

Oxidative 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

Drebrin 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

Tuberous 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.
Docosahexaenoic acid prevents neuronal apoptosis induced by soluble amyloid‐β oligomers
Authors: Florent Sabrina , Malaplate‐Armand Catherine , Youssef Ihsen , Kriem Badreddine , Koziel Violette , Escanyé Marie‐Christine , Fifre Alexandre , Sponne Isabelle , Leininger‐Muller Brigitte , Olivier Jean‐Luc , Pillot Thierry , Oster Thierry
Published: November 2005

A growing body of evidence supports the notion that soluble oligomers of amyloid‐β (Aβ) peptide interact with the neuronal plasma membrane, leading to cell injury and inducing death‐signalling pathways that could account for the increased neurodegeneration occurring in Alzheimer's disease (AD). Docosahexaenoic acid (DHA, C22:6, n‐3) is an essential polyunsaturated fatty acid in the CNS and has been shown in several epidemiological and in vivo studies to have protective effects against AD and cognitive alterations. However, the molecular mechanisms involved remain unknown. We hypothesized that DHA enrichment of plasma membranes could protect neurones from apoptosis induced by soluble Aβ oligomers. DHA pre‐treatment was observed to significantly increase neuronal survival upon Aβ treatment by preventing cytoskeleton perturbations, caspase activation and apoptosis, as well as by promoting extracellular signal‐related kinase (ERK)‐related survival pathways. These data suggest that DHA enrichment probably induces changes in neuronal membrane properties with functional outcomes, thereby increasing protection from soluble Aβ oligomers. Such neuroprotective effects could be of major interest in the prevention of AD and other neurodegenerative diseases.
Neural tube closure depends on nitric oxide synthase activity
Authors: Nachmany Amir , Gold Veronica , Tsur Asaf , Arad Dan , Weil Miguel
Published: November 2005

Neural tube (NT) closure is a multifactorial process that involves yet unresolved molecular mechanisms. It had been shown previously that high levels of nitric oxide (NO) block the process of NT closure in the chick embryo by inhibiting methionine synthase (MS). The MS inhibition and its effect on NT closure could be alleviated by folic acid, suggesting the involvement of the folate–methionine pathway in the process. Here we test the hypothesis that endogenous nitric oxide synthase (NOS) activity regulates the MS activity required in the process of NT closure. The experiments described here reveal that NOS activity per se, is indeed critical for NT closure in the chick embryo. Inhibition of NOS activity with either 2,4‐diamino‐6‐hydroxypyrimidine (DAHP), which blocks biosynthesis of the NOS co‐factor tetrahydrobiopterin (BH4), or with calmidazolium, which blocks calcium–calmodulin binding to NOS, resulted in reduced MS activity and consequently ablated NT closure. Addition of BH4 or the calcium ionophore A23187 restored NOS and MS activities, resulting in NT closure. The results described here imply that NOS and MS activities can serve as functional markers in this developmental process as they are essential in the process of NT closure.
NMDA neuroprotection against a phosphatidylinositol‐3 kinase inhibitor, LY294002 by NR2B‐mediated suppression of glycogen synthase kinase‐3β‐induced apoptosis
Authors: Habas Agata , Kharebava Giorgi , Szatmari Erzsebet , Hetman Michal
Published: November 2005

To identify the intracellular signaling pathways that mediate the pro‐survival activity of NMDA receptors (NMDARs), we studied effects of exogenous NMDA on cultured rat cortical and hippocampal neurons that were treated with a phosphatidylinositol‐3‐kinase (PI3K) inhibitor, LY294002. NMDA at 5 or 10 µm protected against LY294002‐induced apoptosis, suggesting NMDAR‐mediated activation of a survival signaling pathway that is PI3K‐independent. NR2B‐specific NMDAR blockers antagonized anti‐apoptotic effects of NMDA, indicating a critical role of NR2B NMDARs in the neuroprotection. NMDA at 10 µm suppressed LY294002‐induced activation of a pro‐apoptotic kinase, glycogen synthase kinase 3β (GSK3β). GSK3β activation by LY294002 was associated with decreased levels of inhibitory GSK3β phosphorylation at the Ser9 residue. However, NMDA did not prevent the LY294002‐mediated decline of phospho‐Ser9 levels. In addition, NMDA inhibited cortical neuron apoptosis induced by the overexpression of either wild type (wt) or Ser9Ala mutant form of GSK3β, suggesting that NMDA suppressed GSK3β in a Ser9‐independent manner. Finally, inhibition of NR2B NMDARs reduced the NMDA protection against overexpression of GSK3βwt. These data indicate that moderate stimulation of NR2B NMDAR protects against inhibition of PI3K by a Ser9‐independent inhibition of the pro‐apoptotic activity of GSK3β. Hence, the activation of NR2B and the Ser9‐independent inhibition of GSK3β are two newly identified elements of the signaling network that mediates the pro‐survival effects of NMDA.
Inhibitors of Rho‐kinase modulate amyloid‐β (Aβ) secretion but lack selectivity for Aβ42
Authors: Leuchtenberger Stefanie , Kummer Markus P. , Kukar Thomas , Czirr Eva , Teusch Nicole , Sagi Sarah A. , Berdeaux Rebecca , Pietrzik Claus U. , Ladd Thomas B. , Golde Todd E. , Koo Edward H. , Weggen Sascha
Published: November 2005

Certain non‐steroidal anti‐inflammatory drugs (NSAIDs) preferentially inhibit production of the amyloidogenic Aβ42 peptide, presumably by direct modulation of γ‐secretase activity. A recent report indicated that NSAIDs could reduce Aβ42 by inhibition of the small GTPase Rho, and a single inhibitor of Rho kinase (ROCK) mimicked the effects of Aβ42‐lowering NSAIDs. To investigate whether Aβ42 reduction is a common property of ROCK inhibitors, we tested commercially available compounds in cell lines that were previously used to demonstrate the Aβ42‐lowering activity of NSAIDs. Surprisingly, we found that two ROCK inhibitors reduced total Aβ secretion in a dose‐dependent manner but showed no selectivity for Aβ42. In addition, ROCK inhibitors did not increase Aβ38 secretion in cell‐based assays or reduce Aβ production in γ‐secretasein vitroassays, which are critical characteristics of Aβ42‐lowering NSAIDs. The reduction in total Aβ levels by ROCK inhibitors was not accompanied by overall‐changes in amyloid precursor protein processing. Targeting ROCK by expression of dominant‐negative or constitutively active ROCK mutants failed to modulate Aβ secretion, indicating that ROCK inhibition may either be redundant or insufficient for Aβ reduction by ROCK inhibitors. Taken together, these results seem to exclude a mechanistic involvement of ROCK in the Aβ42‐lowering activity of NSAIDs.
Neurochemical characterization of the release and uptake of dopamine in ventral tegmental area and serotonin in substantia nigra of the mouse
Authors: John Carrie E. , Budygin Evgeny A. , Mateo Yolanda , Jones Sara R.
Published: November 2005

In the present report, fast‐scan cyclic voltammetry was used to identify the monoamines that were released by electrical stimulation in mouse brain slices containing ventral tegmental area (VTA), substantia nigra (SN) ‐pars compacta (SNc) and ‐pars reticulata (SNr). We showed that voltammograms obtained in mouse VTA were consistent with detection of a catecholamine, while those in both subregions of the SN were consistent with detection of an indolamine, based on the reduction peak potentials. We used pharmacological blockade and genetic deletion of monoamine transporters to further confirm the identity of released monoamines in mouse midbrain and to assess the control of monoamines by their transporters in each brain region. Inhibition of dopamine and norepinephrine transporters by nomifensine (1 and 10 μm) decreased uptake rates in the VTA, but did not change uptake rates in either subregion of the SN. Serotonin transporter inhibition by fluoxetine (10 μm) decreased uptake rates in the SNc and SNr, but was without effect in the VTA. Selective inhibition of the norepinephrine transporter by desipramine (10 μm) had no effect in any brain region. Using dopamine transporter‐ and serotonin transporter‐knockout mice, we found decreased uptake rates in VTA and SN subregions, respectively. Peak signals recorded in each midbrain region were pulse number dependent and exhibited limited frequency dependence. Thus, dopamine is predominately detected by voltammetry in mouse VTA, while serotonin is predominately detected in mouse SNc and SNr. Furthermore, active uptake occurs in these areas and can be altered only by specific uptake inhibitors, suggesting a lack of heterologous uptake. In addition, somatodendritic dopamine release in VTA was not mediated by monoamine transporters. This work offers an initial characterization of voltammetric signals in the midbrain of the mouse and provides insight into the regulation of monoamine neurotransmission in these areas.
F‐spondin promotes nerve precursor differentiation
Authors: Schubert David , Klar Avihu , Park Minkyu , Dargusch Richard , Fischer Wolfgang H.
Published: November 2005

Cells in the developing nervous system secrete a large number of proteins that regulate the migration and differentiation of their neighbors. It is shown here that a clonal central nervous system cell line secretes a protein that causes both a rat hippocampal progenitor cell line and primary cortical neural cells to differentiate into cells with the morphological and biochemical features of neurons. This protein was identified as F‐spondin. Analysis of F‐spondin isoforms secreted from transfected cells shows that the core protein without the thrombospondin type 1 repeats is sufficient to promote neuronal differentiation when adsorbed to a surface. F‐spondin can also inhibit neurite outgrowth while allowing the expression of nerve‐specific proteins when present in a soluble form at high concentrations. Therefore, F‐spondin can alter cell differentiation in multiple ways, depending upon its concentration and distribution between substrate‐attached and soluble forms.
Chronic Fatigue Syndrome: An Evaluation of a Community Based Management Programme for Adolescents and their Families
Authors: Ashby Bernadette , Wright Barry , Jordan Jo
Published: November 2005

Background:  Young people with chronic fatigue syndrome (CFS), families and clinicians may differ in their attributions about CFS and consequently in their approach to treatment. Research that clarifies the best treatment approaches is clearly needed. We have sought to develop a model that engages young people and their families in a collaborative way. The approach adopts an optimistic and holistic stance using an active rehabilitation model paying attention to the integrated nature of the physiological and psychological aspects of the illness.

Method:  This small study set out to evaluate this approach from a service user perspective. Semi‐structured interviews were carried out with young people and their parents separately in order to elicit their views on key treatment elements and their perceived degree of recovery.

Results:  Improvements are indicated in all key areas addressed and qualitative information suggests that families value this approach.

Conclusion:  Further research is needed to address treatment issues for families who choose not to opt into the service model.
Serum cytokine and soluble cytokine receptor levels in patients with non‐alcoholic steatohepatitis
Authors: Abiru Seigo , Migita Kiyoshi , Maeda Yumi , Daikoku Manabu , Ito Masahiro , Ohata Kazuyuki , Nagaoka Shinya , Matsumoto Takehiro , Takii Yasushi , Kusumoto Koichiro , Nakamura Minoru , Komori Atsumasa , Yano Koji , Yatsuhashi Hiroshi , Eguchi Katsumi , Ishibashi Hiromi
Published: November 2005

Abstract: Background: Although the pathogenesis of non‐alcoholic steatohepatitis (NASH) remains poorly understood, proinflammatory cytokines seem to play an important role in the process of NASH. We have undertaken this study in order to elucidate the role of proinflammatory cytokines and their soluble receptors in NASH patients.

Methods: Serum cytokines and soluble cytokine receptors levels were determined using an enzyme‐linked immunosorbent assay kit in 23 patients with NASH, 21 patients with simple steatosis, and 18 healthy volunteers.

Results: Patients with NASH had significantly higher serum tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) levels than did the simple steatosis patients. Similarly, when compared with simple steatosis, NASH was associated with higher soluble TNF receptor 1 (sTNFR1) and soluble IL‐6 receptor (sIL‐6R) levels, and a significant positive correlation was seen between the levels of sTNFR1 and aminotranferases in NASH patients.

Conclusions: This study shows that circulating TNF‐α/sTNFR1 and IL‐6/sIL‐6R levels are significantly increased in NASH patients as compared with simple steatosis patients and healthy volunteers, and that these increased levels may be implicated in the pathogenesis of NASH.
Effect of celecoxib on experimental liver fibrosis in rat
Authors: Hui Alex Yui , Leung Wai Keung , Yuen Chan Henry Lik , Chan Francis Ka Leung , Yin Go Minnie Yin , Chan Ka Kui , Tang Bao Dong , Hong Chu Eagle Siu , Yiu Sung Joseph Jao
Published: November 2005

Abstract: Background/Aim: Cyclooxygenase‐2 (COX‐2), an inducible enzyme that catalyzes prostaglandin synthesis, has been implicated in a number of hepatic stellate cell (HSC) functions. In the current study, we assessed the in vivo effect of celecoxib, a COX‐2‐selective inhibitor, in experimental liver fibrosis in rats.

Methods: Male Sprague–Dawley rats received experimental treatments for 5 weeks. Serum alanine transminase at the time of sacrifice was measured. Quantitative assessment of liver fibrosis was performed by computerized morphometry. Expression of COX‐2, α smooth muscle actin and connective tissue growth factor (CTGF) was evaluated by immunohistochemistry. Real‐time quantitative PCR was used to determine the expression of genes associated with fibrogenesis and extracellular matrix degradation.

Results: Liver fibrosis was significantly worse in rats that received both carbon tetrachloride (CCl4) and celecoxib, compared with rats that received CCl4 and gavage of water (P=0.037). There was also more HSC activation, and upregulation of collagen α1(I), heat‐shock protein 47, αB crystallin, matrix metalloproteinase (MMP)‐2, MMP‐9 and tissue inhibitor of MMP (TIMP)‐2. The expression of TIMP‐1 and CTGF was not significantly different between the two groups. The pro‐fibrogenic effect of celecoxib in toxin‐induced liver fibrosis in rats was further confirmed in thioacetamide model of liver injury.

Conclusions: Celecoxib potentiates experimental liver fibrosis; further studies are warranted to investigate the potential pro‐fibrogenic effect of celecoxib in other animal models of liver fibrosis and in patients with chronic hepatitis.
Concurrent Management of an Exotic Species and Initial Restoration Efforts in Forests
Authors: Murphy Stephen D.
Published: November 2005

One of the proximate results of forest fragmentation, and a cause of continued microenvironmental change and exacerbation of ecological problems, is increased invasions by weedy plant species. One such example isAlliaria petiolata(Brassicaceae), a serious pest threatening much of eastern North America.Alliaria petiolataimpedes mitigation of fragmentation and restoration efforts because it tends to outcompete and possibly extirpate much of the native understory species on localized scales. As part of a strategy to address the problems of fragmented habitats, an experiment was conducted to determine whetherSanguinaria canadensis(Papaveraceae) could outcompeteA. petiolata. Using an additive design, I transplantedS. canadensisat densities of 0, 1, 2, 3, 5, 7, 9, 11, 15, and 20 ramets/m2in 1997 and allowed them to interact with initialA. petiolatadensities of 128 seedlings and 31 rosettes/m2. As of 2000, multivariate analyses of variance with repeated measures and simple analyses of variance indicated that initialS. canadensisdensities of as little as 5 ramets/m2suppressedA. petiolata. InitialS. canadensisdensities of 9 and 11 ramets/m2resulted in the lowest numbers of late‐spring seedlings, numbers and sizes of year 1 and 2 rosettes, numbers and gross areas of stem leaves, numbers of flowering individuals, number of flowers, number of fruits (siliques), and height at flowering. While it remains to be tested whether this will continue and if the reestablishment ofS. canadensiswill help reassemble forest ecosystems, the experiments indicated that transplantingS. canadensiswas effective at mitigating the spread ofA. petiolata.
Establishment of a Vegetation Cover on Tundra Kimberlite Mine Tailings: 1. A Greenhouse Study
Authors: Reid Neil B. , Naeth M. Anne
Published: November 2005

High erosion potential of dewatered kimberlite mine tailings after diamond extraction has prompted research at the Ekati Diamond Mine in the Canadian subarctic heath tundra ecosystem. Coarse texture, no organic component, lack of available macronutrients, and a serpentine chemistry are the principal limitations of these kimberlite tailings to plant colonization. Structure‐improving (peat moss, lake sediment, sewage sludge, Agri‐Boost, and composted papermill sludge) and nutrient‐providing (fertilizer, calcium carbonate, gypsum, and rock phosphate) amendments were tested in the greenhouse to ameliorate these limitations, thereby facilitating the field establishment of a permanent vegetation cover, which would stabilize the surface materials and promote natural colonization by the surrounding tundra vegetation. Seven native grass species (Arctagrostis latifolia, Calamagrostis canadensis, Poa glauca, Poa alpina, Deschampsia beringensis, Deschampsia caespitosa, and Festuca rubra) were used to measure amendment success. With the addition of structure‐improving and nutrient‐providing amendments, plant growth on kimberlite tailings was significantly enhanced. Tailings properties, including cation exchange capacity, percentage of organic carbon, and macronutrient availability, were also improved by amendment addition.
Establishment of a Vegetation Cover on Tundra Kimberlite Mine Tailings: 2. A Field Study
Authors: Reid Neil B. , Naeth M. Anne
Published: November 2005

High erosion potential of dewatered kimberlite mine tailings after diamond extraction has prompted research at the Ekati Diamond Mine in the Canadian subarctic heath tundra ecosystem. Greenhouse and field studies aimed at establishing a permanent vegetation cover on these dewatered tailings began in spring 2000. Coarse texture, no organic component, lack of available macronutrients, and a serpentine chemistry are the principal limitations of kimberlite tailings to plant colonization. Structure‐improving (peat moss, lake sediment, and sewage sludge) and nutrient‐providing (fertilizer, rock phosphate, calcium carbonate, and gypsum) amendments were tested to ameliorate these conditions, facilitating the establishment of a permanent vegetation cover, which stabilizes surface materials and promotes natural colonization by the surrounding tundra vegetation. Seven native grass species (Arctagrostis latifolia, Calamagrostis canadensis, Poa glauca, Poa alpina, Deschampsia beringensis, Deschampsia caespitosa, and Festuca rubra) were used to measure amendment success. With the addition of structure‐improving and nutrient‐providing amendments, plant growth on these kimberlite tailings under field conditions was significantly improved over unamended tailings material. Tailings properties, including cation exchange capacity, organic carbon, and macronutrient availability, were also improved with amendment addition.
Bullying the Bullies: The Selective Control of an Exotic, Invasive Annual (Rapistrum rugosum) by Oversowing with a Competitive Native Species (Gaillardia pulchella)
Authors: Simmons Mark T
Published: November 2005

Mechanical, biological, and chemical attempts to control invasive plants can be expensive, ecologically damaging, and frequently unsuccessful. This study proposes using the intrinsic biological attributes of the threatened plant community by artificially increasing the density of competitive native species to selectively suppress the growth of the invasive. Evidence from agricultural weed control suggests that oversowing infested areas with species with biological traits similar to those of the invasive species not only reduces productivity of the invasive species but also may eliminate environmental damage associated with standard control techniques. Annual bastard cabbage (Rapistrum rugosum), a Eurasian exotic, is an invader of native plant communities in the continental United States. Control with herbicides has been problematic due to high mortality of adjacent native species and subsequent perpetuation of a disturbed state that facilitates further regeneration of R. rugosum from the seed bank. In a randomized field experiment, sowing native Indian blanket (Gaillardia pulchella) over established seedling colonies of R. rugosum resulted in significant reduction of R. rugosum productivity (F= 3.43; p < 0.05). The highest sowing rate of G. pulchella resulted in a 72% reduction in aboveground productivity of R. rugosum that translated to an estimated 83% decrease in seed set, without significant suppression of adjacent native species. It is proposed that enriching threatened or infested plant communities with selected native species with matching phenologies and competitive characteristics has advantages over conventional control methods in that (1) it reduces the threat to nontarget organisms; (2) once installed, the species could self‐regenerate; and (3) it does not perpetuate a disturbed (early‐successional) state that might aggravate the problem. This may serve as an alternative technique to protect and restore native plant communities.
Establishment of the Woody Grass Arundinaria gigantea for Riparian Restoration
Authors: Dattilo Adam J. , Rhoades Charles C.
Published: November 2005

Canebrakes are dense stands of Arundinaria gigantea (Walt.) Muhl. that covered large areas of the southeastern North America. With agricultural development, canebrakes were quickly converted to crop and pastureland and now occur only in small, isolated patches. There is growing interest in the use of A. gigantea and other temperate bamboo species in riparian and floodplain revegetation in North America, but lack of detailed information on propagation and management of woody perennial grasses hinders reestablishment activities. Our study assesses the influence of nutrient and woodchip mulch amendments on survival and growth of A. gigantea transplanted as part of a riparian restoration project in central Kentucky. After two growing seasons, culm number (aboveground stems) increased 4‐fold and extent of transplanted clumps expanded 26‐fold. The survival rate of transplanted cane clumps was 98%. Hardwood chip mulch significantly increased the emergence of new culms, culm height growth, and clump area. Composted manure, applied at a rate that contributed a similar mass of organic matter as the hardwood mulch, also significantly increased new culm number and clump area. Our findings demonstrate that addition of manure or hardwood mulch can significantly enhance aboveground production of A. gigantea transplants. However, survival and initial growth of untreated clumps were also adequate in this study. It appears that careful site selection, transplantation, and site maintenance may be sufficient to ensure A. gigantea establishment on many sites. Practitioners should assess soil drainage, water stress, and fertility along with herbaceous competition and incidence of overbank flooding before determining the necessity of organic amendments to supplement establishment of A. gigantea or other woody grasses for riparian restoration.
Effects of Unseeded Areas on Species Richness of Coal Mines Reclaimed with Municipal Biosolids
Authors: Halofsky Jessica E. , McCormick Larry H.
Published: November 2005

Land application of municipal biosolids on coal mine spoils can benefit vegetation establishment in mine reclamation. However, the application of biosolids leads to domination by early‐successional species, such as grasses, and low establishment of woody and volunteer species, thus reducing potential for forestry as a postmining land use. In this experiment, tree seedlings were planted in strips (0.6‐, 1‐, and 4‐m wide) that were not seeded with grasses, and the effects of unseeded strip width on seedling growth and species richness were assessed. Planted seedling mortality was high; therefore, the effect of unseeded strip width on seedling growth could not be determined. However, it was found that natural plant invasion and species richness were highest in the 4‐m unseeded strips. The practice of leaving 4‐m‐wide unseeded strips in mine reclamation with biosolids in the eastern United States, along with the improvement of tree seedling planting practices and planting stock, would help promote a more species‐rich plant community that could be utilized for forestry or a variety of other postmining land uses.
Assessing Simple Versus Complex Restoration Strategies for Industrially Disturbed Forests
Authors: Rayfield Bronwyn , Anand Madhur , Laurence Sophie
Published: November 2005

Assessing the community‐level consequences of ecological restoration treatments is essential to guide future restoration efforts. We compared the vegetation composition and species richness of restored sites that received a range of restoration treatments and those of unrestored sites that experienced varying levels of disturbance. Our study was conducted in the industrially degraded landscape surrounding Sudbury, Ontario, Canada. The Great Lakes–St. Lawrence Forest once present in this area was degraded through logging, mining, and smelting activities beginning in the late 1800s until restoration of the most visibly degraded areas began in 1974. Restoration treatments ranged from simple abiotic enhancements to complex, multistage revegetation treatments using native and non‐native species, which included fertilizing, spreading of ground dolomitic limestone, understory seeding, and tree planting. Canonical correspondence analysis was used to determine which restoration treatments explained differences in the community structure among sites. We found that native understory vascular species richness was similar in restored sites that received more complex restoration treatments and unrestored sites that were mildly disturbed; however, the role of planted trees and non‐native species in the restored communities remains unclear. Understory vascular seeding played a key role in determining community composition of vascular understory and overstory communities, but the time since restoration commenced was a more important factor for nonvascular communities because they received no direct biotic enhancements. The use of non‐native species in the vascular seed mix seems to be slowly encouraging the colonization of native species, but non‐natives continue to dominate restored sites 25 years after restoration began.